Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O>[CH2:22]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH:21]=[CH2:20]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 45.8 g (0.20 mole) 2-hydroxy-4-(benzyloxy)benzaldehyde in 250 mL of dimethylformamide was added dropwise over 1 hour to a slurry of 10.6 g (0.26 mole) of 60% sodium hydride/mineral oil dispersion in 100 mL of dimethylformamide. The mixture was stirred under nitrogen for 1 hour at room temperature, and then 28 mL (0.33 mole) of allyl bromide in 30 mL of dimethylformamide was added. The reaction was heated at 60° C. for 4 hours under nitrogen. The solvent was then removed in vacuum and replaced with 500 mL of ethyl acetate. This solution was washed with 500 mL portions of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to give 53.6 g (100%) of the title compounds as a pale yellow solid. 1H-NMR (d6-DMSO): singlet 10.2 δ (1H); doublet of doublets 7.65 δ (1H); multiplet 7.40 δ (5H); doublet 6.80 δ (1H); doublet of doublets 6.75 δ (1H); multiplet 6.05 δ (1H); doublet of doublets 5.45 δ (1H); doublet of doublets 5.30 δ (1H); singlet 5.20 δ (2H); multiplet 4.70 δ (2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:17]([NH:16][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])=[C:18]([CH:23]=1)[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)s1
Product: O=C(Nc1ccc(Cl)cc1C(=O)O)c1ccc(-c2ccc(F)cc2)s1
Yield: 47 %

Procedure:
Using the same method as in Example 3-(i), methyl 5-chloro-2-({[5-(4-fluorophenyl)thiophen-2-yl]carbonyl}amino)benzoate was obtained using 5-(4-fluorophenyl)thiophen-2-carboxylic acid and methyl 2-amino-5-chlorobenzoate. Thereafter, using the same method as in Example 3-(ii), the target 5-chloro-2-({[5-(4-fluorophenyl)thiophen-2-yl]carbonyl}amino)benzoic acid was obtained (yield: 47%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Product: CC1(C)CCC(=O)CC1
Yield: 90.3 %

Procedure:
To 0.1 g of palladium on activated carbon (10%) was added a solution of 4,4-dimethylcyclohex-2-enone (6.23 g, 50 mmol) in petroleum ether. This mixture was stirred under 1 atmosphere of hydrogen for 20 hours. After filtration through celite, the solvent was removed under reduced pressure to afford a white solid (5.7 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:42])[CH:14]([OH:41])[CH:15]([CH3:40])[C:16](=[N:38][OH:39])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:43].[Na].Cl.[N+](=[CH2:48])=[N-]>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:42])[CH:14]([OH:41])[CH:15]([CH3:40])[C:16](=[N:38][OH:39])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:4]([C:5]([O:7][CH3:48])=[O:6])[C:3]=1[OH:43]
Reactant: CCC(C(=NO)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reactant: C=[N+]=[N-]
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Product: CCC(C(=NO)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)OC)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
A solution of 3.55 g of (-)-3-methyl-6-{7-ethyl-4-hydroxy-6-hydroxyimino-3,5-dimethyl-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}salicylic acid, sodium salt in 100 ml methylene chloride was treated with 1N HCl. The solvent layer was separated, washed with water and concentrated under reduced pressure to a solid. A portion (1.3 g) of the solid, equal to 2.15 millimole, was dissolved in ether and treated with 4.25 millimole of an ethereal solution of diazomethane. At the end of 1 hour the solvent was removed at reduced pressure leaving an oil which upon standing under a high vacuum solidified to yield 3-methyl-6-{7-ethyl-4-hydroxy-6-hydroxyimino-3,5-dimethyl-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}salicylic acid, methyl ester, isomer A; [α]D25 + 5.77° (1.03%, CH3OH).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][O:6][CH2:7][C:8]12[CH:19]3[CH2:20][C:15]([CH:27]=[O:28])([C:16]1([C:24]([O-:26])=[O:25])[C:17]([CH:21]([CH3:23])[CH3:22])=[CH:18]3)[CH:14]1[CH:10]([CH:11]([CH3:29])[CH2:12][CH2:13]1)[CH2:9]2.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]12[CH:19]3[CH2:20][C:15]([CH:27]=[O:28])([C:16]1([C:24]([OH:26])=[O:25])[C:17]([CH:21]([CH3:22])[CH3:23])=[CH:18]3)[CH:14]1[CH:10]([CH:11]([CH3:29])[CH2:12][CH2:13]1)[CH2:9]2
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COCC#CCO)C13C(=O)[O-]
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COCCCCO)C13C(=O)O

