Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>CC(C)=O>[Cl:12][C:13]1[CH:23]=[C:22]([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(SC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
2-Methyl-2-propanethiol (7.47 g) was added to a suspension of potassium carbonate (9.52 g) in acetone. Ethyl 2-chloro-4-nitrobenzoate (10 g) was added and the mixture was stirred at room temperature overnight. Further 2-methyl-2-propanethiol (1.0 g) was added and the mixture was stirred and heated to 30° C. for 1 hour. Further 2-methyl-2-propanethiol (1.0 g) was added and the mixture was stirred and heated at reflux for 0.5 hours. Potassium carbonate (9.52 g) and 2-methyl-2-propanethiol was added and the mixture was stirred and heated at reflux overnight. Water was added and it was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give ethyl 2-chloro-4-(1,1-dimethylethylsulphenyl)benzoate (12.1 g) as a red oil NMR (CDCl3) 1.3 (s,9H) 1.35(t,3H) 4.3(q,2H) 7.1-7.7 (m,3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>CS(C)=O.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 533.4 %

Procedure:
Piperidine (362 mg, 0.2 mmol) was added to a solution of 1-fluoro-4-nitro-benzene (200 mg, 1.4 mmol) in DMSO (10 mL) and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 220 mg (75%) of 1-(4-nitro-phenyl)-piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH:12]O)[C:10]#[N:11].[CH3:14][C:15]([CH3:17])=O.[OH-:18].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:18])[NH:11][C:15]([CH3:17])=[CH:14][CH:12]=1
Reactant: [OH-]
Reactant: CC(C)=O
Reactant: N#CC(=CO)c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(Cl)cc2Cl)c(=O)[nH]1
Temperature: 130 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
α-(2,4-dichlorophenyl)-α-hydroxymethylene acetonitrile and 8.8 g of acetone were thoroughly mixed with 110 g of polyphosphoric acid, and the mixture was heated to about 130° C. At this temperature, an exothermic reaction started. The temperature was maintained from 130 to 140° C. for 30 minutes, while heating as the case required. The cooled mixture was poured into ice water, and this suspension was stirred for 18 hours. This crude product was stirred with ethyl acetate and an excess amount of a dilute aqueous potassium hydroxide solution to make it alkaline. The formed precipitate was collected by filtration and washed sequentially with water, ethyl acetate and diethyl ether to obtain 8.0 g (yield: 45%) of the desired product. Melting point: 266-268° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (17 g, crude) in THF/MeOH/water (300 mL) was added sodium hydroxide (4.3 g, 107.5 mmol), and the reaction was stirred at 70° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT, acidified to pH≈5-6 with 1 M HCl and filtered. The solid was collected and dried to give the title compound (16 g, 96%) as a white solid, which was directly used in the next step without further purification. MS (ES+) C14H20N4O4 requires: 308. found: 253 [M−56+H]+.
Reaction SMILES: [C:1]([N:9]1[CH2:14][C@H:13]([CH3:15])[O:12][C@@H:11]([CH3:16])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:9]1[CH2:10][C@H:11]([CH3:16])[O:12][C@@H:13]([CH3:15])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(C(=O)c2ccccc2)C[C@H](C)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2ccccc2)C[C@H](C)O1
Temperature: 55 °C

Procedure:
(2S,6S)-4-benzoyl-2,6-dimethylmorpholine (759 mg, 3.46 mmol) is dissolved in anhydrous THF (40 mL) and treated with LiAlH4 (1.0 M in THF, 6.9 mL, Aldrich). The mixture is stirred with heating at 55° C. for 18 hours. An additional equivalent of LiAlH4 is added and the mixture is stirred with heating at 55° C. for an additional 6 hours. The reaction is quenched by adding water (0.4 mL) followed by 6.0 M NaOH (0.4 mL) followed by water (1.2 mL). The white slurry is diluted with Et2O and filtered. The inorganic salts are washed with and additional portion of Et2O and the combined ethereal washes are dried over Na2SO4. The product is purified on a Biotage Flash 40M+ using a 15% Et2O in pentane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a colorless oil.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[C:2]1([CH2:1][S:8][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1CCCCSCc1ccccc1

