Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:15][C:16]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:39](O)([C:41]([F:44])([F:43])[F:42])=O>>[F:27][C:25]([F:28])([F:26])[C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:14]([C:11]3[CH2:10][CH2:9][N:8]([C:13]4[C:39]([C:41]([F:44])([F:43])[F:42])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:13][CH:12]=3)[NH:15][C:16]=2[C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(-c3ccc(C(F)(F)F)cc3)c(-c3ccc(C(F)(F)F)cc3)[nH]2)CC1
Product: FC(F)(F)c1ccc(-c2nc(C3=CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-[4,5-Bis-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from step (a) above was treated with TFA under the condition of Example 22(c) to give the title compound, which was used directly in the next step without additional purification. MS (ESI, positive ion) m/z: 438 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:26][C:27]([NH2:29])=[O:28])=[C:12]([CH3:25])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[OH-].[Na+]>CCO.O>[NH2:29][C:27](=[O:28])[CH2:26][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[N:13]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:12]=1[CH3:25]
Reactant: CCOC(=O)CCCOc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(CC(N)=O)c2c(OCCCC(=O)O)cccc2n1Cc1ccccc1
Yield: 42.9 %

Procedure:
A solution of 100 mg (0.245 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]butanoic acid ethyl ester and 2 mL of 1N NaOH in 5 mL of EtOH was stirred for 3.0 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (MgSO4), and on concentrating at reduced pressure a precipitate formed that was separated and washed with MeOH to give 40 mg (42% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]butanoic acid, mp, 192°-193° C.
Reaction SMILES: [O:1]=[C:2]1[NH:23][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]4)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH:24]1([NH:30][CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(Cl)Cl>[CH:24]1([N:30]([CH3:31])[C:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:10]3[CH:9]=[CH:8][C:7]4[N:6]=[C:5]5[NH:23][C:2](=[O:1])[NH:3][C:4]5=[CH:13][C:12]=4[CH:11]=3)[CH2:15][CH2:16]2)=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCN(c2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1
Reactant: CNC1CCCCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)C1CCN(c2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1)C1CCCCC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
A stirred mixture of 1-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)-4-piperidinecarboxylic acid (3.12 g, 10 mmol) and N-cyclohexyl-N-methylamine (1.36 g, 12 mmol) were combined in dimethylformamide (200 mL) and cooled to -20° C. Triethylamine (2.91 mL, 21 mmol) and diphenylphosphoryl azide (2.59 mL, 12 mmol) were added, the mixture stirred at -20° C. for 3 hours, and allowed to warm to room temperature. After 18 hours, the mixture was diluted with CH2Cl2 (200 mL), scratched to initiate crystallization, and stirred for an additional 72 hours. The resultant precipitate was collected, washed with CH2Cl2, and dried to give 2.09 g of a pale yellow solid (51%). Crystallization from dimethylformamide (80 mL) gave 1.02 g of pale yellow crystals, m.p. 318°-321° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.[CH3:17][NH:18][NH2:19]>C(O)CO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:7]2[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[N:18]([CH3:17])[N:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CNN
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Solvent: OCCO
Product: COc1cccc(-c2nn(C)c3ccsc23)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.9 %

Procedure:
A mixture of 20 g of (3-bromothien-2-yl) (3-methoxyphenyl)methanone and 17 g of methyl hydrazine in 134 ml of ethylene glycol was stirred under nitrogen at 120°-130° C. The reaction was complete in 2.5 hours. The product was allowed to cool to room temperature, and thereafter quenched with water (200 ml) and extracted with ether (4×200 ml). The organics were dried over anhydrous magnesium sulfate and the solvents were evaporated to give an oil The oil was purified by HPLC (3 1 hexane/ethyl acetate) This yielded 9 g of a solid which was recrystallized from ether to give 8.2 g of crystals, mp 99°-101° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][O:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][O:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
