Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[F:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:53][C:24]([CH3:52])([CH3:23])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([O:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[C:55]([F:54])[CH:56]=1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Reactant: Fc1cc(Br)ccc1Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(Oc2ccccc2)c(F)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 94.4 %

Procedure:
A mixture of palladium acetate (20 mg, 0.08 mmol) and tri-(2-methylphenyl)phosphine (50 mg, 016 mmol) was added to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (Preparation 2)(700 mg, 1.63 mmol), 3-fluoro-4-phenoxy-bromobenzene (Preparation 10)(479 mg, 1.79 mmol), and triethylamine (340 μL, 2.43 mmol) in anhydrous acetonitrile (3 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 14 h. Additional palladium acetate (20 mg, 0.08 mmol) and tri-(2-methylphenyl)phosphine (50 mg, 016 mmol) was added and the mixture was heated for a further 9 h. After being cooled, the mixture was poured into ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride (2×50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexane:ethyl acetate=9:1) to give mainly tert-butyl (3R,5E)-3-({[(1s)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino }carbonyl)-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoate as a colourless oil (949 mg). 1H nmr suggested that two alkene isomers, the (5Z) and (4E), together with the alkene starting material (10%) were also present. The mixture of alkenes was taken onto the next step (see b, below).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1C=CC=C(C)N=1>>[CH3:17][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=1
Reactant: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: Cc1cccc(Cl)n1
Product: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 40, substituting 2-chloro-4,6-dimethylpyridine for 2-chloro-6-methylpyridine in step A. MS (ESI) mass calcd. for C13H19N3, 217.2; m/z found, 218.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37]>ClCCl.O>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH:29][C:36]([O:38][CH2:39][CH:40]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=2[C:47]2[C:52]1=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)OC2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(NC(=O)OCC2c3ccccc3-c3ccccc32)sc2c1CC(CN1C(=O)c3ccccc3C1=O)OC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (4.5 g, 0.011 mole) dissolved in dichloromethane (30 ml), was added sodium bicarbonate (1.0 g, 0.011 mole) dissolved in water (16 ml). The reaction mixture was cooled to 0° C. and 9-fluorenylmethyl chloroformate (3.0 g, 0.012 mole) was added. After stirring for 5 minutes the reaction mixture was warmed to room temperature and stirred vigorously for 16 h. The organic layer was separated and washed with brine (10 ml). The aqueous phase was extracted with dichloromethane (2×20 ml) and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo to give an orange solid which was purified by flash chromatography using dichloromethane as eluent. Pure fractions were collected and evaporated in vacuo affording 5.6 g (81%) of 5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10](Cl)[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[N:18][N:17]=[N:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
Five grams (21.0 mmol) of N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 7, 2.46 g (37.8 mmol) of sodium azide, 1.45 g (10.5 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 15 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 5.05 g of 1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 98.3%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[N:8][CH:9]=1)([OH:3])=[O:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>S(Cl)(Cl)=O.N1C=CC=CC=1>[NH:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([C:1]([O:3][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[O:2])=[CH:9][N:8]=1
Reactant: O=C(O)c1ccc(-c2ncc[nH]2)nc1
Reactant: CCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(-c2ncc[nH]2)nc1
Reaction time: 17 h

