Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.C(OC([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1)=O)(C)(C)C>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:8]([O:10][CH2:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: O=C(OCC1CCNCC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)acetic acid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[N:19]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:26][CH2:27]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CC(CCN2CCN(c3ncccn3)CC2)c2nc3ccccc3n2C1=O

Procedure:
To 60 mL of toluene was added 4.0 g (0.0152 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one, 6.0 g (0.033 mol) of 1-(2-pyrimidyl)piperazine, and 4.0 g (0.04 mol) of triethylamine. The reaction mixture was heated at reflux for 2 days and subsequently washed with 2×50 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. Crystallization from ethyl acetate afforded 4.0 g, 67% of analytically pure crystals, mp 161°-62° C.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:26][NH2:27]>C(O)C>[NH2:5][C:4]1[C:3]2[C:2](=[C:9]([F:10])[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=2)[NH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1
Reaction time: 19 h

Procedure:
A solution of 0.8 g of 2,3-difluoro-4-(4-tert-butoxycarbonylaminophenyl)benzonitrile in 25 mL of absolute ethanol is admixed with 0.35 mL of hydrazine hydrate. The reaction mixture is stirred for 19 hours at the reflux of the solvent and then concentrated under reduced pressure. The solid residue is stirred with 25 mL of distilled water, filtered and washed with 2×5 mL of dichloromethane. After suction treatment, 0.54 g of 3-amino-7-fluoro-6-(4-tert-butoxycarbonylaminophenyl)-1H-indazole is obtained, whose characteristics are as follows:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([OH:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC#N>[Cl:8][C:7]1[C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ncccc2Cl)cc1

Procedure:
2,3-Dichloropyridine (2.66 g, 18.0 mmol), 4-carboxyphenylboronic acid (2.70 g, 16.3 mmol), and Pd(PPh3)4 (0.965 g, 0.835 mmol) were combined in a degassed solution of 1:1 0.5M aq Na2CO3:MeCN (120 mL), heated to 85° C. for 5 hours, filtered, and the filtrate concentrated under reduced pressure to remove most of the MeCN. The concentrate was extracted with CH2Cl2 (10 mL) and acidified with 1N HCl. The acidified solution was filtered and the filter cake dried under reduced pressure to provide the title compound as a solid.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12])=[O:4].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[S:22]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([F:1])[F:13])=[C:6]([F:12])[CH:7]=1)(=[O:23])=[O:21]
Reactant: O=C(c1ccc(O)cc1F)C(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1F)C(F)F

Procedure:
To 2,2-difluoro-1-(2-fluoro-4-hydroxyphenyl)ethanone (39.0 g, 0.2 mol) and Et3N (20.7 g, 0.2 mol) in CH2Cl2 at 0° C. was added Tf2O (58 g, 0.2 mol) dropwise while keeping the temperature at 0° C. The ice-salt bath was removed, and when the temperature rose to 25° C., a solution of saturated NaHCO3 was added. The aqueous phase was extracted with CH2Cl2 and the combined extracts were dried over MgSO4, and concentrated, and the residue was purified by column chromatography (PE/EA 10:1) to afford 4-(difluoroacetyl)-3-fluorophenyl trifluoromethanesulfonate as an brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 90 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 90% of theory, C27H28N6O3 (484.6); Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=485; (M+2H)++=243; (M+H+Na)++=254.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:27]=[C:28]([C:32]2([C:35]#[N:36])[CH2:33][CH2:34]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(C)c1CO
Reactant: N#CC1(c2cccc(O)c2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(C2(C#N)CC2)c1
Reaction time: 16 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (2.81 g, 20.6 mmol) and diisopropyl azodicarboxylate (DIAD, 4.69 g, 23.2 mmol) in THF (20 ml) was added drop wise to a solution of 1-(3-hydroxyphenyl)cyclopropanecarbonitrile (Step B, 3.2 g, 20.1 mmol) and triphenylphosphine (5.37 g, 20.5 mmol) in THF (50 ml) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 16 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:45]([N:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1)([CH3:47])[CH3:46]>C(Cl)Cl>[CH:45]([N:48]1[CH2:53][CH2:52][CH:51]([NH:54][C:8]([C:4]2[NH:5][C:6]([CH3:7])=[C:2]([Br:1])[C:3]=2[CH3:11])=[O:10])[CH2:50][CH2:49]1)([CH3:47])[CH3:46]
Reactant: Cc1[nH]c(C(=O)O)c(C)c1Br
Reactant: CC(C)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(C(C)C)CC2)c(C)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.3 %

