Process for preparing cot inhibitor compounds

Abstract

The invention discloses synthesis of a Cot (large thyroid cancer) inhibitor. The inhibitor has the following formula (I). # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date is March 31, 2021, application number is 202180025717.X (PCT application number is: PCT / US2021 / 025118), and the invention name is "Method for preparing COT inhibitor compounds").

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 004,254, filed April 2, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0004] The present disclosure relates to the field of organic synthesis methodology for preparing Cot (Osaka thyroid cancer) inhibitor compounds and synthetic intermediates thereof. Background Art

[0005] The Cot (Osaka thyroid carcinoma) protein is a serine / threonine kinase and a member of the MAP kinase kinase kinase (MAP3k) family. It is also known as "Tpl2" (tumor progression locus), "MAP3K8" (mitogen-activated protein kinase kinase kinase 8) or "EST" (Ewing sarcoma transformant). Cot was identified by its oncogenic transforming activity in cells and has been shown to regulate oncogenic and inflammatory pathways.

[0006] Cot is known to be upstream in the MEK-ERK pathway and is essential for LPS-induced tumor necrosis factor-α (TNF-α) production. Cot has been shown to be involved in the production and signaling of TNFα. TNFα is a proinflammatory cytokine and plays an important role in inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), diabetes, sepsis, psoriasis, misregulated TNFα expression and transplant rejection.

[0007] Therefore, agents and methods for regulating the expression or activity of Cot can be used to prevent or treat such diseases.

[0008] There remains a need to develop methods for preparing Cot inhibitor compounds, which methods include preparing compound 1:

[0009] Summary of the invention

[0010] In one aspect, a method for preparing compound 1 is provided, the method comprising:

[0011] (2a) In the presence of an organometallic reagent and a Lewis base, compound 2A and compound 2B are reacted:

[0012]

[0013] contacting in a solvent at a temperature sufficient to obtain compound 2C:

[0014]

[0015] (2b) In the presence of a titanium-based or zirconium-based reagent, compound 2C is reacted with

[0016]

[0017] contacting in a solvent at a temperature sufficient to obtain Compound 2D:

[0018]

[0019] (2c) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent

[0020] The temperature at which the contact occurs is sufficient to obtain compound 2E:

[0021]

[0022] (2d) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0023] and (2e) reacting compound 2F with compound 2G in the presence of a palladium catalyst and a base:

[0024]

[0025] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0026]

[0027] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0028] (2a) In the presence of an organometallic reagent and a Lewis base, compound 2A and compound 2B are reacted:

[0029]

[0030] contacting in a solvent at a temperature sufficient to obtain compound 2C:

[0031]

[0032] (2b) In the presence of a titanium-based or zirconium-based reagent, compound 2C is reacted with

[0033]

[0034] contacting in a solvent at a temperature sufficient to obtain Compound 2D:

[0035]

[0036] (2c) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent

[0037] The temperature at which the contact occurs is sufficient to obtain compound 2E:

[0038]

[0039] (2d) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0040] and (2e) reacting compound 2F with compound 2G in the presence of a copper catalyst, a copper catalyst ligand and a base:

[0041]

[0042] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0043]

[0044] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0045] (3a) Compound 2M:

[0046]

[0047] contacting with a chlorinating agent and an additive in a solvent at a temperature sufficient to obtain a compound

[0048] Phys. 3A:

[0049]

[0050] (3b) In the presence of an organometallic reagent, compound 3A and compound 2B are reacted:

[0051]

[0052] contacting in a solvent, followed by addition of a copper or palladium catalyst, an optional zinc additive, and an optional Lewis base, at a temperature sufficient to provide compound 2C:

[0053]

[0054] (3c) In the presence of a titanium-based reagent, compound 2C is reacted with

[0055]

[0056] contacting in a solvent at a temperature sufficient to obtain compound 3B:

[0057]

[0058] (3d) contacting compound 3B with a reducing agent and optionally a ruthenium, palladium or platinum catalyst in a solvent,

[0059] The temperature at the time of contact is sufficient to obtain compound 3C:

[0060]

[0061] (3e) contacting compound 3C with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0062] and (3f) reacting compound 2F with compound 2G in the presence of a palladium catalyst and a base:

[0063]

[0064] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0065]

[0066] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0067] (3a) Compound 2M:

[0068]

[0069] contacting with a chlorinating agent and an additive in a solvent at a temperature sufficient to obtain a compound

[0070] Phys. 3A:

[0071]

[0072] (3b) In the presence of an organometallic reagent, compound 3A and compound 2B are reacted:

[0073]

[0074] contacting in a solvent, followed by addition of a copper or palladium catalyst, an optional zinc additive, and an optional Lewis base, at a temperature sufficient to provide compound 2C:

[0075]

[0076] (3c) In the presence of a titanium-based reagent, compound 2C is reacted with

[0077]

[0078] contacting in a solvent at a temperature sufficient to obtain compound 3B:

[0079]

[0080] (3d) contacting compound 3B with a reducing agent and optionally a ruthenium, palladium or platinum catalyst in a solvent,

[0081] The temperature at the time of contact is sufficient to obtain compound 3C:

[0082]

[0083] (3e) contacting compound 3C with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0084] and (3f) reacting compound 2F with compound 2G in the presence of a copper catalyst, a copper catalyst ligand and a base:

[0085]

[0086] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0087]

[0088] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0089] (4a) In the catalyst and Compound 1H is contacted in the presence of:

[0090]

[0091] The temperature at which the contact is made is sufficient to yield compound 4A:

[0092]

[0093] (4b) In the presence of a base, compound 4A and compound 4B are reacted:

[0094]

[0095] contacting in a solvent, followed by the addition of an optional copper catalyst, an optional Lewis base additive, and an optional zinc additive, at a temperature sufficient to provide compound 2E:

[0096]

[0097] (4c) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0098] and (4d) reacting compound 2F with compound 2G in the presence of a palladium catalyst and a base:

[0099]

[0100] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0101]

[0102] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0103] (4a) In the catalyst and Compound 1H is contacted in the presence of:

[0104]

[0105] The temperature at which the contact is made is sufficient to yield compound 4A:

[0106]

[0107] (4b) In the presence of a base, compound 4A and compound 4B are reacted:

[0108]

[0109] contacting in a solvent, followed by the addition of an optional copper catalyst, an optional Lewis base additive, and an optional zinc additive, at a temperature sufficient to provide compound 2E:

[0110]

[0111] (4c) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0112] and (4d) reacting compound 2F with compound 2G in the presence of a copper catalyst, a copper catalyst ligand and a base:

[0113]

[0114] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0115]

[0116] In another aspect, a method for preparing compound 2M is provided, the method comprising:

[0117] (5a) Compound 2H:

[0118]

[0119] contacting with a chlorinating agent, an optional amine catalyst and an optional acidic additive in a solvent,

[0120] The temperature at which the contact is made is sufficient to obtain compound 2I:

[0121]

[0122] (5b) Compound 2I is reacted with TsHNNH 2 contacting in a solvent at a temperature sufficient to obtain

[0123] Compound 2J:

[0124]

[0125] (5c) In the presence of a base, compound 2J and compound 2K are reacted:

[0126]

[0127] contacting in a solvent at a temperature sufficient to obtain compound 2L:

[0128]

[0129] (5d) contacting compound 2L with a base in a solvent at a temperature sufficient to obtain compound 2M:

[0130]

[0131] In another aspect, a method for preparing compound 2B is provided, the method comprising:

[0132] (6a) Compound 1E:

[0133]

[0134] The copper catalyst, amine ligand and iodide additive are contacted in a solvent at a temperature of

[0135] The degree is sufficient to obtain compound 2O:

[0136]

[0137] (6b) contacting compound 20 with an alkylating agent in a solvent at a temperature sufficient to obtain the alkylating agent.

[0138] Compound 2P:

[0139]

[0140] wherein X is iodide, chloride, bromide, methylsulfate, sulfate, methylcarbonate, carbonate, methanesulfonate, triflate, toluenesulfonate or tetrafluoro

[0141] Borates;

[0142] (6c) contacting compound 2P with an oxidant and a base in a solvent at a temperature sufficient to obtain

[0143] Compound 2B:

[0144]

[0145] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0146] (7a) In the presence of a titanium catalyst and a base, compound 2C and compound 1B are reacted:

[0147]

[0148] contacting in a solvent at a temperature sufficient to obtain compound 5A:

[0149] and (7b) contacting compound 5A in a solvent in the presence of a catalyst and a reagent at a temperature of

[0150] is sufficient to obtain compound 1:

[0151]

[0152] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0153] (8a) Compound 6A and Compound 1B are reacted in the presence of a reagent and an optional additive:

[0154]

[0155] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0156]

[0157] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0158] (9a) Compound 6A:

[0159]

[0160] Contacting with an activating reagent and a base in a solvent at a temperature sufficient to obtain compound 7A:

[0161]

[0162] wherein R is methylsulfonyl, ethylsulfonyl, toluenesulfonyl, benzenesulfonyl, 4-chlorobenzenesulfonyl or 4-nitrobenzenesulfonyl; and

[0163] (9b) In the presence of a base, compound 7A and compound 1B are reacted:

[0164]

[0165] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0166]

[0167] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0168] (22a) In the presence of an organometallic reagent and a Lewis base, compound 2A and compound 2B are reacted:

[0169]

[0170] contacting in a solvent at a temperature sufficient to obtain compound 2C:

[0171]

[0172] (22b) In the presence of a titanium-based or zirconium-based reagent, compound 2C is reacted with contacting in a solvent at a temperature sufficient to obtain compound 3B:

[0173]

[0174] (22c) contacting compound 3B with a reducing agent and optionally a ruthenium, palladium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 3C:

[0175]

[0176] (22d) contacting compound 3C with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0177] and (22e) reacting compound 2F with compound 2G in the presence of a palladium catalyst and a base:

[0178]

[0179] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0180]

[0181]

[0182] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0183] (22a) In the presence of an organometallic reagent and a Lewis base, compound 2A and compound 2B are reacted:

[0184]

[0185] contacting in a solvent at a temperature sufficient to obtain compound 2C:

[0186]

[0187] (22b) In the presence of a titanium-based or zirconium-based reagent, compound 2C is reacted with contacting in a solvent at a temperature sufficient to obtain compound 3B:

[0188]

[0189] (22c) contacting compound 3B with a reducing agent and optionally a ruthenium, palladium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 3C:

[0190]

[0191] (22d) contacting compound 3C with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0192] and (22e) reacting compound 2F with compound 2G in the presence of a copper catalyst, a copper catalyst ligand and a base:

[0193]

[0194] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0195]

[0196] In another aspect, a method for preparing compound 1 is provided, the method comprising:

[0197] (23a) Compound 2M:

[0198]

[0199] contacting with a chlorinating agent and an additive in a solvent at a temperature sufficient to obtain a compound

[0200] Phys. 3A:

[0201]

[0202] (23b) In the presence of an organometallic reagent, compound 3A and compound 2B are reacted:

[0203]

[0204] contacting in a solvent, followed by addition of a copper or palladium catalyst, an optional zinc additive, and an optional Lewis base, at a temperature sufficient to provide compound 2C:

[0205]

[0206] (23c) In the presence of a titanium-based or zirconium-based reagent, compound 2C is reacted with contacting in a solvent at a temperature sufficient to obtain Compound 2D:

[0207]

[0208] (23d) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 2E:

[0209]

[0210] (23e) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0211] and (23f) reacting compound 2F with compound 2G in the presence of a palladium catalyst and a base:

[0212]

[0213] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0214]

[0215] In another aspect, a method for preparing compound 1 is provided, the method comprising: (23a) making compound 2M:

[0216]

[0217] Contacting with a chlorinating agent and an additive in a solvent at a temperature sufficient to obtain compound 3A:

[0218]

[0219] (23b) In the presence of an organometallic reagent, compound 3A and compound 2B are reacted:

[0220]

[0221] contacting in a solvent, followed by addition of a copper or palladium catalyst, an optional zinc additive, and an optional Lewis base, at a temperature sufficient to provide compound 2C:

[0222]

[0223] (23c) In the presence of a titanium-based or zirconium-based reagent, compound 2C is reacted with contacting in a solvent at a temperature sufficient to obtain Compound 2D:

[0224]

[0225] (23d) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 2E:

[0226]

[0227] (23e) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F:

[0228] and (23f) reacting compound 2F with compound 2G in the presence of a copper catalyst, a copper catalyst ligand and a base:

[0229]

[0230] contacting in a solvent at a temperature sufficient to obtain compound 1:

[0231]

[0232] In another aspect, provided is a compound according to the following formula 2F salt:

[0233]

[0234] In another aspect, a method for preparing compound 2O is provided, the method comprising: making compound 14A:

[0235]

[0236] contacting with an iodide reagent in a solvent, the iodide reagent including N-iodosuccinimide, iodine, iodine and iodic acid, bis(pyridinium)iodonium(I) tetrafluoroborate, sodium iodide and bleach, sodium iodide and an oxidizing agent (e.g., potassium persulfate, sodium periodate and periodic acid), 1,3-diiodo-5,5-dimethylhydantoin, iodine monochloride or pyridinium iodine monochloride;

[0237] The solvent includes trifluoromethanesulfonic acid, sulfuric acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, an acid in combination with water, dimethylformamide, methanol, acetonitrile, dichloromethane, tetrahydrofuran or toluene;

[0238] The temperature during contact is from about -30°C to about 60°C to obtain compound 2O:

[0239] DETAILED DESCRIPTION

[0240] Compounds containing triazoles, such as compound 1 disclosed herein, are often prepared from azides. The use of azide-containing materials may be inherently dangerous due to, for example, the potential explosiveness of azides. For example, to avoid such dangers, methods that avoid the use of azides may be desirable.

[0241] Various embodiments are described below. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects described herein. An aspect described in conjunction with a specific embodiment is not necessarily limited to that embodiment and can be practiced together with any other embodiment.

[0242] definition

[0243] As noted above, throughout this disclosure, unless otherwise indicated, the following abbreviations have the following meanings:

[0244] 2-MeTHF 2-Methyltetrahydrofuran

[0245] Ac Acetyl

[0246] ACN Acetonitrile (MeCN)

[0247] ADMP 2-Azido-1,3-dimethylimidazolinium hexafluorophosphate

[0248] BIQ 5-Bromo-isoquinoline

[0249] CAA 3-Chloroanthranilic acid

[0250] CBS Corey Bakshi Shibata

[0251] CNA 2-Chloro-4-nitroaniline

[0252] DBN Diazabicyclo[4.3.0]non-5-ene

[0253] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0254] DCM Dichloromethane (CH 2 C1 2 )

[0255] DIAD Diisopropyl azodicarboxylate

[0256] DIBAL Diisobutylaluminum hydride

[0257] DIPEA Diisopropylethylamine

[0258] DME 1,2-Dimethoxyethane

[0259] DMF Dimethylformamide

[0260] DMF-DMA N,N-Dimethylformamide dimethyl acetal

[0261] DMP Dess-Martin Periodinane

[0262] DMPAO 2,6-Dimethylanilino(oxy)acetic acid

[0263] DMPU N,N'-Dimethylpropyleneurea

[0264] DMSO Dimethyl sulfoxide

[0265] (dppf)PdCl 2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride

[0266] ECEA Ethoxymethylcyanoacetate

[0267] EDC·HCl 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0268] EDCP Ethyl dichlorooxypropionate

[0269] equiv equivalent

[0270] EtOAc Ethyl acetate

[0271] EtOH

[0272] Et Ethyl

[0273] HCl

[0274] IIQ 5-Iodo-isoquinoline

[0275] IPAc Isopropyl acetate

[0276] IPE Isopropyl Ether

[0277] IPA Isopropyl Alcohol

[0278] iPr Isopropyl

[0279] LiHMDS Lithium bis(trimethylsilyl)amide

[0280] LTBA Lithium tri-tert-butoxyaluminum hydride

[0281] MDCP Methyl dichlorooxypropionate

[0282] MeOH Methanol

[0283] Me Methyl

[0284] MsCl Methanesulfonyl chloride

[0285] MTBE Methyl tert-butyl ether

[0286] NaOAc Sodium acetate

[0287] NBS N-bromosuccinimide

[0288] NIS N-iodosuccinimide

[0289] NMBI N-Methylisoquinolinium bromide iodide

[0290] NMP Methyl-2-pyrrolidone

[0291] NMR Nuclear Magnetic Resonance

[0292] Sigamide SN-(3,5-di-tert-butylphenyl)-3-methyl-2-(N-formyl-N-methylamino)butyramide

[0293] TfOH Trifluoromethanesulfonic acid

[0294] THF Tetrahydrofuran Volume 1 liter / kg scaling factor

[0295] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0296] XantPhos-Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'- [Biphenyl]Palladium(II) Pd-G2

[0297] As used herein, the term "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there is a use of the term that is unclear to one of ordinary skill in the art in the context in which the term is used, "about" will mean up to plus or minus 10% of the particular term.

[0298] Unless otherwise specified herein, the description of the range of values ​​herein is intended only to be used as a shorthand method for individually referring to each individual value falling within the range, and each individual value is incorporated into this specification as if it were individually stated herein. Unless otherwise specified herein or otherwise clearly contradictory to the context, all methods described herein can be performed in any suitable order. Unless otherwise specified, the use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the embodiment, and is not intended to limit the scope of the claims. Any language in the specification should not be understood to indicate that any element not protected by the claims is necessary.

[0299] As used herein, "activating reagent" is a compound that enhances the leaving group ability of a leaving group by chemical modification. Non-limiting examples of activating reagents include, but are not limited to, methanesulfonyl chloride, methanesulfonic anhydride, ethanesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, and 4-nitrobenzenesulfonyl chloride.

[0300] As used herein, "acid" or "acidic additive" refers to a proton donor compound that generates hydronium ions in aqueous solution, or to an electron pair acceptor compound combined with an electron pair donor or base. Non-limiting examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid, and oxalic acid.

[0301] As used herein, "alkylating agent" refers to a compound that can introduce an alkyl group into a compound. Non-limiting examples of alkylating agents include, but are not limited to, methyl iodide, trimethylsulfoxide iodide, diazomethane, dimethyl sulfate, 2,2-dimethoxypropane, dimethyl carbonate, dimethyl dicarbonate, methyl fluorosulfonate, methyl methanesulfonate, methyl chloride, methyl bromide, and trimethyloxonium tetrafluoroborate.

[0302] As used herein, "amine catalyst" refers to a compound used to promote a reaction such as a chlorination reaction. Non-limiting examples of amine catalysts include, but are not limited to, L-prolinamide and (2R,5R)-diphenylpyrrolidine.

[0303] As used herein, "amine ligand" refers to a compound that can bind to a metal complex such as copper. Non-limiting examples of amine ligands include, but are not limited to, trans-N,N'-dimethylcyclohexane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N3-dimethylpropane-1,3-diamine, and N1-(2-aminoethyl)ethane-1,2-diamine.

[0304] As used herein, "base" may refer to a metal oxide or other compound that reacts with an acid to neutralize the acid and produce water and a salt. "Base" may also refer to compounds and functional groups containing a basic nitrogen atom with a lone pair of electrons. Bases may 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-amylate, sodium tert-amylate, potassium propionate, potassium trimethylacetate, 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 dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, 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.

[0305] As used herein, "brominating agent" refers to a compound that can introduce a bromine group into a compound. Non-limiting examples of brominating agents include, but are not limited to, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide or bromine; potassium bromide / hypochlorous acid and dibromoisocyanuric acid.

[0306] As used herein, a "carbonyl source" is a compound that can provide a carbonyl group to a compound. Non-limiting examples of carbonyl sources include, but are not limited to, carbon monoxide, iron pentacarbonyl, dicobalt octacarbonyl, N-formyl saccharin, paraformaldehyde, and formic acid.

[0307] As used herein, "catalyst" is a compound that promotes other reactions such as bond formation, and also includes metal catalysts described herein. Non-limiting examples of catalysts include, but are not limited to: Sigamide ((S)-N-(3,5-di-tert-butylphenyl)-3-methyl-2-(N-formyl-N-methylamino)butyramide), RuCl(mesitylene) [(S,S)-Ts-DPEN], RuCl(p-isopropyltoluene) [(R,R)-Teth-Ts-DPEN], CBS-type catalysts, copper hydride-bisoxazoline complexes with stoichiometric reducing agents, chiral phosphine ligands (BINAP, DIPAMP, Segphos, Phanephos, Norphos, Me-DuPhos, PPhos, Josiphos, MeBoPhoz, Chenphos) with transition metals Pd, Ru, Rh or Ir, or chiral formamide catalysts. Other examples include, but are not limited to, cesium carbonate, magnesium sulfate, cesium carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, titanium (IV) isopropoxide, pyrrolidine, piperidine, proline, diisopropylamine, dibutylamine, acetic acid, trifluoroacetic acid, benzoic acid, 4-nitrobenzoic acid, methoxyacetic acid, propionic acid, isobutyric acid, pivalic acid, decanoic acid, hexanoic acid, phenylboric acid, or combinations thereof.

[0308] As used herein, a "copper catalyst" is a compound containing copper and that can promote other reactions such as bond-forming reactions. Non-limiting examples of copper catalysts include, but are not limited to, copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) oxide, copper (I) acetate, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex, and copper (I) bromide triphenylphosphine complex. Additional examples include copper(I) cyanide bis(lithium chloride) complex, copper(I) trifluoromethanesulfonate toluene complex, copper(I) chloride bis(lithium chloride) complex, copper(I) bromide bis(lithium bromide) complex, copper(I) thiocyanate, copper(I) thiophene-2-carboxylate, copper(I) thiophenolate, copper(I) diphenylphosphate, (1,10-phenanthroline)bis(triphenylphosphine) copper(I) nitrate DCM adduct, copper(I) 3-methylsalicylate, copper(I) chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I), copper(I) chloro(1,5-cyclooctadiene) dimer, copper(II) chloride, and copper(II) acetate in combination with triphenylphosphine, tributylphosphine, tri(2-furyl)phosphine, tri(p-tolyl)phosphine, or tri(o-tolyl)phosphine.

[0309] As used herein, "copper catalyst ligand" refers to a compound that can bind to a metal complex such as copper. Non-limiting examples of copper catalyst ligands include, but are not limited to, diamines (N,N'-dimethylethane-1,2-diamine, trans-N,N'-dimethyl-cyclohexane-1,2-diamine), diols (ethane-1,2-diol, propane-1,3-diol), diketones (2-acetylcyclohexanone, acetylacetone, 2,2,6,6-tetramethylheptane-3,5-dione), glycine derivatives (N-methylglycine, N,N-dimethylglycine), ethyl 2-oxocyclohexanecarboxylate, ethylene glycol. , pyridine, 2,2'-bipyridine, 1,10-phenanthroline, new cuprous reagent, 8-hydroxyquinoline, picolinic acid, glyoxal bis(phenylhydrazone), 2,6-dimethylanilino(oxy)acetic acid, 2,6-difluoroanilino(oxy)acetic acid, 2,6-dimethylanilino(oxy)acetic acid, 2,3,4,5,6-pentafluoroanilino(oxy)acetic acid, 3,5-bis(trifluoromethyl)anilino(oxy)acetic acid, 2-fluoro-6-(piperidin-1-sulfonyl)anilino(oxy)acetic acid, N 1 ,N 2 -bis([1,1'-biphenyl]-2-yl)oxalylamide, N 1 ,N 2 -bis(2-phenoxyphenyl)oxalylamide, thiophene-2-carboxylic acid, and pyridinebisoxazoline ligands (such as 2,6-bis((4S,5R)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-tert-butyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-benzyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-tert-butyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-isopropyl-5,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-phenylethyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((4S,5R)-4-methyl-5-phenyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-isopropyl-5,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine and 2,6-bis((3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazol-2-yl)pyridine).

[0310] As used herein, "chlorinating agent" or "chlorinating agent" refers to a compound that can introduce a chlorine group into a compound. Non-limiting examples of chlorinating agents include, but are not limited to, sulfuryl chloride, chlorine, acetyl chloride / cerium ammonium nitrate, lithium diisopropylamide / 4-toluenesulfonyl chloride, iodophenyl dichloride, trichloromethanesulfonyl chloride, 1,3-dichloro-5,5-dimethylhydantoin / ammonium chloride, tetrachlorosilane / urea-hydrogen peroxide, N-chlorosuccinimide, trichloroisocyanuric acid, and 3,5-dichloro-2-hydroxy-4,6-s-triazinedione sodium salt. Other examples include, but are not limited to, oxalyl chloride, phosphorus oxychloride, thionyl chloride, phosgene, triphosgene, methanesulfonyl chloride, and cyanuric chloride.

[0311] As used herein, a "coupling agent" is a compound that improves the coupling of a carboxylic acid and an amine. Non-limiting examples of coupling agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC HCl), carbonyldiimidazole, oxalyl chloride, thionyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, isobutyl chloroformate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate, tri-n-propylphosphonic anhydride, and 2-chloro-4,6-dimethoxy-1,3,5-triazine.

