Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])(=[O:5])[CH3:4].I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:20]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:10][C:11]1=[O:16])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2
Reactant: CCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.7 %

Procedure:
Sodium hydride (21.0 mg, 90.0 mmol) was slowly added into a solution of 6-acetyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Compound 28, 98.0 mg, 45.0 mmol) in 3 mL of DMF at 0° C. After stirring at 0° C. for 10 min, 1-iodoheptane (30.5 mg, 135.0 mmol) was added to the reaction mixture and the ice-bath was removed. The reaction mixture was allowed to stir for 2 h and then quenched with ice water. The resulting solution was then extracted with ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (75:25 hexane/ethyl acetate) yielded the title compound (93.6 mg, 66% yield) as a colorless oil:
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:4])[CH3:3].C(NC(=O)C1CC=CNC=1)C1C=CC=CC=1.O>ClCCl>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:24])[CH:9]=[CH:8][N:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccc(Cl)cc3)cc1C(C)=O)C2=O
Agent: O=C(NCc1ccccc1)C1=CNC=CC1
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccc(Cl)cc3)C=C1C(C)=O)C2=O
Yield: 44.3 %

Procedure:
To a solution of pyridinium salt 131 (75 mg, 0.15 mmol) in dry and degassed dichloromethane (2.5 mL) was added at once N-benzyl-1,4-dihydronicotinamide (BNAH) (32 mg, 1 equiv) at 25° C. under Argon. The reaction was monitored by TLC until the starting material has disappeared (48 h). Then, water and dichloromethane were added. The organic layer was washed twice with water and once with brine, dried over magnesium sulfate and concentrated to dryness. The crude residue was purified by column chromatography (gradient of EtOAc in petroleum ether) to afford the title compound 153 as a yellow solid (Yield 29 mg, 44%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:26])=[C:10]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:15][C:11]2=[C:12](Cl)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1N=C(Cl)C2C=C(C3C=CC(OC)=CC=3)SC=2C=1O)=O)CCC>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:26])=[C:10]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[S:15][C:11]2=[CH:12][N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2sc(-c3ccc(OC)cc3)cc2c1O
Agent: CCCCOC(=O)c1nc(Cl)c2cc(-c3ccc(OC)cc3)sc2c1O
Product: CCCCOC(=O)c1ncc2sc(-c3ccc(OC)cc3)cc2c1O

