Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:39](O)=[O:40]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH:16][C:39]([C:30]2[CH:31]=[CH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]=2[OH:28])=[O:40])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: N[C@H]1C[C@@H](c2ncc(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Product: O=C(N[C@H]1C[C@@H](c2ncc(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4S)-4-amino-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C32H28N3O5 [(M+H)+] 534, obsd. 534.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:55]12[NH:62][CH:59]([CH2:60][CH2:61]1)[CH2:58][CH2:57][CH2:56]2.C1C[O:66]CC1>>[CH:46]([OH:47])=[O:66].[CH:59]12[N:62]([CH2:46][CH2:45][O:44][C:43]3[CH:42]=[C:41]([N:7]4[C:8]([NH:10][C:11]([NH:13][C@@H:14]5[C:23]6[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=6)[C@H:17]([O:24][C:25]6[CH:26]=[CH:27][C:28]7[N:29]([C:31]([N:34]8[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]8[CH3:40])=[N:32][N:33]=7)[CH:30]=6)[CH2:16][CH2:15]5)=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]4)[CH:54]=[CH:53][CH:52]=3)[CH:55]([CH2:61][CH2:60]1)[CH2:56][CH2:57][CH2:58]2
Reactant: C1CC2CCC(C1)N2
Reactant: C1CCOC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5C6CCCC5CC6)c4)c4ccccc43)cn12
Product: O=CO
Yield: 62 %

Procedure:
A solution of Intermediate 154a (50.5 mg, 66 μmol) and 8-aza-bicyclo[3.2.1]octane (38 mg, 0.34 mmol) in THF (1 mL) was heated at 60° C. overnight in a sealed vessel. The reaction mixture was concentrated in vacuo and the residue purified by MDAP (Method 7) to give the title compound as a white solid (32 mg, 62%). LCMS (Method 5): Rt 3.84 min, m/z 772 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.4 Hz), 1.21-1.36 (11H, m), 1.37-1.54 (4H, m), 1.58-1.72 (4H, m), 1.74-2.18 (8H, m), 2.72 (2H, d, J=6.4 Hz), 2.86-2.95 (1H, m), 3.11-3.20 (1H, m), 3.22-3.36 (5H, m), 4.09 (2H, t, J=6.1 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=4.1 Hz), 6.33 (1H, s), 6.94-6.99 (1H, m), 7.04-7.11 (2H, m), 7.14 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=10.2 Hz, 2.1 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=10.2 Hz), 7.69 (1H, d, J=2.0 Hz), 8.17 (1H, s), 8.19 (1.6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[N-:25]=[C:26]=[O:27].[Na+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:25][C:26]([N:20]([OH:21])[CH2:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:22])=[O:27]
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: [N-]=C=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)c(CN(O)C(N)=O)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 53.3 %

Procedure:
To a suspension of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine (500 mg, 1.45 mmol) in 30 ml of 1,4-dioxane and 15 ml of water at 0° C. is added sodium isocyanate (104 mg, 1.59 mmol) followed by 1.59 ml (1.59 mmol) of 1N hydrochloric acid. The reaction mixture is diluted with ethyl acetate and washed once with water, and finally with a saturated solution of sodium chloride. It is further dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue is recrystallized from methylene chloride and dried to give 300 mg (53%) of pure N-(aminocarbonyl)-1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine (53%); mp 151.5°-154° C. dec.
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(OO)(=[O:21])C.O>C(Cl)Cl>[CH2:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]2[CH:15]([O:21]2)[CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOCC1C=CCCC1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCOCC1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirring bar was charged with 16.4g (0.065 mol) 3-decyloxymethylcyclohexene, and 100 mL of methylene chloride. Peracetic acid (15.5 g, 35 wt. % in acetic acid; 0.065 mol) in methylene chloride (80 mL) was added dropwise to above mixture over 30 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 250 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×150 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[N:7][C:6]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[N:14][C:5]1=2.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Si:19]([O:18][CH2:17][CH:2]([OH:1])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[N:7][C:6]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[N:14][C:5]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COc1ccc2ncc(=O)n(CC(O)CO)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.4 %