A solution of triphenylphosphine (118 mg, 0.45 mmol) in methylene chloride (5 mL) cooled to 0° C. was treated with N-bromosuccinimide (91 mg, 0.51 mmol). Upon complete dissolution, the cooled, purple solution was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid (100 mg, 0.30 mmol). The resulting reaction mixture was stirred at 0° C. for 20 min then warmed to 25° C., where it was stirred for another 30 min. The purple reaction mixture was then treated with 2-aminopyrazine (43 mg, 0.45 mmol) and pyridine (0.07 mL, 0.90 mmol) and stirred for 16 h at 25° C. The reaction was then diluted with water (10 mL) and extracted with methylene chloride 3×15 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 1.5/98.5 methylene chloride/methanol) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-furan-3-yl)-propionamide (46 mg, 37%) as a light orange foam: (ES)+-HRMS m/e calcd for C18H20ClN3O4S (M+H)+ 410.0936. found 410.0940.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[CH:37]([C:33]1[CH:32]=[C:31]([N:30]2[C:18](=[O:19])[C:11]3[C@@H:12]4[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]4)[C:10]=3[N:29]2[CH3:27])[CH:36]=[CH:35][CH:34]=1)([CH3:39])[CH3:38]
Reactant: CC(C)c1cccc(NN(C)C(=O)OC(C)(C)C)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1cccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
Triethylamine (0.38 mL, 2.73 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 330 mg, 1.54 mmol) in 1,2-dichloroethane (4 mL) over 1 min. A solution of N′-(3-isopropyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (142 mg, 0.54 mmol) in 1,2-dichloroethane (8 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 1 h. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 5 mL, 20 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h and allowed to cool. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with methanol and then diethyl ether. The residue was dried under high vacuum at 70° C. overnight to give (4S,7R)-2-(3-isopropyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (51 mg, 29%) as a pale yellow solid. ES(+)-MS (M+H) 325.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(O)(=O)C.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[S:11][CH3:12])=[O:10]
Reactant: BrBr
Reactant: CSc1ccc(F)cc1C(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(F)cc1C(=O)CBr
Reaction time: 16 h
Yield: 67.7 %

Procedure:
To a stirring solution of 20c (2.07 g, 11.34 mmol), carbon tetrachloride (62 ml) and glacial acetic acid (2.07 ml) was added at room temperature a solution of bromine (μL 546.6, 10.66 mmol) in carbon tetrachloride (34 ml). The first drop was added and after 20 minutes the solution was added dropwise in 4 hours. After stirring for 16 hours the solvent was distilled and to the residue was added water and solid sodium bicarbonate (to pH 7), the organic phase was separated and water extracted with dichloromethane (3×30 ml), the organic layers were dried and evaporated. The crude product was chromatographed (70% petroleum ether 40-60° in dichloromethane) to give 1.90 g of 21c as a yellowish solid (64% yield). 1H NMR (CDCl3) δ7.47-7.42 (dd, 1H, J=8.85, 2.84 Hz); 7.38-7.18(m, 2H); 4.42 (s, 2H); 2.43 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[N:38]=[N:39][C:40](Cl)=[CH:41][CH:42]=1>C(O)C>[Cl:36][C:37]1[N:38]=[N:39][C:40]([N:1]2[CH2:4][CH:3]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[CH:10][CH:9]=3)=[O:6])[CH2:2]2)=[CH:41][CH:42]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CNC3)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CN(c4ccc(Cl)nn4)C3)cc2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask was added tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate (918 mg, 2.55 mmol) and diisopropylethylamine (0.558 ml, 3.19 mmol) in ethanol (10.6 ml). 3,6-dichloropyridazine (317 mg, 2.128 mmol) was added as a solid in a single portion. The reaction was stirred overnight at 45° C.; and the reaction was cooled and concentrated. Dichloromethane and water were added and the layers were separated. The aqueous layer was extracted three times with dichloromethane and the combined organics were dried with magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography to give the title compound.
Reaction SMILES: C1COCC1.[CH:6]1([C:9]2[CH:14]=[C:13]([C:15](OCC)=[O:16])[CH:12]=[C:11]([O:20][CH2:21][CH3:22])[C:10]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH:6]1([C:9]2[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([O:20][CH2:21][CH3:22])[C:10]=2[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cc(OCC)c(-c2ccc(F)cc2)c(C2CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C=O)cc(C2CC2)c1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
A THF (50 mL) solution of ethyl 2-cyclopropyl-6-ethoxy-4′-fluorobiphenyl-4-carboxylate (10.5 g) was added to a THF (50 mL) suspension of lithium aluminum hydride (1.21 g) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (1.2 mL) and a 15% aqueous sodium hydroxide solution (1.2 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (3.6 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. Manganese dioxide (13.9 g) was added to a toluene (60 mL) solution of the obtained residue, and the mixture was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.79 g).
