Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:9])[CH:5]=[C:6](Br)[CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[C:10]1([C:2]2[CH:3]=[C:4]([Cl:9])[CH:5]=[C:6]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 163.3 %

Procedure:
Into a 1 L four-necked glass flask equipped with a thermometer, a reflux condenser and a stirrer, 3,5-dibromochlorobenzene 20.0 g (74.0 mmol), phenylboronic acid 27.0 g (222 mmol), 2.0 mol/l sodium carbonate aqueous solution 285 ml (570 mmol), and toluene:tetrahydrofuran (1:1) solution 500 ml were added, and nitrogen was passed through the solution for 2 hours and 30 minutes. Tetrakistriphenylphosphine palladium(0) 4.28 g (3.70 mmol) was then added, which was reacted for 28 hours at 73 to 75° C. with stirring followed by further addition of phenylboronic acid 4.10 g (33.6 mmol) and tetrakistriphenylphosphine palladium(0) 1.10 g (950 μmol) and reaction for 24 hours at 73 to 75° C. with stirring. After completion of the reaction, the reaction mixture was cooled down to room temperature and separated with the addition of water and toluene, and after the water layer was extracted with toluene and after the organic layers were combined and washed with water, it was dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by silica-gel column chromatography (eluent: hexane) to obtain 3,5-diphenylchlorobenzene 16.0 g as white solid (isolation yield; 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[H][H]>[C].[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a mixture of 50.1 g of methyl 4-[(E)-2-(4-nitrophenyl)vinyl]benzoate, 600 mL of THF, and 200 mL of N,N-dimethylformamide (DMF) was added 10.3 g of 10% palladium carbon (wetted with 55% H2O), followed by stirring for 8 hours at room temperature in a hydrogen atmosphere (1 atm). The inside of the reaction vessel was purged with argon, and then the insoluble material was removed by filtration by using celite. The filtrate was concentrated under reduced pressure, and 1000 mL of water was added to the residue, followed by stirring for 30 minutes at room temperature. The precipitate was collected by filtration, thereby obtaining 44.0 g of methyl 4-[2-(4-aminophenyl)ethyl]benzoate.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([C:15]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[NH:17][N:16]=1)C1C=CC=CC=1.[C:33]1(OC)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[OH:47][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[CH2:2]([N:17]1[C:18]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[CH:19][CH:15]=[N:16]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cc3ccccc3)n[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Cn2nccc2C2CCNCC2)cc1

Procedure:
To a solution of 4-(3-benzyl-(1H-pyrazol-5-yl))-1-(t-butoxycarbonyl)piperidine TFA salt (from Step A) in methylene chloride (1.5 mL) was added anisole (0.017 mL) and TFA (0.230 mL). After several h at rt, volatiles were removed under reduced pressure. Purification of the residue was done by preparative reverse-phase HPLC using a 9.4×250 mm Semi-preparative Zorbax SB-C18 column with a 15-25% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 6.0 mL per minute to give the title compound (40.7 mg) as a gel.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2>C(OC(=O)C)(=O)C>[CH2:12]1[C:13]2[C:9](=[CH:8][C:7]([NH:6][C:1](=[O:4])[CH3:2])=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: CC(=O)[O-]
Reactant: Nc1ccc2c(c1)CCC2
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 100 °C

Procedure:
A mixture of 70 ml of acetic anhydride and 15 g of sodium acetate is added dropwise, with stirring, to 50 g of-5-aminoindane. At the end of the exothermic reaction, the solution is heated at 100° C. for one hour. The solution is then poured into 500 g of ice; a precipitate is observed to form, which is collected by filtration and taken up in 400 ml of ethyl acetate. The solution is washed with 2×250 ml of water, 2×200 ml of a 20% sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo. The title compound is obtained in the form of a yellow solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:22][C:16](=[O:18])[CH:15]([C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CC(C(=O)Nc1ccccc1)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and aniline were used to obtain N-Phenyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1 as an oily product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[H][H]>[Pd].CO>[NH2:13][C:12]1[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8]
Reactant: [H][H]
Reactant: N#Cc1cccc([N+](=O)[O-])c1NCCO
Agent: [Pd]
Solvent: CO
Product: N#Cc1cccc(N)c1NCCO
Yield: 106.3 %

