Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl[CH2:15][C:16]1[O:17][C:18]([C:21](=[O:29])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:20]=1.O>O1CCCC1.C(OCC)(=O)C>[O:4]=[C:3]([CH3:5])[CH:2]([CH2:15][C:16]1[O:17][C:18]([C:21](=[O:29])[NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:20]=1)[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)o1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 67.9 %

Procedure:
To 9.6 g of tert-butyl acetoacetate was dissolved in 80 ml of tetrahydrofuran, and 2.33 g of 60% oil sodium hydride was added under cooling with ice under stirring. The resulting solution was stirred at the same temperature for 10 minutes. After addition of 13.6 g of 2-(chloromethyl)-5-(phenylcarbamoyl)furan obtained in Reference Example 2 in 80 ml of tetrahydrofuran, the solution was stirred at room temperature for 10 minutes and then at 60° C. for 13 hours under heating. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride successively and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=10/1→3/1] to give 14.0 g of the title compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@@H:14]([O:16]CC=C)[CH2:13][NH:12]2)[O:9][C:8](=[O:20])[NH:7]1.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1COCCN1[CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)O.FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[Li+].[OH-]>CCO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][N:12]2[CH:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:9][C:8](=[O:20])[NH:7]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COCCN1C(c1ccccc1)c1ccccc1
Reactant: C=CCO[C@H]1CN[C@@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)C1
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CCCCN2C(c2ccccc2)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Reaction time: 8 h

Procedure:
Step L (8): (1S,2S)-2-Amino-1-((R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-4-benzhydrylmorpholin-3-yl)oxazolidin-2-one (step L (7), 85 mg, 0.18 mmol) in EtOH (2 mL) was added a solution of LiOH (66 mg, 2.75 mmol) in H2O (1 mL). This reaction mixture was brought to 98° C. and stirred for overnight. Solvent was removed and 1N HCl solution (50 mL) was added to the mixture and washed with diethyl ether. The aqueous phase was basified with 50% aqueous NaOH solution. This mixture was extracted with ethyl acetate. The combined organic layer was dried (Na2SO4), and concentrated in vacuo to give 80 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ 1.94-2.06 (3H, m), 2.30 (1H, dd, J=10, 15 Hz), 2.51-2.59 (1H, m), 2.73-2.81 (1H, m), 2.90 (1H, m), 2.95 (1H, m), 3.08 (1H, m), 3.70 (1H, m), 3.80 (1H, dt, J=5, 10 Hz), 3.91 (1H, m), 4.09 (1H, m), 4.14 (1H, m), 5.05 (1H, s), 6.60-6.68 (3H, m), 7.15-7.31 (6H, m), 7.37 (2H, d, J=10 Hz), 7.42 (2H, d, J=5 Hz). MS (ESI) (M+H)+ 439.20.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].Br[CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([CH2:13][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH2:15][CH2:16]1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC1(F)CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
1.2 g of 2-(3,3,3-trifluoropropyl)malononitrile and 0.76 g of 4-bromomethyl-1,1-difluorocyclohexane were dissolved in 10 ml of N,N-dimethylformamide, 0.99 g of potassium carbonate was added, and the mixture was stirred at room temperature overnight. Thereafter, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.51 g of 2-(4,4-difluorocyclohexyl)methyl-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (83)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CN(C1CCCCC1)C1CCCCC1.[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])[N:9]=2)[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc(C=O)cc2cn[nH]c12
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(C=O)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 5 h

