Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]2[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]#[N:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:26]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:13]=[CH:12][CH:11]=1)[CH2:23][C:22]2([CH3:25])[CH3:24])#[N:27]
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
Ethanesulfonyl chloride (104 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford ethanesulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (120 mg, yield: 60.0%). MS (ESI+APCI) M+1=370.2.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=1.[Cl:27]CCl.[ClH:30].O1CCOCC1>CO>[ClH:27].[ClH:30].[ClH:27].[Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCN2CCCC2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Brc1cn(CCN2CCCC2)c(C2CCNCC2)n1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Combine tert-butyl 4-(4-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (0.80 g, 1.87 mmol), dichloromethane (20 mL), methanol (8 mL), and 4M hydrochloric acid in dioxane (9.36 mL, 20.0 eq) under nitrogen and let stir at room temperature. After 1.5 hours, concentrate in vacuo to give the title compound (0.82 g, 100%). MS (ES) m/z=327 [M]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:13]1([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:3][C:4]=2[C:16]([F:19])([F:18])[F:17])(=[O:10])=[O:9])[CH2:15][CH2:14]1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=S(=O)(NCC1CC1)c1ccc(Nc2ccccc2)cc1C(F)(F)F
Reaction time: 6 h
Yield: 20 %

Procedure:
A mixture of 4-bromo-N-cyclopropylmethyl-2-trifluoromethylbenzenesulfonamide (183 mg, 0.51 mmol), aniline (93 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), BINAP (33 mg, 0.05 mmol) and cesium carbonate (246 mg, 0.75 mmol) in 15 ml toluene was relaxed for 6 hours. Toluene was evaporated in vacuum and crude oil was purified by Combiflash (PE-THF). Yield 20%
Reaction SMILES: COCCOC.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:28][C:29]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[CH:48][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45](Br)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>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.C(OCC)(=O)C.O>[CH2:21]([O:28][C:29]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][CH2:57]2)=[CH:48][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45]([C:8]2[O:7][CH:11]=[CH:10][CH:9]=2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
Ethylene glycol dimethyl ether (2.0 mL), water (0.60 mL), furan-2-boronic acid (0.047 g), sodium carbonate (0.093 g), and bis(triphenylphosphine)palladium(II) dichloride (4.9 mg) were added to tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-bromobenzoate (0.20 g), followed by stirring at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and bis(triphenylphosphine)palladium(II) dichloride (4.9 mg) was added thereto, followed by stirring at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-70% hexane/ethyl acetate] to obtain 0.14 g of tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-(furan-2-yl)benzoate as a light yellow solid.
Reaction SMILES: O[Li].[OH2:3].OO.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH:22]=[O:23])[CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[O-:17])=[CH:9][CH:8]=1.[O-]S([O-])=O.[Na+].[Na+]>O.C1COCC1>[C:10]([O:18][C:16]([N:15]([CH:19]([CH3:21])[CH3:20])[CH2:14][C@H:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)[C:22]([OH:3])=[O:23])=[O:17])([CH3:13])([CH3:11])[CH3:9]
Reactant: O
Reactant: CC(C)N(CC(C=O)c1ccc(Cl)cc1)C(=O)[O-]
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Product: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 200.4 %

Procedure:
LiOH—H2O (168 mg, 4.00 mmol) was added to a stirring solution of THF (30 mL) and water (15 mL) at room temperature until it was dissolved. The mixture was treated with hydrogen peroxide (658 uL of a 35% wt. solution in water, 8.00 mmol) and allowed to stir at room temperature for 10 minutes. The reaction was cooled to 0° C. in an ice bath, and the tert-butyl (S)-3-(S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (1.00 g, 2.00 mmol) was added dropwise via addition funnel as a solution in THF (15 mL) over a 10 minutes. The mixture was allowed to stir overnight at room temperature to completion by LCMS analysis of the crude. The reaction was cooled to 0° C., and then treated with 1M Na2SO3 (9.00 mL) solution via addition funnel over a ten minute period. After the addition was complete, the mixture was allowed to warm to