Method for preparing N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole-4-carboxamide and intermediates thereof

Abstract

A method for preparing the insecticide N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide is disclosed. A method for preparing the intermediate N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide is also disclosed.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 311,276, filed February 17, 2022.

[0002] The field of the disclosure relates generally to methods for preparing N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide and intermediates thereof. [Background technology]

[0003] WO 2015 / 038503 discloses useful insecticidal indazole compounds and methods for preparing same. N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide, corresponding to CAS Registry Number 1689545-27-4, is one of the indazole compounds disclosed. Summary of the Invention [Problem to be solved by the invention]

[0004] There is a need for improved processes for the preparation of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide and related intermediate compounds. [Means for solving the problem]

[0005] One aspect of the present disclosure relates to a method for preparing compound 775, which method comprises the following scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 775.

[0006] Another aspect of the present disclosure relates to methods of preparing compound 200 according to the first scheme, the second scheme, or the third scheme.

[0007] The first such scheme for preparing compound 200 includes steps 1 to 3.

[0008] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 069.

[0009] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound-079.

[0010] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0011] A second such scheme for preparing compound 200 includes steps 1-2.

[0012] Step 1 is the following reaction scheme: [ka] wherein R is selected from COOCH3, COOCH2CH3, COOH, and CN, and each X is independently selected from Cl, Br, and I. and reacting the reaction mixture to form a reaction product mixture comprising compound 905.

[0013] When R is COOCH3, COOCH2CH3 or CN, the method comprises the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 906.

[0014] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0015] When R is COOH, the method can be carried out according to the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0016] A third such scheme for preparing compound 200 includes steps 1 and 2.

[0017] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture by exposing it to light emitted from at least one light source to form a reaction product mixture that includes compound 110.

[0018] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0019] Another aspect of the present disclosure relates to methods for preparing compound 070, which include a first scheme and a second scheme.

[0020] The first scheme involves two steps.

[0021] Step 1 is the following reaction scheme: [ka] followed by substep (b), where substep (a) comprises forming a reaction mixture comprising compound 200, a chlorination reagent, optionally a catalyst, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising an acid chloride intermediate, and substep (b) comprises forming a reaction mixture by combining the reaction product mixture from substep (a) with an ammonia source, and reacting the reaction mixture to form a reaction product mixture comprising compound 144.

[0022] Step 2 is shown in the following reaction scheme: [ka] The method includes substep (a) of forming a reaction mixture comprising compound 144, a base, an oxidizing agent, and a solvent system, followed by substep (b), wherein substep (a) comprises forming a reaction mixture comprising compound 144, a base, an oxidizing agent, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising an N-halocarboxamide intermediate, and substep (b) comprises heating the reaction product mixture comprising the N-halocarboxamide intermediate to form a reaction product mixture comprising compound 070.

[0023] The second scheme involves three steps.

[0024] Step 1 is the following reaction scheme: [ka] (Wherein, R is CONH2, Each X is independently selected from Cl, Br, and I. and reacting the reaction mixture to form a reaction product mixture comprising compound 905.

[0025] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 144.

[0026] Step 3 is shown in the following reaction scheme: [ka] the reaction mixture comprising compound 144, a base, an oxidizing agent, and a solvent system; reacting the reaction mixture to form a reaction product mixture comprising an N-halocarboxamide intermediate; and subsequently heating the reaction product mixture comprising the N-halocarboxamide intermediate to form a reaction product mixture comprising compound 070.

[0027] In one embodiment, compound 905a is useful for the preparation of compound 070, and has the following structure: [ka] It is an intermediate compound having the formula:

[0028] Another aspect of the present disclosure relates to methods for preparing compound 070, which methods include the first, second and third schemes.

[0029] The first scheme is the following scheme: [ka] The method includes step 1 comprising forming a reaction mixture comprising compound 403, an acid, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 070.

[0030] The second scheme involves two steps.

[0031] Step 1 is the following scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 403.

[0032] Step 2 is the following scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 070.

[0033] The third scheme involves three steps.

[0034] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 994.

[0035] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 403.

[0036] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 070.

[0037] Another aspect of the present disclosure relates to a method for preparing compound 070, which comprises the steps of: [ka] The method includes forming a reaction mixture comprising acetonitrile, an ethylmagnesium halide, a titanium reagent, and a solvent, reacting the reaction mixture, adding an acid to the reaction mixture, and further reacting the reaction mixture to form a reaction product mixture comprising compound 070.

[0038] Another aspect of the present disclosure relates to a method for preparing compound 093a, the method comprising steps 1-4.

[0039] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture under photochemical conditions to form a reaction product mixture comprising compound 181a.

[0040] Step 2 includes (i) a combination of steps 2(a) and 2(b), or (ii) step 2 to form compound 378.

[0041] Step 2(a) can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 050.

[0042] Step 2(b) can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 378.

[0043] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 378.

[0044] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 003a.

[0045] Step 4 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 093a, the phosphine or phosphite, and a solvent system, the phosphine being selected from the group consisting of tri(C 1~4 ) alkylphosphines and triarylphosphines, and the phosphite is selected from tri(C 1~4 ) alkyl phosphites and triaryl phosphites.

[0046] Another aspect of the present disclosure relates to a method for preparing compound 093a, the method comprising steps 1-7.

[0047] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 086.

[0048] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 084.

[0049] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 085.

[0050] Step 4 is shown in the following reaction scheme: [ka] The method includes (a) forming a reaction mixture comprising compound 085, a reducing agent, a base, and a solvent system, and reacting the reaction mixture, followed by (a) acidifying to form a reaction product mixture comprising compound 048.

[0051] Step 5 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 083.

[0052] Step 6 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 082.

[0053] Step 7 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 093a.

[0054] Another aspect of the present disclosure relates to a method for preparing compound 093a, the method comprising steps 1-3.

[0055] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 197.

[0056] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 040.

[0057] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 093a.

[0058] Another aspect of the disclosure relates to a method for preparing compounds 093a or 093b according to the first or second scheme.

[0059] Another aspect of the present disclosure relates to an alternative route to compound 093 according to the first or second scheme.

[0060] The first scheme for preparing compound 093a or 093b includes steps 1-2.

[0061] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 182a or 182b, respectively, according to the method of the present invention.

[0062] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 093a or 093b, respectively, according to the method of the present invention.

[0063] A second such scheme for preparing compounds 093a or 093b includes steps 1-3.

[0064] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 115a or 115b, respectively, according to the method of claim 1.

[0065] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture under photochemical conditions to form a reaction product mixture comprising compound 116a, 116b, 116c, or 116d.

[0066] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 093a or 093b, respectively, according to the method of the present invention.

[0067] Another aspect of the present disclosure relates to an alternative method for preparing compounds 182a or 182b, which method comprises the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 182a or 182b, respectively, according to the method of claim 1.

[0068] Another aspect of the present disclosure relates to a method for preparing compound 061, which method comprises the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 061.

[0069] Another aspect of the disclosure relates to methods of preparing compound 038 according to the first, second or third schemes.

[0070] A first such scheme for preparing compound 038 includes steps 1-3.

[0071] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 500.

[0072] Step 2 is shown in the following reaction scheme: [ka] The method includes forming a reaction mixture comprising compound 500, a bromine source or a chlorine source, and a solvent system, and reacting the reaction mixture under photochemical conditions to form a reaction product mixture comprising compound 510a or 510b.

[0073] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 038.

[0074] A second such scheme for preparing compound 038 includes steps 1-3.

[0075] Step 1 is the following reaction scheme: [ka] The method includes forming a reaction mixture comprising compound 400, a bromine source or a chlorine source, and a solvent system, and reacting the reaction mixture by exposing it to a light source to form a reaction product mixture comprising compound 410.

[0076] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 430.

[0077] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 038.

[0078] A third such scheme for preparing compound 038 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 038.

[0079] Another aspect of the present disclosure relates to a method for preparing compound 061, the method comprising the steps of: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound-061.

[0080] Another aspect of the present disclosure relates to a method for preparing compound 038, the method comprising the steps of: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 038.

[0081] In one embodiment, an intermediate compound useful for the preparation of compound 093a has the following structure: [ka] has.

[0082] In one embodiment, an intermediate compound useful for the preparation of compound 093a has the following structure: [ka] has.

[0083] In one embodiment, an intermediate compound useful for the preparation of compound 093a has the structure [ka] has.

[0084] In one embodiment, an intermediate compound useful for the preparation of compound 093a has the following structure: [ka] and the hydrochloride salt.

[0085] In one embodiment, an intermediate compound useful for the preparation of compound 093a has the following structure: [ka] has.

[0086] In one embodiment, an intermediate compound useful for the preparation of compound 093a has the following structure: [ka] has.

[0087] In one embodiment, an intermediate compound useful for the preparation of compound 093a has the structure [ka] has.

[0088] In one embodiment, the compound is compound 520a: [ka] It has the structure:

[0089] In one embodiment, the compound is compound 182a or 182b [ka] It has the structure:

[0090] In one embodiment, the compound is compound 115b: [ka] It has the structure:

[0091] In one embodiment, the compound is Compound 116a-d: [ka] It has the structure:

[0092] In one embodiment, the compound is Compound 500: [ka] It has the structure:

[0093] In one embodiment, the compound is compound 510a or 510b: [ka] It has the structure:

[0094] Another aspect of the present disclosure relates to a method for preparing compound 092, the method comprising steps 1 and 2.

[0095] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 930.

[0096] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 092.

[0097] Another aspect of the present disclosure relates to a method for preparing compound 092, the method comprising the steps of: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 092.

[0098] Another aspect of the present disclosure relates to a method for preparing compound 092, the method comprising the steps of: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 092.

[0099] Another aspect of the present disclosure relates to a method for preparing compound 092, the method comprising the steps of: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 092.

[0100] Another aspect of the present disclosure relates to a method for preparing a salt of compound 092, the method comprising the steps of: [ka] and reacting the reaction mixture to form a reaction product mixture comprising a salt of compound 092.

[0101] Another embodiment of the present disclosure relates to a polymorph of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide designated Form A, characterized by an X-ray powder diffraction pattern according to FIG.

[0102] Another embodiment of the present disclosure relates to a polymorph of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide designated Form B, characterized by an X-ray powder diffraction pattern according to FIG. [Brief description of the drawings]

[0103] [Figure 1] 1 shows an XRPD pattern of Form A of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide prepared according to an embodiment of the present disclosure. [Diagram 2] 1 shows an XRPD pattern of form B of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide prepared according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0104] The present disclosure generally relates to compound 092, referred to herein as compound 092, having the following structure: [ka] The present invention relates to an improved process for the preparation of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide having the formula:

[0105] The term "inorganic base" as used herein generally includes salts of sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Non-limiting examples include phosphates such as dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen phosphate, ammonium dihydrogen phosphate and triammonium phosphate; acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; carbonates such as cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate; ammonium hydroxide; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide. Inorganic bases can be used alone or in combination of two or more thereof.

[0106] The term "organic base" as used herein generally includes primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as pyridine, isopropylamine, trimethylamine, diethylamine, triethylamine, triethanolamine, diisopropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resins. The organic bases may be used alone or in combination of one or more thereof.

[0107] The term "organometallic base" as used herein generally includes organolithium, organomagnesium, organoaluminum or organozinc compounds. Non-limiting examples include organolithium such as methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium; organomagnesium such as methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium bromide; organoaluminum such as trimethylaluminum, triethylaluminum, triisobutylaluminum; diisobutylaluminum hydride; organozinc such as dimethylzinc or diethylzinc. The organometallic base may be used alone or in combination with any of the aforementioned bases.

[0108] The term "inorganic acid" as used herein refers to an acid containing an inorganic component. Examples of inorganic acids include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid. The inorganic acids can be used alone or in combination of two or more thereof.

[0109] The term "organic acid" as used herein refers to an organic compound that acts as an acid. Examples of organic acids include, but are not limited to, carboxylic acids. Examples of organic acids include, but are not limited to, formic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, butanedioic acid, adipic acid, tartaric acid, and citric acid. Organic acids can be used alone or in combination of two or more thereof.

[0110] The term "non-polar solvent" as used herein refers to a solvent in which there are no significant partial charges on any atom or in which the polar bonds are arranged to counteract the effects of the partial charges. Non-limiting examples of non-polar solvents include pentane, hexane, heptane, cyclopentane, cyclohexane, benzene, toluene, xylene, 1,4-dioxane, dichloromethane ("DCM"), methyl tert-butyl ether ("MTBE"), chloroform, carbon tetrachloride, diethyl ether, and combinations thereof.

[0111] The term "aprotic solvent" as used herein refers to a solvent that does not donate hydrogen. As used herein, "polar aprotic solvent" refers to a solvent that has a high dielectric constant and high dipole motion and does not have acidic hydrogen. Non-limiting examples of polar aprotic solvents include tetrahydrofuran ("THF"), methyltetrahydrofuran ("Me-THF"), ethyl acetate ("EA"), acetone, dimethylformamide ("DMF"), dimethylacetamide ("DMAc"), acetonitrile ("ACN"), cyclopentyl methyl ether ("CPME"), petroleum ether, N-methyl-2-pyrrolidone ("NMP"), trifluorotoluene, chlorobenzene, anisole, and dimethylsulfoxide ("DMSO"). In some embodiments, the aprotic solvent is a low molecular weight ester. Non-limiting examples of aprotic low molecular weight ester solvents include methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, i-butyl acetate, propylene glycol methyl ether acetate, monoethyl ether acetate, and combinations thereof.

[0112] The term "polar protic solvent" as used herein refers to a solvent having a labile hydrogen bonded to an oxygen or nitrogen atom. Non-limiting examples of polar protic solvents include formic acid, n-butanol, i-propanol, n-propanol, ethanol, methanol, acetic acid, water, and combinations thereof.

[0113] As used herein, the term "solvent" refers to non-polar solvents, aprotic solvents, polar protic solvents, and combinations thereof.

[0114] As used herein, the term "solvent system" refers to a solvent or mixture of solvents. The solvent system can include or consist primarily of the indicated solvent or combination of solvents. The solvent system can further include residual solvent from one or more previous process steps.

[0115] The term "reducing agent" as used herein refers to a compound that donates electrons directly or via a hydride ("H-"). Non-limiting examples of reducing agents include sodium, potassium, zinc, iron, magnesium, sodium borohydride, potassium borohydride, p-toluenesulfonic acid, sodium bis(2-methoxyethoxy)aluminum hydride, sodium bisulfite, sodium hydrogensulfite, sodium hyposulfite, sodium tetrahydroborate, potassium tetrahydroborate, sodium triacetoxyborohydride, trichlorosilane, triphenylphosphite, triethylsilane, trimethylphosphine, triphenylphosphine, diborane, diethoxymethylsilane, diisobutylaluminum hydride, diisopropylaminoborane, lithium aluminum hydride, and lithium triethylborohydride.

[0116] The term "oxidant" as used herein refers to a compound that accepts electrons. Non-limiting examples of oxidants include hypochlorite, chlorate, and perchlorate; peroxides such as H2O2; O2; O3; N2O; halogens such as F2, Cl2, Br2, and I2; HNO3; KNO3; H2SO4; H2S2O8; and H2SO5.

[0117] As used herein, the terms "halogen," "halo," and "halide" are used interchangeably and refer to any of F, Cl, Br, and I.

[0118] As used herein, the term "alkyl" refers to a saturated, straight or branched chain, monovalent hydrocarbon group. An alkyl group suitably contains 1 to 6 carbon atoms (C 1~6 ), 1 to 4 carbon atoms (C 1~4 ) or 1 to 3 carbon atoms (C 1~3 Non-limiting examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, -CH2CH2CH3), 2-propyl (i-Pr, -CH(CH3)2), 1-butyl (n-Bu, -(CH2)3CH3), and 1,1-dimethylethyl (t-butyl, (CH3)3C-).

[0119] The term "light source" as used herein refers to visible light provided by a light source such as sunlight or a xenon lamp, halogen lamp, fluorescent lamp, diode, or mercury lamp. Filters that cut off wavelengths other than those of interest are within the scope of this disclosure.

[0120] The term "photocatalyst" as used herein refers to a material that exhibits photocatalytic activity upon irradiation with light having an energy higher than a given band gap. In some embodiments, the photocatalyst may be a visible light photocatalyst, non-limiting examples of which include 4CzIP, CZS1, CzS2, 2Cz-DPS, 2TCz-DPSN, fac-Ir(ppy)3, [Ir(ppy)2(dtbbpy)]PF6, [Ir(dF(CF3)ppy)2(bpy)]PF6, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, [Ir(dF(Me)ppy)2(bpy)]PF6, [Ir(F(Me)ppy)2(bpy)]PF6, [Ru(bpy)3](PF6)2, [Acr-Mes]ClO4, Eosin Y, and Rose Bengal. In some embodiments, the photocatalyst can be one or a combination of metal oxide semiconductors, such as, but not limited to, titanium oxide, tungsten oxide, zinc oxide, tin oxide, iron oxide, bismuth oxide, bismuth vanadate, and strontium titanate.

[0121] As used herein, the term "photochemical conditions" refers to the use of a light source or near-visible electromagnetic radiation to drive a reaction.

[0122] Salts of the compounds disclosed herein are within the scope of this disclosure. Salts include both acid addition salts and base addition salts. "Acid addition salts" refers to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from the classes of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. "Base addition salts" refers to salts formed with organic or inorganic bases.

[0123] The term "predominantly" as used herein means greater than 50%, at least 75%, at least 90% or at least 95% on a %, w / w%, w / v% or v / v% basis of the population.

[0124] The term "chemical processing aid" as used herein means a chemical that is added directly to or present in a reaction mixture and is used to aid in processing and whose function does not remain in the product.

[0125] The term "transition metal catalyst" as used herein refers to a catalytically active material that contains at least one element from group III to group XI of the periodic table. Non-limiting examples include iron catalysts, nickel catalysts, palladium catalysts, platinum catalysts, or copper catalysts. Non-limiting examples of iron catalysts where X represents a halogen include Fe, FeX2, FeX3, Fe(acac)3, Fe(NO3)3, or Fe(OTf)3. Non-limiting examples of nickel catalysts include Raney Ni, Ni / C, Ni / SiNi, NiX2, NiX2·nH2O, NiX2(DME), NiX2(diglyme), (bpy)NiX2, Ni(OTf)3, Ni(acac)2, Ni(COD)2, Ni(CO)4, (dppe)NiX2, (dppp)NiX2, (dppb)NiX2, (dppf)NiX2, (dcype)NiX2, (dcypp)NiX2, (dcypb)NiX2, (binap)NiX2, (bpy)NiX2, or solvates thereof. Non-limiting examples of palladium catalysts where X represents a halogen include Pd, Pd / C, Pd / Si, Pd / BaSO4, Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, PdX2, Pd(OAc)2, Pd(OBz)2, [Pd(allyl)X]2, Pd(MeCN)2X2, (COD)PdX2, (2-methylallyl)palladium chloride dimer, Pd(OTf)2, (PPh3)2PdX2, (PCy3)PdX2, (PtBu3)2Pd, Pd[(o-tol)3P] 2, trans-di(μ-acetato)bis[o-(di-o-tolyl-phosphino)benzyl]dipalladium(II), Pd(amphos)X2, (dppe)PdX2, (dppp)PdX2, (dppb)PdX2, (dppf)PdX2, (dppf)PdX2·DCM, (dcype)PdX2, (dcypp)PdX2, (dcypb)PdX2, (binap)PdX2, (xantphos)PdX2, (dpephos)PdX2 or solvates thereof. Non-limiting examples of copper catalysts where X represents a halogen include CuX, CuX2, CuCN, Cu(OTf)2, CuO, Cu2O, CuBr·DMS or solvates thereof.In some aspects, the transition metal catalyst may act as a precursor to the active catalytic species, which may optionally be preformed and then put into the reaction or may be generated in situ. In some aspects, the transition metal catalyst is optionally used with a ligand. In some such aspects, the ligand may optionally be precomplexed with the transition metal before being added to the reaction, or the ligand and the transition metal catalyst may be complexed in situ. In some aspects, the transition metal catalyst may be used alone or in combination with any of the transition metal catalysts previously described.

