Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[Cl:18])(=[O:3])[CH3:2].[Cl:19][C:20](Cl)([Cl:24])[CH2:21][CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([O:17][CH2:22][CH:21]=[C:20]([Cl:24])[Cl:19])=[CH:14][C:15]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCOc1c(Cl)cc(O)cc1Cl
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Yield: 78.4 %

Procedure:
This compound was prepared in a manner analogous to that set forth in Step E of Example 1, using 25.3 grams (0.086 mole) of 4-(2,6-dichloro-4-hydroxyphenoxy)butyl acetate, 19.5 grams (0.1 mole) of 1,1,1,3-tetrachloropropane, and 18 grams (0.13 mole) of potassium carbonate in 250 mL of DMF was heated at 80° C. during a 16 hour period. The crude reaction product was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 27.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([C:7]2([O:17][CH3:18])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C(=O)([O-])O.[Na+].C(OCC)C>O>[CH3:18][O:17][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: COC1(C2CCCCC2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: COC1(C2CCCCC2)CCC(=O)CC1
Temperature: 25 °C
Yield: 107.1 %

Procedure:
A solution of 8-cyclohexyl-8-methoxy-1,4-dioxaspiro[4.5]decane (1.15 g) and acetic acid (40 ml) in water was stirred at 100° C. for 6 hours. After cooling to room temperature, the reaction mixture was added to a mixture of sodium hydrogen carbonate solution and diethyl ether. The organic layer was taken, washed with sodium hydrogen carbonate solution and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 1-methoxy-1,1′-bicyclohexane-4-one (1.018 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[Cl:20][C:21]1[NH:25][N:24]=[C:23]([CH3:26])[CH:22]=1>>[Cl:20][C:21]1[N:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:3]=2)[N:24]=[C:23]([CH3:26])[CH:22]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: Cc1cc(Cl)[nH]n1
Product: Cc1cc(Cl)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine and 5-chloro-3-methyl-1H-pyrazole.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:5]([CH2:13][OH:14])[CH:4]=1)[NH2:2].C(N(CC)CC)C.[CH:22]1([C:28](=O)[CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C(O)C>[CH:32]1([C:30]2[CH:29]=[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:1]([C:3]3[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:10])=[O:11])=[C:5]([CH2:13][OH:14])[CH:4]=3)[N:2]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NNc1ccc(S(N)(=O)=O)c(CO)c1
Reactant: O=C(CC(=O)C1CCCCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C3CCCCC3)cc2-c2ccccc2)cc1CO
Temperature: 100 °C
Reaction time: 72 h
Yield: 15.6 %

Procedure:
To a suspension of 4-hydrazinyl-2-(hydroxymethyl)benzenesulfonamide (224 mg, 0.884 mmol) in ethanol (4.0 mL), triethylamine (246 μL, 1.77 mmol) and 1-cyclohexyl-3-phenylpropan-1,3-dione (185 mg, 0.803 mmol) were added, and the obtained solution was stirred at 100° C. for 72 hours. Water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/chloroformlacetone) to obtain the title compound (51.5 mg, 0.125 mmol, 16%) as a white amorphous product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][CH:9]=[C:8]([C:11]3[S:15][CH:14]=[N:13][CH:12]=3)[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]3[CH:38]=[CH:37][NH:36][C:33]3=[N:34][CH:35]=2)O1>>[O:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[S:10][CH:9]=[C:8]([C:11]4[S:15][CH:14]=[N:13][CH:12]=4)[C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]4[CH:38]=[CH:37][NH:36][C:33]4=[N:34][CH:35]=3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: Clc1nc(N2CCOCC2)c2scc(-c3cncs3)c2n1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: c1cc2cc(-c3nc(N4CCOCC4)c4scc(-c5cncs5)c4n3)cnc2[nH]1

