PROCESS FOR PREPARING IMMUNOCONJUGATES AND INTERMEDIATES THEREOF Cross Reference to Related Applications [0001] This application claims priority to U.S. Provisional Application No.63/379,503, filed October 14, 2022, which is incorporated herein in its entirety for all purposes. Field [0002] The present disclosure relates to the field of organic synthetic methodology for a process for the preparation of immunoconjugates and their intermediates. Background [0003] For many years it has been an aim of scientists in the field of specifically targeted drug therapy to use monoclonal antibodies (MAbs) for the specific delivery of toxic agents to human cancers. Conjugates of tumor-associated MAbs and suitable toxic agents have been developed. [0004] Various immunocongjuates have been approved for the treatment of cancers. Trodelvy ^® (sacituzumab govitecan) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors. Sacituzumab govitecan has been approved for the treatment of advanced urothelial cancer and triple-negative breast cancer (TNBC). [0005] Preparation of immunocongjuates by using CL2A linkers to attach therapeutic drugs, such as SN-38, to antibody moieties has been disclosed (e.g., U.S. Pat. Nos.7,999,083, 8,080,250 and 9,107,960, the disclosure incorporated herein by reference). Many currently available methods for preparing immunoconjugates or their intermediates use reagents that are hazardous, or difficult to handle or store, and may produce undesirable by-products. Therefore, a need exists for more efficient and benign methods of preparing immunoconjugates and their intermediates. This need is especially strong to enable industrial scale manufacturing processes. Summary [0006] The present disclosure relates to the field of organic synthetic methodology for a process for the preparation of immunoconjugates and their intermediates. [0007] In one aspect, the present disclosure provides a process for preparing Compound 1, comprising the steps of

(a) protecting Compound 3 with a hydroxyl protecting reagent in the presence of a base to provide Compound 4, wherein R ¹ is a hydroxyl protecting group; (b) contacting Compound 4 with 4-nitrophenyl chloroformate in the presence of a base in a solvent at a temperature sufficient to provide Compound 5; (c) contacting Compound 5 with Compound 6 in the presence of a base in a solvent at a temperature sufficient to provide Compound 7, wherein R ² is an amino protecting group;

(d) deprotecting Compound 7 in the presence of a deprotecting agent at a temperature sufficient to provide Compound 8; (e) contacting Compound 8 with Compound 9 in the presence of CuSO ₄ in a solvent at a temperature sufficient to provide Compound 10; and

(f) deprotecting Compound 10 with a deprotecting agent in a solvent at a temperature sufficient to provide Compound 1; wherein HX ¹ is selected from the group consisting of dichloroacetic acid, acetic acid, formic acid, propionic acid, ascorbic acid, tartaric acid, benzoic acid, oxalic acid, citric acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p- toluenesulfonic acid, and hydrochloric acid. [0008] In another aspect, the present disclosure provides a process for preparing Compound 7, comprising the steps of (a) contacting Compound 6 with a reagent in a solvent at a temperature to provide mixture A, wherein the reagent is 1,1’-carbonyl-di-(1,2,4-triazole) (CDT), N,N’-disuccinimidyl carbonate, 1,1’-carbonyldiimidazole, phosgene, triphosgene, 1,3-doxolan-2-one, or carbon dioxide/methanesulfonic anhydride; wherein R ² is an amino protecting group; and

Ĩb) contacting Compound 4 with the mixture A in the presence of a base at a temperature sufficient to provide Compound 7, wherein R ¹ is a hydroxyl protecting group. DETAILED DESCRIPTION [0009] Many currently available methods for preparing immunoconjugates or intermediates uses reagents that are hazardous, or difficult to handle or store. Syntheic schemes of some intermediates for immunoconjugates can also yield undesired by-products. For example, triphosgene was used in a preparation of Compound 7 in U.S. Patent No.9,107,960. The use of triphosgene can be inherently hazardous, for example due to potential release of toxic gas in contact with water. Processes that avoid the use of triphosgene can be desirable, for example, to avoid such hazards. Furthermore, processes that reduce the steps of purification of the intermediates can be desirable. Moreover, processes that reduce by-products can also be desirable. [0010] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s). As used above, throughout the disclosure, the following abbreviations, unless otherwise indicated, has the following meanings: 2-MeTHF 2-methyltetrahydrofuran Ac acetyl ACN acetonitrile (MeCN) DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane (CH ₂ C1 ₂ ) DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide equiv equivalent(s) EtOAc ethyl acetate EtOH ethanol Et ethyl HCl hydrochloric acid MeOH methanol Me methyl NMR nuclear magnetic resonance THF tetrahydrofuran [0011] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term. [0012] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential. [0013] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “contains,” “containing,” and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, product-by-process, or composition of matter that comprises, includes, or contains an element or list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, product-by-process, or composition of matter. [0014] As used herein, the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen (e.g., a heavy chain variable domain, a light chain variable domain, and/or one or more CDRs sufficient to confer specific binding to a particular target antigen). Thus, the term antibody includes, for example, and without limitation, human antibodies, non-human antibodies, antibody fragments, and antigen-binding agents that include antibody fragments, inclusive of synthetic, engineered, and modified forms thereof. The term antibody includes, by way of example, both naturally occurring and non-naturally occurring antibodies. In general, an antibody may comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the Abs may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Naturally- produced antibodies are glycosylated, typically on the CH2 domain. Examples of antibodies include monoclonal antibodies, monospecific antibodies, polyclonal antibodies, multispecific antibodies (including bispecific antibodies), engineered antibodies, recombinantly produced antibodies, wholly synthetic antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain- antibody heavy chain pairs, intrabodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, Fab′ fragments, F(ab’)2 fragments, Fd′ fragments, Fd fragments, isolated CDRs, single chain Fvs, polypeptide-Fc fusions, single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), single chain or Tandem diabodies (TandAb®), Anticalins®, Nanobodies®, minibodies, BiTE®s, ankyrin repeat proteins or DARPINs®, Avimers®, DARTs, TCR-like antibodies, Adnectins®, Affilins®, Trans-bodies®, Affibodies®, TrimerX®, MicroProteins,m Fynomers®, Centyrins®, KALBITOR®s, and antigen-binding fragments of any of the above. [0013] As used herein, the drug-to-antibody ratio (DAR) is the average number of drugs conjugated to the antibodies. [0014] As used herein, the term “immunoconjugate”, “conjugate”, “antibody-drug conjugate” or “ADC” generally refers to a compound comprising an antibody targeting a tumor antigen and an anticancer agent payload connected by a linker. [0015] As used herein, “base” can refer to metal oxides or other compounds that react with an acid to neutralize it and produce water and a salt. “Base” can also refer to compounds and functional groups that contain a basic nitrogen atom with a lone pair. Bases can include tertiary amine bases, aromatic amine bases, hydroxide bases, and alkoxide bases. Non-limiting examples of bases include, but are not limited to, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, lithium tert-butoxide, potassium tert-pentoxide, sodium tert-pentoxide, potassium propionate, potassium pivalate, N-methylmorpholine, tri-n-propylamine, N,N- diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4- diazabicyclo[2.2.2]octane, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, sodium acetate, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide, or lithium bis(trimethylsilyl)amide. Additional examples include, but are not limited to, phenyllithium, mesityllithium, tert- butyllithium, sec-butyllithium, isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium chloride lithium chloride complex, phenylmagnesium chloride, sec- butylmagnesium chloride, 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, or sodium bis(trimethylsilyl)amide. [0016] As used herein, a “solvent” is a substance that can dissolve a solute to a solution. A solvent can be a polar solvent or a non-polar solvent. Solvents can include esters, ethers, chlorinated solvents, aromatic solvents, nitriles, water, polar aprotic solvents, and alcohols. Non-limiting examples of solvents include, but are not limited to, water, alkanes such as heptanes, hexanes, and cyclohexane, petroleum ether, alcohols such as methanol, ethanol, propanol, isopropanol, ethylene glycol and polyethylene glycol such as PEG400, alkanoates such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate, acetonitrile, alkanones such as acetone, methyl ethyl ketone (MEK), methyl propyl ketone (MPK) and methyl iso-butyl ketone (MIBK), ethers such as diethyl ether, methyl-t-butyl ether, tetrahydrofuran, methyl- tetrahydrofuran, 1,2-dimethoxy ethane and 1,4-dioxane, aromatics such as anisole, benzene and toluene, halogenated solvents such as methylene chloride, chloroform and carbon tetrachloride, dimethylsulfoxide (DMSO), and dimethylformamide (DMF). Other examples include but are not limited to, diglyme, cyclopentyl methyl ether, diphenyl ether, trifluorotoluene, xylenes, acetic acid, trifluoroacetic acid, propionic acid, dichloroethane, chlorobenzene, tert-butanol, acetonitrile, propionitrile, and butyronitrile. [0017] As used herein, an “amino protecting group” is a moiety that can selectively installed onto and removed from a suitable amine functional group. Amino protective groups, and methods for using them, are described in the authoritative treatise on the subject, P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition (Wiley, 2006). Non-limiting examples of amino protecting groups include para-monomethoxytrityl (MMT), t- butyl carbamate (Boc), 1-adamantyl carbamate (Adoc), diphenylsilyldiethylene (DPSide), 2- (triphenylsilyl)ethoxycarbonyl (Tpseoc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2- trichloroethoxycarbonyl (Troc), 1,2-bis(dimethylsilyl)ethane (Stabase), triisopropylsilyloxycarbonyl (Tsoc), 2-chlorotrityl resin, and trityl resin. [0018] As used herein, an “hydroxyl protecting group” is a moiety that can selectively installed onto and removed from a suitable hydroxy functional group. Non-limiting examples of hydroxyl protecting groups include tert-butyldimethylsilyl (TBS), trialkylsilyl (trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc.), alkylcarbonyl (pivalate (Pv), etc.) arylcarbonyl (benzoyl (Bz), etc.), alkoxycarbonyl (t-butyl carbonate (Boc), 2,2,2-trichloroethoxycarbonyl (Troc), etc.), alkylmethyl (trityl (Tr), etc.), alkoxymethyl (methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), and tetrahydropyranyl (THP). [0019] As used herein, a “deprotecting agent” is a compound that can convert a protected group into a functional group. A “hydroxyl deprotecting agent” may convert a protected hydroxyl into a hydroxyl group. For example, if the hydroxyl group is protected by a silyl, such as tert-butyldimethylsilyl (TBS), the deprotecting agents include acidic (sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, hydrochloric acid, p-toluenesulfonic acid, formic acid, titanium tetrachloride, or zinc bromide etc.); or fluoride [tetrabutyl ammonium fluoride (TBAF) or cesium fluoride (CsF) hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, potassium hydrogen fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride]. An “amino deprotecting agent” may convert a protected amino into an amino group. For example, if the amine is protected by para- monomethoxytrityl (MMT), the deprotecting agents include but are not limited to acetic acid, formic acid, propionic acid, ascorbic acid, tartaric acid, benzoic acid, oxalic acid, citric acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p- toluenesulfonic acid, and hydrochloric acid. [0020] As used herein, a “dessicant” is a compound that can absorb water. Non-limiting examples of dessicants include, but are not limited to, sodium sulfate, calcium sulfate, magnesium sulfate, including trimethyl orthoformate, and triethyl orthoformate. [0021] As used herein, a “scavenger” is a compound that can remove or de-activate impurities and unwanted reaction products. [0022] As used herein, a “catalyst” is a compound that can increase the rate of a chemical reaction without undergoing any permanent chemical change. As used herein, a “coupling- cyclization catalyst” is a catalyst that may increase the rate of azide-alkyne cycloaddition. Non- limiting examples of coupling-cyclization catalysts include ruthenium (including chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium, pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium( II) chloride, chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium (II)), copper (including copper (II) sulfate (CuSO4), copper(II) acetate, copper acetyl acetonate, copper(I) thiophene-2- carboxylate, copper(I) chloride, copper(I) bromide, copper (I) bromide dimethyl sulfide complex, copper(I) triflate toluene complex, copper(I) iodide tetrabutylammonium iodide complex, tetrakis(acetonitrile)copper(I) hexafluorophosphate, copper(I) iodide triethylphosphite complex, and copper(I) bromide triphenylphosphine complex). [0023] As used herein, a “coupling agent” is a compound that improves the coupling of a carboxylic acid and amine. Non-limiting examples of coupling agents include, but are not limited to, N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), quinoline reagents (2-isobutoxy-1- isobutoxycarbonyl-1,2-dihydroquinoline (IIDQ), etc.); triazines (2-chloro-4,6-dimethoxy-1,3,5- triazine (CDMT), etc); phosphorous reagents (propylphosphonic anhydride (T3P), etc), phosphonium reagents (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP)); uronium reagents (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3-oxide hexafluorophosphate (HATU), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), etc.); carbodiimides (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), N,N'- diisopropylcarbodiimide (DIC), etc.), and boric acid, etc. [0024] As used herein, an “acid activator” is compound that increases the activity of a carboxylic acid group. In some embodiment, acid activators include trifluoroacetic anhydride, isobutyl chloroformate, di-2-pyridyl carbonate, triphosgene, and phosgene. Non-limiting examples of acid activator, include but are not limited to, N,N'-dicyclohexylcarbodiimide, N,N'- diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, diphenyl phosphoryl chloride, carbonyldiimidazole, propylphosphonic anhydride, 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridi nium 3-oxide hexafluorophosphate (HATU), thionyl chloride, oxalyl chloride, 2-isobutoxy-1- isobutoxycarbonyl-1,2-dihydroquinoline, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), propylphosphonic anhydride, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 4-nitrophenylchloroformate, 2,3,4,5,6-pentafluorobenzyl chloroformate, and 4-fluorophenyl chloroformate. [0025] As used herein, an “acid” or an “acidic additive” refers to a compound that is a proton donor that yields hydronium ions in water solution or an electron-pair acceptor that combines with an electron-pair donors or a base. Non-limiting examples of acids include, but are not limited to, dichloroacetic acid, acetic acid, formic acid, propionic acid, ascorbic acid, tartaric acid, benzoic acid, oxalic acid, citric acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid. Non-limiting examples of acids include, but are not limited to, BF ₃ , FeBr ₃ and AlCl ₃ . [0026] As used herein, “buffer” refers to solutions or chemicals that when in a solution may resist to changes in pH. Non-limiting examples of buffers include, but are not limited to, ammonium fluoride, phosphate buffer, acetate buffer, phosphate buffered saline (PBS) pH 7.4/ethylenediaminetetraacetic acid (EDTA), 2-(N-morpholino)ethanesulfonic acid (MES) buffer (buffer range pH 5.0 – 9.0), sodium acetate, citrate buffer, trehalose buffer, histidine-acetate buffer (pH 5.5), phosphate/citrate buffer, etc., or any combination thereof. [0027] “Volume” herein uses 1 liter per kilogram scaling factor. [0028] The compounds disclosed herein also include mixtures of all stereoisomers, including enantiomers and diastereomers. As used herein, “stereoisomers” refer to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Examples of stereoisomers include diastereomers and enantiomers. In some embodiments, the compounds described herein are produced in at least greater than about 50%, at least greater than about 60%, at least greater than about 70%, at least greater than about 80%, at least greater than about 90%, at least greater than about 91%, at least greater than about 92%, at least greater than about 93%, at least greater than about 94%, at least greater than about 95%, at least greater than about 96%, at least greater than about 97%, at least greater than about 98%, at least greater than about 99%, at least greater than about 99.5%, or at least greater about 99.9% diastereomeric or chiral purity. 1. COMPOUND 1 SYNTHETIC ROUTE [0029] Scheme 1 is a scheme depicting one embodiment of preparation of Compound 1 (see next page).