[0126] The term "diphosphine ligand" as used herein refers to a substance that contains two phosphino groups linked by a backbone. The diphosphine ligand can be chelated to the transition metal catalyst in a bidentate manner. Non-limiting examples include 1,1-bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, 2,3-bis(diphenylphosphino)butane, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,2-bis(diphenylphosphino)benzene, 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene, bis[(2-diphenylphosphino)phenyl]ether, 4,4'-bi-1,3-benzodioxole-5,5'-diylbis(diphenylphosphane), 5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole, (R,R)-(-)-2,3-bis(tert-butylmethylphosphino)quinoxaline, (S,S)-(-)-2,3-bis(ter t-Butylmethylphosphino)quinoxaline, (R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-t-butylphosphine, (+)-1,2-bis[(2R,5R)-2,5-diethylphosphorano]ethane, 1,1'-bis(diphenylphosphino)ferrocene, 1,2-bis(2,5-dimethylphosphorano)benzene, 1,2-bis(dicyclohexylphosphino)ethane, 1,3-bis(dicyclohexylphosphino)propane, 1,4-bis(dicyclohexyl 1,2-bis(dicyclopentylphosphino)butane, 1,2-bis(dicyclopentylphosphino)ethane, 1,3-bis(dicyclopentylphosphino)propane or 1,4-bis(dicyclopentylphosphino)butane, 1,3-bis(di-tert-butylphosphino)propane, 1,1-bis(dimethylphosphino)methane, 1,2-bis(dimethylphosphino)ethane, 1,3-bis(dimethylphosphino)propane, 1,4-bis(dimethylphosphino)butane, 1,2-bis(diethylphosphino)ethane, 1,Examples of suitable phosphine ligands include 3-bis(diethylphosphino)propane, 1,4-bis(diethylphosphino)butane, 1,2-bis(diamylphosphino)ethane, 1,3-bis(diamylphosphino)propane, and 1,4-bis(diamylphosphino)butane. In some embodiments, the diphosphine ligand is used as a bisphosphonium salt, which is then converted in situ to the free base diphosphine. In some such embodiments, the diphosphonium salt is a hydrochloride, hydrobromide, hydroiodide, tetrafluoroborate, or some combination thereof. In some embodiments, the diphosphine ligand can be optionally added separately from the transition metal catalyst or can be added precomplexed with the transition metal catalyst. In some embodiments, the diphosphine can be optionally oxidized in situ to a monophosphine oxide, which serves as a ligand for the active catalytic species. In some embodiments, the diphosphine ligands can be used alone or in combination with any of the diphosphine ligands previously described.

[0127] Some aspects of the present disclosure relate to the following scheme: [ka] The present invention relates to a method for preparing compound 775, comprising:

[0128] The method includes forming a reaction mixture including compound 223 (3-acetyldihydrofuran-2(3H)-one), CHCl, an alkali metal iodide, a base, and a solvent system, and reacting the reaction mixture to form a reaction product mixture including compound 775 (3-acetyl-3-methyldihydrofuran-2(3H)-one).

[0129] In some embodiments, CH3Cl is present in stoichiometric excess relative to compound 223.

[0130] In some embodiments, the alkali metal iodide is selected from NaI, KI, and LiI. In some such embodiments, the alkali metal iodide is KI. The alkali metal is present in a catalytic amount.

[0131] In some embodiments, the base is an inorganic base. In some such embodiments, the base is a weak inorganic base. In some such embodiments, the base is a carbonate. In some such embodiments, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. In some embodiments, the base may be present in stoichiometric excess relative to compound 223.

[0132] In some embodiments, the solvent system comprises an aprotic solvent or comprises primarily an aprotic solvent. In some such embodiments, suitable solvents can be selected from among acetone, methyl t-butyl ether, acetonitrile, 1,4-dioxane, tetrahydrofuran, and isopropyl acetate. In some such embodiments, the solvent system comprises acetonitrile or the solvent system comprises acetone. In some such embodiments, the solvent system comprises acetone or comprises primarily acetone.

[0133] In some embodiments, the reaction is carried out under reflux. 1 Completion can be monitored by methods known in the art, such as 1 H NMR (CDCl3), high performance liquid chromatography ("HPLC") or ultra performance liquid chromatography ("UPLC").

[0134] This method for preparing compound 775 provides good selectivity and yield for compound 775. This method for preparing compound 775 eliminates certain expensive and dangerous reagents known in the art, such as MeI, organic bases, such as sodium amylate or sodium methoxide, and sodium metal.

[0135] Some embodiments of the present disclosure relate to methods of preparing compound 200 (1-methylcyclopropane-1-carboxylic acid) according to the first scheme, the second scheme, or the third scheme.

[0136] Various methods for cyclopropanation are known in the prior art. See Ebner, et al., "Cyclopropanation Strategies in Recent Total Synthesis", Chem. Rev. 2017, 117, 18, 11651-11679; de Meijere, et al., "Small Ring Compounds in Organic Synthesis VI", Topics in Current Chemistry, January 2000, DOI: 10.1007 / 3-540-48255-5; and Rappaport, Ed., "The Chemistry of the Cyclopropyl Group", Vol 1, Patai's Chemistry of Functional Groups, 1987. Each of these references is incorporated herein by reference.

[0137] The first scheme for preparing compound 200 involves three steps.

[0138] Step 1 of the first scheme for preparing compound 200 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 069 (5-chloro-3-methylpentan-2-one).

[0139] In some embodiments, the HCl is concentrated HCl. In some embodiments, the HCl is hydrogen chloride gas. In some embodiments, the solvent system comprises or is predominantly comprised of an aprotic solvent, water, or a combination thereof. In some embodiments, the aprotic solvent is DCM. In some embodiments, the solvent system comprises less than 70 w / w% water. In some embodiments, the concentrated HCl suitably has an HCl concentration of about 30 w / w% to about 38 w / w%.

[0140] Step 2 of the first scheme for preparing compound 200 can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 079 (methyl-(1-methylcyclopropyl)-ketone).

[0141] In some embodiments, the base is a strong inorganic base. In some such embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is selected from sodium hydroxide and potassium hydroxide.

[0142] In some embodiments, the solvent system comprises or comprises primarily a polar protic solvent, water, or a combination thereof.

[0143] Step 3 of the first scheme for preparing compound 200 can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0144] In some embodiments, the oxidizing agent is selected from sodium hypochlorite, sodium hypobromite, bromine, or chlorine. In some such embodiments, the oxidizing agent is sodium hypochlorite. In some embodiments, the concentration of sodium hypochlorite is that obtained in a commercially available solution.

[0145] In some embodiments, a base is optionally present, hi some embodiments, the base is selected from sodium hydroxide or potassium hydroxide.

[0146] In some embodiments, the solvent system comprises or comprises primarily water.

[0147] In some embodiments, any of compounds 775, 069, 079, and 200 are optionally isolated from the reaction product mixture. In some embodiments, any two or all of the sequential reactions from compound 223 to compound 775, compound 775 to compound 069, compound 069 to compound 079, and compound 079 to compound 200 are carried forward to the next step without isolation or purification.

[0148] The second scheme for preparing compound 200 involves two steps.

[0149] Step 1 of the second scheme for preparing compound 200 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 905.

[0150] R is selected from CO2CH3, CO2CH2CH3, COOH, and CN. In some such embodiments, R can be CO2CH3 or CO2CH2CH3. Each X is independently selected from Cl, Br, and I. In some such embodiments, each X is Cl.

[0151] When R is CO2CH3, CO2CH2CH3, or CN, the method can be carried out according to the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 906.

[0152] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0153] When R is COOH, the method includes step 2', which is represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0154] In some Step 1 embodiments, the base is a strong inorganic base. In some such embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is selected from sodium hydroxide and potassium hydroxide. In some embodiments, the base is present in a molar excess relative to compound 900.

[0155] In some Step 1 embodiments, the CHX3 reagent is chloroform, bromoform, or iodoform. In one embodiment, the CHX3 reagent is chloroform. In some embodiments, the chloroform is present in molar excess relative to compound 900.

[0156] Phase transfer catalysts ("PTCs") are known in the art. In some step 1 embodiments, the PTC is selected from ammonium halide salts, crown ethers, and PEG. Non-limiting examples of suitable PTCs include triethylbenzylammonium chloride, triethylbenzylammonium bromide, tetraethylammonium bromide, tetrabutylammonium bromide, and ethyltrimethylammonium iodide. In one embodiment, the PTC is trimethylbenzylammonium chloride. The PTC is usually present in a catalytic amount.

[0157] In some Step 1 embodiments, suitable solvents include protic solvents, aprotic solvents, and combinations thereof. Non-limiting examples of solvents include water, hexane, pentane, heptane, benzene, toluene, chlorobenzene, dichloromethane, and combinations thereof.

[0158] The reaction temperature may be suitably selected to achieve the desired purity and yield within a commercially acceptable time, and reaction completion may be suitably measured by in-process tests as described elsewhere herein.

[0159] When R is COOCH3, COOCH2CH3 or a nitrile, the method can be carried out according to the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 906.

[0160] In some embodiments of Step 1b, the base is a strong inorganic base. In some such embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is selected from sodium hydroxide and potassium hydroxide.

[0161] In some embodiments of Step 1b, the solvent system suitably comprises or comprises primarily a polar protic solvent. In some such embodiments, the solvent system comprises a C 2 carboxylic acid such as methanol or ethanol. 1~4 In some such embodiments, the solvent system comprises or primarily comprises an alcohol. In some such embodiments, the solvent system comprises methanol. In some such embodiments, the solvent system comprises water. In some such embodiments, the solvent system comprises water and C 1~4 Includes mixtures with alcohol.

[0162] In some embodiments, the reaction product mixture can be optionally post-treated. For example, water can be added and the pH can be adjusted to less than 3, for example about 1-2, with a strong acid such as HCl. The resulting mixture can be extracted with a solvent such as a non-polar solvent (e.g., toluene) to extract compound 906. The extraction mixture can then be optionally evaporated (e.g., under vacuum) to isolate compound 906.

[0163] Step 2 of the second scheme for preparing compound 200 can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0164] In some Step 2 embodiments, the conversion of compound 906 to compound 200 is carried out under dehalogenation conditions that include forming a reaction mixture that includes compound 906, H2, a metal catalyst, a base, and a solvent system, and reacting the reaction mixture to form a reaction product mixture that includes compound 200. The reaction temperature and pressure can be appropriately selected to achieve commercially acceptable yields, purity, and throughput.

[0165] In some embodiments, the suitable solvent is selected from methanol, ethanol, 1-propanol, isopropanol, t-butanol, isobutanol, sec-butanol, 1-hexanol, 2-ethyl-1-hexanol, 2-octanol, benzyl alcohol, n-octane, cyclohexane, xylene, tetrahydrofuran, dioxane, water, monoglyme, diglyme, ethylene glycol, N,N-dimethylformamide, N,N-dimethylsulfoxide, triethylamine, pyridine, and combinations thereof. In some embodiments, the solvent system comprises a polar protic solvent. In some embodiments, the polar protic solvent is selected from C 1~4 In one embodiment, the solvent is t-butanol.

[0166] In some embodiments, the reaction mixture includes a base. Suitable bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, ethylenediamine, and combinations thereof. In some such embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is selected from sodium hydroxide and potassium hydroxide. In some embodiments, the base is an alkali metal alkoxide. In some embodiments, the base is selected from sodium tert-butoxide and potassium tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is in molar excess relative to compound 906.

[0167] In some embodiments, the metal catalyst is a Pt, Pd, Rh, or Ru catalyst. In some embodiments, the metal catalyst is Pd / C, Rh / Al2CO3, Pd / CaCO3, Pd / Pb / CaCO3, or Pt / Al2O3. In one embodiment, the metal catalyst is Pd / C.

[0168] The reaction product mixture may be optionally post-treated. For example, but not limited to, the reaction product mixture may be filtered and the filtrate may be evaporated to remove the solvent. The resulting mixture may be diluted with water and acidified with a strong acid (e.g., HCl) to a pH of less than 3, for example, about 1 to about 2. The resulting mixture may be extracted with a solvent (e.g., DCM) to extract compound 200. In some embodiments, compound 200 may be isolated by evaporation of the solvent to obtain compound 200.

[0169] In some step 2' embodiments, the conversion of compound 905 to compound 200 is carried out under reducing metal conditions and includes forming a reaction mixture comprising compound 905, a reducing metal, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0170] In some embodiments, the solvent system comprises a polar aprotic solvent, a polar protic solvent, or a combination thereof. In some such embodiments, suitable solvents are selected from among tert-butanol, acetic acid, water, isopropanol, THF, ethylene glycol, tetramethylethylenediamine, N,N-dimethylaniline, DMF, diethanolamine, ethylenediamine, triethylamine, ammonium hydroxide, and combinations thereof. In some embodiments, the solvent system may suitably comprise or be predominantly comprised of a polar aprotic solvent. In some embodiments, the solvent is tetrahydrofuran (THF). In some embodiments, the solvent system may comprise a polar aprotic solvent (e.g., THF) and a polar protic solvent (C 1~4 The solvent may comprise or consist primarily of alcohol (such as, for example, methanol or ethanol), water, and combinations thereof.

[0171] In some embodiments, the reducing metal is Na, K, Ca, Mg, or Zn. In some such embodiments, the reducing agent is selected from Na and Zn. In some such embodiments, the reducing agent is sodium metal. In some embodiments, the reducing agent is in molar excess relative to compound 905.

[0172] In some embodiments, when the reducing metal is zinc, the solvent is acetic acid. In some embodiments, when the reducing metal is zinc, a base may optionally be present. In some embodiments, the base is an inorganic base. In some such embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is selected from sodium hydroxide and potassium hydroxide. In some embodiments, the base may also be used as the solvent, for example, triethylamine. In some embodiments, the base is in molar excess relative to compound 905 from step 1.

[0173] In some aspects, the reducing agent may be added in portions over the course of the reaction, hi some aspects, the reducing agent may be added continuously or semi-continuously over the course of the reaction.

[0174] Compound 200 can be isolated by methods known in the art, such as solvent removal. In some embodiments, the reaction product mixture can be optionally worked up. For example, a solution containing compound 200 can be acidified, extracted with a solvent, and isolated by methods known in the art.

[0175] In some embodiments, any of compounds 905, 906, and 200 are optionally isolated from the reaction product mixture. In some embodiments, any two or all of the sequential reactions from compound 900 to compound 905, compound 905 to compound 906, and compound 906 to compound 200 are carried forward to the next step without isolation or purification.

[0176] The third scheme for preparing compound 200 involves two steps.

[0177] Step 1 of the third scheme for preparing compound 200 can be represented by the following reaction scheme: [ka] and reacting the reaction mixture by exposing it to light emitted from at least one light emitting source to form a reaction product mixture comprising compound 110 (methyl 1-methylcyclopropane-1-carboxylate).

[0178] The solvent system may suitably comprise or primarily comprise a polar or non-polar solvent. In some such embodiments, the solvent system comprises a polar aprotic solvent, or the solvent system comprises dimethylformamide (DMF). In some embodiments, the polar solvent comprises or primarily comprises DMF.

[0179] In some embodiments, the base is an inorganic base. In some embodiments, the base is a carbonate. In some embodiments, the base is Cs2CO3. In some embodiments, the base is an organic base.

[0180] In some embodiments, the photocatalyst is a visible light photocatalyst. Non-limiting examples of photocatalysts within the scope of the present disclosure include 4CzIP, CZS1, CzS2, 2Cz-DPS, 2TCz-DPSN, fac-Ir(ppy)3, [Ir(ppy)2(dtbbpy)]PF6, [Ir(dF(CF3)ppy)2(bpy)]PF6, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, [Ir(dF(Me)ppy)2(bpy)]PF6, [Ir(F(Me)ppy)2(bpy)]PF6, [Ru(bpy)3](PF6)2, [Acr-Mes]ClO4, Eosin Y and Rose Bengal. In some embodiments, the photocatalyst is 4CzIP or Ir(ppy)2(dtbbpy)PF6.

[0181] In some embodiments, the light source is a blue light emitting diode.

[0182] Step 2 of the third scheme for preparing compound 200 can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 200.

[0183] In some embodiments, the base is an inorganic base. In some such embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is selected from sodium hydroxide and potassium hydroxide.

[0184] In some embodiments, the solvent system suitably comprises or comprises primarily a polar solvent. In some such embodiments, the solvent system comprises a C 2 carboxylic acid such as methanol or ethanol. 1~4 In some such embodiments, the solvent system comprises water. In some such embodiments, the solvent system comprises water and C 1~4 Includes mixtures with alcohol.

[0185] The reaction product mixture can be optionally post-treated. For example, water can be added and the pH can be adjusted to less than 3, for example about 1 to about 2, with a strong acid such as HCl. The resulting mixture can be extracted with a solvent such as a non-polar solvent (e.g., toluene) to extract compound 200. The extracted mixture can then be optionally evaporated (e.g., under vacuum) to obtain compound 200.

[0186] In some embodiments, compounds 110 and 200 are optionally isolated from the reaction product mixture. In some embodiments, the sequential reactions of compound 100 to compound 110 and compound 110 to compound 200 are carried forward to the next step without isolation.

[0187] Some aspects of the present disclosure relate to a method for preparing compound 070, which includes two steps.

[0188] Step 1 is the following reaction scheme: [ka] followed by substep (b), where substep (a) comprises forming a reaction mixture comprising compound 200 (1-methylcyclopropanecarboxylic acid), a chlorination reagent, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising an acid chloride intermediate, and substep (b) comprises forming a reaction mixture by combining the reaction product mixture from substep (a) with an ammonia source, and reacting the reaction mixture to form a reaction product mixture comprising compound 144 (1-methylcyclopropanecarboxamide).

[0189] In some embodiments of substep (a), the solvent system comprises or comprises primarily an aprotic solvent, hi some embodiments, the solvent system comprises or comprises primarily dichloromethane (DCM), toluene, acetonitrile, or combinations thereof.

[0190] In some embodiments, the reaction mixture of substep (a) may further comprise a catalyst selected from DMF, 4-dimethylaminopyridine (DMAP), triethylamine, N-methyl-2-pyrrolidone (NMP), N-methylformanilide, N-formylpyridine, or pyridine.

[0191] In some embodiments, the chlorinating reagent can be selected from thionyl chloride, triphosgene, or phosgene. In some such embodiments, the chlorinating reagent is thionyl chloride. The chlorinating reagent is preferably in stoichiometric excess relative to compound 200.

[0192] In some embodiments, the solvent system of sub-step 1b comprises primarily the solvent system of step 1a. In some embodiments, the solvent system of sub-step 1b comprises primarily a combination of the solvent system from step 1a and a polar protic solvent. In some embodiments, the solvent system of sub-step 1b comprises primarily a polar protic solvent. In any such embodiment, the polar protic solvent is suitably selected from the group consisting of water, C 1~4 It may be an alcohol or a combination thereof, such as water, methanol, ethanol or a combination thereof.

[0193] In some embodiments of sub-step 1(b), the ammonia source is selected from ammonia, ammonium hydroxide, and ammonia dissolved in a suitable organic solvent known in the art, such as methanol, ethanol, DCM, or toluene. In some such embodiments, the ammonia source is selected from ammonia and ammonium hydroxide. In some embodiments, the ammonia is in molar excess relative to compound 200.

[0194] In some embodiments of substep (b), an acid solution of compound 144 is added to an ammonia source. In some embodiments, an ammonia source can be added to the reaction mixture.

[0195] Compound 144 can optionally be isolated from the reaction mixture by methods known in the art, such as solvent removal or filtration.

[0196] Step 2 is shown in the following reaction scheme: [ka] followed by substep (b), where substep (a) comprises forming a reaction mixture comprising compound 144, a base, an oxidizing agent, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising an N-halocarboxamide intermediate, and substep (b) comprises heating the reaction product mixture comprising the N-halocarboxamide intermediate to form a reaction product mixture comprising compound 070 (1-methylcyclopropylamine).