Procedure:
2-Chloro-4-morpholin-4-yl-7-thiazol-5-yl-thieno[3,2-d]pyrimidine and 5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine were reacted according to General Procedure A to give 318. NMR (DMSO, 400 MHz), 3.86 (4H, t, J=4.4), 4.09 (4H, t, J=5.2), 6.61-6.63 (1H, m), 7.54-7.57 (1H, m), 8.78 (2H, s), 9.03 (1H, s), 9.20 (1H, s), 9.44-9.46 (1H, m), 11.88 (1H, s). MS: (ESI+): MH+=421
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH2:18]1[C:21]2([CH2:25][CH2:24][CH2:23][NH:22]2)[CH2:20][O:19]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:22]2[CH2:23][CH2:24][CH2:25][C:21]32[CH2:18][O:19][CH2:20]3)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: C1CNC2(C1)COC2
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN1CCCC13COC3)CCCN2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (Intermediate 41) (0.19 g, 0.78 mmol) in DCM (10 mL) was added 2-oxa-5-azaspiro[3.4]octane (0.248 g, 1.57 mmol), DIPEA (0.410 mL, 2.35 mmol) and sodium triacetoxyborohydride (0.332 g, 1.57 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was added slowly to water (10 ml). The aqueous was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure to afford the title compound. (UPLC-MS 3) Rt=0.55 min; MS m/z [M+H]+ 334.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH3:15]O>Cl>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Agent: Cl
Product: COC(=O)c1ccc2c(c1)CCCC2=O
Yield: 86 %

Procedure:
A solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (5.14 g, 27.0 mmol) (Peakdale Molecular) in 4N hydrochloric acid in methanol was heated to reflux for eighteen hours. The solution was returned to ambient temperature and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride and dried over magnesium sulfate. Filtration followed by concentration in vacuo provided methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a brown solid (4.76 g, 86% yield). Reversed-phase HPLC on 4.6×50 mm C-18 column, tR=1.90 minutes (10 to 90% acetonitrile/water over 4 minutes at 4 mL/minute with detection 254 nm, at 20° C.); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99-2.08 (m, 2H), 2.58-2.66 (m, 2H), 2.99 (t, J=6.04 Hz, 2H), 3.85 (s, 3H), 7.83-7.87 (m, 1H), 7.91 (d, J=0.81 Hz, 1H), 7.92-7.97 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([BH3-])#N.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Clc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1cccc2c1CCN2
Temperature: 12 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a stirred solution of 4-chloroindole (5 g, 33.0 mmol) in Acetic Acid (50 mL) at 12° C. under nitrogen was added sodium cyanoborohydride (6.84 g, 109 mmol) portionwise. The reaction was stirred at 12° C. for 2 hours. LCMS indicated complete conversion, so the reaction mixture was diluted with water (300 mL), cooled in an ice-bath and quenched with sodium hydroxide pellets portionwise until the mixture was strongly basic. The mixture was then extracted with diethyl ether (3×200 mL) and the combined organics dried over sodium sulfate, concentrated and the residue purified by flash chromatography (0-30% EtOAc in hexanes) to afford 4-chloro-2,3-dihydro-1H-indole (4.0 g) as a colourless oil. LC-MS (ES) m/z=154 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.94 (t, J=8.59 Hz, 2H), 3.47 (td, J=8.72, 1.77 Hz, 2H), 5.83 (br. s., 1H), 6.40 (d, J=7.83 Hz, 1H), 6.50 (d, J=8.08 Hz, 1H), 6.90 (t, J=7.96 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[C:20](=O)[N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][C:9]=23)=[CH:4][CH:3]=1.B.C1COCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[CH2:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][C:9]=23)=[CH:4][CH:3]=1
Reactant: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1Cc2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2C1
Temperature: 25 °C