[0312] As used herein, "formamide-based reagents" refers to compounds that can introduce a one-carbon synthon into a compound. Non-limiting examples of formamide-based reagents include, but are not limited to, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal.

[0313] As used herein, "hydride source" refers to a compound that can introduce hydride into a compound. Non-limiting examples of hydride sources include, but are not limited to, triethylsilane, methyldiethoxysilane, trichlorosilane, polymethylhydrogensiloxane, dimethyl(phenyl)silane, 1,1,2,2-tetramethyldisilane, diphenylsilane, and hydrogen.

[0314] As used herein, "hydroxide base" refers to a metal oxide that reacts with an acid to neutralize the acid and produce water and a salt. Non-limiting examples include, but are not limited to, potassium hydroxide, lithium hydroxide, sodium hydroxide, and ammonium hydroxide.

[0315] As used herein, "iodide additive" refers to a compound that can introduce an iodine group into a compound. Non-limiting examples of iodide additives include, but are not limited to, sodium iodide, lithium iodide, or potassium iodide.

[0316] As used herein, "Lewis base" or "Lewis base additive" refers to a compound or ionic species that can donate an electron pair to an acceptor compound. Non-limiting examples of Lewis bases include, but are not limited to, N,N'-dimethylpropylene urea (DMPU), hexamethylphosphoramide, 2,6-lutidine, pyridine, diglyme, N-methylmorpholine, diisopropylethylamine, and 1,2-dimethoxyethane.

[0317] As used herein, "nitrile reagent" refers to a compound that can introduce a two-carbon synthon into a compound. Non-limiting examples of nitrile reagents include, but are not limited to, acetonitrile.

[0318] As used herein, "organometallic reagents" are compounds containing carbon-metal bonds. Non-limiting examples of organometallic reagents include, but are not limited to, isopropylmagnesium chloride, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride lithium chloride complex, isopropylmagnesium bromide, ethylmagnesium bromide, phenyllithium, mesityllithium, tert-butyllithium, and sec-butyllithium.

[0319] As used herein, an "oxidant" is a compound that can oxidize other compounds. Non-limiting examples of oxidants include, but are not limited to, potassium ferrocyanide, potassium persulfate, lead tetraacetate, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium permonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, m-chloroperbenzoic acid, and magnesium monoperoxyphthalate.

[0320] As used herein, a "palladium catalyst" is a compound containing palladium or a combination of a palladium catalyst and a palladium catalyst ligand that can promote other reactions such as bond formation reactions. Non-limiting examples of palladium catalysts include, but are not limited to, palladium on carbon, chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (XantPhos PdG2), Pd(acac) 2 、Pd(OAc) 2 、Pd(hfac) 2 、PdCl(allyl), PdCl 2 、PdSO 4 ·2H 2 O、Pd(XantPhos)Cl 2, 3 ) 4 and bis(dibenzylideneacetone)palladium(0) / Pd 2 (dba) 3 Other examples include, but are not limited to, 1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride, palladium(II) chloride bis(acetonitrile), bis(triphenylphosphine)palladium chloride, tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), bis(tricyclohexylphosphine)dichloropalladium(II), bis(cyanobenzene)dichloropalladium, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)dichloropalladium(II), and tris(dibenzylideneacetone)dipalladium(0) in combination with triphenylphosphine, tributylphosphine, tri(2-furyl)phosphine, tri(p-tolyl)phosphine, or tri(o-tolyl)phosphine.

[0321] As used herein, "palladium catalyst ligand" refers to a compound that can be combined with a palladium complex. Non-limiting examples of palladium catalyst ligands include, but are not limited to, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and other phosphine ligands understood by those skilled in the art.

[0322] As used herein, a "platinum catalyst" is a compound that contains platinum and can promote other reactions such as hydrogenation reactions. Non-limiting examples include, but are not limited to, platinum on alumina and platinum dioxide.

[0323] As used herein, a "reducing agent" is a compound that can reduce other compounds. Non-limiting examples of reducing agents include, but are not limited to, borane tetrahydrofuran complex, borane dimethyl sulfide complex, NaBH 4 / I 2 , ammonia borane, diethylaniline-borane, NaBH 4 , LiBH 4 KBH 4 , lithium triethylborohydride, potassium tri-sec-butylborohydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium tri[(3-ethyl-3-pentyl)oxy]aluminum hydride, hydrogen, formic acid / triethylamine or 2-propanol.

[0324] As used herein, a "rhodium catalyst" is a compound that contains rhodium and can promote other reactions such as hydrogenation reactions. Non-limiting examples of rhodium catalysts include, but are not limited to, rhodium on alumina.

[0325] As used herein, a "ruthenium catalyst" is a compound containing ruthenium and that can promote other reactions such as hydrogenation reactions. Non-limiting examples of ruthenium catalysts include, but are not limited to, RuCl(mesitylene) [(S,S)-Ts-DPEN] and RuCl(p-isopropyltoluene) [(R,R)-Teth-Ts-DPEN].

[0326] As used herein, "solvent" is a substance that can dissolve a solute into a solution. The solvent can be a polar solvent or a non-polar solvent. The solvent 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 heptane, hexane, 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 isobutyl ketone (MIBK)), ethers (such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane), aromatic solvents (such as benzene and toluene), halogenated solvents (such as dichloromethane, chloroform, and carbon tetrachloride), dimethyl sulfoxide (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, ethylene dichloride, chlorobenzene, tert-butyl alcohol, acetonitrile, propionitrile, and butyronitrile.

[0327] As used herein, a "titanium-based reagent" is a compound containing titanium. Non-limiting examples of titanium-based reagents include, but are not limited to, titanium (IV) ethoxide, titanium (IV) isopropoxide, titanium (IV) butoxide, and titanium (IV) tetrachloride.

[0328] As used herein, a "zinc additive" is a compound containing zinc. Non-limiting examples of zinc additives include, but are not limited to, zinc chloride and zinc bromide.

[0329] As used herein, a "zirconium-based reagent" is a compound containing zirconium. Non-limiting examples of zirconium-based reagents include, but are not limited to, zirconium (IV) tert-butoxide.

[0330] Compounds disclosed herein also include mixtures of all stereoisomers, including enantiomers and diastereomers. As used herein, the term "stereoisomer" refers to compounds having the same chemical composition but with different arrangements of atoms or groups in space. Examples of stereoisomers include diastereomers and enantiomers. In some embodiments, the compounds described herein are produced with a diastereomeric purity or chiral purity of 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 than about 99.9%.

[0331] As used herein, "diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity.

[0332] As used herein, "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0333] As used herein, "chiral" refers to molecules that have the property that their mirror image partner is non-superimposable, while the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0334] name

[0335] The structure of compound (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile is as follows:

[0336]

[0337] In the present disclosure, the above compound is referred to as Compound 1.

[0338] Compound 1 Preparation Route 1

[0339] In a non-limiting example, Scheme 1 is a scheme depicting one embodiment of Compound 1 Manufacturing Route 1. In a non-limiting example, Schemes 1, 2, and 3 depict one embodiment of the synthesis of Compound 1.

[0340] Solution 1

[0341]

[0342] A method for synthesizing compound 1 is a method comprising the following steps: (1a) contacting compound 1A with compound 1B in a solvent in the presence of a copper source, a ligand, and a base at a temperature sufficient to obtain compound 1C; and (1b) contacting compound 1C with compound 1D in a solvent in the presence of a copper catalyst and sodium ascorbate at a temperature sufficient to obtain compound 1.

[0343] In some embodiments of step (1a): (i) the copper source comprises copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) oxide, copper (I) acetate, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex, copper (I) bromide triphenylphosphine complex, copper (II) chloride, copper (II) bromide, copper (II) acetate, or copper(II) sulfate; (ii) the ligand includes a pyridine bisoxazoline ligand, such as 2,6-bis((4S,5R)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-tert-butyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S) -4-benzyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-methyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-isobutyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-phenylethyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((4S,5R)-4-methyl-5-phenyl-4,5-dihydrooxazol-2-yl)pyridine, 2,6-bis((S)-4-isobutyl-4,5-dihydrooxazol-2-yl)pyridine, (iii) the base includes sodium acetate, lithium acetate, potassium acetate, tertiary amines (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, ethylenetriamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2] octane), aromatic amines (e.g., pyridine, 2,6-lutidine and collidine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium fluoride, lithium carbonate and cesium carbonate) or alkoxide bases (e.g., sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-amylate and sodium tert-butoxide); (iv) the solvent includes an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butanol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate) and a diisopropyl ether. , butyl acetate and isobutyl acetate), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane), aromatic solvents (e.g., toluene, benzene and xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide), chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile), or combinations thereof; and / or (v) the temperature is from about -20°C to about 60°C.

[0344] In some embodiments of step (1a), the copper source comprises copper (I) iodide. In some embodiments of step (1a), the ligand comprises 2,6-bis ((4S, 5R) -4,5-diphenyl-4,5-dihydrooxazol-2-yl) pyridine. In some embodiments of step (1a), the base comprises sodium acetate. In some embodiments of step (1a), the solvent comprises acetonitrile and methanol. In some embodiments of step (1a), the temperature is about 0°C to about 20°C. In some embodiments of step (1a), the temperature is about -20°C to about 60°C. In some embodiments of step (1a), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0345] In some embodiments of step (1b): (i) the copper catalyst comprises copper (II) sulfate, copper (II) acetate, copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate toluene complex, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex or copper (I) bromide triphenylphosphine complex; (ii) the solvent comprises water, ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethyl (e.g., alkylene, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), alcohols (e.g., methanol, ethanol, isopropanol and tert-butanol), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile and butyronitrile), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), or combinations thereof; and / or (iii) the temperature is from about 0°C to about 50°C.

[0346] In some embodiments, Compound ID is prepared from Compound 2K as described throughout the specification, such as in Alternative Synthesis 1 (Scheme 18) of Compound 6A.

[0347] In some embodiments of step (1b), the copper catalyst comprises copper (II) sulfate. In some embodiments of step (1b), the solvent comprises 2-methyltetrahydrofuran, acetonitrile and water. In some embodiments of step (1b), the temperature is about 20°C. In some embodiments of step (1b), the temperature is about 0°C to about 50°C. In some embodiments of step (1b), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C or about 50°C.

[0348] Synthesis of compound 1A

[0349] In a non-limiting example, Scheme 2 is a scheme depicting one embodiment of the synthesis of Compound 1A.

[0350] Solution 2

[0351]

[0352] In some embodiments, compound 1A is prepared by a process comprising the following steps: (1c) contacting compound 1E with an organometallic reagent and an electrophilic reagent in a solvent at a temperature sufficient to provide compound 1F; (1d) contacting compound 1F with a methylating agent in a solution at a temperature sufficient to provide compound 1G, wherein X is iodide, chloride, bromide, methylsulfate, sulfate, methylcarbonate, carbonate, mesylate, triflate, tosylate or tetrafluoroborate; (1e) contacting compound 1G with an oxidant and a base in a solvent at a temperature sufficient to provide compound 1H; and (1f) contacting compound 1H with an alkylating agent in a solvent followed by the addition of an acetylating agent at a temperature sufficient to provide compound 1A.

[0353] In some embodiments of step (1c), (i) the organometallic reagent comprises an organolithium reagent (e.g., n-butyllithium, n-hexyllithium, phenyllithium, mesityllithium, tert-butyllithium, and sec-butyllithium) or a Grignard reagent (e.g., isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium chloride lithium chloride complex, phenylmagnesium chloride, sec-butylmagnesium chloride, and 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex); (ii) the electrophilic reagent comprises a formylated amine (e.g., N,N'-dimethylformamide, N,N-diethylformamide, 1-formylpyrrolidine, 4-formylmorpholine, and N-methylformanilide), a formate (e.g., (e.g., cyanomethyl formate, phenyl formate, ethyl formate and trifluoroethyl formate), orthoesters (e.g., trimethyl orthoformate, triethyl orthoformate and diethylphenyl orthoformate), formamide acetals (e.g., N,N-dimethylformamide dipropyl acetal and N,N-dimethylformamide dimethyl acetal) or (chloromethylene) dimethylammonium chloride; (iii) the solvent comprises an ether (e.g., diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran) or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, n-heptane and xylene); and / or (iv) the temperature is from about -100°C to about -50°C.

[0354] In some embodiments of step (1c), the organometallic reagent comprises n-butyllithium. In some embodiments of step (1c), the electrophilic reagent comprises N,N'-dimethylformamide. In some embodiments of step (1c), the solvent comprises tetrahydrofuran. In some embodiments of step (1c), the temperature is about -80°C to about -60°C. In some embodiments of step (1c), the temperature is about -100°C to about -50°C. In some embodiments, the temperature is about -100°C, about -95°C, about -90°C, about -85°C, about -80°C, about -75°C, about -70°C, about -65°C, about -60°C, about -55°C or about -50°C.

[0355] In some embodiments of step (1d): (i) the methylating agent includes iodomethane, bromomethane, chloromethane, trimethylsulfoxide iodide, diazomethane, dimethyl sulfate, carbonates (e.g., dimethyl carbonate and dimethyl dicarbonate), sulfonates (e.g., methyl fluorosulfonate, methyl methanesulfonate, methyl trifluoromethanesulfonate and methyl toluenesulfonate) or trimethyloxonium tetrafluoroborate; (ii) the solvent includes an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butanol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a ketone (e.g., acetone and methyl ethyl ketone), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about -20°C to about 45°C.

[0356] In some embodiments of step (1d), the methylating agent comprises iodomethane. In some embodiments of step (1d), the solvent comprises acetonitrile. In some embodiments of step (1d), the temperature is from about 5°C to about 45°C. In some embodiments of step (1d), the temperature is from about -20°C to about 45°C. In some embodiments of step (1d), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C or about 45°C. In some embodiments of step (1d), X is iodide.

[0357] In some embodiments of step (1e): (i) the oxidant comprises potassium ferrocyanide, potassium persulfate, lead tetraacetate, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium permonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, meta-chloroperbenzoic acid or magnesium monoperoxyphthalate; (ii) the base comprises a hydroxide base (e.g., potassium hydroxide, lithium hydroxide, sodium hydroxide, cesium hydroxide and ammonium hydroxide); (iii) the solvent comprises water, an alcohol solvent (e.g., methanol, ethanol, isopropyl alcohol and tert-butyl alcohol), an ester (e.g., ethyl acetate, isopropyl acetate, n-butyl acetate) or a mixture thereof. propyl acetate and isobutyl acetate), ketones (e.g., acetone and methyl ethyl ketone), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iv) the temperature is from about -5°C to about 70°C.

[0358] In some embodiments of step (1e), the oxidant comprises potassium ferrocyanide. In some embodiments of step (1e), the base comprises potassium hydroxide. In some embodiments of step (1e), the solvent comprises water. In some embodiments of step (1e), the temperature is from about 0°C to about 20°C. In some embodiments of step (1e), the temperature is from about -5°C to about 70°C. In some embodiments of step (1e), the temperature is about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or 70°C.

[0359] In some embodiments of step (1f), (i) the alkylating agent comprises a Grignard reagent (e.g., ethynylmagnesium bromide and ethynylmagnesium chloride) or an organolithium reagent (e.g., lithium acetylide, (trimethylsilyl)lithium acetylide) and sodium acetylide; (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or chlorinated solvents (e.g., dichloromethane, dichloroethane and chloroform); (iii) the acetylation agent includes acetic anhydride, esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, 1-methylvinyl acetate, vinyl acetate, phenyl acetate and 4-chlorophenyl acetate), acetyl chloride or acetyl bromide; and / or (iv) the temperature is from about -20°C to about 50°C.

[0360] In some embodiments of step (1f), the alkylating agent comprises ethynylmagnesium bromide. In some embodiments of step (1f), the solvent comprises dichloromethane. In some embodiments of step (1f), the acetylating agent comprises acetic anhydride. In some embodiments of step (1f), the temperature is about 20°C. In some embodiments of step (1f), the temperature is about -20°C to about 50°C. In some embodiments of step (1f), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C or about 50°C.

[0361] Synthesis of compound 1B

[0362] In a non-limiting example, Scheme 3 is a scheme depicting one embodiment of the synthesis for making Compound 1B of Pathway 1.

[0363] Solution 3

[0364]

[0365] In some embodiments, compound 1B is prepared by a method comprising the following steps: (1g) contacting compound 1I with compound 1J in a solvent in the presence of an amine or carbonate base at a temperature sufficient to obtain compound 1K as a mixture of cis and trans compounds; (1h) contacting compound 1K with a solvent at an elevated temperature at a temperature sufficient to obtain compound 1L; (1i) contacting compound 1L with a chlorinating agent and a base in a solvent at a temperature sufficient to obtain compound 1M; (1j) contacting compound 1M with 2,2-dimethylpropan-1-amine and a base in a solvent at a temperature sufficient to obtain compound 1N; and (1k) contacting compound 1N with a metal catalyst and a hydrogen source in a solvent at a temperature sufficient to obtain compound 1B.

[0366] In some embodiments of step (1g): (i) the amine or carbonate base comprises a tertiary amine (e.g., triethylamine, N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane) or a carbonate base (e.g., sodium carbonate, cesium carbonate and potassium carbonate); (ii) the solvent comprises an alcohol (e.g., ethanol, methanol, isopropanol and tert-butanol) or a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), and / or (iii) the temperature is from about 20°C to about 120°C.

[0367] In some embodiments of step (1g), the base comprises triethylamine. In some embodiments of step (1g), the solvent comprises ethanol. In some embodiments of step (1g), the temperature is about 75°C. In some embodiments of step (1g), the temperature is about 20°C to about 120°C. In some embodiments of step (1g), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C or about 120°C.

[0368] In some embodiments of step (1h): (i) the solvent comprises a high boiling point solvent (e.g., diphenyl ether, diethylene glycol dibutyl ether, paraffin oil, xylene, polyphosphoric acid, Eaton's reagent (phosphorus pentoxide in methanesulfonic acid solution), sulfuric acid / acetic anhydride and triethyl phosphite) or a eutectic mixture (e.g., ); and / or (ii) an elevated temperature of about 50°C to about 300°C.

[0369] In some embodiments of step (1h), the solvent comprises diphenyl ether. In some embodiments of step (1h), the elevated temperature is about 260°C. In some embodiments of step (1h), the elevated temperature is about 50°C to about 300°C. In some embodiments of step (1h), the elevated temperature is about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C, about 150°C, about 155°C, about 160°C, about 165°C, about 170°C, about 175°C, about 180°C, about 185°C, about 190°C, about 195°C, about 200°C, about 205°C, about 210°C, about 215°C, about 220°C, about 225°C, about 230°C, about 235°C, about 240°C, about 245°C, about 250°C, about 255°C, about 260°C, about 265°C, about 270°C, about 275°C, about 280°C, about 285°C, about 290°C or about 300°C.

[0370] In some embodiments of step (1i), (i) the chlorinating agent comprises oxalyl chloride, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosgene, methanesulfonyl chloride, cyanuric chloride or triphenylphosphine dichloride; (ii) the base comprises a tertiary amine (e.g., N,N-diisopropylethylamine, 1-methylimidazole, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane) or an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, (iii) the solvent comprises an ether (e.g., 1,4-dioxane, ethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether) or a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide); and / or (iv) the temperature is from about 20°C to about 80°C.

[0371] In some embodiments of step (1i), the chlorinating agent comprises oxalyl chloride. In some embodiments of step (1i), the base comprises N,N-diisopropylethylamine. In some embodiments of step (1i), the solvent comprises 1,4-dioxane. In some embodiments of step (1i), the temperature is about 60°C. In some embodiments of step (1i), the temperature is about 20°C to about 80°C. In some embodiments of step (1i), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C or about 80°C.

[0372] In some embodiments of step (1j): (i) the base comprises a tertiary amine (e.g., N,N-diisopropylethylamine, 1-methylimidazole, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane) or an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate , tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate); (ii) the solvent comprises an ether (e.g., 1,4-dioxane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether) or a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide); and / or (iii) the temperature is from about 20°C to about 80°C.

[0373] In some embodiments of step (1j), the base comprises N,N-diisopropylethylamine. In some embodiments of step (1j), the solvent comprises 1,4-dioxane. In some embodiments of step (1j), the temperature is about 60°C. In some embodiments of step (1j), the temperature is about 20°C to about 80°C. In some embodiments, the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C.

[0374] In some embodiments of step (1k): (i) the metal catalyst comprises platinum / vanadium on carbon, palladium on carbon, platinum on alumina, palladium hydroxide on carbon, platinum dioxide or rhodium on alumina; (ii) the hydrogen source comprises ammonium formate, hydrogen, formic acid, triethylamine formate complex or 1,4-cyclohexadiene; (iii) the solvent comprises alcohol (e.g., methanol, ethanol, tert-butyl alcohol and isopropyl alcohol), ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), ketone (e.g., acetone and methyl ethyl ketone), ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, etc.); (e.g., furan, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile), halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane), water or a combination thereof; and / or (iv) the temperature is from about 0°C to about 120°C.

[0375] In some embodiments of step (1k), the metal catalyst comprises platinum / vanadium on carbon. In some embodiments of step (1k), the hydrogen source comprises ammonium formate. In some embodiments of step (1k), the solvent comprises isopropanol and water. In some embodiments of step (1k), the temperature is about 50°C to about 70°C. In some embodiments of step (1k), the temperature is about 0°C to about 120°C. In some embodiments of step (1k), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C or about 120°C.

[0376] Compound 1 Preparation Route 2

[0377] In a non-limiting example, Scheme 4 is a scheme depicting one embodiment of a manufacturing route 2 for Compound 1. In a non-limiting example, Schemes 4, 5, 6, and 7 depict one embodiment of the synthesis of Compound 1.

[0378] Solution 4

[0379]

[0380] In a non-limiting example, Scheme 4A is a scheme depicting one embodiment for making the synthesis of Compound 1 by substitution of Compound 2F and Compound 2G for Pathway 2.

[0381] Option 4A

[0382]

[0383] One method for synthesizing compound 1 comprises the following steps: (2a) contacting compound 2A with compound 2B in a solvent in the presence of an organometallic reagent and a Lewis base at a temperature sufficient to obtain compound 2C; (2b) contacting compound 2C with a titanium- or zirconium-based reagent in the presence of a titanium- or zirconium-based reagent.

[0384]

[0385] (2c) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 2E; (2d) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (2e) contacting compound 2F with compound 2G in a solvent in the presence of a palladium catalyst and a base at a temperature sufficient to obtain compound 1.

[0386] One method for synthesizing compound 1 comprises the following steps: (2a) contacting compound 2A with compound 2B in a solvent in the presence of an organometallic reagent and a Lewis base at a temperature sufficient to obtain compound 2C; (2b) contacting compound 2C with a titanium- or zirconium-based reagent in the presence of a titanium- or zirconium-based reagent.

[0387]

[0388] (2c) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 2E; (2d) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (2e) contacting compound 2F with compound 2G in a solvent in the presence of a copper catalyst, a copper catalyst ligand and a base at a temperature sufficient to obtain compound 1.

[0389] In some embodiments of step (2a): (i) the organometallic reagent includes an organomagnesium reagent (e.g., isopropylmagnesium chloride, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride lithium chloride complex, isopropylmagnesium bromide and ethylmagnesium bromide) or an organolithium reagent (e.g., phenyllithium, mesityllithium, tert-butyllithium and sec-butyllithium); (ii) the Lewis base includes N,N'-dimethylpropyleneurea (DMPU), hexamethylphosphoramide, 2,6-dimethyl pyridine, pyridine, diethylene glycol dimethyl ether, N-methylmorpholine, diisopropylethylamine, 1,2-dimethoxyethane or lithium chloride; (iii) the solvent comprises dichloromethane, ether (e.g., diethylene glycol dimethyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether) or a hydrocarbon solvent (e.g., n-hexane, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iv) the temperature is from about -80°C to about 40°C.

[0390] In some embodiments of step (2a), the organometallic reagent comprises isopropylmagnesium chloride. In some embodiments of step (2a), the Lewis base comprises N,N'-dimethylpropyleneurea (DMPU). In some embodiments of step (2a), the solvent comprises dichloromethane. In some embodiments of step (2a), the temperature is about -5°C to about 20°C. In some embodiments of step (2a), the temperature is about -80°C to about 40°C. In some embodiments of step (2a), the temperature is about -80°C, about -75°C, about -70°C, about -65°C, about -60°C, about -55°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, or about 40°C.

[0391] In some embodiments of step (2b): (i) the titanium-based or zirconium-based reagent includes titanium (IV) ethoxide, titanium (IV) isopropoxide, titanium (IV) butoxide, zirconium (IV) tert-butoxide or zirconium (IV) ethoxide; (ii) the solvent includes a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, , 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide) or nitriles (e.g., acetonitrile, propionitrile and butyronitrile); and / or (iii) the temperature is from about 25°C to about 110°C.

