Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1([CH2:31][CH2:32]OS(C2C(C)=CC=CC=2)(=O)=O)[CH:30]=[CH:29][N:28]=[CH:27]1>O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: Cc1ccccc1S(=O)(=O)OCCn1ccnc1
Reactant: Clc1ccc(N2CCN=C2Cc2ccccc2)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(N2CCN=C2C(CCn2ccnc2)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
1-(2,4-Dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole To a stirred solution of 2-(imidazol-1-yl)ethanol (1.9 g, 0.0156 mol), triethylamine (2.8 ml, 0.0187 mol), and 4-N,N-dimethylaminopyridine (20 mg) in dichloromethane (20 ml) at a temperature of -78° C. under nitrogen atmosphere, was added p-toluenesulphonyl chloride (3.6 g, 0.0187 mol) in dichloromethane (10 ml). The reaction mixture was allowed to warm to -10° C. and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. The organic phase was separated and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield colorless crystals of 2-(imidazol-1-yl)-1-toluenesulphonyloxyethane (4.23 g). n-Butyllithium (3.9 ml, 0.0059 mol, 1.5M in hexane) was added to a stirred solution of 1-(2,4-dichlorophenyl)-4,5-dihydro-2-phenylmethylimidazole (1.5 g, 0.0049 mol) in dry tetrahydrofuran (10 ml) at -78° C. under a nitrogen atmosphere. Copper(I)bromide-dimethyl sulphide complex (50 mg, 0.0024 mol) was added to the reaction mixture. After a period of one hour, a solution of 2-(imidazol-1-yl)-1-toluenesulphonyloxyethane (2 g, 0.0072 mol) in tetrahydrofuran (7 ml) was added to the reaction mixture. The resulting mixture was allowed to warm to room temperature and allowed to react for 15 hours before being quenched with saturated aqueous ammonium chloride. The phases were separated and the aqueous phase extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel with ammonia/methanol/ethyl acetate (1:4:45) to yield 1-(2,4-dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole (1 g) which upon treatment with ethereal hydrogen chloride yielded the hydrochloride salt of 1-(2,4-dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole. (Found C, 49.00; H, 5.03; N, 10.76. C21H22N4Cl4.9/4H2O requires C, 49.19; H, 5.21; N, 10.93) having the formula ##STR43##
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:3]=1[C:4]#[N:5].[CH3:17][O-:18].[Na+].O.Cl>COCCOC>[CH3:17][O:18][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(-c2ccccc2)nc(Cl)c1C#N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(-c2ccccc2)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
2-chloro4-methyl-6-phenyl-nicotinonitrile (455 mg, 1.99 mmol) was dissolved in 20 mL of DME, added with 95% sodium methoxide (1.13 g, 19.90 mmol) and then stirred at room temperature for about 1 hour. The mixture was added to cool water and was adjusted to have a pH of about 6 to 7 with 10% HCl and then extracted with ethyl acetate. A silica gel column chromatography (10% EtOAc/Hexane) was performed on the resulting residue and 370 mg (83%) of 2-methoxy-4-methyl-6-phenyl-nicotinonitrile was obtained in white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1.C([Sn](CCCC)(CCCC)[C:34]1[S:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[S:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=[C:34]1[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1
Reactant: COc1ccc(Br)c(NC(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2nc3ccccc3s2)c(NC(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 72.3 %

Procedure:
A mixture of N-(2-bromo-5-methoxyphenyl)-3-fluoro-4-(2-piperidin-1-ylethoxy)benzamide (1.0 g), dichlorobis(triphenylphosphine)palladium(II) (150 mg), xylene (30 ml) and 2-tributylstannylbenzothiazole (1.9 g) was refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (810 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]2=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[O:15]=[C:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][S:21]([C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)(=[O:23])=[O:22])[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Solvent: c1ccncc1
Product: O=C1CCCc2c1[nH]c1c(NS(=O)(=O)c3cccs3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a mixture of 8-amino-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.20 g) and pyridine (20 mL) was added thiophene-2-sulfonyl chloride (1.30 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.94 g, yield 86%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran. The crystals were recrystallized from tetrahydrofuran-hexane. melting point>280° C. (decomposition).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:22][CH3:23])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:20][OH:21])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+].CO>O>[CH2:22]([C:5]1([CH2:4][C:3]([OH:24])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:20][OH:21])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19])[CH3:23]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3=NO
Temperature: 25 °C

