Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]1=2.I[C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1.[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[OH:17][CH:14]([C:6]1[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]2[C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[C:15]#[C:16][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCCOc1cc(C(O)C#Cc2ccc(C(=O)O)cc2)cc2c1C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
5.4 g (15 mmol) of 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol and 2.6 g (11 mmol) of 4-iodobenzoic acid are dissolved in 125 mL of DMF and 50 mL of triethylamine. 110 mg of copper iodide and 210 mg of dichloropalladiumbis(triphenylphosphine) are added, and the reaction medium is stirred at 50° C. for 2 hours 30 minutes. The reaction medium is poured into ammonium chloride solution and extracted with ethyl acetate. The residue is purified on a column of silica (eluent: 6/4 heptane/EtOAc). The desired product is obtained in the form of yellowish crystals (m=2.5 g; yield=50%; m.p.=158° C.) 1H NMR (DMSO D6): 1.12 (t, J=7.0 Hz, 3H); 1.23 (s, 6H); 1.35 (s, 6H); 1.56-1.60 (m, 4H); 3.50 (q, J=7.0 Hz, 2H); 3.75 (m, 2H); 4.06 (m, 2H); 5.52 (d, J=5.0 Hz, 1H); 6.09 (d, J=4.9 Hz, 1H); 6.90 (s, 1H); 7.11 (s, 1H); 7.54 (d, J=8.3 Hz, 2H); 7.93 (d, J=8.3 Hz, 2H), 13.1 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:25]
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2
Reactant: NCCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
3-[2-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (11 g) was dissolved in 150 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. 4-(2-Aminoethyl)morpholine (7.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 11.5 g (80%) of 3-[2-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-N-(2-morpholin-4-ylethyl)-propionamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](=[O:34])(=[O:33])[NH2:35])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
A benzene (30 ml) solution containing 2.00 g (7.30 mmol) of 3-benzyloxy-4-nitrobenzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 1.38 g (8.00 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 2.50 g (yield: 80.0%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[CH3:19]O>>[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CO
Reactant: O=C(O)Cc1ccc2c(c1)NCCC2
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2c(c1)NCCC2
Temperature: 70 °C

Procedure:
Thionyl chloride (13 g; 1.5 equiv.) was added dropwise at 0° C., in the course of 5-10 minutes, to a solution of crude 2-(1,2,3,4-tetrahydroquinolin-7-yl)acetic acid (stage 5; 14 g; 1 equiv.) in 140 ml of methanol, and the resulting reaction mixture was then heated for 6 hours at reflux (70° C.). When the conversion was complete, the reaction solution was concentrated under reduced pressure and the residue was taken up in 150 ml of water, rendered basic (pH 7-8) with sodium carbonate and finally extracted with 2×150 ml of chloroform. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 10-12% ethyl acetate/-hexane). Methyl 2-(1,2,3,4-tetrahydroquinolin-7-yl)acetate (4 g) was obtained in the form of a colorless oil.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][CH2:35][CH3:36])[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH:28]([O:34][CH2:35][CH3:36])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)=[CH:16][CH:17]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
Lithium hydroxide hydrate (77 mg; 1.85 mmole) in water (5.5 ml) was slowly added to a solution of ethyl 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoate (0.77 g; 1.68 mmole) in THF (7.6 ml). After stirring at room temperature for 4 hours the reaction mixture was kept in a freezer for 4 days. THF was removed by evaporation in vacuo. More water was added and the mixture was acidified with hydrochloric acid to pH1. The product was extracted with ethyl acetate, washed twice with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.712 g (98.7% yield) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1nn(CCN2CCCC2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
A solution of 5-bromo-3-(trifluoromethyl)-1H-indazole (282 mg, 1.07 mmol) in DMSO (15 mL) was treated with Cs2CO3 (1.45 g, 4.45 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (376 mg, 2.21 mmol). After stirring for 16 hours at room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, MeOH/EtOAc/hexanes, 0:1:1 to 1.49:50) gave the title compound (250 mg, 65%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.54 (dd, J=8.9, 1.7 Hz, 1H), 7.40 (d, J=8.9, 1H), 4.54 (t, J=7.1 Hz, 2H), 3.01 (t, J=7.1 Hz, 2H), 2.56-2.54 (m, 4H), 1.79-1.75 (m, 4H); ESI MS m/z 362 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([C:22]4[N:23]=[CH:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[C:27](OC(F)(F)F)[CH:26]=5)[C:18]([NH2:21])=[N:19][CH:20]=3)[CH:12]=[N:11]2)[CH2:6][CH2:5]1.[F:37]C1C=C2C(=CC=1)C=NC(OS(C(F)(F)F)(=O)=O)=C2>>[F:37][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([C:17]1[C:18]([NH2:21])=[N:19][CH:20]=[C:15]([C:13]3[CH:12]=[N:11][N:10]([CH:7]4[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]4)[CH:14]=3)[CH:16]=1)=[CH:31]2
Reactant: O=S(=O)(Oc1cc2cc(F)ccc2cn1)C(F)(F)F
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccc(OC(F)(F)F)cc2cn1
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2cc(F)ccc2cn1