Procedure:
A solution of 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one 3A-1 (7 mg, 0.018 mmol) and BH3THF (166 ml, 166 mmol) was stirred at room temperature for 1 hour and at 50° C. for 17 hours. After the reaction mixture was cooled to room temperature, MeOH (5 ml) was added. The reaction mixture was heated under reflux for 2 h, cooled to room temperature, and concentrated in vacuo. The residue was diluted with 4 M HCl/dioxanes (1 ml) and concentrated under vacuum. The residue was dissolved in CH2Cl2 and hexanes were added to precipitate 8A-1 as a colorless solid (2 mg, 27%): +APCI MS (M+H) 372.5; 1H NMR (CD3OD): δ 7.59-7.43 (m, 4H), 7.38 (d, 2H), 7.20 (d, 2H), 4.80-4.65 (m, 2H), 3.91-3.82 (m, 1H), 3.68-3.55 (m, 2H), 1.52 (d, 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:15]([N:17]1[CH2:22][CH2:21][CH2:20][C:19]([N:29]=[N+]=[N-])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)=O)C1C=CC=CC=1>C1COCC1>[CH3:15][N:17]1[CH2:22][CH2:21][CH2:20][C:19]([NH2:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1
Reactant: [N-]=[N+]=NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC(N)(c2ccccc2)C1
Temperature: 65 °C
Yield: 46.7 %

Procedure:
To a suspension of 126 mg (3.15 mmol) LiAlH4 in THF (2.7 ml) at temperature below 10° C. was added dropwise a solution of 530 mg (1.576 mmol) rac-3-azido-3-phenyl-piperidine-1-carboxylic acid benzyl ester in THF (5.3 ml). The ice bath was removed. The temperature rose to 35° C. The mixture was then heated in a 65° C. oil bath for 1 hour. The mixture was cooled to 0° C. Water (125 ul), NaOH 5N (125 ul) and finally water (0.375 ml) were added dropwise maintaining the temperature below 10° C. The mixture was diluted with ethyl acetate. Sodium sulfate was added. The mixture was filtered and the filtrate was concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 0.14 g (47%) of the title compound as a yellow oil. MS (m/e): 191.5 (M+H+)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:14]=[N:13]1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:15]2[CH:14]=[N:13][NH:12][C:17](=[O:18])[CH:16]=2)=[CH:20][CH:21]=1
Reactant: O=c1cc(-c2ccc(F)cc2)cnn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccc(F)cc2)cn[nH]1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Aluminum chloride (11.4 g, 86 mmol) was added to a stirred mixture of 2-benzyl-5-(4-fluorophenyl)pyridazin-3(2H)-one (4.0 g, 14.3 mmol) in toluene (285 ml) and the mixture was stirred at 70° C. for 1 h. After cooling, the reaction was cooled in an ice bath and quenched slowly with water (50 mL). The precipitate was filtered, washed with water, and dried under high-vacuum to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.28 (d, 1H); 7.88 (dd, 2H); 7.35 (t, 2H); 7.13 (d, 1H). LRMS (APCI) calc'd for (C10H8FN2O) [M+H]+, 191.1. found 191.1.
Reaction SMILES: [C:1]1([C:7]2([OH:26])[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[C:15]3=[O:25])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[N+](=[CH2:31])=[N-]>O>[C:1]1([C:7]2([OH:26])[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:31])[CH:20]=4)[C:15]3=[O:25])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccc(O)cc2CCC1CN1CCC(O)(c2ccccc2)CC1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCC(CN1CCC(O)(c3ccccc3)CC1)C2=O

Procedure:
3.51 g. of 2-(4-phenyl-4-hydroxypiperidinomethyl)-6-hydroxy-1-tetralone are dissolved in a mixture of 45 ml. of methanol and 5 ml. of water. An ethereal solution of diazomethane is added at 20° until a faint yellow coloration remains. The mixture is evaporated to give 2-(4-phenyl-4-hydroxypiperidino-methyl)-6-methoxy-1-tetralone, m.p. 163°-165°.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[Br:19]Br>C(O)(=O)C>[Br:19][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([NH2:18])[C:8]3[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=3[C:16]=2[CH:15]=1
Reactant: BrBr
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reaction time: 24 h
Yield: 25.6 %