[0197] In some embodiments, the oxidizing agent is selected from Cl2, NaOCl, Br2, and NaOBr. In some particular embodiments, the oxidizing agent is NaOCl. In some other particular embodiments, the oxidizing agent is Br2.

[0198] In some embodiments, the base is an inorganic base. In some such embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is selected from sodium hydroxide and potassium hydroxide. In some embodiments, the base is present in molar excess relative to compound 144.

[0199] In some embodiments, the solvent system comprises or comprises primarily a polar protic solvent. In some such embodiments, the solvent system comprises or comprises primarily water. In some such embodiments, compound 144 is slurried in the solvent system.

[0200] In some embodiments, a quenching reagent may be added to the reaction product mixture to quench excess oxidizing agent. In some embodiments, the quenching reagent is Na2S2O3.

[0201] In some aspects of the disclosure, a representative example of the sequence of some reaction steps for a particular acrylate-derived cyclopropyl compound can be ordered as shown below. [ka]

[0202] In such embodiments, the general conditions for the reactions in the above schemes are as previously described except as set forth below.

[0203] The reaction of compound 351 to form compound 110 can be carried out according to the following reaction scheme: [ka] The process can be carried out according to the following.

[0204] The reaction of compound 351 to form compound 110 can proceed according to conditions known in the literature for the dehalogenation of alkanes.

[0205] The reaction of compound 110 to form compound 200 can be carried out according to the following reaction scheme: [ka] The process can be carried out according to the following.

[0206] The reaction of compound 110 to form compound 144 can be carried out according to the following reaction scheme: [ka] The process can be carried out according to the following.

[0207] The reaction of compound 110 to form compound 144 can proceed according to conditions known in the literature for the ammonolysis of organic esters to amides.

[0208] The reaction of compound 351 to form compound 145 can be carried out according to the following reaction scheme: [ka] The process can be carried out according to the following.

[0209] The reaction of compound 351 to form compound 145 can proceed according to conditions known in the literature for the ammonolysis of esters to amides.

[0210] The reaction of compound 350 to form compound 145 can be carried out according to the following reaction scheme: [ka] The process can be carried out according to the following.

[0211] The reaction of compound 350 to form compound 145 can proceed according to conditions known in the literature for the ammonolysis of a carboxyl group to an amide.

[0212] The reaction of compound 145 to form compound 146 can be carried out according to the following reaction scheme: [ka] The process can be carried out according to the following.

[0213] The reaction of compound 145 to form compound 144 can be carried out according to the following reaction scheme: [ka] The process can be carried out according to the following.

[0214] The reaction of compound 146 to form compound 070 can be carried out according to the following reaction scheme: [ka] The process can be carried out according to the following.

[0215] Some aspects of the present disclosure relate to a method for preparing compound 070, the method comprising three steps.

[0216] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 994 (1-(1-methylcyclopropyl)ethan-1-one oxime).

[0217] In some embodiments, the amine source is selected from hydroxylamine and a hydroxylamine salt, hi one embodiment, the hydroxylamine salt is an HCl salt.

[0218] In some embodiments, the base is selected from an inorganic base or an organic base, hi some such embodiments, the base is sodium acetate or potassium acetate.

[0219] In some embodiments, the solvent system comprises or comprises primarily a polar protic solvent. In some such embodiments, the solvent system comprises a C 1~4 3. Comprises or comprises primarily an alcohol. In one embodiment, the solvent system comprises or comprises primarily methanol or ethanol.

[0220] In some embodiments, the reaction product mixture comprises (E,Z)-1-(1-methylcyclopropyl)ethan-1-one oxime. In some embodiments, the reaction product mixture comprises (E)-1-(1-methylcyclopropyl)ethan-1-one oxime. In some embodiments, the reaction product mixture comprises (Z)-1-(1-methylcyclopropyl)ethan-1-one oxime.

[0221] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 403 (N-(1-methylcyclopropyl)acetamide).

[0222] In some embodiments, the activating agent is selected from tosyl chloride, hydrogen cyanurate, thionyl chloride, sulfamic acid, phosphorus pentachloride, phosphorus pentoxide, triethylamine, inorganic bases, inorganic acids, organic acids, trimethylsilyl iodide, transition metal catalysts (such as zinc chloride), thiamine hydrochloride, alkylpyridinium salts, chloral, and combinations thereof. In some embodiments, the activating agent is selected from tosyl chloride, hydrogen cyanurate, thionyl chloride, and sulfamic acid. In some such embodiments, the activating agent is tosyl chloride.

[0223] In some embodiments, the solvent system comprises or comprises primarily a polar or non-polar solvent, hi some such embodiments, the solvent system comprises or comprises primarily acetonitrile.

[0224] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 070.

[0225] In some embodiments, the acid is selected from an inorganic acid or an organic acid. In some such embodiments, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, and TsOH. In some such embodiments, the acid is a mineral acid. In one embodiment, the acid is H2SO4.

[0226] In some embodiments, the solvent system comprises or comprises primarily polar protic solvents, hi some such embodiments, the solvent system comprises or comprises primarily water.

[0227] In some embodiments, any of compounds 994, 403, and 070 are optionally isolated from the reaction product mixture. In some embodiments, two or all of the sequential reactions from compound 079 to compound 070 are carried forward to the next step without isolation or purification.

[0228] In some embodiments of the disclosure, compound 070 can be prepared according to the following reaction scheme: [ka] It can be prepared from acetonitrile according to

[0229] In some embodiments, the ethylmagnesium halide reagent may be suitably selected from ethylmagnesium bromide and ethylmagnesium chloride.

[0230] In some embodiments, the solvent may be suitably selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, tert-amyl methyl ether, and cyclopentyl methyl ether.

[0231] In some embodiments, the titanium reagent is selected from titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, titanium(IV) butoxide, titanium(IV) tert-butoxide, titanium(IV) 2-ethylhexyloxide, and methyltitanium(IV) triisopropoxide.

[0232] In some embodiments, the acid is a Lewis acid or a Bronsted acid. In some embodiments, the Lewis acid is selected from boron trifluoride, boron trifluoride diethyl etherate, boron trifluoride tetrahydrofuran complex, boron trifluoride dibutyl etherate, boron trifluoride tert-butyl methyl etherate, boron trichloride, titanium(IV) chloride, aluminum trichloride, cerium(III) trichloride heptahydrate, zinc chloride, nickel(II) bromide trihydrate. In some embodiments, the Bronsted acid is selected from sulfuric acid, phosphoric acid, and acetic acid.

[0233] A challenge in forming cyclopropanamines using this chemistry is the presence of large amounts of metal salts in the reaction mass, which causes great difficulties in the reaction workup and product isolation steps. For example, the polar cyclopropanamine products are water soluble, and typical extractive workups used to remove inorganic salts result in large amounts of product being lost to the aqueous layer. Another challenge is the insoluble titanium dioxide formed during reaction workup, which coats the walls of the reaction vessel and requires vigorous reactor washing protocols to remove (Org.ProcessRes.Dev.2021,25,2351; Org.ProcessRes.Dev.2020,24,1735-1742; Org.ProcessRes.Dev.2012,16,836).

[0234] In some embodiments, chemical processing aids are added after the reaction to facilitate product separation. In some embodiments, the chemical processing aids are selected from tartrates, such as potassium sodium tartrate, lactates, glycolates, ethylenediaminetetraacetate, triethanolamine, and citrates. In some embodiments, the salts are generated from the corresponding acids upon treatment with base. In some embodiments, the processing aid is a flocculant. In some embodiments, the flocculant is selected from aluminum sulfate, ferric chloride, ferrous sulfate, ferric sulfate, sodium silicate, silicates, and silicate / kaolin clays or their hydrates.

[0235] Some embodiments of the present disclosure relate to a method for preparing compound 093a (4-chloro-2-(pyridin-3-yl)-2H-indazole), the method comprising four steps.

[0236] Step 1 is the following reaction scheme: [ka] and forming a reaction mixture comprising compound 339 (1-chloro-2-methyl-3-nitrobenzene), a Br source, optionally a photosensitive radical initiator, and a solvent system, and reacting the reaction mixture under photochemical conditions to form a reaction product mixture comprising compound 181a, according to the method of claim 18.

[0237] In some embodiments, the Br source is selected from N-bromosuccinimide, Br2, or a combination of HBr and H2O2. In some embodiments, the Br source is N-bromosuccinimide.

[0238] In some embodiments, the solvent system comprises or comprises primarily at least one polar aprotic solvent, hi some such embodiments, the solvent system comprises or comprises primarily dichloromethane (DCM) or a combination of DCM and water.

[0239] In some embodiments, the reaction is driven by a light source. In some embodiments, the photochemical conditions involve using a visible light source to drive the reaction. In some such embodiments, the visible light is provided by a light source of about 400 W.

[0240] In some embodiments, a light-sensitive or thermally activated radical initiator is used, hi some such embodiments, the radical initiator is azobisisobutyronitrile.

[0241] Step 2 includes (i) a combination of steps 2(a) and 2(b), or (ii) step 2 to form compound 378.

[0242] (i) Step 2(a) can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 050 ((2-chloro-6-nitrophenyl)methanol).

[0243] In some embodiments, the base is a weak base. In some embodiments, the base is an inorganic base. In some embodiments, the base is a carbonate or bicarbonate. In some such embodiments, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and magnesium carbonate.

[0244] In some embodiments, the solvent system comprises or primarily comprises at least one polar solvent system. In some such embodiments, the solvent system comprises or primarily comprises water. In some such embodiments, the solvent system comprises or primarily comprises acetonitrile. In some such embodiments, the solvent system comprises acetonitrile and water.

[0245] Step 2(b) can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 378 (2-chloro-6-nitrobenzaldehyde).

[0246] In some embodiments, the oxidizing agent is NaOCl.

[0247] In some embodiments, the phase transfer catalyst (PTC) is a quaternary ammonium salt. In some embodiments, the PTC is tetrabutylammonium bromide.

[0248] In some embodiments, the solvent system comprises or comprises primarily a non-polar solvent, hi some such embodiments, the solvent system comprises or comprises primarily toluene.

[0249] (ii) Step 2 is represented by the following reaction scheme: [ka] The method includes forming a reaction mixture comprising compound 181a ((2-(bromomethyl)-1-chloro-3-nitrobenzene), an oxidant, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 378.

[0250] In some embodiments, the oxidizing agent is an N-oxide reagent, hi some such embodiments, the reagent is trimethylamine-N-oxide or N-methylmorpholine-N-oxide.

[0251] In some embodiments, the solvent system comprises or comprises primarily at least one polar solvent, hi some such embodiments, the solvent system comprises or comprises primarily DMSO or DMF.

[0252] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 003a (1-(2-chloro-6-nitrophenyl)-N-(pyridin-3-yl)methanimine).

[0253] In some embodiments, the solvent system comprises or comprises primarily a non-polar solvent, hi some such embodiments, the solvent system comprises or comprises primarily toluene.

[0254] In some embodiments, the acid is an organic acid, hi some such embodiments, the acid is p-toluenesulfonic acid.

[0255] In some embodiments, the reaction is carried out under reflux with azeotropic distillation of water.

[0256] Step 4 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 003a, a phosphine or phosphite, and a solvent system.

[0257] In some embodiments, the solvent system comprises or comprises primarily a polar protic solvent or a non-polar solvent. In some such embodiments, the solvent system comprises a C 1~4 In one such embodiment, the solvent system comprises or primarily comprises isopropyl alcohol. In some embodiments, the solvent system comprises or primarily comprises toluene.

[0258] In some embodiments, the phosphine or phosphite is trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, triphenyl phosphite, trimethyl phosphine, triethyl phosphine, tributyl phosphine, or triphenyl phosphine.

[0259] In some embodiments, the reaction is carried out under reflux.

[0260] In some embodiments, any of compounds 181a, 050, 378, 003a, and 093a are optionally isolated from the reaction product mixture. In some embodiments, any two or all of the sequential reactions from compound 339 to compound 093a are carried out in a telescopic pot scheme.

[0261] Some embodiments of the present disclosure relate to a method for preparing compound 093a, the method comprising seven steps.

[0262] Step 1 is the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 086 (1-(2,6-dichlorophenyl)-N-(pyridin-3-yl)methanimine).

[0263] In some embodiments, the acid is p-toluenesulfonic acid.

[0264] In some embodiments, the solvent system comprises or primarily comprises at least one non-polar solvent. In some such embodiments, the solvent system comprises or primarily comprises toluene. Step 2 is represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 084 (N-(2,6-dichlorobenzyl)pyridin-3-amine).

[0265] In some aspects, the reducing agent is selected from sodium borohydride and sodium cyanoborohydride.

[0266] In some embodiments, the solvent system comprises or comprises primarily a polar protic solvent, or the solvent system comprises a C 1~4 The solvent system may comprise or primarily comprise alcohol, or may comprise or primarily comprise methanol.

[0267] Step 3 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 085 (N-(2,6-dichlorobenzyl)-N-(pyridin-3-yl)nitrosamide).

[0268] In some embodiments, the reagent for converting amines to nitrosamines is a nitrite. In some such embodiments, the reagent for converting amines to nitrosamines is sodium nitrite.

[0269] In some embodiments, the acid is an organic acid, hi some such embodiments, the acid is p-toluenesulfonic acid.

[0270] In some embodiments, the solvent system comprises or comprises primarily at least one polar aprotic solvent, hi some such embodiments, the solvent system comprises or comprises primarily DCM.

[0271] Step 4 is shown in the following reaction scheme: [ka] (a) forming a reaction mixture comprising compound 085, a reducing agent, a base, and a solvent system, and reacting the reaction mixture; and (b) acidifying to form a reaction product mixture comprising compound 048 (1-[(2,6-dichlorophenyl)methyl]-1-(3-pyridyl)hydrazine salt).

[0272] In some embodiments, the reducing agent is thiourea dioxide.

[0273] In some embodiments, the base is an inorganic base. In some such embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is NaOH or KOH.

[0274] In some embodiments, the solvent system comprises or primarily comprises at least one polar protic solvent, hi some such embodiments, the solvent system comprises or primarily comprises water.

[0275] In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is HCl. In some embodiments, the acid is HCl in isopropanol and compound 048 is (3-(1-(2,6-dichlorobenzyl)hydrazinyl)pyridine·HCl).

[0276] Step 5 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 083 (N'-(2,6-dichlorobenzyl)-N'-(pyridin-3-yl)acetohydrazide).

[0277] In some embodiments, the base is an organic base. In some such embodiments, the base is triethylamine.

[0278] In some embodiments, the solvent system comprises or primarily comprises at least one polar aprotic solvent, hi some such embodiments, the solvent system comprises or primarily comprises dichloromethane.

[0279] Step 6 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 082 (1-[4-chloro-2-(3-pyridyl)-3H-indazol-1-yl]ethanone).

[0280] In some embodiments, the ligand is ethylenediamine or trans-dimethylcyclohexyl-1,2-diamine.

[0281] In some embodiments, the transition metal catalyst is selected from metals of Group VIII, IX, X, or XI. In some embodiments, the transition metal catalyst is selected from Pd catalysts and Cu catalysts. In some embodiments, the transition metal catalyst is CuI.

[0282] In some embodiments, the base is an inorganic base. In some such embodiments, the base is KPO.

[0283] In some embodiments, the solvent system comprises or comprises primarily at least one non-polar solvent. In one embodiment, the solvent system comprises primarily dioxane. In another embodiment, the solvent system comprises primarily toluene.

[0284] Step 7 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 093a.

[0285] In some aspects, the base is an inorganic base. In some such aspects, the base is a weak inorganic base. In some aspects, the base is a carbonate. In some aspects, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0286] In some embodiments, the solvent system comprises or comprises primarily polar protic solvents. In some such embodiments, the solvent system comprises a C 1~4 In some such embodiments, the solvent system comprises or primarily comprises methanol.

[0287] In some embodiments, reaction steps 6 and 7 are carried out sequentially in a single vessel.

[0288] Some embodiments of the present disclosure relate to a method for preparing compound 093a, the method comprising three steps.

[0289] In the first step, a reaction mixture solution containing compound 150 (2,6-dichlorobenzaldehyde), acetohydrazine, a solvent system, and an organic acid is formed, and the reaction mixture is reacted with the compound 150 according to the following reaction scheme: [ka] This reaction mixture reacts according to the formula: to form a reaction product mixture containing compound 197 (N-[(2,6-dichlorophenyl)methyleneamino]acetamide).

[0290] In some embodiments, the organic acid is p-toluenesulfonic acid. In some embodiments, the solvent system comprises at least one non-polar solvent. In some such embodiments, the solvent system comprises toluene.

[0291] In some embodiments, the reaction is carried out under reflux with azeotropic distillation of water to facilitate the condensation process.

[0292] In a second step, a reaction mixture is formed containing compound 197, a reducing agent, and a solvent system, and the reaction is carried out according to the following reaction scheme: [ka] This reaction mixture reacts according to the formula: to form a reaction product mixture containing compound 040 (N'-[(2,6-dichlorophenyl)methyl]acetohydrazide).

[0293] In some embodiments, the reducing agent is magnesium or borohydride, hi some such embodiments, the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, and magnesium.

[0294] In some embodiments, the solvent system comprises at least one alcohol, at least one carboxylic acid, or a combination thereof, hi some such embodiments, the solvent system comprises methanol, ethanol, acetic acid, or a combination thereof.

[0295] In the third step, a reaction mixture is formed containing compound 040, 3-bromopyridine, a ligand, a transition metal catalyst, and a solvent system, and the reaction is carried out according to the following reaction scheme: [ka] This reaction mixture reacts according to the formula: to form a reaction product mixture containing compound 093a.

[0296] In some embodiments, the ligand is a diamine ligand, hi some such embodiments, the ligand is selected from trans-N,N'-dimethylcyclohexyldiamine and N,N'-dimethylethylenediamine.

[0297] In some embodiments, the transition metal catalyst is a copper catalyst. In some such embodiments, the transition metal catalyst is CuI.

[0298] In some embodiments, the solvent system comprises a non-polar solvent, hi some such embodiments, the solvent system comprises toluene.

[0299] Some embodiments of the present disclosure relate to a method for preparing compound 093a or 093b (4-chloro-2-(3-pyridyl)indazole or 4-bromo-2-(3-pyridyl)indazole), which method includes two steps.

[0300] In the first step, a reaction mixture solution is formed containing compound 181a or 181b (2-(chloromethyl)-1-chloro-3-nitrobenzene or 2-(bromomethyl)-1-chloro-3-nitrobenzene), compound 520 (3-aminopyridinium salt), and a solvent system, and the reaction is carried out according to the following reaction scheme: [ka] This reaction mixture reacts according to the formula (I) to form a reaction product mixture containing compound 182a or 182b (N-[(2-chloro-6-nitrophenyl)methyl]pyridin-3-amine or N-[(2-bromo-6-nitrophenyl)methyl]pyridin-3-amine).

[0301] In some embodiments, compound 520 is a hydrochloride, hydrobromide, sulfate, hydrogen sulfate, methanesulfonate, or p-toluenesulfonate salt. In some such embodiments, compound 520 can be optionally prepared in situ or can be prepared and isolated prior to use.

[0302] In some embodiments, the solvent system comprises or primarily comprises a polar aprotic solvent. In some such embodiments, the solvent system comprises acetonitrile, benzonitrile, sulfolane, or a combination thereof. In some embodiments, the solvent system comprises a mixture of a non-polar solvent and a polar protic solvent. In some such embodiments, the solvent system is toluene and water or xylene and water. Optionally, a phase transfer catalyst (PTC) may also be included. In some such step 3 embodiments, the PTC is a quaternary ammonium salt. In some such embodiments, the PTC is tetrabutylammonium bromide. In some such embodiments, the PTC is used in a catalytic amount.

[0303] In some embodiments, the product 182a or 182b is isolated as an anilinium bromide salt, a dibromide salt, or a salt mixture with HBr and methanesulfonic acid or p-toluenesulfonic acid. If 182a or 182b is treated with base after the reaction, it is isolated as the free base.