Procedure:
The title compound was prepared from a mixture of 7-chloro-4-hydroxy-2-(4-methoxy-phenyl)-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester and 4-chloro-7-hydroxy-2-(4-methoxy-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester, example 3-c, analogously to experimental conditions for example 1-g; with isolation of the lower Rf isomer. MS: (+) m/z 358.05 (M+1).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)[N:8]=1.CO.[NH2:21][NH2:22]>O1CCCC1>[NH:21]([C:3]1[N:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)[N:8]=1)[NH2:22]
Reactant: NN
Reactant: CSc1nncc(-c2cccc(C(F)(F)F)c2)n1
Solvent: C1CCOC1
Solvent: CO
Product: NNc1nncc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
To a solution of 22.8 g. of 3-methylthio-5-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine in a mixture of 30 ml. of methanol and 35 ml. of tetrahydrofuran is added 4.84 ml. of 95% hydrazine. The mixture is refluxed for 48 hours, cooled and the solid is collected by filtration giving 3-hydrazino-5-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine as yellow needles.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH2:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)[CH3:32]>>[CH2:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:29])[CH3:32]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: CCc1ccccc1B(O)O
Product: CCc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-ethylphenylboronic acid in step C. MS (ESI): mass calcd. for C20H16N4O3, 360.1; m/z found, 361.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 1H), 12.91 (br s, 1H), 8.99 (s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.81 (dd, J=8.2, 1.8 Hz, 1H), 7.77 (s, 1H), 7.40-7.36 (m, 2H), 7.32-7.29 (m, 1H), 7.25 (d, J=7.2 Hz, 1H), 2.59 (q, J=7.5 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H).
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:22]=[CH:21][CH:20]=[CH:19][CH:9]1[CH2:10][CH:11]2[CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:22]=[CH:21][CH:20]=[CH:19][CH:9]1[CH2:10][CH:11]2[CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N+:24]=[N-:25]
Reactant: ClCCCOC12C=CC=CC1CC2CN1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOC12C=CC=CC1CC2CN1CCCCC1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
Sodium iodide (3 g) is added to a stirred solution of 3-(3-chloropropoxy)-1-(1-piperidinylmethyl)benzocyclobutene (0.87 g) in 12 ml of DMF. The reaction mixture is stirred under nitrogen for 12 hours, sodium azide (1.17 g) is added to this solution followed by water (1.2 ml). The resulting suspension is heated at 75° C. for 5 hours. The reaction mixture is partitioned between water and methylene chloride and the organic layer is separated, washed, dried, filtered and evaporated in vacuo yielding the azide product as an oil.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[CH:17]1([NH:20][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(NC1CC1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 292° C. and MS: m/e=251 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and cyclopropylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([NH:45][C:14]([NH:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[C:10]([C:23]([F:24])([F:25])[F:26])[CH:11]=2)=[O:22])[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 79 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (184 mg, 79%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.79 (s, 1H), 8.69 (d, 1H), 7.79 (s, 1H), 7.68 (m, 2H), 7.46 (m, 4H), 7.42 (s, 1H), 7.35 (s, 1H), 7.27 (d, 1H), 6.87 (s, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 585 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[Na+].[Na+].C[C:28]([N:30](C)C)=O>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:30]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(Br)cccc12
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(C#N)cccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 3-(5-bromo-1-isoquinolinyl)propanoate (D34; 60 g, 178 mmol) was taken up in dry DMA (600 ml) followed by the addition of potassium hexacyanoferrate hexahydrate (22.61 g, 53.5 mmol) then palladium acetate (0.801 g, 3.57 mmol) dppf (3.96 g, 7.14 mmol) and then finally sodium carbonate (22.7 g, 214 mmol). The reaction mixture was stirred at 120° C. overnight, cooled and diluted with ethyl acetate (500 ml) and filtered through Celite. The filtrate was concentrated in vacuo. and the dark residue was taken up in DCM (250 ml) and filtered through Celite and cotton wool. The DCM solution (250 ml) was purified by chromatography using a gradient system 0-100% ethyl acetate in isohexane to give the title compound (25.3 g)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1ccccc1
Reaction time: 1 h

Procedure:
(±)-trans-2-Aminocyclohexanol (241 gm) was combined with chloroform (2000 ml), water (2000 ml) and sodium bicarbonate (352 gm) and stirred. Benzoyl chloride (352 gm) was added dropwise to the stirred solution and stirring was continued for 1 hr. The product was filtered and washed with water. The white solid was dried at 80° C. to provide the product (mp 172°-173° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.COC1C2CCCC(=O)NC=2C=CC=1[N+:29]([O-:31])=[O:30]>>[CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[C:6]([N+:29]([O-:31])=[O:30])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CCCC(=O)N2
Reactant: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2
Product: COc1ccc([N+](=O)[O-])c2c1CCCC(=O)N2

Procedure:
Analogous to procedure 107b, 6-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (700 mg, 3.66 mmol) was converted to 6-Methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (380 mg, 44%), purified by ISCO chromatography. 1H-NMR (CDCl3) δ 8.12 (s, 1H), 7.79 (d, J=8.6 Hz, 1H). 6.85 (d, J=8.6 Hz, 1H), 3.95 (s, 3H), 2.95 (t, J=7.2 Hz, 2H), 2.44 (t, J=7.3 Hz, 2H), 2.31 (quint, J=7.2 Hz, 2H); LC/MS (ESI-pos) m/z 237.11 (M+H). Analogously, 6-Methoxy-9-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was also isolated.
Reaction SMILES: [C:1]([N:4]1[CH2:18][CH2:17][C:16]2[C:7](=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[CH3:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:20]O>>[C:1]([N:4]1[CH2:18][CH2:17][C:16]2[C:7](=[N+:8]([O-:20])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[CH3:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Reactant: OO
Product: CC(=O)N1CCc2c(C)c3ccccc3[n+]([O-])c2CC1
Yield: 83.5 %

