Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([CH3:23])[CH:14]=[CH:13][C:12]([O:15][C:16]([CH2:18][CH2:19][C:20](Cl)=[O:21])=[O:17])=[CH:11][CH:10]=1.O=O>CCOCC>[C:20]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:21])[CH2:19][CH2:18][C:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:23])=[CH:14][CH:13]=1)=[O:17]
Reactant: Cc1ccc(OC(=O)CCC(=O)Cl)cc1
Reactant: CC(C)(C)OO
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(OC(=O)CCC(=O)OOC(C)(C)C)cc1
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a vigorously stirred solution of 15.6 g. (0.143 mole) of 82.0% t-butyl hydroperoxide and 57.0 g. (0.143 mole) of aqueous 10% sodium hydroxide at 5°-10° C. was added slowly 24.6 g. (0.109 mole) of 3-(p-tolyloxycarbonyl)propionyl chloride (prepared from p-tolyl 3-carboxypropionate and thionyl chloride) in 50 ml. of diethyl ether. The reaction mixture was then stirred at 5°-10° C. for three hours, after which additional ether was added to the mixture and the resulting ether solution was washed, first with 10% sodium hydroxide solution, and finally with water until the solution was neutral. After drying over anhydrous MgSO4 and removal of the ether in vacuo 28.2 g. (theory, 30.4 g.) of white solid, m.p. 72°-77° C., was obtained. The assay according to "active oxygen" content was 100% and the corrected yield was 92.8%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][C:28]=1[F:37]>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:23])[CH2:18][CH2:19]2)(=[O:34])=[O:35])=[CH:29][C:28]=1[F:37]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Diisopropylethylamine (3.2 ml, 18.5 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.5 g, 2.5 mmol) in DCM (10 ml) at room temperature. To this mixture was added 4-chlorosulfonyl-2-fluoro-benzoic acid methyl ester (0.6 g, 2.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 98% DCM, 2% Methanol) to give the title compound (0.98 g, 87% yield) as a white solid. Tr=2.08 min m/z (ES+) (M+Na+) 439.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[N:3]1.C([Li])CCC.C(O[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(C)C>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[C:6]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)=[C:5]([CH3:7])[CH:4]=[N:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cnn(C)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1,4-Dimethyl-1H-pyrazole (50 mg, 0.5 mmol) was stirred in THF (2 mL) and cooled to 0° C. A solution of 1.6 M n-butyllithium in hexanes (390 mL) was added dropwise by syringe and the mixture was allowed to warm to room temperature for 2 h. The mixture was cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110 mL, 0.52 mmol) was added dropwise by syringe. The mixture was stirred at −78° C. for 15 min. and at 0° C. for 3 h. The mixture was diluted with EtOAc and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel using EtOAc in hexanes gave the sub-title compound. LCMS calc. for C11H20BN2O2 (M+H)+: m/z=223.2. found: 223.0.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=1[S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3c(Cl)cccc3Cl)CC2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)c2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of {4-[1-(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (96 mg, 0.183 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (87.6 mg, 2.1 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. After this time, the reaction mixture was diluted with water (˜20 mL) and then acidified with 1.0 N aqueous HCl (3.66 mL). The resulting mixture was extracted with ethyl acetate (2×25 mL), then the combined extracts were washed with brine (30 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated to provide {4-[1-(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (63 mg, 67%) as a yellow solid. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.1.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3S[CH2:22][CH2:21][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][C:18]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].OO.[S:32]([O-:35])([O-])=[O:33].[Na+].[Na+].O>C(O)(=O)C>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:32](=[O:35])(=[O:33])[CH2:22][CH2:21][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][C:18]=3[CH:29]=2)=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3)cc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
Ethyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (45 g, 109.1 mmol) was suspended in 405 ml of acetic acid and was heated to 60° C. to dissolve. A solution of 30% hydrogen peroxide (25.35 g, 223.6 mmol) in 45 ml of acetic acid was dropped slowly at 60-70° C. After the dropping, the mixture was stirred at 65-70° C. for 3 hours. At that temperature, 40 ml of an aqueous sodium sulfite solution was dropped and disappearance of the peroxide was checked with iodo-starch paper. After dropping 275 ml of water at that temperature, the mixture was cooled and stirred for 2 hours and then was stirred at 0-10° C. for 30 minutes. After filtration, the residue was washed with an ice-cooled, mixed solution of acetic acid/water (45 ml/31.5 ml) and subsequently with 225 ml of water. After vacuum drying (40° C.), 45.9 g (Yield 94.6%) of ethyl 7-(4-propoxyethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate was obtained as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N:7]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:37])([CH3:36])[CH2:27][C:28]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH:29]=O)[CH:25]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:36])([CH3:37])[CH2:27][C:28]([C:31]([F:33])([F:34])[F:32])([OH:35])[CH:29]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:7]3)[CH:25]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2nc(CN3CCOCC3)ccc12
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(CN3CCOCC3)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 180 mg (0.74 mmol) of 5-amino-2-(morpholin-4-ylmethyl)quinoline is reacted with 274 mg (0.89 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 0.8 ml of concentrated acetic acid and 20 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 220 mg (56% of theory) of the product is obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:11]=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH:11]=[CH2:12]
Reactant: C=CCOc1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 100 °C
Yield: 47 %

Procedure:
4-Fluorobenzaldehyde (3.8 mL, 35.1 mmoles) was added to a solution of the product from Example 60A (4.39 g, 29.3 mmoles) and K2CO3 (8.90 g, 64.4 mmoles) in DMF (29.3 mL). The resulting mixture was heated to 100° C. for 2.5 days and then cooled to room temperature. The crude products were diluted with diethyl ether, extracted with sat. NH4Cl, extracted with H2O (2×), washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage column (hexane→9:1 hexane:ethyl acetate) on silica gel to provide the title compound (3.50 g, 81%) as a clear colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31]Br)[C:14]1=[O:33])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(OC(C)C)(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31][N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)[C:14]1=[O:33])=[O:11]
Reactant: CN1CCNCC1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCBr)C1=O)c1cc2ccccc2[nH]1
Solvent: CC(C)OC(C)C
Product: CN1CCN(CCN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-(2-bromoethyl )-5-phenyl-2H-1,4-benzodiazepine-2-one (0.3 g) and 1-methylpiperazine (3.0 ml) was stirred for 4.0 hours at room temperature and diisopropyl ether (20 ml) was added thereto. The resultant precipitates were collected by filtration and dissolved in diluted hydrochloric acid. The solution was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the resultant precipitates were collected by filtration to give (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-[2-(4-methyl-1-piperazinyl)ethyl ]-5-phenyl-2H-1,4-benzodiazepine-2-one (0.20 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:17]=[C:18]=[S:19])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:17]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[CH3:16])[C:18]1=[S:19])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: CC(N=C=S)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(C(C)c2ccc(F)cc2)C1=S
Yield: 33.1 %

Procedure:
A mixture of the crude N-ethyl glycine (18.4 g), 1-(4-fluorophenyl)-ethyl-isothiocyanate (18.1 g), triethyl amine (20.2 g) and chloroform (300 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Crystallization from ethyl acetate afforded the title compound (8.8 g) as a light yellow solid, m.p. 93°-95° C. Anal. Calcd. for. C13H15F N2O S: C, 58.63; H, 5.68; N, 10.52. Found: C, 58.69; H, 5.64; N, 10.58. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[C:11]([CH3:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][Mg]Cl)=[CH:19][CH:18]=1.Cl>CCOCC>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:11]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:14])([CH3:12])[CH3:13])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: COc1ccc(C[Mg]Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)Cc1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Diethylisopropylidenemalonate (6.686 ml, 34.09 mmol) was dissolved in 300 ml Et2O and cooled to −78° C. 4-Methoxybenzylmagnesium chloride (150.000 ml, 37.50 mmol) was added and stirring was continued for 5 h. The temperature was warmed up to 0° C. The reaction was hydrolyzed with 0.5 M HCl and extracted 3×EtOAc. Glass col. Chromatography (10-50% EtOAc in Hex.) provided diethyl 2-(1-(4-methoxyphenyl)-2-methylpropan-2-yl)malonate. MS m/z: 323.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:17][C:5]2=[N:6][C:7]=1[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[H-].[Na+].[CH3:30]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:17][C:5]2=[N:6][C:7]=1[CH2:8][N:9]([CH3:30])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCc1nc2ccn(COCC[Si](C)(C)C)c2cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1nc2ccn(COCC[Si](C)(C)C)c2cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a mixture of tert-butyl (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)methylcarbamate (300 mg, 0.75 mmol) in THF (5 mL) was added NaH (60% dispersion in mineral oil, 110 mg, 2.25 mmol). After stirring at RT for 30 min, CH3I (320 mg, 2.25 mmol) was added, followed by stirring at RT for 3 h. The reaction mixture was quenched by adding a sat'd. aq.solution of NH4Cl and extracted with EtOAc (30 mL×2). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a petroleum ether:EtOAc gradient (10:1 to 1:1) to afford 200 mg (66.6%) of tert-butyl (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl(methyl)carbamate as a brown oil. MS (ESI): m/z=410.3 [M+1]+.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:18]2[N:17]3[CH2:19][CH2:20][CH2:21][C@@H:22]([NH:23][C:24](=O)[C:25](F)(F)F)[C@H:16]3[C:15]3[CH:30]=[CH:31][CH:32]=[CH:33][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][C:9]=1[Cl:34]>CO.O>[Cl:7][C:8]1[C:18]2[N:17]3[CH2:19][CH2:20][CH2:21][C@@H:22]([NH:23][CH2:24][CH2:25][O:4][CH3:1])[C@H:16]3[C:15]3[CH:30]=[CH:31][CH:32]=[CH:33][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][C:9]=1[Cl:34]
Reactant: O=C([O-])[O-]
Reactant: O=C(N[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12)C(F)(F)F
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCN[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12
Yield: 90.2 %

Procedure:
K2CO3 (537 mg, 3.9 mmol) was added to a solution of trans-N-(6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (322 mg, 0.75 mmol) in methanol (28 mL) and water (1.7 mL). The reaction mixture was stirred at reflux temperature for 2 h whereafter the methanol was removed under reduced pressure. Water was added to the remaining product and the water layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to give the crude title compound (266 mg, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N+:19]([O-])=O)[C:12]=3[N:11]=2)=[O:9])[CH2:4][CH2:3]1.[H][H]>C1COCC1.C(O)C.[Pd]>[NH2:19][C:18]1[C:12]2[N:11]=[C:10]([C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])[NH:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)c2nc3c([N+](=O)[O-])cccc3[nH]2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2nc3c(N)cccc3[nH]2)CC1
Yield: 90.6 %

Procedure:
To a solution of (4-methyl-piperazin-1-yl)-(4-nitro-1H-benzoimidazol-2-yl)-methanone (640 mg, 2.21 mmol) in 1:1 THF/ethanol (10 mL, with a few drops of ethyl acetate) was added 10% palladium on carbon (640 mg). The reaction mixture was placed under 1 atm hydrogen for 72 h. The resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel (40 g; 0-10% methanol/CH2Cl2) to afford 519 mg (91%) of the title compound. MS (ESI): mass calculated for C13H17N5O, 259.31; m/z found, 260.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 12.21-11.36 (s, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.94-6.83 (m, 1H), 6.53 (d, J=7.8 Hz, 1H), 4.82-4.78 (m, 2H), 4.43-4.40 (m, 2H), 3.94-3.92 (m, 2H), 2.56-2.54 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[CH3:14][N:15]([C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:25]3[CH2:26][CH2:27][C@@H:23]([N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:24]3)=[O:13])[S:10][C:3]=12
