Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]([CH3:7])[C:4](O)=[O:5].[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[C:27]([CH2:29][NH2:30])[CH:26]=[CH:25][C:24]=2[Cl:31])=[CH:17][C:16]=1[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=1)=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[C:27]([CH2:29][NH:30][C:4]([CH:3]([CH3:7])[C:2]([F:9])([F:8])[F:1])=[O:5])[CH:26]=[CH:25][C:24]=2[Cl:31])=[CH:17][C:16]=1[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=1)=[O:34]
Reactant: COCCOc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reactant: CC(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COCCOc1ccc(NC(=O)c2cc(CNC(=O)C(C)C(F)(F)F)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to example 53d with 3,3,3-trifluoro-2-methyl-propionic acid (10 mg; 0.07 mmol); N-[4-methoxyethoxy-3-(4-bromphenyl)aminocarbonyl-phenyl]-2-chloro-5-aminomethyl-benzamide (32 mg; 0.06 mmol); TBTU (21 mg; 0.07 mmol) in TEA (25 μL; 0.18 mmol) and 3 mL DMF.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:24]([C:31]1[N:32]=[C:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[O:34][C:35]=1[CH2:36]Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH2:24]([C:31]1[N:32]=[C:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[O:34][C:35]=1[CH2:36][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClCc1oc(C2CCCCC2)nc1Cc1ccccc1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(Cc2nc(C3CCCCC3)oc2CN2CCN(c3cccc4[nH]ccc34)CC2)cc1
Yield: 94 %

Procedure:
A mixture containing 4-piperazinoindole (0.2 mmole), potassium carbonate (0.5 mmole), potassium iodide (0.08 mmole) and 4-benzyl-5-chloromethyl-2-cyclohexyl oxazole (0.19 mmole) from example 2 was stirred in acetone (2 ml) for 16 hr. The mixture was concentrated in vacuo, water (10 ml) added, and the product extracted into dichloromethane (2×10 ml). The combined organics was washed with water (5 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the required product as a beige solid (94% yield). An ethanolic solution (5 ml) of the product was treated with fumaric acid (1 equivalent), and the resulting salt crystallized from diethyl ether to afford the titled product as a light beige powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Cl-].C([Al+]CC)C.[C:21](Cl)(=[O:23])[CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: FC(F)(F)Oc1ccc2[nH]ccc2c1
Agent: CC[Al+]CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ccc(OC(F)(F)F)cc12
Reaction time: 0.5 h

Procedure:
To a solution of 5-(trifluoromethoxy)-1H-indole [262593-63-5] (1.00 g, 4.97 mmol) in CH2Cl2 (20 mL), cooled to 0° C., was added dropwise diethylaluminum chloride (1M solution in hexane; 7.46 mL, 7.46 mmol), and stirring was continued for 30 min. A solution of acetyl chloride (0.532 mL, 7.46 mmol) in CH2Cl2 (20 mL) was subsequently added, and the reaction mixture was stirred at 0° C. for 1 h. A 5% aqueous citric acid solution (100 mL) was then added at 0° C., and the mixture was stirred for 15 min at RT. The mixture (two phases) was filtered, and the precipitate was dried at 50° C. in vacuo for 1 h to afford the title compound. Beige solid. MS: 244.0 [M+H]+; tR (HPLC conditions c): 4.60 min. The material thus obtained was used directly in the next step without further purification
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[F:21][CH:22]([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH:22]([F:21])[F:32])[CH:25]=1)[CH3:2]
Reactant: FC(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: [Br-]
Product: CCOC(=O)C(Cc1cccc(OC(F)F)c1)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
N-(Diphenylmethylene)Glycine ethyl ester (500 mg, 1.87 mmol), Tetrabuylammonium Bromide (63 mg, 0.187 mmol) and 3-(Difluoromethoxy)benzyl bromide (0.5 mL, 1.87 mmol) were placed in a flask. The flask was evacuated and backfilled with argon. Anhyd dichloromethane was added to the flask, and the reaction was cooled in dry-ice acetone bath to −78° C. 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (0.7 mL, 2.44 mmol) was added slowly under argon at −78° C. The reaction was allowed to stir at −78° C. for 30 minutes, and then warmed to room temperature over 16 h. The solvent was removed under vacuum. The residue was pre-adsorbed on to SiO2 and the product was isolated via SiO2 to yield 700 mg of light yellow oil. MS 424.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([N:18]2[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:20][C@H:19]2[C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)=[O:30])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:50]([O:52][CH3:53])=[O:51]>ClCCl>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29]([C@H:19]2[N:18]([C:16]([C@H:13]3[CH2:14][CH2:15][C@@H:10]([CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:11][CH2:12]3)=[O:17])[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][N:26]([C:50]([O:52][CH3:53])=[O:51])[CH2:25][CH2:24]3)[CH2:20]2)=[O:30])=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCNCC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(C(=O)OC)CC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the compound prepared in Example 50 (150 mg) in dichloromethane (3 mL) was added triethylamine (0.3 mL) and methyl chloroformate (22 μL). The mixture was stirred at room temperature overnight. Further methyl chloroformate (11 μL) was added and the reaction stirred at room temperature for an additional 4 days. The reaction mixture was partitioned between dichloromethane (20 mL) and brine (20 mL), the organic layer separated, dried and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound (119 mg) as a white solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][C:57]1[CH:65]=[C:64]2[C:60]([CH2:61][CH2:62][C:63]2=[O:66])=[CH:59][CH:58]=1>CO.ClCCl>[Br:1][CH:62]1[CH2:61][C:60]2[C:64](=[CH:65][C:57]([O:56][CH3:55])=[CH:58][CH:59]=2)[C:63]1=[O:66]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(Br)C2

