Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CCOCC.C([Li])CCC.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[CH:33]=[O:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCCCCC>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:33]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[OH:34])[CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C(O)c2cc(OCc3ccccc3)ccc2OC)cn1
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
5-Bromo-2-methoxypyridine (15.87 g) was dissolved in dry tetrahydrofuran (50 ml) and the solution cooled with mechanical stirring under nitrogen to -100° (ether/liquid nitrogen). A solution of n-butyl lithium in hexane (53 ml of a 1.6M solution) was added dropwise, maintaining the temperature below -90°; a white precipitate appeared. After 5 minutes, 5-benzyloxy-2-methoxybenzaldehyde (17.04 g) in dry tetrahydrofuran (150 ml) was added dropwise, maintaining the temperature below -95°. After the addition was complete, the mixture was stirred to 5°. The dark solution was quenched with excess saturated ammonium chloride, the organic layer removed, the aqueous extracted with ethyl acetate, then the combined organics dried with anhydrous magnesium sulphate and evaporated. The residue crystallised from ether/petroleum spirit to give 1-(5-benzyloxy-2-methoxyphenyl)-1-(6-methoxy-3-pyridyl)methanol (17.83 g, 72%), m.p. 80°-82°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[N+:21]([O-])=O)[N:17]([CH3:24])[C:16](=[O:25])[C:15]3([CH3:27])[CH3:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](O)(=O)C>[Pd]>[CH3:24][N:17]1[C:18]2[CH:19]=[C:20]3[N:21]=[C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][C:4]([CH3:28])=[CH:3][CH:2]=4)[NH:11][C:12]3=[CH:13][C:14]=2[C:15]([CH3:27])([CH3:26])[C:16]1=[O:25]
Reactant: CN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Reactant: CC(=O)O
Agent: [Pd]
Product: Cc1ccc(CCc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4C)cc1

Procedure:
A solution of 3-phenyl-N-(1,3,3-trimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-propionamide (532 mg) in acetic acid (8 ml) is hydrogenated at 2-4 bar at RT using Pd/C (10%, 80 mg), where upon ring closure occurs. After evaporation of the solvent the residue is taken-up in NaOH solution (2 N) and extracted with EtOAc (2×20 ml). The combined organic layer is washed with brine, dried over Na2SO4 and evaporated. The residual material is triturated with acetone to give the desired compound (466 mg).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=O)[CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[C:5]2[C:10](=[C:11]([F:12])[C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1C=Nc2c(ccc(F)c2F)C1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(F)c(F)ccc2c1Cl
Temperature: 95 °C
Yield: 97.9 %

Procedure:
A suspension of 26 g of ethyl 7,8-difluoro-4-oxoquinoline-3-carboxylate in 212 g of phosphorus oxychloride was heated at 95° C. for 4 hours, with stirring. After treatment, 27.3 g of ethyl 4-chloro-7,8-difluoroquinoline-3-carboxylate was obtained in the form of a white solid, which melted at 114° C.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].O=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][O:18][C:17]2[CH:26]=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=[CH:29][C:16]1=2>C1COCC1.C(OCC)(=O)C>[CH2:33]([O:32][C:30]([C:27]1[CH:28]=[CH:29][C:16]2[C:15](=[CH:3][C:1]#[N:2])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]=2[CH:26]=1)=[O:31])[CH3:34]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(=O)c1ccc2c(c1)OCc1ccccc1C2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)OCc1ccccc1C2=CC#N
Reaction time: 1 h
Yield: 58 %

Procedure:
Diethyl (cyanomethyl)phosphonate (52 ml) was dissolved in 200 ml of THF, and 12.8 g of sodium hydride (60% oily) was added to the solution under ice cooling, followed by stirring for one hour. To the mixture was added 200 ml of a solution of 17.3 g of ethyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-3-carboxylate in THF, and the mixture was heated under reflux for 3 hours. After cooling, ice chips were added to the reaction mixture, and the mixture was then diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (2/1)] to give 11.5 g (58%) of the product as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10]CC)=[O:9])=[CH:5][C:4]2[O:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:3]1=2.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4]2[O:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:3]1=2
Reactant: CCOC(=O)Cc1cc2c(n1C)C(=O)c1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(CC(=O)O)cc2c1C(=O)c1ccccc1CO2
Yield: 57 %