[0392] In some embodiments of step (2b), the titanium-based or zirconium-based reagent comprises titanium (IV) ethoxide. In some embodiments of step (2b), the solvent comprises toluene. In some embodiments of step (2b), the temperature is from about 70°C to about 75°C. In some embodiments, the temperature is from about 25°C to about 110°C. In some embodiments, the temperature is about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 100°C, about 105°C, or about 110°C.

[0393] In some embodiments of step (2c): (I) the reducing agent comprises borane tetrahydrofuran complex, borane dimethyl sulfide complex, NaBH 4 / I 2 , amine-borane complexes (e.g., ammonia borane and diethylaniline-borane), borohydride reagents (e.g., NaBH 4 , LiBH 4 KBH 4, lithium triethylborohydride and potassium tri-sec-butylborohydride), aluminum hydride reagents (e.g., diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium tri-tert-butoxyaluminum hydride and lithium tri[(3-ethyl-3-pentyl)oxy]aluminum hydride), hydrogen, formic acid / triethylamine or 2-propanol; (ii) the ruthenium, palladium, rhodium or platinum catalyst, if present, comprises a Noyori-type Ru catalyst (e.g., RuCl(mesitylene)[(S,S)-Ts-DPEN], RuCl(p-isopropyltoluene)[(R,R)-Teth-Ts-DPEN]) or a heterogeneous hydrogenation catalyst (e.g., palladium on carbon, alumina on rhodium and platinum on carbon); (iii) the solvent comprises an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol and tert-butanol), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iv) the temperature is from about -40°C to about 100°C. In some embodiments of step (2c), compound 2E is produced in a diastereomeric purity of 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 95%, or at least greater than about 99%.

[0394] In some embodiments of step (2c), the reducing agent comprises a borane tetrahydrofuran complex. In some embodiments of step (2c), there is no ruthenium, palladium, rhodium or platinum catalyst. In some embodiments of step (2c), the solvent comprises 2-methyltetrahydrofuran. In some embodiments of step (2c), the temperature is about -10°C to about 0°C. In some embodiments of step (2c), the temperature is about -40°C to about 100°C. In some embodiments of step (2c), the temperature is about -40°C, about -35°C, about -30°C, about -25°C, -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C. In some embodiments of step (2c), Compound 2E is produced in a diastereomeric purity of at least greater than about 99%.

[0395] In some embodiments of step (2d): (i) the acid comprises hydrochloric acid, hydrobromic acid, sulfonic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid), trifluoroacetic acid, phosphoric acid, formic acid or oxalic acid; (ii) the solvent comprises water, esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), alcohols (e.g., ethanol, ethylene glycol, propylene glycol, methanol, isopropanol and tert-butyl alcohol), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, 1,4-dioxane ... (e.g., methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iii) the temperature is from about 0°C to about 70°C.

[0396] In some embodiments of step (2d), the acid comprises hydrochloric acid. In some embodiments of step (2d), the solvent comprises water. In some embodiments of step (2d), the temperature is about 20°C to about 50°C. In some embodiments of step (2d), the temperature is about 0°C to about 70°C. In some embodiments of step (2d), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0397] In some embodiments of step (2e): (i) the palladium catalyst comprises a palladium (II) catalyst (e.g., XantPhos Pd G2, Pd(acac) 2 、Pd(OAc) 2 、Pd(hfac) 2 、PdCl(allyl), PdCl 2 、PdSO 4 ·2H 2 O), palladium precatalyst (e.g., Pd(XantPhos)Cl 2 , XantPhos Pd G3, N-XantPhos Pd G4, tBuXPhos Pd G3, tBuBrettPhos Pd G3, RockPhos Pd G3, JosiPhos-J009 Pd G3, AdBrettPhos Pd G3, and TrixiePhos Pd G3) or a palladium(0) catalyst (e.g., Pd 2 (dba) 3 、Pd(PPh3 ) 4 ); (ii) the base includes an alkoxide base (e.g., potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, potassium propionate and potassium trimethylacetate), a tertiary amine (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine and collidine), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate), a hydroxide base (e.g., (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide) or lithium bis(trimethylsilyl)amide; (iii) the solvent comprises an alcohol (e.g., methanol, ethanol, tert-amyl alcohol, isopropanol and tert-butyl alcohol), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a combination thereof; and / or (iv) the temperature is from about 20°C to about 120°C.

[0398] In some embodiments of step (2e), the palladium catalyst comprises chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (XantPhos Pd G2). In some embodiments of step (2e), the base comprises potassium tert-butoxide. In some embodiments of step (2e), the solvent comprises tetrahydrofuran and toluene. In some embodiments of step (2e), the temperature is from about 60°C to about 75°C. In some embodiments of step (2e), the temperature is from about 20°C to about 120°C. In some embodiments, the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, or about 120°C.

[0399] In some embodiments of step (2e): (i) the copper catalyst comprises copper (II) acetate, copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate toluene complex, copper (I) iodide, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex, copper (I) bromide triphenylphosphine complex, copper (I) oxide or copper (II) oxide; (ii) the copper catalyst The ligands include diamines (e.g., N,N'-dimethylethane-1,2-diamine and trans-N,N'-dimethyl-cyclohexane-1,2-diamine), diols (e.g., ethane-1,2-diol, propane-1,3-diol), diketones (e.g., 2-acetylcyclohexanone, acetylacetone, 2,2,6,6-tetramethylheptane-3,5-dione), glycine derivatives (e.g., N-methylglycine and N,N-dimethylglycine), ethyl 2-oxocyclohexanecarboxylate, ethylene glycol, pyridine, 2-hydroxycyclohexanecarboxylate, and the like. ,2'-bipyridine, 1,10-phenanthroline, new cuprous reagent, 8-hydroxyquinoline, picolinic acid, glyoxal bis(phenylhydrazone), 2,6-dimethylanilino(oxy)acetic acid, 2,6-difluoroanilino(oxy)acetic acid, 2,6-dimethyloxyanilino(oxy)acetic acid, 2,3,4,5,6-pentafluoroanilino(oxy)acetic acid, 3,5-bis(trifluoromethyl)anilino(oxy)acetic acid, 2-fluoro-6-(piperidin-1-sulfonyl)anilino(oxy)acetic acid, N1,N2- (iii) the base includes an alkoxide base (e.g., sodium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, potassium propionate and potassium trimethylacetate), a tertiary amine (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2] octane), aromatic amines (pyridine, 2,6-lutidine and collidine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate), hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide) or lithium bis(trimethylsilyl)amide; (iv) the solvent includes alcohols (e.g., tert-amyl alcohol, isopropanol and tert-butyl alcohol), ethers (e.g., (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether and 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or combinations thereof; and / or (v) the temperature is from about 0°C to about 140°C.

[0400] In some embodiments of step (2e), the copper catalyst comprises copper (I) iodide. In some embodiments of step (2e), the copper catalyst ligand comprises 2,6-dimethylanilino (oxo) acetic acid (DMPAO). In some embodiments of step (2e), the base comprises tripotassium phosphate. In some embodiments of step (2e), the solvent comprises N-methyl-2-pyrrolidone. In some embodiments of step (2e), the temperature is about 100°C to about 120°C. In some embodiments of step (2e), the temperature is about 0°C to about 140°C. In some embodiments, the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, or about 140°C.

[0401] Synthesis of compound 2A

[0402] In a non-limiting example, Scheme 5 is a scheme depicting one embodiment for making Pathway 2 to synthesize Compound 2A via Compound 2M.

[0403] Solution 5

[0404]

[0405] In some embodiments, compound 2A is prepared by a process comprising the following steps: (2f) contacting compound 2H with a chlorinating agent, an optional amine catalyst, and an optional acidic additive in a solvent at a temperature sufficient to obtain compound 2I; (2g) contacting compound 2I with TsHNNH 2 (2h) contacting compound 2J with compound 2K in a solvent in the presence of a base at a temperature sufficient to obtain compound 2L; (2i) contacting compound 2L with a base in a solvent at a temperature sufficient to obtain compound 2M; and (2j) contacting compound 2M with MeNHOMe·HCl, a coupling agent and a base in a solvent at a temperature sufficient to obtain compound 2A.

[0406] In some embodiments of step (2f): (i) the chlorinating agent comprises sulfuryl chloride, chlorine gas or an electrophilic chlorine source (e.g., acetyl chloride / cerium ammonium nitrate, lithium diisopropylamide / 4-toluenesulfonyl chloride, iodophenyl dichloride, trichloromethanesulfonyl chloride, 1,3-dichloro-5,5-dimethylhydantoin / ammonium chloride, tetrachlorosilane / urea-hydrogen peroxide, N-chlorosuccinimide, trichloroisocyanuric acid and 3,5-dichloro-2-hydroxy-4,6-s-triazinedione sodium salt); (ii) the amine catalyst, if present, comprises a pyrrolidine-type organic catalyst (e.g., L-prolinamide and (2R,5R)-diphenylpyrrolidine); (iii) the acidic additive, if present, comprises a Bronsted acid (e.g. , methanesulfonic acid, p-toluenesulfonic acid and hydrochloric acid); (iv) the solvent comprises a carboxylic acid (e.g., acetic acid, trifluoroacetic acid and propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (v) the temperature is from about 30°C to about 70°C.

[0407] In some embodiments of step (2f), the chlorinating agent comprises sulfuryl chloride. In some embodiments of step (2f), there is no amine catalyst. In some embodiments of step (2f), there is no acidic additive. In some embodiments of step (2f), the solvent comprises acetic acid. In some embodiments of step (2f), the temperature is about 35°C to about 50°C. In some embodiments of step (2f), the temperature is about 30°C to about 70°C. In some embodiments of step (2f), the temperature is about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0408] In some embodiments of step (2g): (i) the solvent comprises a carboxylic acid (e.g., acetic acid, trifluoroacetic acid, and propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate, and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol, tert-butanol), a nitrile (e.g., acetonitrile, propionitrile, and butyronitrile), or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene); and / or (ii) the temperature is from about 30°C to about 70°C.

[0409] In some embodiments of step (2g), the solvent comprises acetic acid. In some embodiments of step (2g), the temperature is about 35°C to about 50°C. In some embodiments of step (2g), the temperature is about 30°C to about 70°C. In some embodiments of step (2g), the temperature is about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, or about 70°C.

[0410] In some embodiments of step (2h): (i) the base comprises a tertiary amine base (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), a hydroxide base (e.g., lithium hydroxide, potassium hydroxide, and sodium hydroxide), a carbonate base (e.g., potassium carbonate, sodium carbonate, and cesium carbonate), a bicarbonate base (e.g., sodium bicarbonate and potassium bicarbonate), a tetraalkylammonium hydroxide (e.g., tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, and choline hydroxide), an alkoxide base (e.g., sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide) ) or a phosphate base (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate); (ii) the solvent comprises water, a nitrile (e.g., acetonitrile, propionitrile and butyronitrile), a hydrocarbon solvent (e.g., toluene, 2-methyltetrahydrofuran, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an ether solvent (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol) or a combination thereof; and / or (iii) the temperature is from -20°C to about 60°C.

[0411] In some embodiments of step (2h), the base includes potassium carbonate. In some embodiments of step (2h), the solvent includes 2-methyltetrahydrofuran and water or acetonitrile. In some embodiments of step (2h), the temperature is about -20 ° C to about 20 ° C. In some embodiments of step (2h), the temperature is about -20 ° C to about 60 ° C. In some embodiments of step (2h), the temperature is about -20 ° C, about -15 ° C, about -10 ° C, about -5 ° C, about 0 ° C, about 5 ° C, about 10 ° C, about 15 ° C, about 20 ° C, about 25 ° C, about 30 ° C, about 35 ° C, about 40 ° C, about 45 ° C, about 50 ° C, about 55 ° C or about 60 ° C.

[0412] In some embodiments of step (2i): (i) the base comprises a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, and potassium hydroxide); (ii) the solvent comprises water, a nitrile solvent (e.g., acetonitrile, propionitrile, and butyronitrile), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an ether solvent (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether), an alcohol solvent (e.g., methanol, ethanol, isopropanol, and tert-butanol), or a combination thereof; and / or (iii) the temperature is from about -10°C to about 80°C.

[0413] In some embodiments of step (2i), the base comprises sodium hydroxide. In some embodiments of step (2i), the solvent comprises 2-methyltetrahydrofuran and water. In some embodiments of step (2i), the temperature is about 15°C to about 25°C. In some embodiments of step (2i), the temperature is about 20°C. In some embodiments of step (2i), the temperature is about -10°C to about 80°C. In some embodiments of step (2i), the temperature is about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C or about 80°C.

[0414] In some embodiments of step (2j), (i) the coupling agent comprises a peptide coupling agent (e.g., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC HCl), carbonyldiimidazole, oxalyl chloride, thionyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, isobutyl chloroformate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, (benzotriazole-1 (ii) the base includes a tertiary amine (e.g., N-methylmorpholine, triethylamine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0] undec-7-ene and 1,4-diazabicyclo[2.2.2]octane) or an aromatic amine (e.g., pyridine, 2,6-lutidine and collidine); (iii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a hydrocarbon solvent (e.g., benzene, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene) or a nitrile (e.g., acetonitrile, propionitrile and butyronitrile); and / or (iv) the temperature is from about -20°C to about 120°C.

[0415] In some embodiments of step (2j), the coupling agent comprises 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC HCl). In some embodiments of step (2j), the base comprises triethylamine. In some embodiments of step (2j), the solvent comprises acetonitrile. In some embodiments of step (2j), the temperature is about 0°C to about 20°C. In some embodiments of step (2j), the temperature is about -20°C to about 120°C. In some embodiments of step (2j), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C. About 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C or about 120°C.

[0416] Synthesis of compound 2B

[0417] In a non-limiting example, Scheme 6 is a scheme depicting one embodiment of the synthesis for making Compound 2B of Route 2.

[0418] Solution 6

[0419]

[0420] In some embodiments, compound 2B is prepared by a method comprising the following steps: (2k) contacting compound 1E with a copper catalyst, an amine ligand, and an iodide additive in a solvent at a temperature sufficient to obtain compound 2O; (2l) contacting compound 2O with an alkylating agent in a solvent at a temperature sufficient to obtain compound 2P, wherein X is iodide, chloride, bromide, methylsulfate, sulfate, methylcarbonate, carbonate, methanesulfonate, triflate, toluenesulfonate, or tetrafluoroborate; (2m) contacting compound 2P with an oxidant and a base in a solvent at a temperature sufficient to obtain compound 2B.

[0421] In some embodiments of step (2k): (i) the copper catalyst comprises copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) oxide, copper (I) acetate, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex or copper (I) bromide triphenylphosphine complex; (ii) the amine ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N3-dimethylpropane-1,3-diamine or N1-(2-aminoethyl)ethane-1,2-diamine; (iii) the iodine The iodide additive includes sodium iodide, lithium iodide or potassium iodide; (iv) the solvent includes an ether (e.g., diethylene glycol dimethyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a halogenated solvent (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (v) the temperature is from about 50°C to about 150°C.

[0422] In some embodiments of step (2k), the copper catalyst comprises copper (I) iodide. In some embodiments of step (2k), the amine ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine. In some embodiments of step (2k), the iodide additive comprises sodium iodide. In some embodiments of step (2k), the solvent comprises diethylene glycol dimethyl ether. In some embodiments of step (2k), the temperature is about 80°C to about 130°C. In some embodiments of step (2k), the temperature is about 50°C to about 150°C. In some embodiments of step (2k), the temperature is about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C or about 150°C.

[0423] In some embodiments of step (21): (i) the alkylating agent includes iodomethane, trimethylsulfoxide iodide, diazomethane, dimethyl sulfate, 2,2-dimethoxypropane, carbonates (e.g., dimethyl carbonate and dimethyl dicarbonate), sulfonates (e.g., methyl fluorosulfonate and methyl methanesulfonate), chloromethane, bromomethane or trimethyloxonium tetrafluoroborate; (ii) the solvent includes an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butanol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a ketone (e.g., acetone and methyl ethyl ketone), an ether (e.g., ethyl acetate), or a ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about 0°C to about 100°C.

[0424] In some embodiments of step (21), the alkylating agent comprises iodomethane. In some embodiments of step (21), the solvent comprises acetonitrile. In some embodiments of step (21), the temperature is about 20°C to about 40°C. In some embodiments of step (21), the temperature is about 0°C to about 100°C. In some embodiments of step (21), the temperature is about 30°C. In some embodiments of step (21), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C. In some embodiments of step (21), X is iodide.

[0425] In some embodiments of step (2m): (i) the oxidant comprises potassium ferrocyanide, potassium persulfate, lead tetraacetate, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium permonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, meta-chloroperbenzoic acid or magnesium monoperoxyphthalate; (ii) the base comprises a hydroxide base (e.g., lithium hydroxide, potassium hydroxide and ammonium hydroxide); (iii) the solvent comprises water, an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate); esters), ketones (e.g., acetone and methyl ethyl ketone), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iv) the temperature is from about 0°C to about 70°C.

[0426] In some embodiments of step (2m), the oxidant comprises potassium ferrocyanide. In some embodiments of step (2m), the base comprises potassium hydroxide. In some embodiments of step (2m), the solvent comprises water. In some embodiments of step (2m), the temperature is about 5°C to about 20°C. In some embodiments of step (2m), the temperature is about 0°C to about 70°C. In some embodiments of step (2m), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0427] Synthesis of compound 2G

[0428] In a non-limiting example, Scheme 7 is a scheme depicting one embodiment for making Route 2 to synthesize Compound 1B via Compound 2G.

[0429] Solution 7

[0430]

[0431] In some embodiments, compound 2G is prepared by a process comprising the following steps: (2n) contacting compound 2Q with a brominating agent in a solvent at a temperature sufficient to obtain compound 2R; (2o) contacting compound 2R with a formamide-based reagent in a solvent at a temperature sufficient to obtain compound 2S; (2p) contacting compound 2S with an optional nitrile reagent and a base in a solvent at a temperature sufficient to obtain compound 2T; (2q) contacting compound 2T with a chlorinating agent and a base in a solvent at a temperature sufficient to obtain compound (2U); and (2r) contacting compound 2U with 2,2-dimethylpropan-1-amine and a base in a solvent at a temperature sufficient to obtain compound 2G.

[0432] In some embodiments of step (2n), (i) the brominating agent comprises N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide or bromine; (ii) the solvent comprises a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide) or a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about 0°C to about 40°C.

[0433] In some embodiments of step (2n), the brominating agent comprises N-bromosuccinimide. In some embodiments of step (2n), the solvent comprises N,N-dimethylformamide. In some embodiments of step (2n), the temperature is about 15°C to about 25°C. In some embodiments of step (2n), the temperature is about 20°C. In some embodiments of step (2n), the temperature is about 0°C to about 40°C. In some embodiments of step (2n), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C.

[0434] In some embodiments of step (2o): (i) the formamide-based reagent comprises N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal or N,N-dimethylformamide diisopropyl acetal; (ii) the solvent comprises a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal or N,N-dimethylformamide diisopropyl acetal; and / or (iii) the temperature is from about 20°C to about 150°C.

[0435] In some embodiments of step (2o), the formamide-based reagent comprises N,N-dimethylformamide dimethyl acetal. In some embodiments of step (2o), the solvent comprises N,N-dimethylformamide. In some embodiments of step (2o), the temperature is about 100°C to about 120°C. In some embodiments of step (2o), the temperature is about 110°C. In some embodiments of step (2o), the temperature is about 20°C to about 150°C. In some embodiments of step (2o), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C or about 150°C.

[0436] In some embodiments of step (2p): (i) the nitrile reagent, if present, comprises acetonitrile; (ii) the base comprises an organolithium reagent (e.g., phenyllithium, mesityllithium, tert-butyllithium, and sec-butyllithium), a Grignard reagent (e.g., isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium chloride lithium chloride complex, phenylmagnesium chloride, sec-butylmagnesium chloride, and 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex), an alkoxide base (e.g., potassium tert-butoxide and tert-butyllithium); (e.g., potassium bis(trimethylsilyl)amide) or an amide base (e.g., lithium diisopropylamide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and lithium bis(trimethylsilyl)amide); (iii) the solvent comprises an ether (e.g., tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether); and / or (iv) the temperature is from about -80°C to about 40°C.

[0437] In some embodiments of step (2p), the nitrile reagent, if present, comprises acetonitrile. In some embodiments of step (2p), the base comprises lithium bis(trimethylsilyl)amide. In some embodiments of step (2p), the solvent comprises tetrahydrofuran. In some embodiments of step (2p), the temperature is about -10°C to about 0°C. In some embodiments of step (2p), the temperature is about -80°C to about 40°C. In some embodiments of step (2p), the temperature is about -80°C, about -75°C, about -70°C, about -65°C, about -60°C, about -55°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C.

[0438] In some embodiments of step (2q): (i) the chlorinating agent comprises oxalyl chloride, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosgene, triphosgene, methanesulfonyl chloride or cyanuric chloride; (ii) the base comprises an amine base (e.g., N,N-diisopropylethylamine, 1-methylimidazole, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate) or an aromatic amine (e.g., pyridine, 2,6-lutidine and collidine); (iii) the solvent comprises an ether (e.g., 1,2-dimethoxyethane, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), an ester solvent (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene) or a polar aprotic solvent (e.g., N,N-dimethylformamide); and / or (iv) the temperature is from about 20°C to about 80°C.

[0439] In some embodiments of step (2q), the chlorinating agent comprises oxalyl chloride. In some embodiments of step (2q), the base comprises N,N-diisopropylethylamine. In some embodiments of step (2q), the solvent comprises 1,2-dimethoxyethane. In some embodiments of step (2q), the temperature is about 55°C to about 65°C. In some embodiments of step (2q), the temperature is about 60°C. In some embodiments of step (2q), the temperature is about 20°C to about 80°C. In some embodiments of step (2q), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C or about 80°C.

[0440] In some embodiments of step (2r): (i) the base comprises an amine base (e.g., N,N-diisopropylethylamine, 1-methylimidazole, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, and cesium carbonate) or an aromatic amine (e.g., pyridine, 2,6-lutidine, and collidine); (ii) the solvent comprises an alcohol (e.g., methanol, ethanol, tert-butyl alcohol, sec-butyl alcohol and isopropanol), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), hydrocarbons (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide) or nitriles (e.g., acetonitrile, propionitrile and butyronitrile); and / or (iii) the temperature is from about 20°C to about 100°C.

[0441] In some embodiments of step (2r), the base comprises N,N-diisopropylethylamine. In some embodiments of step (2r), the solvent comprises isopropanol. In some embodiments of step (2r), the temperature is about 70°C to about 80°C. In some embodiments of step (2r), the temperature is about 75°C. In some embodiments of step (2r), the temperature is about 20°C to about 100°C. In some embodiments of step (2r), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0442] In some embodiments, compound 1B is prepared by a process comprising the following steps: (2s) contacting compound 2G with acetamide, a palladium catalyst or a copper catalyst, a palladium catalyst ligand or a copper catalyst ligand, and a base in a solvent at a temperature sufficient to provide an acetamide intermediate; and (2t) contacting the acetamide intermediate with a reagent in a solvent at a temperature sufficient to provide compound 2G.

[0443] In some embodiments of step (2s): (i) the palladium catalyst or copper catalyst comprises a copper source (e.g., copper (I) iodide, copper (I) bromide, and copper (I) chloride) or a palladium source (e.g., palladium (II) acetate, palladium (II) chloride, palladium (II) bromide, and bis(triphenylphosphine) palladium (II) dichloride, allyl palladium (II) chloride, and tetrakis(triphenylphosphine) palladium (0)); (ii) the palladium catalyst ligand or copper catalyst ligand comprises 1,2-dimethylethane for the copper catalyst. (iii) the base includes a tertiary amine (for example, N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (for example, pyrrolidone), or a phosphine ligand for a palladium catalyst (for example, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)); (iv) the solvent comprises a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, cyclohexane, heptane, t-butyl alcohol ... , xylene and benzene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile, butyronitrile and benzonitrile), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether); and / or (iv) the temperature is from about 20°C to about 100°C.

[0444] In some embodiments of step (2s), the palladium catalyst or copper catalyst comprises palladium (II) acetate. In some embodiments of step (2s), the palladium catalyst ligand or copper catalyst ligand comprises 4,5-bis (diphenylphosphino) -9,9- dimethylxanthene (Xantphos). In some embodiments of step (2s), the base comprises potassium carbonate. In some embodiments of step (2s), the temperature is about 80 ° C. In some embodiments of step (2s), the temperature is about 20 ° C to about 100 ° C. In some embodiments of step (2s), the temperature is about 20 ° C, about 25 ° C, about 30 ° C, about 35 ° C, about 40 ° C, about 45 ° C, about 50 ° C, about 55 ° C, about 60 ° C, about 65 ° C, about 70 ° C, about 75 ° C, about 80 ° C, about 85 ° C, about 90 ° C, about 95 ° C or about 100 ° C.