Procedure:
In dichloromethane (30 ml) was dissolved 4-(2,3-dihydroxypropyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.34 g, 5.32 mmol). To the solution were added tert-butyldimethylsilyl chloride (882 mg, 5.85 mmol), triethylamine (0.96 ml, 6.92 mmol) and 4-dimethylamino pyridine (130 mg, 1.06 mmol) under cooling on ice and the reaction mixture was stirred for 15 hours while the temperature was raised to room temperature. Saturated sodium bicarbonate water was added to the reaction solution, which was extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 1.35 g (70%) of the title compound in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14]Br>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([CH:7]([NH2:8])[CH2:4][CH:5]([CH3:9])[CH3:6])[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Cl)cc1
Product: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Yield: 56.2 %

Procedure:
As described in article (Chinese Journal of Pharmaceuticals, 2001, 32(8): 337-339), p-chlorobenzyl cyanide was condensed with 1,3-dibromopropane, cycled to give cyclobutyl intermediate, and then through Grignard reaction and reduction reaction to give title compound (56.2% yield).
Reaction SMILES: Cl[Mg][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br-].[CH2:10]([O:12][CH:13]([O:23][CH2:24][CH3:25])[CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][C:15]1=[O:22])[CH3:11].C(Cl)[Cl:27]>>[Cl:27][C:3]1[CH:8]=[CH:7][C:6]([C:15]2([OH:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19][CH:14]2[CH:13]([O:12][CH2:10][CH3:11])[O:23][CH2:24][CH3:25])=[CH:5][CH:4]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOC(OCC)C1CC(C)(C)CCC1=O
Reactant: ClCCl
Agent: [Br-]
Product: CCOC(OCC)C1CC(C)(C)CCC1(O)c1ccc(Cl)cc1

Procedure:
Another route involves reacting dimethylcyclohexanone (1A) with a prepared solution of diethoxycarbenium fluoroborate to provide 2-(diethoxymethyl)-4,4-dimethylcyclohexanone (8). The reaction is typically performed below room temperature in a solvent such as but not limited to methylene chloride. Chlorophenyl magnesium bromide is then added to a solution of 2-(diethoxymethyl)-4,4-dimethylcyclohexanone (8) to provide 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol (9). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 1-(4-Chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol (9) can be treated with an acid such as but not limited to HCl, to provide the aldehyde intermediate (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde) (4).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.Cl[CH:14](Cl)[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:23]=2)[CH2:18][CH2:17][N:16]=1>CCO.C(Cl)Cl>[CH3:32][O:31][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][C:22]=1[O:25][CH2:26][C:27]([F:30])([F:28])[F:29])[C:15]([CH2:14][S:3][C:4]1[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=1)=[N:16][CH:17]=[CH:18]2
Reactant: COc1cc2c(cc1OCC(F)(F)F)C(C(Cl)Cl)=NCC2
Reactant: Sc1nc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2ccnc(CSc3nc4ccccc4[nH]3)c2cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of 514.8 mg of 86% KOH (7.87 mmol) in 20 ml of 99% EtOH were added 434.1 mg of 2-mercaptobenzimidazole (II-1) (2.89 mmol) and 900.1 mg of 1-dichloromethyl-6-methoxy-7-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinoline (IV-1) (2.63 mmol) in order. After stirring for 30 min. at room temperature, the mixture was refluxed for 3 hr. and concentrated under reduced pressure. The residue was mixed with water and extracted with CHCl3. The objective compound existing as an insoluble material was filtered and combined with CHCl3 extract to give 722.5 mg of the crude product. It was dispersed in 15 ml of CH2Cl2, filtered and washed with CH2Cl2 to give 666.5 mg of the titled compound 2-{[6-methoxy-7-(2,2,2-trifluoroethoxy)isoquinolin-1-yl]methylthio}-benzimidazole (Ia-7) (Yield: 60.4%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][C:36](O)=[C:35]([C:40]([O:42][CH3:43])=[O:41])[CH:34]=3)[N:32]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])[CH3:17].C(N(CC)CC)C.O>ClCCl>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:35]([C:40]([O:42][CH3:43])=[O:41])[CH:34]=3)[N:32]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)OC)c3)cs2)cc1OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1ccc(-c2nc(-c3ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c3)cs2)cc1OCC
Yield: 95.4 %