[0304] In a second step, a reaction mixture solution is formed containing 182a or 182b, a reducing agent, a base, and a solvent system, and reacted according to the following reaction scheme: [ka] This reaction mixture reacts according to the formula: to form a reaction product mixture containing compound 093a or 093b.

[0305] In some embodiments, the reductant is a reducing agent, hi some embodiments, the reducing agent is selected from zinc, iron, or titanium tetrachloride.

[0306] In some embodiments, the base is an inorganic base. In some such embodiments, the base is a hydroxide base. In some such embodiments, the base is selected from sodium hydroxide, potassium hydroxide, or cesium hydroxide. When titanium tetrachloride is the reducing agent, the base is triethylamine.

[0307] In some embodiments, the solvent system consists of a mixture of a non-polar or polar solvent and a polar protic solvent. In some embodiments, the solvent system is selected from water and 1,4-dioxane, water and isopropanol, water and tetrahydrofuran, water and toluene, water and xylene, water and N-methylpyrrolidone, water and sulfolane, or water and dimethylacetamide. In some embodiments, the solvent system comprises or is predominantly comprised of a polar protic solvent. In some such embodiments, the solvent system is water.

[0308] In some embodiments, any of compounds 182a, 182b, 093a, or 093b is optionally isolated from the reaction product mixture. In some embodiments, any two sequential reactions of compounds 181a or 181b to 093a or 093b or all of the sequential reactions of compounds 181a or 181b to 093a or 093b are carried out in a telescopic pot scheme.

[0309] Some embodiments of the present disclosure relate to an alternative method for the preparation of compound 182a or 182b (N-[(2-chloro-6-nitrophenyl)methyl]pyridin-3-amine or N-[(2-bromo-6-nitrophenyl)methyl]pyridin-3-amine), which is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 182a or 182b.

[0310] In some such embodiments, the reducing agent is magnesium. In some such embodiments, the reducing agent is borohydride. In some such embodiments, the reducing agent is selected from sodium borohydride or sodium cyanoborohydride.

[0311] In some embodiments, the solvent system comprises at least one C 1~4 In some such embodiments, the solvent system comprises methanol, ethanol, acetic acid, or a combination thereof.

[0312] Some embodiments of the present disclosure relate to methods for preparing compounds 093a or 093b (4-chloro-2-(3-pyridyl)indazole or 4-bromo-2-(3-pyridyl)indazole) according to a scheme that includes three steps.

[0313] Step 1 for preparing compound 093a or 093b is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 115a or 115b (3-chloro-2-methylaniline or 3-bromo-2-methylaniline), an oxidant, and a solvent system according to the method of the present invention.

[0314] In some step 1 embodiments, the oxidizing agent is potassium hydrogen persulfate, sodium perborate, sodium percarbonate, hydrogen peroxide, peracetic acid, or 3-chloroperbenzoic acid.

[0315] In some Step 1 embodiments, the solvent system comprises or primarily comprises at least one polar aprotic solvent and at least one polar protic solvent, hi some such embodiments, the solvent system comprises or primarily comprises dichloromethane and water or dichloroethane and water.

[0316] In some Step 1 embodiments, compounds 115a or 115b can optionally be isolated from the reaction product mixture.

[0317] Step 2 for preparing compound 093a or 093b is shown in the following reaction scheme: [ka] and reacting the reaction mixture under photochemical conditions to form a reaction product mixture comprising compounds 116a-d (1-chloro-2-(chloromethyl)-3-nitrosobenzene, 1-chloro-2-(bromomethyl)-3-nitrosobenzene, 1-bromo-2-(chloromethyl)-3-nitrosobenzene, or 1-bromo-2-(bromomethyl)-3-nitrosobenzene).

[0318] In some Step 2 embodiments, the Br source is N-bromosuccinimide, Br2 or HBr and hydrogen peroxide. In some Step 2 embodiments, the Cl source is N-chlorosuccinimide, trichloroisocyanuric acid, Cl2 or HCl and hydrogen peroxide.

[0319] In some Step 2 embodiments, the photochemical conditions involve driving the reaction using a light source. In some such Step 2 embodiments, the photochemical conditions involve driving the reaction using visible light.

[0320] In some Step 2 embodiments, a light-sensitive or thermally activated radical initiator is used. In some such embodiments, the radical initiator is azobisisobutyronitrile.

[0321] In some Step 2 embodiments, the solvent system comprises or primarily comprises at least one polar aprotic solvent and at least one polar protic solvent, hi some such embodiments, the solvent system comprises or primarily comprises dichloromethane and water or dichloroethane and water.

[0322] In some Step 2 embodiments, compounds 116a-d can optionally be isolated from the reaction product mixture.

[0323] Step 3 of the first scheme for preparing compound 093a or 093b can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compounds 093a-093b.

[0324] In some Step 3 embodiments, compound 520 is a hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, formate, methanesulfonate, or paratoluenesulfonate salt. In some such Step 3 embodiments, compound 520 can optionally be prepared in situ or can be prepared and isolated prior to use.

[0325] In some Step 3 embodiments, the solvent system comprises or primarily comprises a polar aprotic solvent. In some such embodiments, the solvent system comprises or primarily comprises dichloromethane, dichloroethane, or acetonitrile. In some Step 3 embodiments, the solvent system comprises or primarily comprises at least one aprotic solvent and at least one polar protic solvent. In some such embodiments, the solvent system comprises or primarily comprises dichloromethane and water, dichloroethane and water, acetonitrile and water, toluene and water, or combinations thereof.

[0326] In some Step 3 embodiments, a phase transfer catalyst is used. In some such Step 3 embodiments, the phase transfer catalyst is a quaternary ammonium salt. In some such Step 3 embodiments, the phase transfer catalyst is tetrabutylammonium chloride, tetrabutylammonium bromide, or tetrabutylammonium iodide.

[0327] In some Step 3 embodiments, compounds 093a or 093b may optionally be isolated from the reaction product mixture.

[0328] In some embodiments, any of compounds 115a or 115b, 116a-d, or 093a or 093b are optionally isolated from the reaction product mixture. In some embodiments, any two sequential reactions of compounds 114a or 114b with 093a or 093b or all of the sequential reactions of compounds 114a or 114b with 093a or 093b are carried out in a telescopic pot scheme.

[0329] Some embodiments of the present disclosure relate to a first method for preparing compound 061 (2-(pyridin-3-yl)-2H-indazole-4-carboxylic acid), which method comprises the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 061.

[0330] In some embodiments, the catalyst is selected from a transition metal catalyst. In some embodiments, the catalyst is selected from a palladium catalyst, a nickel catalyst, a platinum catalyst, and a copper catalyst. In some embodiments, the catalyst is selected from a palladium catalyst. In some such embodiments, the catalyst is selected from palladium on carbon or palladium acetate.

[0331] In some embodiments, the ligand is a diphosphine ligand. In some such embodiments, the ligand is 1,3-bis(dicyclohexylphosphinium)propane bis(tetrafluoroborate), 1,3-bis(dicyclohexylphosphino)propane, 1,3-bis(diphenylphosphino)propane, or 1,3-bis(diphenylphosphonium)bis(tetrafluoroborate). In one such embodiment, the ligand is 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate).

[0332] In some such embodiments, the base is an inorganic base. In some such embodiments, the base is a carbonate. In some such embodiments, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. In some such embodiments, the base is potassium carbonate.

[0333] In some embodiments, the reaction atmosphere comprises or primarily comprises a mixture of CO and N. In some embodiments, the reaction atmosphere comprises or primarily comprises CO. In some embodiments, the reaction temperature is at least 100° C.

[0334] In some embodiments, the solvent system comprises or primarily comprises a polar aprotic solvent. In some embodiments, the solvent system comprises or primarily comprises dimethylsulfoxide. In some embodiments, the solvent system further comprises water. In one such embodiment, the solvent system comprises dimethylsulfoxide and water.

[0335] Some embodiments of the present disclosure relate to a second method for preparing compound 061 (2-(3-pyridyl)indazole-4-carboxylic acid), which method comprises the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 061.

[0336] In some embodiments, the base is an alkali metal hydroxide. In some such embodiments, the base is potassium hydroxide or sodium hydroxide. In some such embodiments, the base is sodium hydroxide.

[0337] In some embodiments, the solvent system comprises or primarily comprises water and a polar organic solvent, hi one embodiment, the solvent system comprises or primarily comprises water and at least one solvent selected from acetone, acetonitrile, isopropanol, methanol, ethanol, dimethylsulfoxide, dimethylacetamide, dimethylformamide, N-methylpyrrolidone, and combinations thereof.

[0338] Some embodiments of the present disclosure relate to methods of preparing compound 038 (methyl 2-(3-pyridyl)indazole-4-carboxylate) according to the first, second or third schemes.

[0339] The first scheme for preparing compound 038 involves three steps.

[0340] Step 1 of the first scheme for preparing compound 038 is shown in the following reaction scheme: [ka] and forming a reaction mixture comprising compound 400 (methyl 3-amino-2-methylbenzoate), an oxidizing agent, and a solvent system; and reacting the reaction mixture to form a reaction product mixture comprising compound 500 (methyl 2-methyl-3-nitrosobenzoate).

[0341] In some step 1 embodiments, the oxidizing agent is potassium hydrogen persulfate, sodium perborate, sodium percarbonate, hydrogen peroxide, peracetic acid, or 3-chloroperbenzoic acid.

[0342] In some Step 1 embodiments, the solvent system comprises or primarily comprises at least one polar aprotic solvent and at least one polar protic solvent, hi some such embodiments, the solvent system comprises or primarily comprises dichloromethane and water or dichloroethane and water.

[0343] In some Step 1 embodiments, compound 500 may optionally be isolated from the reaction product mixture.

[0344] Step 2 of the first scheme for preparing compound 038 is shown in the following reaction scheme: [ka] and reacting the reaction mixture under photochemical conditions to form a reaction product mixture comprising compound 510a or 510b (methyl 2-(bromomethyl)-3-nitrosobenzoate or methyl 2-(chloromethyl)-3-nitrosobenzoate).

[0345] In some step 2 embodiments, the Br source is N-bromosuccinimide, Br2 or HBr and hydrogen peroxide. In some step 2 embodiments, the Cl source is N-chlorosuccinimide, trichloroisocyanuric acid, Cl2 or HCl and hydrogen peroxide.

[0346] In some step 2 embodiments, the photochemical conditions involve promotion of a reaction by a light source.

[0347] A light-sensitive or thermally activated radical initiator can optionally be used in some Step 2 embodiments. In some such embodiments, the radical initiator is azobisisobutyronitrile.

[0348] In some Step 2 embodiments, the solvent system comprises or primarily comprises at least one polar aprotic solvent and at least one polar protic solvent, hi some such embodiments, the solvent system comprises or primarily comprises dichloromethane and water or dichloroethane and water.

[0349] In some Step 2 embodiments, compounds 510a or 510b can optionally be isolated from the reaction product mixture.

[0350] Step 3 of the first scheme for preparing compound 038 can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 038.

[0351] In some Step 3 embodiments, compound 520 is a hydrochloride or hydrobromide, hydroiodide, sulfate, hydrogen sulfate, methanesulfonate, or p-toluenesulfonate salt. In some embodiments, compound 520 is a hydrochloride salt. In some such Step 3 embodiments, compound 520 can be optionally prepared in situ or can be prepared and isolated prior to use.

[0352] In some Step 3 embodiments, the solvent system comprises or primarily comprises a polar aprotic solvent. In some such embodiments, the solvent system comprises or primarily comprises dichloromethane, dichloroethane, or acetonitrile. In some Step 3 embodiments, the solvent system comprises or primarily comprises at least one aprotic solvent and at least one polar protic solvent. In some such embodiments, the solvent system comprises or primarily comprises dichloromethane and water, dichloroethane and water, acetonitrile and water, or toluene and water.

[0353] In some Step 3 embodiments, a phase transfer catalyst is used. In some such Step 3 embodiments, the phase transfer catalyst is a quaternary ammonium salt. In some such embodiments, the phase transfer catalyst is tetrabutylammonium chloride or tetrabutylammonium bromide.

[0354] In some Step 3 embodiments, compound 038 may optionally be isolated from the reaction product mixture.

[0355] In some embodiments, any of compounds 500, 510a or 510b or 038 is optionally isolated from the reaction product mixture. In some embodiments, any two sequential reactions of compounds 400 through 038 or all of the sequential reactions of compounds 400 through 038 are carried out in a telescopic pot scheme.

[0356] The second scheme for preparing compound 038 involves three steps.

[0357] Step 1 of the second scheme for preparing compound 038 is shown in the following reaction scheme: [ka] The method includes forming a reaction mixture including compound 400 (where "Protec" represents an amine protecting group), a bromine source or a chlorine source, and a solvent system, and reacting the reaction mixture by exposing the reaction mixture to a light source to form a reaction product mixture including compound 410 (methyl 3-amino-2-(bromomethyl)benzoate or methyl 3-amino-2-(chloromethyl)benzoate).

[0358] In some Step 1 embodiments, the Br source is Br2 and hydrogen peroxide. In some Step 1 embodiments, the Cl source is Cl2. In some Step 1 embodiments, the Cl source is Cl2 and hydrogen peroxide.

[0359] In some embodiments, the protected amine is an acetamide of the structure -NHC(O)CH3.

[0360] In some Step 1 embodiments, the solvent system comprises or comprises primarily at least one polar aprotic solvent and at least one polar protic solvent, hi some such embodiments, the solvent system comprises or comprises primarily dichloromethane and water.

[0361] In some Step 1 embodiments, compound 410 can optionally be isolated from the reaction product mixture.

[0362] The protecting group is removed from compound 400 prior to the formation of compound 430 in step 2. If the protected amine is an acetamide, deprotection by diacylation of the secondary amine can be suitably carried out by reacting 410 with a weak inorganic or organic base in water, a polar protic solvent, or a polar aprotic solvent.

[0363] Step 2 of the second scheme for preparing compound 038 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 430 ((E)-2-bromo-6-(pyridin-3-yldiazenyl)benzyl acetate or (E)-2-chloro-6-(pyridin-3-yldiazenyl)benzyl acetate).

[0364] In some Step 2 embodiments, the acid is an organic acid. In some such embodiments, the acid is acetic acid.

[0365] In some Step 2 embodiments, the solvent system comprises or comprises primarily acetic acid.

[0366] In some Step 2 embodiments, compound 430 can optionally be isolated from the reaction product mixture.

[0367] Step 3 of the second scheme for preparing compound 038 can be represented by the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 038.

[0368] In some Step 3 embodiments, the strong acid is an inorganic acid. In some such embodiments, the acid is a mineral acid. In some such embodiments, the acid is HCl.

[0369] In some Step 3 embodiments, the solvent system comprises or primarily comprises at least one polar protic solvent, hi some such embodiments, the solvent system comprises or primarily comprises water, methanol, ethanol, isopropanol, acetic acid, or combinations thereof.

[0370] In some Step 3 embodiments, compound 038 may optionally be isolated from the reaction product mixture.

[0371] The third scheme for preparing 038 (methyl 2-(3-pyridyl)indazole-4-carboxylate) involves one step. This method is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 038.

[0372] In some embodiments, the catalyst is a transition metal catalyst. In some such embodiments, the catalyst is selected from a palladium catalyst, a nickel catalyst, or a copper catalyst. In some such embodiments, the catalyst is palladium on carbon or palladium(II) acetate.

[0373] In some embodiments, the ligand is a diphosphine ligand, hi some such embodiments, the ligand is selected from 1,3-bis(dicyclohexylphosphino)propane, 1,3-bis(dicyclohexylphosphonium)propane bis(tetrafluoroborate), 1,3-bis(diphenylphosphino)propane, or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0374] In some embodiments, the base is one or more inorganic weak bases. In some such embodiments, the base is a carbonate or a phosphate. In some such embodiments, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trisodium phosphate, and tripotassium phosphate, or combinations thereof. In some embodiments, the base is an organic base. In some such embodiments, the base is triethylamine.

[0375] In some embodiments, the solvent system comprises or primarily comprises a non-polar solvent and methanol. In some such embodiments, the solvent system comprises or primarily comprises xylene and methanol, o-xylene and methanol, or toluene and methanol. In some embodiments, the solvent system comprises or primarily comprises a polar aprotic solvent and methanol. In some such embodiments, the solvent system comprises DMSO and methanol, DMF and methanol, NMP and methanol.

[0376] In some embodiments, the reaction atmosphere is composed of a mixture of CO and N. In some embodiments, the reaction atmosphere is composed primarily of CO. In some embodiments, the reaction temperature is at least 100° C.

[0377] In some embodiments, the resulting compound 038 can be converted in situ to compound 061 (2-(3-pyridyl)indazole-4-carboxylic acid) using hydrolysis in basic or acidic conditions. In some such embodiments, the hydrolysis is carried out using an alkali metal hydroxide base. In some such embodiments, the hydrolysis is carried out using sodium hydroxide or potassium hydroxide.

[0378] Another aspect of the present disclosure relates to an alternative method for preparing compound 038 (methyl 2-(3-pyridyl)indazole-4-carboxylate), which method is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 038.

[0379] In some embodiments, the acid is an inorganic acid. In some such embodiments, the acid is selected from sulfuric acid or hydrochloric acid. In some such embodiments, the acid is an organic acid. In some such embodiments, the acid is p-toluenesulfonic acid.

[0380] In some embodiments, the additive is a dehydrating agent, such as a molecular sieve.

[0381] In some embodiments, the solvent system comprises or comprises primarily a non-polar solvent and methanol, hi some such embodiments, the solvent system comprises or comprises primarily methanol, toluene, hexane, or combinations thereof.

[0382] Some embodiments of the present disclosure relate to a method for preparing compound 092 ((N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole-4-carboxamide) by a two-step process.

[0383] Step 1 for preparing compound 092 (N-(1-methylcyclopropyl)-2-(3-pyridyl)indazole-4-carboxamide) is shown in the following reaction scheme: [ka] and forming a reaction mixture comprising compound 061 (2-(pyridin-3-yl)-2H-indazole-4-carboxylic acid), a chlorinating reagent, and a solvent system; and reacting the reaction mixture to form a reaction product mixture comprising the HCl salt of compound 930 (2-(3-pyridyl)indazole-4-carbonyl chloride).

[0384] In some step 1 embodiments, the solvent system comprises or primarily comprises a non-polar solvent, a polar aprotic solvent, or a combination thereof. In some such embodiments, the solvent system comprises or primarily comprises toluene and N,N-dimethylformamide. In some such embodiments, the solvent system comprises or primarily comprises toluene. In some such embodiments, the solvent system comprises or primarily comprises acetonitrile and N,N-dimethylformamide. In some such embodiments, the solvent system comprises or primarily comprises acetonitrile.

[0385] In some step 1 embodiments, the reaction mixture optionally further comprises a catalyst. Suitable catalysts can be selected from among N,N-dimethylformamide, 4-dimethylaminopyridine, triethylamine, N-methyl-2-pyrrolidone, N-methylformanilide, N-formylpyridine, and pyridine. In some such embodiments, the catalyst is N,N-dimethylformamide. In some such embodiments, the catalyst is pyridine.

[0386] In some embodiments, the chlorinating reagent can be selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, cyanuric chloride, diphosgene, triphosgene, and phosgene. The chlorinating reagent is preferably in stoichiometric excess relative to compound 930.

[0387] In some Step 1 embodiments, compound 930 can optionally be isolated from the reaction product mixture.

[0388] Step 2 is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 092.

[0389] In some step 2 embodiments, the solvent system comprises or primarily comprises a non-polar solvent, a polar aprotic solvent, or a combination thereof. In some step 2 embodiments, the solvent system can be selected from among toluene, xylene, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, dimethylacetamide, isopropyl acetate, tetrahydrofuran, dichloromethane, pyridine, and sulfolane. In some such embodiments, the solvent system comprises or primarily comprises a polar solvent. In some such embodiments, the solvent system comprises one or more polar solvents. In some such embodiments, the solvent system comprises acetonitrile or primarily comprises acetonitrile. In some such embodiments, the solvent system comprises acetonitrile and N-methyl-2-pyrrolidone. In some such embodiments, the solvent system comprises or primarily comprises a non-polar solvent. In some such embodiments, the solvent system comprises toluene or primarily comprises toluene. In some such embodiments, the solvent system comprises toluene and N-methyl-2-pyrrolidone.