Procedure:
Following the procedure for 5-(1-Piperidin-4-yl-1H-pyrazol-4-yl)-3-(7-trifluoromethoxy-isoquinolin-3-yl)-pyridin-2-ylamine trihydrochloride, using trifluoromethanesulfonic acid 6-fluoroisoquinolin-3-yl ester, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.27-2.39 (m, 4H), 3.18-3.26 (m, 2H), 3.51-3.60 (m, 2H), 4.57-4.70 (m, 1H), 7.79-7.86 (m, 1H), 7.96-8.04 (m, 2H), 8.36 (s, 1H), 8.40 (s, 1H), 8.56 (dd, J=9.2, 5.4 Hz, 1H), 8.70 (s, 1H), 8.74 (s, 1H), 9.77 (s, 1H). MS (ES+): m/z=389.18 [MH+]. HPLC: tR1.68 min (ZQ2, polar—5 min).
Reaction SMILES: [OH-:1].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4].O.Cl>CS(C)=O>[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[OH:1])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reaction time: 8 h

Procedure:
87.6 g of finely powdered sodium hydroxide was added in portions over an 8-hour period to a stirred solution of 165.0 g of 2-nitro-4-(trifluoromethyl)chlorobenzene in 220 ml of dimethyl sulfoxide at room temperature. The mixture was allowed to stand overnight, then poured into 1.5 liters of cold water. The resulting mixture was acidified to pH 1 with concentrated hydrochloric acid. An oil formed; it was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent under reduced pressure. The residue was mixed with cold sodium hydroxide solution and the mixture was extracted with petroleum ether. The water layer was acidified with concentrated hydrochloric acid. The resulting oil was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent to give 2-nitro-4-(trifluoromethyl)phenol (6A).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:18])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]([CH2:15][OH:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].CO[C:21](OC)([CH3:23])[CH3:22]>C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(N(CC)CC)C>[Br:1][C:2]1[CH:17]=[C:6]([C:7]([N:9]2[C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:15][O:16][C:21]2([CH3:23])[CH3:22])=[O:8])[CH:5]=[N:4][C:3]=1[Cl:18]
Reactant: CC(C)C[C@H](CO)NC(=O)c1cnc(Cl)c(Br)c1
Reactant: COC(C)(C)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H]1COC(C)(C)N1C(=O)c1cnc(Cl)c(Br)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
5-Bromo-6-chloro-N—((R)-1-hydroxymethyl-3-methyl-butyl)-nicotinamide (2.6 g, 8.0 mmol) was dissolved in 2,2-dimethoxypropane (25 mL, 200 mmol). To the solution was added camphorsulfonic acid (19 mg, 0.08 mmol) and the reaction mixture was stirred for 24 h at 60° C. After cooling drops of triethylamine were added and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica (cyclohexane/ethyl acetate gradient) to yield 2.0 g of the title compound as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.CCOC(C)=O.[Pd]>[CH:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: COc1cccc(C2(O)CCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc(C2CCC2)c1
Yield: 89 %