Procedure:
The product of Step A (0.182 g, 0.55 mmol), K2CO3 (0.1 g, 0.71 mmol) and a MeOH--H2O mixture (10 ml-1 ml) were refluxed for 3 h. The reaction mixture was cooled to room temperature and the methanol was removed. To the reaction mixture was added 10 ml H2O, which was then acidified using 1N HCl. The aqueous phase was extracted with EtOAc, which was dried (MgSO4), evaporated and triturated using hexane to yield a solid, m.p. 165°-168° C. (dec.).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:35]=[N:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:18]([O:17][C:16]([NH:15][C:11]1([C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:29]=[C:30]4[CH:31]=[CH:32][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N:34][N:35]4[C:2]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:10][CH:9]=2)[CH2:12][CH2:13][CH2:14]1)=[O:22])([CH3:20])([CH3:19])[CH3:21]
Reactant: CCOC(=O)c1ccc(N)nn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Yield: 90 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (3.3 g, ˜80% purity, 5.79 mmol), ethyl 6-aminopyridazine-3-carboxylate (CAS-Nr. 98548-01-7, 1 g, 5.57 mmol), N,N-diisopropylethylamine (0.97 mL, 5.57 mmol) and activated 3 Å molecular sieves in isopropanol (30.4 mL) was heated for 20 hours under reflux. On cooling the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo, taken up in DCM and washed with dilute aqueous hydrochloric acid (1N) and brine, dried and concentrated in vacuo to give the crude title compound. Purification was achieved by chromatography on silica (gradient elution: Hexane:EtOAc 9:1 to Hexane:EtOAc 1:1) to give the title compound (2.80 g, 92% purity, 90% yield).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:16][CH2:15][C:13](=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].CCN(S(F)(F)[F:23])CC>C1COCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:16][CH2:15][C:13]([F:23])=[CH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CC=C(F)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
4-N-Boc-aminomethyl cyclohexanone (4.95 g, 21.8 mmol) was dissolved in 80 mL of THF. DAST (4.3 mL, 32.7 mmol) was added dropwise and the solution was stirred at 50° C. for 5 h. The solvent was concentrated and the product purified by silica gel flash chromatography using 3:1/hexanes:EtOAc as eluent. Yield: 1.62 g (30%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.36-1.42 (m, 1 H), 1.44 (s, 9 H), 1.70-1.80 (m, 2 H), 1.82-1.90 (m, 1 H), 2.09-2.17 (m, 1 H), 2.17-2.29 (m, 2 H), 3.04-3.11 (m, 2 H), 4.61 (s, 1 H), 5.11-5.15 (m, 0.5 H), 5.16-5.19 (m, 0.5 H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.Br[CH2:33][CH2:34][CH2:35][C:36](OCC)=[O:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[N:26]1([C:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:10]3[N:9]=[C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([N:1]5[CH2:33][CH2:34][CH2:35][C:36]5=[O:37])[CH2:3]4)[CH:16]=[CH:15][C:11]=3[C:12]([NH2:14])=[O:13])=[CH:23][CH:22]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCC[C@@H](N3CCCC3=O)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 100 °C
Yield: 28 %