Procedure:
49.2 g (102 mmol) of tetra-n-butylammonium tribromide are added in fractions over the course of 15 minutes, at room temperature, to 16.2 g (100 mmol) of 6-methoxy-indan-1-one dissolved in 400 ml of methanol and 1 litre of dichloromethane, and the mixture is then stirred overnight at room temperature. After evaporation, the residue is taken up in 500 ml of dichloromethane and washed twice with 250 ml of N hydrochloric acid. Drying over magnesium sulphate and concentration, and then rapid filtration over 500 g of silica (eluant:dichloromethane) yield 23.4 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH2:26]([CH:28]=[CH:29][CH2:30][NH2:31])[CH3:27]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:31][CH2:30][CH2:29][CH2:28][CH:26]=[CH2:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: CCC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCNCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Preparation 39, 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and ethylallylamine in tetrahydrofuran are reacted to give 8-bromo-1-[(allylethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 43 8-(Trifluoromethyl)-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH:12]1([CH2:18][C:19](O)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:19](=[O:20])[CH2:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CC1CCCCC1
Reactant: COc1cccc(CCN)c1
Solvent: CCOC(C)=O
Product: COc1cccc(CCNC(=O)CC2CCCCC2)c1
Temperature: 30 °C
Yield: 72.4 %

Procedure:
A stirred mixture of 20 g of 3-methoxy-benzeneethanamine and 15.2 g of cyclohexylacetic acid was heated at 190°-200° C. under an inert atmosphere for 45 minutes and was then cooled to 30° C. The product was dissolved in ethyl acetate and the solution was washed successively with N sodium hydroxide solution, N hydrochloric acid and water and was evaporated to dryness. The 29 g of oil residue was crystallized from petroleum ether (b.p.=40°-70° C.) and the product was dried to obtain 21.3 g of N-[2-(3-methoxyphenyl)-ethyl]cyclohexane-acetamide in the form of a white solid melting at 74° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([F:27])([F:26])C(C1C=CC=CC=1)=O>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:17]([F:27])[F:26])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1cc(OC(F)F)ccc1Br
Temperature: 80 °C
Yield: 78.3 %

