Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+:26].[Na].O1CCCC1>CO.C(#N)C>[F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:26])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [NH4+]
Reactant: CC(=O)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-fluoro-8-(3-fluorophenyl)quinolin-7-yl]ethanone (0.32 g, 1.1 mmol) and ammonium acetate (0.871 g, 11.3 mmol) in methanol (3.0 mL) and acetonitrile (3.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohyride in tetrahydrofuran (2.8 mL, 2.8 mmol). The reaction was heated at 65° C. overnight, then cooled to room temperature and quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined extracts were dried over MgSO4 and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C17H15F2N2 (M+H)+: m/z=285.1; Found: 285.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].[C:17]([Si:21]([CH3:31])([CH3:30])[O:22][CH:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:17]([Si:21]([CH3:31])([CH3:30])[O:22][CH:23]1[CH2:28][CH2:27][CH:26]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH2:25][CH2:24]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1ccc(OC(F)(F)F)c(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccc(OC(F)(F)F)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 66 %

Procedure:
(4-Trifluoromethoxy-3-trifluoromethyl-phenyl)-amine (735 mg, 3 mmol) and 4-(tert-butyl-dimethyl-silyloxy)-cyclohexanone (685 mg, 3 mmol) were dissolved in dichloromethane (25 mL). Next, sodium triacetoxyborohydride (1.27 g, 6 mmol) was added. The resulting mixture was stirred at room temperature for 6 days. Afterward, the mixture was diluted with dichloromethane (25 mL), washed with water (20 mL), washed with HCl 1N (20 mL), washed with water (20 mL), and washed with brine (20 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford an oily residue. The residue was purified by column chromatography on silica gel (pentane/ether gradient). The desired product was isolated as a colorless oil (900 mg of 1:1 mixtures of cis and trans isomers, 66% yield).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:10]=1[CH:11]=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: COc1cc(C=O)c(OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(O)c(C=O)cc1OC
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a stirred solution of 2-(benzyloxy)-4,5-dimethoxybenzaldehyde (246, 5.05 g, 18.6 mmol) in ethyl acetate (100 mL) was added 10% palladium on charcoal (250 mg). The flask was purged with hydrogen and then the reaction mixture was stirred under a hydrogen atmosphere (1 atm) for 15 hours, filtered through a celite pad, the filtrate was evaporated under reduced pressure, and the resulting solid dried under vacuum to afford 243b as a white solid (3.3 g, 98% yield). 1H NMR: (DMSO) δ 11.39 (s, 1H), 9.68 (s, 1H), 6.90 (d, J=2.5 Hz, 1H), 6.47 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22].O>ClCCl>[Cl:19][CH2:20][C:21]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:11]=1)=[O:22]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of commercially available 4-tert-butylbenzylamine (8.16 g, 50 mmol) and potassium carbonate (7.95 g, 57.5 mmol) in dichloromethane (100 ml) was added drop wise a solution of 2-chloroacetyl chloride (6.21 g, 55 mmol) in dichloromethane (25 ml) at room temperature. After stirring the reaction mixture at room temperature for 30 min, the reaction mixture was refluxed for 4 h. The reaction mixture was cooled and water (100 ml) was added. The phases were separated and the organic phase was dried over MgSO4 and evaporated in vacuo. The title compound was obtained as a white crystalline material which was used in the next step without any further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([CH3:19])[CH:5]=1.[CH3:20][S-:21].[Na+].CO>O>[CH3:19][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:13](=[O:14])[C:4]([CH2:3][S:21][CH3:20])=[CH:5]1
Reactant: C[S-]
Reactant: Cn1cc(CCl)c(=O)c2ccc(C(F)(F)F)cc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSCc1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C