[0445] In some embodiments of step (2t): (i) the reagent comprises an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid) or a base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, and ammonium hydroxide); (ii) the solvent comprises an alcohol (e.g., methanol, ethanol, isopropanol, tert-butanol, 1-butanol, and 2-butanol) or water; and / or (iii) the temperature is about 50°C to about 100°C.

[0446] In some embodiments of step (2t), the reagent comprises hydrochloric acid. In some embodiments of step (2t), the solvent comprises ethanol. In some embodiments of step (2t), the temperature is about 60°C to about 75°C. In some embodiments of step (2t), the temperature is about 50°C to about 100°C. In some embodiments of step (2t), the temperature is about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0447] Compound 1 Preparation Route 3

[0448] In a non-limiting example, Scheme 8 is a scheme depicting one embodiment of an alternative synthesis for making Compound 2F of Pathway 3. In a non-limiting example, Schemes 8, 5, 6, and 7 depict one embodiment of the synthesis of Compound 1.

[0449] Solution 8

[0450]

[0451] One method for synthesizing compound 1 is a method comprising the following steps: (3a) contacting compound 2M with a chlorinating agent and an additive in a solvent at a temperature sufficient to obtain compound 3A; (3b) contacting compound 3A with compound 2B in a solvent in the presence of an organometallic reagent, followed by the addition of a copper or palladium catalyst, an optional zinc additive, and an optional Lewis base, at a temperature sufficient to obtain compound 2C; (3c) contacting compound 2C with a chlorinating agent in the presence of a titanium-based or zirconium-based reagent.

[0452]

[0453] (3d) contacting compound 3B with a reducing agent and optionally a ruthenium, palladium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 3C; (3e) contacting compound 3C with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (3f) contacting compound 2F with compound 2G in a solvent in the presence of a palladium catalyst and a base at a temperature sufficient to obtain compound 1.

[0454] One method for synthesizing compound 1 is a method comprising the following steps: (3a) contacting compound 2M with a chlorinating agent and an additive in a solvent at a temperature sufficient to obtain compound 3A; (3b) contacting compound 3A with compound 2B in a solvent in the presence of an organometallic reagent, followed by the addition of a copper or palladium catalyst, an optional zinc additive, and an optional Lewis base, at a temperature sufficient to obtain compound 2C; (3c) contacting compound 2C with a chlorinating agent in the presence of a titanium-based or zirconium-based reagent.

[0455]

[0456] (3d) contacting compound 3B with a reducing agent and optionally a ruthenium, palladium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 3C; (3e) contacting compound 3C with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (3f) contacting compound 2F with compound 2G in a solvent in the presence of a copper catalyst, a copper catalyst ligand and a base at a temperature sufficient to obtain compound 1.

[0457] In some embodiments of step (3a): (i) the chlorinating agent comprises oxalyl chloride, thionyl chloride, cyanuric chloride or phosphorus oxychloride; (iii) the solvent comprises a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, xylene and benzene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate) or a polar aprotic solvent (e.g., N,N-dimethylformamide); and / or (iv) the temperature is from about 0°C to about 100°C.

[0458] In some embodiments of step (3a), the chlorinating agent comprises oxalyl chloride. In some embodiments of step (3a), the solvent comprises dichloromethane or toluene. In some embodiments of step (3a), the solvent comprises dichloromethane. In some embodiments of step (3a), the solvent comprises toluene. In some embodiments of step (3a), the temperature is from about 10°C to about 30°C. In some embodiments of step (3a), the temperature is from about 0°C to about 100°C. In some embodiments of step (3a), the temperature is from about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C. In some embodiments of step (3a), the additive comprises N,N-dimethylformamide.

[0459] In some embodiments of step (3b): (i) the organometallic reagent includes isopropylmagnesium chloride, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride lithium chloride complex, isopropylmagnesium bromide, ethylmagnesium bromide; (ii) the copper or palladium catalyst includes a copper catalyst (e.g., copper (I) bromide dimethyl sulfide complex, copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) cyanide bis (lithium chloride) complex, tris (triphenyl) bromide) phosphine), copper(I) trifluoromethanesulfonate toluene complex, copper(I) chloride bis(lithium chloride) complex, copper(I) bromide bis(lithium bromide) complex, copper(I) thiocyanate, copper(I) thiophene-2-carboxylate, copper(I) thiophenolate, copper(I) diphenylphosphate, (1,10-phenanthroline)bis(triphenylphosphine) nitrate copper(I) DCM adduct, copper(I) 3-methylsalicylate, copper(I) chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I), chloro(1, 5-cyclooctadiene) copper (I) dimer, copper (II) chloride, copper (II) bromide and copper (II) acetate) or palladium (0) precatalyst (for example, tetrakis (triphenylphosphine) palladium (0) and bis (dibenzylideneacetone) palladium (0)); (iii) the zinc additive, if present, comprises zinc chloride or zinc bromide; (iv) the Lewis base, if present, comprises N,N'-dimethylpropylene urea, hexamethylphosphoramide, 2,6-lutidine, pyridine, diethylene glycol dimethyl ether, N-methylmorpholine, diisopropyl ethylamine, dimethoxyethane or lithium chloride; (v) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether and diethylene glycol dimethyl ether), a hydrocarbon solvent (e.g., n-hexane, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene) or a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (vi) the temperature is from about -80°C to about 60°C.

[0460] In some embodiments of step (3b), the organometallic reagent comprises isopropylmagnesium chloride. In some embodiments of step (3b), the copper or palladium catalyst comprises copper (I) bromide dimethyl sulfide complex. In some embodiments of step (3b), there is no zinc additive. In some embodiments of step (3b), there is no Lewis base. In some embodiments of step (3b), the solvent comprises tetrahydrofuran and toluene. In some embodiments of step (3b), the temperature is about -20°C to about 0°C. In some embodiments of step (3b), the temperature is about -80°C to about 60°C. In some embodiments of step (3b), the temperature is about -80°C, about -75°C, about -70°C, about -65°C, about -60°C, about -55°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0461] In some embodiments of step (3c): (i) the titanium-based or zirconium-based reagent comprises titanium (IV) ethoxide, titanium (IV) isopropoxide, titanium (IV) butoxide, zirconium (IV) tert-butoxide or zirconium (IV) ethoxide; (ii) the solvent comprises a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide) or nitriles (e.g., acetonitrile, propionitrile and butyronitrile); and / or (iii) the temperature is from about 25°C to about 110°C.

[0462] In some embodiments of step (3c), the titanium-based or zirconium-based reagent comprises titanium (IV) ethoxide. In some embodiments of step (3c), the solvent comprises toluene. In some embodiments of step (3c), the temperature is about 60°C to about 75°C. In some embodiments of step (3c), the temperature is about 25°C to about 110°C. In some embodiments of step (3c), the temperature is about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C or about 110°C.

[0463] In some embodiments of step (3d): (i) the reducing agent comprises lithium tri-tert-butoxyaluminum hydride, borane dimethyl sulfide complex, NaBH 4 / I 2 , amine π borane complexes (e.g., ammonia borane and diethylaniline-borane), borohydride reagents (e.g., sodium borohydride, lithium borohydride, potassium borohydride, lithium triethylborohydride and potassium tri-sec-butylborohydride), aluminum hydride reagents (e.g., diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride and lithium tri[(3-ethyl-3-pentyl)oxy]aluminum hydride), hydrogen, formic acid / triethylamine or 2-propanol; (ii) the ruthenium, palladium or platinum catalyst, if present, comprises a Noyori-type Ru catalyst (e.g., RuCl(mesitylene)[(S,S)-Ts-DPEN] and RuCl(p-isopropyltoluene)[(R,R)-Teth-Ts-DPEN]) or a heterogeneous hydrogenation catalyst (iii) the solvent comprises an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol, tert-butyl alcohol and 1-propanol), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene) or a nitrile (e.g., acetonitrile, propionitrile and butyronitrile); and / or (iv) the temperature is from about -40°C to about 100°C. In some embodiments of step (3d), compound 3C is produced in a diastereomeric purity of 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 95%, or at least greater than about 99%.

[0464] In some embodiments of step (3d), the reducing agent comprises lithium tri-tert-butoxyaluminum hydride. In some embodiments of step (3d), there is no ruthenium, palladium or platinum catalyst. In some embodiments of step (3d), the solvent comprises dichloromethane. In some embodiments of step (3d), the temperature is about -20°C to about 0°C. In some embodiments of step (3d), the temperature is about -40°C to about 100°C. In some embodiments of step (3d), the temperature is about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C. In some embodiments of step (3d), compound 3C is produced in a diastereomeric purity of at least greater than about 99%.

[0465] In some embodiments of step (3e): (i) the acid comprises hydrochloric acid, hydrobromic acid, sulfonic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid), trifluoroacetic acid, phosphoric acid, formic acid or oxalic acid; (ii) the solvent comprises water, an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iii) the temperature is from about 0°C to about 70°C.

[0466] In some embodiments of step (3e), the acid comprises hydrochloric acid. In some embodiments of step (3e), the solvent comprises water. In some embodiments of step (3e), the temperature is about 20°C to about 50°C. In some embodiments of step (3e), the temperature is about 0°C to about 70°C. In some embodiments of step (3e), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, or about 70°C.

[0467] In some embodiments of step (3f): (i) the palladium catalyst comprises a palladium (II) catalyst (e.g., XantPhos Pd G2, Pd(acac) 2 、Pd(OAc) 2 、Pd(hfac) 2 、PdCl(allyl), PdCl 2 、PdSO 4 ·2H 2 O), palladium precatalyst (e.g., Pd(XantPhos)Cl 2 , XantPhos Pd G3, N-XantPhos Pd G4, tBuXPhos Pd G3, tBuBrettPhos Pd G3, RockPhos Pd G3, JosiPhos-J009 Pd G3, AdBrettPhos Pd G3, and TrixiePhos Pd G3) or a palladium(0) catalyst (e.g., Pd 2 (dba) 3 and Pd(PPh 3 ) 4 ); (ii) the base includes an alkoxide base (e.g., potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, potassium propionate and potassium trimethylacetate), a tertiary amine (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine and collidine), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate), a hydroxide base (e.g., (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide) or lithium bis(trimethylsilyl)amide; (iii) the solvent comprises an alcohol (e.g., methanol, ethanol, tert-amyl alcohol, isopropanol and tert-butyl alcohol), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a combination thereof; and / or (iv) the temperature is from about 20°C to about 120°C.

[0468] In some embodiments of step (3f), the palladium catalyst comprises XantPhos Pd G2. In some embodiments of step (3f), the base comprises potassium tert-butoxide. In some embodiments of step (3f), the solvent comprises tetrahydrofuran and toluene. In some embodiments of step (3f), the temperature is about 60°C to about 75°C. In some embodiments of step (3f), the temperature is about 20°C to about 120°C. In some embodiments of step (3f), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C or about 120°C.

[0469] In some embodiments of step (3f): (i) the copper catalyst comprises copper (II) acetate, copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate toluene complex, copper (I) iodide, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex, copper (I) bromide triphenylphosphine complex, copper (I) oxide or copper (II) oxide; (ii) the copper catalyst The ligands include diamines (e.g., N,N'-dimethylethane-1,2-diamine and trans-N,N'-dimethyl-cyclohexane-1,2-diamine), diols (e.g., ethane-1,2-diol, propane-1,3-diol), diketones (e.g., 2-acetylcyclohexanone, acetylacetone, 2,2,6,6-tetramethylheptane-3,5-dione), glycine derivatives (e.g., N-methylglycine and N,N-dimethylglycine), ethyl 2-oxocyclohexanecarboxylate, ethylene glycol, pyridine, 2-hydroxycyclohexanecarboxylate, and the like. ,2'-bipyridine, 1,10-phenanthroline, new cuprous reagent, 8-hydroxyquinoline, picolinic acid, glyoxal bis(phenylhydrazone), 2,6-dimethylanilino(oxy)acetic acid, 2,6-difluoroanilino(oxy)acetic acid, 2,6-dimethyloxyanilino(oxy)acetic acid, 2,3,4,5,6-pentafluoroanilino(oxy)acetic acid, 3,5-bis(trifluoromethyl)anilino(oxy)acetic acid, 2-fluoro-6-(piperidin-1-sulfonyl)anilino(oxy)acetic acid, N1,N2- (iii) the base includes an alkoxide base (e.g., sodium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, potassium propionate and potassium trimethylacetate), a tertiary amine (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2] octane), aromatic amines (pyridine, 2,6-lutidine and collidine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate), hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide) or lithium bis(trimethylsilyl)amide; (iv) the solvent includes alcohols (e.g., tert-amyl alcohol, isopropanol and tert-butyl alcohol), ethers (e.g., (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether and 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or combinations thereof; and / or (v) the temperature is from about 0°C to about 140°C.

[0470] In some embodiments of step (3f), the copper catalyst comprises copper (I) iodide. In some embodiments of step (3f), the copper catalyst ligand comprises 2,6-dimethylanilino (oxo) acetic acid (DMPAO). In some embodiments of step (3f), the base comprises tripotassium phosphate. In some embodiments of step (3f), the solvent comprises N-methyl-2-pyrrolidone. In some embodiments of step (3f), the temperature is about 100°C to about 120°C. In some embodiments of step (3f), the temperature is about 0°C to about 140°C. In some embodiments, the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, or about 140°C.

[0471] Synthesis of compound 2M

[0472] In a non-limiting example, Scheme 5 is a scheme depicting one embodiment for making Pathway 3 to synthesize Compound 2A via Compound 2M.

[0473] In some embodiments, compound 2M is prepared by a method comprising the following steps: (3g) contacting compound 2H with a chlorinating agent, an optional amine catalyst, and an optional acidic additive in a solvent at a temperature sufficient to obtain compound 2I; (3h) contacting compound 2I with TsHNNH 2 (3i) contacting compound 2J with compound 2K in a solvent in the presence of a base at a temperature sufficient to obtain compound 2L; (3j) contacting compound 2L with a base in a solvent at a temperature sufficient to obtain compound 2M.

[0474] In some embodiments of step (3g): (i) the chlorinating agent comprises sulfuryl chloride, chlorine gas or an electrophilic chlorine source (e.g., acetyl chloride / cerium ammonium nitrate, lithium diisopropylamide / 4-toluenesulfonyl chloride, iodophenyl dichloride, trichloromethanesulfonyl chloride, 1,3-dichloro-5,5-dimethylhydantoin / ammonium chloride, tetrachlorosilane / urea-hydrogen peroxide, N-chlorosuccinimide, trichloroisocyanuric acid and 3,5-dichloro-2-hydroxy-4,6-s-triazinedione sodium salt); (ii) the amine catalyst, if present, comprises a pyrrolidine-type organic catalyst (e.g., L-prolineamide and (2R,5R)-diphenylpyrrolidine); (iii) the acidic additive, if present, comprises a Bronsted acid (e.g., (e.g., methanesulfonic acid, p-toluenesulfonic acid and hydrochloric acid); (iv) the solvent comprises a carboxylic acid (e.g., acetic acid, trifluoroacetic acid and propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol and tert-butanol), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (v) the temperature is from about 30°C to about 70°C.

[0475] In some embodiments of step (3g), the chlorinating agent comprises sulfuryl chloride. In some embodiments of step (3g), there is no amine catalyst. In some embodiments of step (3g), there is no acidic additive. In some embodiments of step (3g), the solvent comprises acetic acid. In some embodiments of step (3g), the temperature is about 35°C to about 50°C. In some embodiments of step (3g), the temperature is about 30°C to about 70°C. In some embodiments of step (3g), the temperature is about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0476] In some embodiments of step (3h): (i) the solvent comprises a carboxylic acid (e.g., acetic acid, trifluoroacetic acid, and propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate, and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol, tert-butanol), a nitrile (e.g., acetonitrile, propionitrile, and butyronitrile), or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene); and / or (ii) the temperature is from about 30°C to about 70°C.

[0477] In some embodiments of step (3h), the solvent comprises acetic acid. In some embodiments of step (3h), the temperature is from 35°C to about 50°C. In some embodiments of step (3h), the temperature is from about 30°C to about 70°C. In some embodiments of step (3h), the temperature is about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, or about 70°C.

[0478] In some embodiments of step (3i): (i) the base comprises a tertiary amine base (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), a hydroxide base (e.g., lithium hydroxide, potassium hydroxide, and sodium hydroxide), a carbonate base (e.g., potassium carbonate, sodium carbonate, and cesium carbonate), a bicarbonate base (e.g., sodium bicarbonate and potassium bicarbonate), a tetraalkylammonium hydroxide (e.g., tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, and choline hydroxide), an alkoxide base (e.g., sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide) or a phosphate base (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate); (ii) the solvent comprises water, a nitrile (e.g., acetonitrile, propionitrile and butyronitrile), a hydrocarbon solvent (e.g., toluene, 2-methyltetrahydrofuran, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an ether solvent (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol) or a combination thereof; and / or (iii) the temperature is from about -20°C to about 60°C.

[0479] In some embodiments of step (3i), the base comprises potassium carbonate. In some embodiments of step (3i), the solvent comprises 2-methyltetrahydrofuran and water or acetonitrile. In some embodiments of step (3i), the temperature is -20°C to about 20°C. In some embodiments of step (3i), the temperature is about -20°C to about 60°C. In some embodiments of step (3i), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0480] In some embodiments of step (3j): (i) the base comprises a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, and potassium hydroxide); (ii) the solvent comprises water, a nitrile solvent (e.g., acetonitrile, propionitrile, and butyronitrile), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an ether solvent (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether), an alcohol solvent (e.g., methanol, ethanol, isopropanol, and tert-butanol), or a combination thereof; and / or (iii) the temperature is from about -10°C to about 80°C.

[0481] In some embodiments of step (3j), the alkali comprises sodium hydroxide. In some embodiments of step (3j), the solvent comprises 2-methyltetrahydrofuran and water. In some embodiments of step (3j), the temperature is about 15°C to about 25°C. In some embodiments of step (3j), the temperature is about 20°C. In some embodiments of step (3j), the temperature is about -10°C to about 80°C. In some embodiments of step (3j), the temperature is about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C or about 80°C.

[0482] Synthesis of compound 2B

[0483] In a non-limiting example, Scheme 6 is a scheme depicting one embodiment of the synthesis for making Compound 2B of Pathway 3.

[0484] In some embodiments, compound 2B is prepared by a method comprising the following steps: (3k) contacting compound 1E with a copper catalyst, an amine ligand, and an iodide additive in a solvent at a temperature sufficient to obtain compound 2O; (3l) contacting compound 2O with an alkylating agent in a solvent at a temperature sufficient to obtain compound 2P, wherein X is iodide, chloride, bromide, methylsulfate, sulfate, methylcarbonate, carbonate, methanesulfonate, triflate, toluenesulfonate, or tetrafluoroborate; (3m) contacting compound 2P with an oxidant and a base in a solvent at a temperature sufficient to obtain compound 2B.

[0485] In some embodiments of step (3k): (i) the copper catalyst comprises copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) oxide, copper (I) acetate, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex or copper (I) bromide triphenylphosphine complex; (ii) the amine ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N3-dimethylpropane-1,3-diamine or N1-(2-aminoethyl)ethane-1,2-diamine; (iii) the iodine The iodide additive includes sodium iodide, lithium iodide or potassium iodide; (iv) the solvent includes an ether (e.g., diethylene glycol dimethyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a halogenated solvent (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (v) the temperature is from about 50°C to about 150°C.

[0486] In some embodiments of step (3k), the copper catalyst comprises copper (I) iodide. In some embodiments of step (3k), the amine ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine. In some embodiments of step (3k), the iodide additive comprises sodium iodide. In some embodiments of step (3k), the solvent comprises diethylene glycol dimethyl ether. In some embodiments of step (3k), the temperature is about 80°C to about 130°C. In some embodiments of step (3k), the temperature is about 50°C to about 150°C. In some embodiments of step (3k), the temperature is about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C or about 150°C.

[0487] In some embodiments of step (31): (i) the alkylating agent includes iodomethane, trimethylsulfoxide iodide, diazomethane, dimethyl sulfate, 2,2-dimethoxypropane, carbonates (e.g., dimethyl carbonate and dimethyl dicarbonate), sulfonates (e.g., methyl fluorosulfonate and methyl methanesulfonate), chloromethane, bromomethane or trimethyloxonium tetrafluoroborate; (ii) the solvent includes an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butanol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a ketone (e.g., acetone and methyl ethyl ketone), an ether (e.g., ethyl acetate), or a ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about 0°C to about 100°C.

[0488] In some embodiments of step (31), the alkylating agent comprises iodomethane. In some embodiments of step (31), the solvent comprises acetonitrile. In some embodiments of step (31), the temperature is about 20°C to about 40°C. In some embodiments of step (31), the temperature is about 30°C. In some embodiments of step (31), the temperature is about 0°C to about 100°C. In some embodiments of step (31), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C. In some embodiments of step (31), X is iodide.

[0489] In some embodiments of step (3m): (i) the oxidant comprises potassium ferrocyanide, potassium persulfate, lead tetraacetate, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium permonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, meta-chloroperbenzoic acid or magnesium monoperoxyphthalate; (ii) the base comprises potassium hydroxide, lithium hydroxide, potassium hydroxide or ammonium hydroxide; (iii) the solvent comprises a hydroxide base (e.g., lithium hydroxide, potassium hydroxide and ammonium hydroxide); (iv) the solvent comprises water, an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), an ester (e.g., ethyl acetate, acetic acid isopropyl acetate, n-propyl acetate and isobutyl acetate), ketones (e.g., acetone and methyl ethyl ketone), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iv) the temperature is from about 0°C to about 70°C.

[0490] In some embodiments of step (3m), the oxidant comprises potassium ferrocyanide. In some embodiments of step (3m), the base comprises potassium hydroxide. In some embodiments of step (3m), the solvent comprises water. In some embodiments of step (3m), the temperature is about 5°C to about 20°C. In some embodiments of step (3m), the temperature is about 0°C to about 70°C. In some embodiments of step (3m), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0491] Synthesis of compound 2G

[0492] In a non-limiting example, Scheme 7 is a scheme depicting one embodiment for making Pathway 3 to synthesize Compound 1B via Compound 2G.

[0493] In some embodiments, compound 2G is prepared by a process comprising the following steps: (3n) contacting compound 2Q with a brominating agent in a solvent at a temperature sufficient to obtain compound 2R; (3o) contacting compound 2R with a formamide-based reagent in a solvent at a temperature sufficient to obtain compound 2S; (3p) contacting compound 2S with an optional nitrile reagent and a base in a solvent at a temperature sufficient to obtain compound 2T; (3q) contacting compound 2T with a chlorinating agent and a base in a solvent at a temperature sufficient to obtain compound 2U; and (3r) contacting compound 2U with 2,2-dimethylpropan-1-amine and a base in a solvent at a temperature sufficient to obtain compound 2G.

[0494] In some embodiments of step (3n): (i) the brominating agent comprises N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide or bromine; (ii) the solvent comprises a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide) or a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about 0°C to about 40°C.

[0495] In some embodiments of step (3n), the brominating agent comprises N-bromosuccinimide. In some embodiments of step (3n), the solvent comprises N,N-dimethylformamide. In some embodiments of step (3n), the temperature is about 15°C to about 25°C. In some embodiments of step (3n), the temperature is about 20°C. In some embodiments of step (3n), the temperature is about 0°C to about 40°C. In some embodiments of step (3n), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C.

[0496] In some embodiments of step (3o): (i) the formamide-based reagent comprises N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal or N,N-dimethylformamide diisopropyl acetal; (ii) the solvent comprises a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal or N,N-dimethylformamide diisopropyl acetal; and / or (iii) the temperature is from about 20°C to about 150°C.

[0497] In some embodiments of step (3o), the formamide-based reagent comprises N,N-dimethylformamide dimethyl acetal. In some embodiments of step (3o), the solvent comprises N,N-dimethylformamide. In some embodiments of step (3o), the temperature is about 100°C to about 120°C. In some embodiments of step (3o), the temperature is about 110°C. In some embodiments of step (3o), the temperature is about 20°C to about 150°C. In some embodiments of step (3o), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C or about 150°C.

[0498] In some embodiments of step (3p): (i) the nitrile reagent, if present, comprises acetonitrile; (ii) the base comprises an organolithium reagent (e.g., phenyllithium, mesityllithium, tert-butyllithium, and sec-butyllithium), a Grignard reagent (e.g., isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium chloride lithium chloride complex, phenylmagnesium chloride, sec-butylmagnesium chloride, and 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex), an alkoxide base (e.g., potassium tert-butoxide and tert-butyllithium); (e.g., potassium bis(trimethylsilyl)amide) or an amide base (e.g., lithium diisopropylamide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and lithium bis(trimethylsilyl)amide); (iii) the solvent comprises an ether (e.g., tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether); and / or (iv) the temperature is from about -80°C to about 40°C.