Procedure:
To a solution of 4-bromo-3-fluoro-phenol (962 mg, 5.037 mmol) in acetonitrile (25 mL) was added a solution of potassium carbonate (28.3 g, 181 mmol) dissolved in water (25 mL) all under nitrogen. To the reaction mixture was added 2-chloro-2,2-difluoroacetophenone (5 g, 25 mmol) and the reaction was heated to 80° C. for 4 hours. The reaction was cooled to room temperature and extracted with ethyl acetate (3×50 mL). The organic layer was dried with sodium sulfate, filtered and concentrated onto silica gel. Silica gel chromotography (5% ethyl acetate 95% heptane to 100% ethyl acetate over 55 minutes) furnished a clear oil (950 mg, 78%). LCMS m/z 531.7 (M−1)1H NMR (400 MHz, METHANOL-d4) δ ppm 6.85 (s, 1H) 6.92 (dd, J=8.88, 2.63 Hz, 1H) 7.05 (t, 1H) 7.38 (t, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[C:24]([F:32])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:19])([CH3:18])[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[C:8]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)=[O:30])=[C:24]([F:32])[CH:23]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Ethyl-3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (200 mg, 0.691 mmol) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (161 mg, 0.691 mmol), HATU (315 mg, 0.830 mmol) and TEA (0.482 mL, 3.46 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 2 h, and then the solution was distributed between DCM and H2O. The combined organic extract was dried over MgSO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM, Rf=0.5) to yield a light yellow oil of ethyl 3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (320 mg, 0.571 mmol, 83.0% yield): 1H NMR (400 MHz, MeOH-d4) δ 7.94 (d, J=1.54 Hz, 1H), 7.68 (d, J=8.38 Hz, 1H), 7.27-7.36 (m, 2H), 7.22 (d, J=8.38 Hz, 1H), 6.90-6.97 (m, 1H), 4.09-4.18 (m, 2H), 3.74 (s, 2H), 3.07 (s, 2H), 1.20-1.25 (m, 3H), 1.15 (s, 6H); ES-LCMS m/z 504 (M+H).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[O:1]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:2]1[O:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: OCc1ccccc1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: CCOCC
Product: O[C@@H]1[C@@H](OCc2ccccc2)OC[C@@H](O)[C@@H]1O
Temperature: -5 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
A mixture of D-lyxose (10 g, 66.6 mmol) and benzyl alcohol (50 ml) was cooled to -5° C. and hydrogen chloride was bubbled through it for 3 to 5 hours while monitoring the reaction on tlc (ethyl acetate-ethyl alcohol 7:1). To this reaction mixture diethyl ether (100 ml) was added with stirring and the mixture was allowed to stand at 5° C. for 12 hours. The crystals were filtered, washed with ether and air dried to give 4 (14.1 g, 88.1%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[OH:15]O.N>C(O)C>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:14])=[O:15]
Reactant: OO
Reactant: N#Cc1cnn(C2CCOCC2)c1N
Agent: N
Solvent: CCO
Product: NC(=O)c1cnn(C2CCOCC2)c1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A stirred solution of 5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbonitrile (˜228 mmol) in ethanol (300 mL) was treated with 35% aqueous H2O2 (100 mL) followed by aqueous ammonia (300 mL). The reaction mixture was stirred for 48 h at ambient temp and then quenched with aq saturated sodium thiosulfate (800 mL) and concentrated under reduced pressure to remove most of the ethanol. The resulting solid was removed by filtration and washed with water (2×200 mL) and ether (2×150 mL). The solid was dried in vacuo to constant weight (31 g, 65% yield for 2 steps). 400 MHz 1H NMR (CD3OD) δ 7.67 (s, 1H), 4.27-4.21 (m, 1H), 4.03 (dd, J=11.6, 4.6 Hz, 2H), 3.28 (t, J=1.7 Hz, 2H), 2.14-2.04 (m, 2H), 1.81-1.78 (m, 2H). MS: (M1H m/z=382.2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37]1([CH3:49])[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)[S:45]([C:38]2[C:39]([CH3:44])=[CH:40][C:41]([CH3:43])=[CH:42][C:37]=2[CH3:49])(=[O:47])=[O:46])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: c1ccc(COc2ccc(NCc3cccc(OC4CCCCO4)c3)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.3 %

Procedure:
To a solution of (4-benzyloxy-phenyl)-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (12.7 g, 32.6 mmol) in 25 mL methylene chloride at 0° C. was added triethylamine (14.0 mL, 97.8 mmol), DMAP (0.400 g, 3.27 mmol) and 2-mesitylenesulfonyl chloride (14.3 g, 65.2 mmol). The reaction mixture was stirred at room temperature for 17 hr. The reaction mixture was diluted to a volume of 800 mL with methylene chloride and was washed with water (3×200 mL) and saturated aqueous sodium chloride (1×200 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography (10% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 8.82 g of the title compound of Step C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Br)cn1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Yield: 69.5 %

