Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:16]2[CH2:22][CH:21]3[N:23]([C:24]([O:26][C@@H:27]4[CH2:31][CH2:30][O:29][CH2:28]4)=[O:25])[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:32][N:33]([CH3:37])[C:34]([N:8]1[CH2:7][C:4]2([CH2:3][CH2:2][N:1]([CH:16]3[CH2:22][CH:21]4[N:23]([C:24]([O:26][C@@H:27]5[CH2:31][CH2:30][O:29][CH2:28]5)=[O:25])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH2:6][CH2:5]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:35]
Reactant: CN(C)C(=O)Cl
Reactant: O=C(O[C@@H]1CCOC1)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)O[C@@H]3CCOC3)CC2)C1
Reaction time: 0.17 h

Procedure:
(R)-tetrahydrofuran-3-yl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.047 mmol) was dissolved in CH2Cl2 (1 mL) and treated with a solution of dimethylcarbamic chloride (20 mg, 0.13 mmol) in CH2Cl2 (100 μL). A solution of diisopropyl ethylamine (20 μL, 14.8 mg, 0.11 mmol) was added. The resulting mixture was allowed to stand at room temperature for 10 min and was then purified by LC/MS (10-99% CH3CN—H2O, with 0.03% TFA, 9 min) to provide (R)-tetrahydrofuran-3-yl 3-(2-(dimethylcarbamoyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC/MS m/z [M+H]+ 497.4, retention time 2.15 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:12]=2[N:11]=[CH:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([N:11]2[C:12]3[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[CH:15]=[CH:14][C:13]=3[N:9]=[CH:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NC(=O)c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2ncn(-c3cncc(Cl)n3)c2c1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloropyrazine (2.0 g, 13.4 mmol), 1H-benzimidazole-5-carboxamide (2.0 g, 12.3 mmol) and cesium carbonate (5.6 g, 17.2 mmol) in DMF (10 mL) was heated at 90° C. for 3 h. The solution was cooled to RT and diluted with ethyl acetate (20 mL) and filtered. The solid material was washed with chloroform-methanol (20 mL, 4:1) and the combined filtrates concentrated in vacuo. The residue thus obtained (3.02 g) was used without further purification.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:12]
Reactant: c1ccc(CCCNCn2nnc3ccccc32)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.6 %

Procedure:
To a mixture of 3.44 g (0.056 g-atom) of zinc powder (−325 mesh) and 60 mL of anhydrous tetrahydrofuran was added 5.0 mL (0.039 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 5.1 mL (0.039 mole) of ethyl bromodifluoroacetate in 5 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 7 g (0.026 mole) of benzotriazol-1-ylmethyl-(3-phenyl-propyl)-amine in 30 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-80:20) to give 1.1 g of 2,2-difluoro-3-(3-phenyl-propylamino)-propionic acid ethyl ester as a oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3c(C(F)(F)F)cccc23)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 5-(5-(8-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 14 (430 mg, 1.02 mmol) in CH2Cl2 (15 mL) was added at 0° C. triethylamine (173 μL, 1.21 mmol), methanesulfonyl chloride (95 μL, 1.21 mmol). The solution was stirred at RT for 1 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=95:05. (5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 19 was obtained (188 mg, 37% yield) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J32) (263 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (257 mg, 60%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[C:31]([OH:38])[C:30]=2[CH:39]([CH3:41])[CH3:40])=[O:27])[CH2:21][CH2:20]1>[F-].[K+].C(#N)C>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:36])[CH3:37])=[CH:33][CH:32]=[C:31]([O:38][CH2:2][CH2:1][O:3][CH2:4][CH3:5])[C:30]=2[CH:39]([CH3:41])[CH3:40])=[O:27])[CH2:21][CH2:20]1
Reactant: CCOCCBr
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCOc1ccc(C(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c1C(C)C
Reaction time: 41 h
Yield: 70 %

Procedure:
2-Bromoethyl ethyl ether (2 ml) and potassium fluoride catalyst carried on alumina (40 wt %, 225 mg, 1.51 mmol) were added to a solution of 2-[4-[2-(benzoxazol-2ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (150 mg, 0.30 mmol) in acetonitrile (3 ml) followed by stirring for 41 hours. The catalyst was filtered off and the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, chloroform:ammonia-saturated methanol=20:1) and the resulting crude crystals were recrystallized from ethyl acetate-hexane to provide 120 mg (yield 70%) of the desired compound as colorless powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]3)=[N:16][CH:15]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCC(O)C3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C
Reaction time: 1.6 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (2.5 mL) was added 3-pyrrolidinol (0.029 mL, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 120° C. and stirring continued for 1.6 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 1-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)pyrrolidin-3-ol as a yellow solid. Mass Spectrum (ESI) m/e=376.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]3[C:17](=[O:18])[NH:16][S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:20].[C:21]([N:24]1[CH2:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:21]([N:24]1[CH2:25][CH:26]=[C:27]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]4[C:17](=[O:18])[NH:16][S:15][C:8]=4[N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:20])[CH2:28][CH2:29]1)(=[O:23])[CH3:22]
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(Br)cc1n2C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(C)=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1CC=C(c2cc3c(cc2F)c(=O)c2c(=O)[nH]sc2n3C2CC2)CC1
Yield: 98 %