[0499] In some embodiments of step (3p), the nitrile reagent, if present, comprises acetonitrile. In some embodiments of step (3p), the base comprises lithium bis(trimethylsilyl)amide. In some embodiments of step (3p), the solvent comprises tetrahydrofuran. In some embodiments of step (3p), the temperature is about -10°C to about 0°C. In some embodiments of step (3p), the temperature is about -80°C to about 40°C. In some embodiments of step (3p), the temperature is about -80°C, about -75°C, about -70°C, about -65°C, about -60°C, about -55°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C.

[0500] In some embodiments of step (3q): (i) the chlorinating agent comprises oxalyl chloride, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosgene, triphosgene, methanesulfonyl chloride or cyanuric chloride; (ii) the base comprises an amine base (e.g., N,N-diisopropylethylamine, 1-methylimidazole, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate) or an aromatic amine (e.g., pyridine, 2,6-lutidine and collidine); (iii) the solvent comprises an ether (e.g., 1,2-dimethoxyethane, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), an ester solvent (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene) or a polar aprotic solvent (e.g., N,N-dimethylformamide); and / or (iv) the temperature is from about 20°C to about 80°C.

[0501] In some embodiments of step (3q), the chlorinating agent comprises oxalyl chloride. In some embodiments of step (3q), the base comprises N,N-diisopropylethylamine. In some embodiments of step (3q), the solvent comprises 1,2-dimethoxyethane. In some embodiments of step (3q), the temperature is about 55°C to about 65°C. In some embodiments of step (3q), the temperature is about 60°C. In some embodiments of step (3q), the temperature is about 20°C to about 80°C. In some embodiments of step (3q), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C or about 80°C.

[0502] In some embodiments of step (3r): (i) the base comprises an amine base (e.g., N,N-diisopropylethylamine, 1-methylimidazole, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, and cesium carbonate) or an aromatic amine (e.g., pyridine, 2,6-lutidine, and collidine); (ii) the solvent comprises an alcohol (e.g., methanol, ethanol, tert-butyl alcohol, sec-butyl alcohol and isopropanol), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), hydrocarbons (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide) or nitriles (e.g., acetonitrile, propionitrile and butyronitrile); and / or (iii) the temperature is from about 20°C to about 100°C.

[0503] In some embodiments of step (3r), the base comprises N,N-diisopropylethylamine. In some embodiments of step (3r), the solvent comprises isopropanol. In some embodiments of step (3r), the temperature is about 70°C to about 80°C. In some embodiments of step (3r), the temperature is about 75°C. In some embodiments of step (3r), the temperature is about 20°C to about 100°C. In some embodiments of step (3r), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0504] Compound 1 Preparation Route 4

[0505] In a non-limiting example, Scheme 9 is a scheme depicting one embodiment of an alternative synthesis for making Compound 2E of Pathway 4. In a non-limiting example, Schemes 9, 10, 5, and 7 depict one embodiment of the synthesis of Compound 1.

[0506] Solution 9

[0507]

[0508] In a non-limiting example, Scheme 9A is a scheme depicting one embodiment of the synthesis of Compound 4A by substitution of Compound 1H for making Route 4. In a non-limiting example, Schemes 9, 9A, 10, 5, and 7 depict one embodiment of the synthesis of Compound 1.

[0509] Scheme 9A

[0510]

[0511] One method for synthesizing compound 1 comprises the following steps: (4a) reacting a catalyst and In the presence of, contacting compound 1H in a solvent,

[0512] The temperature during contact is sufficient to obtain compound 4A; (4b) contacting compound 4A with compound 4B in a solvent in the presence of a base, followed by the addition of an optional copper catalyst, an optional Lewis base additive, and an optional zinc additive, at a temperature sufficient to obtain compound 2E; (4c) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (4d) contacting compound 2F with compound 2G in a solvent in the presence of a palladium catalyst and a base, at a temperature sufficient to obtain compound 1.

[0513] One method for synthesizing compound 1 comprises the following steps: (4a) reacting a catalyst and In the presence of, contacting compound 1H in a solvent,

[0514] The temperature during contact is sufficient to obtain compound 4A; (4b) contacting compound 4A with compound 4B in a solvent in the presence of a base, and then adding an optional copper catalyst, an optional Lewis base additive and an optional zinc additive, and the temperature during contact is sufficient to obtain compound 2E; (4c) contacting compound 2E with an acid in a solvent, and the temperature during contact is sufficient to obtain compound 2F; and (4d) contacting compound 2F with compound 2G in a solvent in the presence of a copper catalyst, a copper catalyst ligand and a base, and the temperature during contact is sufficient to obtain compound 1.

[0515] In some embodiments of step (4a): (i) the catalyst comprises an inorganic catalyst (e.g., magnesium sulfate, a carbonate base (e.g., potassium carbonate, sodium carbonate, and cesium carbonate), a hydroxide base (e.g., potassium hydroxide, lithium hydroxide, and sodium hydroxide) and titanium (IV) isopropoxide), an organic catalyst (e.g., a secondary amine (e.g., pyrrolidine, piperidine, proline, diisopropylamine, and dibutylamine), an organic acid (e.g., acetic acid, trifluoroacetic acid, benzoic acid, 4-nitrobenzoic acid, methoxyacetic acid, propionic acid, isobutyric acid, pivalic acid, decanoic acid, hexanoic acid, or phenylboric acid)) or a combination thereof; ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a hydrocarbon solvent (e.g., n-hexane, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or an ester (ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate); and / or (iii) the temperature is from about -20°C to about 65°C.

[0516] In some embodiments of step (4a): (i) the catalyst comprises cesium carbonate, magnesium sulfate, potassium carbonate, sodium carbonate, hydroxide bases (potassium hydroxide, lithium hydroxide and sodium hydroxide), titanium (IV) isopropoxide, pyrrolidine or piperidine; (ii) the solvent comprises ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), hydrocarbon solvents (e.g., n-hexane, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or esters (ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate); and / or (iii) the temperature is from about -20°C to about 65°C.

[0517] In some embodiments of step (4a), the catalyst comprises cesium carbonate. In some embodiments of step (4a), the solvent comprises 2-methyltetrahydrofuran. In some embodiments of step (4a), the temperature is about 20°C to about 30°C. In some embodiments of step (4a), the temperature is about 25°C. In some embodiments of step (4a), the temperature is about -20°C to about 65°C. In some embodiments of step (4a), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C or 65°C.

[0518] In some embodiments of step (4a), the catalyst comprises a combination of pyrrolidine and propionic acid. In some embodiments of step (4a), the solvent comprises toluene. In some embodiments of step (4a), the temperature is about 50°C. In some embodiments of step (4a), the temperature is about -20°C to about 65°C. In some embodiments of step (4a), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C or 65°C.

[0519] In some embodiments of step (4b), (i) the base comprises a Grignard reagent (e.g., isopropylmagnesium chloride lithium chloride complex, isopropylmagnesium chloride, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, sec-butylmagnesium chloride lithium chloride complex, isopropylmagnesium bromide, and ethylmagnesium bromide) or an organolithium reagent (e.g., n-hexyllithium, phenyllithium, mesityllithium, n-butyllithium, tert-butyllithium, or sec-butyllithium); (ii) the copper catalyst, if present, comprises a copper catalyst (e.g., copper(I) iodide, copper(II) bromide, Copper(I), copper(I) chloride, copper(I) cyanide bis(lithium chloride) complex, tris(triphenylphosphine) copper(I) bromide, copper(I) trifluoromethanesulfonate toluene complex, copper(I) chloride bis(lithium chloride) complex, copper(I) bromide bis(lithium bromide) complex, copper(I) thiocyanate, copper(I) thiophene-2-carboxylate, copper(I) thiophenolate, copper(I) diphenylphosphate, (1,10-phenanthroline)bis(triphenylphosphine) nitrate copper(I) DCM adduct, 3-methylsalicylate copper(I), chloride[1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I), chloro(1,5-cyclooctadiene)copper(I) dimer, copper(II) chloride, copper(II) bromide and copper(II) acetate); (iii) the zinc additive, if present, includes zinc chloride and zinc bromide; (iv) the Lewis base additive, if present, includes N,N'-dimethylpropyleneurea, hexamethylphosphoramide, 2,6-lutidine, pyridine, diethylene glycol dimethyl ether, N-methylmorpholine, N,N-diisopropyl (v) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether and diglyme), a hydrocarbon solvent (e.g., n-hexane, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene) or a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iv) the temperature is from about -80°C to about 60°C. In some embodiments of step (4b), compound 2E is produced in a diastereomeric purity of 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 95%, or at least greater than about 99%.

[0520] In some embodiments of step (4b), the base comprises isopropylmagnesium chloride lithium chloride complex. In some embodiments of step (4b), there is no copper catalyst. In some embodiments of step (4b), there is no zinc additive. In some embodiments of step (4b), there is no Lewis base additive. In some embodiments of step (4b), the solvent comprises tetrahydrofuran. In some embodiments of step (4b), the temperature is about 0°C to about 25°C. In some embodiments of step (4b), the temperature is about -80°C to about 60°C. In some embodiments of step (4b), the temperature is about -80°C, about -75°C, about -70°C, about -65°C, about -60°C, about -55°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C. In some embodiments of step (4b), Compound 2E is produced in a diastereomeric purity of at least greater than about 99%.

[0521] In some embodiments of step (4c): (i) the acid comprises hydrochloric acid, hydrobromic acid, sulfonic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid), trifluoroacetic acid, phosphoric acid, formic acid or oxalic acid; (ii) the solvent comprises water, ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), alcohol (e.g., ethanol, ethylene glycol, propylene glycol, methanol, isopropanol and tert-butyl alcohol), ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, 1,4-dioxane ... (e.g., methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iii) the temperature is from about 0°C to about 70°C.

[0522] In some embodiments of step (4c), the acid comprises hydrochloric acid. In some embodiments of step (4c), the solvent comprises water. In some embodiments of step (4c), the temperature is about 20°C to about 50°C. In some embodiments of step (4c), the temperature is about 0°C to about 70°C. In some embodiments of step (4c), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0523] In some embodiments of step (4d): (i) the palladium catalyst comprises a palladium (II) catalyst (e.g., XantPhos Pd G2, Pd(acac) 2 、Pd(OAc) 2 、Pd(hfac) 2 、PdCl(allyl), PdCl 2 and PdSO 4 ·2H 2 O), palladium precatalyst (e.g., Pd(XantPhos)Cl 2 , XantPhos Pd G3, N-XantPhos Pd G4, tBuXPhos Pd G3, tBuBrettPhos Pd G3, RockPhos Pd G3, JosiPhos-J009 Pd G3, AdBrettPhos Pd G3, and TrixiePhos Pd G3) or a palladium(0) catalyst (e.g., Pd 2 (dba) 3 and Pd(PPh 3 ) 4 ); (ii) the base includes an alkoxide base (e.g., potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, potassium propionate and potassium trimethylacetate), a tertiary amine (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine and collidine), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate), a hydroxide base (e.g., (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide) or lithium bis(trimethylsilyl)amide; (iii) the solvent comprises an alcohol (e.g., methanol, ethanol, tert-amyl alcohol, isopropanol and tert-butyl alcohol), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a combination thereof; and / or (iv) the temperature is from about 20°C to about 120°C.

[0524] In some embodiments of step (4d), the palladium catalyst comprises chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (XantPhos Pd G2). In some embodiments of step (4d), the base comprises potassium tert-butoxide. In some embodiments of step (4d), the solvent comprises tetrahydrofuran and toluene. In some embodiments of step (4d), the temperature is from about 60°C to about 75°C. In some embodiments of step (4d), the temperature is from about 20°C to about 120°C. In some embodiments of step (4d), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C or about 120°C.

[0525] In some embodiments of step (4d): (i) the copper catalyst comprises copper (II) acetate, copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate toluene complex, copper (I) iodide, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex, copper (I) bromide triphenylphosphine complex, copper (I) oxide or copper (II) oxide; (ii) the copper catalyst The ligands include diamines (e.g., N,N'-dimethylethane-1,2-diamine and trans-N,N'-dimethyl-cyclohexane-1,2-diamine), diols (e.g., ethane-1,2-diol, propane-1,3-diol), diketones (e.g., 2-acetylcyclohexanone, acetylacetone, 2,2,6,6-tetramethylheptane-3,5-dione), glycine derivatives (e.g., N-methylglycine and N,N-dimethylglycine), ethyl 2-oxocyclohexanecarboxylate, ethylene glycol, pyridine, 2-hydroxycyclohexanecarboxylate, and the like. ,2'-bipyridine, 1,10-phenanthroline, new cuprous reagent, 8-hydroxyquinoline, picolinic acid, glyoxal bis(phenylhydrazone), 2,6-dimethylanilino(oxy)acetic acid, 2,6-difluoroanilino(oxy)acetic acid, 2,6-dimethyloxyanilino(oxy)acetic acid, 2,3,4,5,6-pentafluoroanilino(oxy)acetic acid, 3,5-bis(trifluoromethyl)anilino(oxy)acetic acid, 2-fluoro-6-(piperidin-1-sulfonyl)anilino(oxy)acetic acid, N1,N2- (iii) the base includes an alkoxide base (e.g., sodium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, potassium propionate and potassium trimethylacetate), a tertiary amine (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2] octane), aromatic amines (pyridine, 2,6-lutidine and collidine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate), hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide) or lithium bis(trimethylsilyl)amide; (iv) the solvent includes alcohols (e.g., tert-amyl alcohol, isopropanol and tert-butyl alcohol), ethers (e.g., (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dibutyl ether and 1,4-dioxane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or combinations thereof; and / or (v) the temperature is from about 0°C to about 140°C.

[0526] In some embodiments of step (4d), the copper catalyst comprises copper (I) iodide. In some embodiments of step (4d), the copper catalyst ligand comprises 2,6-dimethylanilino (oxo) acetic acid (DMPAO). In some embodiments of step (4d), the base comprises tripotassium phosphate. In some embodiments of step (4d), the solvent comprises N-methyl-2-pyrrolidone. In some embodiments of step (4d), the temperature is about 100°C to about 120°C. In some embodiments of step (4d), the temperature is about 0°C to about 140°C. In some embodiments, the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, or about 140°C.

[0527] Synthesis of compound 4B

[0528] In a non-limiting example, Scheme 9 is a scheme depicting one embodiment of the synthesis for making compound 4B of pathway 4.

[0529] In some embodiments, compound 4B is prepared by a process comprising: (4e) contacting compound 2M with a base in a solvent in the presence of a brominating agent at a temperature sufficient to yield compound 4B.

[0530] In some embodiments of step (4e): (i) the brominating agent comprises N-bromosuccinimide, potassium bromide / hypochlorous acid, pyridinium tribromide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid or bromine; (ii) the base comprises sodium acetate, potassium hydroxide, lithium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium acetate, potassium acetate or potassium phosphate; (iii) the solvent comprises water, ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene) or chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iv) the temperature is from about 0°C to about 100°C.

[0531] In some embodiments of step (4e), the brominating agent comprises N-bromosuccinimide. In some embodiments of step (4e), the base comprises sodium acetate. In some embodiments of step (4e), the solvent comprises water. In some embodiments of step (4e), the temperature is about 70°C to about 90°C. In some embodiments of step (4e), the temperature is about 0°C to about 100°C. In some embodiments of step (4e), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0532] Alternative synthesis for making compound 1H of route 4

[0533] In a non-limiting example, Scheme 10 is a scheme depicting one embodiment of an alternative synthesis for making Compound 1H of Route 4.

[0534] Solution 10

[0535]

[0536] In some embodiments, compound 1H is prepared by a process comprising the following steps: (4f) contacting compound 1E with an alkylating agent in a solvent at a temperature sufficient to provide compound 4C, wherein X is iodide, chloride, bromide, methyl sulfate, sulfate, methyl carbonate, carbonate, methanesulfonate, triflate, toluenesulfonate, or tetrafluoroborate; (4g) contacting compound 4C with an oxidant and a hydroxide base in a solvent at a temperature sufficient to provide compound 4D; (4h) contacting compound 4D with a palladium or copper catalyst, a carbonyl source, a hydride source, and a base in a solvent at a temperature sufficient to provide compound 1H.

[0537] In some embodiments of step (4f): (i) the alkylating agent comprises iodomethane, methyl bromide, methyl chloride, trimethyl sulfoxide iodide, diazomethane, dimethyl sulfate, 2,2-dimethoxypropane, carbonates (e.g., dimethyl carbonate and dimethyl dicarbonate), sulfonates (e.g., methyl fluorosulfonate and methyl methanesulfonate) or trimethyloxonium tetrafluoroborate; (ii) the solvent comprises an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butanol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a ketone (e.g., acetone and methyl ethyl ketone), an ether (e.g., ethyl acetate), or a ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about -20°C to about 45°C.

[0538] In some embodiments of step (4f), the alkylating agent comprises iodomethane. In some embodiments of step (4f), the solvent comprises acetonitrile. In some embodiments of step (4f), the temperature is from about 0°C to about 35°C. In some embodiments of step (4f), the temperature is from about -20°C to about 45°C. In some embodiments of step (4f), the temperature is from about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 40°C, or about 45°C. In some embodiments of step (4f), X is iodide.

[0539] In some embodiments of step (4g): (i) the oxidant comprises potassium ferrocyanide, potassium persulfate, lead tetraacetate, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium permonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, m-chloroperbenzoic acid or magnesium monoperoxyphthalate; (ii) the hydroxide base comprises a hydroxide base (e.g., potassium hydroxide, lithium hydroxide, sodium hydroxide and ammonium hydroxide); (iii) the solvent comprises water, an alcohol solvent (e.g., methanol, ethanol, isopropyl alcohol and tert-butyl alcohol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), ketones (e.g., acetone and methyl ethyl ketone), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iv) the temperature is from about -5°C to about 70°C.

[0540] In some embodiments of step (4g), the oxidant comprises potassium ferrocyanide. In some embodiments of step (4g), the hydroxide base comprises potassium hydroxide. In some embodiments of step (4g), the solvent comprises water. In some embodiments of step (4g), the temperature is from about 0°C to about 20°C. In some embodiments of step (4g), the temperature is from about -5°C to about 70°C. In some embodiments of step (4g), the temperature is about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0541] In some embodiments of step (4h): (i) the palladium or copper catalyst comprises a palladium catalyst (e.g., 1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride, palladium(II) acetate, palladium(II) dichloride bis(acetonitrile), bis(triphenylphosphine)palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride, bis(tricyclohexylphosphine)palladium(II) dichloride, bis(cyanobenzene)palladium(II) dichloride, acetylacetonate palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium(II) dichloride (ii) the carbonyl source comprises carbon monoxide, iron pentacarbonyl, dicobalt octacarbonyl, N-formylsaccharin, paraformaldehyde or formic acid; (iii) the hydride source comprises silane (e.g., triethylsilane, methyldiethoxysilane); (iv) the hydride source comprises silane (e.g., triethylsilane, methyldiethoxysilane); (v) the hydride source comprises tris(dibenzylideneacetone)dipalladium(0) in combination with a tertiary phosphine (e.g., triphenylphosphine, tributylphosphine, tri(2-furanyl)phosphine, tri(p-tolyl)phosphine and tri(o-tolyl)phosphine); (v) the hydride source comprises tris(dibenzylideneacetone)dipalladium(0) in combination with a tertiary phosphine (e.g., triphenylphosphine, tributylphosphine, tri(2-furanyl)phosphine, tri(p-tolyl)phosphine and tri(o-tolyl)phosphine); , trichlorosilane, polymethylhydrogensiloxane, dimethyl(phenyl)silane, 1,1,2,2-tetramethyldisilane and diphenylsilane) or hydrogen; (iv) the base includes a tertiary amine (for example, triethylamine, N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane and tetramethylethylenediamine), an aromatic amine (for example, pyridine, 2,6-lutidine and collidine) or an inorganic base (for example, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, (v) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene) or a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide); and / or (vi) the temperature is from about 0°C to about 100°C.

[0542] In some embodiments of step (4h), the palladium or copper catalyst comprises 1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride. In some embodiments of step (4h), the carbonyl source comprises carbon monoxide. In some embodiments of step (4h), the hydride source comprises triethylsilane. In some embodiments of step (4h), the base comprises triethylamine. In some embodiments of step (4h), the solvent comprises N,N-dimethylformamide. In some embodiments of step (4h), the temperature is about 80°C. In some embodiments of step (4h), the temperature is about 0°C to about 100°C. In some embodiments of step (4h), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0543] Synthesis of compound 2M

[0544] In a non-limiting example, Scheme 5 is a scheme depicting one embodiment for making Pathway 4 to synthesize Compound 2A via Compound 2M.

[0545] In some embodiments, compound 2M is prepared by a method comprising the following steps: (4i) contacting compound 2H with a chlorinating agent, an optional amine catalyst, and an optional acidic additive in a solvent at a temperature sufficient to obtain compound 2I; (4j) contacting compound 2I with TsHNNH 2 (4k) contacting compound 2J with compound 2K in a solvent in the presence of a base at a temperature sufficient to obtain compound 2L; (4l) contacting compound 2L with a base in a solvent at a temperature sufficient to obtain compound 2M.

[0546] In some embodiments of step (4i): (i) the chlorinating agent comprises sulfuryl chloride, chlorine gas or an electrophilic chlorine source (e.g., acetyl chloride / cerium ammonium nitrate, lithium diisopropylamide / 4-toluenesulfonyl chloride, iodophenyl dichloride, trichloromethanesulfonyl chloride, 1,3-dichloro-5,5-dimethylhydantoin / ammonium chloride, tetrachlorosilane / urea-hydrogen peroxide, N-chlorosuccinimide, trichloroisocyanuric acid and 3,5-dichloro-2-hydroxy-4,6-s-triazinedione sodium salt); (ii) the amine catalyst, if present, comprises a pyrrolidine-type organic catalyst (e.g., L-prolinamide and (2R,5R)-diphenylpyrrolidine); (iii) the acidic additive, if present, comprises a Bronsted acid (e.g. , methanesulfonic acid, p-toluenesulfonic acid and hydrochloric acid); (iv) the solvent comprises a carboxylic acid (e.g., acetic acid, trifluoroacetic acid and propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (v) the temperature is from about 30°C to about 70°C.

[0547] In some embodiments of step (4i), the chlorinating agent comprises sulfuryl chloride. In some embodiments of step (4i), there is no amine catalyst. In some embodiments of step (4i), there is no acidic additive. In some embodiments of step (4i), the solvent comprises acetic acid. In some embodiments of step (4i), the temperature is about 35°C to about 50°C. In some embodiments of step (4i), the temperature is about 30°C to about 70°C. In some embodiments of step (4i), the temperature is about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0548] In some embodiments of step (4j): (i) the solvent comprises a carboxylic acid (e.g., acetic acid, trifluoroacetic acid, and propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate, and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol, and tert-butanol), a nitrile (e.g., acetonitrile, propionitrile, and butyronitrile), or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene); and / or (ii) the temperature is from about 30°C to about 70°C.

[0549] In some embodiments of step (4j), the solvent comprises acetic acid. In some embodiments of step (4j), the temperature is about 35°C to about 50°C. In some embodiments of step (4j), the temperature is about 30°C to about 70°C. In some embodiments of step (4j), the temperature is about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, or about 70°C.

[0550] In some embodiments of step (4k): (i) the base comprises a tertiary amine base (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), a hydroxide base (e.g., lithium hydroxide, potassium hydroxide, and sodium hydroxide), a carbonate base (e.g., potassium carbonate, sodium carbonate, and cesium carbonate), a bicarbonate base (e.g., sodium bicarbonate and potassium bicarbonate), a tetraalkylammonium hydroxide (e.g., tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, and choline hydroxide), an alkoxide base (e.g., sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide) or a phosphate base (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate); (ii) the solvent comprises water, a nitrile (e.g., acetonitrile, propionitrile and butyronitrile), a hydrocarbon solvent (e.g., toluene, 2-methyltetrahydrofuran, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an ether solvent (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol) or a combination thereof; and / or (iii) the temperature is from about -20°C to about 60°C.

[0551] In some embodiments of step (4k), the base comprises potassium carbonate. In some embodiments of step (4k), the solvent comprises 2-methyltetrahydrofuran and water or acetonitrile. In some embodiments of step (4k), the temperature is about -20°C to about 20°C. In some embodiments of step (4k), the temperature is about -20°C to about 60°C. In some embodiments of step (4k), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0552] In some embodiments of step (41): (i) the base comprises a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, and potassium hydroxide); (ii) the solvent comprises water, a nitrile solvent (e.g., acetonitrile, propionitrile, and butyronitrile), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an ether solvent (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether), an alcohol solvent (e.g., methanol, ethanol, isopropanol, and tert-butanol), or a combination thereof; and / or (iii) the temperature is from about -10°C to about 80°C.