Procedure:
8.5 g of trifluoromethanesulfonic acid anhydride was added to a solution of 10 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)thiazole dissolved in 100 ml of dichloromethane. Thereto was dropwise added 6 ml of triethylamine with stirring under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. Thereto was added 40 ml of water for phase separation. The organic layer was dried and subjected to distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 12.7 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-trifluoromethanesulfonyloxyphenyl)thiazole as a white powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:13](O)=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CNC.C=O>O>[CH2:13]=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(CCc1ccccc1)C(=O)O
Agent: C=O
Agent: CNC
Solvent: O
Product: C=C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenylethylmalonic acid (1.8 g), 40% aqueous dimethylamine (1.08 ml, 1 eq) and 37% aqueous formaldehyde (0.64 ml, 1 eq) in water (10 ml) was stirred at room temperature overnight. After cooling at 0° C. the solid was filtered off, washed with water and dried. The white solid was heated at 170° C. for 10 minutes and cooled to room temperature. The resulting gum was dissolved in ethyl acetate (20 ml), washed with 10% potassium hydrogen sulphate solution (10 ml), water (2×10 ml), saturated brine (10 ml), dried (MgSO4) and evaporated to give crude 2-methylene-4-phenylbutanoic acid. δH (CDCl3) 2.55-2.90 (4H, m, 2×CH2), 5.65, 6.85 (2H, 2×s, H), 7.25 (5H, m, Ph).
Reaction SMILES: [CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23](OC)[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1(N)CCC=CC1.C1(=O)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:1]1([N:6]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:5][CH2:4][CH:3]=[CH:2][CH2:28]1
Reactant: NC1CC=CCC1
Reactant: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Solvent: O=C1CCCCC1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CC=CCC2)C2CCCCC2)s1

Procedure:
Prepared in accordance with the procedure for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using cyclohex-3-enylamine, cyclohexanone and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester as starting material.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:11]=2[CH3:28])[CH2:4][O:3]1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[O:3][CH2:4][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:38])[C:11]=2[CH3:28])[CH2:6][O:7]1
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Reaction time: 0.75 h
Yield: 61.9 %

Procedure:
To a toluene (20 ml)-methanol (2 ml) solution of the 2-(((4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (424 mg, 1.03 mmol) obtained in the step (11g), a toluene (1 ml)-methanol (1 ml) solution of 3-chloroperbenzoic acid (246 mg, 0.927 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 45 minutes in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 20 g, elution solvent: dichloromethane, dichloromethane/methanol=10/1). The fractions containing the title compound were collected with ethyl acetate and concentrated. To the residue, diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (274 mg, yield: 61.9%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[N:23][C:22]=2[CH:31]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[N:23][C:22]=3[CH:31]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Reactant: ClCc1ccc2oc(-c3cccs3)nc2c1
Product: c1cc(CCCn2ccnc2)cc(OCc2ccc3oc(-c4cccs4)nc3c2)c1
Yield: 76 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 5-chloromethyl-2-(2-thienyl)benzoxazole to give 5-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. The yield was 76%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 86-87° C.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:21])[CH3:2]>C1C=CC=CC=1.C>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CCC2=O