Procedure:
The alcohol obtained above was dissolved in methanol and palladium hydroxide on carbon (Pearlman's catalyst) was added. The reaction mixture was stirred under one atmosphere of hydrogen for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound. 1H NMR (CDCl3): δ0.82 (3H, d, J=6.9), 0.95 (3H, d, J=6.7), 1.02 (3H, d, J=6.8), 1.20-2.10 (15H, m), 2.33 (1H, m), 2.37 (1H, m), 3.26-4.00 (6H, m), 6.02 (1H, m), 9.88 (1H, s).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:20]Cl>C(O)(=O)C>[Cl:20][C:8]1[CH:7]=[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: ClCl
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc2c1OCC2
Solvent: CC(=O)O
Product: CC(C)(CC(=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Yield: 100 %

Procedure:
A solution of 4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (20.8 g, 76.2 mmol) in 200 mL of acetic acid was treated with a solution of chlorine gas in acetic acid (˜1.19 M). The reaction was monitored by 1H-NMR. The mixture was quenched with 500 mL of water and solid sodium bicarbonate (˜500 g) was added carefully during 1 hour. The mixture was poured onto 500 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with three 500 mL portions of ethyl acetate. The combined organic layers were washed with two 100 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 23.4 g of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (100%), which was used without purification.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:22][OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[NH:25][CH:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:36][CH3:37].C(O)CCC.C(N(CC)CC)C>>[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:25][C@@H:26]3[C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[CH2:28][C@@H:27]3[O:36][CH3:37])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:22][OH:23])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC1Cc2cc(Cl)ccc2C1NCl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2cc(Cl)ncn2)C[C@H]1CO
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Temperature: 148 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-chloropyrimidin-4-yl)oxy]cyclopentyl}methanol (15) (11.2 g, 0.0312 mol) and N,5-dichloro-2-methoxy-2,3-dihydro-1H-inden-1-amine (9.00 g, 0.0384 mol) in 1-butanol (99.2 mL, 1.09 mol), in a 350 mL sealable reaction vessel, was added triethylamine (21.7 mL, 0.156 mol). The vessel was sealed and then heated with stirring to 148° C. in an oil bath for 72 hours. The vessel was cooled to room temperature and the volatiles were removed in vacuo and Et2O (200 mL) was added to the resulting residue. The solids were homogenized by sonication, filtered, and rinsed with Et2O (50 mL). To the filtrate was added Celite® (100 mL) and the volatiles were removed in vacuo. The product adsorbed onto Celite® was added to a dry load cartridge and purified via column chromatography (400 g column, eluent 0-80% EtOAc:hexanes over 80 min) to afford {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (11.5 g, 71%). LCMS: (FA) ES+ 520; 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.24-7.13 (m, 3H), 5.75 (s, 1H), 5.56 (s, 1H), 5.45 (dt, J=2.9, 5.8, 2H), 4.57 (dd, J=5.9, 11.2, 1H), 4.19 (td, J=1.3, 4.7, 1H), 3.84-3.77 (m, 1H), 3.75-3.65 (m, 1H), 3.37 (s, 3H), 3.10 (d, J=16.6, 1H), 2.97 (dd, J=4.5, 16.7, 1H), 2.58 (dd, J=4.8, 7.4, 1H), 2.43-2.32 (m, 1H), 2.23-2.06 (m, 3H), 1.90 (dd, J=8.0, 14.2, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:6]=1.O.[NH2:20][NH2:21]>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:20][NH2:21])=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(-n2cnc(Cl)c2)c(OC)c1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)NN)ccc1-n1cnc(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxybenzoate (25.5 mg) in methanol (1 mL) was added hydrazine monohydrate (0.019 mL) at room temperature, the mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (12.7 mg).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]1[CH2:16][CH2:15][O:14][CH2:13]1)=[O:10].Cl.[C:18]([C:20]1[CH:37]=[CH:36][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:34])[CH3:33])[NH2:31])[CH3:27])=[CH:22][CH:21]=1)#[N:19].O>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:33])[CH3:34])[NH:31][C:9]([O:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[O:10])[CH3:27])=[CH:36][CH:37]=1)#[N:19]
Reactant: O=C(Cl)OC1CCOC1
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)OC1CCOC1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
1.0 g of N-methylmorpholine, and subsequently 0.7 g of 3-tetrahydrofuranyl chloroformate were added to a suspension containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 100 ml of methylene chloride at -20° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of white powder (yield: 61%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].CCN(CC)CC.Br[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH2:21][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrCC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
To a stirred solution of N-hydroxyphthalimide (10.0 g, 61.30 mmol) in DMF (40 mL) at RT was added NEt3 (9.40 mL, 67.43 mmol) and, in a dropwise fashion, (bromomethyl)cyclohexane (9.41 mL, 67.43 mmol). The reaction was then stirred for 15 hours at 50° C., after which it was allowed to cool to RT and then concentrated under vacuum. The residue was dissolved in Et2O (100 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1 to 3:1) to afford N-(cyclohexylmethoxy)phthalimide (8.40 g, 53%), as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]([NH:20][C@H:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH3:22])=[O:19])[CH:11]=[CH:10]2)[CH2:4][CH2:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:47](=O)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[OH-].[Na+]>O.ClCCl>[CH2:47]([N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]([NH:20][C@H:21]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[CH3:22])=[O:19])[CH:11]=[CH:10]2)[CH2:6][CH2:7]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(CC4CCNCC4)c23)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(CC4CCN(Cc5ccccc5)CC4)c23)cc1
Reaction time: 72 h
Yield: 72.2 %