Procedure:
3-Chloromethyl-1-methyl-7-trifluoromethyl-4-quinolone hydrochloride (4.7 g.) was added to a stirred solution of sodium methanethiolate in methanol (16 ml. containing 0.039 mole NaSMe) at 0° during 5 minutes. The resulting mixture was allowed to warm to room temperature then poured into water (100 ml.). The resulting precipitate was collected, dried and crystallized from dichloromethane:petroleum ether (b.p. 60°-80°) to give the novel 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone, m.p. 182°-184°.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18]C)([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2].[B].O>C(Cl)Cl>[N+:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][OH:18])([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: COCC1(C)CCc2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Agent: [B]
Solvent: O
Solvent: ClCCl
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(CO)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
9.5 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman was dissolved in 80 ml of methylene chloride and 31.4 ml of a 1M boron tribromidemethylene chloride solution was added under a nitrogen gas flow at 0° C., followed by stirring at 0° C. for 3 hours. After the completion of the reaction, the reaction solution was poured into water and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 4.5 g of the objective product.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1)=O.[CH3:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.Cl[Si](C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([CH:36]=[C:3](/[CH:1]=[CH:37]/[C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:8][N:9]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(C=O)cn34)cn2)CC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of compound 19a (50.0 mg, 0.101 mmol) in DMF (3 mL) was added 2-methylquinoline (13.2 μL, 0.101 mmol) and chlorotrimethylsilane (38.6 μL, 0.304 mmol). The reaction mixture was stirred in a 10 mL sealed tube for 2 h at 80° C. After cooling to rt, the reaction mixture was poured into water (20 mL). The mixture was adjusted to basic using saturated NaHCO3 solution, and was extracted with DCM (2×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Compound 19b was obtained as a yellow solid (40.0 mg, 64% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C35H38N8O3: 619.3 (M+H). found: 619.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[O:20])=[CH:12][CH:11]=2)[C:3]=1[N+:32]([O-])=O.[H][H]>CO.[Pd]>[NH2:32][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:24])=[O:23])=[O:20])=[CH:12][CH:11]=2)=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3[N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Yield: 84.1 %

Procedure:
To a solution of 4,6-dimethyl-2-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}anilino)-3-nitropyridine (step 3, 11.4 g, 23.6 mmol) in methanol (250 mL) was added 10% Pd—C (2.0 g). The resulting mixture was stirred under the medium pressure of hydrogen (4.0 kgf/cm2) for 4 h. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate to afford 9.0 g (85%) of the title compound as off white solids.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:23])C(=O)C1.Cl(O)(=O)(=O)=O.O>C(Cl)(Cl)Cl>[Cl:23][C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccsc1-c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Cl)sc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-phenylthiophene-3-carboxylate and NCS in CHCl3 was added perchloric acid, followed by stirring at 50° C. for overnight. To the reaction mixture was added water, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 5-chloro-2-phenylthiophene-3-carboxylate as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]3[CH:11]=[C:12]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:13]=[C:14]([O:16]CC4C=CC(OC)=CC=4)[CH:15]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]3[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc(COc2cc(Nc3cccnc3)cc(-c3cccc4sccc34)c2)cc1
Solvent: ClCCl
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(Nc2cccnc2)cc(-c2cccc3sccc23)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
[3-benzo[b]thiophen-4-yl-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine (35 mg, 0.08 mmol) was dissolved in CH2Cl2 (1 mL) and thioanisole (188 μL, 1.60 mmol) was added. The solution was cooled to 0° C. and trifluoroacetic acid (0.1 mL) was added. The reaction mixture was stirred at room temperature for 5 h and was then quenched with water (3 mL). Sat. NaHCO3 solution was added until pH 7 and the mixture was extracted with CH2Cl2 (4×10 mL). The combined organics were washed with brine (5 mL), dried (Na2SO4) and concentrated. Flash chromatography (SiO2, CH2Cl2/MeOH 95:5) provided 3-benzo[b]thiophen-4-yl-5-(pyridin-3-ylamino)-phenol (17 mg, 58%). 3-Benzo[b]thiophen-4-yl-2-(4-methoxy-benzyl)-5-(pyridin-3-ylamino)-phenol was also isolated from this reaction. 3-Benzo[b]thiophen-4-yl-5-(pyridin-3-ylamino)-phenol 1H NMR (300 MHz, methanol-d4): δ 8.2 (d, 1H), 7.8 (d, 1H), 7.7 (d, 1H), 7.45 (d, 1H), 7.4 (two d, 2H), 7.2 (m, 2H), 7.1 (dd, 1H), 6.4 (s, 1H), 6.35 (s, 1H), 6.3 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-])=O)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl-].[NH4+]>CO.O.[Zn]>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([NH2:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(N)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methyl ester (prepared as in Example 14, 1.50 g, 4.22 mmol) in methanol (30 mL) was treated with a solution of ammonium chloride (474 mg, 8.86 mmol) in water (3 mL). The reaction mixture was stirred at 25° C. for 5 min and then treated with zinc dust (2.70 g, 41.36 mmol). The reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The filtrate was concentrated in vacuo. The resulting orange oil was dissolved in ethyl acetate, dried over magnesium sulfate, filtrated, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.49 g, 98%) as a white solid: mp 98–100° C.; EI-HRMS m/e calcd for C16H23NO4S (M+) 325.1348, found 325.1358.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20]C(=O)C4C=CC=CC=4)[CH2:16][CH2:15]3)=[N:9]2)=[CH:5][CH:4]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([CH2:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nnc(C[C@H]3CC[C@H](OC(=O)c4ccccc4)CC3)n2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2nnc(C[C@H]3CC[C@H](O)CC3)n2)cc1
Reaction time: 48 h