Scheme 1 [0030] In one embodiment, R ¹ in the compounds disclosed herein is tert-butyldimethylsilyl (TBS), trialkylsilyl (trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS)); alkylcarbonyl (pivalate (Piv)); arylcarbonyl (benzoyl (Bz)); alkoxycarbonyl (t-butyl carbonate (Boc) 2,2,2-trichloroethoxycarbonyl (Troc)); triarylmethyl (trityl (Tr)); or alkoxymethyl (methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), or tetrahydropyranyl (THP)). In one embodiment, R ¹ is tert-butyldimethylsilyl (TBS). [0031] In one embodiment, R ² in the compounds disclosed herein is para-monomethoxytrityl (MMT), H, t-butyl carbamate (Boc), 1-adamantyl carbamate (Adoc), diphenylsilyldiethylene (DPSide), 2-(triphenylsilyl)ethoxycarbonyl (Tpseoc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), 1,2-bis(dimethylsilyl)ethane (Stabase), triisopropylsilyloxycarbonyl (Tsoc), 2-chlorotrityl resin, or trityl resin. In one embodiment, R ² in the compounds disclosed herein is para-monomethoxytrityl (MMT). [0032] In one embodiment, HX ¹ in the compounds disclosed herein is dichloroacetic acid, acetic acid, formic acid, propionic acid, ascorbic acid, tartaric acid, benzoic acid, oxalic acid, citric acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p- toluenesulfonic acid, or hydrochloric acid. In one embodiment, HX ¹ in the compounds disclosed herein is dichloroacetic acid. 1.1. Protection of Compound 3 [0033] Scheme 2 is a scheme depicting one embodiment of synthesis of Compound 4. Scheme 2 [0034] In one embodiment, Compound 4 is prepared from a process comprising step (102) contacting Compound 3 with a hydroxyl protecting reagent in the presence of a base at a temperature sufficient to provide Compound 4. [0035] In one embodiment, the hydroxyl protecting reagent is a silyl chloride (including chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert- butyldiphenylsilyl chloride, chlorodimethylphenylsilane, chlorotriphenylsilane); a silyl trifluoromethanesulfonate (including trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate); a silyl bromide (including bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, bromotriphenylsilane); a silyl iodide (including iodotrimethylsilane), N,O-bis(trimethylsilyl)acetamide, N,O- bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, benzyl halides (including 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide); carbonates (dibenzyl carbonate); acid chlorides (including pivaloyl chloride, 1-adamantanecarbonyl chloride); anhydrides (di-tert-butyl carbonate), chloroformates (including methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 2-(trimethylsilyl)ethyl chloroformate); triarylmethyl chlorides (including trityl chloride, methoxymethyl trityl chloride); or alkoxymethyl chlorides (including methoxymethyl chloride, 2- (trimethylsilyl)ethoxymethyl chloride). In one embodiment, the hydroxyl protecting reagent is tert-butyldimethylsilyl (TBS) chloride. [0036] In one embodiment, for step (102), the base is tertiary amines (including N- methylmorpholine, tripropylamine, triethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec- 7-ene, 1,4-diazabicyclo[2.2.2]octane); aromatic amines (including pyridine, 2,6-lutidine, 2,3,5-collidine, 2,3,4-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,46-collidine, 3,4,5-collidine, 1-methylimidazole); or inorganic bases (including potassium carbonate, cesium carbonate, lithium sulfide, sodium hydride, potassium hydride). In one embodiment, the base is N,N- diisopropylethylamine. [0037] In one embodiment, for step (102), the solvent is ethers (including tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, 1,4-dioxane, diethyl ether); halogenated solvents (including 1,2-dichloroethane, chloroform, dichloromethane, chlorobenzene); polar aprotic solvents (including acetonitrile, propionitrile, butyronitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, sulfolane); or any combination of listed solvents. In one embodiment, the solvent is dichloromethane. [0038] In one embodiment, for step (102), a catalyst is present, and the catalyst is imidazole, N-methylimidazole, pyridine, 4-dimethylaminopyridine, 2,6-dimethylpyridine, 4- pyrrolidinopyridine, 4-piperidinopyridine, or 9-azajulolidine. In one embodiment, a catalyst is not present. [0039] In one embodiment, for step (102), the temperature is from about −10 °C to about 120 °C. In one embodiment, the temperature is from about 0 °C to about 110 °C. In one embodiment, the temperature is from about 0 °C to about 100 °C. In one embodiment, the temperature is from about 0 °C to about 90 °C. In one embodiment, the temperature is from about 0 °C to about 80 °C. In one embodiment, the temperature is from about 0 °C to about 70 °C. In one embodiment, the temperature is from about 0 °C to about 60 °C. In one embodiment, the temperature is from about 5 °C to about 50 °C. In one embodiment, the temperature is from about 5 °C to about 40 °C. In one embodiment, the temperature is from about 10 °C to about 30 °C. 1.2. Reaction with para-nitrophenol chlorocarbonate [0040] Scheme 3 is a scheme depicting one embodiment of synthesis of Compound 5. Scheme 3 [0041] In one embodiment, Compound 5 is prepared from a process comprising step (103) contacting Compound 4 with 4-nitrophenyl chloroformate in the presence of a base in a solvent at a temperature sufficient to provide Compound 5. [0042] In one embodiment, for step (103), the base is 4-dimethylaminopyridine (DMAP), tertiary amines (including N-methylmorpholine, triethylamine, tripropylamine, N,N- diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4- diazabicyclo[2.2.2]octane, DABCO, N,N,N′,N′-tetramethylethylenediamine), aromatic amines (including 4-pyrrolidinopyridine, 4-piperidinopyridine, 9-azajulolidine, pyridine, 2,6-lutidine, 2,3,5-collidine, 2,3,4-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,46-collidine, 3,4,5-collidine, 1- methylimidazole), or a combination thereof. In one embodiment, the base is 4-dimethylaminopyridine (DMAP). [0043] In one embodiment, for step (103), a desiccant is present. In one embodiment, the desiccant comprises inorganic salts (including sodium sulfate, calcium sulfate, magnesium sulfate), trialkyl orthoformates (including trimethyl orthoformate, triethyl orthoformate), or a combination thereof. In one embodiment, the desiccant is calcium chloride, calcium oxide, calcium hydride, silicon gel, or molecular sieve. In one embodiment, the desiccant is sodium sulfate. In one embodiment, a desiccant is not present. [0044] In one embodiment, for step (103), the solvent comprises halogenated solvents (including dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), esters (including ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, methyl acetate), ethers (including 2-methyltetrahydrofuran , tetrahydrofuran, diethyl ether, 1,4-dioxane, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diisopropyl ether, diphenyl ether, di-n-butyl ether), aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes), hydrocarbon solvents (including cyclohexane, methyl cyclohexane, hexanes, heptanes), or any combination thereof. In one embodiment, the solvent is dichloromethane. [0045] In one embodiment, for step (103), the temperature is from about 0 °C to about 100 °C. In one embodiment, the temperature is from about 0 °C to about 90 °C. In one embodiment, the temperature is from about 0 °C to about 80 °C. In one embodiment, the temperature is from about 0 °C to about 70 °C. In one embodiment, the temperature is from about 0 °C to about 60 °C. In one embodiment, the temperature is from about 0 °C to about 50 °C. In one embodiment, the temperature is from about 5 °C to about 40 °C. In one embodiment, the temperature is from about 10 °C to about 30 °C. 1.3. Reaction with Compound 6 to protected Compound 7 [0046] Scheme 4 is a scheme depicting one embodiment of synthesis of Compound 7.