Procedure:
To a solution of 7-methyl-1H-indazole-5-carbaldehyde (5.0 g, 31.25 mmol) and N-methyl-dicyclohexylamine (13.5 mL, 62.35 mmol) in dry tetrahydrofuran (120 mL) at 0° C., was added 2-(trimethylsilyl)ethoxymethyl chloride (6.65 mL, 39.5 mmol). The ice-bath was removed and stirring continued for 5 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated in vacuo. Column chromatography afforded 8.5 g (93%). 1H-NMR (400 MHz, CDCl3) δ 12.3 (br., 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.42 (s, 1H), 6.12 (d, J=7.0 Hz, 1H), 5.31 (d, J=7.0 Hz, 1H), 3.80 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:18](Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC>C(Cl)Cl.C(OCC)C.O1CCCC1.[Zn]>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[CH:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCc1ccc(CC=O)cc1
Agent: [Li]CCCC
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCc1ccc(CCCCCCCC)cc1

Procedure:
p-(n-Octyl)phenylacetaldehyde (1 mmole, prepared as described in paragraph A of this example) is dissolved in methylene chloride, and treated with carbontetrabromide (4 mmole), triphenylphosphine (4 mmole) and zinc dust (4 mmole) at room temperature. The reaction mixture is then diluted with ethyl ether and filtered. The filtrate is washed with water, dried and evaporated to give an oily residue. This residue is dissolved in tetrahydrofuran and treated with n-butyl lithium (2.1 mmole) at -78° C. for one hour and then at room temperature until the reaction ceases. The reaction mixture is poured onto water, the pH adjusted to 7, and extracted with methylene chloride. The methylene chloride extract is washed with water, dried and the solvent removed by evaporation. Distillation under reduced pressure affords p-(n-octyl)benzylacetylene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-].[K+].[K+].I[CH3:23]>CS(C)=O.C(OCC)(=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:23])([CH3:9])[C:16]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C(=O)C1
Reactant: CI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)C(=O)CCN(Cc2ccccc2)C1=O
Reaction time: 24 h
Yield: 37.1 %

Procedure:
A mixture of 1.44 gm (7.1 mMol) 1-benzyl-2,4-dioxopiperidine, 4.0 gm (28.9 mMol) potassium carbonate, and 1.5 mL (24.1 mMol) iodomethane in 14 mL dimethylsulfoxide was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the organic phases was washed sequentially with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 35% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.61 gm (37%) of the desired compound.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[F:12][CH:13]([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH3:23])[C:18](SC)=[N:19][CH:20]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+].[S:32]([O-:35])([O-])=[O:33].[Na+].[Na+]>C(Cl)Cl>[F:24][CH:13]([F:12])[O:14][C:15]1[CH:16]=[C:17]([CH3:23])[C:18]([S:32]([CH3:2])(=[O:35])=[O:33])=[N:19][CH:20]=1
Reactant: O=S([O-])[O-]
Reactant: CSc1ncc(OC(F)F)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(OC(F)F)cnc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Solid 3-chloroperbenzoic acid (60 percent, 18.1 g, 68.6 mmol) was added in portions over 1 hour to a chilled (6° C.) solution of 5-difluoromethoxy-3-methyl-2-methylsulfanylpyridine (6.4 g, 31.2 mmol) in methylene chloride (200 mL). The reaction was stirred overnight while warming to room temperature. Aqueous 1N sodium hydroxide (65 mL) was added in portions, raising the pH to ca. 6. Saturated aq. sodium bicarbonate (60 mL) was added, raising the pH of the aqueous phase to ca. 8. Aqueous 10 percent sodium sulfite was added, and after stirring for 10 minutes, the layers were separated. The aqueous layer was extracted with methylene chloride (50 mL) and the organic layers were combined, washed with brine, and dried (Na2SO4). Filtration and removal of solvent left a clear oil, 8 g, that was purified by chromatography on silica, eluting with 1.5 vol percent acetonitrile in methylene chloride to give product, 6.3 g, 26.6 mmol, 85 percent yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].CN(C)CCN>CS(C)=O>[CH3:29][S:30]([C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)(=[O:32])=[O:31]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Reactant: CS(=O)[O-]
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 125 °C
Reaction time: 5 h
Yield: 12 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 29, sodium methanesulfinate (90 mg, 0.436 mmol) and unsymmetrical N,N-dimethylethylene diamine (6 mg, 0.066 mmol) in anhydrous DMSO (1 mL) at rt was flushed with a stream of argon for 15 min. To the resulting mixture was added copper (I) trifluoromethane-sulfonate benzene complex (20 mg, 0.0328 mmol). The reaction vessel was sealed and the mixture was heated with stirring at 125° C. for 5 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (12 mg, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.85-8.95 (br m, 2H), 8.61 (s, 1H), 8.02 (d, J=7.3 Hz, 1H), 7.69 (s, 1H), 7.18-7.35 (m, 2H), 5.56 (s, 2H), 4.79 (br s, 1H), 3.25-3.60 (m, 5H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.70 (m, 2H), 1.08-1.36 (m, 4H). LCMS (ESI) m/z 458 (M+H)+.
Reaction SMILES: C(O)(=O)C.C(O)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[C:19]1[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[N:21]([CH3:32])[N:20]=1>[Fe].C(OCC)(=O)C>[NH2:16][C:12]1[C:13]([Cl:15])=[CH:14][C:9]([Cl:8])=[C:10]([C:19]2[C:23]([C:24]([F:25])([F:26])[F:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[N:21]([CH3:32])[N:20]=2)[CH:11]=1
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)c(C(F)(F)F)c1C(F)(F)F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(N)c(Cl)cc2Cl)c(C(F)(F)F)c1C(F)(F)F
Reaction time: 2 h