Procedure:
To a solution of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 41.6 mmol) in acetic acid (150 mL) was added Br2 (10.0 g, 62.6 mmol), and after 24 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in a saturated aqueous solution of NaHSO3, after which it was again collected and stirred with a 2 M solution of Na2CO3 for 18 h. The solid was collected by filtration, washed with H2O, and azeotropically dried with toluene on a rotary evaporator. Purification on silica gel (7%–10% methanol in CH2Cl2 gradient) afforded 3.4 g of 8-bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[NH:14][CH:15]([CH3:17])[CH3:16])([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([O:4][C:5]1[C:6]([NH:14][CH:15]([CH3:17])[CH3:16])=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cc([N+](=O)[O-])ccc1OC(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)Nc1cc(N)ccc1OC(C)C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A suspension of 2-isopropoxy-N-isopropyl-5-nitrobenzenamine 29 (385 mg, 1.62 mmol, 1 equiv) in ethanol (3 mL) was charged with 10% Pd/C (50% water, 253 mg, 0.162 mmol, 0.10 equiv) and air was evacuated with vacuum. The vacuum was replaced with a balloon filled with hydrogen gas, and the reaction was allowed to stir for 2 hours. The catalyst was filtered off using a pad of celite and rinsed with ethanol. The filtrate was concentrated, and the crude product was purified by flash chromatography and eluted with hexane:EtOAc=100:0 to 50:50 using 5% EtOAc increments to give 6-isopropoxy-N1-isopropylbenzene-1,3-diamine 31 (263 mg, 78%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][N+:10]([O-])=O)=[CH:4][CH:3]=1>[Pd].CO>[NH2:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:13]
Reactant: O=[N+]([O-])CC(O)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: NCC(O)c1ccc(F)cc1
Reaction time: 22 h
Yield: 97 %

Procedure:
A recovery flask was charged with 520 mg (2.81 mmol) of the optically active 1-(4-fluorophenyl)-2-nitroethanol obtained in Example 14, 52 mg of 10% Pd/C, and 2.8 ml of methanol, and stirring was carried out under an atmosphere of hydrogen at atmospheric pressure and 30° C. for 22 hours. After the reaction was completed, the catalyst was filtered off and the solvent was distilled off under vacuum to give 421 mg (yield 97%, 1H-NMR) of optically active 2-amino-1-(4-fluorophenyl)ethanol as white crystals. The amino group of the amino alcohol so obtained was monobenzoylated by reaction with benzoyl chloride, and when it was analyzed using a CHIRALCEL OD column (eluant; n-hexane:2-propanol=30:1), it was found that the optical purity was 96% ee.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[CH:22]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][CH:6]=3)(=[O:11])=[O:12])[N:14]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2nc(C3CCCC3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)n2nc(C3CCCC3)c3ccccc32)cc1
Reaction time: 15 h
Yield: 63 %

Procedure:
Combine 4-(3-Cyclopentyl-indazole-1-sulfonyl)-benzoic acid methyl ester (2.045 g, 5.325 mmoles) in 50 ml of THF. Add 3 ml of 5 N NaOH and allow to stir for 15 hrs. Make the reaction acidic with HCl and extract into diethyl ether. Dry organic layer over MgSO4 and concentrate to isolate 1.243 g (Yield=63%) of the title compound: MS ES+ 369.47; MS ES− 369.46.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([OH:11])=[C:5]([F:12])[C:4]=1[F:13])#[N:2].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>C(Cl)(Cl)(Cl)Cl>[C:14]([O:11][C:6]1[C:5]([F:12])=[C:4]([F:13])[C:3]([C:1]#[N:2])=[C:8]([F:9])[C:7]=1[F:10])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Reactant: C=C(C)C(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Reaction time: 48 h
Yield: 83.7 %