[0390] In some Step 2 embodiments, the base is an inorganic base or an organic base. In some embodiments, the organic base can be selected from among triethylamine, N,N-diisopropylethylamine, pyridine, 3-methylpyridine, dimethylaniline, N-methylimidazole, N-methylmorpholine, DABCO, and DBU. In some Step 2 embodiments, the organic base is triethylamine. In some Step 2 embodiments, the organic base is N,N-diisopropylethylamine. In some embodiments, the inorganic base can be selected from among sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.

[0391] Some embodiments of the present disclosure relate to an alternative method for preparing compound 092 (N-(1-methylcyclopropyl)-2-(3-pyridyl)indazole-4-carboxamide), which method is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 092.

[0392] Aminocarbonylation reactions remain challenging even after decades of research in the field. In particular, achieving good yields and selectivities using unreactive electrophiles such as aryl chlorides often requires the use of more demanding conditions such as high loadings of palladium (often at least 2 mol%), which can make the process uneconomical. Furthermore, branched primary amines such as tert-butylamine are also often problematic due to their stringent steric structure, sometimes resulting in low yields, down to as low as 46%. Although strategies have been reported that utilize the formation of reactive activated ester-type species, followed by conversion to the desired amides by acyl transfer, an effective direct aminocarbonylation chemistry is still highly desired (Org. Chem. Front., 2022, 9, 2491; Org. Process Res. Dev. 2008, 12, 4, 566; Angew. Chem. Int. Ed. 2007, 46, 8460; ACS Catal. 2018, 8, 6, 5350).

[0393] In some embodiments, the catalyst is a transition metal catalyst. In some embodiments, the catalyst is selected from a palladium catalyst, a nickel catalyst, or a platinum catalyst. In some such embodiments, the palladium catalyst is selected from palladium on carbon or palladium(II) acetate.

[0394] In some embodiments, the ligand is a diphosphine ligand, hi some such embodiments, the ligand is selected from 1,3-bis(dicyclohexylphosphino)propane and 1,3-bis(dicyclohexylphosphonium)propanebis(tetrafluoroborate).

[0395] In some embodiments, the base is at least one inorganic weak base. In some such embodiments, the base is a carbonate or a phosphate. In some such embodiments, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, disodium hydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, and tripotassium phosphate, or a combination thereof. In some embodiments, the base is aluminum hydroxide. In some embodiments, the base is an acetate base. In some such embodiments, the base is potassium acetate. In some embodiments, the base is an alkoxide base. In some such embodiments, the base is lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, or a combination thereof. In some embodiments, the base is an organic base. In some such embodiments, the base is an amine base. In some such embodiments, the base is selected from trimethylamine, triethylamine, tributylamine, DBU, DABCO, and N,N-diisopropylethylamine.

[0396] In some embodiments, the solvent system comprises or primarily comprises a polar aprotic solvent. In some embodiments, the solvent system is selected from diglyme, dioxane, acetonitrile, DMF, DMAc, sulfolane, DMSO, or some combination thereof. In some such embodiments, the solvent system comprises or primarily comprises dimethylsulfoxide.

[0397] In some embodiments, the reaction atmosphere comprises or primarily comprises a mixture of CO and N. In some embodiments, the reaction atmosphere comprises or primarily comprises CO. In some embodiments, the reaction temperature is at least 100° C.

[0398] Some embodiments of the present disclosure relate to an alternative method for the preparation of compound 092 (N-(1-methylcyclopropyl)-2-(3-pyridyl)indazole-4-carboxamide), which method is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 092.

[0399] In some embodiments, the activating agent is an acyl chloride, anhydride, alkyl chloroformate, sulfonyl chloride, acylimidazole, or triazine chloride. In some such embodiments, the acyl chloride is selected from acetyl chloride, pivaloyl chloride, benzoyl chloride, or phosgene. In some such embodiments, the anhydride is selected from acetic anhydride, pivalic anhydride, or di-tert-butyl dicarbonate. In some such embodiments, the alkyl chloroformate is selected from methyl chloroformate, ethyl chloroformate, or isobutyryl chloroformate. In some such embodiments, the sulfonyl chloride is selected from benzenesulfonyl chloride, p-toluenesulfonyl chloride, or methanesulfonyl chloride. In some such embodiments, the acylimidazole is selected from 1,1'-carbonyldiimidazole. In some such embodiments, the triazine chloride is selected from cyanuric chloride or 2-chloro-4,6-dimethosyl-1,3,5-triazine.

[0400] In some embodiments, the base is an organic base. In some such embodiments, the base is a tertiary amine base such as triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, diazobicyclo[5.4.0]undec-7-ene, tributylamine, or N,N-dimethylbenzylamine. In some embodiments, the base is a heterocyclic amine base such as pyridine, 2,6-lutidine, 3-picoline, imidazole, or N-methylimidazole.

[0401] In some embodiments, the solvent system comprises or primarily comprises at least one non-polar solvent or polar aprotic solvent. In some such embodiments, the solvent system comprises or primarily comprises acetonitrile, N-methylpyrrolidine, toluene, or combinations thereof. In some embodiments, the solvent system consists primarily of acetonitrile.

[0402] Some embodiments of the present disclosure relate to an alternative method for the preparation of compound 092 (N-(1-methylcyclopropyl)-2-(3-pyridyl)indazole-4-carboxamide), which method is shown in the following reaction scheme: [ka] and reacting the reaction mixture to form a reaction product mixture comprising compound 092.

[0403] In some embodiments, the base is an organometallic base. In some embodiments, the base is selected from an organomagnesium base or an organoaluminum base. In some such embodiments, the base is an organomagnesium base, such as, but not limited to, isopropylmagnesium chloride, isopropylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, methylmagnesium chloride, or methylmagnesium bromide. In some embodiments, the base is an organoaluminum base. In some such embodiments, the organoaluminum base is a trialkylaluminum base. In some such embodiments, the base is selected from trimethylaluminum, triethylaluminum, or triisobutylaluminum. In some embodiments, the base is lithium aluminum hydride.

[0404] In some embodiments, the solvent system comprises or comprises primarily a non-polar solvent or a polar aprotic solvent, hi some such embodiments, the solvent system comprises or comprises primarily tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethylene glycol dimethyl ether, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, or cyclopentyl methyl ether.

[0405] Some embodiments of the present disclosure relate to a method for preparing a salt of compound 092, the method comprising the steps of: [ka] and reacting the reaction mixture to form a reaction product mixture comprising a salt of compound 092.

[0406] In some embodiments, the solvent system comprises or comprises primarily a non-polar solvent, a polar solvent, or a combination thereof.

[0407] In some embodiments, the acid is an inorganic acid or an organic acid. In some embodiments, the inorganic acid can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. In some embodiments, the organic acid can be selected from acetic acid, glucuronic acid, oxalic acid, malic acid, citric acid, tartaric acid, maleic acid, fumaric acid, succinic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, and trifluoroacetic acid.

[0408] In some embodiments, compound 092 can be isolated. In some embodiments, compound 092 can be crystallized from its solution in an organic solvent by seeding the solution of compound 092 with compound 092 crystals, followed by water over a period of time and cooling. The crystalline form of compound 092 can then be isolated by methods known in the art (such as filtration or centrifugation) and optionally washed with water. The isolated crystalline form of compound 092 can then be optionally dried. In such embodiments, step 2 can further include the following sequence of steps: (i) exchanging the solvent system for an organic solvent system suitable for crystallization to form a solution of compound 092 in the organic solvent system, (ii) adding thereto water and optional seed crystals of compound 092 to form a slurry, (iii) cooling the slurry, and (iv) isolating the crystalline form of compound 092.

[0409] In some embodiments, the organic solvent is a polar solvent. In some embodiments, the polar solvent is water, a ketone, a nitrile, an amide, C 1~4 In some embodiments, the polar solvent is selected from water, N-methylpyrrolidone, acetonitrile, dichloromethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane, methyl ethyl ketone, ethanol, methanol, propanol, butanol, isopropanol, and combinations thereof.

[0410] In some embodiments, the solution containing compound 092 is a concentrated solution, but below the saturation point of the solvent at elevated temperature. Some non-limiting examples of suitable temperatures include about 75°C to about 95°C or about 85°C to about 95°C. However, one of skill in the art will recognize that higher or lower temperature ranges may be suitable depending on the boiling point of the solvent. In some embodiments, about 1% to about 5% seed crystals of compound 092 are added, followed by the addition of water over a period of time to form a slurry of compound 092 in crystalline form. In some embodiments, the water addition step can be performed at about the same temperature as the solution of compound 092 in the organic solvent. The volume ratio of water to organic solvent is suitably about 0.5:1, about 0.75:1, about 1:1, about 1.25:1, about 1.5:1, about 2:1, about 2:5:1, or about 3:1, and any range consisting therein, such as about 0.5:1 to about 3:1 or about 1:1 to about 1.5:1. The addition of water can be suitably carried out over a period of about 1 hour to about 10 hours, such as about 1 hour, about 2 hours, about 3 hours, about 4 hours or about 5 hours. The slurry of compound 092 can then be cooled over a period of time until crystallization of compound 092 is complete. The cooling time is suitably about 1 hour to about 24 hours or about 2 hours to about 12 hours, such as about 3 hours, about 5 hours or about 8 hours. The final temperature is suitably about 5° C., about 10° C., about 15° C., about 20° C. or about 25° C. The crystalline form of compound 092 is then isolated, washed with water and dried. In some such embodiments, the polar solvent is C 1~4 In some embodiments, the polar solvent is ACN and the crystalline form of Compound 092 is predominantly Form B.

[0411] In some embodiments, the crystalline form of Compound 092, Form A, is characterized by an X-ray powder diffraction pattern generally in accordance with FIG.

[0412] In some embodiments, the crystalline form of Compound 092, Form B, is characterized by an X-ray powder diffraction pattern generally in accordance with FIG. EXAMPLES

[0413] Example 1 below: [ka] Compound 775 was generated by methylation of compound 223 with chloromethane as shown in the above.

[0414] A 25 L autoclave was charged with K2CO3 powder (325 mesh, 1.55 kg, 1.2 equiv.), potassium iodide (155.4 g, 0.1 equiv.) and acetone (7.2 L, 6 V) at 25-30 °C, followed by the addition of α-acetylbutyrolactone (compound 223) (1.2 kg, 1 equiv.). The autoclave vessel was closed and methyl chloride (2 equiv.) was charged to the autoclave until the pressure reached approximately 25 psi. The reaction mixture was heated and maintained at 40-45 °C until compound 223 was less than 2 A% as monitored by HPLC. After the reaction was complete, the reaction product mixture was cooled to room temperature, filtered and washed with acetone. The filtrate containing crude compound 775 was concentrated under vacuum at 40-45 °C to give a brown liquid (1.3 kg). HPLC of the isolated crude material: Compound 223 (not detected), Compound 775 (94.13 A%), O-methylated by-product (1.01 A%). The yield of Compound 775 was 91.2% (93.2% by weight).

[0415] Example 2 Methylation of compound 223 with chloromethane without addition of KI: K2CO3 (1.4 eq.) and acetone (6V) were charged in an autoclave, followed by the addition of α-acetylbutyrolactone (compound 223, 2 g). Methyl chloride (condensed at -30°C, 3 eq.) was charged in the autoclave and the autoclave was closed. The reaction mass was heated to 55-60°C and maintained for 18 hours. The progress of the reaction was followed by HPLC. After completion of the reaction, the reaction mass was cooled to room temperature, filtered and washed with acetone. The filtrate containing compound 775 was concentrated under vacuum at 40-45°C. MTBE was added to the crude product and stirred, after which the mass was filtered and washed with MTBE. The filtrate was concentrated under vacuum at 40°C to obtain crude compound 775 as a light brown liquid. HPLC of the isolated crude material: Compound 223 (28.32 A%), Compound 775 (38.31 A%), O-methylated by-product (23.9 A%).

[0416] Example 3 Methylation of compound 223 with dimethyl sulfate to produce compound 775: Compound 223 (1 eq.), solvent, dimethyl sulfate (1.2 eq.), base (1.4 eq.) and PTC were placed in a multi-necked round-bottom flask and stirred at 25-30° (reactions 6 and 7) or 50-55° (reactions 1-5 and 8-12) for 1 h. Completion of the reaction was followed by HPLC. The results are reported in Table 1, with "ND" standing for not detected and "NR" standing for not reported.

[0417] [Table 1]

[0418] Example 4 Preparation of compound 069: A round bottom flask was charged with concentrated HCl (37%, 3V) and heated to 55-60°C. Compound 775 (1.3 kg, 92.1 wt%) was slowly added into the hot HCl with accompanying evolution of CO2 gas. The reaction was maintained at this temperature for 1 hour and then cooled to room temperature. DCM was added to the reaction mass and stirred. The two layers were separated and DCM was removed under vacuum at 40°C to give crude 069 (1.14 kg, 91.2% yield, 92.2 wt% by GC).

[0419] Example 5 Preparation of Compound 079: A round bottom flask was charged with KOH powder (1.05 equiv.) and water (2 V) at room temperature and the solution was heated to 50-55°C. Compound 069 (1.14 kg, 92.2 wt%) was added to the heated reaction mass over 1 h and kept at this same temperature until compound 069 was less than 2 A% by GC. After completion of the reaction, the reaction mass was cooled to 15-20°C and the pH was adjusted to about pH=2 with 25% aqueous H2SO4. Compound 079 (591 g, 60.4% yield for three steps, 94 wt% by GC) was isolated by separating the two layers and distilling the crude oil (751 g, 87.2% yield, 89 wt% by GC) at 45-90°C under vacuum (10-20 mbar).

[0420] Example 6 Preparation of compound 200: A multi-necked round bottom flask was charged with 9.6% NaOCl (3.5 equiv.) and the solution was cooled to 10-15 °C. Compound 079 (500 g) was slowly charged into the cooled solution. The reaction was kept at room temperature until compound 079 was less than 2 A% by HPLC. The reaction mass was cooled to 10-15 °C and quenched with aqueous sodium bisulfite (~0.5 equiv.). CHCl3 and aqueous layers were separated and the aqueous layer was washed once with MTBE (5 V). The aqueous layer was then cooled to 10-15 °C and acidified to pH = 2 with concentrated H2SO4 (~630 mL) while maintaining the temperature below 25 °C. The aqueous layer was extracted with DCM (2 x 5 V) and the combined DCM layers were reduced to 5 V by distillation. The DCM solution of compound 200 was carried forward to the next step.

[0421] Preparation of compound 144: A multi-necked round bottom flask was charged with a solution of compound 200 (0.03 equiv.) in 5 V of DCM and DMF. Thionyl chloride (1.05 equiv.) was added slowly. After the addition was complete, the reaction was kept at room temperature until compound 200 was less than 2.0 A% by HPLC. In another multi-necked round bottom flask, aqueous NH3 solution (30% in water, 2.5 equiv.) was charged and cooled to 0-5°C. The acid chloride solution was added slowly to the cooled ammonia solution and the reaction was kept for 1 h. Water (2 V) was added to the reaction mass and DCM was distilled off at 40°C. The reaction mass was cooled to 10-15°C, filtered and the filter cake was washed with water (1 V). The solid was dried at 40-45°C to give compound 144 (420 g, 82% yield for three steps, 98.6 wt % by HPLC).

[0422] Example 7 Preparation of 1-methylcyclopropanamine (compound 070) Preparation of Compound 070: 50% NaOH aqueous solution (4.0 equiv.) and water (5V) were placed in a round bottom flask and cooled to 0-5°C. Compound 144 (400 g) was charged and NaOCl (10.1%, 1.5 equiv.) was added slowly to the slurry while maintaining the temperature below 10°C. The reaction mass was kept at 0-5°C for 2 hours. The reaction mass was then brought to 20-25°C and held for 2 hours, heated to 40-45°C and held for 2 hours. Compound 070 was distilled from the reaction mass and collected along with water (290 g, 79.5 wt% by GC, 80.4% yield). Compound 070 was further fractionally distilled through a 1 ft packed column to obtain compound 070 with a purity of 95.6 wt% by GC (70.6% yield).

[0423] Example 8 Preparation of 2,2-dichloro-1-methylcyclopropanecarboxylic acid: In a 500 mL 4-neck round bottom flask, KOH (56.1 g, 1 mol) was added portionwise to a mixture of chloroform (81 mL, 1 mol), methyl methacrylate (26.7 mL, 0.25 mol), and benzyltriethylammonium chloride (2.85 g, 0.012 mol) at 15-20° C. The reaction was maintained at 15-20° C. until complete consumption of the starting material was observed.

[0424] After the reaction was completed, methanol (22 mL, 0.52 mol) and KOH (21.04 g, 0.38 mol) were added and the mixture was heated at 65 °C for 6-7 h. Then water (300 mL) was added and the reaction mass was acidified with concentrated HCl to pH = 1-2. The aqueous layer was extracted with toluene (250 mL), the layers were separated, the organic layer was dried over sodium sulfate and the solvent was removed under vacuum to give 2,2-dichloro-1-methyl-cyclopropanecarboxylic acid as a brown crystalline solid (41 g) in 88% yield (85 wt % by GC).

[0425] Example 9 Example 8 was repeated using ethyl methacrylate. The yield of 2,2-dichloro-1-methylcyclopropyl carboxylic acid was 90%.

[0426] Example 10 In a dry autoclave reactor, a mixture of t-butanol (100 mL, 1.04 mol), 2,2-dichloro-1-methylcyclopropanecarboxylic acid (5 g, 0.029 mol), KOH (11.76 g, 0.17 mol), and 5% Pd / C (1.04 g, 0.0002 mol) was stirred under hydrogen (45 bar) at 130 °C. The reaction was held for 12-14 h. The reaction mass was filtered through a bed of Celite and washed with t-butanol. The filtrate was distilled to remove most of the t-butanol. The filtrate was then added with water (50 mL) and acidified with concentrated HCl to pH = 1-2, followed by extraction with dichloromethane to give a dark brown liquid containing 1-methylcyclopropyl carboxylic acid (2.1 g) in 42.5% yield (59.3 wt % by HPLC).

[0427] Example 11 Example 10 was repeated using 2,2-dibromo-1-methylcyclopropanecarboxylic acid. A 48% yield of 1-methylcyclopropylcarboxylic acid was obtained.

[0428] Example 12 Under nitrogen atmosphere, THF (120 mL, 1.44 mol) was placed in a 3 L 4-neck round bottom flask followed by 2,2-dichloro-1-methylcyclopropanecarboxylic acid (20 g, 0.12 mol). 15% aqueous methanol (790 mL) and sodium (109.88 g, 4.72 mol) were added simultaneously in small portions over about 4-5 h and then held for an additional 6-7 h. Most of the organic solvent was removed and the remaining residue was diluted with water and acidified to pH = 1-2 with concentrated HCl. The reaction mass was extracted with dichloromethane and the solvent was removed under vacuum to give 1-methylcyclopropyl carboxylic acid as a brown liquid (11.4 g, 93% yield, 92.9 A% GC).

[0429] Example 13 2,2-Dichloro-1-methylcyclopropanecarboxylic acid (25 g, 0.14 mol), zinc dust (384.6 g, 5.91 mol) and KOH pellets (33.2 g, 0.59 mol) were refluxed together in 300 mL of t-butanol for 46-48 h. The reaction mass was cooled to 30°C, vacuum filtered and the cake was washed with t-butanol. The combined filtrate was vacuum distilled until most of the solvent was removed. The residue was then taken up in water and subsequently acidified with concentrated HCl to pH=1-2. The aqueous layer was extracted with dichloromethane and the solvent was evaporated to give 1-methylcyclopropylcarboxylic acid as a pale yellow liquid (13.9 g, 92.8% yield, 98.7% by weight by HPLC).