Scheme 4 [0047] In one embodiment, Compound 7 is prepared from a process comprising step (104) contacting Compound 5 with Compound 6 in the presence of a base in a solvent at a temperature sufficient to provide Compound 7. [0048] In one embodiment, for step (104), the base comprises tertiary amines (including N- methylmorpholine, triethylamine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO, N,N,N′,N′- tetramethylethylenediamine), aromatic amines (including 4-pyrrolidinopyridine, 4- piperidinopyridine, 9-azajulolidine, pyridine, 2,6-lutidine, 2,3,5-collidine, 2,3,4-collidine, 2,3,6- collidine, 2,4,5-collidine, 2,46-collidine, 3,4,5-collidine, 1-methylimidazole, 4-dimethylaminopyridine (DMAP)), or a combination thereof. In one embodiment, the base is 4-dimethylaminopyridine (DMAP). [0049] In one embodiment, for step (104), the solvent comprises halogenated solvents (includeing dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), esters (including ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, butyl acetate, methyl acetate), ethers (including 2-methyltetrahydrofuran , tetrahydrofuran, diethyl ether, 1,4-dioxane, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diisopropyl ether, diphenyl ether, di-n-butyl ether), aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes), hydrocarbon solvents (including cyclohexane, methyl cyclohexane, hexanes, heptanes), polar aprotic solvents (including acetonitrile, propionitrile, butyronitrile, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, sulfolane), or any combination of thereof. In one embodiment, the solvent is dichloromethane. [0050] In one embodiment, for step (104), the temperature is from about 0 °C to about 100 °C. In one embodiment, the temperature is from about 0 °C to about 90 °C. In one embodiment, the temperature is from about 0 °C to about 80 °C. In one embodiment, the temperature is from about 0 °C to about 70 °C. In one embodiment, the temperature is from about 0 °C to about 60 °C. In one embodiment, the temperature is from about 0 °C to about 50 °C. In one embodiment, the temperature is from about 50 °C to about 40 °C. In one embodiment, the temperature is from about 10 °C to about 30 °C. 1.4. Deprotection of Compound 7 to Compound 8 [0051] Scheme 5 is a scheme depicting one embodiment of synthesis of Compound 8. Scheme 5 [0052] In one embodiment, Compound 8 is prepared from a process comprising step (105) deprotecting Compound 7 in the presence of a deprotecting agent in a solvent at a temperature sufficient to provide Compound 8. [0053] In one embodiment, for step (105), the deprotecting agent comprises base (including sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium acetate, potassium carbonate, potassium tert-butoxide, methylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene), acid [including protic acids (such as sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, hydrochloric acid, p-toluenesulfonic acid, and formic acid), and lewis acids (such as titanium tetrachloride, zinc bromide)], fluoride (including tetrabutyl ammonium fluoride (TBAF), cesium fluoride (CsF), hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, potassium hydrogen fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, tetrabutylammonium difluorotriphenylsilicate), oxidative agent (including sodium periodate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone), reductive agent (including hydrazine, sodium borohydride, (tetrakis(triphenylphosphine)palladium(0)/borazine(Pd(PPh ₃ ) ₄ /NH ₃ •BH ₃ , tetrakis(triphenylphosphine)palladium(0)/borane dimethylamine complex (Pd(PPh3)4/Me2NH•BH3), hydrogen/palladium on carbon, ammonium formate/palladium on carbon, zinc dust), or any combination thereof. In one embodiment, the deprotecting agent is tetrabutyl ammonium fluoride (TBAF) or cesium fluoride (CsF). [0054] In one embodiment, for step (105), a buffer is present. In one embodiment, the buffer comprises acetic acid, ammonium fluoride, phosphate buffer, or acetate buffer. In one embodiment, the buffer comprises acetic acid and acetate. In one embodiment, a buffer is not present. [0055] In one embodiment, for step (105), the solvent comprises ethers (including tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diisopropyl ether, diphenyl ether, di-n-butyl ether), aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes), hydrocarbon solvents (including cyclohexane, methyl cyclohexane, hexanes, heptanes), halogenated solvents (including dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (including methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol), polar aprotic solvents (including N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2- pyrrolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile), water, or any combinations thereof. In one embodiment, the solvent comprises dichloromethane, methanol, tetrahydrofuran, or a combination thereof. [0056] In one embodiment, for step (105), the temperature is from about −20 °C to 100 °C. In one embodiment, the temperature is from about -10 °C to about 90 °C. In one embodiment, the temperature is from about -10 °C to about 80 °C. In one embodiment, the temperature is from about -10 °C to about 70 °C. In one embodiment, the temperature is from about -10 °C to about 60 °C. In one embodiment, the temperature is from about 0 °C to about 50 °C. In one embodiment, the temperature is from about 5 °C to about 40 °C. In one embodiment, the temperature is from about 10 °C to about 30 °C. 1.5. Reaction of Compound 8 and Compound 9 to Compound 10 [0057] Scheme 6 is a scheme depicting one embodiment of synthesis of Compound 10 (see next page).

Scheme 6 [0058] In one embodiment, Compound 10 is prepared from a process comprising step (106) of contacting Compound 8 with Compound 9 in the presence of a coupling-cyclization catalyst in a solvent at a temperature sufficient to provide Compound 10. [0059] In one emobidment, for step (106), the coupling-cyclization comprises ruthenium (including chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium, pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium( II) chloride, chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium (II)), copper (including copper (II) sulfate (CuSO ₄ ), copper(II) acetate, copper acetyl acetonate, copper(I) thiophene-2- carboxylate, copper(I) chloride, copper(I) bromide, copper (I) bromide dimethyl sulfide complex, copper(I) triflate toluene complex, copper(I) iodide tetrabutylammonium iodide complex, tetrakis(acetonitrile)copper(I) hexafluorophosphate, copper(I) iodide triethylphosphite complex, copper(I) bromide triphenylphosphine complex), or any combination thereof. In one embodiment, the coupling-cyclization catalyst is CuSO ₄ , wherein the coupling-cyclization catalyst might be CuSO4 anhydrous, or CuSO4 hydrate. In one embodiment, the coupling- cyclization catalyst is CuSO4 ·5H2O. [0060] In one embodiment, for step (106), an additional reagent is present. In one embodiment, the additional reagent is sodium ascorbate, air, tris[(1-benzyl-1H-1,2,3-triazol-4- yl)methyl]amine. In one embodiment, the additional reagent is sodium ascorbate. In one embodiment, the additional reagent is not present. [0061] In one embodiment, for step (106), a base is present. In one embodiment, the base comprises aromatic amines (2,6-lutidine, pyridine, 2,3,5 collidine, 2,3,4 collidine, 2,3,6- collidine, 2,4,5-collidine, 2,4,6-collidine, 3,4,5-collidine, imidazole, N, N- dimethylaminopyridine), tertiary amines (including N,N-diisopropylethylamine, N- methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), inorganic bases (potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, cesium carbonate, ammonium hydroxide, lithium hydroxide, or potassium hydroxide), or any combination thereof. In one embodiment, the base is 2,6-lutidine. In one embodiment, a base is not present in step (106). [0062] In one embodiment, for step (106), the solvent comprises halogenated solvents (including dichloromethane, 1,2-dichloroethane, chlorobenzene, chloroform, trifluorotoluene), polar aprotic solvents (including N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2- pyrrolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, benzonitrile), alcohols (including methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, tert- butanol), ethers (including tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, di-n-butyl ether, 1,4-dioxane), esters (including ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, butyl acetate, methyl acetate), aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes), hydrocarbon solvents (including cyclohexane, methyl cyclohexane, hexanes, heptanes), water, or any combination thereof. In one embodiment, the solvent comprises dichloromethane. In one embodiment, the solvent comprises dichloromethane and water. [0063] In one embodiment, for step (106), the temperature is from about −30 °C to about 60 °C. In one embodiment, the temperature is from about -20 °C to about 50 °C. In one embodiment, the temperature is from about -10 °C to about 40 °C. In one embodiment, the temperature is from about -5 °C to about 35 °C. In one embodiment, the temperature is from about 0 °C to about 30 °C. 1.6. Deprotection of Compound 10 to Compound 1 [0064] Scheme 7 is a scheme depicting one embodiment of synthesis of Compound 1. Scheme 7 [0065] In one embodiment, Compound 1 is prepared from a process comprising step (107) deprotecting Compound 10 with a deprotecting agent in a solvent at a temperature sufficient to provide Compound 1. [0066] In one embodiment, for step (107), the deprotecting agent comprises organic acids (including dichloroacetic acid, dibromoacetic acid, tribromoacetic acid, acetic acid, formic acid, propionic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and iodoacetic acid), inorganic acids (including hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, ammonium chloride), oxidative conditions (including sodium periodate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone), fluoride (tetrabutylammonium floride, cesium fluoride, hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, potassium hydrogen fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, tetrabutylammonium difluorotriphenylsilicate), reductive agent (hydrazine, sodium borohydride, (tetrakis(triphenylphosphine)palladium(0)/borazine(Pd(PPh ₃ ) ₄ /NH ₃ •BH ₃ , tetrakis(triphenylphosphine)palladium(0)/borane dimethylamine complex (Pd(PPh3)4/Me2NH•BH3), hydrogen/palladium on carbon, ammonium formate/palladium on carbon, zinc dust), or any combination thereof. In one embodiment, the deprotecting agent is dichloroacetic acid. [0067] In one embodiment, for step (107), a scavenger is present. In one embodiment, the scavenger comprises anisole, thioanisole, pentamethylbenzene, cysteine, triethyl silane, or triisopropyl silane. In one embodiment, the scavenger is anisole. In one embodiment, a scavenger is not present in step (107). [0068] In one embodiment, for step (107), the solvent comprises dichloromethane, alcohols (including methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, tert-butanol), halogenated solvents (including 1,2-dichloroethane, chlorobenzene, chloroform, trifluorotoluene), ethers (including tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, di-n-butyl ether, 1,4-dioxane), esters (including ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, butyl acetate, methyl acetate), aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes), hydrocarbon solvents (including cyclohexane, methyl cyclohexane, hexanes, heptanes), or any combination thereof. In some embodiments, the solvent is dichloromethane. [0069] In one embodiment, for step (107), the temperature is from about −15 °C to about 55 °C. In one embodiment, the temperature is from about −10 °C to about 50 °C. In one embodiment, the temperature is from about −5 °C to about 45 °C. In one embodiment, the temperature is from about 0 °C to about 40 °C. In one embodiment, the temperature is from about 5 °C to about 35 °C. In one embodiment, the temperature is from about 10 °C to about 30 °C. In one embodiment, the temperature is from about 15 °C to about 25 °C. 2. COMPOUND 7 ALTERNATIVE SYNTHETIC ROUTE 2.1. Coupling of Compound 6 and Compound 4 to Compound 7 [0070] Scheme 8 is a scheme depicting one embodiment of synthesis of Compound 7. Scheme 8 [0071] In one embodiment, Compound 7 is prepared from a process comprising step (108a) contacting Compound 6 with a reagent in a solvent at a temperature to provide mixture A, wherein the reagent is a source of CO ²⁺ (-CO-); and step (108b) contacting Compound 4 with the mixture A in the presence of a base at a temperature sufficient to provide Compound 7. [0072] In one embodiment, for step (108a), the reagent of is 1,1’-carbonyl-di-(1,2,4-triazole) (CDT), N,N’-disuccinimidyl carbonate, 1,1’-carbonyldiimidazole, phosgene, triphosgene, 1,3- doxolan-2-one, or carbon dioxide/methanesulfonic anhydride. In one embodiment, the reagent is 1,1’-carbonyl-di-(1,2,4-triazole) (CDT). [0073] In one embodiment, for step (108b), the base is tertiary amines (including N- methylmorpholine, triethylamine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO, N,N,N′,N′- tetramethylethylenediamine), aromatic amines (including 4-dimethylaminopyridine (DMAP), 4- pyrrolidinopyridine, 4-piperidinopyridine, 9-azajulolidine, pyridine, 2,6-lutidine, 2,3,5 collidine, 2,3,4 collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, 3,4,5-collidine, or 1- methylimidazole), or any combination thereof. In one embodiment, the base is 4- dimethylaminopyridine (DMAP). [0074] In one embodiment, for step (108a) and (108b), the solvent comprises ethers (including 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diisopropyl ether, diphenyl ether, di-n-butyl ether), aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes), hydrocarbon solvents (including cyclohexane, methyl cyclohexane, hexanes, heptanes), halogenated solvents (including dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), polar aprotic solvents (including N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile), or any combination thereof. In one embodiment, the solvent is dichloromethane. [0075] In one embodiment, for step (108a) and (108b), the temperature is from about −20 °C to about 40 °C. In one embodiment, the temperature is from about −10 °C to about 40 °C. In one embodiment, the temperature is from about 0 °C to about 40 °C. In one embodiment, the temperature is from about 10 to about 30 °C.