Procedure:
A mixture of 1-(3-methoxy-phenyl)-cyclobutanol and 10% Pd/C (60 mg) in ethanol (10 ml) was hydrogenated under 45 psi hydrogen atmosphere for 3 hours. The mixture was diluted with EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 1-cyclobutyl-3-methoxy-benzene (162 mg, 89%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(I)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.7 %

Procedure:
A mixture of 4-iodo-2-methylphenol (700 mg, 3.0 mmol), benzyl bromide (563 mg, 3.3 mmol), potassium carbonate (620 mg, 4.5 mmol), and acetonitrile (15 ml) was stirred at the ambient temperature for three days. The reaction was concentrated in vacuum and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 5% to 30% of ethyl acetate in heptane gave the target product as a colorless solid (950 mg, 98%). 1H NMR (500 MHz, CDCl3) δ 7.48 (d, 1H), 7.38-7.45 (m, 5H), 7.33-7.37 (m, 1H), 6.66 (d, J=8.54 Hz, 1H), 5.07 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: [NH:1]([C:3](=[O:21])[CH2:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[CH:10][C:8]=2[N:9]=1)[NH2:2].C[C:23]1([CH2:30][C:31](O)=O)[S:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]>>[O:28]=[C:26]1[NH:25][C:24](=[O:29])[CH:23]([CH2:30][C:31]2[O:21][C:3]([CH2:4][C:5]3[S:6][C:7]4[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH:11]=[CH:10][C:8]=4[N:9]=3)=[N:1][N:2]=2)[S:27]1
Reactant: CC(C)(C)OC(=O)c1ccc2nc(CC(=O)NN)sc2c1
Reactant: CC1(CC(=O)O)SC(=O)NC1=O
Product: CC(C)(C)OC(=O)c1ccc2nc(Cc3nnc(CC4SC(=O)NC4=O)o3)sc2c1
Yield: 38 %