[0553] In some embodiments of step (41), the base comprises sodium hydroxide. In some embodiments of step (41), the solvent comprises 2-methyltetrahydrofuran and water. In some embodiments of step (41), the temperature is about 15°C to about 25°C. In some embodiments of step (41), the temperature is about 20°C. In some embodiments of step (41), the temperature is about -10°C to about 80°C. In some embodiments of step (41), the temperature is about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C or about 80°C.

[0554] Synthesis of compound 2G

[0555] In a non-limiting example, Scheme 7 is a scheme depicting one embodiment for making Route 4 to synthesize Compound 1B via Compound 2G.

[0556] In some embodiments, compound 2G is prepared by a process comprising the following steps: (4m) contacting compound 2Q with a brominating agent in a solvent at a temperature sufficient to obtain compound 2R; (4n) contacting compound 2R with a formamide-based reagent in a solvent at a temperature sufficient to obtain compound 2S; (4o) contacting compound 2S with an optional nitrile reagent and a base in a solvent at a temperature sufficient to obtain compound 2T; (4p) contacting compound 2T with a chlorinating agent and a base in a solvent at a temperature sufficient to obtain compound 2U; and (4q) contacting compound 2U with 2,2-dimethylpropan-1-amine and a base in a solvent at a temperature sufficient to obtain compound 2G.

[0557] In some embodiments of step (4m): (i) the brominating agent comprises N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide or bromine; (ii) the solvent comprises a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide) or a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about 0°C to about 40°C.

[0558] In some embodiments of step (4m), the brominating agent comprises N-bromosuccinimide. In some embodiments of step (4m), the solvent comprises N,N-dimethylformamide. In some embodiments of step (4m), the temperature is about 15°C to about 25°C. In some embodiments of step (4m), the temperature is about 20°C. In some embodiments of step (4m), the temperature is about 0°C to about 40°C. In some embodiments of step (4m), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C.

[0559] In some embodiments of step (4n): (i) the formamide-based reagent comprises N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal or N,N-dimethylformamide diisopropyl acetal; (ii) the solvent comprises a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal or N,N-dimethylformamide diisopropyl acetal; and / or (iii) the temperature is from about 20°C to about 150°C.

[0560] In some embodiments of step (4n), the formamide-based reagent comprises N,N-dimethylformamide dimethyl acetal. In some embodiments of step (4n), the solvent comprises N,N-dimethylformamide. In some embodiments of step (4n), the temperature is about 100°C to about 120°C. In some embodiments of step (4n), the temperature is about 110°C. In some embodiments of step (4n), the temperature is about 20°C to about 150°C. In some embodiments of step (4n), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C or about 150°C.

[0561] In some embodiments of step (4o): (i) the nitrile reagent, if present, comprises acetonitrile; (ii) the base comprises an organolithium reagent (e.g., phenyllithium, mesityllithium, tert-butyllithium, and sec-butyllithium), a Grignard reagent (e.g., isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium chloride lithium chloride complex, phenylmagnesium chloride, sec-butylmagnesium chloride, and 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex), an alkoxide base (e.g., potassium tert-butoxide and tert-butyllithium); (e.g., potassium bis(trimethylsilyl)amide) or an amide base (e.g., lithium diisopropylamide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and lithium bis(trimethylsilyl)amide); (iii) the solvent comprises an ether (e.g., tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether); and / or (iv) the temperature is from about -80°C to about 40°C.

[0562] In some embodiments of step (4o), the nitrile reagent, if present, comprises acetonitrile. In some embodiments of step (4o), the base comprises lithium bis(trimethylsilyl)amide. In some embodiments of step (4o), the solvent comprises tetrahydrofuran. In some embodiments of step (4o), the temperature is about -10°C to about 0°C. In some embodiments of step (4o), the temperature is about -80°C to about 40°C. In some embodiments of step (4o), the temperature is about -80°C, about -75°C, about -70°C, about -65°C, about 60°C, about -55°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C.

[0563] In some embodiments of step (4p): (i) the chlorinating agent comprises oxalyl chloride, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosgene, triphosgene, methanesulfonyl chloride or cyanuric chloride; (ii) the base comprises an amine base (e.g., N,N-diisopropylethylamine, 1-methylimidazole, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate) or an aromatic amine (e.g., pyridine, 2,6-lutidine and collidine); (iii) the solvent comprises an ether (e.g., 1,2-dimethoxyethane, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), an ester solvent (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene) or a polar aprotic solvent (e.g., N,N-dimethylformamide); and / or (iv) the temperature is from about 20°C to about 80°C.

[0564] In some embodiments of step (4p), the chlorinating agent comprises oxalyl chloride. In some embodiments of step (4p), the base comprises N,N-diisopropylethylamine. In some embodiments of step (4p), the solvent comprises 1,2-dimethoxyethane. In some embodiments of step (4p), the temperature is about 55°C to about 65°C. In some embodiments of step (4p), the temperature is about 60°C. In some embodiments of step (4p), the temperature is about 20°C to about 80°C. In some embodiments of step (4p), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C or about 80°C.

[0565] In some embodiments of step (4q): (i) the base comprises an amine base (e.g., N,N-diisopropylethylamine, 1-methylimidazole, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, and cesium carbonate) or an aromatic amine (e.g., pyridine, 2,6-lutidine, and collidine); (ii) the solvent comprises an alcohol ( For example, methanol, ethanol, tert-butyl alcohol, sec-butyl alcohol and isopropanol), ethers (for example, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (for example, ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), hydrocarbons (for example, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), polar aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-methyl-2-pyrrolidone and dimethyl sulfoxide) or nitriles (for example, acetonitrile, propionitrile, butyronitrile); and / or (iii) the temperature is about 20°C to about 100°C.

[0566] In some embodiments of step (4q), the base comprises N,N-diisopropylethylamine. In some embodiments of step (4q), the solvent comprises isopropanol. In some embodiments of step (4q), the temperature is about 70°C to about 80°C. In some embodiments of step (4q), the temperature is about 75°C. In some embodiments of step (4q), the temperature is about 20°C to about 100°C. In some embodiments of step (4q), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0567] Synthesis of compound 2M

[0568] In a non-limiting example, Scheme 5 shows an embodiment for preparing compound 2M. In one aspect, compound 2M is prepared by a method comprising the following steps: (5a) contacting compound 2H with a chlorinating agent, an optional amine catalyst, and an optional acidic additive in a solvent at a temperature sufficient to obtain compound 2I; (5b) contacting compound 2I with TsHNNH 2(5c) contacting compound 2J with compound 2K in a solvent in the presence of a base at a temperature sufficient to obtain compound 2L; (5d) contacting compound 2L with a base in a solvent at a temperature sufficient to obtain compound 2M.

[0569] In some embodiments of step (5a): (i) the chlorinating agent comprises sulfuryl chloride, chlorine gas or an electrophilic chlorine source (e.g., acetyl chloride / cerium ammonium nitrate, lithium diisopropylamide / 4-toluenesulfonyl chloride, iodophenyl dichloride, trichloromethanesulfonyl chloride, 1,3-dichloro-5,5-dimethylhydantoin / ammonium chloride, tetrachlorosilane / urea-hydrogen peroxide, N-chlorosuccinimide, trichloroisocyanuric acid and 3,5-dichloro-2-hydroxy-4,6-s-triazinedione sodium salt); (ii) the amine catalyst, if present, comprises a pyrrolidine-type organic catalyst (e.g., L-prolinamide and (2R,5R)-diphenylpyrrolidine); (iii) the acidic additive, if present, comprises a Bronsted acid (e.g., (e.g., methanesulfonic acid, p-toluenesulfonic acid and hydrochloric acid); (iv) the solvent comprises a carboxylic acid (e.g., acetic acid, trifluoroacetic acid and propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol and tert-butanol), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (v) the temperature is from about 30°C to about 70°C.

[0570] In some embodiments of step (5a), the chlorinating agent comprises sulfuryl chloride. In some embodiments of step (5a), there is no amine catalyst. In some embodiments of step (5a), there is no acidic additive. In some embodiments of step (5a), the solvent comprises acetic acid. In some embodiments of step (5a), the temperature is about 35°C to about 50°C. In some embodiments of step (5a), the temperature is about 30°C to about 70°C. In some embodiments of step (5a), the temperature is about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0571] In some embodiments of step (5b): (i) the solvent comprises a carboxylic acid (e.g., acetic acid, trifluoroacetic acid, propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate, and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol, and tert-butanol), a nitrile (e.g., acetonitrile, propionitrile, and butyronitrile), or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene); and / or (ii) the temperature is from about 30°C to about 70°C.

[0572] In some embodiments of step (5b), the solvent comprises acetic acid. In some embodiments of step (5b), the temperature is about 35°C to about 50°C. In some embodiments of step (5b), the temperature is about 30°C to about 70°C. In some embodiments of step (5b), the temperature is about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, or about 70°C.

[0573] In some embodiments of step (5c): (i) the base comprises a tertiary amine base (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), a hydroxide base (e.g., lithium hydroxide, potassium hydroxide, and sodium hydroxide), a carbonate base (e.g., potassium carbonate, sodium carbonate, and cesium carbonate), a bicarbonate base (e.g., sodium bicarbonate and potassium bicarbonate), a tetraalkylammonium hydroxide (e.g., tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, and choline hydroxide), an alkoxide base (e.g., sodium methoxide or potassium methoxide, sodium ethoxide, or potassium ethoxide) or a phosphate base (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate); (ii) the solvent comprises water, a nitrile (e.g., acetonitrile, propionitrile and butyronitrile), a hydrocarbon solvent (e.g., toluene, 2-methyltetrahydrofuran, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an ether solvent (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol) or a combination thereof; and / or (iii) the temperature is from about -20°C to about 60°C.

[0574] In some embodiments of step (5c), (i) the base comprises potassium carbonate. In some embodiments of step (5c), the solvent comprises 2-methyltetrahydrofuran and water or acetonitrile. In some embodiments of step (5c), the temperature is about -20°C to about 20°C. In some embodiments of step (5c), the temperature is about -20°C to about 60°C. In some embodiments of step (5c), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0575] In some embodiments of step (5d): (i) the base comprises a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, and potassium hydroxide); (ii) the solvent comprises water, a nitrile solvent (e.g., acetonitrile, propionitrile, and butyronitrile), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an ether solvent (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether), an alcohol solvent (e.g., methanol, ethanol, isopropanol, and tert-butanol), or a combination thereof; and / or (iii) the temperature is from about -10°C to about 80°C.

[0576] In some embodiments of step (5d), the alkali comprises sodium hydroxide. In some embodiments of step (5d), the solvent comprises 2-methyltetrahydrofuran and water. In some embodiments of step (5d), the temperature is about 15 ° C to about 25 ° C. In some embodiments of step (5d), the temperature is about 20 ° C. In some embodiments of step (5d), the temperature is about -10 ° C to about 80 ° C. In some embodiments of step (5d), the temperature is about -10 ° C, about -5 ° C, about 0 ° C, about 5 ° C, about 10 ° C, about 15 ° C, about 20 ° C, about 25 ° C, about 30 ° C, about 35 ° C, about 40 ° C, about 45 ° C, about 50 ° C, about 55 ° C, about 60 ° C, about 65 ° C, about 70 ° C, about 75 ° C or about 80 ° C.

[0577] Synthesis of compound 2B

[0578] In a non-limiting example, Scheme 6 shows an embodiment for preparing compound 2B. In one aspect, compound 2B is prepared by a method comprising the following steps: (6a) contacting compound 1E with a copper catalyst, an amine ligand, and an iodide additive in a solvent at a temperature sufficient to obtain compound 2O; (6b) contacting compound 2O with an alkylating agent in a solvent at a temperature sufficient to obtain compound 2P, wherein X is iodide, chloride, bromide, methylsulfate, sulfate, methylcarbonate, carbonate, mesylate, triflate, tosylate, or tetrafluoroborate; (6c) contacting compound 2P with an oxidant and a base in a solvent at a temperature sufficient to obtain compound 2B.

[0579] In some embodiments of step (6a): (i) the copper catalyst comprises copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) oxide, copper (I) acetate, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex or copper (I) bromide triphenylphosphine complex; (ii) the amine ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N3-dimethylpropane-1,3-diamine or N1-(2-aminoethyl)ethane-1,2-diamine; (iii) the iodine The iodide additive includes sodium iodide, lithium iodide or potassium iodide; (iv) the solvent includes an ether (e.g., diethylene glycol dimethyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a halogenated solvent (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (v) the temperature is from about 50°C to about 150°C.

[0580] In some embodiments of step (6a), the copper catalyst comprises copper (I) iodide. In some embodiments of step (6a), the amine ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine. In some embodiments of step (6a), the iodide additive comprises sodium iodide. In some embodiments of step (6a), the solvent comprises diethylene glycol dimethyl ether. In some embodiments of step (6a), the temperature is about 80°C to about 130°C. In some embodiments of step (6a), the temperature is about 50°C to about 150°C. In some embodiments of step (6a), the temperature is about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C or about 150°C.

[0581] In some embodiments of step (6b): (i) the alkylating agent includes iodomethane, trimethylsulfoxide iodide, diazomethane, dimethyl sulfate, 2,2-dimethoxypropane, carbonates (e.g., dimethyl carbonate and dimethyl dicarbonate), sulfonates (e.g., methyl fluorosulfonate and methyl methanesulfonate), chloromethane, bromomethane or trimethyloxonium tetrafluoroborate; (ii) the solvent includes an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butanol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a ketone (e.g., acetone and methyl ethyl ketone), an ether (e.g., ethyl acetate), or a ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about 0°C to about 100°C.

[0582] In some embodiments of step (6b), the alkylating agent comprises iodomethane. In some embodiments of step (6b), the solvent comprises acetonitrile. In some embodiments of step (6b), the temperature is about 20°C to about 40°C. In some embodiments of step (6b), the temperature is about 30°C. In some embodiments of step (6b), the temperature is about 0°C to about 100°C. In some embodiments of step (6b), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C. In some embodiments of step (6b), X is iodide.

[0583] In some embodiments of step (6c): (i) the oxidant comprises potassium ferrocyanide, potassium persulfate, lead tetraacetate, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium permonosulfate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, periodic acid, potassium bromate, m-chloroperbenzoic acid or magnesium monoperoxyphthalate; (ii) the base comprises a hydroxide base (e.g., lithium hydroxide, potassium hydroxide and ammonium hydroxide); (iii) the solvent comprises water, an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate); esters), ketones (e.g., acetone and methyl ethyl ketone), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iv) the temperature is from about 0°C to about 70°C.

[0584] In some embodiments of step (6c), the oxidant comprises potassium ferrocyanide. In some embodiments of step (6c), the base comprises potassium hydroxide. In some embodiments of step (6c), the solvent comprises water. In some embodiments of step (6c), the temperature is about 5°C to about 20°C. In some embodiments of step (6c), the temperature is about 0°C to about 70°C. In some embodiments of step (6c), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C.

[0585] Compound 1 Alternative Pathway 1

[0586] In a non-limiting example, Scheme 23 is a scheme depicting one embodiment of the alternative synthesis of Compound 1.

[0587] Solution 23

[0588]

[0589] A method for synthesizing compound 1 is a method comprising the following steps: (7a) contacting compound 2C with compound 1B in a solvent in the presence of a titanium catalyst and a base at a temperature sufficient to obtain compound 5A; and (7b) contacting compound 5A in a solvent in the presence of a catalyst and a reagent at a temperature sufficient to obtain compound 1.

[0590] In some embodiments of step (7a): (i) the titanium catalyst comprises a titanium Lewis acid (e.g., titanium (IV) tetrachloride, titanium (IV) ethoxide, or titanium (IV) isopropoxide); (ii) the base comprises a tertiary amine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, and 1,4-diazabicyclo[2.2.2]octane); (iii) ) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene) or a nitrile (e.g., acetonitrile, propionitrile and butyronitrile); and / or (iv) the temperature is from about -10°C to about 120°C.

[0591] In some embodiments of step (7a), the titanium catalyst comprises titanium (IV) tetrachloride. In some embodiments of step (7a), the base comprises 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). In some embodiments of step (7a), the solvent comprises acetonitrile. In some embodiments of step (7a), the temperature is about 40°C to about 60°C. In some embodiments of step (7a), the temperature is about 50°C. In some embodiments of step (7a), the temperature is about -10°C to about 120°C. In some embodiments of step (7a), the temperature is about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C.

[0592] In some embodiments of step (7b): (i) the catalyst comprises Sigamide ((S)-N-(3,5-di-tert-butylphenyl)-3-methyl-2-(N-formyl-N-methylamino)butanamide), Noyori-type Ru or Rh catalysts (e.g., RuCl(mesitylene) [(S,S)-Ts-DPEN] and RuCl(p-isopropyltoluene) [(R,R)-Teth-Ts-DPEN]), CBS-type catalysts, copper hydride-bis(oxadiazole) A phenazine complex with a stoichiometric amount of a reducing agent, a chiral phosphine ligand (e.g., BINAP, DIPAMP, Segphos, Phanephos, Norphos, Me-DuPhos, PPhos, Josiphos, MeBoPhoz and Chenphos) with a transition metal Pd, Ru, Rh or Ir, and a chiral formamide catalyst; (ii) the reagent includes trichlorosilane, hydrogen or a hydrogen equivalent (e.g., ammonium formate, iPrOH and formic acid-triethylamine) , chiral borane reagents (e.g., Alpine borane and ipc-borane), chiral borohydride reagents (e.g., Alpine-hydride), borane or amine π borane reagents with chiral CBS-type catalysts (e.g., borane π THF, borane π DMS, ammonia borane and diethylaniline-borane), silanes (e.g., triethoxysilane, triphenylsilane and triethylsilane) with chiral DMF or chiral copper catalysts; (iii) the solvent includes an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate) and isobutyl acetate), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), chlorinated solvents (e.g., chloroform, dichloromethane, dichloroethane and chlorobenzene), alcohols (e.g., methanol, ethanol, isopropanol, tert-butyl alcohol and 1-propanol), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iv) the temperature is from about -40°C to about 120°C.

[0593] In some embodiments of step (7b), the catalyst comprises Sigamide ((S)-N-(3,5-di-tert-butylphenyl)-3-methyl-2-(N-formyl-N-methylamino)butanamide). In some embodiments of step (7b), the reagent comprises trichlorosilane. In some embodiments of step (7b), the solvent comprises dichloromethane. In some embodiments of step (7b), the temperature is about 20°C to about 40°C. In some embodiments of step (7b), the temperature is about 30°C. In some embodiments of step (7b), the temperature is about -40°C to about 120°C. In some embodiments of step (7b), the temperature is about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C or about 120°C.

[0594] Compound 1 Alternative Pathway 2

[0595] In a non-limiting example, Scheme 24 is a scheme depicting one embodiment of the alternative synthesis 2 of Compound 1.

[0596] Solution 24

[0597]

[0598] One method for synthesizing Compound 1 is a method comprising the following steps: (8a) contacting Compound 6A with Compound 1B in a solvent in the presence of a reagent and an optional additive at a temperature sufficient to obtain Compound 1.

[0599] In some embodiments of step (8a): (i) the reagent includes a tertiary phosphine (e.g., triphenylphosphine, tributylphosphine, tri(2-furyl)phosphine, tri(p-tolyl)phosphine, and tri(o-tolyl)phosphine) and a coupling agent (e.g., diisopropyl azodicarboxylate, dicyclohexylcarbodiimide, diisopropylcarbodiimide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), carbonyldiimidazole, isobutyl chloroformate, 3-[bis(dimethylamino)methyl cation radical]-3H-benzotriazole-1-oxide hexafluorophosphate, 1-[bis(dimethylamino)methyl cation radical]-3H-benzotriazole-1-oxide hexafluorophosphate (Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N-[(7-aza-1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylammonium tetrafluoroborate N-oxide, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate, O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate fluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate, oxalyl chloride, thionyl chloride; (ii) the additive, if present, comprises 4-dimethylaminopyridine, hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole; (iii) the solvent comprises an ether (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentane methyl ether, diphenyl ether and dibutyl ether), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iv) the temperature is from about 0°C to about 100°C.

[0600] In some embodiments of step (8a), the reagent includes diisopropyl azodicarboxylate and triphenylphosphine. In some embodiments of step (8a), there is no additive. In some embodiments of step (8a), the solvent includes tetrahydrofuran. In some embodiments of step (8a), the temperature is about 20°C to about 30°C. In some embodiments of step (8a), the temperature is about 25°C. In some embodiments of step (8a), the temperature is about 0°C to about 100°C. In some embodiments of step (8a), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0601] Compound 1 Alternative Pathway 3

[0602] In a non-limiting example, Scheme 25 is a scheme depicting one embodiment of the alternative synthesis 3 of compound 1.

[0603] Solution 25

[0604]

[0605] A method for synthesizing compound 1 is a method comprising the following steps: (9a) contacting compound 6A with an activating reagent and a base in a solvent at a temperature sufficient to obtain compound 7A, wherein R is methanesulfonyl, ethylsulfonyl, toluenesulfonyl, benzenesulfonyl, 4-chlorobenzenesulfonyl or 4-nitrobenzenesulfonyl; and (9b) contacting compound 7A with compound 1B in a solvent in the presence of a base at a temperature sufficient to obtain compound 1.

[0606] In some embodiments of step (9a): (i) the activating reagent comprises methanesulfonic anhydride or a sulfonyl chloride (e.g., methanesulfonyl chloride, ethanesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, and 4-nitrobenzenesulfonyl chloride); (ii) the base comprises a tertiary amine (e.g., triethylamine, N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undecane- 7-ene and 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-dimethylpyridine and collidine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, cesium carbonate and sodium hydride), alkoxide bases (e.g., (e.g., potassium tert-butoxide and sodium tert-butoxide) or a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide); (iii) the solvent includes an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iv) the temperature is from about 0°C to about 100°C.

[0607] In some embodiments of step (9a), the activating reagent comprises mesyl chloride. In some embodiments of step (9a), the base comprises triethylamine. In some embodiments of step (9a), the solvent comprises dichloromethane. In some embodiments of step (9a), the temperature is from about 0°C to about 25°C. In some embodiments of step (9a), the temperature is from about 0°C to about 100°C. In some embodiments of step (9a), the temperature is from about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C. In some embodiments of step (9a), R is mesyl.

[0608] In some embodiments of step (9b), (i) the base comprises a tertiary amine (e.g., 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylmorpholine, tri-n-propylamine, triethylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, and collidine), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, cesium carbonate, and sodium hydride), an alkoxide base (e.g., potassium tert-butoxide and sodium tert-butoxide), or a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide); (ii) the solvent includes an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about 0°C to about 100°C.

[0609] In some embodiments of step (9b), the base comprises 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In some embodiments of step (9b), the solvent comprises dichloromethane. In some embodiments of step (9b), the temperature is about 20°C to about 30°C. In some embodiments of step (9b), the temperature is about 25°C. In some embodiments of step (9b), the temperature is about 0°C to about 100°C. In some embodiments of step (9b), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C.

[0610] Synthesis of compound 2M by substitution with ethyl pyruvate

[0611] In a non-limiting example, Scheme 11 is a scheme depicting one embodiment of the synthesis of Compound 2M by substitution with ethyl pyruvate.

[0612] Solution 11

[0613]

[0614] In some embodiments, compound 2M is prepared by a process comprising the following steps: (10a) contacting compound 10A with a chlorinating agent, an optional amine catalyst, and an optional acidic additive in an optional solvent at a temperature sufficient to obtain compound 10B; (10b) contacting compound 10B with TsHNNH 2 (10c) contacting compound 10C with compound 2K in a solvent in the presence of a base at a temperature sufficient to obtain compound 10D; (10d) contacting compound 10D with a base in a solvent at a temperature sufficient to obtain compound 2M.

[0615] In some embodiments of step (10a): (i) the chlorinating agent comprises sulfuryl chloride, chlorine gas or an electrophilic chlorine source (e.g., acetyl chloride / cerium ammonium nitrate, lithium diisopropylamide / 4-toluenesulfonyl chloride, iodophenyl dichloride, trichloromethanesulfonyl chloride, 1,3-dichloro-5,5-dimethylhydantoin / ammonium chloride, tetrachlorosilane / urea-hydrogen peroxide, N-chlorosuccinimide, trichloroisocyanuric acid and sodium dichloroisocyanurate); (ii) the amine catalyst, if present, comprises a pyrrolidine-type organic catalyst (e.g., L-prolineamide and (2R,5R)-diphenylpyrrolidine); (iii) the acidic additive, if present, comprises p-toluenesulfonic acid or a Bronsted acid (e.g., hydrochloric acid and methanesulfonic acid); acid); (iv) the solvent, if present, comprises a carboxylic acid (e.g., trifluoroacetic acid, acetic acid, formic acid, and propionic acid), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate, and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, and diphenyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol, tert-butyl alcohol), a nitrile (e.g., acetonitrile, propionitrile, and butyronitrile), or a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene); and / or (v) the temperature is from about 40° C. to about 80° C.