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 37 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (1.05 g, 4.94 mmole), SOCl2 (10 ml), tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate 34b (0.989 g, 4.94 mmole) and Et3N (0.689 ml, 4.94 mmole) in a manner as previously described for example 9d to give a brown oil (0.723 g, 0.30%). 1H NMR (300 MHz, CDCl3) δ 8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.82 (1H, m), 3.93 (3H, m), 3.63 (1H, m), 2.82 (3H, s), 2.12 (2H, m), 1.47 (9H, s); ESIMS (MH+): 396.05.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Br:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.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>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: OB(O)c1cc(Br)cc(Br)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Br)cc(Br)c1)C(F)(F)F
Temperature: 80 °C
Yield: 75.8 %

Procedure:
A mixture of 3,5-dibromophenylboronic acid (2.58 g, 9.2 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (2.42 g, 13.8 mmol), K2CO3 (2.54 g, 18.4 mmol) and Pd(PPh3)2Cl2 (129 mg, 0.18 mmol) in THF (12 mL) and H2O (6 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (2.3 g; 76% yield) as colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](O)=[O:27]>>[NH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1)=[O:27]
Reactant: Nc1ccsc1C(=O)O
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Nc1ccsc1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 40 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-amino-2-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless needles, melting at 138°-140° C., in a 40% yield.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[CH3:16]I>O1CCCC1.O>[CH3:16][O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (12.5 g, 66.70 mmol) was dissolved in tetrahydrofuran (334 mL) and the reaction mixture cooled to 0° C. in an ice bath. The reaction mixture was treated with 80% sodium hydride in mineral oil (2.20 g, 73.3 mmol) and stirred until back at room temperature. The reaction mixture was then treated with methyl iodide (14.5 g, 100.0 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100 mL) and concentrated in vacuo until just the aqueous remained. The aqueous solution was treated with ethyl acetate (750 mL), the organic layer separated, dried over magnesium sulphate and concentrated in vacuo to yield the title product as a brown oil, 12.48 g. 1H NMR (CDCl3, 400 MHz) δ: 1:41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1H)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][C:5]([CH3:12])=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.O[CH2:16][CH2:17][NH:18][CH:19]([CH3:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:29]([CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:19]([N:18]2[CH2:17][CH2:16][O:11][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:14])([F:13])[F:1])[S:4][C:5]=3[CH3:12])[CH2:9]2)[CH3:33])=[CH:22][CH:23]=1)([O:31][CH3:32])=[O:30]
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: Cc1sc(C(F)(F)F)nc1C(=O)CBr
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3nc(C(F)(F)F)sc3C)C2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Prepared by analogy to Example 32 by reaction of 4.2 g (0.0146 mol) of 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 8 g (0.03 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine in methylene chloride by stirring at room temperature for 20 hours and heating under reflux for 2 hours. The reduction is carried out in 28 ml of trifluoroacetic acid using 2.4 g (0.02 mol) of triethylsilane. The crude product is purified on a silica gel column using toluene/ethyl acetate=7:3 as eluant.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 43 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with t-butyl-1-piperazinecarboxylate as described in Step 2 of Example 29 to afford 4-(3-formyl-1-phenyl-1H-indol-2-yl)piperazine-1-carboxylic acid tert-butyl ester (43% yield) as a yellow solid. ESI/MS 300 (M), 306 [M−CO2C(CH3)3], 350 [M−C(CH3)3], 406 (M+H; RT=3.89 min; NMR 10.15 (1H, s); 8.14 (1H, d, J=9 Hz); 7.69 (5H, m); 7.22 (2H, m); 6.94 (1H, d, J=9 Hz); 3.22 (8H, 2 br m); 1.37 (9H, s).