Procedure:
To 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (570 mg) in DCM (15 mL) was added DIEA (2.11 g), HATU (994 mg) and 1-isopropyl-piperidin-4-ylamine (372 mg). The mixture was stirred for 16 h at RT after which it was concentrated. The residue was purified by preparative HPLC to give 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (65 mg) which was directly used in the next step.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[Mg]>C(O)(C)C>[N:6]1[CH:7]=[CH:8][C:3]([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:16])=[CH:4][CH:5]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccncc1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-cyanopyridine (5.2 g, 0.05 mole) and benzophenone (9.1 g, 0.05 mole) in iso-propanol was added acetic acid (6.0 g, 0.1 mole) and magnesium metal (1.2 g, 0.05 mole). The resulting mixture was stirred at room temperature for 4 h. The precipitated product was filtered and washed with acetone, and upon analysis found to be 4-pyridyl diphenyl carbinol.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)OB([C:27]2[CH:31]=[CH:30][N:29]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:28]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:31]=[CH:30][N:29]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[CH:28]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.51 mmol) in 1,4-dioxane (5.0 mL) and water (3 drops) was added 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[tris(propan-2-yl)silyl]-1H-pyrrole (356 mg, 1.02 mmol), Pd(PPh3)4 (29.4 mg, 0.03 mmol), and sodium carbonate (108.1 mg, 1.01 mmol) with stirring for 1 hour at 90° C. under an atmosphere of nitrogen. The resulting mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) to give methyl 3-[methyl(propan-2-yl)amino]-2-[1-[tris(propan-2-yl)silyl]-1H-pyrrol-3-yl]quinoxaline-6-carboxylate as a yellow solid (130 mg, 53%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]2=[O:15])[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[O:15]=[C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][N:8]1[CH:5]1[CH2:6][CH2:7][CH:2]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:3][CH2:4]1
Reactant: O=C1CCC(n2cc(Cl)ccc2=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(Cl)ccc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-(4-oxo-cyclohexyl)-5-chloro-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20].[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH2:39]O)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:19]([C:18]([CH3:22])([CH3:21])[CH2:17][C:11]1[CH:12]=[C:13]([O:16][CH2:39][C:35]2[CH:34]=[C:33]([CH:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][N:36]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])#[N:20]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C#N)c1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C#N)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of 3-(2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl)-2,2-dimethylpropanenitrile (151 mg), ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (168 mg) and tributylphosphine (0.25 mL) in toluene (5.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (256 mg), and the mixture was stirred at room temperature for 3 hr. Hexane was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (234 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:17])=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8]([Cl:17])=[O:9])[N:3]=1
Reactant: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OCF)C(=O)Cl)ns1
Temperature: -12 °C
Reaction time: 0.33 h