[0616] In some embodiments of step (10a), the chlorinating agent comprises sulfuryl chloride. In some embodiments of step (10a), there is no amine catalyst. In some embodiments of step (10a), the acidic additive comprises p-toluenesulfonic acid. In some embodiments of step (10a), there is no solvent. In some embodiments of step (10a), the temperature is about 65°C to about 75°C. In some embodiments of step (10a), the temperature is about 40°C to about 80°C. In some embodiments of step (10a), the temperature is about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C or about 80°C.

[0617] In some embodiments of step (10b): (i) the solvent comprises carboxylic acids (e.g., propionic acid, trifluoroacetic acid, acetic acid, and formic acid), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate, and isobutyl acetate), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, and diphenyl ether), chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), alcohols (e.g., methanol, ethanol, isopropanol, tert-butanol), nitriles (e.g., acetonitrile, propionitrile, and butyronitrile), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene); and / or (ii) the temperature is from about 20°C to about 60°C.

[0618] In some embodiments of step (10b), the solvent comprises propionic acid. In some embodiments of step (10b), the temperature is about 25°C. In some embodiments of step (10b), the temperature is about 20°C to about 60°C. In some embodiments of step (10b), the temperature is about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C.

[0619] In some embodiments of step (10c), (i) the base comprises a tertiary amine (e.g., N,N-diisopropylethylamine, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, and collidine) or an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, and cesium carbonate); (ii) the solvent comprises an alcohol (e.g., methanol , isopropanol, t-butyl alcohol, ethanol and 1-propanol), ethers (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl t-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), hydrocarbon solvents (e.g., benzene, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), or combinations thereof; and / or (iii) the temperature is from about -20°C to about 60°C.

[0620] In some embodiments of step (10c), the base comprises N,N-diisopropylethylamine. In some embodiments of step (10c), the solvent comprises acetonitrile and ethanol. In some embodiments of step (10c), the temperature is about 0°C to about 20°C. In some embodiments of step (10c), the temperature is about -20°C to about 60°C. In some embodiments of step (10c), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0621] In some embodiments of step (10d): (i) the base comprises a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, and potassium hydroxide) or potassium trimethylsilanolate; (ii) the solvent comprises water, an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether), an alcohol (e.g., methanol, ethanol, isopropanol, tert-butyl alcohol, and 1-propanol), a hydrocarbon solvent (e.g., benzene, toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene), a nitrile (e.g., acetonitrile, propionitrile, and butyronitrile), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), or a combination thereof; and / or (iii) the temperature is from about 0°C to about 100°C.

[0622] In some embodiments of step (10d), the alkali comprises sodium hydroxide. In some embodiments of step (10d), the solvent comprises ethanol and water. In some embodiments of step (10d), the temperature is from about 10°C to about 70°C. In some embodiments of step (10d), the temperature is from about 0°C to about 100°C. In some embodiments of step (10d), the temperature is from about 0°C to about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0623] Synthesis of compound 2L via click chemistry substitution

[0624] In a non-limiting example, Scheme 12 is a scheme depicting one embodiment of the synthesis of Compound 2L via click chemistry substitution.

[0625] Solution 12

[0626]

[0627] In some embodiments, compound 2L is prepared by a process comprising the following steps: (11a) contacting compound 2K with an azide reagent and a base in a solvent at a temperature sufficient to obtain compound 1D; (11b) contacting compound 1D with

[0628]

[0629] The copper reagent and optional reagent are contacted in a solvent at a temperature sufficient to provide compound 2L.

[0630] In some embodiments of step (11a): (i) the azide reagent comprises 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP), imidazole-1-sulfonyl azide hydrochloride, imidazole-1-sulfonyl azide sulfate, imidazole-1-sulfonyl azide tetrafluoroborate or p-toluenesulfonyl azide; (ii) the base comprises a tertiary amine (e.g., N,N-diisopropylethylamine, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), diethylamine or dibutylamine; (iii) the solvent comprises ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), alcohols (e.g., methanol, ethanol, isopropanol and tert-butanol), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or hydrocarbon solvents (e.g., trifluorotoluene, toluene, cyclohexane, n-heptane and xylene); and / or (iv) the temperature is from about 0°C to about 50°C.

[0631] In some embodiments of step (11a), the azide reagent comprises 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP). In some embodiments of step (11a), the base comprises N,N-diisopropylethylamine. In some embodiments of step (11a), the solvent comprises acetonitrile. In some embodiments of step (11a), the temperature is about 20°C. In some embodiments of step (11a), the temperature is about 0°C to about 50°C. In some embodiments of step (11a), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C.

[0632] In some embodiments, step (11a) is performed in batch mode. In some embodiments, compound 2K is contacted with an azide reagent and a base in a solvent at a certain temperature to obtain a stoichiometric amount of compound 1D. In some embodiments, producing a stoichiometric amount of compound 1D comprises adding compound 2K, an azide reagent, a base and a solvent to a batch reactor at the same time. In some embodiments, a stoichiometric amount of compound 1D is contacted with azide reagent and a base in a solvent at a certain temperature to obtain a stoichiometric amount of compound 1D.

[0633]

[0634] The copper reagent and optional reagent are contacted in a solvent at a temperature sufficient to provide compound 2L.

[0635] In some embodiments, step (11a) is performed in a continuous flow process. In some embodiments, compound 2K, an azide reagent, a base, and a solvent are added to a continuous flow reactor to produce compound 1D. In some embodiments, compound 1D is reacted with

[0636]

[0637] The copper reagent and optional reagents are contacted in a solvent at a temperature sufficient to provide compound 2L. In some embodiments, compound ID produced in a continuous flow reactor is continuously fed to a batch reactor containing methyl propiolate, copper reagent, sodium ascorbate, solvent, and optional reagents to provide compound 2L.

[0638] In some embodiments, step (11a) is carried out as follows to obtain compound 2L in a continuous flow process. In some embodiments, methyl propiolate, copper sulfate, sodium ascorbate, toluene and water are added to the reactor. In some embodiments, compound 2K, diisopropylethylamine and acetonitrile are mixed in a second container. In some embodiments, 2-azido-1,3-dimethylimidazoline hexafluorophosphate (ADMP) and acetonitrile are mixed in a third container. In some embodiments, the mixture containing compound 2K and ADMP in the second container and the third container, respectively, is mixed in a tubular or continuous flow reactor to form compound 1D, and the resulting mixture containing compound 2L is collected in the first reactor containing methyl propiolate.

[0639] Compound 2A was synthesized from ethyl 1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazole-4-carboxylate

[0640] In a non-limiting example, Scheme 13 is a scheme depicting one embodiment of the substitutional synthesis of Compound 2A from ethyl 1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazole-4-carboxylate (Compound 10D).

[0641] Solution 13

[0642]

[0643] In some embodiments, compound 2A is prepared by a method comprising: (12a) contacting compound 10D with MeNHOMe·HCl and a base in a solvent at a temperature sufficient to obtain compound 2A;

[0644] In some embodiments of step (12a): (i) the base comprises an organomagnesium reagent (e.g., isopropylmagnesium chloride, tert-butylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium chloride lithium chloride complex and 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex), an organolithium reagent (e.g., phenyllithium, mesityllithium, tert-butyllithium and sec-butyllithium) or an amide base (e.g., lithium bis(trimethylsilyl)amide, lithium diisopropylamide, (ii) the solvent comprises an ether (e.g., tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether) or a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iii) the temperature is from about -40°C to about 60°C.

[0645] In some embodiments of step (12a), the base comprises lithium bis(trimethylsilyl)amide. In some embodiments of step (12a), the solvent comprises tetrahydrofuran. In some embodiments of step (12a), the temperature is about -10°C to about 10°C. In some embodiments of step (12a), the temperature is about -40°C to about 60°C. In some embodiments of step (12a), the temperature is about -40°C, about -35°C, about -30°C, about -35°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0646] Alternative Synthesis of Ethyl 1-(Bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazole-4-carboxylate (Compound 10D)

[0647] In a non-limiting example, Scheme 14 is a scheme depicting one embodiment of an alternative synthesis of ethyl 1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazole-4-carboxylate (Compound 10D).

[0648] Solution 14

[0649]

[0650] In some embodiments, compound 10D is prepared by a process comprising: (13a) contacting compound 13A with compound 2K and an acid in a solvent at a temperature sufficient to yield compound 10D.

[0651] In some embodiments of step (13a): (i) the acid comprises acetic acid, trifluoroacetic acid, benzoic acid, pivalic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, propionic acid; (ii) the solvent comprises an alcohol (e.g., methanol, ethanol, isopropanol and tert-butanol), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether) or a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide); and / or (iii) the temperature is from about 0°C to about 60°C.

[0652] In some embodiments of step (13a), the acid comprises acetic acid. In some embodiments of step (13a), the solvent comprises ethanol. In some embodiments of step (13a), the temperature is about 35°C. In some embodiments of step (13a), the temperature is about 0°C to about 60°C. In some embodiments of step (13a), the temperature is about -40°C to about 60°C. In some embodiments of step (12a), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0653] Alternative Synthesis of 5-Iodoisoquinoline (Compound 2O)

[0654] In a non-limiting example, Scheme 15 is a scheme depicting one embodiment of an alternative synthesis of 5-iodoisoquinoline (Compound 20).

[0655] Solution 15

[0656]

[0657] In some embodiments, compound 20 is prepared by a process comprising: (14a) contacting compound 14A with an iodide reagent in a solvent at a temperature sufficient to yield compound 20.

[0658] In some embodiments of step (14a): (i) the iodide reagent comprises N-iodosuccinimide, iodine, iodine and iodic acid, bis(pyridinium)iodonium(I) tetrafluoroborate, sodium iodide and bleach, sodium iodide and an oxidizing agent (e.g., potassium persulfate, sodium periodate and periodic acid), 1,3-diiodo-5,5-dimethylhydantoin, iodine monochloride, pyridinium iodine monochloride; (ii) the solvent comprises trifluoromethanesulfonic acid, sulfuric acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, an acid in combination with water, dimethylformamide, methanol, acetonitrile, dichloromethane, tetrahydrofuran or toluene; and / or (iii) the temperature is from about -30°C to about 60°C.

[0659] In some embodiments of step (14a), the iodide reagent includes N-iodosuccinimide. In some embodiments of step (14a), the solvent includes trifluoromethanesulfonic acid. In some embodiments of step (14a), the temperature is about -20°C to about 0°C. In some embodiments of step (14a), the temperature is about -30°C to about 60°C. In some embodiments of step (14a), the temperature is about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C or about 60°C.

[0660] Alternative synthesis of compound 2B

[0661] Scheme 16 is a scheme depicting one embodiment of an alternative synthesis of compound 2B.

[0662] Scheme 16

[0663]

[0664] In some embodiments, compound 2B is prepared by a process comprising the steps of: (15a) contacting compound 4D with a copper catalyst, an amine ligand, and an iodide additive in a solvent at a temperature sufficient to obtain compound 2B.

[0665] In some embodiments of step (15a): (i) the copper catalyst comprises copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (I) oxide, copper acetate, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex or copper (I) bromide triphenylphosphine complex; (ii) the amine ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine, N,N'-dimethylethane-1,2-diamine, N,N'-dimethylpropane-1,3-diamine or N1-(2-aminoethyl)ethane-1,2-diamine; (iii) the iodide The additive includes sodium iodide, lithium iodide or potassium iodide; (iv) the solvent includes an ether (e.g., diethylene glycol dimethyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a halogenated solvent (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (v) the temperature is from about 50°C to about 150°C.

[0666] In some embodiments of step (15a), the copper catalyst comprises copper (I) iodide. In some embodiments of step (15a), the amine ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine. In some embodiments of step (15a), the iodide additive comprises sodium iodide. In some embodiments of step (15a), the solvent comprises diethylene glycol dimethyl ether. In some embodiments of step (15a), the temperature is about 80°C to about 130°C. In some embodiments of step (15a), the temperature is about 50°C to about 150°C. In some embodiments of step (15a), the temperature is about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C or about 150°C.

[0667] Alternative synthesis of compound 2C

[0668] In a non-limiting example, Scheme 17 is a scheme depicting one embodiment of an alternative synthesis of Compound 2C.

[0669] Solution 17

[0670]

[0671] In some embodiments, compound 2C is prepared by a method comprising the following steps: (16a) contacting compound 1A with a base in a solvent at a temperature sufficient to obtain compound 16A; (16b) contacting compound 16A with compound 1D in a solvent in the presence of a copper catalyst and an optional reagent at a temperature sufficient to obtain compound 6A; (16c) contacting compound 6A in a solvent in the presence of an oxidant and an optional base at a temperature sufficient to obtain compound 2C.

[0672] In some embodiments of step (16a): (i) the base comprises a hydroxide base (e.g., potassium hydroxide, lithium hydroxide, sodium hydroxide, and ammonium hydroxide) or a carbonate base (e.g., sodium carbonate, potassium carbonate, and cesium carbonate); (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether), an alcohol (e.g., ethylene glycol, propylene glycol, methanol, ethanol, isopropanol, and tert-butyl alcohol), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), or a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide); and / or (iii) the temperature is from about 0°C to about 50°C.

[0673] In some embodiments of step (16a), the base comprises potassium hydroxide. In some embodiments of step (16a), the solvent comprises tetrahydrofuran. In some embodiments of step (16a), the temperature is about 15°C to about 30°C. In some embodiments of step (16a), the temperature is about 0°C to about 50°C. In some embodiments of step (16a), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C.

[0674] In some embodiments of step (16b), (i) the copper catalyst comprises copper (II) sulfate, copper (II) acetate, copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate toluene complex, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex, copper (I) bromide triphenylphosphine complex; (ii) the reagent, if present, comprises sodium ascorbate; (iii) the solvent comprises water, an ether (e.g., 2-methyltetrahydrofuran, diethyl ether, 1,4-dihydrogen iodide, heterocyclohexane, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), alcohols (e.g., methanol, ethanol, isopropanol and tert-butanol), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iv) the temperature is from about 0°C to about 50°C.

[0675] In some embodiments of step (16b), the copper catalyst comprises copper (II) sulfate. In some embodiments of step (16b), the reagent, if present, comprises sodium ascorbate. In some embodiments of step (16b), the solvent comprises 2-methyltetrahydrofuran, acetonitrile and / or water. In some embodiments of step (16b), the temperature is about 20°C. In some embodiments of step (16b), the temperature is about 0°C to about 50°C. In some embodiments of step (16b), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C or about 50°C.

[0676] In some embodiments of step (16c), (i) the oxidant comprises Dess-Martin periodinane (DMP), dimethyl sulfoxide and an activator (e.g., oxalyl chloride, cyanuric chloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, methyl chloroglyoxylate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride, trichloroacetonitrile, 2-chloro-1,2-dimethylimidazolinium chloride, polyphosphoric acid, phosphorus trichloride, phosphorus pentoxide, triphenylphosphine dichloride, triphenylphosphine dibromide, phosphorus oxychloride, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl dichlorophosphate, diphenyl chlorophosphate, diethyl chlorophosphate and ethoxyacetylene), TEMPO / bleach, chromium trioxide or 2-iodoacetylbenzoic acid; (ii) the base, if present, includes a tertiary amine (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine and trimethylol pyridine), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate and cesium carbonate) or a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide and ammonium hydroxide); (iii) the solvent includes an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), a ketone (e.g., acetone and methyl ethyl ketone), an ether (e.g., diethyl ether, 1 , 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or halogenated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iv) the temperature is from about -20°C to about 100°C.

[0677] In some embodiments of step (16c), the oxidant comprises Dess-Martin periodinane. In some embodiments of step (16c), there is no base. In some embodiments of step (16c), the solvent comprises dichloromethane. In some embodiments of step (16c), the temperature is about 25°C. In some embodiments of step (16c), the temperature is about -20°C to about 100°C. In some embodiments of step (16c), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0678] In some embodiments, compound 1D is prepared by a process comprising: (16d) contacting compound 2K with an azide reagent and a base in a solvent at a temperature sufficient to yield compound 1D.

[0679] In some embodiments of step (16d): (i) the azide reagent comprises 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP), imidazole-1-sulfonyl azide hydrochloride, imidazole-1-sulfonyl azide sulfate, imidazole-1-sulfonyl azide tetrafluoroborate or p-toluenesulfonyl azide; (ii) the base comprises a tertiary amine (e.g., N,N-diisopropylethylamine, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), diethylamine or dibutylamine; (iii) the solvent comprises ether (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), alcohols (e.g., methanol, ethanol, isopropanol and tert-butanol), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iv) the temperature is from about 0°C to about 50°C.

[0680] In some embodiments of step (16d), the azide reagent comprises 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP). In some embodiments of step (16d), the base comprises N,N-diisopropylethylamine. In some embodiments of step (16d), the solvent comprises acetonitrile. In some embodiments of step (16d), the temperature is about 20°C. In some embodiments of step (16d), the temperature is about 0°C to about 50°C. In some embodiments of step (16d), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C.

[0681] In some embodiments, steps (16d) and (16b) are performed in batch mode. In some embodiments, compound 2K is contacted with an azide reagent and a base in a solvent at a certain temperature to obtain a stoichiometric amount of compound 1D. In some embodiments, the generation of a stoichiometric amount of compound 1D includes adding compound 2K, an azide reagent, a base and a solvent to a batch reactor at the same time. In some embodiments, a stoichiometric amount of compound 1D is contacted with compound 16A, a copper catalyst and an optional reagent in a solvent at a temperature sufficient to obtain compound 6A.

[0682] In some embodiments, steps (16d) and (16b) are performed in a continuous flow process. In some embodiments, compound 2K, an azide reagent, a base and a solvent are added to a continuous flow reactor to produce compound 1D. In some embodiments, compound 1D is contacted with compound 16A, a copper catalyst and an optional reagent in a solvent in a batch reactor, and the temperature during contact is sufficient to obtain compound 6A. In some embodiments, the compound 1D produced in the continuous flow reactor is continuously fed into a batch reactor containing compound 16A, a copper catalyst, sodium ascorbate, a solvent and an optional reagent to obtain compound 6A.

[0683] Alternative synthesis of compound 6A 1

[0684] In a non-limiting example, Scheme 18 is a scheme depicting one embodiment of the Alternative Synthesis 1 of Compound 6A.

[0685] Scheme 18

[0686]

[0687] In some embodiments, compound 6A is prepared by a method comprising the following steps: (17a) contacting compound 1A with compound 1D in a solvent in the presence of a copper catalyst and an optional reagent at a temperature sufficient to obtain compound 17A; (17b) contacting compound 17A in a solvent in the presence of a base at a temperature sufficient to obtain compound 6A.

[0688] In some embodiments of step (17a), (i) the copper catalyst comprises copper (II) sulfate, copper (II) acetate, copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate toluene complex, copper (I) iodide, copper (I) iodide tetrabutylammonium iodide complex, tetrakis (acetonitrile) copper (I) hexafluorophosphate, copper (I) iodide triethylphosphite complex or copper (I) bromide triphenylphosphine complex; (ii) the reagent, if present, comprises sodium ascorbate; (iii) the solvent comprises water, an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, (e.g., 1,2-dimethylformamide, 1,2-dimethylacetamide, 1,2-dimethylpyrrolidone, and 1,2-dimethylsulfoxide), nitriles (e.g., acetonitrile, propionitrile, and butyronitrile), or hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane, and xylene), or combinations thereof; and / or (iv) the temperature is from about 0° C. to about 50° C.

[0689] In some embodiments of step (17a), the copper catalyst comprises copper (II) sulfate. In some embodiments of step (17a), the reagent, if present, comprises sodium ascorbate. In some embodiments of step (17a), the solvent comprises 2-methyltetrahydrofuran, acetonitrile and / or water. In some embodiments of step (17a), the temperature is about 20°C. In some embodiments of step (17a), the temperature is about 0°C to about 50°C. In some embodiments of step (17a), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C or about 50°C.

[0690] In some embodiments of step (17b): (i) the base comprises a hydroxide base (e.g., potassium hydroxide, lithium hydroxide, sodium hydroxide, and ammonium hydroxide) or a carbonate base (e.g., sodium carbonate, potassium carbonate, and cesium carbonate); (ii) the solvent comprises an ether (e.g., tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, and dibutyl ether), an alcohol (e.g., ethylene glycol, propylene glycol, methanol, ethanol, isopropanol, and tert-butyl alcohol), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane, and chlorobenzene), or a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide); and / or (iii) the temperature is from about 0°C to about 50°C.

[0691] In some embodiments of step (17b), the base comprises potassium hydroxide. In some embodiments of step (17b), the solvent comprises tetrahydrofuran. In some embodiments of step (17b), the temperature is about 10°C to about 30°C. In some embodiments of step (17b), the temperature is about 0°C to about 50°C. In some embodiments of step (17b), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C.

[0692] In some embodiments, compound 1D is prepared by a process comprising: (17c) contacting compound 2K with an azide reagent and a base in a solvent at a temperature sufficient to yield compound 1D.

[0693] In some embodiments of step (17c): (i) the azide reagent comprises 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP), imidazole-1-sulfonyl azide hydrochloride, imidazole-1-sulfonyl azide sulfate, imidazole-1-sulfonyl azide tetrafluoroborate or p-toluenesulfonyl azide; (ii) the base comprises a tertiary amine (e.g., N,N-diisopropylethylamine, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane), diethylamine or dibutylamine; (iii) the solvent comprises ether (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), alcohols (e.g., methanol, ethanol, isopropanol and tert-butanol), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), nitriles (e.g., acetonitrile, propionitrile and butyronitrile) or hydrocarbon solvents (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iv) the temperature is from about 0°C to about 50°C.

[0694] In some embodiments of step (17c), the azide reagent comprises 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP). In some embodiments of step (17c), the base comprises N,N-diisopropylethylamine. In some embodiments of step (17c), the solvent comprises acetonitrile. In some embodiments of step (17c), the temperature is about 20°C. In some embodiments of step (17c), the temperature is about 0°C to about 50°C. In some embodiments of step (17c), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C.

[0695] In some embodiments, steps (17c) and (17a) are performed in batch mode. In some embodiments, compound 2K is contacted with an azide reagent and a base in a solvent at a certain temperature to obtain a stoichiometric amount of compound 1D. In some embodiments, the generation of a stoichiometric amount of compound 1D includes adding compound 2K, an azide reagent, a base and a solvent to a batch reactor at the same time. In some embodiments, a stoichiometric amount of compound 1D is contacted with compound 1A, a copper catalyst and an optional reagent in a solvent at a temperature sufficient to obtain compound 17A.

[0696] In some embodiments, steps (17c) and (17a) are performed in a continuous flow process. In some embodiments, compound 2K, an azide reagent, a base, and a solvent are added to a continuous flow reactor to produce compound 1D. In some embodiments, compound 1D is contacted with compound 1A, a copper catalyst, and an optional reagent in a solvent in a batch reactor, and the temperature during contact is sufficient to obtain compound 17A. In some embodiments, compound 1D produced in a continuous flow reactor is continuously fed into a batch reactor containing compound 1A, a copper catalyst, sodium ascorbate, a solvent, and an optional reagent to obtain compound 17A.

[0697] Alternative synthesis of compound 6A 2

[0698] In a non-limiting example, Scheme 19 is a scheme depicting one embodiment of Alternative Synthesis 2 of Compound 6A.

[0699] Solution 19

[0700]

[0701] In some embodiments, compound 6A is prepared by a process comprising: (18a) contacting compound 2B with compound 18A in a solvent in the presence of an organometallic reagent at a temperature sufficient to yield compound 6A.

[0702] In some embodiments of step (18a): (i) the organometallic reagent comprises an organomagnesium reagent (e.g., isopropylmagnesium chloride lithium chloride complex, butylmagnesium chloride, tert-butylmagnesium chloride, isopropylmagnesium chloride, sec-butylmagnesium chloride lithium chloride complex, isopropylmagnesium bromide and ethylmagnesium bromide); (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene) or a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about -20°C to about 50°C.

[0703] In some embodiments of step (18a), the organometallic reagent comprises isopropylmagnesium chloride lithium chloride complex. In some embodiments of step (18a), the solvent comprises tetrahydrofuran. In some embodiments of step (18a), the temperature is from about 0°C to about 50°C. In some embodiments of step (18a), the temperature is from about -20°C to about 50°C. In some embodiments of step (18a), the temperature is from about -20°C to about 50°C. In some embodiments of step (18a), the temperature is from about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C or about 50°C.