[0430] Example 14 In a 2 L 4 neck round bottom flask, 1-methylcyclopropanecarboxylic acid (48 g, 0.48 mol) and dimethylformamide (1.12 mL, 0.01 mol) were added to dichloromethane (460 mL, 8.48 mol) under nitrogen atmosphere. The reaction mass was cooled to 0-5°C and thionyl chloride (40 mL, 0.55 mol) was added slowly while maintaining the temperature of the reaction mass below 5°C. After the addition was complete, the temperature was increased to 23-25°C and held till consumption of starting material was observed. In another 2 L 4 neck round bottom flask, ammonia in methanol solution (268 mL, 1.44 mol) was added and cooled to 0-5°C. The acid chloride solution was added slowly to the ammonia in methanol solution while maintaining the temperature at 5-10°C. After the addition was complete, the temperature was increased to 20-25°C and held for 1 hour. After the reaction was completed, most of the solvent was distilled off. Dichloromethane (800 mL, 7.0 mol) was added to the residue, the solution was filtered, and the solvent was removed under vacuum to give 1-methylcyclopropanecarboxamide (44.3 g) as a white solid (88% yield, 95% by weight by HPLC).

[0431] Example 15 Preparation of 1-(1-methylcyclopropyl)ethanone oxime: A reaction flask was charged with compound 079 (20 g, 94.3 wt%), EtOH (100 mL, 5 V) and NH2OH·HCl (19.7 g, 1.45 eq) under stirring at 22 °C. NaOAc (24.6 g, 1.55 eq) was added in one portion. The reaction mass was stirred at room temperature and monitored by HPLC. Upon completion of conversion, the reaction mass was quenched slowly with saturated aqueous NaHCO3 (400 mL, 20 V). The reaction mass was extracted with EtOAc (3 x 10 V). The combined organic layers were dried over NaSO4 and concentrated under reduced pressure. 1-(1-methylcyclopropyl)ethanone oxime was obtained as a white solid (21.1 g, 95.3 wt%, 92% yield).

[0432] Example 16 Preparation of N-(1-methylcyclopropyl)acetamide: 1-(1-methylcyclopropyl)ethanone oxime (20.0 g), TsCl (1.6 g, 0.05 equiv.) and MeCN (120 mL, 6 V) were added to a reaction flask and stirred. The reaction mass was heated to 80° C. and the progress of the reaction was followed by HPLC. After complete conversion, the reaction mass was cooled to ambient temperature and charged with activated charcoal (1.5 g, 7.5% wt / wt) and stirred for 3 h. The slurry was filtered through a bed of celite and washed with MeCN (100 mL, 5 V). The filtrate was concentrated under reduced pressure to obtain crude compound N-(1-methylcyclopropyl)acetamide as an orange solid (21.1 g, 80.2 wt%, yield 89%).

[0433] Example 17 Preparation of 1-Methylcyclopropanamine (070): Compound N-(1-methylcyclopropyl)acetamide (6 g) and water (42 mL, 7 V) were taken into a reaction flask under stirring. The reaction was heated to 80°C. Concentrated sulfuric acid (5.38 mL) was added in 215 μL portions to the heated solution at 15 min intervals over 6 h. The reaction was kept at 80°C and followed by GC. After the conversion was complete (~42 h), the reaction mass was cooled to 0-5°C. The pH was adjusted to pH=10-11 with 50% NaOH aqueous solution (~15 g) while maintaining the temperature below 15°C. The reaction mass was analyzed for 1-Methylcyclopropanamine (1.86 g, 60% yield).

[0434] Example 18 Preparation of 1-Methylcyclopropanamine (070): Acetonitrile (2 kg), tetrahydrofuran (14.1 kg) and titanium(IV) isopropoxide (16.2 kg) were charged in a jacketed reactor at 25-30°C and stirred. The reaction mass was cooled to 5-10°C and ethylmagnesium chloride (49 kg, 2M in tetrahydrofuran) was added while maintaining the internal temperature below 20°C. After the addition was complete, the reaction was allowed to warm up to 25-30°C and stirred for 2 hours. The conversion of acetonitrile was followed by GC. After the reaction was completed, the reaction mass was cooled to 5-10°C and boron trifluoride diethyl etherate (14.1 kg) was charged while maintaining the internal temperature below 20°C. After the addition was complete, the reaction mass was allowed to warm up to 25-30°C and stirred for 1 hour. The reaction was then cooled to 5-10°C and a solution of sodium potassium tartrate tetrahydrate (8.4 kg dissolved in 32 kg water) was added to the reaction mass while maintaining the internal temperature below 20°C. After addition was complete, the reaction mass was allowed to warm to 25-30°C and stirred for 1 hour before being filtered to remove solids. The filtrate was collected and kept aside. The filter cake was again placed back into the reactor and reslurried with tetrahydrofuran / water solution (10 kg / 12 kg). After stirring for 30 minutes, the slurry was filtered. The filtrate was collected and kept aside and the filter cake was once again reslurried. After filtration, the filter cake was washed twice with tetrahydrofuran / water solution (4.4 kg / 5 kg). The combined filtrate was placed into a jacketed reactor and the organic solvent was distilled off. After completion of distillation, the reaction mass was cooled to 5-10°C and the pH of the reaction mass was adjusted to about pH 12 with aqueous sodium hydroxide (5.6 kg in 18 kg water). After stirring the reaction mass for some time, compound 070 was isolated by distillation along with water (7 kg, 30.1 wt%, 60.9% yield).

[0435] Example 19 Preparation of 1-Methylcyclopropanamine (070): Acetonitrile (15 kg), tetrahydrofuran (105.6 kg) and titanium(IV) isopropoxide (119.4 kg) were charged in a jacketed reactor at 25-30°C and stirred. The reaction mass was cooled to 5-10°C and ethylmagnesium chloride (383.6 kg, 2M in tetrahydrofuran) was added while maintaining the internal temperature below 20°C. After addition was complete, the reaction was allowed to warm up to 25-30°C and stirred for 2 hours. The conversion of acetonitrile was followed by GC. After reaction was completed, the reaction mass was cooled to 5-10°C and boron trifluoride diethyl etherate (103.7 kg) was charged while maintaining the internal temperature below 20°C. After addition was complete, the reaction mass was allowed to warm up to 25-30°C and stirred for 1 hour. The reaction was then cooled to 5-10°C and a solution of sodium potassium tartrate tetrahydrate (63 g dissolved in 240 kg water) was added to the reaction mass while maintaining the internal temperature below 20°C. After the addition was complete, the reaction mass was allowed to warm to 25-30°C and stirred for 1 hour after which the organic solvent was removed by distillation. In the middle of the distillation, 300 kg water was added to the reaction mass. After the distillation was completed, the reaction mass was cooled to 5-10°C and the pH of the reaction mass was adjusted to about 12 with 50% aqueous sodium hydroxide solution (138.6 kg). After stirring the reaction mass for a period of time, compound 070 was isolated by distillation along with water (fraction 1-40.6 kg, 34.6 wt%; fraction 2-88.6 kg, 1.3 wt%; yield 58.7%).

[0436] Example 20A Preparation of 2-chloro-6-nitrobenzaldehyde (compound 378) The reactor was charged with a solution of 2-(bromomethyl)-1-chloro-3-nitrobenzene (compound 181a) (92.6 A% by HPLC) in dichloromethane and the solution was concentrated to 1 V. DMF (1.0 V) was added to the reactor and the solution was concentrated to 1 V. DMF (2.0 V) was added to the reactor. Trimethylamine-N-oxide (2.2 eq, 50 wt% in water) was added to the reactor and the mixture was heated to 50° C. The reaction mass was held at 50° C. until HPLC showed completion of the reaction to compound 378. The reaction mass was 83.7 A% compound 378 by HPLC analysis.

[0437] Example 20B Preparation of 4-chloro-2-(3-pyridyl)indazole (compound 093a) 2-Chloro-6-nitrotoluene (compound 339) (200.0 g) was placed in a reactor under nitrogen and dissolved in 5 V of dichloromethane (DCM) with stirring. Water (1 V), N-bromosuccinimide (1.25 equiv.) and azobisisobutyronitrile (0.05 equiv.) were added and a 400 W Hg lamp was switched on to initiate photochemical bromination at a reaction temperature of 40-45 °C. The reaction was periodically sampled for IPC analysis by HPLC until compound 339 was less than 1 area %. The reaction was cooled to room temperature and quenched with 4 V of 10% aqueous sodium sulfite. The aqueous layer was separated and the DCM layer was washed with an additional 4 V of water. The aqueous layer was separated and combined with the first aqueous layer and extracted with 2 V of DCM. All organic layers were combined and washed with 4 V of 5% aqueous sodium sulfite. The organic layer was again separated and washed with 4 V of saturated aqueous sodium chloride. The organic layer was separated and distilled to 1 V. Acetonitrile (2 V) was added and the combined solvents were distilled to 1 V ACN at room temperature. This solution was carried on to the next step.

[0438] A solution of 2-(bromomethyl)-1-chloro-3-nitrobenzene (compound 181a) from step 1 (about 270 g of compound 181a) was placed in a reactor and acetonitrile (970 mL) was added. Sodium carbonate (181 g) and water (1269 mL) were added to the reactor under nitrogen and the reaction mass was stirred at room temperature for 10 minutes. The reaction was then heated to 80-85°C for 14-16 hours or until compound 181a was less than 1 area % as analyzed by HPLC. The reaction mixture was cooled to 50°C and acetonitrile was distilled off until the acetonitrile content was less than 5 area % as analyzed by gas chromatography. The reaction mass was cooled to 25-30°C and 500 mL of toluene was added. The mixture was stirred at this temperature for 20 minutes and then the layers were allowed to separate. The toluene layer was set aside and the aqueous layer was returned to the reactor and extracted with another 250 mL of toluene. Both the toluene layers were combined and washed with 212 mL of water. The toluene solution containing (2-chloro-6-nitrophenyl)methanol (compound 050) was carried on to the next step.

[0439] A toluene solution of compound 050 was charged to a reactor at 25-30°C and the reactor was inerted with nitrogen. Tetrabutylammonium bromide (TBAB, 1.04 g) and sodium bicarbonate (108.7 g) were added under nitrogen followed by slow addition of NaOCl solution (1121.6 g) over 2 hours while maintaining the reaction temperature below 30°C. The pH of the solution was 9-10. If it was above 10, it was adjusted with 6N HCl until the pH was in the target range. The reaction mass was stirred at 25-30°C for 2 hours or heated until compound 050 was less than 1 area % as analyzed by HPLC. Stirring was discontinued and the layers were allowed to separate. A 5% aqueous solution of sodium thiosulfate was prepared by dissolving 10.55 g of Na2S2O3 in 212 mL of water. This solution was added to the reaction mass and stirred at room temperature for an additional 25-30 minutes at which point the layers separated. The toluene layer was washed with water (2×212 mL) and the toluene solution containing 2-chloro-6-nitrobenzaldehyde (compound 378) was carried on to the next step.

[0440] Under nitrogen, the toluene layer containing compound 378 was charged to a reactor along with 3-aminopyridine (98.8 g) and p-toluenesulfonic acid (0.095 g). The reaction mass was heated to 105-110°C. As the temperature increased, the slurry became a dark homogenous solution. The reaction was stirred at this temperature for 12-16 hours and water was azeotropically distilled until compound 378 was less than 2 area % as analyzed by HPLC. The reaction mixture was cooled to room temperature and the toluene solution of 1-(2-chloro-6-nitrophenyl)-N-(pyridin-3-yl)methanimine (compound 003a) was carried forward to the next step.

[0441] Triethyl phosphite (670.9 g) was added to the toluene solution of compound 003a at 25-30° C. under nitrogen. The reaction mixture was heated at 105-110° C. for 20-25 hours or until compound 003a was less than 2 area % as analyzed by HPLC. At this point the temperature was reduced to 45-50° C. and toluene was vacuum distilled at 50 mbar until less than 5 area % as analyzed by GC. The reaction mass was cooled to 25-30° C. and 92.7 mL of isopropanol was added. The slurry was stirred for 30 minutes and then 1110 mL of water was added. The reaction mass was then cooled to 10-15° C. and stirred for 2 hours. The resulting solid was isolated by filtration and washed with 277.5 mL of water. The solid was then slurried in 92.7 mL of isopropanol and 370 mL of water, filtered and washed with 370 mL of water. The solid was dried under vacuum at 50 °C until the water content was less than 1% as analyzed by KFT. The assay-corrected yields for steps 1-5 were 45-47%, which corresponds to 98.0-100% by weight of 4-chloro-2-(3-pyridyl)indazole (compound 093a).

[0442] Compound 093a (56 kg), DMSO (4 V) and water (1 V) were charged to a reactor with nitrogen purging. Pd / C (50 wt% water, 0.0015 eq.), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (0.0030 eq.) and potassium carbonate (1.5 eq.) were then added with nitrogen purging. The reaction mass was degassed with nitrogen, the pressure was released and the reactor was pressurized with 130-135 psi of carbon monoxide and heated at 100-110°C for 26 hours or until 093a (4-chloro-2-(3-pyridyl)indazole) was less than 3% by HPLC area percent analysis. The reaction mass was cooled to room temperature and diluted with 5 V of water followed by stirring for 25-30 minutes. Then 1 V of 10% aqueous NaOH was added and stirred for another 15 minutes before filtering through a bed of celite. The aqueous reaction mass was extracted with toluene (2 x 2.25 V) and the separated aqueous layer was acidified with 3N HCl to a pH of 3-4. The resulting slurry was stirred at room temperature for 1 h, at which point crystals of Compound 061 (2-(3-pyridyl)indazole-4-carboxylic acid) were isolated by filtration, washed with water, and dried to constant weight (54.4 kg, 93.5%).

[0443] Example 21 The above procedure was repeated using compound 093b (4-bromo-2-(3-pyridyl)indazole). Analysis by UHPLC showed the following area percentages for the reaction mixture: compound 061 (2-(3-pyridyl)indazole-4-carboxylic acid) (93.5%), compound 093b (0.3%).

[0444] Example 22 Preparation of 4-chloro-2-(3-pyridyl)indazole (compound 093a) In a suitably sized reactor equipped with a column and condenser (or Dean-Stark trap), 2,6-dichlorobenzaldehyde (compound 150) (450 g) and p-toluenesulfonic acid (0.0005 equiv.) were dissolved in 5 V of toluene. The solution was heated to 105-110 °C with continuous distillation of water until the reaction was complete (approximately 16 h). The toluene was distilled and the resulting crude solid was suspended in 0.5 V of isopropanol and 2 V of hexane. The slurry was stirred at room temperature for 1 h and the solid was isolated by filtration and dried under vacuum at below 45 °C. The yield of 1-(2,6-dichlorophenyl)-N-(pyridin-3-yl)methanimine (compound 086) was 560 g (86.7%).

[0445] Compound 086 (100 g) was dissolved in 10 V of methanol in a 2 L round bottom flask at room temperature. The solution was cooled to 0-5 °C and sodium borohydride (0.8 equiv.) was added in 4 portions over 1 h. The reaction was complete in 2 h. The reaction was then quenched with 20 V of water, stirred, and allowed to warm to room temperature over 1 h. The resulting slurry was filtered and the solid was washed with 3 V of water and dried under vacuum at 50 °C to give 88.0 g (87%) of N-(2,6-dichlorobenzyl)pyridin-3-amine (compound 084).

[0446] Compound 084 (300 g) was dissolved in 6 V of DCM in a reactor at room temperature. The solution was cooled to 0° C. with stirring, and then NaNO2 (1.2 eq.) and p-toluenesulfonic acid (1.2 eq.) were added in four portions each while maintaining the temperature at 0° C. The reaction mass was then allowed to warm to room temperature and stirred for 6 hours. The reaction was then filtered through a bed of celite and the DCM solution was evaporated to dryness to give compound 085 (300 g, 90%) as a brown solid.

[0447] In a glass reaction flask, compound 085 (35.0 g) was dissolved in 13.5 V of methanol. The solution was stirred at room temperature while adding thiourea dioxide (3.5 eq.). The reaction mass was stirred for 5 minutes and then cooled to -10°C. Sodium hydroxide (3 eq. of 1N aqueous solution) was added and the reaction mass was warmed to 50°C and stirred for 5 hours. The reaction was then cooled to 25-30°C and diluted with 15 V of ethyl acetate. The organic layer was separated and washed with brine. The organic layers were combined and dried over sodium sulfate followed by filtration and distillation of the ethyl acetate to obtain a 30 g crude sample of the free base of compound 3-(1-(2,6-dichlorobenzyl)hydrazinyl)pyridine (compound 048).

[0448] Crude compound 048 free base (18.0 g) was dissolved in 4 V of ethyl acetate. The solution was cooled to 15-20°C and 5 equivalents of HCl in isopropanol was added slowly while maintaining this temperature. A solid formed upon addition of HCl. The reaction mass was stirred for 1 hour and the solid was isolated by filtration and washed with 2 V of ethyl acetate. It was dried under vacuum at 50°C to give 14 g of 048 (68%). By UHPLC analysis, the sample was approximately 95.7 area percent of the HCl salt of compound 048 and was contaminated with 3.0 A% of the amine by-product.

[0449] Column and method information: Acquity BEH C18 (2.1 mm x 50 mm, 1.7 um), mobile phase A: 0.05% formic acid in water, B: 0.05% formic acid in acetonitrile. Time (min) / %B: 0 / 10; 0.4 / 10; 4 / 100; 6 / 100; 6.1 / 10; 7 / 10. Column temperature 35°C. Flow rate 0.5 mL / min.

[0450] The HCl salt of compound 048 (15.0 g) was suspended in 10 V of dichloromethane and the resulting slurry was cooled to 5-10 °C. Triethylamine (5 eq.) was added and the solution was stirred for 15 min, followed by the addition of acetic anhydride (3 eq.). The reaction was allowed to warm to room temperature and stirred for 8 h. The solvent was distilled to 2 V and the mass was cooled to 25-30 °C and kept at this temperature while 5 V of water was added over 30 min. The resulting slurry was filtered and the solid was washed with 3 V of water before drying under vacuum at 50 °C. 12.2 g of N'-(2,6-dichlorobenzyl)-N'-(pyridin-3-yl)acetohydrazide (compound 083) was isolated in 80.2% yield.

[0451] Compound 083 (5.0 g) was placed in a reactor and dissolved in 6 V of toluene. K3PO4 (2.5 eq) was added and the slurry was stirred at room temperature for 10 minutes. Then trans-N,N-dimethylcyclohexane-1,2-diamine (0.5 eq) and copper iodide (0.1 eq) were added and the reaction mass was heated to 95-100°C. The reaction was stirred at this temperature for 20 hours after which the toluene was distilled off. 5 V of methanol was added and the reaction temperature was increased to 60-65°C. The reaction was stirred at this temperature for 2 hours. Methanol was distilled to 1 V and then 6 V of water was added to precipitate out the solid. The solid was filtered and washed with 2 V of water to give 2.7 g (71.6%) of compound 093a.

[0452] Example 23 Preparation of 4-chloro-2-(3-pyridyl)indazole (compound 093a) A reaction flask equipped with a column and Dean-Stark trap was charged with 2,6-dichlorobenzaldehyde (100 g) and acetohydrazide (1.05 equiv.) and dissolved in toluene (10 V). p-TSA (0.0005 equiv.) was added to the solution and the reaction was heated to 90-95 °C for 8 h with azeotropic distillation of water. The reaction mass was cooled to 40-45 °C and toluene was removed by vacuum distillation to approximately 1 V. Heptane (3 V) was added to precipitate the solid and the slurry was stirred at 25-30 °C for 1 h. The solid N-[(E)-(2,6-dichlorophenyl)methyleneamino]acetamide (compound 197) was filtered, washed with 1 V of heptane and isolated in 87.5% yield. Purity by HPLC analysis was 99.36 area %.