Procedure:
In 200 ml of carbon tetrachloride, 19.1 g (0.100 mol) of 4-cyano-2,3,5,6-tetrafluorophenol and 13.0 g (0.125 mol) of methacrylic acid chloride were dissolved. To the resultant solution was added 20 g of molecular sieve 3 Å in diameter. The resultant mixture was refluxed as agitated for 48 hours. The reaction mixture so produced was cooled and then filtered to separate the molecular sieve. The filtrate was dried with magnesium sulfate and then evaporated to dryness with a rotary evaporator. Consequently, there was obtained 21.7 g of 4-cyano-2,3,5,6-tetrafluorophenyl methacrylate (yield 83.8% based on 4-cyano-2,3,5,6-tetrafluorophenol, purity 96.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].ClC1C=C2C([CH:16]=[CH:17][N:18]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)C2=O)=CC=1F>>[F:10][C:9]1[CH:8]=[C:7]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:6])[N:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH:17]=[CH:16]2
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Reactant: Cc1cc(C=O)ccc1F
Product: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1

Procedure:
Starting from 3-methyl-4-fluoro benzaldehyde, the title compound was prepared following a similar sequence as described for 7-chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (62). Rt=1.83 min (Method B). Detected mass: 298.1 (M+H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1.Cl[CH2:11][C:12]1[C:13]([CH3:18])=[N:14][O:15][C:16]=1[CH3:17]>CN(C)C=O>[CH3:18][C:13]1[C:12]([CH2:11][N:3]2[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: Cc1noc(C)c1CCl
Reactant: O=Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(C=O)cn1
Temperature: 0 °C

Procedure:
Add N,N-dimethylformamide (3 mL) to sodium hydride (0.092 g, 2.29 mmol) and stir at 0° C. Add 1-H-pyrazole-4-carboxaldehyde (0.200 g, 2.08 mmol) and stir at 0° C. for 20 min. Dissolve 4-chloromethyl-3,5-dimethylisoxazole (0.318 g, 2.18 mmol) in N,N-dimethylformamide (4 mL) and add to reaction mixture. Stir reaction at room temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution. Add ethyl acetate and separate organic layer. Extract aqueous layer twice with ethyl acetate. Dry combined organic layers (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 25:75 to 75:25 ethyl acetate:hexanes), to give the title preparation (387 mg, 91%). GC-MS: m/z=205 [M+].
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:13]N)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].O=[C:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.CCCCCC.C(OCC)(=O)C>CC(O)=O.C(OCC)(=O)C.CCOCC>[Br:3][C:4]1[CH:5]=[C:6]2[C:7](=[C:8]([C:9]([OH:11])=[O:10])[CH:12]=1)[NH:13][C:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][C:17]2=1
Reactant: NNc1ccc(Br)cc1C(=O)O
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2[nH]c3c(C(=O)O)cc(Br)cc3c2C1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a stirred suspension of 5-bromo-2-hydrazinylbenzoic acid dihydrochloride (3.08 g, 10.13 mmol) in AcOH, (˜0.5M) (20 mL) was added ethyl 4-oxocyclohexanecarboxylate (1.759 g, 10.34 mmol) at room temperature. The cream-colored reaction mixture was then stirred under reflux for 4 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford a yellow solid. The solid was then dissolved in ethyl acetate, washed with 1N aqueous HCl and brine solution. The organic phase was dried over Na2SO4 and concentrated to give the crude product, which was then suspended in ether and the yellow solid was collected by filtration, air-dried. Additional quantity was obtained by combining the filtrate followed by silica gel column chromatography (hexane/ethyl acetate=50/50-0/100) to give 2.1 g of 6-bromo-3-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid. MS (ESI) m/z 367.2 (M+H). 1H NMR (DMSO-d6) δ ppm 13.2 (br s, 1H), 10.8 (s, 1H), 7.8 (s, 1H), 7.6 (s, 1H), 3.92 (m, 4H), 3.77 (q, 2H, J=7.8 Hz), 2.52-2.81 (m, 7H), 1.3 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O)[CH3:2].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Br:16])[CH3:2]
Reactant: CCOc1c(CO)cccc1[N+](=O)[O-]
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1c(CBr)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a mixture of the compound (3.13 g) obtained in Example 417b, carbon tetrabromide (5.26 g) and methylene chloride (100 ml), triphenylphosphine (4.16 g) was added under ice cooling. The reaction mixture was stirred under ice cooling for 30 min and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate: n-hexane=1:9) to give 3.59 g of the titled compound (yield, 87%).