Procedure:
A solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (80 mg) and ethyl 4-bromobutanoate (37 mg, 1 eq.) in DMF (1 mL) was treated with Cs2CO3 (184 mg, 3 eq) and heated at 100° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with water, 10% LiCl, and concentrated. The residue was purified by MPLC chromatography (ISCO, 7% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 26 mg of (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinamide as a light yellow solid. LCMS: (M+H)+=493.27. 1H NMR (500 MHz, CDCl3) δ ppm 11.18 (1H, s), 7.67 (2H, d, J=8.80 Hz), 7.53 (1H, d, J=8.80 Hz), 7.36 (2H, d, J=8.80 Hz), 6.06 (1H, d, J=8.80 Hz), 5.68 (2H, br. s.), 4.20-4.45 (2H, m), 3.98-4.19 (1H, m), 3.71 (8H, br. s.), 3.42-3.49 (1H, m), 3.33-3.41 (1H, m), 2.92-3.00 (1H, m), 2.83-2.91 (1H, m), 2.44 (2H, t, J=8.25 Hz), 2.05 (2H, qd, J=7.61, 7.42 Hz), 1.94 (1H, dd, J=11.82, 3.57 Hz), 1.81-1.89 (1H, m), 1.59-1.80 (2H, m).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]
Reactant: Nc1ccccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: Nc1ccccc1-c1nccs1
Yield: 24.1 %

Procedure:
2-Tributylstannanyl-thiazole (600 mg, 1.6 mmol) was reacted with 2-bromoaniline (200 mg, 1.2 mmol) according to general procedure [B] for the preparation of substituted anilines described above, which gave the title compound (51 mg, 25%). [M+1] 177.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][N:8]=1.[Li][CH2:15]CCC.CI.[NH4+].[Cl-]>CCOCC>[Cl:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:6]2[CH:5]=[CH:4][S:3][C:2]=2[CH3:15])[CH:12]=1
Reactant: [Li]CCCC
Reactant: Clc1ccnc(-c2ccsc2Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: Cc1sccc1-c1cc(Cl)ccn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2-bromo-thiophen-3-yl)-4-chloro-pyridine (80 mg, 0.3 mmol) in Et2O (3 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 0.2 mL). After 10 min, MeI (70 mg, 0.5 mmol) was added. The resulting mixture was maintained at −78° C. for 2 h, then was warmed to room temperature and stirred for 3 h. The reaction mixture was treated with 2 M aqueous NH4Cl and extracted with EtOAc. The organic layer was dried and concentrated to yield a residue. The residue was purified by preparative TLC (hexanes/EtOAc) to yield 4-chloro-2-(2-methyl-thiophen-3-yl)-pyridine as a solid.
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].CC1C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[K+]>C(OCC)C>[CH3:2][CH:3]1[CH2:4][N@:5]1[C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC1CN1C(=O)OC(C)(C)C

Procedure:
To a solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (756 mg, 4.31 mmol) and 4-methylbenzene-1-sulfonyl chloride (905 mg, 4.75 mmol) in ethyl ether (30 mL) was added powdered potassium hydroxide (968 mg, 17.26 mmol) and reaction was refluxed for 2 hr. The reaction mixture was poured into a separatory funnel that contained crushed ice and extracted with ether (2×20 mL). The organics were combined, dried with sodium sulfate, filtered, and concentrated. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.16 (d, J=5.43 Hz, 3H) 1.38 (s, 9H) 1.83 (d, J=3.73 Hz, 1H) 2.17 (d, J=5.76 Hz, 1H) 2.40 (qd, J=5.65, 3.73 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.[Br:12][C:13]1[CH:18]=[C:17](F)[CH:16]=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:12][C:13]1[CH:18]=[C:17]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:2]2)[CH:16]=[C:15]([F:20])[CH:14]=1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Reactant: Fc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc(-n2ccc(-c3ccccn3)c2)c1
Temperature: 140 °C
Yield: 27.8 %