[0453] Compound 197 (5 g) was placed in a reaction flask and dissolved in methanol (10 V). Sodium cyanoborohydride (2 eq.) and acetic acid (3 V) were added and the reaction was stirred at room temperature for 10 h. After the reaction was complete, water (20 V) and toluene (10 V) were added. The organic layer was separated and the aqueous layer was washed with toluene (10 V). The organic layers were combined and the toluene was removed under vacuum to about 1 V. Hexane (3 V) was added to precipitate the solid N'-[(2,6-dichlorophenyl)methyl]acetohydrazide (compound 040), which was filtered and washed with hexane (1 V). Yield: 2.5 g (50%), 98.07 area % purity by HPLC analysis. Up to 70% of the material can be isolated by basifying the reaction mass with saturated Na2CO3 to pH 8-9 instead of performing neutral extraction.

[0454] Compound 040) (0.5 g), 3-bromopyridine (1.0 equiv.), trans-N,N'-dimethylcyclohexyldiamine (0.5 equiv.) or N,N'-dimethylethylenediamine (0.5 equiv.), copper iodide (0.3 equiv.) and toluene were placed in a reaction flask under nitrogen. The reaction mixture was heated to 105-110 °C for 24 h. In-process testing at this point indicated approximately 60 area % 1-[4-chloro-2-(3-pyridyl)-3H-indazol-1-yl]ethanone (Compound 082) and approximately 10% Compound 093a.

[0455] Example 24 Preparation of compound 4-chloro-2-(3-pyridyl)indazole (compound 093a) 3-Aminopyridine (20.0 g, 0.213 mol) was dissolved in 30 mL of acetonitrile. Methanesulfonic acid (21.4 g, 0.223 mol) was added dropwise over 5 minutes. The reaction was stirred for 2 hours, at which point a thick beige slurry formed. The solid was isolated by filtration, washed with acetonitrile (2×5 mL), and dried under vacuum at room temperature to give 39.24 g of the methanesulfonate salt of 3-aminopyridine (compound 520a). Under nitrogen, compound 520a (11.4 g, 0.060 mol) was suspended in sulfolane (115 mL). The slurry was heated to 60° C. 2-(Bromomethyl)-1-chloro-3-nitrobenzene (compound 181a) (10.0 g, 0.040 mol) was added and the solution was heated until it reached 110° C. The reaction was stirred at this temperature for a total of approximately 20 hours. HPLC area percent analysis at a wavelength of 220 nm showed the following distribution of reactants and products: 21.5% compound 520a, 14.6% 2-(bromomethyl)-1-chloro-3-nitrobenzene (compound 182a), 47.2% of the desired product, the protonated salt of N-[(2-chloro-6-nitrophenyl)methyl]pyridin-3-amine, 11.1% 2-chloro-6-nitrophenyl)methanol (compound 050) and 3.7% compound 181a.

[0456] Compound 182a (0.1 g, 0.38 mmol) and zinc dust (0.100 g, 1.52 mmol) were weighed into a 20 mL scintillation vial equipped with a magnetic stir bar. Tetrahydrofuran (2 mL) was added and the grey suspension was stirred at room temperature. Once stirring was started, 2 mL of aqueous NaOH (0.152 g, 3.80 mmol) was added dropwise and the reaction was stirred at room temperature for 4 hours. The organic layer was sampled and analyzed by HPLC, which showed the formation of compound 093a in 71 area % along with 29% N-[(2-chloro-6-aminophenyl)methyl]pyridin-3-amine.

[0457] Example 25 Screening of 3-aminopyridine salts (compound 520) for the synthesis of compound 182 Compound 181a (1.0 equiv.), the appropriate 3-aminopyridine·HA salt (compound 520) (1.5 equiv.) and solvent were placed in a round bottom flask. The reaction mass was then heated to the temperature indicated and the conversion was followed by HPLC analysis. The results are reported in Table 2, with "ND" standing for not detected and "NR" standing for not reported.

[0458] [Table 2]

[0459] Example 26 Preparation of N-[(2-chloro-6-nitrophenyl)methyl]pyridin-3-amine (compound 182a) 1-(2-Chloro-6-nitrophenyl)-N-(pyridin-3-yl)methanimine (compound 003a) (1 g, 3.82 mmol) was dissolved in 10 mL of methanol. Sodium borohydride (0.145 g, 3.82 mmol) was added portionwise as a solid until bubbling ceased. The solution was then heated to reflux at 65° C. for 20 minutes and cooled to room temperature. Water (10 mL) was added to precipitate an orange solid, which was collected by vacuum filtration, washed with water (10 mL), and dried under vacuum at room temperature to give compound 182a, 0.99 g (99%).

[0460] Example 27 Preparation of 4-chloro-2-(3-pyridyl)indazole (compound 093a) A flask under nitrogen was charged with 3-chloro-2-methylaniline (114a) (1.0 equiv.) and dichloroethane (20 V). Potassium hydrogen persulfate (4.0 equiv.) in water (80 V) was added in one portion and the reaction was held at 25° C. until HPLC showed the reaction was complete to 3-chloro-2-methylnitrosobenzene (115a). The layers were separated and the dichloroethane solution of 116 (91.6 A% by HPLC) was carried on to the next step.

[0461] The solution of 115a in dichloroethane in a vessel was charged with water (40 V) and bromine (1.7 equiv.) and sealed. The vessel was heated to 70° C. and irradiated using a 4 W white LED lamp. The reaction was held at 70° C. until HPLC showed the reaction was complete to 3-chloro-2-(bromomethyl)-nitrosobenzene (116b). The layers were separated and the solution of 116b in dichloroethane (72.2 A% by HPLC) was carried forward.

[0462] A solution of compound 116b in dichloroethane was charged with water (10V) and 3-aminopyridinium chloride (compound 520b) (2.5 equiv). The reaction was then heated to 70° C. and held overnight. Additional water (10V) and compound 520b (0.5 equiv) were added, after which the reaction was held at 70° C. until HPLC showed completion of the reaction to 4-chloro-2-(3-pyridyl)indazole (compound 093a). The layers were separated. The solution of compound 093a in dichloroethane showed 32.0 A% by HPLC.

[0463] Example 28 Preparation of methyl 2-(pyridin-3-yl)-2H-indazole-4-carboxylate (compound 038) Compound 038 was prepared by repeating the procedure from Example 27 starting from compound 400 (methyl 3-amino-2-methylbenzoate) to give a solution of compound 038 in dichloroethane (20.0 A% by HPLC).

[0464] Example 29 Preparation of N-(1-methylcyclopropyl)-2-(3-pyridyl)indazole-4-carboxamide (compound 092) A 100 mL HEL Hastelloy pressure reactor was charged with compound 093a (4-chloro-2-(3-pyridyl)indazole) (4.98 g, 21.6 mmol), 1,3-bis(cyclohexylphosphino)propane tetrafluoroborate (0.1336 g, 0.44 mmol), potassium carbonate (7.64 g, 55.9 mmol) and Pd / C (wet) (0.1278 g, 0.25 mol%) at room temperature. The reactor was then purged with nitrogen by pressurizing to 3 bar and releasing it three times. DMSO (50 mL), compound 070 (1-methylcyclopropanamine) (7.8 mL, 86.4 mmol) and pentane (48 mL) were then injected. The reactor was heated to 60° C. and the vent line was opened to purge the pentane / water azeotrope. The reactor system was closed and purged again with nitrogen three times, then purged with carbon monoxide. The reactor was then pressurized to approximately 100-120 psi with carbon monoxide and heated to 110°C with stirring at 200 rpm. Stirring was continued under these conditions for 20 hours, after which the reactor was cooled to room temperature and purged with nitrogen for IPC sampling. Analysis by UHPLC showed the following area %: compound 061 (2-(3-pyridyl)indazole-4-carboxylic acid) (4.04 RRT, 7.8%), compound 092 (4.99 RRT, 85.6%), compound 093a (9.00 RRT, 0.56%). RRT = relative retention time.

[0465] Example 30 The above procedure was repeated with compound 093b (4-bromo-2-(3-pyridyl)indazole) using Pd / C (0.15 mol%). Analysis by UHPLC showed the following area % of the reaction mixture: compound 061 (2-(3-pyridyl)indazole-4-carboxylic acid) (4.04 RRT, 8.3%), compound 092 (4.99 RRT, 87.9%). RRT = relative retention time.

[0466] Example 31 Preparation of N-(1-methylcyclopropyl)-2-(3-pyridyl)indazole-4-carboxamide (compound 092) A 600 mL Parr pressure reactor was charged with compound 093a (4-chloro-2-(3-pyridyl)indazole) (41.35 g, 180.0 mmol), 1,3-bis(cyclohexylphosphino)propane tetrafluoroborate (0.661 g, 1.08 mmol), tripotassium phosphate (43.96 g, 207.05 mmol) and Pd / C (dried) (0.575 g, 0.30 mol%) at room temperature. The reactor was then purged with nitrogen by pressurizing to 3 bar and releasing it three times. DMSO (300 mL) and compound 070 (13.44 g, 189.04 mmol) were then injected. The reactor was then pressurized to 75 psi with carbon monoxide and heated to 110° C. with stirring at 200 rpm. Stirring was continued under these conditions for 8 hours, after which the reactor was cooled to room temperature and purged with nitrogen for IPC sampling. Analysis by UHPLC showed the following area percentages: Compound 061 (2-(3-pyridyl)indazole-4-carboxylic acid) (4.04 RRT, 5.4%), Compound 092 (4.99 RRT, 91.8%), Compound 093a (9.00 RRT, 0.30%). RRT = relative retention time. The typical reaction yield is about 78% after filtration of the catalyst residue and recrystallization from DMSO using water as anti-solvent.

[0467] Example 32 Part A. Compound 093a (4.6 g, 1.0 equiv.), 10 wt. % Pd / C, 1,3-bis(cyclohexylphosphino)propane tetrafluoroborate (Pd:ligand 2:1), base, compound 070 (4 equiv.) and DMSO (10-11V) were charged to a reactor which was purged with nitrogen and then pressurized with CO (100 psi). The reaction mass was then heated to 110° C. and stirred for 20 hours. The reaction mass was then analyzed using HPLC area % analysis. The results are reported in Table 3.

[0468] [Table 3]

[0469] Part B. Compound 093a (4.6 g, 1.0 equiv.), 10 wt.% Pd / C (0.41 mol%), 1,3-bis(cyclohexylphosphino)propane tetrafluoroborate (Pd:ligand 2:1), K3PO4:K2HPO4 (3:1, 2 equiv.), compound 070 (4 equiv.) and solvent (10V) were charged to a reactor which was purged with nitrogen and then pressurized with CO (100 psi). The reaction mass was then heated to 110° C. and stirred for 20 hours. The reaction mass was then analyzed using HPLC area % analysis. The results are reported in Table 4.

[0470] [Table 4]

[0471] Example 33: Effect of CO partial pressure on the consumption rate of compound 093 in an aminocarbonylation reaction to form compound 092 Compound 093 (5.74 g, 1.0 equiv.), Pd (0.3 mol%) (added as 10 wt.% Pd on carbon), 1,3-bis(cyclohexylphosphino)propane tetrafluoroborate (ligand:Pd 2:1), K3PO4 base (1.2 equiv.), compound 070 (1.5 equiv.) and DMSO (7.3 V) were charged to a reactor, which was purged with nitrogen, purged with CO, and then pressurized with CO to the target pressure. The reaction mass was then heated to 110° C. and stirred for 20 hours. CO gas uptake was measured to determine the rate and conversion of each reaction as a function of time. The CO consumption and reaction conversion of each reaction after 5.1 hours are shown in Table 5. The final reaction mass after 20 hours was analyzed using HPLC area % analysis. The results are reported in Table 6. The data shows that the selectivity of the reaction is nearly the same at full conversion, regardless of the CO pressure or reaction rate.

[0472] [Table 5]

[0473] [Table 6]

[0474] Example 34 Preparation of methyl 2-(3-pyridyl)indazole-4-carboxylate (compound 038) A 100 mL HEL Hastelloy pressure reactor was charged with compound 093a (4-chloro-2-(3-pyridyl)indazole) (4.00 g, 0.015 mol), 1,3-bis(cyclohexylphosphino)propane tetrafluoroborate (0.106 g, 0.17 mmol), sodium phosphate (4.28 g, 0.026 mol) and palladium acetate (0.0195 g, 0.087 mmol) at room temperature. The reactor was then purged with nitrogen by pressurizing to 3 bar and releasing it three times. Xylene (36.4 mL) and methanol (8.5 mL) were then injected. The reaction was closed and purged again with nitrogen three times, followed by carbon monoxide. The reactor was then pressurized to about 60 psi with carbon monoxide and heated to 140° C. with stirring at 800 rpm. The gauge pressure was about 75 psi. Stirring was continued under these conditions for 20 hours, after which the reactor was cooled to room temperature and purged with nitrogen for IPC sampling. Analysis by UHPLC showed the following area %: Compound 061 (2-(3-pyridyl)indazole-4-carboxylic acid) (4.04 RRT, 5.6%), Compound 038 (7.06 RRT, 91.3%), Compound 093a (4-chloro-2-(3-pyridyl)indazole) (9.00 RRT, 0.3%). RRT = relative retention time.

[0475] Example 35 Preparation of methyl 2-(3-pyridyl)indazole-4-carboxylate (compound 038) and its in situ conversion to 2-(3-pyridyl)indazole-4-carboxylic acid (compound 061) A dry reactor under nitrogen was charged with 4-bromo-2-(3-pyridyl)-indazole (compound 93b) (25.59 kg, 1.0 equiv.), o-xylene (6V), methanol (1.5V) and triethylamine (1.01V) and the reaction mass was then degassed with nitrogen. Palladium acetate (2.0 mol%) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4 mol%) were then added and the reaction was further degassed with nitrogen. The reactor was then pressurized with CO (60-70 psi) and heated to 75° C. until the reaction was complete to compound 038 by HPLC analysis. Analysis by HPLC showed the following A%: compound 93 (0.22 A%), compound 38 (95.55 A%) and compound 061 (0.64 A%). The reaction mass was then returned to atmospheric pressure and purged with nitrogen. Aqueous NaOH (3N, 9V) was added and the reaction mass was then heated to 80° C. until completion of the reaction to compound 061 was confirmed by HPLC analysis. Analysis by HPLC showed the following A%: compound 061 (95.04 A%). Activated charcoal (2.95 kg) was charged to the reaction mass and the reaction was filtered through a celite bed (14.79 kg) and the celite bed was washed with water (5.0 V). The organic and aqueous layers were separated and the aqueous layer was washed with a mixture of ethyl acetate (5 V) and toluene (10 V). The aqueous layer was acidified to pH 3 using concentrated hydrochloric acid and then additional water (5 V) was added. The aqueous layer was then filtered and the solid was dried to give compound 61 (14.0 kg). Additional compound 061 was recovered from the organic layer and the celite bed to give a total of 20.5 kg of compound 061.

[0476] Example 36 Preparation of methyl 2-(pyridyl)indazole-4-carboxylate (compound 038) Under nitrogen, 2-(3-pyridyl)indazole-4-carboxylic acid (compound 061) (7 g) and methanol (14.3 V) were placed in a flask. Sulfuric acid (3.0 equiv.) was added dropwise over 2 min. The reaction was then heated to 60° C. and held at that temperature until HPLC indicated complete activation. The reaction was then cooled to 0° C. Aqueous sodium bicarbonate (194 mL, 5 wt %) was then added dropwise over 20 min. The slurry was then filtered and the filter cake was washed with the filtrate. The solid was dried under vacuum at 90° C. to give crude compound 038 as a tan solid (10 g, 95.6 A%).

[0477] Example 37 Preparation of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (compound 092) 2-(3-pyridyl)indazole-4-carboxylic acid (5.0 g) (compound 061), tosyl chloride (1.2 eq) and acetonitrile (15 V) were placed in a jacketed reactor under nitrogen with stirring. The reaction mass was heated to 80° C. N-methylimidazole (2.0 eq) was then added slowly to the reaction mass over 5 minutes. The reaction was held at 80° C. until HPLC showed the activation was complete. 1-Methylcyclopropanamine (compound 070) (1.2 eq) was then added slowly to the reaction mass over 5 minutes. The reaction was held at 80° C. until HPLC showed the reaction was complete to compound 092. Water (10 V) was then added slowly over 10 minutes and the reaction mass was heated back to 80° C. The slurry was then filtered, washed with the filtrate and washed with water (2×10 V). The solid was dried under vacuum at 60° C. to give compound 092 as an off-white solid (4.52 g, 95.1 wt %, 70.3% yield).

[0478] Example 38 Preparation of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (compound 092) Methyl 2-(pyridin-3-yl)-2H-indazole-4-carboxylate (compound 038) (200 mg), THF (10 V) and 1-methylcyclopropanamine (compound 070) (2.5 eq) were placed in a dry flask under nitrogen with stirring. The reaction mass was cooled to 0° C. Isopropylmagnesium chloride (2.0 eq) was then added slowly over 5 minutes while keeping the reaction temperature below 10° C. The reaction was then held at 0° C. for 4 hours. Water (5 V) was then added slowly over 5 minutes followed by additional water (15 V) and the reaction mass was stirred at 23° C. for 10 minutes. The slurry was filtered and washed with water (3×15 V). The solid was dried under vacuum at 80° C. to give compound 092 as a pale yellow solid (200 mg, 98 A%, 86.6% yield).

[0479] Example 39 Preparation of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (compound 092) Part A. 2-(3-pyridyl)indazole-4-carboxylic acid (25 g) (compound 061), toluene (5 V) and catalyst (0.05 eq) were placed in a jacketed reactor under nitrogen with stirring. Thionyl chloride (1.25 eq) was added dropwise to the reaction mass. After addition was complete, the reaction mass was heated to 85-90°C and held until the reaction was complete by HPLC. Toluene (2 V) was distilled under vacuum (about 300 torr) at 85-90°C. The reaction mass was cooled to 40°C and fresh toluene (3 V) was charged to the reaction mass. In some cases, N-methyl-2-pyrrolidone (1 V) was charged in place of 1 V of toluene.

[0480] Part B. A solution of 1-methylcyclopropanamine (1.2 eq) (compound 070) in toluene (2V) was added dropwise to the reaction mass from Part A and stirred for 20 minutes. Base was then added dropwise to the reaction mass followed by heating the reaction mass to 60-65°C. The reaction was held at this temperature until HPLC analysis showed that the reaction was complete. The yield of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (compound 092) was determined by HPLC weight % analysis. This is shown in Table 7.

[0481] [Table 7]

[0482] Example 40 Preparation of Form A of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (Compound 092) Part A. 2-(3-pyridyl)indazole-4-carboxylic acid (100 g) (compound 061), toluene (5 V) and N,N-dimethylformamide (0.05 eq) were placed in a jacketed reactor under nitrogen with stirring. Thionyl chloride (2 eq) was added dropwise to the reaction mass. After addition was complete, the reaction mass was heated to 70-75°C and held until reaction was complete by HPLC. The reaction mass was cooled to 40-50°C and toluene was vacuum distilled until 1 V remained. Residual thionyl chloride was removed by charging additional toluene (2 V) and distilling until 1 V remained. Heptane (2 V) was charged and distilled until 1 V remained. The reaction mass was cooled to room temperature and charged additional heptane (5 V). The slurry was filtered under a blanket of N2 and the wet cake of the reaction product (compound 930), which is the acid chloride, was used directly in the next step.

[0483] Part B. The acid chloride from Part A, acetonitrile (14V) and N-methylpyrrolidone (1V) were charged in a jacketed reactor under nitrogen with stirring. Then 1-methylcyclopropanamine (1.2 eq) (compound 070) was added slowly to the reaction mass. Finally, triethylamine (2.1 eq) was charged slowly to the reaction mass while maintaining the temperature below 40°C. The reaction mass was heated to 60-65°C and held until HPLC showed completion of the reaction to compound 092. Acetonitrile was distilled off under vacuum at below 50°C to about 3V. The reaction mass was cooled to room temperature and charged with N-methylpyrrolidone (2V). The reaction mass was heated to 95-100°C, held for 10 minutes, cooled to 90°C and held for 15 minutes, followed by seeding with 3 wt% N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (compound 092). Water (2.5V) was charged at 90°C over 3 hours. The slurry was cooled to 20°C over 5 hours, stirred for 20 minutes, filtered and washed with water (4.5V). The solid was dried at 60°C to give N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (compound 092) as an off-white solid (106.5g, 97.4 wt%, 84.9% yield). The solid was identified as polymorphic form A.