Procedure:
Ethyl 5,10-dihydro-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetate (196 mg, 0.66 mmol) is dissolved in ethanol and 2.5 N aqueous sodium hydroxide (2 ml, 5 mmol) is added dropwise at reflux under nitrogen. The reaction is heated for an additional ten minutes, then the solution is cooled and diluted with water (5 ml). The resulting mixture is acidified with 2.5 N aqueous HCl (3 ml). The product separates as an oil, then solidifies on scratching. The solid is filtered, washed with water and dried to give 160 ml crude product. The product is recrystallized from ethanol to give 102 mg of 5,10-dihydro-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetic acid, M.P. 114°-116° (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[Cl:25]CCl.C([Li])CCC>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:25])=[N:17][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(OCc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a mixture of 1-benzyloxy-4-(2-nitro-ethyl)-benzene described in Manufacturing Example 229-1-2 (39 g, 0.15 mol), tetrahydrofuran (350 mL) and dichloromethane (350 mL) was added n-butyl lithium (63 mL, 2.6 M n-hexane solution, 0.17 mol) at −78° C., which was stirred for 20 minutes at the same temperature. To the reaction mixture was added titanium (IV) chloride (25 mL, 0.23 mol) at the same temperature, and the mixture was warmed gradually to 10° C. After cooling the reaction mixture to 0° C., water (500 mL) and ethyl acetate (700 mL) were added, and the reaction mixture was warmed to room temperature. This organic layer was separated, washed with water (500 mL) and saturated sodium chloride water, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. This residue was filtered with neutral silica gel (ethyl acetate:heptane=1:1), and this filtrate was concentrated under a reduced pressure. The obtained residue was washed with diethyl ether-heptane (1:10) to obtain the title compound (33 g, 78%).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].O=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[N:16]1[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:18]=[C:17]1[C:26]([O:28]CC)=O>C(O)(=O)C>[O:28]=[C:26]1[NH:5][C:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][C:8]=2[N:16]2[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:18]=[C:17]12
Reactant: [NH4+]
Reactant: CCOC(=O)c1cn(C2Cc3ccccc3C2=O)c(C(=O)OCC)n1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3
Yield: 37.7 %

Procedure:
51.2 g of ammonium acetate are added in small portions to a solution of 2 g of diethyl 1-(1-oxoindan-2-yl)imidazole-2,4-dicarboxylate in 80 ml of acetic acid and the mixture is heated to reflux for 2 hours. After cooling to a temperature close to 20° C. the precipitate formed is filtered off and rinsed with distilled water and then with methyl ethyl ketone (2×10 ml) to give 0.65 g of ethyl 4,5-dihydro-4-oxo-10H-imidazol[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in the form of a beige solid melting above 260° C. (analysis % calculated C: 65.08, H: 4.44, N: 14.23; % found C: 65.2, H: 4.3, N: 13.8).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([N:12]([CH3:32])[C:13]([CH2:15][N:16]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)C(=O)C(F)(F)F)=[O:14])[CH:6]=1.C(O)(=O)C>CO.O>[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([N:12]([CH3:32])[C:13](=[O:14])[CH2:15][NH:16][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:6]=1
Reactant: Cc1cc(C)nc(N(C)C(=O)CN(C(=O)C(F)(F)F)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1cc(C)nc(N(C)C(=O)CNc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Lithium hydroxide monohydrate (56 mg, 1.34 mmol) was added to a solution of N-{[(4,6-Dimethyl-pyridin-2-yl)-methyl-carbamoyl]-methyl}-2,2,2-trifluoro-N-(4-nitro-phenyl)-acetamide (550 mg, 1.34 mmol) in methanol (20 mL) at 0° C. and stirred for 1 h. The pH was adjusted to approximately pH 6 by the addition of acetic acid. Methanol was evaporated in vacuo to yield a solid residue, which was stirred in water and filtered to afford N-(4,6-dimethyl-pyridin-2-yl)-N-methyl-2-(4-nitro-phenylamino)-acetamide (350 mg, 53%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.ClC(OCC)=O.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([NH:42][C:43]2[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[O:45][N:44]=2)=[O:41])=[CH:35][CH:34]=1>C(Cl)Cl>[C:48]([C:46]1[O:45][N:44]=[C:43]([NH:42][C:40](=[O:41])[NH:39][C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:14](=[O:16])[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:13][N:12]=3)=[CH:38][CH:37]=2)[CH:47]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)no1
Reactant: CN1CCN(c2ccc(C(=O)O)nc2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
To a stirred solution of 5-(4-methylpiperazin-1-yl)picolinic acid (185 mg, 0.46 mmol) in 5 mL of DCM was added DIEA (82 μL, 0.46 mmol) and ethyl chloroformate (45 μL, 0.46 mmol). The resulting mixture was stirred at rt for 15 min, sonicated for 10 min. 1-(4-Aminophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (128 mg, 0.46 mmol) was added. The resulting mixture was refluxed for 30 min. LC-MS indicated the reaction mostly done. Solvent was then removed under reduced pressure and residue was purified on reverse phase HPLC to give N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(4-methylpiperazin-1-yl)picolinamide (65 mg, 29%) as a white foamy solid. LC-MS (ESI) m/z 478 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.48 (s, 1H), 8.79 (s, 1H), 8.36 (d, J=2.45 Hz, 1H), 7.96 (d, J=8.85 Hz, 1H), 7.80 (d, J=8.85 Hz, 2H), 7.47 (dd, J=2.64, 8.85 Hz, 1H), 7.41 (d, J=9.04 Hz, 2H), 6.50 (s, 1H), 3.35 (br. s., 8H), 2.26 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]([CH3:31])([OH:30])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH3:31][C:11]1([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[O:30][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(O)(CN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(CN2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a solution of 1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenoxy)-piperidin-1-yl]propan-2-ol prepared in Example 230 (225 mg, 0.49 mmol) in DMF (2.5 ml), sodium hydride (23 mg, 0.59 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice-water and ethyl acetate were added. The precipitates were filtered off, washed with water, recrystallized from methylene chloride-diisopropyl ether and then washed with n-hexane to afford 2-methyl-6-nitro-2-[4-(4-trifluoromethylphenoxy)piperidin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (80 mg, yield 39%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=[C:4](F)[CH:3]=1.BrCC1C=CC([C:42]#[N:43])=CC=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([C:11]1[N:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:42]#[N:43])=[CH:34][CH:33]=2)=[CH:9][CH:10]=1)([F:32])[F:31]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Product: N#Cc1ccc(COc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1