Procedure:
5-Carboxy-2-(2-imidazolyl)-pyridine (1.89 g, 0.01 mol) is refluxed in 10 ml of thionyl chloride for 2 h. The solution is evaporated to dryness and the residue dissolved in 20 ml of dichloromethane. The latter solution is added dropwise to a mixture of 1-hexadecanol (2.68 g, 0.011 mol) in 1.6 ml of pyridine. After 17 h at room temperature, the precipitate is filtered off and the filtrate evaporated to dryness. The resulting residue is crystallized in toluene to yield the title compound, m.p. 97°-98°.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]2[NH:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[C:11]=3[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.I[CH3:24]>CN(C)C=O.C(OCC)C>[CH:3]1([C:8]2[N:12]([CH3:24])[C:11]3[C:13]([O:21][CH3:22])=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[N:9]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc(OC)c2nc(C3CCCC3)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1nc(C1CCCC1)n2C
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A suspension of sodium hydride (0.55 g, 60% dispersion in mineral oil) in dimethylformamide (1 ml), cooled to 0° C., was treated with a solution of methyl 2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [3.61 g, Reference Example 3(t)]) in dimethylformamide (34 ml). The resulting mixture was stirred for 40 minutes then treated with iodomethane (0.82 ml). The reaction mixture was allowed to stand at 4° C. for 2 days then diluted with diethyl ether, then washed with brine, then dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica to give methyl 2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate (3.18 g), [NMR (CDCl3): δ 1.70 (m, 2H), 1.90(m, 2H), 2,16(m, 4H), 3.25(m, 1H), 3.95(s, 6H), 4.00(s, 3H), 6.64(d, J=8 Hz, 1H), 7.89(d, J=8 Hz, 1H)]; and methyl 2-(cyclopentyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate (0.37 g), [M+288, NMR (CDCl3): δ 1.70(m, 2H), 1.90(m, 2H), 2.14(m, 4H), 3.25(m, 1H), 3.92(s, 6H), 4.02(s, 3H), 6.64(d, J=8 Hz, 1H), 7.75(d, J=8 Hz, 1H)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of methyl 3-(4-(4-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (153.4 mg, 0.33 mmol, 1.00 equiv) and sodium hydroxide (66 mg, 1.65 mmol, 5.00 equiv) in tetrahydrofuran/MeOH (1:1) (12 mL) was placed in a 50-mL round bottom flask and stirred for 5 h at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid, then concentrated under vacuum. The resulting solid was washed with methanol affording 47 mg (31%) of 3-(4-(4-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=O)[CH3:8])=[O:6].[NH:28]1[CH2:31][CH:30]([N:32]2[CH2:37][CH2:36][N:35]3[C:38](=[O:42])[CH2:39][CH2:40][CH2:41][CH:34]3[CH2:33]2)[CH2:29]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:67]>>[ClH:67].[ClH:67].[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH2:11][CH2:12][N:28]1[CH2:29][CH:30]([N:32]2[CH2:37][CH2:36][N:35]3[C:38](=[O:42])[CH2:39][CH2:40][CH2:41][CH:34]3[CH2:33]2)[CH2:31]1)[CH3:8])=[O:6]
Reactant: O=C1CCCC2CN(C3CNC3)CCN12
Reactant: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CC(N2CCN3C(=O)CCCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 100 mg, 0.22 mmol) and 2-azetidin-3-yloctahydro-6H-pyrido[1,2-a]pyrazin-6-one (see Method 4; 58 mg, 0.28 mmol) in methylene chloride (3 mL) were added DIPEA (116 mg, 0.90 mmol) and sodium triacetoxyborohydride (66 mg, 0.31 mmol). The reaction mixture was stirred under nitrogen at RT for 2 h. The solution was washed twice with aqueous NaHCO3 and the organic solvent dried by a phase separator column. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (ammonia saturated methanol-methylene chloride 1% to 10%). The right fractions were combined and concentrated on a rotavapor and the residue was then dissolved in a small amount of acetonitrile/water. A few drops of diluted hydrochloric acid were added and the water was removed by freeze-drying. There was obtained 114 mg (70%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): 1.4-3.8 (cm, 27H), 4.6 (d, 1H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 640 (M+1)+.
Reaction SMILES: [CH:1]1([C:7]2[O:11][C:10]([CH3:12])=[C:9]([C:13]([OH:15])=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:13]([C:9]3[CH:8]=[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[O:11][C:10]=3[CH3:12])=[O:15])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1oc(C2CCCCC2)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1oc(C2CCCCC2)cc1C(=O)Nc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
5-Cyclohexyl-2-methyl-furan-3-carboxylic acid (83 mg, 0.365 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (83 mg, 0.4 mmol), and triethylamine (154 uL, 1.09 mmol) were dissolved in 5 mL of DMF and chilled in an ice bath. To this solution was added BOP (169 mg, 0.383 mmol) in one portion. The mixture was stirred at room temperature for one hour and then diluted with 30 mL ethyl acetate. The ethyl acetate solution was washed with saturated sodium bicarbonate (2×10 mL) and saturated sodium chloride (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness under vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexane to yield 5-cyclohexyl-2-methyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide as a light grey powder (87 mg, 64%). ES-MS calcd for C21H27N3O3 (m/e) 369.5, obsd 370.3 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.Cl.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]3[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=3)[CH:31]=2)[N:15]=1>C1COCC1>[CH3:1][N:2]([CH3:3])[S:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:32]2[CH:31]=[C:30]([C:16]3[N:15]=[C:14]([C:13]([F:12])([F:46])[F:47])[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:17]=3)[CH:35]=[CH:34][N:33]=2)[CH:37]=1)(=[O:43])=[O:44]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 90.5 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of dimethylamine solution (60% in water) (0.27 ml, 3.21 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.5 g, 97%). MS (ISP) 552.7 [(M+H)+]; mp 225° C.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:20])[O:5][N:4]=1)[CH3:2].Cl.[CH3:22][NH:23][CH3:24].Cl.[CH2:26]=O>C(O)C>[CH3:22][N:23]([CH3:26])[CH2:24][CH2:18][C:17]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:7]1[C:3]([CH2:1][CH3:2])=[N:4][O:5][C:6]=1[CH3:20])=[O:19]
Reactant: C=O
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(C)=O
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCN(C)C