[0484] Example 41 Preparation of Form B of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (Compound 092) Part A. 2-(3-pyridyl)indazole-4-carboxylic acid (15 g) (compound 061), toluene (15 V) and N,N-dimethylformamide (0.1 V) were taken in a 250 mL multi-necked round bottom flask under nitrogen with stirring. Thionyl chloride (2 eq.) was slowly charged to the reaction mass. After the addition was complete, the reaction mass was heated to 70-75°C and held till the reaction was complete by HPLC. The reaction mass was cooled to 40-50°C and toluene was vacuum distilled. Fresh toluene (3 V) was charged and distilled again. A third charge of fresh toluene (3 V) was charged and then distilled off. The reaction mass was cooled to 40-45°C and N-methylpyrrolidone (1 V) was charged. The reaction mass was distilled to remove most of the remaining toluene. Then the reaction mass was cooled to 25-30°C and charged with acetonitrile (14V) followed by 1-methylcyclopropanamine (1.2 eq) (compound 070) was added slowly to the reaction mass. Finally, triethylamine (2 eq) was added slowly to the reaction mass. The reaction mass was heated to 60-65°C and held until HPLC showed completion of the reaction to compound 092. Acetonitrile was vacuum distilled to about 3V below 50°C. The reaction mass was cooled to 25-30°C. 1% NaOH aqueous solution (10V) was added to the reaction mass and stirred for 1 hour. The reaction mass was filtered to collect the solid and washed with water (5V). The solid was dried under vacuum at 45-50 °C to give N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide (compound 092) as an off-white solid (14.5 g, 98.8 wt%, 78.3% yield), which was identified as polymorphic form B.

[0485] Example 42 Preparation and Analysis of Crystalline Form A of Compound 092 by Single Crystal X-ray Diffraction Compound 092 solid (109.1 mg) was combined with EtOH (4 mL) with stirring at approximately 72°C, and the resulting slurry was left stirring at approximately 72-73°C. After approximately 1 day, the majority of the solid in the sample was isolated by positive pressure filtration. A small amount of solid remained in the original vial after filtration, from which a single crystal was selected for analysis. Dimensions: approximately 0.55 x 0.04 x 0.03 mm 3A colorless needle with dimensions of was attached to the polymer loop in a random orientation. Preliminary examination and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube (CuKαλ=1.54184 Å) and a Dectris Pilatus3 R200K hybrid pixel array detector. Form A is the anhydrous / nonsolvated form of compound 092. The crystallographic data and data collection parameters of compound 092 form A are shown in Table 8.

[0486] [Table 8]

[0487] [Table 9]

[0488] Example 43 Preparation of crystalline compound 092 form B and analysis by single crystal X-ray diffraction Compound 092 solid (102.6 mg) was mixed with ACN (4 mL) while stirring at approximately 72-73 °C, and the resulting slurry was left stirring at approximately 72-73 °C. After 1 day, the solids in the sample were separated by positive pressure filtration, and the warm filtrate was placed directly on the lab bench to cool to room temperature. After standing at room temperature for 6 days, a clear liquid and a white solid consisting of thin, needle-like spherulites were observed. The needles were sorted and analyzed. Approximately 0.31 × 0.03 × 0.02 mm 3 A colorless needle with dimensions of 0.01 mm was attached to the polymer loop in a random orientation. Preliminary examination and data collection were performed on a Rigaku Super Nova diffractometer equipped with a copper anode microfocus sealed X-ray tube (CuKαλ=1.54184 Å) and a Dectris Pilatus3 R200K hybrid pixel array detector. Form B is the anhydrous / nonsolvated form of compound 092. The crystallographic data and data collection parameters of compound 092 form B are shown in Table 9.

[0489] [Table 10]

[0490] [Table 11]

[0491] Example 44 Characterization of Compound 092 by X-ray Powder Diffraction for Identification of Polymorphic Forms Powder X-ray diffraction was used to identify the crystalline phases of various samples of compound 092. X-ray diffraction patterns were collected on a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer using an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptical graded multilayer mirror was used to focus the Cu Kα X-rays through the specimen and onto the detector. Prior to analysis, a silicon specimen (NIST SRM640e) was analyzed to confirm that the observed position of the Si111 peak was consistent with the NIST certified position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and anti-scatter knife edges were used to minimize background caused by air. Soller slits were used on the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning position detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.5.5.

[0492] The diffraction maxima were identified from the X-ray diffractograms generated by the software. A characteristic subset of the 2θ diffraction maxima for polymorph A of compound 092 is shown in Table 1. A characteristic subset of the 2θ diffraction maxima for polymorph B of compound 092 is shown in Table 2. Because the X-ray diffraction patterns of polymorph A and polymorph B of compound 092 are distinct from one another, the polymorphic form of a sample of unknown polymorphic form can be readily determined by comparing its characteristic 2θ X-ray maxima to the characteristic 2θ maxima shown in Tables 1 and 2, respectively.

[0493] An X-ray powder diffraction (XRPD) diagram of compound 092 form A is shown in Figure 1. An XRPD diagram of compound 092 form B is shown in Figure 2.

[0494] [Table 12]

[0495] [Table 13]

[0496] Example 45 Screening for stable polymorphic forms of compound 092 Slurry experiments were performed to identify stable forms at various conditions. In these experiments, saturated solutions of various solvents containing excess undissolved solids (starting with Form A plus a small amount of Form B) were stirred for extended periods of time. Slurries at room temperature (RT) and 2-8°C were typically stirred for approximately 2 weeks, while slurries at 72-73°C were stirred for shorter periods (1 day) to minimize potential decomposition. In nearly all slurries, the Form B component was converted to Form A. This suggests that Form A is more stable than Form B at 2°C-73°C. Results are shown in Table 12, where times and temperatures are approximate.

[0497] [Table 14]

[0498] Example 46 Investigation of the interconversion of Forms A and B of Compound 092 The relative thermodynamic stability of anhydrous / nonsolvated Forms A and B was investigated by interconversion (competitive) slurries at 2-8°C, room temperature (RT) and 71-72°C. In these slurries, the given solvent system was pre-saturated with Compound 092 (Form A + a small amount of Form B) at the indicated temperature and a portion of the liquid phase was filtered to a solid mixture containing approximately equal amounts of Forms A and B. The 2-8°C and RT interconversion slurries were stirred for 22 days while the 71-72°C slurries were stirred for a shorter period (2-4 days). Nearly all of the competitive slurries showed conversion to Form A, indicating that Form A is the thermodynamically stable form at 2°C-72°C. The results are reported in Table 13 below, where the liquid phase of each slurry was pre-saturated with as-received Form A + a small amount of Form B, the solvent ratios are v / v, the water activity values ​​were calculated using a UNIFAC calculator at RT, and the times and temperatures are approximate.

[0499] [Table 15]

[0500] The examples are used herein to disclose the invention, including the best mode, and also to enable those skilled in the art to practice the invention, including making and using any device or system, and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements that do not differ substantially from the literal language of the claims.

[0501] It should be noted that the term "a" or "an" entity refers to one or more of that entity. For example, a "solvent system" is understood to represent one or more solvent systems. Thus, the terms "a," "an," "one or more," and "at least one" can be used interchangeably herein.

[0502] Efforts have been made to ensure accuracy with respect to numbers used (including but not limited to temperature, concentrations, etc.) but some experimental errors and deviations can be accounted for.

[0503] Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in an open sense unless the context requires otherwise. It is understood that embodiments and aspects described herein include those that "consist essentially of", "consist of" and / or "consist essentially of".

[0504] The term "predominantly" as used herein means, for example and without limitation, greater than 50%, at least 75%, at least 90%, at least 95% or at least 99% by relevant criteria such as population %, w / w%, w / v%, v / v% and area %.

[0505] Where a range of values ​​is presented, unless the context clearly dictates otherwise, it is understood that each value between the upper and lower limit of that range and each of the other stated or intervening values ​​in the stated range is encompassed herein to the tenth of the unit of the lower limit. The upper and lower limits of these smaller ranges that may be independently included within these smaller ranges are also encompassed herein, subject to any explicitly excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those inclusive limits are also included herein.

[0506] Many modifications and other embodiments and aspects of the inventions described herein will come to mind to one skilled in the art to which these inventions pertain, having the benefit of the teachings presented in the foregoing description. It is to be understood, therefore, that the invention is not limited to the specific embodiments and aspects disclosed, and that modifications and other embodiments and aspects are intended to be within the scope of the appended claims. Although specific terms may be employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. The following scheme 【Chemistry 1】 A method for preparing compound 775 according to the method of claim 1, comprising reacting compound 223 with CH 3 forming a reaction mixture comprising Cl, an alkali metal iodide, a base, and a solvent system; and reacting the reaction mixture to form a reaction product mixture comprising compound 775.

2. (1) The alkali metal iodide is KI, (2) (a) the base is an inorganic base; (b) the base is a carbonate; (c) the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; or (d) the base is potassium bicarbonate; and / or (3) The method of claim 1, wherein: (a) the solvent system comprises an aprotic solvent system; (b) the solvent system comprises acetonitrile; or (c) the solvent system comprises acetone.

3. A method of preparing compound 200 according to the first scheme, the second scheme, or the third scheme, comprising: (1) The first scheme for preparing compound 200 comprises: (i) The following reaction scheme: 【Chemistry 2】 Step 1 comprises forming a reaction mixture comprising compound 775, HCl, and a solvent system, and reacting said reaction mixture to form a reaction product mixture comprising compound 069, according to (ii) the following reaction scheme: 【Transformation 3】 and reacting said reaction mixture to form a reaction product mixture comprising compound 079; (iii) the following reaction scheme: 【Chemistry 4】 and reacting the reaction mixture to form a reaction product mixture comprising compound 200. Including, (2) The second scheme for preparing compound 200 comprises: (i) The following reaction scheme: 【Transformation 5】 (Wherein R is COOCH 3 , COOCH 2 CH 3 , COOH and CN; each X is independently selected from the group consisting of Cl, Br, and I. According to the method, compound 900 and CHCX 3 forming a reaction mixture comprising: a base; a solvent system; and a phase transfer catalyst; and reacting the reaction mixture to produce a reaction product comprising compound 905. and forming a mixture, wherein: (ii) When R is COOCH3, COOCH2CH3 or CN, the process may be carried out according to the following reaction scheme: 【Transformation 6】 Step 1 further comprises step 1b comprising forming a reaction mixture comprising compound 905, a base, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 906 according to the formula: (iii) the following reaction scheme: 【Transformation 7】 and reacting the reaction mixture to form a reaction product mixture comprising compound 200, wherein R is COOH, the method may proceed according to the following scheme: 【Transformation 8】 Step 2 includes step 2' including forming a reaction mixture including compound 905, a reducing agent, and a solvent system, and reacting the reaction mixture to form a reaction product mixture including compound 200, according to Including, (3) The third scheme for preparing compound 200 comprises: (i) The following reaction scheme: 【Chemistry 9】 and reacting the reaction mixture by exposing it to light emitted from at least one light emitting source to form a reaction product mixture comprising compound 110; (ii) the following reaction scheme: 【Chemistry 10】 and step 2 comprising forming a reaction mixture comprising compound 110, a solvent system, and a base, and reacting the reaction mixture to form a reaction product mixture comprising compound 200, according to the method of claim 1. A method comprising:

4. The method of claim 3, wherein compound 775 is prepared by the method of claim 1 or 2.

5. For step 1 of the third scheme for preparing compound 200, (1) (a) the base is a strong inorganic base, or (b) the base is Cs 2 CO 3 and (2) The photocatalyst is 4CzIPN and Ir(ppy) 2 (dtbbpy)PF 6 is selected from (3) the light source is a blue light emitting diode; and (4) The method of claim 3, wherein (a) the solvent system comprises a polar aprotic solvent, or (b) the solvent system comprises dimethylformamide.

6. For step 2 of the third scheme for preparing compound 200, (1) (a) the base is an inorganic base; (b) the base is an alkali metal hydroxide; or (c) the base is selected from sodium hydroxide and potassium hydroxide; and (2) (a) the solvent system comprises a polar solvent; and (b) the solvent system comprises a C 1 ~ 4 4. The method of claim 3, comprising alcohol, water, or a combination of any of the foregoing.

7. A method for preparing compound 070, including a first and second scheme, The first scheme is (1) The following reaction scheme 【Chemistry 11】 Step 1 comprises substep (a) comprising forming a reaction mixture comprising compound 200, a chlorinating reagent, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising an acid chloride intermediate, followed by substep (b) comprising forming a reaction mixture by combining the reaction product mixture from substep (a) with an ammonia source, and reacting the reaction mixture to form a reaction product mixture comprising compound 144, according to (2) The following reaction scheme 【Chemistry 12】 and step 2 comprising substep (a) of forming a reaction mixture comprising compound 144, a base, an oxidizing agent, and a solvent system, and reacting said reaction mixture to form a reaction product mixture comprising an N-halocarboxamide intermediate, followed by substep (b) of heating said reaction product mixture comprising the N-halocarboxamide intermediate to form a reaction product mixture comprising compound 070, according to the method of claim 1. Including, The second scheme is (1) The following reaction scheme 【Chemistry 13】 (In the formula, R is CONH 2 and each X is independently selected from Cl, Br, and I; According to the method, compound 900 and CHCX 3 Step 1 comprising forming a reaction mixture comprising a base, a solvent system, and a phase transfer catalyst, and reacting the reaction mixture to form a reaction product mixture comprising compound 905; (2) The following reaction scheme 【Chemistry 14】 Step 2 comprises forming a reaction mixture comprising compound 905, a reducing agent, and a solvent system according to the method of claim 1, and reacting said reaction mixture to form a reaction product mixture comprising compound 144; (3) The following reaction scheme 【Chemistry 15】 forming a reaction mixture comprising compound 144, a base, an oxidizing agent, and a solvent system; and reacting the reaction mixture to form a reaction product mixture comprising an N-halocarboxamide intermediate according to the method of claim 1. followed by step 3 comprising heating said reaction product mixture comprising said N-halocarboxamide intermediate to form a reaction product mixture comprising compound 070; A method comprising:

8. Regarding step 1 of the first scheme, (1) (a) the chlorinating reagent is selected from thionyl chloride, triphosgene, or phosgene, or (b) the chlorinating reagent is thionyl chloride; (2) (a) the catalyst is selected from DMF, DMAP, triethylamine, NMP, N-methylformanilide, N-formylpyridine, and pyridine; (3) (a) the solvent system of substep (a) comprises at least one aprotic solvent; or (b) the solvent system comprises dichloromethane, toluene, acetonitrile, or a combination thereof; (4) the ammonia source is selected from ammonia and ammonium hydroxide; and (5) The solvent system of substep (b) comprises the solvent system from substep (a), or comprises a combination of the solvent system from substep (a) with a polar protic solvent, or comprises a polar protic solvent, or the polar protic solvent is selected from the group consisting of water, C 1 ~ 4 8. The method of claim 7, wherein the solvent is selected from the group consisting of ethanol, ethanol, ethanolic acid, ethanolic esters ...

9. Regarding step 2 of the second scheme, (1) (a) the reducing agent is a strong reducing agent; (b) the reducing agent is a metal selected from Na, K, Ca, Mg, and Zn; or (c) the reducing agent is selected from Na and Zn; and (2) (a) the solvent system comprises a polar aprotic solvent, a polar protic solvent, or a combination thereof; or (b) the solvent system comprises a C 1 ~ 4 (c) the solvent system comprises tetrahydrofuran, C acetic acid, water, tetrahydrofuran, ethylene glycol, tetramethylethylenediamine, N,N-dimethylaniline, dimethylformamide, diethanolamine, ethylenediamine, triethylamine, ammonium hydroxide, or a combination thereof; 1 ~ 4 8. The method of claim 7, wherein the solvent system comprises alcohol, water, or a combination of any of the foregoing.

10. Regarding step 2 of the first scheme or step 3 of the second scheme, (1) (a) the base is a strong inorganic base; (b) the base is an alkali metal hydroxide; or (c) the base is selected from sodium hydroxide and potassium hydroxide; (2) (a) The oxidizing agent is Cl 2 ,Br 2 , NaOCl and NaOBr, or (b) the oxidizing agent is selected from Br 2 or the oxidizing agent is NaOCl; (3) (a) the solvent system comprises a polar protic solvent, or (b) the solvent system comprises water, or (c) the solvent system comprises a combination of the foregoing; (4) The method of any one of claims 7 to 9, wherein the reaction product mixture containing the N-halocarboxamide intermediate is heated to a temperature greater than 25°C.

11. The following structure: 【Chemistry 16】 A compound useful for the preparation of compound 070, having the formula:

12. Regarding step 1 of the second scheme, (1) (a) the base is a strong inorganic base; (b) the base is an alkali metal hydroxide; or (c) the base is selected from sodium hydroxide and potassium hydroxide; (2) the phase transfer catalyst is selected from (a) ammonium halide salts, crown ethers, and PEG; (b) triethylbenzylammonium chloride, triethylbenzylammonium bromide, tetraethylammonium bromide, tetrabutylammonium bromide, and ethyltrimethylammonium iodide; or (c) triethylbenzylammonium chloride; and (3) The method of any one of claims 7, 9, or 10, wherein the solvent is (a) a protic solvent, an aprotic solvent, or a combination thereof, or (b) the solvent is selected from water, hexane, pentane, heptane, benzene, toluene, chlorobenzene, dichloromethane, and combinations of any of the foregoing.

13. The method of any one of claims 7 to 12, wherein compound 200 is prepared according to the method of any one of claims 3 to 7.

14. A method for preparing compound 070, comprising: (1) The following reaction scheme 【Chemistry 17】 Step 1 comprises forming a reaction mixture comprising compound 079, a hydroxylamine source, a base, and a solvent system, and reacting said reaction mixture to form a reaction product mixture comprising compound 994, according to (2) The following reaction scheme [Chemistry 18] Step 2 comprises forming a reaction mixture comprising compound 994, an activating agent, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 403, according to (3) The following reaction scheme 【Chemistry 19】 forming a reaction mixture comprising compound 403, an acid, and a solvent system according to the formula: reacting the mixture to form a reaction product mixture comprising compound 070; A method comprising:

15. For step 1 for preparing compound 070: (1) (a) the amine source is selected from hydroxylamine and hydroxylamine salts, or (b) the amine source is hydroxylamine hydrochloride; (2) (a) the base is an inorganic base, or (b) the base is sodium acetate, and / or (3) (a) the solvent system comprises a polar protic solvent; or (b) the solvent system comprises a C 1 ~ 4 15. The method of claim 14, wherein (c) the solvent system comprises an alcohol; or (d) the solvent system comprises ethanol.

16. For step 2 to prepare compound 070: (1) the activating agent is selected from tosyl chloride, hydrocyanuric acid chloride, thionyl chloride and sulfamic acid; and / or (2) The method of claim 14 or 15, wherein the solvent system (a) comprises a polar protic solvent or (b) comprises acetonitrile.

17. For step 3 to prepare compound 070: (1) The acid is (a) a strong inorganic acid, (b) a mineral acid, or (c) H 2 SO 4 and / or (2) The method of any one of claims 14 to 16, wherein (a) the solvent system comprises a polar protic solvent system, or (b) the solvent system comprises water.

18. 18. The method of any one of claims 14 to 17, wherein any of compounds 994, 403 and 070 is optionally isolated from the reaction product mixture.

19. The method of any one of claims 14 to 17, wherein two or all of the sequential reactions from compound 079 to compound 070 are carried to the next step without isolation.

20. A method for preparing compound 070 according to the following scheme: 【Chemistry 20】 forming a reaction mixture comprising acetonitrile, an ethylmagnesium halide, a titanium reagent, and a solvent; reacting the reaction mixture; adding an acid to the reaction mixture; and further reacting the reaction mixture to form a reaction product mixture comprising compound 070 according to the method of claim 1.

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