3. COMPOUND 6 ALTERNATIVE SYNTHETIC ROUTE Scheme 9 [0076] Scheme 9 is a scheme depicting one embodiment of synthesis of Compound 6. 3.1. Coupling of 4-aminobenzyl alcohol and Compound 12 to Compound 13 [0077] Scheme 10 is a scheme depicting one embodiment of synthesis of Compound 13. Scheme 10 [0078] In one embodiment, Compound 13 is prepared by a process comprising step (110) contacting Compound 12 with 4-aminobenzyl alcohol in the presence of a coupling agent in a solvent at a temperature sufficient to provide Compound 13. [0079] In some embodiments, R ³ in the compounds disclosed herein is H. In some embodiments, R ³ in the compounds disclosed herein is carbamates (including fluorenylmethoxycarbonyl (Fmoc), (1,1-dioxobenzo[b]thiophene-2-yl)methyloxycarbonyl (Bsmoc), 1,1-dioxonaphtho[1,2-b]thiophene-2-ylmethyloxycarbonyl (α-Nsmoc), 2-(4- sulfophenylsulfonyl)ethoxycarbonyl (Sps), 2-(4-biphenyl)isopropoxycarbonyl (Bpoc), tert- butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), 2,2,2- trichloroethyloxycarbonyl (Troc), 2-(3,4-methylenedioxy-6-nitrophenyl) propyloxycarbonyl (MNPPOC), azidomethylcarbonyl (Azoc), p-nitrobenzyloxycarbonyl (pNZ)); amides (trifluoroacetyl (TFA), and tetrachloro-phthaloyl (TCP)); N-alkyl and N-aryl amines (trityl (Trt)); imine derivatives (benzylidene); enamine derivatives (1-(4,4-dimethyl-2-6- dioxocyclohex-1-ylidene)ethyl (Dde)); N-heteroatom derivatives (2-nitrophenylsulfenyl (Nps)). In some embodiments, R ³ is fluorenylmethoxycarbonyl (Fmoc). [0080] In some embodiments, for step (110), the coupling agent is 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), quinoline reagents (including N- ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), and 2-isobutoxy-1-isobutoxycarbonyl- 1,2-dihydroquinoline (IIDQ)); triazines (2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), etc); phosphorous reagents (propylphosphonic anhydride (T3P), etc), phosphonium reagents (including benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP)); uronium reagents (including 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3-oxide hexafluorophosphate (HATU), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU)); carbodiimides (including 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), and N,N'- diisopropylcarbodiimide (DIC)), or boric acid. In some embodiments, the coupling agent is N- ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ) or 4-(4,6-dimethoxy-1,3,5-triazin-2- yl)-4-methyl-morpholinium chloride (DMTMM), optionally DMTMM is made in situ from triazines (2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and methylmopholine. In some embodiments, the coupling agent is EEDQ. In some embodiments, the coupling agent is DMTMM, optionally DMITMM is made in situ from CDMT and methylmopholine. [0081] In some embodiments, for step 110, a base is not present. In some embodiments, a base is present. The base is tertiary amines (N-methylmorpholine, tripropylamine, N,N- diisopropylethylamine, triethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4- diazabicyclo[2.2.2]octane); aromatic amines (pyridine, 2,6-lutidine, 2,3,5-collidine, 2,3,4-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,46-collidine, 3,4,5-collidine, 1- methylimidazole); inorganic bases (sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, or potassium phosphate tribasic, potassium fluoride, lithium carbonate, cesium carbonate). In some embodiments, the base is N-methylmorpholine. [0082] In some embodiments, for step (110), a catalyst/additive is not present. In some embodiments, for step (110), a catalyst/additive is present. In some embodiments, the catalyst/additive is hydroxybenzoltriazoles (including 1-hydroxy-1H-benzotriazole (HOBt), 1- hydroxy-7-azabenzotriazole (HOAt)); or pyridines (including 4-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine, 9-azajulolidine). [0083] In some embodiments, for step 110, the solvent is halogenated solvents (including dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene); polar aprotic solvents (including N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, benzonitrile, etc); aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes); hydrocarbon solvents (including cyclohexane, methyl cyclohexane, hexanes, heptanes); ethers (including 2- methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran , tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether); esters (including ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n- butyl acetate); or any combination of listed solvents. In some embodiments, for step (110), the solvent is dichloromethane or 2-methyltetrahydrofuran. [0084] In some embodiments, for step (110), the temperature is from about −10 °C to about 110 °C. In some embodiments, the temperature is from about −5 °C to about 100 °C. In some embodiments, the temperature is from about 0 °C to about 90 °C. In some embodiments, the temperature is from about 0 °C to about 80 °C. In some embodiments, the temperature is from about 0 °C to about 70 °C. In some embodiments, the temperature is from about 0 °C to about 60 °C. In some embodiments, the temperature is from about 0 °C to about 50 °C. In some embodiments, the temperature is from about 5 °C to about 40 °C. In some embodiments, the temperature is from about 10 °C to about 30 °C. 3.2. Deprotection of Compound 13 to Compound 14 Scheme 11 [0085] Scheme 11 is a scheme depicting one embodiment of synthesis of Compound 14 by deprotecting Compound 13 when R ³ is an amine protecting group. [0086] In one embodiment, Compound 14 is prepared a process comprising the step (111) deprotecting Compound 13 in the presence of a deprotecting agent in a solvent at a temperature sufficient to provide Compound 14. [0087] In one embodiment, for step (111), the deprotecting agent is base (1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), primary amines (including ethylamine, n-propylamine, n-butylamine, benzylamine, cyclohexylamine, ethanolamine, 4-(aminomethyl)piperidine); secondary amines (including diethylamine, dimethylamine, diethanolamine, piperidine, 4- methylpiperidine, piperazine, morpholine, dicyclohexylamine, 1,4-bis-(3- aminopropyl)piperazine, polyethylenimine, etc); tertiary amines (including N- methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n- butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 4- dimethylaminopyridine, tris(2-aminoethyl)amine, 1,8-bis(dimethylamino)naphthalene (proton sponge)); inorganic bases (including sodium carbonate, sodium phosphate dibasic, sodium phosphate tribasic, sodium acetate, potassium carbonate, potassium phosphate dibasic, potassium phosphate tribasic, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, cesium carbonate); hydroxide bases (including sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide)); acid [ including organic acids (acetic acid, methanesulfonic acid, trichloroacetic acid, trifluoroacetic acid, thiomalic acid)]; inorganic acids (hydrobromic acid, hydrochloric acid); reductant [including hydrazine, sodium borohydride, (tetrakis(triphenylphosphine)palladium(0)/borazine(Pd(PPh3)4 /NH3•BH3, tetrakis(triphenylphosphine)palladium(0)/borane dimethylamine complex (Pd(PPh3)4/Me2NH•BH3), hydrogen/palladium on carbon, ammonium formate/palladium on carbon, zinc dust]; hn (light); or any combination of the above reagents. In one embodiment, the deprotecting agent is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or thiomalic acid. [0088] In some embodiments, for step (111), the solvent is halogenated solvents (chloroform, dichloroethane, chlorobenzene); polar aprotic solvents (N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, benzonitrile, etc); aromatic solvents (benzene, toluene, trifluorotoluene, xylenes); hydrocarbon solvents (cyclohexane, methyl cyclohexane, hexanes, heptanes); ethers (diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether); esters (methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, n-propyl acetate, isobutyl acetate); alcoholic solvent (methanol, ethanol, isopropanol, n-butanol, t-butanol); water; or any combination of thereof. In some embodiments, the solvent is methanol or 2- methyltetrahydrofuran. [0089] In some embodiments, for step (111), the temperature is from about −10 °C to about 110 °C. In some embodiments, the temperature is from about 0 °C to about 100 °C. In some embodiments, the temperature is from about 0 °C to about 90 °C. In some embodiments, the temperature is from about 0 °C to about 80 °C. In some embodiments, the temperature is from about 0 °C to about 70 °C. In some embodiments, the temperature is from about 0 °C to about 60 °C. In some embodiments, the temperature is from about 0 °C to about 50 °C. In some embodiments, the temperature is from about 0 °C to about 40 °C. In some embodiments, the temperature is from about 0 to about 30 °C. 3.3. Coupling of Compound 14 and Compound 15 to Compound 6 Scheme 12

[0090] Scheme 12 is a scheme depicting one embodiment of synthesis of Compound 6. [0091] In some embodiments, Compound 6 is prepared by a process compring step (112) contacting Compound 14 with Compound 15 in the presence of a coupling agent in a solvent at a temperature sufficient to provide Compound 6. [0092] In some embodiments, for step (112), the coupling agent is 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), quinoline reagents (N- ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 2-isobutoxy-1-isobutoxycarbonyl-1,2- dihydroquinoline (IIDQ)); triazines (2-chloro-4,6-dimethoxy-1,3,5-triazine, etc); phosphorous reagents (propylphosphonic anhydride (T3P), phosphonium reagents (benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP)); uronium reagents (2-(1H- benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridi nium 3-oxide hexafluorophosphate (HATU), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU)); or carbodiimides (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), N,N'- diisopropylcarbodiimide (DIC)). In some embodiments, the coupling agent is N-ethoxycarbonyl- 2-ethoxy-1,2-dihydroquinoline (EEDQ) or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl- morpholinium chloride (DMTMM). [0093] In some embodiments, for step (112), a base is not present. In some embodiment, a base is present. In some embodiments, the base is tertiary amines (tripropylamine, N,N- diisopropylethylamine, triethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4- diazabicyclo[2.2.2]octane); aromatic amines (pyridine, 2,6-lutidine, 2,3,5-collidine, 2,3,4-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,46-collidine, 3,4,5-collidine, 1- methylimidazole); inorganic bases (sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, potassium fluoride, lithium carbonate, cesium carbonate). In some embodiments, the base is N-methylmorpholine. [0094] In some embodiments, for step (112), a catalyst/additive is not present. In some embodiments, for step (112), a catalyst/additive is present. In some embodiments, the catalyst/additive is hydroxybenzoltriazoles (1-hydroxy-1H-benzotriazole (HOBt), 1-hydroxy-7- azabenzotriazole (HOAt)); pyridines (4-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine, 9-azajulolidine). [0095] In some embodiments, for step (112), the solvent comprises halogenated solvents (including chloroform, 1,2-dichloroethane, chlorobenzene), polar aprotic solvents (including N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, benzonitrile, etc); aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes); hydrocarbon solvents (including cyclohexane, methyl cyclohexane, hexanes, heptanes); ethers (including diethyl ether, 1,4- dioxane, 2-methyltetrahydrofuran , tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether); esters (including ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate); or any combinations of thereof. In some embodiments, the solvent is toluene or 2-methyltetrahydrofuran. [0096] In some embodiments, for step (112), the temperature is from about −10 °C to about 110 °C. In some embodiments, the temperature is from about 0 °C to about 100 °C. In some embodiments, the temperature is from about 0 °C to about 90 °C. In some embodiments, the temperature is from about 0 °C to about 80 °C. In some embodiments, the temperature is from about 0 °C to about 70 °C. In some embodiments, the temperature is from about 0 °C to about 60 °C. In some embodiments, the temperature is from about 0 °C to about 50 °C. In some embodiments, the temperature is from about 10 °C to about 40 °C.