Procedure:
A mixture containing 7-bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7, 100.0 mg, 0.28 mmol), 1-acetyl-4-tributylstannyl-1,2,3,6-tetrahydropyridine (190.0 mg, 0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (16.0 mg, 0.014 mmol), and dimethylformamide (6.0 mL) Is sparged with argon gas and irradiated with microwaves (5×10 min irradiations at 130° C.). (For cross-coupling experiments described previously using C with conventional thermal heating, see: (a) Laborde, E.; Kiely, J. S.; Culbertson, T. P.; Lesheski, L. E. J. Med. Chem. 1993, 36, 1964-1970. (b) Kiely, J. S.; Laborde, E.; Lesheski, L. E.; Bucsh, R. A. J. Heterocyclic Chem. 1991, 28, 1581-1585. (c) Laborde, E.; Kiely, J. S.; Lesheski, L. E.; Schroeder, M. C. J Heterocyclic Chem. 1990, 28, 191-198) The resulting yellow solution is evaporated to dryness under reduced pressure (−6 mm Hg, 60° C.). The recovered solid is dissolved in a mixture containing 10% methanol in methylene chloride (10 mL), precipitated via addition of hexanes (100 mL), and collected by filtration. This process is repeated once. The product is purified further by flash column chromatography (eluting with 10% methanol in methylene chloride, Rf 0.50) to give pure 26 as a yellow solid (98% purity by HPLC). mp 243-244° C. 1H NMR (CDC3/CD3OD (12:1 v/v), 50° C.): δ 1.32 (m, 2H, c-Pr CH2), 1.45 (m, 2H, c-Pr CH2), 2.18 (s, 3H, NC(O)CH3), 2.65 (m, 2H, NCH2CH2), 3.45 (m, 1H, c-Pr CH), 3.73 (m, 1H, NCH2CH2), 3.87 (m, 1H, NCH2CH2), 4.23 (m, 1H, NCH2CH), 4.31 (m, 1H, NCH2CH), 6.19 (m, 1H, NCH2CH), 7.88 (d, JH-F=6.0 Hz, 1H, quinolone H-8), 8.08 (d, JH-F=11.0 Hz, 1H, quinolone H-5). 19F{1H} NMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ −119.4 (s). NMR spectroscopic data collected at room temperature indicated that two conformational isomers were present. LCMS m/z calcd for C20H18FN3O3S ([M]+) 399. Found 400 ([M+H]+). HRMS m/z calcd for C20H18FN3NaO3S ([M+Na]+) 422.0951. Found 422.0951.
Reaction SMILES: [C:1]([O:4][CH:5]([C:36]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH2:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:38][CH:37]=1)[C@H:6]([CH:33]([CH3:35])[CH3:34])[CH2:7][C@H:8]1[C@H:12]([CH2:13][NH:14][C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[O:11]C(C)(C)[N:9]1C(OC(C)(C)C)=O)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]([O:4][CH:5]([C:36]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH2:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:38][CH:37]=1)[C@H:6]([CH:33]([CH3:34])[CH3:35])[CH2:7][C@H:8]([NH2:9])[C@@H:12]([OH:11])[CH2:13][NH:14][C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:3])[CH3:2]
Reactant: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(OC(C)=O)c1ccc2cnn(CCCOC)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@@H](N)C[C@@H](C(C)C)C(OC(C)=O)c1ccc2cnn(CCCOC)c2c1
Reaction time: 2 h
Yield: 61 %

Procedure:
(4S,5S)-tert-butyl 4-((S)-2-(acetoxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-5-((2,2-dimethylhexanamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate (25 mg, 0.036 mmol) was dissolved 20% TFA/CH2Cl2 (6 mL) at 0° C. and the stirred for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give (2S,4S,5S)-4-amino-6-(2,2-dimethylhexanamido)-5-hydroxy-2-isopropyl-1-(1-(3-methoxypropyl)-1H-indazol-6-yl)hexyl acetate (12 mg, 52%). 1H NMR (400 MHz, CD3OD): 0.84-1.00 (m, 9H), 1.11-1.32 (m, 10H), 1.58 (m, 3H), 1.95 (m, 1H), 2.14 (m, 6H), 3.12 (m, 2H), 3.45 (m, 1H), 3.83 (m, 1H), 4.50 (m, 2H), 5.91 (m, 1H), 7.12 (m, 1H), 7.53 (m, 1H), 7.75 (t, 3H), 8.04 (m, 1H). MS: 644 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]1([S:15][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(I)c1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Brc1cccc(Sc2ccccc2)c1
Yield: 90.5 %

Procedure:
The general procedure in example 39 was followed. 3-bromoiodobenzene (283 mg, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 μL) were used to obtain the 3-bromophenyl phenyl sulfide (240 mg, 91% yield) as colorless liquid. Column chromatography solvent (hexane). Rf=0.6 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.11-7.22 (m, 2 H), 7.28-7.40 (m, 7 H). 13C NMR (CDCl3, 75 MHz) δ 139.2, 134.1, 132.5, 132.4, 130.6, 129.8, 129.7, 128.6, 128.2, 123.2. MS (EI) m/z (relative intensity) 266 (40), 264 (40).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.C(B(CC)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:12][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Nc1cc(Br)ccc1S(N)(=O)=O
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cc(-c2cccnc2)ccc1S(N)(=O)=O
Yield: 96.3 %