Procedure:
3-Acetyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline 6-oxide was prepared analogous to Example 111 from 3-acetyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and hydrogen peroxide.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[S:6]1)#[N:4].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(OCC)(=O)C>CN(C)C=O.O>[C:3]([C:5]1([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:26]3[O:28][CH2:27]3)=[CH:21][CH:22]=2)[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[S:6]1)#[N:4]
Reactant: ClCC1CO1
Reactant: CN1C(=O)C(C#N)(c2ccc(O)cc2)Sc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C#N)(c2ccc(OCC3CO3)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 54.5 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.7 g) in anhydrous dimethylformamide (5 ml), 2-cyano-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (5.0 g, compound No. 10) dissolved in anhydrous dimethylformamide (15 ml) is added under nitrogen atmosphere and ice-cooling, and the mixture is stirred for 7 minutes at room temperature. Epichlorohydrin(2.6 ml) is added to the reaction mixture, and the mixture is stirred for 1 hour at 65°-75° C. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 3.2 g (54.5%) of the titled compound.
Reaction SMILES: C1([C:7]2[C:13]3=[CH:14][NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=43)[C:10](=[O:20])[NH:9][N:8]=2)C=CC=CC=1.N1C2C=CC=C(C(OC)=O)C=2C=C1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:44]=[CH:43][C:39](C(Cl)=O)=[CH:38][CH:37]=1.[Cl-].[Al+3].[Cl-].[Cl-].O.NN>ClC(Cl)C.CO.Cl>[F:34][C:35]([F:46])([F:45])[C:36]1[CH:44]=[CH:43][C:39]([C:14]2[C:13]3=[CH:7][N:8]=[N:9][C:10](=[O:20])[C:11]4[C:12]3=[C:16]([CH:17]=[CH:18][CH:19]=4)[N:15]=2)=[CH:38][CH:37]=1
Reactant: O=C1NN=C(c2ccccc2)c2c[nH]c3cccc1c23
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)c1cccc2[nH]ccc12
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Solvent: CC(Cl)Cl
Product: O=c1nncc2c3c(cccc13)N=C2c1ccc(C(F)(F)F)cc1

Procedure:
In a manner similar to that described for Compound 28, a solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (3 mL) was treated with p-trifluoromethylbenzoyl chloride (445 mg, 2.14 mmol) and aluminum chloride (572 mg). The intermediate ketone (95 mg, 0.27 mmol) in MeOH (3 mL) and conc. HCl (0.05 mL) was treatewd, as described, with hydrazine hydrate (0.1 mL). The reaction was quenched at 0° C. with w M NaOAc and the aqueous layer was adjusted to pH=8 with 1 M NaOH. The product was isolated by extraction with CH2Cl2, and recrystallized (CH2Cl2/hexanes) to give 1,5-dihydro-3-(4-trifluoromethylphenyl-[1,2]diazepino[4,5,6-cd]indol-6-one, 30 mg (34%) as a yellow solid: 1H NMR (300 MHz, d6-DMSO) δ 7.24 (app br t, 1H), 7.29 (d, J=2.8 Hz, 2H), 7.60 (m, 2H), 7.82 (m, 4H), 10.57 (s, 1H), 12.01 (s, 1H). HRMS (FAB, Mna+) Calcd for C11H10N3Ona: 352.0674. Found: 352.0668.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1
Reactant: COC(=O)CCCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCc1ccncc1