Procedure:
8 g (0.14 mol) of iron powder, 53 ml of glacial acetic acid and 24 ml of ethanol were heated to 70° C. and the mixture was treated with 11.7 g (29 mmol) of 3-(2,4-dichloro-5-nitrophenyl)-1-methyl-4,5-di(trifluoromethyl)-1H-pyrazole. After the mixture had been stirred for 2 hours at reflux temperature, it was treated with 200 ml of ethyl acetate. It was then filtered through kieselguhr. The filtrate was concentrated. Yield: quantitative.
Reaction SMILES: [C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:6][CH2:5]1)(=[O:3])[CH3:2].[C:15](OCC)(=O)[C:16]([O:18]CC)=[O:17].[H-].[Na+]>O1CCCC1>[O:3]=[C:1]1[CH:2]=[C:15]([C:16]([OH:18])=[O:17])[O:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:6][CH2:5][C:4]1=2
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C1CSc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(=O)c2c(o1)-c1ccccc1SC2
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-acetyl-4-thiochromanone (6.18 g, 0.03 mole, described in Example 5) and diethyl oxalate (4.38 g, 0.03 mole) in tetrahydrofuran (25 ml) is added dropwise to a stirred suspension of 57% sodium hydride (3.79 g, 0.09 mole) in tetrahydrofuran (25 ml) under an atmosphere of nitrogen at 70°. After the addition is completed, the mixture is heated under an atmosphere of nitrogen at 70° C for 17 hr and the solvent removed by evaporation under reduced pressure. The residue is dissolved in water and washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid (15 ml) in the presence of chloroform and the mixture is stirred for 1.5 hr at room temperature. The organic phase is separated and the aqueous phase is extracted with chloroform. The combined organic extracts are dried, evaporated and the resulting residue crystallized from chloroform to give the title compound; m.p. 251°-253° C, νmaxnujol 2500, 1890, 1730, 1640, 1575, 1550 and 1265 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][C@H:18]([NH:17][C:14](=[O:16])[C:11]2[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=2)[CH2:27][CH2:26]3)[CH2:29][CH2:30]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(-c4ccc(O)cc4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4'-Hydroxy-4-biphenylcarboxylic acid (0.40 g, 1.9 mmol) was dissolved in thionyl chloride (10 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (120 mg, 0.51 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.74 mmol) in methylene chloride (20 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:6:0.5) as the eluent. Yield: 95 mg (44%) of the title compound as white crystals: mp 261-262° C.; EIMS (70 eV) m/z (relative intensity) 441 (2, M+).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]3[CH2:20][CH2:21][CH2:22][C:15]=3[C:14]=2[CH:23]=1)(=O)=O.[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]1[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[C:11]([O:24][CH3:25])=[CH:12][C:13]3[O:18][C:17](=[O:19])[C:16]4[CH2:20][CH2:21][CH2:22][C:15]=4[C:14]=3[CH:23]=2)[CH2:38][CH2:39]1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCC3
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2cccc(C)c2C)CC1)CCC3
Yield: 84 %

