Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37]([CH2:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)(=[O:39])=[O:38].Cl.C([O-])(O)=O.[Na+]>>[C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:45][C:44]4[CH:46]=[CH:47][C:41]([CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:42][CH:43]=4)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Nc5ccc(CS(C)(=O)=O)cc5)n4)ccc3n2C)cc1

Procedure:
To a solution of {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-(4-methoxy-phenyl)-carbamic acid tert-butyl ester (100 mg, 0.20 mmol) and 4-[(methylsulfonyl)methyl]aniline (37 mg, 0.20 mmol) was added cat HCl and the reaction was heated to 70 C overnight. The reaction was neutralized with solid NaHCO3, filtered and concentrated. The crude material as purified through silica gel to give the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.24 (s, 1H), 7.82 (d, J=6.0 Hz, 1H), 7.65-7.74 (m, 3H), 7.54 (d, J=1.5 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.24 (dd, J=8.7 and 1.5 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 5.72 (d, J=5.7 Hz, 1H), 4.32 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.46 (s, 3H), 2.84 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=644 [M+H]+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[C:19]2[NH:18][C:17](=[O:20])[CH2:16][CH2:15][C:14]=2[C:13]([CH:21]=[O:22])=[CH:12][CH:11]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:26]>C(OCC)(=O)C.O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:18]2[C:19]3[C:10]([O:9][CH3:8])=[CH:11][CH:12]=[C:13]([CH:21]=[O:22])[C:14]=3[CH2:15][CH2:16][C:17]2=[O:20])=[CH:29][CH:28]=1)([O:24][CH3:23])=[O:26]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(C=O)c2c1NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2C(=O)CCc3c(C=O)ccc(OC)c32)cc1
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
Sodium hydride (60% in oil) (2.87 g) was added at 0° C. to a DMF solution (100 ml) of 8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde (13.4 g), followed by stirring for 30 minutes. Methyl 4-bromomethyl benzoate (18.0 g) was added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4→1:2). The purified product was recrystallized from a chloroform-diisopropyl ether mixed solvent to thereby obtain 14.43 g (yield: 62%) of 1-(4-carbomethoxybenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:13](=[O:23])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)[N:16]=[C:7]12)[CH3:2].[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:24])[NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:13](=[O:23])[C:14]([Br:25])=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)[N:16]=[C:7]12)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)NC1CCCCn2c1nc(-c1ccncn1)cc2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)NC1CCCCn2c1nc(-c1ccncn1)c(Br)c2=O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a solution of 0.080 g (0.24 mmol) of (4-oxo-2-pyrimidin-4-yl -4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-yl)-carbamic acid ethyl ester in dimethylformamide (4 mL) were added 0.21 g (1.21 mmol) of N-bromosuccinimide and 0.03 g (0.12 mmol) of benzoyl peroxide. The solution was stirred at room temperature for 10 min and at 50° C. for 20 min. The reaction was quenched by adding a saturated solution of ammonium chloride. The product was extracted with dichloromethane, the organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 95/5 to afford 58 mg of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[S:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20]3[S:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=3)[CH2:17][CH2:18]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1csc(NC2CCNCC2)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)n1
Reaction time: 4.5 h

Procedure:
4-Chlorobenzoyl chloride (0.19 mL) was added to a mixture of ethyl (2E)-3-[2-(4-piperidylamino)-1,3-thiazol-4-yl]acrylate dihydrochloride (0.5 g) and triethylamine (0.63 mL) in DMF (10 ml) under ice-cooling and the mixture was stirred at same temperature for 4.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and the mixture was extracted with an AcOEt. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl (2E)-3-(2-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-1,3-thiazol-4-yl)acrylate (0.48 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([CH:26]4[CH2:28][CH2:27]4)[N:24]=3)[N:19]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.C([Cl:40])(=O)C>CO>[ClH:40].[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([CH:26]4[CH2:28][CH2:27]4)[N:24]=3)[N:19]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=2)=[O:16])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)C1
Reactant: CC(=O)Cl
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCNC2)c2nc(C3CC3)cnc21
Product: Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 105.9 %

Procedure:
In a 25 mL round-bottomed flask, 3-{[2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.435 g, 0.84 mmol) was dissolved in MeOH (7 mL). The solution was cooled to 0° C. and acetyl chloride (1.2 mL, 16.8 mmol) was added dropwise over 10 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated at room temperature and the residue was dried under high vacuum to afford 402 mg of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid piperidin-3-ylamide hydrochloride as a light yellow foam which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][NH:6]1)=[O:4].CC(C[AlH]CC(C)C)C.CO.O.[CH3:20][C:21]#[N:22]>C1(C)C=CC=CC=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>[NH:22]1[CH2:20][CH:21]1[CH:1]1[O:2][CH:3]([OH:4])[CH:5]2[N:6]1[CH2:7]2
Reactant: COC(=O)C1CN1
Reactant: CC#N
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: OC1OC(C2CN2)N2CC12
Temperature: -78 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a flame dried Schlenk tube equipped with a magnetic stirring bar, a rubber septum and a N2 inlet was added aziridine-2-carboxylic acid methyl ester 1d (1.01 g, 10 mmol) dissolved into 25 ml of anhydrous toluene. The reaction flask was cooled to −78° C., at which point 13 ml of a 1.5M solution of DIBAL in toluene was added slowly via syringe to the reaction mixture over a period of 30 minutes. The reaction was allowed to stir for 5 hours or until completed by TLC. MeOH was added via syringe to the reaction mixture over a period of 15 minutes while maintaining a temperature of −78° C. After the addition of MeOH, the reaction mixture was allowed to warm to room temperature and stir for 30 minutes. A few drops of saturated aqueous Na2SO4 were used to cause precipitation of aluminum salts, which were filtered off after stirring for another 30 minutes. The filtrate was concentrated under reduced pressure to yield a thick clear oil, which was pure enough by NMR to use in subsequent transformations. An analytically pure sample can be obtained by subjecting the crude product to flash column chromatography (silica gel; 20% water in MeCN, Rf=0.32) to yield the title compound as a colourless oil in 76% yield. The compound is water soluble. 1H NMR (CDCl3 with D2O present, 400 MHz) δ: 5.33 (s, 0.5H), 5.27 (s, 1H), 4.92 (s, 1H), 4.91 (s, 0.5H), 2.62 (dd, J=5.2 Hz, 3.2 Hz, 1H), 2.53 (dd, J=5.6 Hz, 3.6 Hz, 0.5H), 2.47-2.43 (m, 1H), 2.39 (quintet, J=3.2 Hz, 0.5H), 2.29 (d, J=3.6 Hz, 0.5H), 2.10 (d, J=6.4 Hz, 0.5H), 1.86 (d, J=6.4 Hz, 1H), 1.76 (d, J=5.2 Hz, 1H), 1.70 (dd, J=5.2 Hz, 3.6 Hz, 1.5H), 1.26 (d, J=3.2 Hz, 1H), 1.21 (d, J=3.2 Hz, 0.5H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 96.6 (major), 95.7 (minor), 95.6 (minor), 94.8 (major), 44.8 (minor), 44.0 (major), 31.9 (minor), 31.6 (major), 28.0 (major), 27.6 (minor), 21.3 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH:17]2[CH2:20][N:19](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18]2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].CCOC(C)=O>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH:17]2[CH2:18][NH:19][CH2:20]2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2c(c1)OC(C)(C)C2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC2CNC2)c2c(c1)OC(C)(C)C2
Reaction time: 8 h
Yield: 113.6 %

Procedure:
Palladium on carbon (108 mg) was added to a solution of 4-(1-benzhydryl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193b) (740 mg, 1.67 mmol) in 1:1 EtOAc and MeOH. The mixture was stirred under H2 balloon overnight. The mixture was filtered through Celite and concentrated to give a pale yellow solid (526 mg, 100% yield). LCMS for C15H19NO4 m/z 278.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1S(=O)(=O)Cl
Reactant: NCc1ccccn1
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1S(=O)(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzenesulfonyl chloride (i.e. the product of Step B) (0.2 g, 0.42 mmol) in acetonitrile (20 mL) was added 2-(aminomethyl)pyridine (0.108 mL, 1.05 mmol). The reaction mixture was heated to reflux, and then allowed to stir at ambient temperature for 0.5 h. The mixture was then concentrated to dryness and the crude product was purified by silica gel chromatography using hexane:ethyl acetate (80:20) as eluent. The isolated product was triturated with a mixture of ether and hexane to afford the title product, a compound of the present invention, as a white solid (59 mg), m.p. 57-58° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[N:32]1([CH2:31][CH2:30][CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCN2CCOCC2)C3)nc1
Temperature: 90 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 4-(3-chloropropyl)morpholine (0.191 g, 1.16 mmol) in DMF (5.3 mL). Heat at 90° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1× 50 mL), brine (1× 50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 10% (2.0 M NH) in methanol) in acetone to give the title compound: MS ES+ 411.2 (M+H)+, HRMS calcd for C23H31N4O3 411.2396 (M+H)+, found 411.2389 time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=5.7 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:28])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OC(C)=O)cc4)cc3)sc2c1
Yield: 94.3 %

Procedure:
Prepared as described in the Amide Coupling section above using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.25 g, 0.976 mmol) and 4-acetoxybenzoyl chloride (0.22 g, 1.07 mmol) in dry pyridine (10 ml) to give the title compound (0.385 g, 94%) as a colourless solid after work-up.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8]2)=[C:4]([Cl:16])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>CN(C=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8]2)=[C:4]([Cl:16])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]c(C3CCCC3)nc2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
A mixture 2,6-dichloro-8-cyclopentyl-7H-purine (0.2 g, 0.78 mmol) and potassium carbonate (0.32 g, 2.34 mmol) was taken in DMF (2.5 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (0.38 g, 2.34 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 4 hours, diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine solution and dried over Na2SO4 and concentrated. The residue was purified by column chromatography to obtain 2,6-dichloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-7H-purine (0.12 g, 40%) as yellow oil.
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([CH3:36])[C:28]=1[S:29]([CH2:32][N+:33]([O-:35])=[O:34])(=[O:31])=[O:30])[NH2:25].Cl>O1CCCC1.O>[CH3:36][C:27]1[CH:26]=[C:24]([NH:25][S:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:23]=[C:22]([CH3:21])[C:28]=1[S:29]([CH2:32][N+:33]([O-:35])=[O:34])(=[O:31])=[O:30]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
1.33 ml (16.4 mmol) of pyridine, dried over potassium hydroxide, and 2.54 g (12.3 mmol) of 4-methoxybenzenesulphonyl chloride are successively added to a solution, maintained under a nitrogen atmosphere, of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 40 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 24 h at room temperature and is then maintained at 40° C. for 1 h, after which it is poured into a mixture of water and ice. The aqueous solution obtained is brought to pH 1 by addition of 1N hydrochloric acid and is extracted with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and recrystallization from a mixture of hexane and ethyl acetate, to give 1.1 g (33%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-methoxybenzenesulphonamide.