Procedure:
Compound 9 was prepared in a similar manner to compound 1 from 4-(bromomethyl)benzonitrile to afford a white solid (80 mg, 33%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.24 (s, 1H), 7.72 (d, J=7.5 Hz, 2H), 7.75-7.52 (m, 3H), 7.43 (br s, 1H), 7.39-7.35 (m, 1H), 7.31-7.29 (m, 1H), 6.78-6.74 (m, 1H), 6.70-6.67 (m, 1H), 5.51 (d, J=14.0 Hz, 1H), 5.18 (s, 2H), 5.13 (d, J=14.0 Hz, 1H). MS (ESI): m/z 485 [M+1]. HPLC: 97.12%.
Reaction SMILES: B(Br)(Br)Br.C([O:12][CH2:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][N:15]=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>ClCCl>[N+:23]([C:20]1[CH:21]=[C:22]2[C:14]([CH2:13][OH:12])=[N:15][NH:16][C:17]2=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cnc2[nH]nc(COCc3ccccc3)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2[nH]nc(CO)c2c1
Reaction time: 1 h
Yield: 87.3 %

Procedure:
BBr3 (7.4 mL, 7.4 mmol, 1M in heptane) was added to a solution of 3-(benzyloxymethyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.70 g, 2.46 mmol) in dichloromethane (25 mL) at −78° C., and the reaction mixture was stirred at this temperature for 1 hour. Saturated aqueous NaHCO3 was added, followed by addition of ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford (5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (417 mg, 87%), as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]([F:33])[CH:26]=[C:27]2[C:31]=1[NH:30][C:29](=[O:32])[CH2:28]2>>[Br:22][C:23]1[CH:24]=[C:25]([F:33])[CH:26]=[C:27]2[C:31]=1[NH:30][C:29](=[O:32])/[C:28]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 73.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b obtained from step 1 of Example 4 as starting materials to obtain (Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 50 (51 mg, yield 73.2%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K].C(Cl)Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:32]2[C:31](=[O:33])[C:30]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]3[C:28]2=[O:38])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
A suspension of 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.35 g) and potassium phthalimide (0.7 g) in dimethylformamide (10 ml) is warmed at 50° to 60° C. for 3 hours. The reaction mixture is shaken with methylene chloride. The methylene chloride layer is washed with water and saturated aqueous saline solution in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is crystallized from ethyl acetate/ether to give 5-chloro-2-[3-(2-phthalimido-acetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone as crystals melting at 251° to 253° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)([OH:21])[CH3:22])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1 g, 4.6 mmol) in DMF (10 mL) was stirred at RT for 5 min. NaH (60%, 933 mg, 23.33 mmol) was added and the reaction mixture was stirred at RT for 10 min. 3-(2-methyloxiran-2-yl)pyridine (1.26 g, 9.34 mmol) was added to the reaction mixture and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-water and extracted with EtOAc (200 mL).The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by column chromatography using silica gel:100-200 mesh and 10% MeOH/DCM/1 mL NH4OH to obtain 600 mg of 1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.74 (s, 1H), 8.54 (d, 1H), 7.71 (d, 1H), 7.26 (s, 1H), 7.27 (m, 1H), 7.19 (d, 1H), 6.96 (d, 1H), 4.26 (dd, 2H), 2.91 (m, 2H), 2.9 (m, 4H), 2.74 (m, 2H), 2.44 (s, 6H), 1.63 (s, 3H). Separation by chiral HPLC provided enantiomers II-135a-b.