Procedure:
Benzyl mercaptan (8.2 g, 66.4 mmol) was reacted with sodium hydride (52.4% in oil, 3.35 g, 73.0 mmol), and then with N-(4-bromobutyl)-phthalimide (19.7 g, 69.7 mmol) as described in Example A, to give the title compound. NMR (CDCl3): thiobenzyl methylene, and methylene bonded to nitrogen, both at δ 3.7. Methylene bonded to sulfur at δ 2.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:12][Si](C)(C)C)=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[F:17]OC(F)(F)F>C(Cl)(Cl)(Cl)F>[F:17][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12]
Reactant: FOC(F)(F)F
Reactant: CCOC(=Cc1ccccc1)O[Si](C)(C)C
Solvent: FC(Cl)(Cl)Cl
Product: CCOC(=O)C(F)c1ccccc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A solution of 21.28 g (0.09 mol) of β-ethoxy-β-trimethylsiloxystyrene (from above) in 200 ml of CFCl3 was cooled to -70° C. and 9.4 g (0.09 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 3 hours. The reaction mixture was warmed to room temperature and then distilled to give 12.52 g (77% yield) of ethyl α-fluorobenzeneacetate as a colorless liquid: bp 96°-98° C. (4.8 mm); 19F NMR (CFCl3) δ-180.1 ppm (d,J=48 Hz); 1H NMR (CFCl3) δ 1.10 ppm (t,J=7 Hz, 2H), 4.10 ppm (q,J=7 Hz, 2H), 5.66 ppm (d,J=48 Hz, 1H) and 7.1-7.6 ppm (m, 5H). Anal. Calcd. for C10H11FO2 : C, 65.92; H, 6.07; F, 10.43; Found: C, 66.09; H, 6.13; F, 10.33.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[NH2:24]>>[CH3:35][N:34]([CH3:31])[CH:39]=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]=2[CH3:1])=[O:18])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH2:30][CH2:29]1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Cl)c1
Product: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(Cl)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 123.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.6 g) and 3-chloro-4-(4-morpholinopiperidin-1-yl)aniline (0.61 g), the title compound (0.79 g) was obtained, melting point: 252–256° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[N:10][C:9]=1[CH3:29])C.C(OC(=O)CCSC1SC(N)=NC=1C)C>>[CH:23]1([N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[C:9]([CH3:29])[N:10]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)CCSc1sc(NC(=O)N(C2CCCCC2)C2CCCCC2)nc1C
Agent: CCOC(=O)CCSc1sc(N)nc1C
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCC(=O)O

Procedure:
Prepared as described in general procedures (A) and (B) using 3-[2-(3,3-dicyclohexyl-ureido)-4-methyl-thiazol-5-yl-sulfanyl]-propionic acid ethyl ester and 3-(2-amino-4-methyl-thiazol-5-ylsulfanyl)-propionic acid ethyl ester
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31]>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:14]3[C:10]4[C:9]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=[C:2]([NH2:31])[C:11]=4[N:12]=[C:13]3[CH2:28][CH2:29][CH3:30])[O:20][N:19]=2)=[CH:22][CH:23]=1
Reactant: CCCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reactant: N
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c]quinoline (0.806 g, 1.92 mmol) and 7 N ammonia in methanol (40 mL) was sealed in a pressure vessel and heated at 150° C. for 18 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the resulting solid was stirred with 0.5 N sodium hydroxide in methanol. The solid was isolated by filtration, washed with diethyl ether, purified by column chromatography on silica gel (eluting with 5% to 10% CMA in chloroform), triturated with diethyl ether, isolated by filtration, and dried to provide 0.123 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 226.0-227.0° C.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([NH:18]C(=O)C)[CH2:12][C:11]1([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>>[NH2:18][CH:13]1[CH2:14][C:15]([CH3:16])([CH3:17])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:22])([CH3:23])[CH2:12]1
Reactant: CCCCCCCCON1C(C)(C)CC(NC(C)=O)CC1(C)C
Agent: Cl
Product: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Yield: 82.6 %