Reaction SMILES: CO[C:3]([C:5]1([C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH2:9])[CH2:7][CH2:6]1)=[O:4].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:10]([CH:8]1[C:5]2([CH2:6][CH2:7]2)[C:3](=[O:4])[N:19]([CH2:18][C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[O:15][CH3:14])[CH2:9]1)=[O:11]
Reactant: C=C(C(=O)OC)C1(C(=O)OC)CC1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(Cc2ccc(OC)cc2OC)C(=O)C12CC2

Procedure:
To a solution of 1-(1-methoxycarbonylvinyl)cyclopropanecarboxylic acid methyl ester (720 mg) in toluene (3.6 ml) was added 2,4-dimethoxybenzylamine (587 μl) at room temperature, and then the mixture was stirred at reflux for 20 hours. This reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (567 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][C:20]([NH:31][S@@](C(C)(C)C)=O)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:22]([CH3:24])=[CH2:23])C(=O)OC(C)(C)C)[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][CH2:18][CH2:19][C:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([NH2:31])[CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)CC(CCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccc(Br)cc1)(N[S@](=O)C(C)(C)C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)CC(N)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
A mixture of tert-butyl (S)-1-(4-bromophenyl)ethyl(3-((R)-1,1-dimethylethylsulfinamido)-5-methyl-3-phenylhex-5-enyl)carbamate (6.5 g, 0.011 mol) in HCl/dioxane (70 mL) was stirred for 1 hour at 0° C. The mixture was concentrated to give the residue, which was treated with satd aq Na2CO3. The resulting mixture was extracted with EtOAc, and the combined organic layer was concentrated to afford crude N1—((S)-1-(4-bromophenyl)ethyl)-5-methyl-3-phenylhex-5-ene-1,3-diamine (2.97 g, 70%), which was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[C:8]=2[C:14]([F:17])([F:16])[F:15])[N:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([O:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)[C:8]=2[C:14]([F:17])([F:16])[F:15])[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12])(=[O:32])[CH3:31]
Reactant: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(O)c1C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(C)c(C)nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c12
Temperature: 122.5 °C

Procedure:
A solution of 3.4 g of 4-(4-trifluoromethoxyphenoxy)-3-trifluoromethyl-aniline, 2.4 g of ethyl 2-methylacetoacetate, and 0.3 g of p-toluenesulfonic acid dissolved in 100 mL of xylene was heated under reflux for 36 hr. This reaction solution was cooled, and the precipitated crystals were collected by filtration to give 1.73 g of 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-7-trifluoromethyl-quinoline. The filtrate was concentrated under the reduced pressure to give 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline. Acetic anhydride (40 mL) was added to 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline obtained from the filtrate, and the mixture was heated at 120 to 125° C. for one hr. This reaction solution was concentrated under the reduced pressure, ethyl acetate was then added to the concentrate, and the mixture was washed with brine. Thereafter, the solvent was removed under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 0.35 g of 4-acetoxy-2,3-dimethyl-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:16])[CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]([OH:16])[CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)/C=C1\CC(=O)c2c(F)cc(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)/C=C1\CC(O)c2c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
A suspension of (E)-2-(4,6-difluoro-3-oxo-1-indanylidene)acetamide (0.100 g, 0.45 mmol) and sodium borohydride (0.017 g, 0.45 mmol) in 95% ethanol was stirred at ambient temperature for 2 hours. The mixture was cooled in an ice bath and quenched with 0.1N hydrochloric acid (3 mL). The ethanol was evaporated in vacuo, and the residue was dissolved in ethyl acetate (50 mL), washed successively with water (2×30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated in vacuo. The resudue was washed successively with cold ethyl acetate, hexane, and diethyl ether to give 0.046 g (45%) of (E)-2-(4,6-difluoro-3-hydroxy-1-indanylidene)acetamide as a white solid; mp 232-237° C. (dec.) 1H-NMR (DMSO-d6): δ7.06-7.42 (m, 4H), 6.49 (s, 1H), 5.52 (d, 1H), 5.30 (m, 1H), 3.44 (m, 1H), 3.03 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccc(O)cc1