Procedure:
To a mixture of methyl 4-[(1S)-1-({[1-(piperidin-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate hydrochloride (150 mg) and dichloromethane (2.0 mL) were added sodium triacetoxyborohydride (210 mg) and benzaldehyde (70 mg) at room temperature, followed by stirring for 3 days. To the reaction mixture was added water. In addition, the mixture was alkalified by adding a 1 M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 4-{(1S)-1-[({1-[(1-benzyl piperidin-4-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoate (121 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[CH3:15][NH:16][O:17][CH3:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([N:16]([O:17][CH3:18])[CH3:15])=[O:8]
Reactant: COc1cc(Br)cc(C(=O)Cl)c1Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Product: COc1cc(Br)cc(C(=O)N(C)OC)c1Cl
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To a solution of acid chloride 59 (3.41 g, 14.3 mmol) in CH2Cl2 (70 mL) was added dropwise N,O-dimethylhydroxylamine hydrochloride (4.18 g, 42.9 mmol) at 0° C. under an atmosphere of nitrogen. Then, TEA (12.0 mL, 85.8 mmol) was added to the mixture at 0° C. After being stirred for 18 hours, the mixture was partitioned between EtOAc (150 mL) and water (100 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the product 60 (3.45 g, 80%) as a white solid.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>CO>[CH2:1]([NH:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCNc1cccc(O)c1
Yield: 57 %