[0704] Alternative synthesis of compound 6A 3

[0705] In a non-limiting example, Scheme 20 is a scheme depicting one embodiment of the Alternative Synthesis 3 of Compound 6A.

[0706] Solution 20

[0707]

[0708] In some embodiments, compound 6A is prepared by a process comprising: (19a) contacting compound 2C with a catalyst and a hydride source in a solvent at a temperature sufficient to yield compound 6A.

[0709] In some embodiments of step (19a): (i) the catalyst comprises (R)-(–)-2-methyl-CBS-oxazaborolidine, (R)-(+)-o-tolyl-CBS-oxazaborolidine, (R)-(+)-2-butyl-CBS-oxazaborolidine, trans-RuCl 2 [(R)-xylbinap]-[(R)-diapen], RuBr 2 [(R)-BINAP], [RuCl(PhH)(R)-BINAP)]Cl, RuCl(p-isopropyltoluene)[(S,S)-Ts-DPEN], RuCl(mesitylene)[(S,S)-Ts-DPEN], RuBF 4(i) the hydride source comprises borane N,N-diethylaniline complex, borane dimethyl sulfide complex, borane tetrahydrofuran complex, borane trimethylamine complex, borane triethylamine complex, catechol borane, hydrogen, formic acid / triethylamine or 2-propanol; (ii) the hydride source comprises borane N,N-diethylaniline complex, borane dimethyl sulfide complex, borane tetrahydrofuran complex, borane trimethylamine complex, borane triethylamine complex, catechol borane, hydrogen, formic acid / triethylamine or 2-propanol; (iii) the solvent comprises ether (e.g., tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), hydrocarbon solvents (e.g., n-hexane, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene) or nitriles (e.g., acetonitrile, propionitrile and butyronitrile); and / or (iv) the temperature is from about -20°C to about 50°C.

[0710] In some embodiments of step (19a), the catalyst comprises (R)-(-)-2-methyl-CBS-oxazaborolidine. In some embodiments of step (19a), the hydride source comprises borane N,N-diethylaniline complex. In some embodiments of step (19a), the solvent comprises tetrahydrofuran. In some embodiments of step (19a), the temperature is about 0°C to about 20°C. In some embodiments of step (19a), the temperature is about -20°C to about 50°C. In some embodiments of step (19a), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C.

[0711] Alternative synthesis of compound 2E

[0712] In a non-limiting example, Scheme 21A is a scheme depicting one embodiment of an alternative synthesis of Compound 2E.

[0713] Scheme 21A

[0714]

[0715] In some embodiments, compound 2E is prepared by a method comprising the following steps: (20a) contacting compound 10D with morpholine and a reducing agent in a solvent at a temperature sufficient to obtain compound 18A; (20b) contacting compound 18A with morpholine in the presence of a catalyst.

[0716]

[0717] The step of contacting in a solvent at a temperature sufficient to obtain Compound 20A; (20c) contacting Compound 20A with Compound 2B in a solvent in the presence of an organometallic reagent at a temperature sufficient to obtain Compound 20B and Compound 2E.

[0718] In some embodiments of step (20a): (i) the reducing agent comprises borane dimethyl sulfide complex, NaBH 4 / I 2 , amine-borane complexes (e.g., ammonia borane and diethylaniline-borane), borohydride reagents (e.g., sodium borohydride, lithium borohydride, potassium borohydride, lithium triethylborohydride and potassium tri-sec-butylborohydride), aluminum hydride reagents (e.g., diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium tri-tert-butoxyaluminum hydride and lithium tri[(3-ethyl-3-pentyl)oxy]aluminum hydride), hydrogen, formic acid / triethylamine, 2-propanol; (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene) or a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iii) the temperature is from about -20°C to about 30°C.

[0719] In some embodiments of step (20a), the reducing agent comprises diisobutylaluminum hydride. In some embodiments of step (20a), the solvent comprises tetrahydrofuran. In some embodiments of step (20a), the temperature is about 0°C to about 20°C. In some embodiments of step (20a), the temperature is about -20°C to about 30°C. In some embodiments of step (20a), the temperature is about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, or about 30°C.

[0720] In some embodiments of step (20b): (i) the catalyst comprises titanium (IV) isopropoxide, magnesium sulfate, cesium carbonate, potassium carbonate, sodium carbonate or a hydroxide base (e.g., potassium hydroxide, lithium hydroxide and sodium hydroxide); (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene) or a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iii) the temperature is from about 0°C to about 30°C.

[0721] In some embodiments of step (20b), the catalyst comprises titanium (IV) isopropoxide. In some embodiments of step (20b), the solvent comprises tetrahydrofuran. In some embodiments of step (20b), the temperature is about 20°C. In some embodiments of step (20b), the temperature is about 0°C to about 30°C. In some embodiments of step (20b), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, or about 30°C.

[0722] In some embodiments of step (20c): (i) the organometallic reagent comprises an organomagnesium reagent (e.g., isopropylmagnesium chloride lithium chloride complex, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, sec-butylmagnesium chloride lithium chloride complex, as well as isopropylmagnesium chloride, isopropylmagnesium bromide, ethylmagnesium bromide); (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a chlorinated solvent (e.g., chloroform, dichloromethane, dichloroethane and chlorobenzene) or a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iii) the temperature is from about -78°C to about 40°C.

[0723] In some embodiments of step (20c), the organometallic reagent includes isopropylmagnesium chloride lithium chloride complex. In some embodiments of step (20c), the solvent includes dichloromethane. In some embodiments of step (20c), the temperature is about 0°C to about 20°C. In some embodiments of step (20c), the temperature is about -78°C to about 40°C. In some embodiments of step (20c), the temperature is about -78°C, about -75°C, about -70°C, about -65°C, about -60°C, about -55°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C.

[0724] In a non-limiting example, Scheme 21B is a scheme depicting one embodiment of an alternative synthesis of compound 3C.

[0725] Scheme 21B

[0726]

[0727] In some embodiments, compound 3C is prepared by a method comprising the following steps: (20d) reacting compound 18A with

[0728]

[0729] The step of contacting in a solvent at a temperature sufficient to obtain compound 20C; (20e) contacting compound 20C with compound 2B in a solvent in the presence of an organometallic reagent at a temperature sufficient to obtain compound 3C and compound 20D.

[0730] In some embodiments of step (20d): (i) the catalyst comprises titanium (IV) isopropoxide, magnesium sulfate, cesium carbonate, potassium carbonate, sodium carbonate or a hydroxide base (e.g., potassium hydroxide, lithium hydroxide and sodium hydroxide); (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene) or a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iii) the temperature is from about 0°C to about 30°C.

[0731] In some embodiments of step (20d), the catalyst comprises titanium (IV) isopropoxide. In some embodiments of step (20d), the solvent comprises tetrahydrofuran. In some embodiments of step (20d), the temperature is about 20°C. In some embodiments of step (20d), the temperature is about 0°C to about 30°C. In some embodiments of step (20d), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, or about 30°C.

[0732] In some embodiments of step (20e): (i) the organometallic reagent comprises an organomagnesium reagent (e.g., isopropylmagnesium chloride lithium chloride complex, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, sec-butylmagnesium chloride lithium chloride complex, isopropylmagnesium chloride, isopropylmagnesium bromide and ethylmagnesium bromide); (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a chlorinated solvent (e.g., chloroform, dichloromethane, dichloroethane and chlorobenzene) or a hydrocarbon (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene); and / or (iii) the temperature is from about -78°C to about 40°C.

[0733] In some embodiments of step (20e), the organometallic reagent includes isopropylmagnesium chloride lithium chloride complex. In some embodiments of step (20e), the solvent includes dichloromethane. In some embodiments of step (20e), the temperature is about 0°C to about 20°C. In some embodiments of step (20e), the temperature is about -78°C to about 40°C. In some embodiments of step (20e), the temperature is about -78°C, about -75°C, about -70°C, about -65°C, about -60°C, about -55°C, about -50°C, about -45°C, about -40°C, about -35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, about -5°C, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C.

[0734] Alternative Synthesis of Compound 2F Salt

[0735] In a non-limiting example, Scheme 22 is a scheme depicting one embodiment of an alternative synthesis of Compound 2F (salt form).

[0736] Solution 22

[0737]

[0738] In some embodiments, compound 2F is prepared by a method comprising the following steps: (21a) reacting compound 2C with HONH in the presence of a base. 2 (21c) contacting compound 21B with a chiral acid in a solvent at a temperature sufficient to obtain a salt of compound 2F.

[0739] In some embodiments of step (21a): (i) the base comprises a tertiary amine (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium acetate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, and cesium carbonate), an alkoxide base (e.g., potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide) or a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide, and ammonium hydroxide) or an aromatic amine (e.g., pyridine, 2,6-lutidine, and collidine). (ii) the solvent comprises an alcohol solvent (e.g., methanol, ethanol, isopropanol and tert-butanol), an ester (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a polar aprotic solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), a hydrocarbon solvent (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile) or a halogenated solvent (e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene and dibromoethane); and / or (iii) the temperature is from about 0°C to about 120°C.

[0740] In some embodiments of step (21a), the base comprises pyridine. In some embodiments of step (21a), the solvent comprises ethanol. In some embodiments of step (21a), the temperature is about 80°C. In some embodiments of step (21a), the temperature is about 0°C to about 120°C. In some embodiments of step (21a), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C or about 120°C.

[0741] In some embodiments of step (21b): (i) the reagents include a Lewis acid (e.g., zirconium tetrachloride, zirconium tetrachloride / aluminum oxide, titanium tetrachloride) with a borohydride (e.g., sodium cyanoborohydride and sodium borohydride), a hydride (e.g., lithium aluminum hydride), a borane with lithium chloride and Amberlyst 15, a metal (e.g., zinc, magnesium, sodium) with an acid (e.g., hydrochloric acid, acetic acid, Amberlyst 15, ammonium formate), a metal (e.g., zinc) and a base (e.g., sodium hydroxide and ammonia), samarium (II) iodide and a base (e.g., potassium hydroxide), or a palladium catalyst (e.g., palladium on carbon) and a proton source (e.g., hydrogen, hydrochloric acid, acetic acid and ammonium formate); (ii) the solvent includes alcohols (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), water, ethers (e.g., tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dimethoxyethane). butyl ether), esters (e.g., ethyl acetate, isopropyl acetate, n-propyl acetate and isobutyl acetate), ketones (e.g., acetone and methyl ethyl ketone), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide), hydrocarbons (e.g., toluene, trifluorotoluene, cyclohexane, n-heptane and xylene) or chlorinated solvents (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene); and / or (iii) the temperature is from about 0°C to about 100°C.

[0742] In some embodiments of step (21b), the reagent comprises zinc and hydrochloric acid. In some embodiments of step (21b), the solvent comprises tetrahydrofuran. In some embodiments of step (21b), the temperature is about 60°C. In some embodiments of step (21b), the temperature is about 0°C to about 100°C. In some embodiments of step (21b), the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C or about 100°C.

[0743] In some embodiments of step (21c): (i) the chiral acid comprises N-acetyl-L-leucine, (R)-mandelic acid, lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1R,3S)-(+)-camphoric acid, (1S)-(+)-camphor-10-sulfonic acid, (R)-(+)-N-(1-phenylethyl)succinamic acid, benzyloxycarbonyl-L-proline, dibenzoyl-L-tartaric acid, (R)-(+)-3-methyladipic acid, (+)-menthoxyacetic acid, (-)-pyroglutamic acid, N-Boc-D-leucine, N-(+)-Boc-phenylalanine, (-)-quinic acid, (+)-n-acetyl-L-phenylalanine acid, (+)-N-Boc-isoleucine, L-(-)-acetylglutamic acid or (-)-acetylmandelic acid; (ii) the solvent comprises an ether (e.g., diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether and dibutyl ether), a hydrocarbon solvent (e.g., benzene, toluene, trifluorotoluene, cyclohexane, n-heptane and xylene), a chlorinated solvent (e.g., dichloromethane, chloroform, dichloroethane and chlorobenzene), an alcohol (e.g., methanol, ethanol, isopropanol and tert-butyl alcohol), a ketone (e.g., acetone, methyl ethyl ketone and methyl isobutyl ketone), a nitrile (e.g., acetonitrile, propionitrile and butyronitrile), water or a mixture thereof; and / or (iii) the temperature is from about 10°C to about 70°C. In some embodiments of step (21c), compound 2F is produced with a chiral purity of 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 95%, or at least greater than about 99%.

[0744] In some embodiments of step (21c), the chiral acid comprises N-acetyl-L-leucine. In some embodiments of step (21c), the solvent comprises acetonitrile and water. In some embodiments of step (21c), the temperature is from about 40°C to about 60°C. In some embodiments of step (21c), the temperature is from about 10°C to about 70°C. In some embodiments of step (21b), the temperature is from about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C or about 70°C. In some embodiments of step (21c), compound 2F is produced with a chiral purity of at least greater than about 95%.

[0745] In a non-limiting example, Scheme 26 is a scheme depicting one embodiment of an alternative synthesis of Compound 2F. In a non-limiting example, Scheme 26 is a scheme depicting one embodiment of the synthesis of Compound 1.

[0746] Scheme 26

[0747]

[0748] One method for synthesizing compound 1 comprises the following steps: (22a) contacting compound 2A with compound 2B in a solvent in the presence of an organometallic reagent and a Lewis base at a temperature sufficient to obtain compound 2C; (22b) contacting compound 2C with a titanium- or zirconium-based reagent in the presence of a titanium- or zirconium-based reagent.

[0749]

[0750] (22c) contacting compound 3B with a reducing agent and optionally a ruthenium, palladium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 3C; (22d) contacting compound 3C with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (22e) contacting compound 2F with compound 2G in a solvent in the presence of a palladium catalyst and a base at a temperature sufficient to obtain compound 1.

[0751] One method for synthesizing compound 1 comprises the following steps: (22a) contacting compound 2A with compound 2B in a solvent in the presence of an organometallic reagent and a Lewis base at a temperature sufficient to obtain compound 2C; (22b) contacting compound 2C with a titanium- or zirconium-based reagent in the presence of a titanium- or zirconium-based reagent.

[0752]

[0753] (22c) contacting compound 3B with a reducing agent and optionally a ruthenium, palladium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 3C; (22d) contacting compound 3C with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (22e) contacting compound 2F with compound 2G in a solvent in the presence of a copper catalyst, a copper catalyst ligand and a base at a temperature sufficient to obtain compound 1.

[0754] In a non-limiting example, Scheme 27 is a scheme depicting one embodiment of an alternative synthesis of Compound 2F. In a non-limiting example, Scheme 27 is a scheme depicting one embodiment of the synthesis of Compound 1.

[0755] Scheme 27

[0756]

[0757] One method for synthesizing compound 1 is a method comprising the following steps: (23a) contacting compound 2M with a chlorinating agent and an additive in a solvent at a temperature sufficient to obtain compound 3A; (23b) contacting compound 3A with compound 2B in a solvent in the presence of an organometallic reagent, and then adding a copper or palladium catalyst, an optional zinc additive, and an optional Lewis base, at a temperature sufficient to obtain compound 2C; (23c) contacting compound 2C with a chlorinating agent in the presence of a titanium-based or zirconium-based reagent.

[0758]

[0759] (23d) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 2E; (23e) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (23f) contacting compound 2F with compound 2G in a solvent in the presence of a palladium catalyst and a base at a temperature sufficient to obtain compound 1.

[0760] One method for synthesizing compound 1 is a method comprising the following steps: (23a) contacting compound 2M with a chlorinating agent and an additive in a solvent at a temperature sufficient to obtain compound 3A; (23b) contacting compound 3A with compound 2B in a solvent in the presence of an organometallic reagent, and then adding a copper or palladium catalyst, an optional zinc additive, and an optional Lewis base, at a temperature sufficient to obtain compound 2C; (23c) contacting compound 2C with a chlorinating agent in the presence of a titanium-based or zirconium-based reagent.

[0761]

[0762] (23d) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 2E; (23e) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F; and (23f) contacting compound 2F with compound 2G in a solvent in the presence of a copper catalyst, a copper catalyst ligand and a base at a temperature sufficient to obtain compound 1.

[0763] The invention thus generally described will be more readily understood by reference to the following examples which are provided by way of illustration and are not intended to be limiting of the invention.

[0764] Example

[0765] Example 1: Compound 1 Preparation Route 1

[0766] Compound 1A and compound 1B are subjected to propargyl amination to compound 1C :

[0767]

[0768] Copper iodide (0.0024 equivalents), ligand 1 (0.003 equivalents) and 1:1 v / v acetonitrile: methanol (7.5 volumes) were added to the reactor. Compound 1B (1.0 equivalents, scale factor), compound 1A (1.1 equivalents), sodium acetate (1.25 equivalents) and 1:1 v / v acetonitrile: methanol (7.5 volumes) were added to a separate reactor, and the mixture was cooled to about 0°C. The catalyst mixture in the first reactor was added to the second reactor, and the reactants were stirred for about 20 hours. An aqueous solution of 5 wt% ammonium chloride (10 volumes) was added, the slurry was warmed to about 20°C and filtered. The filter cake was rinsed with water (5 volumes) and MTBE (5 volumes). The wet cake was mixed with acetone (20 volumes) at about 50°C, then cooled to about 20°C and filtered. The filtrate was concentrated to about 8 volumes, and then water (8 volumes) was added at about 50°C. The slurry was cooled to about 20°C, filtered, and the solid was rinsed with water (5 volumes). The filter cake was dried at about 50 °C to give compound 1C. 1 H NMR (400MHz, DMSO): δ8.31ppm (s, 1H), 8.28 (dd, J=8.2, 0.8Hz, 1H), 8.08 (dd, J=7.5, 1.2Hz ,1H),7.56(d,J=7.8Hz,1H),7.55(m,1H),7.52(d,J=2.2Hz,1H),7.36(d,J=2.0Hz,2H),7. 12(d,J=8.2Hz,1H),6.68(d,J=7.7Hz,1H),6.15(dd,J=8.1,2.0Hz,1H),3.80(dd,J=13.9, 7.0Hz, 1H), 3.63 (dd, J=13.9, 6.5Hz, 1H), 3.56 (d, J=2.2Hz, 1H), 3.51 (s, 3H), 0.92 (s, 9H).

[0769] Compound 1C and compound 1D were reacted to obtain compound 1 :

[0770]

[0771] 2-Azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP, 1.37 equiv) and acetonitrile (2.4 vol) were added to the reactor at about 20°C. Compound 2K (1.26 equiv), acetonitrile (1.8 vol) and diisopropylethylamine (2.33 equiv) were added to the second reactor at about 20°C. Copper sulfate (0.1 equiv), sodium ascorbate (0.3 equiv), compound 1C (scale factor, 1.0 equiv), 2-methyltetrahydrofuran (5 vol) and water (0.7 vol) were added to the third reactor at about 20°C. The mixture of ADMP and compound 2K in the first and second reactors was mixed in a tubular reactor to form compound 1D, and the resulting mixture was collected in the first reactor containing compound 1C. The mixed reaction mixture was stirred at about 20°C for about 4 hours, and then MTBE (4 vol) was added. The mixture was cooled to about 0°C, and the resulting slurry was filtered. The solid was rinsed with MTBE (3 volumes), water (3 volumes) and MTBE (3 volumes). The solid was deliquated, then mixed with DMF (7 volumes) and heated to about 50°C. Water (1 volume) and compound 1 seed were added, a...

Claims

1. A method for preparing compound 1, comprising: (2a) In the presence of an organometallic reagent and a Lewis base, compound 2A and compound 2B are reacted: contacting in a solvent at a temperature sufficient to obtain compound 2C: (2b) In the presence of a titanium-based or zirconium-based reagent, compound 2C is reacted with contacting in a solvent at a temperature sufficient to obtain Compound 2D: (2c) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 2E: (2d) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F: as well as (2e) In the presence of a palladium catalyst and a base, compound 2F and compound 2G are reacted: contacting in a solvent at a temperature sufficient to obtain compound 1:

2. A method for preparing compound 1, comprising: (2a) In the presence of an organometallic reagent and a Lewis base, compound 2A and compound 2B are reacted: contacting in a solvent at a temperature sufficient to obtain compound 2C: (2b) In the presence of a titanium-based or zirconium-based reagent, compound 2C is reacted with contacting in a solvent at a temperature sufficient to obtain Compound 2D: (2c) contacting compound 2D with a reducing agent and optionally a ruthenium, palladium, rhodium or platinum catalyst in a solvent at a temperature sufficient to obtain compound 2E: (2d) contacting compound 2E with an acid in a solvent at a temperature sufficient to obtain compound 2F: as well as (2e) In the presence of a copper catalyst, a copper catalyst ligand and a base, compound 2F and compound 2G are reacted: contacting in a solvent at a temperature sufficient to obtain compound 1:

3. The method according to claim 2, wherein for step (2a): (i) the organometallic reagent includes isopropylmagnesium chloride, cyclohexylmagnesium chloride, butylmagnesium chloride, tert-butylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride lithium chloride complex, isopropylmagnesium bromide, ethylmagnesium bromide, phenyllithium, mesityllithium, tert-butyllithium or sec-butyllithium; (ii) the Lewis base includes N,N'-dimethylpropylene urea (DMPU), hexamethylphosphoramide, 2,6-lutidine, pyridine, diglyme, N-methylmorpholine, diisopropylethylamine, 1,2-dimethoxyethane or lithium chloride; (iii) the solvent comprises dichloromethane, diethylene glycol dimethyl ether, ethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, n-hexane, toluene, trifluorotoluene, cyclohexane, n-heptane or xylene; and / or (iv) the temperature is from about -80°C to about 40°C.

4. The method according to any one of claims 3, wherein for step (2a): (i) the organometallic reagent comprises isopropylmagnesium chloride; (ii) the Lewis base comprises N,N'-dimethylpropylene urea (DMPU); (iii) the solvent comprises dichloromethane; and / or (iv) the temperature is from about -5°C to about 20°C.

5. The method according to claim 1 or claim 2, wherein for step (2b): (i) the titanium-based or zirconium-based reagent comprises titanium (IV) ethoxide, titanium (IV) isopropoxide, titanium (IV) butoxide or zirconium (IV) tert-butoxide; (ii) the solvent comprises toluene, trifluorotoluene, cyclohexane, n-heptane, xylene, dichloromethane, chloroform, dichloroethane, chlorobenzene, ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile or butyronitrile; and / or (iii) the temperature is from about 25°C to about 110°C.

6. The method according to claim 5, wherein for step (2b): (i) the titanium-based or zirconium-based reagent comprises titanium (IV) ethoxide; (ii) the solvent comprises toluene; and / or (iii) the temperature is from about 70°C to about 75°C.

7. The method according to claim 1 or claim 2, wherein for step (2c): (i) the reducing agent includes borane tetrahydrofuran complex, borane dimethyl sulfide complex, NaBH4 / I2, ammonia borane, diethylaniline-borane, NaBH4, LiBH4, KBH4, lithium triethylborohydride, potassium tri-sec-butylborohydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium tri[(3-ethyl-3-pentyl)oxy]aluminum hydride, hydrogen, formic acid / triethylamine or 2-propanol; (ii) the ruthenium, palladium, rhodium or platinum catalyst, if present, comprises RuCl(mesitylene) [(S,S)-Ts-DPEN], RuCl(p-isopropyltoluene) [(R,R)-Teth-Ts-DPEN], palladium on carbon, rhodium on alumina or platinum on carbon, (iii) the solvent includes 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, ethyl ether, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, dichloromethane, chloroform, dichloroethane, chlorobenzene, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, propionitrile, butyronitrile, toluene, trifluorotoluene, cyclohexane, n-heptane or xylene; (iv) the temperature is from about -40°C to about 100°C; and / or (v) Compound 2E is produced in a diastereomeric purity of 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 95%, or at least greater than about 99%.

8. The method according to claim 7, wherein for step (2c): (i) the reducing agent comprises a borane tetrahydrofuran complex; (ii) the absence of ruthenium, palladium, rhodium or platinum catalyst; (iii) the solvent comprises 2-methyltetrahydrofuran; (iv) the temperature is from about -10°C to about 0°C; and / or (v) Compound 2E is produced in a diastereomeric purity of at least greater than about 99%.

9. The method of claim 1 or claim 2, wherein for step (2d): (i) the acid comprises hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid or oxalic acid; (ii) the solvent comprises water, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, ethanol, ethylene glycol, propylene glycol, methanol, isopropyl alcohol, tert-butyl alcohol, ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, diphenyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, toluene, trifluorotoluene, cyclohexane, n-heptane, xylene, acetonitrile, propionitrile, butyronitrile, dichloromethane, chloroform, dichloroethane, chlorobenzene or dibromoethane; and / or (iii) the temperature is from about 0°C to about 70°C.

10. The method according to claim 9, wherein for step (2d): (i) the acid comprises hydrochloric acid; (ii) the solvent comprises water; and / or (iii) the temperature is from about 20°C to about 50°C.

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