Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(C2C=CC(CCN(C[C@H:26]([OH:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)C(=O)OC(C)(C)C)=CC=2)=CC=1N(C(C)C)C)=O.OO.Cl([O-])=[O:42].[Na+]>C(#N)C.C(OCC)(=O)C>[C:26]([OH:33])(=[O:42])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)N(C)c1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C=O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Temperature: 20 °C
Reaction time: 10 h
Yield: 47.8 %

Procedure:
To a solution of tert-butyl [2-[4′-formyl-3′-[isopropyl(methyl)amino]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (310 mg) in acetonitrile (3.5 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1.6 ml) were added 30% hydrogen peroxide solution (60 μl) and 80% sodium chlorite (110 mg) below 10° C. The reaction mixture was stirred at 20° C. for 10 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=15/1) to give a benzoic acid product (35 mg). To a solution of the product in ethyl acetate (0.5 ml) was added 4N hydrogen chloride in ethyl acetate (0.5 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-[isopropyl(methyl)amino]-4-biphenylcarboxylic acid dihydrochloride (23 mg).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[C@H:16]2[C@H:17]([O:23][CH3:24])[O:18][CH:19]=[C:20]([CH2:21][OH:22])[C@H:15]2[CH2:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.CCCCCC.C(OC(=O)C)C>[Si:3]([O:10][CH2:11][C:12]1[C@H:16]2[C@H:17]([O:23][CH3:24])[O:18][CH:19]=[C:20]([CH2:21][O:22][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[C@H:15]2[CH2:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: CO[C@@H]1OC=C(CO)[C@H]2CC=C(CO[Si](C)(C)C(C)(C)C)[C@@H]12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(COCC2=CO[C@@H](OC)[C@@H]3C(CO[Si](C)(C)C(C)(C)C)=CC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
0.402 g (10.04 mmol) of sodium hydride was introduced into a reaction vessel and 10ml of dried dimethylformanide was added thereto under nitrogen atmosphere. After the reaction temperature was lowered to 5° C., 3 g (8.37 mmol) of (1R,4aS,7aS)-7-(t-butyldimethylsilyloxymethyl)-4-hydroxymethyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran which is diluted in advance in 20 ml of dried dimethylfor- mamide was slowly added dropwise thereto. After stirring for one hour, 1.36 ml (10.04 mmol) of p-methoxybenzylchloride was added to the solution, which was then stirred for 6 hours while its temperature being slowly raised to room temperature. Saturated aqueous sodium bicarbonate solution was added to stop the reaction. The reaction solution was extracted with diethylether and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane/ethylacetate=8/1, v/v) to obtain 1.578 g (Yield 42.2%) of (1R,4aS,7aS)-7-(t-butyldimethylsilyloxymethyl)-1-methoxy-4-(p-methoxybenzyloxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>CCO>[C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:8]=1)#[N:26]
Reactant: CCOC(=O)c1cnc(-c2cccnc2)nc1Oc1cccc(C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(Oc2nc(-c3cccnc3)ncc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of Compound 14e (1.06 g; 3.06 mmol) in EtOH (50 mL) was added 0.5N NaOH (9 mL; 4.5 mmol). The reaction was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to 2 with 1N HCl. The resultant white solid was collected by filtration to afford Compound 14f. 1H NMR (300 MHz, DMSO d6): δ 9.21 (s, 1H), 9.18 (d, 1H), 8.70 (d, 1H), 8.35 (dd, 1H), 7.95 (s, 1H), 7.85 (dd, 1H), 7.75 (m, 2H), 7.50 (dd, 1H); MS: m/z 319.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(/[C:14](=[N:21]\[O:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])/[CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>>[C:8]1(/[C:14](=[N:21]\[O:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])/[CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)CCCCO/N=C(/Cn1ccnc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCO/N=C(/Cn1ccnc1)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
Trifluoroacetic acid (1.3 ml) is added dropwise at -10° C. to 0.23 g (0.643 mmoles) of tert-butyl (E)-5-[1-phenyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoate. The mixture is stirred at -10° C. for 1 hour and 30 minutes. A cooled saturated sodium hydrogencarbonate solution is added to the reaction mixture at 0° C. till pH=7 and the mixture is extracted with ethyl acetate. The aqueous phase is cooled, acidified with acetic acid and extracted twice with ethyl acetate. The organic phase is dried and evaporated. The residue is taken up twice with toluene and evaporated under vacuum without heating, yielding 0.11 g (57%) of (E)-5-[1-phenyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].[CH3:36][O:37][C:38]([C:40]1[CH:41]=[N:42][CH:43]=[C:44](Br)[CH:45]=1)=[O:39].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH3:36][O:37][C:38](=[O:39])[C:40]1[CH:45]=[C:44]([C:6]2[CH:5]=[CH:4][C:3]([CH:17]([CH3:35])[C:18]([OH:23])([C:24]3[CH:25]=[CH:26][C:27]4[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=4[CH:34]=3)[C:19]([F:20])([F:21])[F:22])=[C:2]([Cl:1])[CH:7]=2)[CH:43]=[N:42][CH:41]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cncc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)c1
Temperature: 65 °C
Yield: 52 %