4. COMPOUND 9 SYNTHETIC ROUTE 1 Scheme 13 [0097] Scheme 13 is a scheme depicting one embodiment of synthesis of Compound 9. 4.1. Activation of Compound 16 to Compound 17 Scheme 14 [0098] Scheme 14 is a scheme depicting one embodiment of synthesis of Compound 17. [0099] In some embodiments, Compound 17 is prepared by a process comprising step (114) contacting Compound 16 with a reagent in the presence of a base and an acid activator at a temperature sufficient to provide Compound 17. [0100] In some embodiments, for step (114), the reagent is N,N′-disuccinimidyl carbonate, N,N′-disuccinimidyl oxalate, N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate, dipyrrolidino(N-succinimidyloxy)carbenium hexafluorophosphate, diphenyl N-succinimidyl phosphate, or N-succinimidyl trifluoroacetate. In some embodiments, the reagent is N-hydroxysuccinimide. [0101] In some embodiments, for step (114), the base is tertiary amines (N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, triethylamine, tributylamine, triethanolamine); aromatic amines (pyridine, 2,4,6-collidine, 2,6-lutidine, 2,3,5-collidine, 2,3,4-collidine, 2,3,6- collidine, 2,4,5-collidine, 3,4,5-collidine, 1-methylimidazole, 1,8- bis(dimethylamino)naphthalene). In some embodiments, the base is 2,4,6-collidine. [0102] In some embodiments, for step (114), the acid activator is trifluoroacetic anhydride, isobutyl chloroformate, di-2-pyridyl carbonate, triphosgene, or phosgene. In some embodiments, the acid activator is trifluoroacetic anhydride. [0103] In some embodiments, for step (114), the solvent comprises halogenated solvents (including chloroform, dichloromethane, 1,2-dichloroethane, chlorobenzene,etc.); polar aprotic solvents (including N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2- pyrrolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, benzonitrile, etc); aromatic solvents (including benzene, toluene, trifluorotoluene, xylenes); ethers (including diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran , tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether); esters (including ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate); or amines (including pyridine, triethylamine, tributylamine, 2,6-lutidine); or any combination thereof. In some embodiments, the solvent is dichloromethane or N,N-dimethylformamide, or any combination thereof. [0104] In some embodiments, for step (114), the temperature is −10 °C to 90 °C. In some embodiments, the temperature is from about −10 °C to about 80 °C. In some embodiments, the temperature is from about −10 °C to about 70 °C. In some embodiments, the temperature is from about −10 °C to about 60 °C. In some embodiments, the temperature is from about −10 °C to about 50 °C. In some embodiments, the temperature is from about −10 °C to about 40 °C. In some embodiments, the temperature is from about 0 °C to about 30 °C. 4.2. Amidation of Compound 17 with propargyl amine to Compound 9 Scheme 15 [0105] Scheme 15 is a scheme depicting one embodiment of synthesis of Compound 9, wherein HX ² is inorganic acid (including hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and boronic acid); or organic acids (including benzenesulfonic acid, methanesulfonic acid, para-toluenesulfonic acid, mesylic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, formic acid, tartaric acid, oxalic acid, citric acid, latic acid, malic acid, and succinic acid); and n is 0 or 1. [0106] In some embodiments, Compound 9 is prepared by a process comprising step (115) contacting Compound 17 with HC≡C-CH2NH2·(HX ² )n in the presence of a base at a temperature sufficient to provide Compound 9, wherein HX ² is inorganic acid (including hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and boronic acid); or organic acids (including benzenesulfonic acid, methanesulfonic acid, para-toluenesulfonic acid, mesylic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, formic acid, tartaric acid, oxalic acid, citric acid, latic acid, malic acid, and succinic acid); and n is 0 or 1. [0107] In some embodiments, for step (115), n is 0. In some embodiments, n is 1. In some embodiments, for step (115), HX ² is hydrochloric acid. [0108] In some embodiments, for step (115), the base is tertiary amines (N,N- diisopropylethylamine, N-methylmorpholine, tripropylamine, triethylamine, tributylamine, triethanolamine); aromatic amines (pyridine, 2,6-lutidine, 2,3,5-collidine, 2,3,4-collidine, 2,3,6- collidine, 2,4,5-collidine, 3,4,5-collidine, 1-methylimidazole, or 1,8- bis(dimethylamino)naphthalene). In some embodiments, the base is N,N-diisopropylethylamine. [0109] In some embodiments, for step (115), the solvent comprises halogenated solvents (including dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene); polar aprotic solvents (including N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2- pyrrolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, and benzonitrile, etc); aromatic solvents (including benzene, toluene, trifluorotoluene, and xylenes); ethers (including diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran , tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether); esters (including ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, and n-butyl acetate); amines (including pyridine, triethylamine, tributylamine, and 2,6-lutidine); or any combination thereof. In some embodiments, the solvent is dichloromethane. [0110] In some embodiments, for step (115), the temperature is from about −10 °C to about 50 °C. In some embodiments, the temperature is from about −10 °C to about 40 °C. In some embodiments, the temperature is from about −5 °C to about 30 °C. 5. COMPOUND 9 SYNTHETIC ROUTE 5.1. Amidation of Compound 16 with propargyl amine to Compound 9 Scheme 16 [0111] Scheme 16 is a scheme depicting one embodiment of synthesis of Compound 9, wherein HX ² is inorganic acid (including hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and boronic acid); or organic acids (including benzenesulfonic acid, methanesulfonic acid, para-toluenesulfonic acid, mesylic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, formic acid, tartaric acid, oxalic acid, citric acid, latic acid, malic acid, and succinic acid); and n is 0 or 1. Scheme 16.1 [0112] Scheme 16.1 is a scheme depicting another embodiment of synthesis of Compound 9. [0113] In some embodiments, Compound 9 is prepared by a process comprising step (116) contacting Compound 16 with HC≡C-CH ₂ NH ₂ ·(HX ² ) _n in the presence of an acid activator and a base in a solvent at a temperature sufficient to provide Compound 9, wherein HX ² is inorganic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, boronic acid; or organic acids, benzenesulfonic acid, methanesulfonic acid, para-toluenesulfonic acid, mesylic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, formic acid, tartaric acid, oxalic acid, citric acid, latic acid, malic acid, or succinic acid; and n is 0 or 1. [0114] In some embodiments, for step (116), n is 0. In some embodiments, n is 1. In some embodiments, for step (116), HX ² is hydrochloric acid. [0115] In some embodiments, for step (116), the acid activator is 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, diphenyl phosphoryl chloride, carbonyldiimidazole, propylphosphonic anhydride, 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridi nium 3-oxide hexafluorophosphate (HATU), thionyl chloride, oxalyl chloride, 2-isobutoxy-1- isobutoxycarbonyl-1,2-dihydroquinoline, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), propylphosphonic anhydride, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 4-nitrophenylchloroformate, 2,3,4,5,6-pentafluorobenzyl chloroformate, or 4-fluorophenyl chloroformate. In some embodiments, the acid activator is 4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), optionally DMTMM is prepared in situ from CDMT and N-methylmorpholine (NMM). [0116] In some embodiments, for step (116), the base is tertiary amines (N,N- diisopropylethylamine, tripropylamine, triethylamine, tributylamine, triethanolamine); aromatic amines (pyridine, 2,6-lutidine, 2,3,5-collidine, 2,3,4-collidine, 2,3,6-collidine, 2,4,5-collidine, 3,4,5-collidine, 1-methylimidazole, 1,8-bis(dimethylamino)naphthalene), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate, or sodium phosphate). In some embodiments, the base is N-methylmorpholine (NMM). [0117] In some embodiments, for step (116), a promoter is present. In some embodiments, a promoter is not present. In some embodiments, the promoter is N-methylimidazole, 1-hydroxy- 7-azabenzotriazole, 1-hydroxybenzotriazole, 4-dimethylaminopyridine. [0118] In some embodiments, for step (116), the solvent comprises halogenated solvents (chloroform, 1,2-dichloroethane, chlorobenzene); polar aprotic solvents (N,N- dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, propionitrile, butyronitrile, benzonitrile, etc); aromatic solvents (benzene, toluene, trifluorotoluene, xylenes); ethers (diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran , tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether); esters (ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n- butyl acetate), or any combination thereof. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent comprises acetonitrile and water. [0119] In some embodiments, for step (116), the temperature is from about −50 °C to about 100 °C. In some embodiments, the temperature is from about −40 °C to about 90 °C. In some embodiments, the temperature is from about −30 °C to about 80 °C. In some embodiments, the temperature is from about −20 °C to about 70 °C. In some embodiments, the temperature is from about −10 °C to about 60 °C. In some embodiments, the temperature is from about −10 °C to about 50 °C. In some embodiments, the temperature is from about −10 °C to about 40 °C. In some embodiments, the temperature is from about −5 °C to about 30 °C.

6. BIOCONJUGATION ROUTE TO IMMUNOCONJUGATES Scheme 17 [0120] Scheme 17 is a scheme depicting one embodiment of synthesis of immunoconjugates from Antibody 18 and Compound 1A. 6.1. Reduction of antibody Scheme 18 [0121] Scheme 18 is a scheme depicting one embodiment of synthesis of anitbody comprising reduced sulfhydryl, wherein m is average drug-to-antibody ratio (DAR), and m is 7 to 10. In some embodiments, m is 7-8. In some embodiments, the antibody is hRS7 IgG1κ. In some embodiments, the antibiody is hMN-14. [0122] In some embodiments, antibody comprising sulfhydryl is prepared by modification of antibody’s lysine groups of the antibody. Methods for introducing thiol groups onto antibodies by modifications of MAB’s lysine groups are well known in the art (Wong in Chemistry of protein conjugation and crosslinking, CRC Press, Inc., Boca Raton, Fla. (1991), pp 20-22). [0123] In some embodiments, antibody comprising reduced sulfhydryl is prepared from a process comprising step (118) contacting antibody with a reductant in a solvent at a temperature sufficient to provide antibody comprising reduced sulfhydryl (Antibody 11). [0124] In some embodiments, for step (118), the antibody is selected from an antibody, including a bispecific or multispecific antibody, described in US Patent No.9,102,735. [0125] In some embodiments, for step (118), the antibody is LLI (anti-CD74), LL2 or RFB4 (anti-CD22), veltuzumab (hA20, anti-CD20), rituxumab (anti-CD20), obinutuzumab (GA101, anti-CD20), lambrolizumab (anti-PD-I receptor), nivolumab (anti-PD-I receptor), ipilimumab (anti-CTLA-4), RS7 (anti-epithelial glycoprotein-I (EGP-I, also known as TROP-2)), PAM4 or KC4 (both anti-mucin), MN-14 (anti-carcinoembryonic antigen (CEA, also known as CD66e or CEACAM5), MN-15 or MN-3 (anti-CEACAM6), Mu-9 (anti-colon-specific antigen-p), Immu 31 (an anti-alpha-fetoprotein), Rl (anti-IGF-IR), A19 (anti-CD19), IMMU-H2B (anti-H2B), IMMU-H3 (anti-H3), IMMU-H4 (anti-H4), TAG-72 (e.g., CC49), Tn, J591 or HuJ591 (anti- PSMA (prostate-specific membrane antigen)), AB-PGIXGI-026 (anti-PSMA dimer), D2/B (anti-PSMA), G250 (an anti-carbonic anhydrase IX MAb), L243 (anti-HLA-DR) alemtuzumab (anti-CD52), bevacizumab (anti-VEGF), cetuximab (anti-EGFR), gemtuzumab (anti-CD33), ibritumomab tiuxetan (anti-CD20); panitumumab (anti-EGFR); tositumomab (anti-CD20); PAM4 (aka clivatuzumab, anti-mucin) and trastuzumab (anti-ErbB2). [0126] In some embodiments, for step (118), the antibody is a monospecific or multispecific (e.g., bispecific, trispecific) antibody, or an antigen-binding fragment thereof, in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, or Fab derivative. In some embodiments, the antibody is non-immunoglobulin antibody mimetic (e.g., including adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein (DARPin ^® ), fynomer, knottin, Kunitz domain peptide, monobody, and nanoCLAMPs). [0127] In some embodiments, for step (118), the antibody is a blocking antibody. In some embodiments the antibody is a neutralizing antibody. In some embodiments, the antibody is an agonistic or activating antibody. In some embodiments the antibody is an antagonistic or inhibitory antibody. [0128] In some embodiments, for step (118), the antibody is an IgG antibody or antigen- binding fragment thereof. The IgG antibody or antigen-binding fragment thereof can be of various isotypes, such as IgG1, IgG2, IgG3 or IgG4. In some embodiments the antibody comprises human IgG1 hinge and constant region sequences. The antibody can be a chimeric human-mouse, a chimeric human-primate, a humanized (human framework and murine hypervariable (CDR) regions), or a fully human antibody, as well as a variation thereof. In some embodiments the antibody is a half-IgG4 antibody (referred to as "unibody"), as described, e.g., by van der Neut Kolfschoten et al. (Science 2007; 317:1554-1557). In some embodiments the antibody or antigen-binding fragment thereof is designed or selected to comprise human constant region sequences that belong to specific allotypes, which may result in reduced immunogenicity when the antibody or ADC is administered to a human subject. In some embodiments, the antibody or antigen-binding fragment thereof is of a non-Glml allotype (nGlml), such as Glm3, Glm3,1, Glm3,2 or Glm3,1,2. In some embodiments, the allotype is selected from the group consisting of the nGlml, Glm3, nGlml, 2 and Km3 allotypes. In one embodiment, the antibody is hRS7 IgG1κ. In one embodiment, the antibiody is hMN-14. [0129] In one embodiment, for step (118), the antibody is hRS7 IgG1κ (sacituzumab). In one embodiment, the antibody is hMN-14 (labetuzumab). [0130] In some embodiments, for step (118), the solvent comprises phosphate buffered saline (PBS) pH 7.4, 2-(N-morpholino)ethanesulfonic acid (MES) buffer, succinate buffer, Dulbecco′s phosphate buffered saline (dPBS), sodium acetate buffer, or any combination thereof. In some embodiments, the solvent is phosphate buffered saline (PBS) pH 7.4. [0131] In some embodiments, for step (118), the reducant is tris(2-carboxyethyl)phosphine (TCEP), tris(3-hydroxypropyl)-phosphine (THPP), triphenylphosphine-3,3′,3′′-trisulfonic acid trisodium salt (TPPTS), tris-(hydroxymethyl) phosphine (THMP), 1,4-dithiotretiol (DTT), dithioerythritol (DTE), N,N’-dimethyl-N,N’-bis(mercaptoacetyl)hydrazine (DMH), meso-2,5- dimercapto-N,N,N’,N’-tetramethyladipamide (meso-DMH), bis(2-mercaptoethyl) sulfone (BMS), (2S)-2-amino-1,4-dimercaptobutane DTBA), 2,3-bis(mercaptomethyl)pyrazine (BMMP), 2-(dibenzylamino)butane-1,4-dithiol (DABDT), 4-azidobenzoic acid (4-ABA), 2- mercaptoethanol, aminoethanethiol, or thioredoxin/thioredoxin reductase. In some embodiments, the reducant is tris(2-carboxyethyl)phosphine (TCEP). [0132] In some embodiments, for step (118), a buffer is present. In some embodiments, the buffer is aqueous sodium phosphate monobasic (buffer range pH 5.0 – 9.0), 4- morpholineethanesulfonic acid (MES), succinate buffer, sodium acetate, or any combination thereof. In some embodiments, the buffer is aqueous sodium phosphate monobasic (buffer range pH 5.0 – 9.0). [0133] In some embodiments, for step (118), a chelating agent is present. In some embodiments, the chelating agent is ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid (DTPA), or ascorbic acid. In some embodiments, the chelating agent is ethylenediaminetetraacetic acid. In some embodiments, for step (118), a chelating agent is not present. [0134] In some embodiments, for step (118), the temperature is from about 0 °C to about 40 °C. In some embodiments, the temperature is from about 5 to about 35 °C. In some embodiments, the temperature is from about 10 to about 30 °C. In some embodiments, the temperature is from about 15 to about 25 °C. In some embodiments, the temperature is from about 20 to about 25 °C.