Procedure:
Methanol (500 ml) and Pd/activated charcoal 5% (wet, 3.45 g) are added to 2-[(2-hydroxyethyl)amino]-3-nitrobenzonitrile (69 g, 0.333 mol). The suspension is shaken in a Parr apparatus under 20 psi pressure of hydrogen for 1 hour. The mixture is then filtered on Celite and evaporated to dryness to give the desired material (62.7 g). This product is used in the next step without further purification.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CS(C)=O>[C:13]([S:15][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH3:14]
Reactant: CC([O-])=S
Reactant: BrCCCCOc1ccccc1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)SCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
4-Phenoxybutyl bromide (5.73 g) was dissolved in dimethyl sulfoxide, and potassium thioacetate (10.71 g) was added thereto, followed by stirring at room temperature for 18 hours. The reaction solution was subjected to partitioning between ethyl acetate and water, and the organic layer was successively washed with water and a satureted saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-acetylthio-4-phenoxybutane (Compound XIX-1, 5.53 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@@H:11]([CH2:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14].Cl[C:19]1[C:20]2[S:36][C:35]([NH2:37])=[N:34][C:21]=2[N:22]=[C:23]([S:25][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])[N:24]=1.O>CN1C(=O)CCC1>[NH2:37][C:35]1[S:36][C:20]2[C:19]([NH:10][CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][OH:17])=[N:24][C:23]([S:25][C@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])=[N:22][C:21]=2[N:34]=1
Reactant: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1
Reactant: CC(C)C[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CC(CO)Nc1nc(S[C@@H](C)c2ccccc2)nc2nc(N)sc12
Temperature: 120 °C
Yield: 55.1 %

Procedure:
DIPEA (400 mg, 3 mmol) and D-leucinol (400 mg, 3.4 mmol) were added to 7-chloro-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (300 mg, 0.9 mmol) in NMP (6 mL) and the mixture was heated to 120° C. for 24 h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4), evaporated and the residue was purified by flash column chromatography (EtOAc) to give the title compound (200 mg, 54% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1cccc(-c2ccccc2)c1)c1ccccc1

Procedure:
The title product was prepared from 3-phenylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (52%, colorless oil). HPLC-MS: m/z=304.2 (M+1); Rt: 4.75 min.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9]1)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9]1
Reactant: CC=CCC1CC(=O)c2ccccc2O1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCC1CC(=O)c2ccccc2O1
Reaction time: 2 h
Yield: 99 %

Procedure:
An ozone stream (3.5 g ozone/hour) was conducted while stirring for 2 hours through a solution, cooled to -70°, of 24.6 g of (RS)-2-(2-buten-1-yl)-4-chromanone in 450 ml of anhydrous dichloromethane and 150 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 15 minutes. After the addition of 13.4 ml of dimethyl sulfide, the mixture was stirred at room temperature for 20 hours. The reaction mixture was subsequently evaporated in a vacuum. The residue was treated with 250 ml of dichloromethane and, after the addition of 40 ml of water and 40 ml of trifluoroacetic acid, stirred at room temperature for 4 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 70 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 120 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 22.7 g (99%) of 2-(2-oxoethyl)-4-chromanone were obtained as a yellow oil which was used in the next reaction without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13]1([C:19]2[N:23]=[C:22]([CH2:24][C:25](O)=[O:26])[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1>C(O)C>[CH2:11]([O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:24]([C:22]3[O:21][N:20]=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:23]=3)[C:25](=[O:26])[O:1]2)=[CH:6][CH:7]=1)[CH3:12]
Reactant: O=C(O)Cc1nc(-c2ccccc2)no1
Reactant: CCOc1ccc(C=O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1ccc2cc(-c3nc(-c4ccccc4)no3)c(=O)oc2c1

Procedure:
5 parts of 2-hydroxy-4-ethoxy benzaldehyde and 7 parts of the ethyl ester of 3-phenyl-1,2,4-oxadiazole-5-acetic acid are dissolved in 80 parts of ethanol, then 0.3 part of piperidine is added. The mixture is heated under reflux for one hour, then the precipitate obtained after cooling is filtered. 8 parts of 7-ethoxy-3-(3-phenyl 1,2,4-oxadiazol-5-yl) coumarin are obtained which melts at 229° C. after crystallization in dioxane.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:30][Si](C)(C)C>CC(CC)=O>[ClH:30].[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)NCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1.5 h