Procedure:
Compound 188d was prepared from Compound 188c in 38% yield as a white solid using the general procedure given for Compound 1a. LCMS=1.88 min using analytical method (B), 447.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=1.1 Hz, 1H), 8.14 (dd, J=8.6, 1.5 Hz, 1H), 8.04 (d, J=8.6 Hz, 1H), 4.82 (dd, J=9.2, 4.2 Hz, 1H), 4.76 (s, 2H), 3.82-3.76 (m, 1H), 3.49 (m, 1H), 1.64 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)=[CH:11][C:10]=2[P:25](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)=[CH:11][C:10]=2[P:25](=[O:38])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:39][CH:40]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Oc3ccc([N+](=O)[O-])cc3)c(P(=O)(c3ccccc3)c3ccccc3)c2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccc(Oc3ccc(N)cc3)c(P(=O)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
Into a 250 mL Paar Hydrogenation flask was charged [2,5-bis(4-nitrophenoxy) phenyl]diphenylphosphine oxide (5.4 g, 0.0098 mol) and 1,4-dioxane (100 mL). The solution was warmed to effect dissolution with subsequent cooling to room temperature upon which 10% Pd/C (0.59 g) was added. The mixture was degassed prior to the introduction of hydrogen gas. The mixture was agitated under a hydrogen atmosphere for ˜24 hours at room temperature. After degassing the solution, the Pd/C was removed by filtration and the solution added to stirred water to afford an off white solid. The crude solid was collected via filtration, washed with water, and dried at room temperature to, afford 4.1 g (76% crude yield). The solid exhibited a broad endothermic peak at 200.7° C. as determined by DSC at a heating rate of 10° C./min. Recrystallization from aqueous ethanol afforded a tan solid (3.2 g, 80% yield) exhibiting a broad endothermic peak at 204.12° C. by DSC.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][C:26]([F:27])([F:29])[F:28]
Reactant: OCc1ccc(Cl)c(OCC(F)(F)F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(OCC(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 4.41 (2H, d, J=7.6 Hz), 5.20 (2H, s), 5.73 (1H, d, J=2.0 Hz), 7.08 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.14 (1H, d, J=2.0 Hz), 7.41-7.44 (2H, m), 7.57 (1H, d, J=1.6 Hz), 8.05 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H12ClF3N4O2, 409. Found, 409.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:13]=[CH:14][C:15]=1[O:16]C)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>ClCCCl>[OH:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: COc1ccc(C(=O)c2ccccc2)c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc(O)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a stirred suspension of 3-Hydroxy4-methoxy-2-nitrobenzophenone (8.3 g, 30.38 mmol) in 1,2-dichloroethane (100 ml) at room temperature under argon was added aluminium chloride (4.46 g, 33.45 mmol) in one portion followed by pyridine (9.61 g, 9.81 ml, 121.5 mmol) giving rise to an exothermic reaction. the mixture was stirred at reflux for one hour, allowed to cool to room temperature and then poured onto ice-water (300 ml). Hydrochloric acid (2N, 70 ml) was added and the mixture was stirred for one hour (initial orange precipitate gradually became yellow in appearance. The solid was removed by filtration, washed by water (30 ml) and dried under vacuum to give the product as a yellow solid 6.99 g, (89%) of melting point 153–155° C. The organic phase of the filtrate was separated and the aqueous phase was extracted by dichloromethane (20 ml). The combined organic phases were washed by brine (30 ml), dried over anhydrous sodium sulphate and the solvent removed on a rotary evaporator (bath temp. 40° C.) to leave a yellow solid (0.7 g) which was not purified further.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C=O.[C:39]([BH3-])#N.[Na+]>CO.CC(O)=O>[CH3:39][N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[C:20]1[N:19]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[CH:21]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc([C@H]4CCCN4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC[C@@H]1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into an 8 mL vial was weighed 20.7 mg (40 μmol) of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-4-((R)-pyrrolidin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole. The material was dissolved in MeOH (400 μL) and HOAc (100 μL). The solution was treated with 20 μL (240 μmol) of 37% aqueous formaldehyde solution, and then 8 mg (125 μmol) of sodium cyanoborohydride was added at ambient temperature. After stirring for 15 minutes at ambient temperature LC/MS analysis of the reaction showed complete conversion to product. The reaction solution was directly injected into the reverse phase preparative HPLC and eluted with acetonitrile/water. (Phenomenex Axia Gemini C18 30×100 mm 5 μm, A=H2O with 0.1% trifluoroacetic acid, B=acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 10% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3×), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 4-((R)-1-methylpyrrolidin-2-yl)-1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole was isolated as a white foam, yield: 16.9 mg (79%); 1H NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.93-7.90 (m, 1H), 7.83-7.79 (m, 1H), 7.72-7.68 (m, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.54-7.48 (m, 4H), 7.43-7.38 (m, 1H), 7.27-7.18 (m, 4H), 3.41-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.08 (s, 3H), 2.44 (s, 3H), 2.41-2.26 (m, 2H), 2.13-1.94 (m, 2H), 1.90-1.79 (m, 1H); MS (ES): 526.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][CH:14]=1.[K+].[Br-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(-c3ccc(F)cc3)[nH]c2c1
Yield: 76 %

Procedure:
Prepared from 4-nitrophenylenediamine and 4-fluorobenzoic acid, in a manner similar to that of Example 9b. Yield: 76%; Rf (7/3 toluene/ethyl acetate): 0.54; IR (KBr): 3312, 1601, 1498, 1333 cm−1.
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[CH2:12]([CH:19]1[CH2:20][CH2:21][N:22]([C:25](=[O:29])[C:26]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1](=[O:10])(=[O:2])[NH2:11])=[CH:8][CH:7]=2)=[O:27])[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from sulfanilamide (Aldrich) and (4-benzyl-piperidin-1-yl)-oxo-acetic-acid (Example 5b) according to the method described in Example 1c. Melting Point: 184-187° C. (diethylether)