Procedure:
A solution of ester 10-4 (10.0 g, 56 mmol), 1N NaOH (84 ml, 84 mmole) and CH3OH (200 ml) was stiffed at ambient temperature for 1.0 h. Concentrated HCl (7.0 ml, 84 mmol) was added followed by concentration. The residue was dissolved in CHCl3, dried (MgSO4) and concentrated to give acid 10-5 as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[N:12]=[C:11]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:13]1[CH:9]([C:4]2[CH:3]=[C:2]([C:36]3[CH:37]=[CH:38][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:34][CH:35]=3)[C:7]([F:8])=[CH:6][CH:5]=2)[CH2:10][C:11]([C:22]([F:27])([F:28])[C:23]([F:26])([F:25])[F:24])=[N:12]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(F)c(Br)c2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccc2F)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
5-(3-Bromo-4-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (250.0 mg, 0.53 mmol) prepared in Step 5 of Preparation 7, 4-methylsulfonylphenylboronic acid (116.0 mg, 0.58 mmol), Pd(PPh3)4 (61.0 mg, cat.) and a 2N sodium carbonate solution (3.5 mL) were added to a mixed solvent of ethanol (3.5 mL) and N,N-dimethylformamide (15.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 150.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl.N[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[Br:14].N([O-])=O.[Na+].[C:19]([Cu])#[N:20].[C-]#N.[Na+]>O.CCOC(C)=O>[Br:14][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[C:19]#[N:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1ccc(N)c(Br)c1
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#N)c(Br)c1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a three necked 3 L round bottomed flask with a mechanical stirrer was added 3 M aqueous HCl (790 mL), followed by ethyl 4-amino-3-brombenzoate (195 g, 0.8 mol) and the mixture was stirred for 15 min. After cooling to 5° C., a solution of 4M aqueous NaNO2 (240 mL, 0.96 mol) was added over a period of 30–45 min. The resulting mixture was further stirred for 30 min. and an almost homogenous solution was obtained. The mixture was filtered through glass wool to remove the insoluble residue. The solution was then added to a vigorously stirred solution of CuCN (111 g, 1.24 mol) and NaCN (162 g, 3.3 mol) in H2O (1 L) and EtOAc (500 mL) at room temperature in a 6 L Erlenmeyer flask over ˜45 min. The resulting mixture was further stirred at r.t. for 30 min., filtered through celite and extracted with EtOAc. The EtOAc extract was washed with brine, 0.5 M aqueous NaOH, dried (MgSO4) and concentrated. Chromatography over silica gel and elution with hexanes:EtOAc (6:1), then (3:1), swished with hexanes and small amount of Et2O to give a light brown powder. The mother liquor was concentrated and swished again. Combined yield of the title compound was 119 g (58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].CI.[C:30](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)(=[O:17])=[O:18])[CH3:30])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To a solution of [(R)-4-(3-chloro-4-fluoro-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (150 mg, 0.36 mmol, prepared as described in example 4-1, 1st step) in acetonitrile (10 mL) was added methyl iodide (154 mg, 1.1 mmol) and potassium carbonate (151 mg, 1.1 mmol). The reaction mixture was stirred at 65° C. for 5 hours, then cooled to room temperature and filtered through a glass funnel. The filtrate was evaporated under reduced pressure and purified by column chromatography (gradient elution, 0-10% methanol in dichloromethane) to afford {(R)-4-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (150 mg, 96%) as a yellow solid. MS cald for C18H21ClN3O4S 429, obsd. (ESI+) [(M+H)+]: 430.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: Clc1nsc2ccccc12
Product: Cc1[nH]c2ccc(F)cc2c1-c1nsc2ccccc12

Procedure:
The title compound was prepared from 5-fluoro-2-methylindole and 3-chloro-1,2-benzisothiazole by the method of Example 31, step a).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C1C(=O)N([Br:19])C(=O)C1.C(OCC)(=O)C.CCCCCC>CC#N>[NH2:1][C:2]1[C:7]([Br:19])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1c(O)cc([N+](=O)[O-])cc1Br
Reaction time: 1 h

Procedure:
A solution of 2-amino-5-nitrophenol (97, 24 g, 156 mmol) in CH3CN (1 L) was treated with NBS (28.8 g, 160.8 mmol) at room temperature. After stirring for 1 hour, the solvent was removed to afford brown precipitate, which was taken up with ethyl acetate:hexane (1:1). The precipitate was filtered and was used for the next step without further purification (33 g, 91%). A small amount of sample was purified by column chromatography on silica gel for analysis; 1H NMR (500 MHz, CD3OD): δ 4.93 (brs, 3H), 7.50 (d, 1H, J=2.4 Hz), 7.89 (d, 1H, J=2.4 Hz); 13C NMR (125 MHz, CD3OD): δ 105.5, 108.7, 121.8, 138.5, 143.7, 144.8; HRMS (FAB) calcd for C6H5BrN2O3 (M+) 231.9484, found 231.9479.