room temperature for 10 minutes. The mixture was concentrated to remove the THF, and then diluted with water. The aqueous layer was washed twice with ethyl acetate (discarded). The aqueous layer was partitioned with ethyl acetate, then treated dropwise while stirring with 1M HCl until pH 2-3 was attained. The aqueous layer was extracted twice with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The colorless oil product was dried under high vacuum for one hour to afford (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid as a viscous oil/foam (685 mg, 100%). LC/MS (APCI+) m/z 242.1 [M-Boc]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([F:45])[C:33]=1[O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:29]Br.Cl>CN(C=O)C>[CH2:1]([O:4][C:5]([C:7]([CH2:29][C:28]1[CH:27]=[C:26]([F:25])[C:33]([O:34][Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:38])[CH3:37])=[C:32]([F:45])[CH:31]=1)([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)[Si](Oc1c(F)cc(CBr)cc1F)(C(C)C)C(C)C
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.17 g (10.14 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate (Example 48A) are dissolved in 30 ml of DMF and, at 0° C., 0.45 g (11.15 mmol) of 60% sodium hydride is added in portions, and the mixture is stirred at RT for 30 minutes. After renewed cooling to 0° C., a solution of 5 g (13.18 mmol) of 3,5-difluoro-4-triisopropylsilanyloxybenzyl bromide in 20 ml of DMF is added dropwise, and the mixture is stirred while warming to room temperature overnight. The mixture is poured into ice, weakly acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane, then cyclohexane/ethyl acetate 10:1). 4.57 g (73% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[C:7](=[O:12])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>CN(C)C=O.[Cu]>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[C:7](=[O:12])[CH2:8][C:9](=[O:11])[N:10]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3cc(F)ccc32)C(C)C)cc1
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
A mixture of 0.880 g of 2-(7-Fluoro-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part D, (2.20 mmol), 420 mg of copper powder (6.61 mmol, 3 equiv), 476 mg of potassium acetate (4.85 mmol, 2.2 equiv), and 0.290 mL of 3-bromopyridine (4.85 mmol, 2.2 equiv) in 10 mL of dimethylformamide is heated at 100° C. under nitrogen for 3 hrs. An additional 0.132 mL of 3-bromopyridine (2.43 mmol, 1.1 equiv) is added and the reaction is maintained for an additional 2 hrs. The reaction mixture is cooled to ambient temperature, filtered through a sintered glass funnel and then evaporated in vacuo to a residue. The residue is partitioned between ethyl acetate and aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL). After separating the layers, the organic layer is washed with aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL), and then saturated aqueous brine. The organic phase is then extracted three times with aqueous HCl (1N). The acid layers were combined and neutralized with aqueous sodium hydroxide (1N). The neutralized mixture is extracted twice with methylene chloride. The methylene chloride layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue is triturated with hexane and then concentrated in vacuo to provide 0.705 g of 2-(7-Fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a tan solid: H NMR (300 MHz, CDCl3) δ8.60 (m, 2H), 8.08 (s, br, 1H), 7.54 (s, 1H), 7.39 (m, 1H), 7.15 (m, 2H), 7.00 (m, 3H), 6.57 (dd, 1H, J=2.7, 9.2), 4.95 (m, 1H), 4.32 (d, 1H, J=17.9), 4.14 (d, 1H, J=17.8), 3.85 (s, 3H), 3.61 (d, 1H, J=12.1), 3.52 (d, 1H, J=12.1), 1.06 (d, 6H, J=6.8); low resolution MS (FAB)m/e 477 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br.Br[CH2:20][CH2:21][NH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3([C:10]([F:13])([F:11])[F:12])[NH:22][CH2:21][CH2:20][O:14]3)=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: NCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)NCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (594 mg), 2-bromoethylamine-hydrobromide (860 mg) and potassium carbonate (871 mg) were dissolved in DMF (5 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (2×20 mL). The extracts were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2; 40% ethyl acetate/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4]CC.CCN(CC)CC.[ClH:14].[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[N:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28]2)[CH2:24][CH2:23]1>CO>[ClH:14].[OH:15][CH:16]1[CH:17]([N:22]2[CH2:23][CH2:24][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28]3)[CH2:26][CH2:27]2)[CH2:18][C:19]2[C:20](=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:21]1