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.CC(OC)(C)C.[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]\[C:49]([OH:51])=[O:50]>CCO>[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.[C:46]([O-:53])(=[O:52])/[CH:47]=[CH:48]\[C:49]([O-:51])=[O:50]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CCO
Solvent: COC(C)(C)C
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Nilotinib base form A (4.00 g, 7.55 mmol) was stirred with EtOH abs (40 mL, 10V) and the suspension was heated to 80° C. Stirring was continued at the same temperature for 30 min. To the stirred suspension was added a solution of maleic acid (0.96 g, 8.31 mol. 1.1 eq) in EtOH abs (10 mL, 2.5V) in one portion. The resulting mixture was stirred at 80° C. for 1 h and then cooled to room temperature and stirred for another 6 h. The solids were isolated by filtration to give Nilotinib maleate form V. The obtained Nilotinib maleate form V was dried in a vacuum oven (35 mmHg) at 60° C. for 16 hours. The dried product was analyzed by PXRD and was found to be Nilotinib maleate form V. Mono maleate was obtained as confirmed by assay determination.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[ClH:13].[Br:1][C:2]1[C:3]([NH2:10])=[CH:4][C:5]([CH2:8][Cl:13])=[N:6][CH:7]=1
Reactant: Nc1cc(CO)ncc1Br
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: Nc1cc(CCl)ncc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 -Bromo-4 -amino-2 -hydroxymethylpyridine (0.60 g, 0.003 M) in chloroform (15 ml) was cooled to -10 ° and thionyl chloride (0.64 ml, 1.05 g, 0.0089 M) in chloroform (5 ml) added dropwise over 20 minutes so that the temperature of the reaction mixture did not rise above -10°. The reaction mixture was stirred for 1 hour at -10 ° and then allowed to warm to room temperature and stirred for 21 hours (if the reaction is not complete at this stage, further portions of thionyl chloride can be added (at -10 °), followed by reflux if necessary).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([OH:16])=O)[CH:4]=1.CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([NH:51][C:48]2[CH:49]=[CH:50][N:46]([CH3:45])[N:47]=2)=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc2c1OC(C)(C)C2
Reactant: Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2ccn(C)n2)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (24 g, 0.11 mol) in CH2Cl2(500 mL) were added EDCI (31.6 g, 1.08 mol), NMM (54.5 g, 0.54 mol), HOBt (22 g, 0.16 mol) and 1-methyl-1H-pyrazol-3-ylamine (11 g, 0.11 mol) sequentially. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/1) showed the reaction was complete. The mixture was washed with water (250 mL), sat. aq. citric acid (250 mL×2), sat. NaHCO3 (250 mL) and brine (250 mL) sequentially. The organic phase was dried over Na2SO4 and concentrated to give a white solid. The crude solid was purified by column chromatography (EtOAc/petroleum ether=1/10˜1/1) to give the title compound (9.6 g, 30%) as a white solid. 1H NMR (400 MHz, DMSO): δ 10.49 (s, 1H), 7.49 (s, 1H), 7.44 (s, 2H), 6.48 (s, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.96 (s, 2H), 1.35 (s, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:21]([NH:23][CH2:24][CH:25]3[O:30][CH2:29][CH2:28][N:27]([C:31]4[CH:43]=[CH:42][CH:41]=[CH:40][C:32]=4[C:33]([O:35]C(C)(C)C)=[O:34])[CH2:26]3)=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:11][CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:21]([NH:23][CH2:24][CH:25]3[O:30][CH2:29][CH2:28][N:27]([C:31]4[CH:43]=[CH:42][CH:41]=[CH:40][C:32]=4[C:33]([OH:35])=[O:34])[CH2:26]3)=[O:22])=[C:18]([CH3:20])[N:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CN(c2ccccc2C(=O)OC(C)(C)C)CCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CN(c2ccccc2C(=O)O)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butyl 2-[2-[[2-(4-chlorophenyl)-4-methylthiazole-5-carbonyl]aminomethyl]morpholin-4-yl]benzoate (113 mg, 0.214 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 2 hours. Subsequently, the solvent was removed and a 1 mol/L aqueous potassium hydroxide solution was added to the residue to make it basic. The mixture was then made acidic by the addition of 2 mol/L hydrochloric acid. The crystallized powdery product was collected by filtration and washed with water to give 78.2 mg (78%) of the desired compound as a colorless powder.