Procedure:
Method B (20 h at 60° C.); starting materials: 2,3-dihydro-8-[3-(methanesulfonyloxy)propoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 82) and 1-(2,3-dimethylphenyl)-piperazine; yield 84%; fusion point 164°-166° C. (from ethanol). Fumarate: method E; yield 94%; fusion point 235°-237° C. (from acetone).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][N:28]2[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC2CC2)CC1
Yield: 51 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-h]pyridin-2-yl]-methanone (example 13), sodium hydride and cyclopropylmethyl bromide, to give the desired product as a light brown oil (51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.C(N(CC)CC)C.[C:35]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36]1.CC[O:45]CC>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:26][O:25][C:24]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19](/[CH:18]=[CH:17]/[C:15]([CH2:14][C:12](/[CH:11]=[CH:10]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)=[O:13])=[O:16])[CH:27]=1.[C:35]([O-:41])(=[O:42])[CH2:36][CH2:37][CH2:38][C:39]([O-:45])=[O:40]
Reactant: O=C1CCCC(=O)O1
Reactant: CCOCC
Agent: CN(C)c1ccncc1
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 80 °C

Procedure:
In a 500 mL round bottom flask curcumin (3.00 g), DMAP (168 mg) and triethyl amine (4 ml) were taken in 150 mL of THF. Glutaric anhydride (2.35 ml) in 15 mL of THF was added drop-wise under anhydrous conditions. The mixture was refluxed for 20 hours at 80° C. The solution was evaporated in a rotovop. The thick residue was taken in 150 mL of ethyl acetate, washed with 50 mL of 0.5 N HCl. The HCl wash was extracted with 50 mL of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and was concentrated under vacuum to get 4.80 g. This was co-evaporated with ether several times to get a solid, 2.5 g. NMR was consistent with the structure.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[O:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[Li+].[OH-].Cl>C1COCC1.CO>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][C:26](=[O:27])[N:25]([CH2:24][C:15]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=2)[CH2:37][CH3:38])=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To {2′-[3-(4-chloro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.196 g, 0.35 mmol) in THF (2 mL) and MeOH (2 mL) was added 1N aqueous LiOH (2 mL), and the reaction was stirred at room temperature for 2 hours. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.Cl.[NH:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:20]2[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]2)=[CH:13][CH:12]=1
Reactant: O[C@@H]1CCNC1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Diisopropylethylamine (1.57 ml, 9.00 mmol) was added to a solution (15 ml) of 1.50 g (6.00 mmol) of 4-bromobenzyl bromide and 1.11 g (9.00 mmol) of (R)-pyrrolidin-3-ol hydrochloride in dimethylformamide and the mixture was stirred at room temperature for one hr. The solvent was removed by distillation under the reduced pressure. Water and 1 N hydrochloric acid were then added to the residue, and the mixture was washed with ethyl acetate. A 5 N aqueous sodium hydroxide solution and an aqueous sodium hydrogencarbonate solution were added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure to give 1.09 g (yield 71%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(B(O)O)c2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)c1

Procedure:
The title compound was prepared from 3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.10) (0.407 g, 1.14 mmol) and commercially available 3-bromobenzenesulfonamide (177 mg, 1.14 mmol) according to the general procedure VI. Obtained as a white solid (0.052 g, 10%). MS (ISP) 469.4 [(M+H)+]; mp 200° C.