Procedure:
To a methanol (10 mL) solution of trans-benzoic acid 4-[2-(4-methoxy-benzyl)-2H-tetrazol-5-ylmethyl]-cyclohexyl ester (610 mg) obtained in Example (44c), sodium methoxide (28% methanol solution, 0.29 mL) was added at room temperature. After 2 days, the reaction mixture was concentrated. The residue was purified by column chromatography (hexane/ethyl acetate=5:1→1:1 and then dichloromethane/methanol=50:1) to obtain the title compound (396 mg, 87%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Br[CH2:30][CH2:31][C:32]1[C:33]([CH3:38])=[N:34][NH:35][C:36]=1[CH3:37]>ClCCl>[CH3:38][C:33]1[C:32]([CH2:31][CH2:30][O:17][C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[S:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=4[C:2]([NH2:1])=[N:3][C:4]=3[CH:5]=2)=[C:36]([CH3:37])[NH:35][N:34]=1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: Cc1n[nH]c(C)c1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCCc4c(C)n[nH]c4C)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
A mixture of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (245 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 4-(Bromoethyl)-3,5-dimethyl-1H-pyrazole (223 mg, 1.1 mmol) was added in portions over a period of 30 minutes. The reaction mixture was stirred for 20 minutes and then the heat source was removed. The reaction mixture was diluted with water (250 mL), stirred overnight, and then filtered. The isolated solid was rinsed with water and then dried to provide a tan powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-30% CMA in chloroform 700 mL and then with 30% CMA in chloroform over 200 mL. The resulting solid was recrystallized from 50:1 acetonitrile:methanol (40 mL) to provide 205 mg of 7-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-2-ethylthiazolo[4,5-c]quinolin-4-amine as an off white solid, mp 195.0-197.0° C. MS (APCI) m/z 368 (M+H)+; Anal. calcd for C19H21N5OS: C, 62.10; H, 5.764; N, 19.06. Found C, 61.95; H, 5.53; N, 19.09.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=3[CH3:26])=[CH:13][C:8]=2[C:7](=[O:27])[N:6]([CH3:28])[C:5]2[CH:29]=[CH:30][CH:31]=[N:32][C:4]1=2)[CH3:2].[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[O:22])=[CH:19][C:18]=3[CH3:26])=[CH:13][C:8]=2[C:7](=[O:27])[N:6]([CH3:28])[C:5]2[CH:29]=[CH:30][CH:31]=[N:32][C:4]1=2)[CH3:2]
Reactant: Nc1ccncc1
Reactant: CCN1c2ncc(CCOc3ccc(C(=O)Cl)cc3C)cc2C(=O)N(C)c2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1c2ncc(CCOc3ccc(C(=O)Nc4ccncc4)cc3C)cc2C(=O)N(C)c2cccnc21
Yield: 103.7 %