Procedure:
5-{2-[2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (200 mg, obtained in Example 186, step 1), methyl-5-bromopyridine-3-carboxylate (169 mg, [CAS Reg. No. 29681-44-5]) and dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II)dichloromethane adduct (29 mg) were dissolved in dioxane (5 mL) and water (1.7 mL). To the reaction mixture was added 2.0 M aqueous Na2CO3 (0.29 mL). The mixture was heated to 65° C. over night. The reaction mixture was cooled, poured into ice/water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (110 mg, 52%). MS (m/e)=521.1 [M+H+].
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]([F:27])([F:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1>CO>[NH2:11][C@@H:12]([CH2:17][C:18]([F:26])([F:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a three-neck flask, methyl (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenyl-pentanoate (1.0 g, 2.65 mmol) was dissolved in 25 ml of methanol. After repeated evacuation and sparging with argon, 350 mg of Pd/C (10%) were added. After degassing and sparging with argon again, the argon atmosphere was replaced by hydrogen (balloon with H2 gas). The mixture was stirred at RT for 3 h. Owing to incomplete conversion, a further 350 mg of catalyst were added and the mixture was hydrogenated at RT for a further 5 h. On completion of conversion, the reaction mixture was filtered. The mixture was washed with 20 ml of methanol and the filtrate was concentrated by evaporation under reduced pressure. A waxy residue was obtained which, as well as the desired product, also contained smaller amounts of the monodefluorinated and didefluorinated product. This residue was used without further purification for the further reaction.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].OO.S([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C.CCCCCCC.C(OCC)(=O)C.C(#N)C>[CH3:22][C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH2:23][O:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC#N
Product: CC(C)(CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)c1ccccc1
Temperature: 61 °C
Reaction time: 1.25 h
Yield: 10 %