Procedure:
A mixture of 12 g. (0.045 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-acetyl indole, 4 g. (0.049 mole) of dimethylamine hydrochloride, and 0.5 ml. concentrated hydrochloric acid in 70 ml. of ethanol is heated to reflux and treated by the portionwise addition of 14 g. (0.470 mole) of paraformaldehyde over 5 hours. The resulting mixture is refluxed an additional 24 hours, cooled and evaporated in vacuo. The residue is then dissolved in 300 ml. methylene chloride and washed with 200 ml. 2N hydrochloric acid, the aqueous acid is cooled and made basic with 2N sodium hydroxide and extracted with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether to give 3-dimethylamino-1-[2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indol-3-yl]-1-propanone, m.p. 146°-148° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1.[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[C:21]([C:22]([NH:14][C:11]2[CH:12]=[C:13]3[C:5]([O:4][CH2:3][CH2:2][F:1])=[N:6][NH:7][C:8]3=[N:9][CH:10]=2)=[O:23])=[C:20]([F:25])[C:19]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:18][CH:17]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]nc(OCCF)c2c1
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]nc(OCCF)c3c2)c1F

Procedure:
6-Chloro-2-fluoro-N-(3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide was prepared according to the general procedure of Example 78, Step D, using 3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.035 g, 0.18 mmol) and 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.058 g, 0.20 mmol). The crude material was purified by silica gel flash column chromatography (5 to 7% 7N NH3-MeOH in CH2Cl2) to afford the desired product which was triturated with Et2O (51 mg, 60% yield). LRMS (ACPI pos) m/e 474.0 (M+1). 1H NMR (400 MHz, d6-DMSO) δ 12.68 (s, 1H), 11.10 (s, 1H), 9.99 (br s, 1H), 8.58 (d, 1H), 8.54 (d, 1H), 7.55 (t, 1H), 7.46 (d, 1H), 4.91 (m, 1H), 4.78 (m, 1H), 4.63 (m, 1H), 4.55 (m, 1H), 3.16 (t, 2H), 1.75 (m, 2H), 0.99 (t, 3H); 19F NMR (376 MHz, DMSO) δ−124.0, −223.1.
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5](OCC)[O:6]CC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]=[O:6]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(OCC)/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(C=O)=C\COc1ccc(Cl)cc1Cl
Reaction time: 5 h
Yield: 87.2 %

Procedure:
In 100 ml dimethylformamide there is combined 34.9 g (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene, 24.0 g 2,4-dichlorophenol, 40.5 g potassium carbonate and 2.37 g potassium iodide and stirred under nitrogen for about five hours. The resulting solution is poured into 500 ml deionized water and the solution extracted with two 200 ml portions diethylether which are then combined and washed first with 300 ml 10% aqueous potassium carbonate solution and then with three 400 ml portions of deionized water. The ether solution is treated with magnesium sulfate and activated charcoal then filtered. The filtrate is evaporated to dryness and the yellow-brown oil is taken up in a mixture of 120 ml acetone and 20 ml water and stirred under nitrogen as 3.0 g p-toluenesulfonic acid is added. Thirty minutes after the addition, the solution is evaporated to dryness and the residue taken up in 200 ml diethylether and this solution washed with two 200 ml portions deionized water. The ether solution is treated with magnesium sulfate and activated carbon and then filtered. The filtrate is evaporated to dryness to yield 31.47 g purple oil which is purified by chromatography on a Waters Prep. 500 LC using a silica gel cartridge yielding 25.31 g of a yellow oil. The oil is recrystallized from diethylether-hexane yielding 18.22 g solid product, m.p. 58.5°-59.5° C. Elemental Analysis. Calculated: C,53.90; H,4.11; Cl,20.93. Found: C,53.86; H,4.00; Cl,28.78.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br.ClCCl>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: BrCCCCBr
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Brc1ccc(N2CCCC2)nc1

Procedure:
4.95 g (28.6 mmol) of 2-amino-5-bromopyridine was dissolved in 40 ml of toluene. 9.95 ml (57.2 mmol) of diisopropylethylamine, 6.15 g (28.6 mmol) of 1,4-dibromobutane and 100 mg (0.82 mmol) of 4-(dimethylamino)pyridine were added to the solution, and they were stirred for three nights. After the treatment with dichloromethane as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH3:6])=[C:2]=[S:3].CN(C)C=O.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>O>[CH2:4]([NH:1][C:2](=[S:3])[NH:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:5][CH3:6]
Reactant: COC(=O)c1ccsc1N
Reactant: CCCN=C=S
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=S)Nc1sccc1C(=O)OC
Temperature: 132.5 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
In a sulfonation flask, 2.02 g (0.02 mol) of 1-isothiocynatopropane are added dropwise to 30 ml dimethylformamide and 3.0 g (0.019 mol) of methyl 2-aminothiophene-3-carboxylate. The reaction mixture is then stirred at 130-135° C. for 12 hours and after cooling added to 120 ml of water. The resulting mixture is then extracted three times with ethylacetate and the separeted organic phase dried over sodium sulfate. The solvent is then removed in a water-jet vacuum, giving the crude product as a dark oil, which is purified by column chromatography over silica gel (eluant: tert.butylmethylether/hexane=2:3). 2.0 g of methyl 2-(3-propylthioureido)thiophene-3-carboxylate are obtained in the form of a yellow powder having a melting point of 122-124° C.