Procedure:
A mixture of 4-bromo-2-aminobenzenesulfonamide (250 mg, 1.0 mmol), diethyl-3-pyridylborane (225 mg, 1.5 mmol), Pd(PPh3)2Cl2 (35 mg, 5 mol %) in 1,2-dimethoxyethane 30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO3 (20 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 240 mg (96%) of 2-amino-4-(3-pyridyl)-benzenesulfonamide as colorless powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 240-243° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:21]([NH:27][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reactant: CCCCCCN
Product: CCCCCCNc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 80 °C
Yield: 86 %

Procedure:
A mixture of compound 6 (23.5 mg, 0.059 mmol) and n-hexylamine (1 mL) was heated for 4.5 days at 80° C. After evaporation of volatiles, the residue was purified by preparative TLC (chloroform-methanol, 20:1) to give compound 14 (23.5 mg, 86.0%). 1H NMR (DMSO-d6) δ 0.84 (m, 3 H, CH3), 1.25 (m, 6 H, CH2), 1.45 (m, 2 H, CH2), 3.17 (m, 2 H, CH2), 3.54 (s, 3 H, 9-CH3), 4.58 (br s, 2 H, CH2), 6.32 (br s, 1 H, exchangeable with D2O, NH), 7.09 (pseudo t, J=7.8 and 7.6 Hz, 1 H, H-16), 7.35 (d, J=7.8 Hz, 1 H, H-17), 7.57 (d, J=7.7 Hz, 1 H, H-15), 7.66 (s, 1 H, H-13), 7.71 (s, 1 H, H-8), 7.82 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2I)[CH2:3][CH2:2]1.[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:37]>>[CH:1]1([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:37])[N:18]([CH3:17])[CH:27]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(CCC2CC2)c(I)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2CCC2CC2)c2ccccc2c1=O

Procedure:
The title compound of Example 315, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 315, step 4 to give the title compound. 1H NMR (CD3OD, 400 MHz): δ 8.67 (d, J=8.0 Hz, 1H), 8.21 (dd, J1=2.0 Hz, J2=6.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.92-7.86 (m, 2H), 7.82-7.79 (m, 1H), 7.61 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 3.91 (s, 3H), 3.38 (s, 3H), 2.94-2.89 (m, 1H), 2.83-2.77 (m, 1H), 1.64-1.55 (m, 2H), 0.75-0.71 (m, 1H), 0.51-0.47 (m, 2H), 0.01-0.00 (m, 2H). LCMS: 382 (M+1)+
Reaction SMILES: C([NH:8][C:9]([C:11]1[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[S:14][C:15]=1[OH:16])=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:16][C:15]1[S:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:9]([NH2:8])=[O:10]
Reactant: [H][H]
Reactant: O=C(NCc1ccccc1)c1c(O)sc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1c(O)sc2ccccc12

Procedure:
A mixture of N-benzyl-2-hydroxybenzo(b)thiophene-3-carboxamide (4.3 g, 0.016 m), 10% palladium on carbon (2.0 g), and ethanol are stirred under a hydrogen atmosphere (40 p.s.i.) at 35° C. until hydrogen uptake is completed. The reaction mixture is filtered, the cake washed well with warm ethanol, and the combined filtrates concentrated in vacuo to yield 2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[N:7](C)[C:8](=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[NH3:18]>O1CCCC1>[CH3:17][O:16][C:15]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:10]([NH2:18])=[O:9])=[C:6]([NH:7][CH3:8])[CH:14]=1
Reactant: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Reactant: N
Solvent: C1CCOC1
Product: CNc1cc(OC)c(OC)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.40 g (10.1 mmol) 6,7-Dimethoxy-1-methyl-1H-benzo(d)(1,3)oxazine-2,4-dione were dissolved in 30 ml tetrahydrofuran and 15.0 ml ammonia (25%) added at 0° C. The solution was stirred for 30 min at 0° C. and for 30 min at room temperature. THF was distilled under vacuum and the remaining suspension was neutralized with diluted hydrogen chloride acid. The product was isolated by filtration.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>O1CCCC1.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CCCOCc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 50 °C

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.0 g (11.5 mmol.) of imidazole (101e), followed by addition of 5 ml of water and 1.84 g (46 mmol) of sodium hydroxide, and then, 250 mg (0.8 mmol) of n-tetrabutylammonium bromide and 2.3 g (14 mmol) of 4-chloromethylpyridine hydrochloride were further added. The mixture was stirred under heating at 50° C. for 8 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) to provide 2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole (136c) as oil. To thus-obtained oil (136c) was added 27 ml of concentrated hydrochloric acid and the mixture was heated at 110° C. for 2 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 3.8 g (yield 76%) of 3-(5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)-propan-1-ol (137c) as crystals. mp 106-107° C.