Procedure:
A solution of 0.077 g (0.39 mmol) of ferrous chloride tetrahydrate in 2.2 g of water is added to a mixture of 5.00 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 16 ml of t-butylbenzene, and 28 ml of acetonitrile that has been heated to 61° C. A solution of 5.03 g (74 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2 hours to the reaction mixture while the temperature is maintained at 65°. After the peroxide is added, the mixture is stirred for 1.25 hours at 65°. The reaction mixture is cooled to 30° and stirred with 20 ml of 10% aqueous sodium sulfite solution to decompose excess peroxide. The crude reaction mixture is diluted with ethyl acetate, and the organic layer is concentrated. Purification by flash chromatography with 100:1 and then 25:1 heptane-ethyl acetate affords 0.75 g (10% yield) of the title compound, a pale yellow oil. Structure is confirmed by NMR and mass spectrometry.
Reaction SMILES: [N:1]([CH:4]([CH3:28])[CH2:5][O:6][CH:7]1[CH2:27][C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)=[C:17]([F:26])[CH:16]=3)[O:14][C:10]=2[CH2:9][CH2:8]1)=[N+]=[N-].C1C[O:32][CH2:31][CH2:30]1>[C].[Pd]>[CH:23]1([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[O:14][C:10]4[CH2:9][CH2:8][CH:7]([O:6][CH2:5][CH:4]([NH:1][C:31](=[O:32])[CH3:30])[CH3:28])[CH2:27][C:11]=4[N:12]=3)=[CH:16][C:17]=2[F:26])[CH2:25][CH2:24]1
Reactant: CC(COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1)N=[N+]=[N-]
Reactant: C1CCOC1
Agent: [Pd]
Product: CC(=O)NC(C)COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(2-azidopropoxy)-2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazole (3.08 g), 10% palladium-carbon (containing water (50%), 500 mg) and THF (10 mL) was stirred at room temperature for 10 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. To the obtained residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (2.80 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])C(O)=O)=[O:4].C(Cl)(=O)[C:17]([Cl:19])=[O:18]>ClCCl.CN(C)C=O>[F:15][C:2]([F:1])([F:14])[C:3]([NH:5][CH2:6][CH2:10][CH2:11][CH2:12][CH2:13][C:17]([Cl:19])=[O:18])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCC(NC(=O)C(F)(F)F)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCCNC(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
735 mg(3 mmol) (2,2,2-trifluoro-acetylamino)-hexanoic acid were dissolved in 5 mL dried dichloromethane and stirred under argon flux at 0° C. Then, 0.6 mL (6.6 mmol) oxalyl chloride were added dropwise at 0° C., a few drops of dried dimethylformamide were also added dropwise which lead to gas development and yellow colouring of the previously white mixture. The mixture, was stirred at room temperature for 70 min. Then the mixture was repeatedly evaporated with dichloromethane. The crude product was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])([O-])([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OCC)(=O)C>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)CCc1ccccc1
Temperature: 30 °C
Reaction time: 27 h
Yield: 79.2 %

Procedure:
3.0 g of ethyl 2-oxo-4-phenylbutyrate, 0.49 g of the above-mentioned wet cell, 3.0 mg of NAD+, 4.5 g of glucose and 30 ml of 100 mM phosphate buffering solution (pH 7.0) were mixed and stirred at 30° C. for 27 hours. During stirring, 2M sodium carbonate aqueous solution was added gradually so that the reaction solution had a pH of 7.0. Thereafter, to the reaction liquid was added 50 ml of ethyl acetate, then, centrifugal separation was performed to obtain an organic layer. This organic layer was dehydrated over magnesium sulfate, and ethyl acetate was distilled off, to obtain 2.4 g of ethyl 2-hydroxy-4-phenylbutyrate. The optical purity of the resulting ethyl 2-hydroxy-4-phenylbutyrate was measured, to find 98.5% e.e. for (R) configuration.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[CH3:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[CH3:23])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCCN(C)C(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCCN(C)C(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Yield: 67.3 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[3-[N-methyl-(4-pyridine-2-ylbenzoyl)amino]propoxy]phenyl]propionate (200 mg). which is the product of Example 71, was reacted with aqueous sodium hydroxide solution (1N, 1.20 ml) and the reaction mixture was treated to give the title compound (127 mg) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6][CH2:5]1.[BrH:29]>O>[OH2:23].[BrH:29].[BrH:29].[BrH:29].[NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6][CH2:5]1
Reactant: COc1ccc(Cn2c(NC3CCN(CCN)CC3)nc3ccccc32)cc1
Agent: Br
Solvent: O
Product: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(O)cc2)CC1
Yield: 57 %