Reactant: OC1CCCCC1N1CCC2(C=Cc3ccccc32)CC1
Reactant: CCCCCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: OC1Cc2ccccc2CC1N1CCC2(C=Cc3ccccc32)CC1

Procedure:
A biphasic mixture of the bromohydrin (1.14 g, 5.0 mmol) in 2M aq. NaOH (100mL) and CHCl3 (100 mL) was refluxed for 2.5 h. TLC (silica gel; 50% hexane-CH2Cl2) confirmed that formation of the epoxide was complete. The mixture was cooled to room temperature and the two layers were separated. The aq. phase was re-extracted with CHCl3 (2×30 mL) and discarded. The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield the crude epoxide as a pale yellow syrup which was redissolved in EtOH (30 mL) and Et3N (2 mL). Spiro[1H-indene-1,4'-piperidine]hydrochloride (1.11 g, 5.0 mmol) was added to this solution, and the resulting mixture was refluxed overnight. After 17 h, heating was stopped. The mixture was cooled to room temperature and concentrated to a residue in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and the solution was washed with satd aq. NaHCO3 (30 mL). The aqueous extract was washed with CH2Cl2 (30 mL) and discarded. The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated to a residue. The latter was dissolved in a minimum volume of CH2Cl2 and applied to a short column of silica gel which was subsequently eluted with 25% acetone-hexane. Concentration of the eluent yielded the product (0.91 g, 55%) as a brown syrup. The latter was estimated by tlc (silica gel, acetone(25):hexane (74):Et3N (1)) to be greater than 97% pure. The corresponding hydrochloride was prepared in MeOH as outlined for (11a) above, and recrystallized from isopropyl alcohol; mp 254°-257° C.; 1H NMR (CDCl3) δ1.46 (d, 2, piperidyl β-Heq., J= 12.8 Hz), 2.17 (m, 2, piperidyl β-Hax.), 2.86-3.49 (m, 8, tetrahydronaphthyl C1-H, C3-H, C4-H & piperidyl α-Hax.,eq.), 3.93-4.20 (m, 3, piperidyl α-Heq & C HOH), 6.79 (d, 1, indenyl C2-H, J=5.6 Hz), 6.90 (d, 1, indenyl C3-H, J=5.7 Hz), 7.03-7.42 (m, 8, aryl).
Reaction SMILES: [C:1]1([CH:7]([N:14]=[C:15]=[S:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:17].[K+:18].CC(C)=O.C(O)(C)(C)C.C(Br)Br>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH:7]([NH:14][C:15](=[S:17])[S-:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[K+:18]
Reactant: S=C=NC(c1ccccc1)c1ccccc1
Reactant: [SH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: BrCBr
Solvent: CCN(CC)CC
Product: S=C([S-])NC(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
Potassium diphenylmethyldithiocarbamate was prepared from diphenylmethyl isothiocyanate and potassium hydrosulfide in a t-butyl alcohol acetone mixture. A mixture of 29.7 g. of this salt, 26.1 g. of methylene bromide, and 10.1 g. of triethylamine in 200 ml. of dimethylformamide was stirred for about one hour keeping the initial reaction temperature below 30° C. by cooling. The mixture was poured into ice-water, partitioned into ethylene chloride, and gave 24.0 g. of crude product upon evaporation of the ethylene chloride. Purification by dry column chromatography on silica gel using 20% methylene chloride in hexane for developing gave 5.5 g. of solids which were recrystallized from isopropyl alcohol to give 4.4 g. of white crystals, m.p. 106.5°-107.5° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:26])([OH:25])[CH2:12][N:13]2[CH2:18][CH:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O>CN(C=O)C>[CH3:26][C@@:11]1([CH2:12][N:13]2[CH2:18][CH:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:25][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CC=C(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CC=C(c3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
(S)-1-(2-Chloro-4-nitro-imidazol-1-yl)-2-methyl-3-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)propan-2-ol prepared in Example 275 (0.492 g, 1.31 mmol) was dissolved in DMF (8 ml). To the solution, sodium hydride (63 mg, 1.57 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 3 hours. To the reaction mixture, water was added. After extraction with ethyl acetate, the organic phase was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=4/1) and recrystallized from methylene chloride-ethyl acetate to afford (S)-2-methyl-6-nitro-2-(4-phenyl-1,2,3,6-tetrahydropyridin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole (0.059 g, yield 13%) as a light yellow solid.