Procedure:
Hydrogenate 13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (0.5 g.) in benzene (25 cc.) at atmospheric pressure using a 10% palladized charcoal catalyst (0.025 g.). After the absorption of 1.1 molar equivalents of hydrogen, hydrogenation becomes very slow; remove the catalyst by filtration and evaporate the filtrate to obtain the title product which crystallizes from methanol in colorless plates (0.35 g.), m.p. 235°-9°; ultra-violet absorption peak at 280.5 mμ (ε15,500).
Reaction SMILES: [F:1][C:2]([F:18])([O:6][C:7]1[N:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].COCCO[AlH2-]OCCOC.[Na+].CC(C)=O.O>O1CCCC1>[F:18][C:2]([F:1])([O:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4]
Reactant: CCOC(=O)c1cccc(OC(F)(F)C(F)F)n1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OCc1cccc(OC(F)(F)C(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-(1,1,2,2-tetrafluoroethoxy)-pyridine-2-carboxylate (5.65 g, 21.2 mmol) in tetrahydrofuran (60 ml) was added Red-Al (registered trademark, 6.11 g, 21.2 mmol). The reaction solution was stirred at room temperature for 30 min. and acetone (2 ml) was added. Water (100 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl-acetate=4:1) to give the objective substance (4.2 g, 88%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[NH:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:40][N:39]=[N:38][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2.[CH2:19]([Mg]Br)C>CCOCC>[CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11]([CH3:19])([OH:16])[CH2:12]2
Reactant: CC[Mg]Br
Reactant: CCC(CCCCC1CCC2CC(=O)CC12)OC
Solvent: CCOCC
Product: CCC(CCCCC1CCC2CC(C)(O)CC12)OC

Procedure:
2-(5-Methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} (4 g, 0.0158 moles) diluted in ether is added dropwise to a stirring solution of ethyl magnesium bromide (0.0158 moles) dissolved with diethyl ether. The mixture is cooled in an ice bath during the addition. The ice bath is removed and the solution stirred for an additional hour. The reaction is quenched with water and a 15% sulfuric acid solution. The organic phase is separated and the solvent removed under vacuum. The aqueous layer is extracted with ether (2×200 ml) and the extracts are combined with the organic layer and dried over anhydrous sodium sulfate. The solid is filtered off and the remaining solvent removed leaving a clear, pale yellow oil. The crude product is subsequently chromatographed on silica gel yielding desired product as a clear colorless oil (1.7 g, 6.3 mmoles).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27].[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C>ClCCl.Cl>[C:28]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1N(C[C@@H]2CCCN2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Yield: 83.7 %

Procedure:
A solution of 1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.23 g, 0.62 mmol), acetic anhydride (0.09 mL, 0.95 mmol) and triethylamine (0.17 mL, 1.2 mmol) in dichloromethane (4 mL) was stirred at ambient temperature for 40 min. The reaction was diluted with 0.2 M hydrochloric acid (50 mL) and extracted with dichloromethane (3×25 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/diethyl ether (4:1) afforded 1′-{[(2S)-1-acetylpyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.21 g, 84%) as an off-white solid: mp 103-108° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.54, 7.53 (d, J=7.8 Hz, 1H), 7.35, 7.34 (dd, J=8.1, 7.7 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.06 (dd, J=7.5 Hz, 1H), 6.49, 6.46 (s, 1H), 6.42, 6.41 (s, 1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.68, 4.67 (d, J=9.0 Hz, 1H), 4.54, 4.53 (t, J=8.7 Hz, 2H), 4.49-4.42 (m, 1H), 3.95-3.80 (m, 2H), 3.61-3.54 (m, 1H), 3.46-3.36 (m, 1H), 3.00, 2.99 (t, J=8.6 Hz, 2H), 2.26-1.76 (m, 4H), 2.11-2.08 (s, 3H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ 178.49, 178.47, 170.2, 161.9, 161.8, 161.5, 161.4, 142.6, 142.4, 132.5, 132.3, 129.36, 129.33, 123.8, 123.7, 123.6, 123.5, 120.4, 120.2, 120.0, 119.9, 119.2, 118.7, 110.01, 109.96, 93.4, 93.2, 80.9, 80.8, 72.5, 57.9, 55.0, 54.8, 47.9, 41.5, 41.2, 29.2, 29.1, 28.0, 27.8, 23.9, 22.92, 22.90; MS (ES+) m/z 405.1 (M+1).