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexyl)-N-(1H-indol-3-ylmethyl)acetamide (213 mg, 0.54 mmol) was dissolved in ethyl methyl ketone with gentle heating and chlorotrimethylsilane (0.103 ml, 0.82 mmol) was added. After 1.5 h it was possible to obtain the hydrochloride as a colourless solid in a yield of 93% (214 mg) with an m.p. of 233-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]C)=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1.O>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=2)=[CH:5][CH:4]=1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C)c([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
To a solution of 4-methoxyphenyl-boronic acid (500 mg, 3.29 mmol) in toluene (5.2 mL) and ethanol (1.3 mL), potassium carbonate (910 mg, 6.58 mmol), tetrakis(triphenylphosphine)-palladium (228.1 mg, 0.099 mmol) and 4-bromo-1-ethyl-2-nitrobenzene (711 mg, 3.29 mmol) are added and stirred at 100° C. for 7 hours. The mixture is poured into water and extracted with ethyl acetate two times. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the 4′-methoxy-4-methyl-3-nitrobiphenyl as a yellow solid.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20]O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=S(Cl)Cl.[N-:26]=[N+:27]=[N-:28].[Na+].CCOC(C)=O>C(Cl)Cl>[N:26]([CH2:20][C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:15]2=[N:16][CH:17]=1)=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CO)cnc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CN=[N+]=[N-])cnc32)cc1
Reaction time: 4 h
Yield: 84.3 %

Procedure:
To a solution of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (35.8 g, 118 mmol) in DCM (600 mL) was added SOCl2 (21.5 mL, 295 mmol). After about 4 h at ambient temperature, additional SOCl2 (8.60 mL, 118 mmol) was added. After about 16 h, the reaction was concentrated under reduced pressure and washed with saturated aqueous NaHCO3 (1000 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (600 mL) and re-subjected to SOCl2 (21.51 mL, 295 mmol). After about 16 h at ambient temperature, the reaction was concentrated under reduced pressure followed by the addition of DCM (500 mL) and saturated aqueous NaHCO3 (500 mL). The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. To the resulting residue was added DMF (500 mL) followed by NaN3 (38.3 g, 589 mmol). After about 16 h, at ambient temperature EtOAc (500 mL) was added and the organic solution was washed with water:brine (1:1, 2000 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (500 mL). The combined organic layers were washed with brine (3×1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide 2-(azidomethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (32.65 g, 82% yield) as a tan solid: LC/MS (Table 2, Method a) Rt=2.31 min; MS m/z: 329 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:9]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][CH:3]=1.[F:25][C:26]([F:47])([F:46])[C:27]1[CH:28]=[C:29]([C@@H:37](OC(=N)C(Cl)(Cl)Cl)[CH3:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.[H+].[B-](F)(F)(F)F>CCOCC>[F:25][C:26]([F:46])([F:47])[C:27]1[CH:28]=[C:29]([C@H:37]([O:14][C@H:13]2[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH3:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O)CC[C@@H]1C(=O)OCC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 9.09 g (26.9 mmol) of the first eluting isomer diethyl (1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step D) and 21.5 g (53.5 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (step E) in 250 mL of cyclohexane/1,2chloroethane (3/1) under nitrogen atmosphere at −5° C. was added 0.51 mL (3.58 mmol) of 54% HBF4 in ether. The reaction mixture was stirred at −5° C. to at 0° C. for 2 hr then diluted with ether. The mixture was washed with sat. aq. NaHCO3. The organic layer was dried over drying agent, filtered and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes (1/4) to give 9.2 g of the title compound as an oil. 1H-NMR (CDCl3): δ: δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, t, J=8.5 Hz), 4.43 (1H, q, J=6.0 Hz), 4.20–4.10 (2H, m), 3.80–3.73 (2H, m), 3.36 (1H, m), 2.90–2.76 (2H, m), 2.40 (1H, m), 2.28 (1H, m), 1.63–1.55 (2H, m), 1.33 (3H, d, J=6.0 Hz), 1.25 (3H, t, J=7.2 Hz), 0.82 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: [Na+:1].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[C:21]2[C:20]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:14][CH:13]=1)=[O:10])([O-])=O.[H][H]>[Pd].O>[Na+:1].[Na+:1].[NH2:3][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[C:21]2[C:20]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:14][CH:13]=1)=[O:10]
Reactant: [H][H]
Reactant: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cccc(S(=O)(=O)[O-])c23)c1
Reaction time: 0.33 h