Procedure:
2-(1H-Pyrrol-3-yl)pyridine (2.0 g, 17 mmol), 1-bromo-3,5-diflurobenzene (6.6 g, 34 mmol), potassium carbonate (2.4 g, 34 mmol) were combined in DMF (30 mL) under argon. The reaction mixture was heated at 140° C. overnight. The reaction mixture was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (300 mL), and washed with H2O (3×300 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil which solidified when pumped down under high vacuum. The crude product was purified by column chromatography eluting with 2:8 EtOAc:hexanes to afford 2-[1-(3-bromo-5-fluorophenyl)-1H-pyrrol-3-yl]pyridine (1.5 g, 35% yield) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.61-8.62 (d, 1H), 8.50-8.53 (t, 1H), 8.40 (s, 1H), 8.35-8.36 (d, 1H), 7.78-7.81 (m, 2H), 7.57-7.62 (m, 1H), 7.54-7.57 (d, 1H), 7.43-7.46 (d, 1H), 7.11 (s, 1H), MS 319.1 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH:13]([CH3:15])[CH3:14])([O-])=O.[H][H]>CO.[Pt]=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([O:12][CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(OC(C)C)c1
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc(N)c(OC(C)C)c1
Yield: 101.6 %

Procedure:
A solution of 5.0 g of 1-nitro-4-methoxy-2-(propan-2-yloxy)benzene in 300 ml of methanol is hydrogenated on 2.5 g of platinum oxide at a hydrogen pressure of 15 bar, for 2 h at ambient temperature. The mixture is filtered and the filtrate is concentrated to dryness under reduced pressure, so as to obtain 4.36 g of 4-methoxy-2-(propan-2-yloxy)aniline.
Reaction SMILES: [OH:1][C:2]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=1)=[O:3].[H][H]>[Pt]=O.C(O)(=O)C>[CH:8]([CH:7]1[CH2:11][CH2:12][CH:4]([C:2]([OH:3])=[O:1])[CH2:5][CH2:6]1)([CH3:10])[CH3:9]
Reactant: [H][H]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)C1CCC(C(=O)O)CC1
Yield: 96.3 %

Procedure:
Platinum oxide (500 mg) as a catalyst was suspended in acetic acid (50 ml) and cumic acid (10 g, 61 mmole) was added thereto. The mixture thus obtained was stirred vigorously for 2 hours at room temperature under a pressure of hydrogen 5 kg/cm2. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to a solid state. The resultant substance was distilled under reduced pressure of 1 mmHg (1.3×10-3 kg/cm2), at 113°-116° C. to obtain 4-isopropylcyclohexane carboxylic acid yielding 10 g (96%) ij a ratio of 3 parts of cis-form per 1 part of trans-form by weight.
Reaction SMILES: Br[C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.O>C(OCC)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]([C:2]5[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=5)[OH:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: Cn1ccnc1Br
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cn1ccnc1C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: -75 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
2-Bromo-1-methyl-1H-imidazole (47 μL, 0.48 mmol) was dissolved in diethyl ether (2 mL) and cooled to −75° C. under argon. Butyl lithium (2.5 M in hexanes; 192 μL, 0.48 mmol) was added dropwise and the mixture stirred at −75° C. for 1 hour. A solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (252 mg, 0.5 mmol) in diethyl ether (2 mL) was added dropwise. The reaction mixture was stirred for 16 hours whilst warming slowly to room temperature. The reaction mixture was cooled and treated with water (10 mL) and the phases separated. The organic phase was extracted with further diethyl ether (×2) followed by dichloromethane (×2). The combined organic phases were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 17.5 to 25% acetone in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)-(R/S)-methanol as a white powder (82 mg) LCMS (Method A, ESI): RT 2.74 min, m+H=588.1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.CO.[BH4-].[Na+]>O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][CH2:10][NH:9][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:13]=1
Reactant: O=Cc1ccncc1
Reactant: NCCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1cncc(CCNCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
4-Pyridinecarbaldehyde (5.36 g, 50 mmol) and 3-(2-aminoethyl)pyridine (6.5 ml, 50 mmol) were added to methanol (100 ml), and stirred at room temperature for 7 hours. The resulting mixture was cooled to 0° C. Sodium borohydride (2.8 g, 74 mmol) was added to the mixture, and stirred at 0° C. for 1 hour. Water was then added to the reaction mixture to distill the methanol off under reduced pressure. The residue was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=95:5→85:5). The purified product was concentrated under reduced pressure to thereby obtain 10.03 g (yield: 94%) of (2-pyridin-3-ylethyl)pyridin-4-ylmethylamine as a colorless oil.