6.2. Bioconjugation of Compound 1 salt to immunoconjugates Scheme 19 [0135] Scheme 19 is a scheme depicting one embodiment of synthesis of immunoconjugate 2. [0136] In some embodiments, immunoconjugates are prepared by a process comprising step (119) contacting the antibody comprising reduced sulfhydryl (Antibody 11) with compound 1 in a solvent at a temperature sufficient to provide immunoconjugates. In one embodiment, the immunoconjugate is sacituzumab govitecan. In one embodiment, the immunoconjugate is labetuzumab govitecan. [0137] In some embodiments, for step (119), Compound 1 is the compound wherein n is 0. In some embodiments, n is 1. In some embodiments, Compound 1 is the compound wherein in HX ¹ is dichloroacetic acid, acetic acid, formic acid, propionic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, or hydrochloric acid. In some embodiments, Compound 1 is the compound wherein in HX ¹ is dichloroacetic acid. [0138] In some embodiments, for step (119), the solvent comprises dimethyl sulfoxide, N,N- dimethylacetamide, N,N dimethylformamide, N-methyl-2-pyrrolidinone, sulfolane, or any combination thereof. In some embodiment, the solvent is dimethyl sulfoxide. [0139] In some embodiments, for step (119), a chelating agent is not present. In some embodiments, a chelating agent is present. In some embodiments, the chelating agent is ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), or ascorbic acid. [0140] In some embodiments, for step (119), a buffer is present. In some embodiments, the buffer is phosphate buffered saline (PBS) pH 7.4/ethylenediaminetetraacetic acid (EDTA), succinate buffer, sodium acetate buffer, citrate buffer, Dulbecco′s phosphate buffered saline (dPBS), histidine-acetate buffer (pH 5.5), or any combination thereof. In some embodiments, the buffer is phosphate buffered saline (PBS) pH 7.4/ethylenediaminetetraacetic acid (EDTA). [0141] In some embodiments, for step (119), the temperature is from about 0 °C to about 30 °C. In some embodiments, the temperature is from about 5 °C to about 30 °C. In some embodiments, the temperature is from about 10 °C to about 30 °C. In some embodiments, the temperature is from about 15 °C to about 25 °C. [0142] In some embodiments, the immunoconjugate is prepared by a process further comprising step (119a) contacting the solution from step (119) with a quenching agent. In some embodiments, the quenching agent is diaazido ethylene glycols (1,8-diazido-3,6-dioxaoctane, 1,11-diazido-3,6,9-trioxaundecane, 1,14-diazido-3,6,9,12-tetraoxatetradecane, 1,17-diazido- 3,6,9,12,15-pentaoxaheptadecane, iodoacetamide, or bromacetamide. In some embodiments, the immunoconjugate is prepared by a process wherein subsequent to step (119a), a quenching agent is not applied to the solution from step (119). [0143] In some embodiments, the immunoconjugate is prepared by a process further comprising step (119b) purifying the solution from step (119a) by buffer exchange with a buffer. In some embodiments, the buffer is 2-(N-morpholino)ethanesulfonic acid (MES), sodium acetate, citrate buffer, trehalose buffer, histidine-acetate buffer (pH 5.5), phosphate/citrate buffer, or any combination thereof. In some embodiments, the buffer is 2-(N- morpholino)ethanesulfonic acid (MES). [0144] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES Example 1: Compound 1A Manufacturing Route Procedures Example 1.1: Protection of Compound 3 to Compound 4A: [0145] A reaction vessel was charged with Compound 3 (1.0 equiv, scaling factor) and dichloromethane (9 volumes) then cooled to about 10 °C. N,N-Diisopropylethylamine (2.75 equiv) was charged and then a solution of tert-butyldimethylsilyl chloride (2.6 equiv) in dichloromethane (3 volumes) was charged while maintaining the reaction temperature below about 25 °C. The resulting mixture was agitated at about 20 °C until the reaction was deemed complete. The reaction mixture was quenched with a prepared solution of hydrochloric acid (37 wt%, 1.0 equiv) in 8 wt% aqueous sodium chloride (13 volumes), and then the organic layer was washed with 10 wt% aqueous sodium chloride (9 volumes). The organic layer was concentrated to about 14 volumes and then dichloromethane (5 volumes) was charged. The solution was further concentrated to about 6 volumes and then adjusted to about 40 °C. Dichloromethane or ethyl acetate (2 volumes) was charged to the vessel followed by n-heptane (14 volumes), then the mixture was cooled to about 0 °C. The slurry was filtered, washed with n-heptane (6 volumes) and dried to afford Compound 4A. ¹ H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.0 Hz, 1H), 7.61 (s, 1H), 7.40 – 7.38 (m, 2H), 5.76 (d, J = 16.2 Hz, 1H), 5.31 (d, J = 16.2 Hz, 1H), 5.24 (s, 2H), 3.72 (s, 1H), 3.12 (q, J = 7.7 Hz, 2H), 1.92 – 1.87 (m, 2H), 1.39 (t, J = 7.7 Hz, 3H), 1.05 (m, 12H), 0.31 (s, 6H). Process A: [0146] A reaction vessel was charged with Compound 4A (1.0 equiv, scaling factor), dichloromethane (16 volumes), 4-dimethylaminopyridine (3.3 equiv), and sodium sulfate (3.6 equiv). The mixture was cooled to about 10 °C and agitated for approximately 1 h. A solution of 4-nitrophenyl chloroformate (1.2 equiv) in dichloromethane (5 volumes) was added at about 15 °C and the reaction mixture was aged for approximately 3 h to give Compound 5A as a solution with 4-dimethylaminopyridine in dichloromethane. This solution is carried forward directly to the next process step. ¹ H NMR (400 MHz, CDCl3): δ 8.21 (m, 2H), 8.11 (m, 1H), 7.42 – 7.38 (m, 4H), 7.32 (s, 1H), 5.71 (d, J = 17.2 Hz, 1H), 5.41 (d, J = 17.2 Hz, 1H), 5.24 (m, 2H), 3.12 (m, 2H), 2.37 – 2.34 (m, 1H), 2.26 – 2.23 (m, 1H), 1.38 (t, J = 7.6 Hz, 3H), 1.05 (m, 12H), 0.32 (s, 6H). Process B: [0147] A reaction vessel was charged with Compound 4A (1.0 equiv, scaling factor), dichloromethane (13 volumes) and the contents were cooled to about 0 °C. To the cooled solution was added 4-dimethylaminopyridine (0.9 equiv), followed by 4-nitrophenyl chloroformate (1.2 equiv). Dichloromethane (3 volumes) was used in the transfer. The contents were warmed to about 20 °C and agitated for approximately 9 h to give Compound 5A as a solution with 4-dimethylaminopyridine in dichlormethane. This solution is carried forward directly to the next process step. Example 1.3: para-Nitrophenol carbonate displacement of Compound 5A to form Compound 7A: Process A: [0148] A solution of Compound 5A (1.0 equiv, scaling factor) containing 4-dimethylaminopyridine (2.2 equiv) in dichloromethane (16 volumes) was combined with a solution of Compound 6A (0.95 equiv) in dichloromethane (9 volumes) and agitated at about 20 °C until the reaction is deemed complete. The organic solution was then washed three times with 50 mM aqueous sodium acetate solution (8 volumes) and once with 10 % aqueous sodium chloride solution (9 volumes). Sodium sulfate (7.0 equiv) was charged to the organic layer and the mixture was agitated for approximately 1 h. The mixture was filtered to give Compound 7A as a solution in dichloromethane. Process B: [0149] A solution of Compound 5A (1.0 equiv, scaling factor) in dichloromethane (12 volumes) was combined with 4-dimethylaminopyridine (1.2 equiv) and a 60 wt% solution of Compound 6A in toluene (0.90 equiv) and agitated at about 0 °C until the reaction is deemed complete to give Compound 7A as a solution in dichloromethane. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.74 (s, br, 1H), 8.11 (m, 1H), 7.58 (m, 2H), 7.49 (m, 1H), 7.45 – 7.39 (m, 5H), 7.34 (m, 2H), 7.29 – 7.22 (m, 4H), 7.18 – 7.13 (m, 4H), 7.05 (m, 1H), 6.78 (m, 2H), 5.69 (d, J = 17.1 Hz, 1H), 5.39 (d, J = 17.1 Hz, 1H), 5.23 (s, 2H), 5.14 (d, J = 12.0 Hz, 1H), 4.97 (d, J = 12.0 Hz, 1H), 4.59 – 4.53 (m, 1H), 4.17 – 4.16 (m, 1H), 4.13 (m, 1H), 4.02 (m, 1H), 4.01 (m, 1H), 3.76 (s, 3H), 3.66 – 3.53 (m, 34H), 3.49 – 3.46 (m, 2H), 3.37 – 3.35 (m, 2H), 3.13 – 3.08 (m, 2H), 2.28 – 2.21 (m, 1H), 2.18 – 2.09 (m, 3H), 1.99 – 1.90 (m, 1H), 1.73 – 1.65 (m, 1H), 1.57 – 1.46 (m, 3H), 1.44 – 1.34 (m, 5H), 1.05 (s, 9H), 0.97 (t, J = 7.4 Hz, 3H), 0.31 (s, 6H). In this example, synthesis of Compound 7A avoids use of triphosgene. By contrast, the procedures of U.S. Patent No.9,107,960 used triphosgene. Example 1.4: Coupling of Compound 6A and Compound 4A with carbonyl di-triazole to Compound 7A [0150] To a Compound 6A (1.0 equiv, scaling factor) in dichloromethane (20 volumes) was charged 1,1-carbonyl-di-(1,2,4-triazole) (CDT, 1.1 equiv) and agitated at about 20 °C until the reaction is deemed complete. To this mixture was charged Compound 4A (1.1 equiv) and DMAP (0.3 equiv) and the contents were agitated at about 20 °C until the reaction is deemed complete. The organic contents was washed with water, sodium dihydrogen phosphate buffer, water and an aqueous solution of sodium chloride. The contents were distilled to give Compound 7A as a solution in dichloromethane. In this example, Compound 7A is prepared from Compound 6A through an one-pot reaction. By contrast, in the procedures of U.S. Patent No. 9,107,960, an interemediate was separated. Example 1.5: Deprotection of Compound 7A to Compound 8A: Process A: [0151] To a solution of Compound 7A (1.0 equiv, scaling factor) in dichloromethane (12 volumes) was charged a mixture of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.1 equiv), acetic acid (2.4 equiv) and dichloromethane (2 volumes). The resulting mixture was agitated at about 20 °C until the reaction is deemed complete. The organic solution was then washed twice with an aqueous citric acid/sodium chloride solution (14 volumes). Sodium sulfate (7.0 equiv) was added to the organic layer and the mixture was agitated for approximately 1 h then filtered. The crude Compound 8A in dichloromethane was purified by column chromatography (dichloromethane/methanol as eluent). The product-containing fractions were collected and concentrated to give Compound 8A. Process B: [0152] To a solution of Compound 7A (1.0 equiv, scaling factor) in dichloromethane (7 volumes) was charged a solution of cesium fluoride (1.2 equiv) in methanol (1 volume). The mixture was agitated at about 20 °C until the reaction is deemed complete. The organic solution was washed with water (4 volumes) then passed through an activated carbon, rinsing twice with dichloromethane (4.5 volumes). The resulting solution was then washed with a solution of sodium dithionite (4.4 equiv) and sodium bicarbonate (0.48 equiv) in water (4 volumes), followed by a solution of citric acid (1.9 equiv) and sodium hydroxide (4.8 equiv) in water (4 volumes). The organic layer was washed further with water (4 volumes) followed by two washes with 10 wt% aqueous solution of sodium chloride (4 volumes). The organic layer was concentrated approximately 10 volumes to give Compound 8A as a solution in dichloromethane. ¹ H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 8.06 (m, 1H), 7.46 – 7.38 (m, 9H), 7.38 – 7.32 (m, 2H), 7.26 – 7.22 (m, 4H), 7.17 – 7.13 (m, 4H), 6.77 (m, 2H), 5.72 (m, 1H), 5.37 (m, 1H), 5.21 (m, 1H), 5.15 (s, 1H), 4.92 (m, 1H), 4.47 – 4.40 (m, 1H), 4.16 – 4.02 (m, 5H), 3.75 (s, 3H), 3.65 – 3.55 (m, 34H), 3.54 – 3.46 (m, 2H), 3.35 (m, 2H), 3.09 – 2.96 (m, 2H), 2.25 – 2.05 (m, 6H), 1.94 – 1.85 (m, 1H), 1.69 – 1.59 (m, 1H), 1.54 – 1.44 (m, 2H), 1.43 – 1.24 (m, 5H), 1.02 (t, J = 7.4 Hz, 3H). Example 1.6: Reaction of Compound 8A and Compound 9 to Compound 10A Process A: [0153] A reaction vessel was charged with Compound 8A (1.00 equiv, scaling factor), Compound 9 (1.24 equiv), dichloromethane (12 volumes), 4.2 wt% aqueous copper(II) sulfate (0.15 equiv) and 2.9 wt% aqueous sodium ascorbate (0.20 equiv). The mixture was agitated at about 3 °C until the reaction was deemed complete. An aqueous solution of 3.3 wt% di-sodium ethylenediaminetetraacetic acid dihydrate (4 volumes, pH = 5.5) was added and the mixture was agitated for approximately 0.5 h before separating the layers and this washing process was repeated two more times. The organic layer was then concentrated to about 4 volumes. The concentrated mixture was purified by chromatography. Column fractions containing Compound 10A were combined and concentrated under vacuum to about 3 volumes dichloromethane. The contents were diluted with dichloromethane (7 volumes) and concentrated to 3 volumes. This process was repeated two more times to provide Compound 10A as a solution in DCM. Process B: [0154] A reaction vessel was charged with Compound 8A (1.0 equiv, scaling factor), Compound 9 (1.8 equiv), and dichloromethane (9.5 volumes). The mixture was adjusted to about 3 °C and 2,6-lutidine (1.05 equiv), 2.8 wt% aqueous copper(II) sulfate (0.1 equiv) and 2.7 wt% aqueous sodium ascorbate (0.15 equiv) were added. The mixture was agitated at about 3 °C until the reaction was deemed complete. An aqueous solution containing 3.6 wt% sodium ethylenediaminetetraacetic acid (6.8 volumes, pH = 5.5) was added and the mixture was agitated for approximately 0.5 h at about 20 °C. The layers were separated, and the organic layer was washed with the 3.6 wt% sodium ethylenediaminetetraacetic acid (6.8 volumes, pH = 5.5) five more times. The organic layer was concentrated to about 3 volumes and then purified by chromatography. Column fractions containing Compound 10A were combined and concentrated under vacuum to about 3 volumes. ¹ H NMR (500 MHz, DMSO-d6): δ 10.33 (br, s, 1H, 10.15 (s, 1H), 8.18 (t, J = 5.81H), 8.15 (d, J = 8.0, 1H), 8.07 (t, J = 5.6, 1H), 8.04 (d, J = 9.4, 1H), 7.81 (s, 1H), 7.60 (m, 2H), 7.42 (m, 1H), 7.41 (m, 1H), 7.37 (m, 2H), 7.31 (m, 2H), 7.26 (m, 2H), 7.25 (m, 2H), 7.25 (m, 2H), 7.14 (t, J = 7.2, 1H), 7.14 (J = 7.2, 1H), 6.99 (s, 2H), 6.95 (s, 1H), 6.81 (m, 2H), 5.51 (m, 2H), 5.30 (m, 1H), 5.27 (m, 1H), 5.13 (d, J = 12.2 Hz, 1H), 5.06 (d, J = 12.1 Hz, 1H), 4.47 (t, J = 5.3 Hz, 1H), 4.47 (m, 1H), 4.25 (d, J = 5.6 Hz, 2H), 4.03 (m, 1H), 4.01 (m, 1H), 4.00 (d, J = 15.0 Hz, 1H), 3.95 (d, J = 15.0 Hz, 1H), 3.77 (t, J = 5.2 Hz, 2H), 3.69 (s, 3H), 3.50 – 3.46 (m, 28H), 3.42 (t, J = 6.0 Hz, 2H), 3.25 (m, 2H), 3.22 (d, J = 7.0 Hz, 2H), 3.08 (q, J = 7.6 Hz, 2H), 2.41 (t, J = 7.4 Hz, 1H), 2.16 (m, 2H), 2.06 (tt, J = 12.1 Hz, 3.5 Hz, 1H), 1.95 (m, 2H), 1.71 (m, 2H), 1.70 (m, 1H), 1,62 (m, 1H), 1.61 (m, 2H), 1.52 (m, 1H), 1.48 (m, 2H), 1.34 (m, 2H), 1.29 ( t, J = 7.6 Hz, 3H), 1.27 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H), 0.89 (m, 2H). Compared to CuI used in U.S. Patent No.9,107,960, CuSO ₄ provides less by-products in this example. Example 1.7: Deprotection of Compound 10A to Compound 1A Process A: [0155] To a reaction vessel was charged with Compound 10A as a solution in dichloromethane (1.0 equiv, scaling factor, 7 volumes). The mixture was adjusted to about 0 °C and anisole (4 equiv) and dichloroacetic acid (10 equiv) were added. The reaction mixture was agitated at about 20 °C until the reaction was deemed complete. Dichloromethane was added (1.4 volumes) and the reaction mixture was transferred to a second vessel containing tert-butyl methyl ether (30 volumes) at about 20 °C. The mixture was agitated at about 20 °C for approximately 12 h. The contents were filtered and washed three times with a mixture of dichloromethane in tert-butyl methyl ether (50 volumes). The solids were suspended in tert- butyl methyl ether (17 volumes). The mixture was agitated at about 20 °C for about approximately 0.5 h and filtered. The filter cake was washed with tert-butyl methyl ether (1 volume) and then dried to afford Compound 1A. Process B: [0156] To a reaction vessel was charged with Compound 10A as a solution in dichloromethane (1.0 equiv, scaling factor, 7 volumes). The mixture was adjusted to about 0 °C and dichloroacetic acid (10 equiv) was charged. The contents were agitated at about 20 °C until the reaction was deemed complete. Dichloromethane was added (4 volumes) and the reaction mixture was transferred to a second vessel containing tert-butyl methyl ether (30 volumes) at about 0 °C. The mixture was filtered and the filter cake was washed twice with tert-butyl methyl ether (20 volumes) and then dried to afford Compound 1A. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 10.22 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.20 (t, J = 6.0 Hz, 1H), 8.10 (t, J = 5.5 Hz, 1H), 8.05 (m, 1H), 7.87 (br, s, 2H), 7.82 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.43 (m, 1H), 7.43 (m, 1H) 7.32 (d, J = 8.5 Hz, 2H), 7.00 (s, 2H), 6.95 (s, 1H), 6.20 (s, 1H), 5.51 (s, 2H), 5.29 (m, 2H), 5.13 (d, J = 12.5 Hz, 1H), 5.07 (d, J = 12.5 Hz, 1H), 4.48 (m, 2H), 4.47 (m, 1H), 4.26 (d, J = 5.5 Hz, 2H), 4.04 (m, 2H), 4.00 (m, 2H), 3.78 (t, J = 5.5, 2H), 3.51 – 3.44 (m, 30H), 3.29 (m, 2H), 3.23 (d, J = 7.0 Hz, 2H), 3.09(m, 2H), 2.79 (br, s, 2H), 2.16 (m, 2H), 2.06 (m, 1H), 1,76, (m, 1H), 171 (m, 2H), 1.69 (m, 1H), 1.62 (m, 2H), 1.57 (m, 2H), 1.52 (m, 1H), 1.36 (m, 2H), 1.30 (m, 3H), 1.28 (m, 2H), 0.90 (m, 3H), 0.89 (m, 2H).