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 10.0 g (45.42 mmol) of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)fluoromethoxyiminoacetic acid were stirred at room temperature to completely dissolve the latter in the former, followed by cooling to -12° C. Added dropwise to the reaction mixture was a chlorinating reagent, which had been prepared beforehand by gradually adding 7.65 g (49.89 mmol) of phosphorus oxychloride at 5° C. into a mixture of 20 ml of THF and 3.7 g (49.93 mmol) of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. Subsequent to their reaction for 60 minutes with the temperature maintained at -15° C., the reaction mixture was poured into 150 ml of ice water and was then stirred for 20 minutes to precipitate crystals. The crystals were collected by filtration, washed twice with 15 ml aliquots of ice water and then, under reduced pressure, dried, whereby the title compound was obtained. Yield: 8.50 g (77.9%). Purity: 95.7%.
Reaction SMILES: [OH:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[S:13](Cl)([CH3:16])(=[O:15])=[O:14].Cl>C(Cl)Cl>[CH3:16][S:13]([O:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])(=[O:15])=[O:14]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](OS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of (S)-methyl 2-hydroxy-2-phenylacetate (20.0 g, 120 mmol) in DCM (240 mL) maintained at 0° C. under N2 flowstream, are added mesylchloride (11.2 mL, 144 mmol) and TEA (20.1 mL, 144 mmol) and the mixture is stirred at RT for 1 hour (UPLC-MS monitoring: complete conversion). The mixture is cooled to 0° C., 0.1N HCl (240 mL) is added and the desired compound is extracted with DCM (2×200 mL). The combined DCM phases are dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by filtration through a silica bed eluting with DCM, obtaining 22.4 g of the title compound as white solid (76% yield).
Reaction SMILES: O.NN.O[N:5]1C2C=CC=CC=2N=[N:6]1.Cl.C(N=C=NCCCN(C)C)C.[CH2:26]([O:33][C:34]([NH:36][C@H:37]1[CH2:45][O:44][C@H:40]([C:41](O)=[O:42])[CH2:39][CH2:38]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[NH:5]([C:41]([C@H:40]1[O:44][CH2:45][C@H:37]([NH:36][C:34](=[O:35])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:38][CH2:39]1)=[O:42])[NH2:6]
Reactant: On1nnc2ccccc21
Reactant: O=C(N[C@@H]1CC[C@@H](C(=O)O)OC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)[C@@H]1CC[C@@H](NC(=O)OCc2ccccc2)CO1
Reaction time: 18 h
Yield: 86.1 %

Procedure:
Hydrazine monohydrate (0.23 ml, 3.86 mmol), 1-hydroxybenzotriazole (434 mg, 3.21 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (740 mg, 3.86 mmol) were added to an N,N-dimethylformamide (16 ml) solution of the compound (898 mg, 3.21 mmol) obtained in Step 3 above at room temperature and the resulting mixture was stirred for 18 hours. The reaction mixture was subjected to extraction with chloroform:methanol [10:1 (v/v)] and the organic layer was washed with saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography [dichloromethane:methanol=49:1→13:1 (v/v)] to give 811 mg (86%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:17][C:18]1([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](O)[CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:17][C:18]1([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]([O:16][C:13]2[CH:14]=[CH:15][C:10]([C@@H:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH3:9])=[O:7])=[CH:11][CH:12]=2)[CH2:19]1
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: CC1(C)CC(O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CC(C)(C)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 3,3-dimethylindan-1-ol (110 mg, 0.669 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (101 mg, yield: 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[NH2:40][C@H:41]([C:46]([OH:48])=[O:47])[CH2:42][C:43]([OH:45])=[O:44]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[NH2:40][C@H:41]([C:46]([O-:48])=[O:47])[CH2:42][C:43]([O-:45])=[O:44]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of L-aspartic acid (0.038 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give Nilotinib L-aspartate form II.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([CH:31]([C:36]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])([C:40](Cl)=[O:41])[CH:37]([F:39])[F:38])[C:32]([O:34][CH3:35])=[O:33])C1C=CC=CC=1.ClC(C(C(F)F)C(C)C(OC)=O)=O>>[CH:17](=[N:16][C:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:40](=[O:41])[C:36]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])([CH:37]([F:39])[F:38])[CH:31]([CH3:24])[C:32]([O:34][CH3:35])=[O:33])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)N=Cc1ccccc1
Reactant: COC(=O)C(Cc1ccccc1)C(C(=O)Cl)(C(=O)OCc1ccccc1)C(F)F
Agent: COC(=O)C(C)C(C(=O)Cl)C(F)F
Product: COC(=O)C(C)C(C(=O)OCc1ccccc1)(C(=O)C(Cc1ccccc1)(N=Cc1ccccc1)C(=O)OC(C)(C)C)C(F)F

Procedure:
1-t-butyl 6-methyl 2-benzylideneamino-2-benzyl-4-benzyloxycarbonyl-4-difluoromethyl-5-methyl-3-oxohexanedioate is prepared in a similar manner except that t-butyl 3-phenyl-2-benzylideneaminopropionate is used in place of t-butyl 2-benzylideneaminopropionate and methyl 2-benzyl-3-benzyloxycarbonyl-3-chloroformyl-4,4-difluorobutanoate and methyl 3-benzyloxycarbonyl-3-chloroformyl-4,4-difluoro-2-methyl butanoate are used respectively in place of methyl 3-chloroformyl-4,4-difluoro-2-methylbutanoate.