Procedure:
A mixture of 25.0 g of 4-(m-nitrobenzamido)-1,5-naphthalenedisulfonic acid disodium salt (prepared as in Example 5), 200 ml of water and 2.0 g of 10% palladium on charcoal is hydrogenated in a Parr shaker for 4 hours and 20 minutes at room temperature with an initial pressure of 42 pounds of hydrogen. During this time a total of 11.0 pounds of hydrogen is absorbed. The mixture is heated to dissolve some precipitated product and is filtered through diatomaceous earth to remove the catalyst. The filtrate is then evaporated to a small volume in vacuo at 55°-60° C. until crystal formation. The material is then diluted with absolute ethyl alcohol and is triturated. The crystals are then collected by filtration and the product is washed first with two 100 ml portions of absolute ethyl alcohol followed by two 100 ml portions of ether. The product of the example is then oven dried overnight at 120° C.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:21][CH3:22])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH:19]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][NH:29][CH2:19][C:9]1[CH:10]=[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH3:18])[C:12]2=[N:13][C:8]=1[N:7]([CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:21][CH3:22]
Reactant: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A mixture of 6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (5.3 g, 17.0 mmol) and 3,5-bis-trifluoromethylbenzylamine (4.7 g, 0.019 mol) in MeOH and acetic acid (2 drops) was stirred at RT for 30 min. After cooling to 0° C., sodium cyanoborohydride (2.2 g, 35.0 mmol) was added slowly over a period of about 10 min. After stirring atRT for 30 min, the reaction mixture was concentrated in vacuo. Water (50 mL) was added to the residue and stirred for 30 min. The solid was filtered off, washed with water followed by petroleum ether, and dried in vacuo to yield colorless solid (yield: 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][N:13]=1>N1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([C:16]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[C:4]#[N:5])=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(N)c(C#N)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)c(C#N)c1
Yield: 18.1 %

Procedure:
A mixture of 2-amino-5-methyl-benzonitrile (80 mg, 0.61 mmol) and 6-chloronicotinoyl chloride (162 mg, 0.92 mmol) in anhydrous pyridine (5 ml) was refluxed for 4 hours. The mixture was diluted with 50 ml of hexane:ethyl acetate (1:1), wash with 2 N HCl (25 ml), water (25 ml), followed by saturated aqueous NaCl (25 ml), dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography using hexane:ethyl acetate (2:1) to give 30 mg (18% yield) of the title compound as pale pink solid. 1H NMR (DMSO-d6): 10.82 (s, 1H), 8.99 (d, J=2.4 Hz, 1H), 8.38 (dd, J=2.4, 8.1 Hz, 1H), 7.78-7.73 (m, 2H), 7.61-7.48 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: N.O.S[C:4]1[N:5]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:6]([C:9]([NH2:11])=[O:10])=[CH:7][N:8]=1>[Ni].C(O)C>[C:14]1([CH:12]([N:5]2[C:6]([C:9]([NH2:11])=[O:10])=[CH:7][N:8]=[CH:4]2)[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(c1ccccc1)n1c(C(N)=O)cnc1S
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: CC(c1ccccc1)n1cncc1C(N)=O
Temperature: 25 °C

Procedure:
To 80 parts of ethanol, previously saturated with gaseous ammonia, are added 2.3 parts of (+) -2-mercapto-1-(1-phenylethyl)-1H-imidazole-5-carboxamide hydrate and 6 parts of Raney-nickel. The mixture is stirred and refluxed for 2 hours and thereafter allowed to cool to room temperature. The Raney-nickel is filered off and the filter-cake is washed with ethanol. The filtrate is evaporated in vacuo and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxamide, essentially free of its (-)-isomer, as a residue.