Procedure:
A mixture of 7.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-methoxyphenyl)methyl]-1H-benzimidazol-2-amine and 225 parts of a hydrobromic acid solution 48% in water was stirred and heated over week-end. After cooling, the precipitated product was filtered off and dried, yielding 7.3 parts (57%) of 4-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1H-benzimidazol-1-yl]methyl]phenol trihydrobromide monohydrate; mp. >250° C. (intermediate 139).
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=C.[OH2:14]>CO>[C:12]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=2)[C:11]([OH:14])=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: C=COc1cccc2ccccc12
Reactant: O
Solvent: CO
Product: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Temperature: -10 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
62.4 mg (0.20 mmol) of O-vinylnaphthol and 1.3 mg (0.002 mmol) of Co (OAc) (L3) were dissolved in 50 μl of methanol under the atmosphere, 18 μl (1.0 mmol) of water was added to the mixture, and the mixture was then stirred at −10° C. After 5 hours, the reaction solution was analyzed by HPLC, to find that 89% of the O-vinylnaphthol was left with an optical purity of 10% ee. Further, the reaction solution was purified by silica gel column chromatography to obtain the reaction product binaphthol in a yield of 11%. Also, the kre1 value showing the selectivity of reactions at this time was 11.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:25]([OH:27])[CH3:26]>O1CCOCC1>[OH:27][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CC(O)I
Reactant: O=C(CCc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(CCc1ccccc1)c1ccc(OCCO)cc1

Procedure:
A mixture of 1-(4-hydroxy-phenyl)-3-phenyl-propan-1-one from Example K (6.9 g, 30.5 mmol), and cesium carbonate (19.9 g, 61 mmol) was dissolved in dioxane (300 mL). This mixture was heated to reflux for 1 hour then treated with iodoethanol (2.85 mL, 36.5 mmol) and refluxed overnight; the reaction mixture was cooled and concentrated. The product was partitioned between EtOAc and 1N HCl. The organic layer was dried (MgSO4) and concentrated to dryness. Purification by silica gel chromatography, eluting with EtOAc:hexane (30:70 to 50:50) gave the title compound, m.p. 41-43° C. 1H NMR (CDCl3) δ 1.96 (t, 1 H), 3.02 (t, 2 H), 3.22 (t, 2 H), 3.95 (m, 2 H), 4.10 (m, 2 H), 6.92 (d, 2 H), 7.15-7.28 (m, 5 H), 7.90 (d, 2 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH3:14])[CH2:13][O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)C>O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:14][C:11]([OH:12])([CH3:13])[CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(CCOCc2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(O)(CCOCc1ccccc1)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2-[2-(Benzyloxy)ethyl]-2-methyloxirane (2.60 g, 13.5 mmol), 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (4.14 g, 14.9 mmol), tripotassium phosphate (1.15 g, 5.4 mmol) and ethanol (26 ml) were mixed and stirred at 80 to 90° C. overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→30:70) to afford the title compound as a pale yellow oil (6.16 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[O:27][CH3:28])/[C:25]#[N:26])=[CH:19][C:17]=2[CH:18]=1.Cl.C[OH:31]>[OH-].[Na+]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[O:27][CH3:28])/[C:25]([NH2:26])=[O:31])=[CH:19][C:17]=2[CH:18]=1
Reactant: CO/C(C#N)=C\c1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CO/C(=C\c1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(N)=O

Procedure:
A solution of (Z)-3-[2-(5-methyl-2-phenyl-4-oxazolyl) methyl- 5-benzofuranyl]-2-methoxy-2-propenenitrile (0.10 g, 0.27 mmol) in methanol (10 ml) and sodium hydroxide (2 ml) was heated to reflux for 3 hours then cooled, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (ethyl acetate/methanol/acetic acid, 75:1:1) and obtained as a solid (31 mg, m.p. 166°-169° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC(S(=O)(=O)c3cccc(Cl)c3)CC2)nc1
Yield: 27.6 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-5-nitropyridine (122 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (40 mg), a yellow solid, in 28% yield.