Procedure:
A mixture of 40.0 grams (0.123 mol) of N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl) acetamide and 6N hydrochloric acid is heated at reflux for three hours. The reaction mixture is cooled and extracted with 2×150 ml). The aqueous layer is made basic and extracted with 3:1 ether:dichloromethane (3×150 ml). The three organic extracts are combined, dried over anhydrous magnesium sulfate and then concentrated to an oil. Purification by Kugelrohr distillation at 110°-120° C./0.5 mm affords 28.9 grams (83% yield) of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[S:26][C:25]([CH2:27]O)=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[Cl:21][C:22]1[S:26][C:25]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)=[CH:24][CH:23]=1
Reactant: OCc1ccc(Cl)s1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl) methanol (166 mg) and tributylphosphine (388 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (422 mg), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (16.1 mg) as a white solid.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:18])=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH:9]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C1C=CC=CC=1.CCOCC>[Pd].C(OCC)(=O)C.CO>[ClH:18].[CH2:23]([CH:9]1[C:10]2[N:11]=[C:12]([C:19]([F:22])([F:20])[F:21])[N:13]=[CH:14][C:15]=2[CH2:16][CH2:17][NH:8]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)C(Cc1ccccc1)N(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CO
Product: Cl
Product: FC(F)(F)c1ncc2c(n1)C(Cc1ccccc1)NCC2
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 420 mg (1.005 mmol) of 7,8-dibenzyl-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine from Step C and 63 mg of 10% palladium on carbon in 4 mL of ethyl acetate and 7 mL of methanol was stirred under an atmosphere of hydrogen for 2 h. The mixture was filtered through a 0.45 micron syringe filter, washing with methanol, and concentrated to give a white solid. Trituration with ether gave 330 mg (100%) of the title compound as a white powder. LC-MS 294.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30](/[N:33]=[CH:34]/[C:35]2[S:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:39]=2)=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:60](=O)[CH2:61][CH3:62].C(=O)([O-])O.[Na+]>ClCCCl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:34][C:35]2[S:36][CH:37]=[C:38]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:39]=2)[CH2:60][CH2:61][CH3:62])=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: COC(=O)CCc1ccc(N(Cc2ccc(/N=C/c3nc(-c4ccccc4)cs3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(Cc1nc(-c2ccccc2)cs1)c1ccc(CN(c2ccc(CCC(=O)OC)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 80 %

Procedure:
The yellow oil obtained in Example 50 was dissolved in 1,2-dichloroethane (20 mL), sodium triacetoxyborohydride (1.26 g, 6.0 mmol) was added at room temperature by small portions, and the mixture was stirred at room temperature for 60 hr. Propionaldehyde (200 mg, 3.0 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into 10% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (5%-70% ethyl acetate/hexane) to give the title compound (549 mg, yield 80%, 2 steps) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([S:13](Cl)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([S:13](=[O:15])(=[O:14])[NH:20][CH2:19][CH2:17][OH:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1c[nH]c(-c2ccc(Cl)cc2)n1
Reactant: NCCO
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(NCCO)c1c[nH]c(-c2ccc(Cl)cc2)n1
Yield: 28.3 %

Procedure:
To a solution of 2-(4-chlorophenyl)-4-chlorosulfonylimidazole (1.3 g 0.005 m) in dioxane (15 ml) was added ethanolamine (0.61 g 0.01 ml). After 15 minutes the dioxane was removed under reduced pressure (20 mm) to yield a gum. The gum was slurried with water to yield a solid. The solid was filtered and recrystallized from acetonitrile to give 400 mg of 2-(4-chlorophenyl)-4-(2-hydroxyethylsulfamoyl)imidazole melting at 210°-212°. (20% yield). What is claimed is:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[C:37]([F:38])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[F:27][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:26])[N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=1)[C:4]([C@@H:2]([NH:1][C:29]1[C:30]3[C:37]([F:38])=[CH:36][NH:35][C:31]=3[N:32]=[CH:33][N:34]=1)[CH3:3])=[N:5]2
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: Fc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]cc(F)c12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (76 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.4 mL) at 23° C. was added 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (38 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 43 mg of the title compound (42% yield).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:14]([F:17])([F:16])[F:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[N:11][CH:10]=[CH:9]2)([O-])=O.C(O)(=O)C.[OH-].[NH4+]>C(O)C.O.[Zn]>[NH2:1][C:4]1[C:5]([C:14]([F:17])([F:15])[F:16])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[N:11][CH:10]=[CH:9]2
Reactant: O=[N+]([O-])c1c(C(F)(F)F)ccc2ccncc12
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c(C(F)(F)F)ccc2ccncc12