Procedure:
Using 5-bromopyrazine-2-carboxylic acid (203 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (191 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (261 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=O.[CH2:10]([O:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH3:11].C(O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH2:8][N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:26])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=CC1=C(Br)CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(Br)CCCC3)CC2)cc1

Procedure:
A 100 mL round bottom flask was charged with 2-bromocyclohex-1-enecarbaldehyde, (prepared as described by Arnold, A. et. al. Collect. Czech. Chem. Commun., 1961, 26, 3059-3073.), (42 mmol), 4-piperazin-1-yl-benzoic acid ethyl ester (42 mmol) and ethanol (50 ml). The mixture was stirred and sodium cyanoborohydride (42 mmol) was added. Acetic acid was used to adjust pH to 5-6. The reaction mixture was stirred under N2 at room temperature overnight. The reaction mixture was filtered and washed with ethanol. The filtered solid was discarded and the combined organic layers were concentrated under vacuum. The mixture was purified by silica gel chromatography eluting with 5-10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].Cl[CH2:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:31])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:31])=[CH:40][CH:41]=1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: O=C(NCc1ccccn1)c1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NCc1ccccn1)c1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Yield: 90.1 %

Procedure:
8-(2-nitrobenzenesulfonyl)amino-5,6,7,8-tetrahydroquinoline (402 mg, 1.20 mmol), 4-Chloromethyl-N-pyridin-2-ylmethyl-benzamide (314 mg, 1.20 mmol), and K2CO3 (498 mg, 3.60 mmol) were heated to reflux in CH3CN (4 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, then brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 50% ethyl acetate in CH2Cl2, afforded the title compound (603 mg, 90%) as white foam. 1H NMR (CDCl3) δ 1.56-1.61 (m, 1H), 1.74-2.05 (m, 2H), 2.32-2.36 (m, 1H), 2.58-2.64 (m, 2H), 3.95 (d, 1H, J=16.2 Hz), 4.74 (d, 2H, J=4.5 Hz), 4.85 (d, 1H, J=15.9 Hz), 5.30 (dd, 1H, J=11.1, 17.4 Hz), 7.05 (dd, 1H, J=4.5, 7.5 Hz), 7.22-7.29 (m, 2H), 7.34 (dd, 2H, J=7.5, 7.8 Hz), 7.48-7.73 (m, 8H), 8.12-8.15 (m, 1H), 8.20-8.24 (m, 1H), 8.45-8.59 (m, 1H); ES-MS m/z 558.2 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CSC>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(Br)ccc1I
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1cc(Br)ccc1I
Temperature: 65 °C
Yield: 96.1 %

Procedure:
To a stirred mixture of acid 2-iodo-5-bromobenzoic acid (15.0 g, 45.9 mmol) in dry THF (100 mL) under argon was added neat BH3.DMS (16.0 mL, 169 mmol) dropwise over 20 minutes. The resulting mixture was heated at 65° C. for 8 hours, cooled to room temperature and quenched by the dropwise addition of water (40 mL). The reaction mixture was concentrated in vacuo. The crude alcohol was diluted with of EtOAc (300 mL), washed with 1N NaOH (2×30 mL), 1N HCl (1×30 mL), saturated aqueous NaHCO3 solution (1×30 mL) and brine (1×30 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 2-iodo-5-bromobenzyl alcohol (13.8 g, 96%). 1H NMR (CDCl3): δ 7.56 (d, 1H, J=8.25 Hz), 7.54 (s, 1H), 7.04 (d, 1H, J=8.25 Hz), 4.47 (s, 2H). HPLC: Rt=3.12 min. m/z=312 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45](O)=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCCC2)c(C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Pyridine (0.83 mL, 12 mmol) and trifluoromethanesulfonic anhydride (1.2 mL, 7.1 mmol) were added to a solution of 4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclopentyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenol (Example 33-(1); 2.6 g, 6.9 mmol) in dichloromethane (26 mL) at −10° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (1.8 g, 51%).