Reaction SMILES: NN.CC([CH2:7][N:8]([CH2:12][CH2:13][CH:14]([N:21]1C(=O)C2C(=CC=CC=2)C1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:11])[O-:10])(C)C>C1COCC1.CO>[NH2:21][CH:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][CH2:12][N:8]([CH3:7])[C:9](=[O:11])[O:10][C:15]([CH3:20])([CH3:16])[CH3:14]
Reactant: CC(C)(C)CN(CCC(c1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)[O-]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCC(N)c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 0.2 %

Procedure:
NH2NH2 (1.7 mL, 54.2 mmol) was added to a THF/MeOH (50 mL/10 mL) solution of 1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]methylcarbamate (2.7 g, 6.8 mmol) and stirred overnight. After 12 hours, the solution was absorbed onto silica and purified by column chromatography using 5% MeOH in CHCl3 containing 0.5% NH4OH to give the title compound (1.4 mg, 77%) as a white solid: LC-MS (ES) m/z=265 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][O:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=O>CS(C)=O>[CH3:6][O:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:3][C:2]#[CH:1]
Reactant: COC(=O)CCCCCCCC=O
Reactant: [Li]CCCC
Solvent: CS(C)=O
Product: C#CC=CCCCCCCCC(=O)OC

Procedure:
n-Butyl lithium (750 μL, 2M) was added methyl sulfoxide (6 mL) under argon at room temperature. The solution was stirred for half an hour, and (3-trimethylsillyl-2-propynyl)-triphenylphosphonium bromide (1 mmole) in methyl sulfoxide was added and stirred for one hour. 9-Oxo-nonanoic acid methyl ester in methyl sulfoxide was added to the reaction mixture and stirred for 4.5 hours. The reaction mixture was poured onto ice water and extracted with ethyl acetate three times. The organic layers were combined and dried to obtain crude mixture, which was further purified through Si gel column chromatography. The product contained trans and cis isomers in about 8:2 ratio.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>O1CCCC1.CC(C)=O.CCOCC>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:8][CH2:9][CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COC(c1ccccc1)c1ccccc1)N1CCC(c2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(C2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A solution of 7.4 g (18.6 mmole) of 1-[(diphenylmethoxy) acetyl]-4-phenylpiperidine in 60 cm3 of tetrahydrofuran was added to a solution of 1.1 g (29.7 mmole) of lithium aluminum hydride in 100 cm3 of tetrahydrofuran. The mixture was heated to a reflux for 12 hours and, after cooling to room temperature, hydrolyzed with 5.5 cm3 of water. 200 cm3 of ether was added. The alkaline residues were washed with ether. The ethereal solutions were collected, dried on sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 30 cm3 of acetone. A solution of 1.7 g (18.9 mmole) of oxalic acid in 150 cm3 of acetone was added. The 1-[2-(diphenylmethoxy)ethyl]-4-phenyl piperidine oxalate precipitate was filtered, then recrystallized from an acetone-ethanol mixture.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=[O:27])[C:10](=[CH:23]OCC)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:29]O>C(O)C>[CH:6]1([C:9]2[O:27][N:29]=[CH:23][C:10]=2[C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:8][CH2:7]1
Reactant: CCOC=C(C(=O)c1ccc(SC)cc1OC)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(SC)ccc1C(=O)c1cnoc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (7.87 g) was added to a stirred mixture of 3-cyclopropyl-2-ethoxymethylene-1-(2-methoxy-4-methylsulphenylphenyl)propan-1,3-dione (30.6 g) and hydroxylamine hydrochloride (8.0 g) in ethanol. The mixture was stirred at room temperature overnight, then evaporated to dryness and the residue was dissolved in ethyl acetate, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether and filtered to give 5-cyclopropyl-4-(2-methoxy-4-methylsulphenylbenzoyl)isoxazole, compound 249 as a white solid, m.p. 107.5°-108.5° C.
Reaction SMILES: Cl[C:2]1N=C2C(=CC=1OCC)C=C1N2C(C)CNC1.[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([C@H:40]([O:42][CH3:43])[CH3:41])=[C:32]([CH2:44][OH:45])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].CI>>[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([C@H:40]([O:42][CH3:43])[CH3:41])=[C:32]([CH2:44][O:45][CH3:2])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CO[C@H](C)c1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CCOc1cc2cc3n(c2nc1Cl)C(C)CNC3
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCc1cc2c(nc1[C@@H](C)OC)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-7-hydroxymethyl-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.