Procedure:
A solution of 4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylbenzoyl chloride (47.4 mg, 0.11 mmol), 4-aminopyridine (9.88 mg, 0.11 mmol) and Et3N (15.3 μL, 0.11 mmol) in CH2Cl2 (4 mL) was stirred at 25° C. for 5 h. The reaction mixture was diluted with EtOAc and the resulting solution was successively washed with aqueous saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (58 mg, 100% yield) as a colorless oil.
Reaction SMILES: S([O-])(O)(=O)=O.[CH2:6]([C:11]1[CH:15]=[S+:14][S:13][C:12]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([CH3:10])([CH3:9])[CH3:8].N.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:12]1([C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:15][S:14][S:13]1)[CH3:22]
Reactant: CC(C)(C)Cc1c[s+]sc1C(C)(C)C
Reactant: CCO
Agent: N
Agent: O=S(=O)([O-])O
Product: CCOC1(C(C)(C)C)SSC=C1CC(C)(C)C
Temperature: 25 °C
Yield: 61 %

Procedure:
Into a mixture of 32 grams of Example 1B, i.e., 4-neopentyl-3-tertiarybutyl 1,2-dithiolium hydrogen sulfate, and 300 cc of ethanol was introduced dry ammonia gas until the mixture was saturated. During the reaction, the mixture was kept at a temperature below 18° C. After the introduction of ammonia gas was completed, the mixture was stirred for an additional hour at room temperature. The solid, which precipitated during the reaction, was filtered off. After removal of the ethanol from the filtrate under diminished pressure, there was isolated 16.5 grams (61% of theory) of 3-ethoxy-3-t-butyl-4-neopentyl 1,2-dithiole.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3]1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1ccccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: CS(=O)(=O)c1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methylsulfonylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:12]1([C:18]#[C:19][Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: Br[Mg]C#Cc1ccccc1
Reactant: COc1ccc(F)cc1C=O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
To a stirred solution of 5-fluoro-2-methoxybenzaldehyde (933 mg, 6.05 mmol) in anhydrous THF (15 mL) at 0° C. was added phenylethynyl magnesium bromide solution (1M in THF, 9.0 mL, 9.08 mmol). The temperature was allowed to increase to RT over the course of the reaction. After 18 h, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc (20 mL). The organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 30% EtOAc in cyclohexane) to afford the title compound (1.19 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 7.42-7.32 (m, 6H), 7.16-7.09 (m, 1H), 7.06-7.02 (m, 1H), 6.16-6.13 (d, 1H), 5.78-5.75 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH2:8][C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)c1cc(Cc2cc[nH]c2)cc(C(C)(C)C)c1O

Procedure:
For example, using 2-methylsulfonyl-4-[2-(3,5-di-t-butyl-4-hydroxyphenyl)-1-oxo-ethyl]pyrrole in this generation reaction together with eight molar equivalents of LAH yields 2-methylsulfonyl-4-[2-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]pyrrole (a compound according to Formula X wherein: m is 2; n is 0; R is H; and X is SO2CH3 ; and Y and Z are each H). Likewise, using 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole in this general reaction together with eight molar equivalents of LAH yields 3-(3,5-di-t-butyl-4-hydroxybenzyl)pyrrole (a compound according to Formula X wherein: m is 1; n is 0; R is H; and X, Y and Z are each H).
Reaction SMILES: [Na+].[OH:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([C:9]([O-:11])=[O:10])[CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>[OH-].[Na+]>[OH:2][C@H:3]1[CH2:8][N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:6][C@@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])[C@@H]1CNC[C@H](O)C1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.6 %

Procedure:
To cis-(3RS,5RS)-5-hydroxy-3-piperidinecarboxylic acid sodium salt (5.2 g; 31.0 mmol) in 0.5 N NaOH (100 ml) was added benzyl chloroformate (7.0 ml; 50.0 mmol) and the reaction was allowed to stir at room temperature under N2 for 14 hours. The reaction was extracted with diethyl ether (2×50 ml), acidified with 6N HCl (pH=2) and extracted with EtOAc (4×100 ml). The combined organic extracts were dried with Na2SO4, the solvents were removed to provide the desired compound (6.2 g; 72%).