Product: O=C(Nc1ccc(O)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 4-aminophenol (56.0 mg, 0.51 mmol). The title compound was obtained as a solid (10 mg, 5% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.34 (1H, s), 9.36 (1H, m), 9.00 (2H, s), 8.66 (1H, m), 7.42 (2H, m), 6.74 (2H, m). MS m/z: 440.14, 442.17 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[C:3]1([N:9]2[C:17]([N:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:19]([NH:18][C:17]1[N:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C(=Nc1c2ccccc2nn1-c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(CNc2c3ccccc3nn2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
Sodium borohydride (245 mg, 6.46 mmol) was added to a suspension of (2-phenyl-2H-indazol-3-yl)-[1-phenyl-methylidene]-amine (480 mg, 1.61 mmol) in ethanol (13 ml) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 12 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting yellow oil was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (314 mg, 1.05 mmol; 65%) as yellow oil. MS: m/e=300.4 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([S:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.BrC1C=C(Br)C=C2C=1C=C(S(NC1C=CC(OC)=CC=1)(=O)=O)C(=O)N2.OC1C=C(C2C3C(=CC=CC=3)NC(=O)C=2S(N)(=O)=O)C=CC=1OC.NC1C=C(NS(C2C(=O)NC3C(C=2)=CC=CC=3)(=O)=O)C=CC=1F.ClC1C=C2C(C=C(S(NC3C=CC(F)=C(N)C=3)(=O)=O)C(=O)N2)=CC=1.BrC1C=C(Br)C=C2C=1C=C(C(NC1C=CC(F)=C(N)C=1)=O)C(=O)N2.BrC1C=CC(NS(C2C(=O)NC3C(C=2)=CC=CC=3)(=O)=O)=CC=1.BrC1C=C(Br)C=C2C=1C=C(S(NC1C=CC(Br)=CC=1)(=O)=O)C(=O)N2>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][S:13]([C:7]2[C:8](=[O:12])[NH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[CH:2][CH:11]=3)(=[O:15])=[O:14])=[CH:18][CH:19]=1
Reactant: COc1ccc(NS(=O)(=O)c2cc3ccc(Cl)cc3[nH]c2=O)cc1
Agent: COc1ccc(-c2c(S(N)(=O)=O)c(=O)[nH]c3ccccc23)cc1O
Agent: COc1ccc(NS(=O)(=O)c2cc3c(Br)cc(Br)cc3[nH]c2=O)cc1
Agent: Nc1cc(NC(=O)c2cc3c(Br)cc(Br)cc3[nH]c2=O)ccc1F
Product: COc1ccc(NS(=O)(=O)c2cc3ccccc3[nH]c2=O)cc1

Procedure:
7-chloro-1,2-dihydro-N-(4-methoxyphenyl)-2-oxoquinoline-3-sulfonamide; 5,7-dibromo-1,2-dihydro-N-(4-methoxyphenyl)-2-oxoquinoline-3-sulfonamide; 1,2-dihydro-N-((3-hydroxy-4-methoxyphenyl)-2-oxoquinoline-3-sulfonamide; 7-chloro-1,2-dihydro-N-((3-hydroxy-4-methoxyphenyl)-2-oxoquinoline-3-sulfonamide; 5,7-dibromo-1,2-dihydro-N-((3-hydroxy-4-methoxyphenyl)-2-oxoquinoline-3-sulfonamide; 1,2-dihydro-N-(3-amino-4-fluorophenyl)-2-oxoquinoline-3-sulfonamide; 7-chloro-1,2-dihydro-N-(3-amino-4-fluorophenyl)-2-oxoquinoline-3-sulfonamide; 5,7-dibromo-1,2-dihydro-N-(3-amino-4-fluorophenyl)-2-oxoquinoline-3-carboxamide; 1,2-dihydro-N-(4-bromophenyl)-2-oxoquinoline-3-sulfonamide; 7-chloro-1,2-dihydro-N-(4-bromophenyl)-2-oxoquinoline-3-sulfonxamide; 5,7-dibromo-1,2-dihydro-N-(4-bromophenyl)-2-oxoquinoline-3-sulfonamide; mixtures thereof; and salts thereof.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:15]([Li])CCC.IC>O1CCCC1>[CH3:15][CH:9]1[CH2:8][CH2:7][CH2:6][CH:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]1=[O:3]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: [Li]CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCC(C)C1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (5.0 g, 0.125 mol) in tetrahydrofuran (250 mL) was added a solution of ethyl 2-oxocyclohexanecarboxylate (19.9 mL, 0.125 mol) in tetrahydrofuran (30 mL) whilst maintaining the temperature of the mixture between 10° C. and 15° C. by means of an ice bath. After stirring at 5° C. for 1 hour, butyl lithium (52.5 mL, 2.5 M solution in hexanes, 131 mmol) was added dropwise while maintaining the temperature below 12° C. After stirring at 5° C. for 30 minutes, iodomethane (7.8 mL, 125 mmol) was added. The reaction mixture was stirred at 5° C. for 1.5 hours and then quenched with a saturated solution of ammonium chloride. The mixture was diluted with ethyl ether, washed with water. The organic extracts were dried over magnesium sulfate and concentrated. The resulting residue was distilled (100–110° C., 0.1 torr) to obtain the title compound as a colorless oil.