Procedure:
According to the procedure in Example 12, 8-nitro-7-trifluoromethylisoquinoline is heated with zinc and acetic acid in ethanol and water on a steam bath for five minutes and the reaction mixture is cooled, made alkaline with aqueous ammonium hydroxide and extracted with ethyl acetate. Removing the solvent from the extract in vacuo gives, as the residue, 8-amino-7-trifluoromethylisoquinoline.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][CH:21]([CH3:23])[CH:20]=[C:19]([C:42]1[CH:43]=[C:38]([C:35](=[O:37])[CH3:36])[CH:39]=[CH:40][CH:41]=1)[C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 56.2 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.0 mmol), 3-acetylphenylboronic acid (2.5 g, 15 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×50 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (40 g, 10% ethyl acetate/petroleum ether) afforded 1-(3-(3-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)phenyl)ethanone (1.5 g, 56.3%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 7.90 (dd, 1H, J1=7.8 Hz, J2=1.5 Hz), 7.81 (dd, 1H, J1=8.1 Hz, J2=1.8 Hz), 7.68-764 (m, 3H), 7.45-7.16 (m, 6H), 6.58 (s, 1H), 6.18 (d, 1H, J=10.2 Hz), 2.67-2.65 (m, 1H), 2.44 (s, 3H), 1.17-1.12 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.N1C2C(=C(C3C=C(C=C(NC4C=NC=CC=4)C=3)C#N)C=CC=2)C=C1>>[Br:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([NH:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: Nc1cccnc1
Reactant: N#Cc1cc(Br)cc(Br)c1
Agent: N#Cc1cc(Nc2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Product: N#Cc1cc(Br)cc(Nc2cccnc2)c1

Procedure:
3-Bromo-5-(pyridin-3-ylamino)-benzonitrile was prepared from 3,5-dibromobenzonitrile and pyridin-3-ylamine as described for Example 36, except that the reaction was run at 130° C. This material was converted to 3-(1H-indol-4-yl)-5-(pyridin-3-ylamino)-benzonitrile by the method of Example 35. 1H NMR (400 MHz, CDCl3): δ 8.47 (s, 2H), 8.28 (d, J=4.3 Hz, 1H), 7.55-7.49 (m, 3H), 7.44 (d, J=8.2 Hz, 1H), 7.30-7.23 (m, 4H), 7.12 (dd, J=7.3, 0.9 Hz, 1H), 6.63 (t, J=2.5 Hz, 1H), 6.05 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH2:11]=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH-:3].[OH:8][C:7]1[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4](=[O:5])[C:6]=1[CH2:11][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: C=O
Product: CC1(C)OC(=O)C(C[n+]2ccccc2)=C(O)O1
Product: [OH-]
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Meldrum's acid (20 g, 0.139 mol) was dissolved in 50 ml of pyridine. The solution immediately turned yellow and was somewhat exothermic. After dissolution was complete, a 37% aqueous solution of formaldehyde (10.4 ml, 0.139 mol) was added in one portion. The reaction mixture was allowed to stir for one hour under argon. The solvent was removed in vacuo at 55° C. after which yellow crystals were isolated. These crystals were then stirred with 200 ml of hexanes for 30 minutes and filtered providing 32.24 g (0.127 mol, 91.6%) of the desired title product. Melting point: >350° C. NMR (ppm): 1.62 (s, 6H (CH3)); 5.58 (bs, 2H (CH2)); 7.71 (t, 2H (Ar-H)); 8.17 (t, 1H (Ar-H)); 9.0 (d, 2H (Ar-H)). MS: 235.23.