Example 2: COMPOUND 13A SYNTHETIC Route Procedures Example 2.1: Coupling of 4-aminobenzyl alcohol and Compound 12A to Compound 13A: Process A: [0157] A reaction vessel was charged with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 1.1 equiv) and 2-methyltetrahydrofuran (8 volumes), cooled to about 15 °C, and 4- methylmorpholine (NMM, 1.2 equiv) charged while maintaining temperature at about 25 °C. The mixture was cooled to about 20 °C, and Compound 12A (1.00 equiv, scaling factor) and 4- aminobenzyl alcohol (1.04 equiv) were charged. The mixture was agitated at about 20 °C until the reaction was deemed complete. The reaction mixture was filtered, then washed sequentially with aqueous citric acid buffer, aqueous sodium chloride/potassium bicarbonate, and aqueous sodium chloride. The mixture was concentrated to about 3 volumes, diluted with 2

methyltetrahydrofuran and concentrated to about 3 volumes. The product was carried forward as a stock solution of Compound 13A stock solution in 2-methyltetrahydrofuran. Process B: [0158] A reaction vessel was charged with Compound 12A (1.0 equiv, scaling factor), 4- aminobenzyl alcohol (1.04 equiv), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 1.04 equiv) and dichloromethane (5 volumes). The mixture was agitated at about 20 °C until the reaction was deemed complete. The product was carried forward as a stock solution of Compound 13A in dichloromethane. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.98 (s, 1H), 8.00 – 6.80 (m, 27H), 5.11 (m, 1H), 4.44 – 4.10 (m, 6H), 3.69 (s, 3H), 2.43 (m, 1H), 2.00 – 1.10 (m, 8H). Example 2.1: Deprotection of Compound 13A to Compound 14A: Process A: [0159] A reaction vessel was charged with Compound 13A stock solution in 2- methyltetrahydrofuran (1.0 equiv, prepared from Compound 12A, scaling factor Compound 12A) and methanol (0.7 volumes), and cooled to about 0 °C. Thiomalic acid (1.6 equiv) was charged, then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.2 equiv) charged while maintaining the temperature at about 10 °C. The mixture was warmed to about 20 °C until the reaction was deemed complete. The reaction mixture was washed sequentially with aqueous ammonium chloride/sodium chloride, aqueous sodium carbonate, and aqueous sodium chloride. The product was carried forward as a Compound 14A stock solution in 2-methyltetrahydrofuran. Process B: [0160] A reaction vessel was charged with Compound 13A stock solution in dichloromethane (1.0 equiv, scaling factor). The solution was cooled to about 10 °C and diethylamine (3.07 equiv) was charged over approximately 1 h. The reaction mixture was allowed to warm to about 15 °C and agitated until the reaction was deemed complete before concentrating to about 3 volumes. The reaction mixture was then diluted with toluene (6 volumes) and concentrated to about 3 volumes. This co-distillation was repeated two more times. The residue was diluted with toluene (6 volumes) and filtered. The product was carried forward as a stock solution of Compound 14A in toluene. ¹ H NMR (400 MHz, DMSO-d6): δ 9.76 (s, br, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.40 – 7.10 (m, 14H), 6.83 (d, J = 8.0 Hz, 2H), 5.10 (t, J = 6.0 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H), 3.25 (m, 1H), 2.42 (m, 1H), 2.00 – 1.20 (m, 10H). Example 2.2: Coupling of Compound 14A and Compound 15 to Compound 6A: Process A: [0161] A reaction vessel was charged with Compound 14A stock solution in 2- methyltetrahydrofuran (1.0 equiv, scaling factor), the mixture concentrated to about 3 volumes, diluted with 2-methyltetrahydrofuran, and concentrated to about 3 volumes. The water content is tested, and the dilution/concentration sequence repeated until the limit is met. Compound 15 (1.00 equiv) and 2-methyltetrahydrofuran (0.8 volumes) were charged, and the Compound 14A/Compound 15 solution held. [0162] A separate reaction vessel was charged with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 1.1 equiv), 2-methyltetrahydrofuran (12 volumes), and 4-methylmorpholine (NMM, 1.2 equiv) and stirred at about 20 °C for approximately 2 h. The Compound 14A/Compound 15 solution was charged and agitated at about 20 °C until the reaction was deemed complete. The reaction mixture was washed sequentially with aqueous potassium bicarbonate, aqueous citric acid buffer, and aqueous sodium chloride. The mixture was concentrated to about 3 volumes, diluted with ethyl acetate (8.5 volumes), and concentrated to about 4 volumes. The dilution/concentration sequence was repeated two times and n-heptane (0.33 volumes) was charged. The mixture was purified by column chromatography. The eluted fractions were concentrated to about 3 volumes, diluted with toluene (6 volumes), and concentrated again to about 3 volumes to provide Compound 6A as a stock solution in toluene.

Process B: [0163] A reaction vessel was charged with Compound 15 (1.0 equiv, scaling factor) and Compound 14A as a solution in toluene (1.02 equiv) then N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline (EEDQ, 1.03 equiv). The reactor mixture was agitated at about 20 °C until the reaction was deemed complete before concentrating to about 3 volumes. The residue was diluted with ethyl acetate (8 volumes) and concentrated under vacuum to about 3 volumes. Ethyl acetate was charged until a homogeneous solution was formed. The product was purified by chromatography to give Compound 6A. ¹ H NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 8.12 (m, 1H), 8.06 (m, 1H), 7.54 (m, 2H), 7.40 – 7.10 (m, 14H), 6.83 (m, 2H), 5.09 (m, 1H), 4.50 – 4.40 (m, 3H), 4.10 – 3.95 (m, 4H), 3.70 (s, 3H), 3.60 – 3.35 (m, 34H), 3.25 (m, 2H), 2.42 (m, 1H), 2.00 – 1.20 (m, 8H). Example 3: Compound 9 Synthetic Route Procedures Example 3.1: Activation of Compound 16 to Compound 17 [0164] To a reaction vessel was charged n-hydroxysuccimide (2.5 equiv) followed by N,N-dimethylformamide (14 volumes). The contents were cooled to about 0 °C. To the contents were charged trifluoroacetic anhydride (2.0 equiv) over approximately 0.5 h. Then 2,4,6- collidine (2.0 equiv) was charged and the contents were agitated at about 0 °C for approximately 0.25 h. To a separate vessel was charged Compound 16 (1.0 equiv, scaling factor) followed by dichloromethane (10 volumes). The contents were cooled to approximately 0 °C and 2,4,6- collidine (1.8 equiv) was charged. Then the n-hydroxysuccimide mixture was charged maintaining the internal temperature at about 10 °C. After the addition the contents were heated to about 20 °C and aged until the reaction was deemed complete. To the contents were charged dichloromethane (10 volumes) followed by 1 M hydrochloride acid (10 volumes). The contents in organic layer were collected. The contents were washed two more times with 1 M hydrochloric acid (10 volumes). Then the contents were washed with 10 wt% aqueous sodium chloride (10 volumes). The organic layer was dried using magnesium sulfate and filtered. The filtrate was transferred to another vessel using dichloromethane (5 volumes) to aid in the the transfer. The contents were concentrated to about 5 volumes. tert-Butyl methyl ether (10 volumes) was charged and the contents were concentrated to about 5 volumes. This co- distillation with tert-butyl methyl ether (10 volumes) was repeated two more times. The mixture was filtered and the cake was washed with tert-butyl methyl ether (10 volumes). The contents were dried to give Compound 17. ¹ H NMR (400 MHz, DMSO-d6): δ 7.0 (s, 2 H), 3.2 – 3.3 (d, J = 8 Hz, 2 H), 2.8 (s, 4 H), 2.6 – 2.75 (dddd, J = 4, 4, 12, 12 Hz, 1H), 1.95 – 2.1 (dd, J = 4, 12 Hz, 2H), 1.65 – 1.75 (dd, 2H, J = 4, 12 Hz), 1.5-1.6 (m, 1H), 1.3-1.5 (ddd, J = 4, 12, 24 Hz, 2 H), 0.9 – 1.1 (ddd, J = 4, 12, 24 Hz, 2H). Example 3.2: Amidation of Compound 17 with propargyl amine to Compound 9 [0165] To a vessel was charged propargyl amine (1.2 equiv), dichloromethane (1.6 volumes) and N,N-diisopropylethylamine (1.1 equiv). To a separate reaction vessel was charged Compound 17 (1.0 equiv, scaling factor) and dichloromethane (33 volumes). The contents were agitated and cooled to about 2 °C Then the mixture of propargyl amine was charged to this vessel maintaining the temperature at about 5 °C. After the addition the contents were heated to 22 °C and aged at this temperature until the reaction was deemed complete. To the contents were charged 1 M hydrochloric acid (20 volumes). The aqueous layer was discharged and dichloromethane (20 volumes) was charged to the vessel containing the organic layer. The organic layer was washed two times with saturated aqueous sodium bicarbonate (19 volumes). The organic layer was dried over magnesium sulfate and filtered using dichloromethane (1 volume) to aid in the filtration. The contents were concentrated to about 10 volumes and ethyl acetate (13 volumes) was charged and the contents were concentrated to about 10 volumes again. Then a 1:1 mixture of ethyl acetate and n-heptane (14 volumes) was charged and the contents were concentrated to about 10 volumes. Finally, n-heptane (14 volumes) was charged and the contents were concentrated to about 10 volumes. The contents were filtered and the cake was washed two times with n-heptane (7 volumes) and dried to give Compound 9. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.15 (t, J = 5.5 Hz, 1H), 7.01 (s, 2H), 3.813 (dd, J = 2.5, 5.5 Hz, 2H), 3.24 (d, J = 7.0 Hz, 2H), 3.05 (t, J = 2 Hz, 1H), 3.07 – 2.01 (m, 1H), 1.72 – 1.61 (m, 4H), 1.56 – 1.49 (m, 1 H), 1.31 – 1.22 (m, 2H), 0.93 – 0.85 (m, 2H). Process A: To a reaction vessel is charged Compound 16 (1.0 equiv, scaling factor) followed by acetonitrile (10 volumes). The contents were cooled to about 0 °C and propargyl amine hydrochloride (1.1 equiv) was charged. Then 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.2 equiv) and N,N- diisopropylethylamine (2.5 equiv) was charged. The contents were agitated at about 0 °C until the reaction was deemed complete. To the contents was charged water (10 volumes) and the contents were aged at about 0 °C for approximately 1 h. The contents were filtered and the filter cake was washed two times with first with water (2 volumes) and then tert-butyl methyl ether (2.6 volumes). The solids were dried to give Compound 9. Process B: To a reaction vessel was charged Compound 16 (1.0 equiv, scaling factor) and 2-chloro-4,6- dimethoxy-1,3,5-triazine (1.1 equiv) followed by acetonitrile (5 volumes). The contents were cooled to about 0 °C and N-methylmorpholine (2.3 equiv) was charged slowly maintaining the internal temperature at about 10 °C. The resulting slurry was agitated at about 5 °C for approximately 1 h, and then a solution of propargylamine hydrochloride (1.1 equiv) in water (5 volumes) was charged slowly maintaining the internal temperature at about 10 °C. The resulting slurry was agitated at about 5 °C until the reaction was deemed complete. To the contents was charged water (10 volumes) and the contents were aged at about 10^°C for approximately 1 h. The contents were filtered. The filter cake was washed two times with water (4 volumes each) and then tert-butyl methyl ether (5.4 volumes). The solids were dried to give Compound 9.

Example 4: Sacituzumab Govitecan Synthetic Route Procedures Reduction and conjugation of Compound 1A to ADC 2A [0166] To a tank was transferred a solution of hRS7 IgG1 ^ (1.0 equiv, scaling factor) and agitated at about 20 °C. Then 0.2 M aqueous ethylenediaminetetraacetic acid (EDTA) (2.6% v/v of antibody solution volume) was charged and mixed prior to charging 0.04 M phosphate buffered saline (PBS) (pH 7.4, 4.5% v/v antibody solution volume) and agitated for approximately 1 h. Then a solution of 0.04 M tris(2-carboxyethyl)phosphine (TCEP) in PBS buffer (7 equiv) or water was charged. The contents were incubated at about 20 °C for approximately 3 h. After this amount of time, the pH was adjusted to approximately 6.5 using an aqueous sodium phosphate buffered solution (0.1 – 1.0 molar). The contents were agitated for about 1 h at approximately 20 °C. The temperature of the tank was adjusted to about 25 °C and dimethyl sulfoxide (5% v/v antibody solution volume) was charged. Then a solution of Compound 1A in dimethyl sulfoxide (0.016 M, 10 equiv) was added to the tank and the vessel formerly containing Compound 1A was rinsed with dimethyl sulfoxide (0.5% v/v antibody solution volume) and added to the tank. The contents were incubated for approximately 0.5 h. Then a 10 mg/mL aqueous solution of N-ethylmaleimide (NEM) (1 mL/g IgG) was charged to the tank and the contents were aged for approximately 35 min. The material was then purified by buffer exchange with 0.025 M 2-(N-morpholino)ethanesulfonic acid (MES) using tangential flow filtration (TFF) and concentrated to approximately 20 mg/mL ADC 2A (sacituzumab govitecan) in MES buffer. UV-SE-UPLC (Size-exclusion UPLC) UV detection 280 nm: 6.40 min; SEC-MALS: 152 kDa ±0.037%; Cell Binding to PC-3 Cells: K _D = 1 nM; Potency (in-vitro cyctotoxicity assay with PC-3 cells): EC50 = 0.6 nM; Drug-to-Antibody Ratio (DAR) was determined by HIC-HPLC and LC-MS: 7.5. [0167] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims. [0168] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of” excludes any element not specified. [0169] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. [0170] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. [0171] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. [0172] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure. [0173] Other embodiments are set forth in the following claims.