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[N:27]=[C:28]([NH:31][CH:32]([CH3:34])[CH3:33])[S:29][CH:30]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35]([OH:37])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41]([C:43]1([NH2:48])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:42])[CH3:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[N:27]=[C:28]([NH:31][CH:32]([CH3:33])[CH3:34])[S:29][CH:30]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](=[O:37])[NH:48][C:43]1([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1CC1(N)C(=O)OCC
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3csc(NC(C)C)n3)nc2c1
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 81 %

Procedure:
Compound 21 (300 mg, 0.56 mmol) was reacted with 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (130 mg, 0.84 mmol) as described in Example 5 which gave the title compound (302 mg, 80%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][C:10]2=[O:20])=[CH:6][CH:5]=1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].CCOCC>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][C:10]2=[O:20])=[CH:21][CH:22]=1
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (18 g.; 60% w/w dispersion in oil, washed as described in Example 1) was stirred in dry dimethylformamide (300 ml.), and 1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (64.7 g.) was added, followed by diethyl oxalate (55 g.). The mixture was stirred at room temperature for 2.5 hours with occasional external cooling to keep the temperature below 25° C. Ether (2 l.) was added, and the mixture was filtered. The solid residue was washed with ether (500 ml.), and then suspended in dimethylformamide (200 ml.) and acidified to pH 2 by the addition of concentrated hydrochloric acid. The resultant mixture was added to water (3 l.), and the mixture filtered, and the solid residue washed with water (2 l.), drained well, and crystallised from ethanol to give ethyl 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylpyruvate, m.p. 180°-182° C.
Reaction SMILES: C[N:2]([CH3:32])/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]([S:17]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([N:27]3[CH:31]=[N:30][N:29]=[CH:28]3)[CH2:22]2)(=[O:19])=[O:18])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)=O.N[C:34]1[CH:38]=C[NH:36][N:35]=1>C(O)(=O)C>[N:35]1[N:36]2[C:5]([C:7]3[CH:8]=[C:9]([S:17]([NH:20][C@H:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([N:27]5[CH:28]=[N:29][N:30]=[CH:31]5)[CH2:22]4)(=[O:18])=[O:19])[CH:10]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:12]=3)=[CH:4][CH:3]=[N:2][C:32]2=[CH:38][CH:34]=1
Reactant: Nc1cc[nH]n1
Reactant: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@H]2CCC[C@@H](n3cnnc3)C2)c1
Solvent: CC(=O)O
Product: O=S(=O)(N[C@H]1CCC[C@@H](n2cnnc2)C1)c1cc(-c2ccnc3ccnn23)cc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
A mixture of 9b (40.0 mg, 0.085 mmol) and 3-aminopyrazole (8.5 mg, 0.102 mmol) in acetic acid (1.50 mL) was placed in a sealed tube and heated in a microwave reactor at 110° C. for 20 min. After cooling to rt, the reaction mixture was concentrated in vacuo, resuspended in 10% NH4OH/MeOH and reconcentrated. The crude residue was purified by preparative thin layer chromatography on silica gel (10% MeOH/DCM as eluent) to afford the title compound, 9c. m/z (ES) 492 (MH)+; IC50=5.9 nM