Procedure:
0.11 mol of n-butyl bromide and 0.1 mol NaHCO3 are added to 0.1 mol of m-aminophenol in 150 ml of methanol, and the mixture is refluxed for 5 h. After cooling, it is filtered and the solvent is removed in vacuo. The oil which remains is fractionated in vacuo, to give 3-(n-butylamino)phenol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[N:5][O:4][CH3:3])[C:7]1=[O:15])[CH3:17]
Reactant: CON=C1C(=O)Nc2ccccc21
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN1C(=O)C(=NOC)c2ccccc21)OCC
Temperature: 70 °C
Reaction time: 45 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (prepared by washing 50 g of 60% oily sodium hydride with hexane) in 1 l of N,N-dimethylformamide was added dropwise a solution of 176 g of 3-methoxyiminoindolin-2-one in 3 l of N,N-dimethylformamide at 0° C. in a nitrogen stream. To the mixture were added 1 l of N,N-dimethylformamide and 330 ml of bromoacetaldehyde diethyl acetal, and the mixture was heated to 70° C., at which it was stirred for 45 hours. The reaction mixture was concentrated, and the concentrate was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 284 g (97%) of 1-(2,2-diethoxyethyl)-3-methoxyiminoindolin-2-one.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C(Cl)Cl>[C:20]([O:19][C:17]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]1)=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: OCC1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5.0 g (43.4 mmol) of 3-hydroxymethyl-piperidine in 200 ml of CH2Cl2, was added 6.05 ml (43.4 mmol) of triethylamine (Et3N), followed by 9.8 ml (43.4 mmol) of (BOC2O). The reaction mixture was stirred for 1 hour at room temperature and then washed with 75 ml of a 0.1N hydrochloric acid solution (HCl), dried over Na2SO4, filtered and then concentrated in vacuo.
Reaction SMILES: O.[OH-].[K+].Br[C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[N:11][OH:12].COCCO>[Cu].ClCCl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:6]3[S:7][CH:8]=[CH:9][C:5]=3[O:12][N:11]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=NO)c2sccc2Br)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2noc3ccsc23)cc1
Temperature: 60 °C
Yield: 64 %

Procedure:
Add to a solution of water (20 mL) and potassium hydroxide (7.2 g, 0.128 mol), (3-bromothiophen-2-yl)-(4-methoxyphenyl)-methanone oxime (19.6 g, 0.0628 mol) and 2-methoxyethanol (200 mL). Stir the solution and then treat under nitrogen with copper powder (1.0 g, 0.0157 g-atom 0.25 equiv.). Heat the stirred mixture to 60° C. for four hours, and then pour into a mixture of water (800 mL) and dichloromethane (450 mL). Add hydrochloric acid (10 mL, 6N), filter the mixture, and wash the copper with dichloromethane and water. Separate the filtrate, and wash the organic phase twice with water, dry (Na2SO4), filter and evaporate. Dissolve the residue in dichloromethane and chromatograph the compound over alumina, eluted with 4:1 heptane:dichloromethane, and then with 3:1 heptane:dichloromethane. Evaporate the fractions, triturate the residue with heptane, and collect the solid and dry at 60° C. to give the title compound (9.3 g, 64% yield), m.p. 93–94° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][C:6]4=[O:14])[CH2:28][CH2:29]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: O=c1oc2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1oc2ccccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 47 %

Procedure:
A mixture of 4.7 parts of 3-(3-chloropropyl)-2(3H)-benzoxazolone, 5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The residue is boiled in a mixture of 4-methyl-2-pentanone, 2-propanol and methanol. The whole is cooled and the product is filtered off and dried, yielding 4 parts (47%) of 5-chloro-1-{1-[3-(2-oxo-3(2H)-benzoxazolyl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 212.3° C.
Reaction SMILES: [NH2:1][S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9]CC1C=CC=CC=1)=[O:8])(=[O:4])=[O:3]>CO.[Pd]>[NH2:1][S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([OH:9])=[O:8])(=[O:4])=[O:3]
Reactant: C[C@@H](CS(N)(=O)=O)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](CS(N)(=O)=O)C(=O)O
Reaction time: 24 h
Yield: 97.9 %

Procedure:
A 100 mL Fisher/Porter vessel was charged with 1.1 g of crude benzyl 3-aminosulfonyl-2(R)-methylpropionate in 35 mL MeOH and a catalytic amount of 10% Pd—C. The mixture was hydrogenated at 50 psi for 24 hours, filtered through Celite and concentrated in vacuo to yield 700 mg of 3-aminosulfonyl-2(R)-methylpropionic acid as a clear oil. The crude acid was used without further purification.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[CH2:57]([N:64]1[CH2:68][CH2:67][C:66](=[O:69])[CH2:65]1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.Cl.[OH-].[Na+]>>[CH2:57]([N:64]1[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65]1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: Cl
Agent: NC(=O)C1=CN([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)C=CC1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC1CCN(Cc2ccccc2)C1
Temperature: 30 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
The culture of the recombinant Escherichia coli HB101(pNTDRG1) as obtained in Example 8 was subjected to ultrasonic cell disruption using SONIFIRE 250 (product of BRANSON). To 20 ml of this cell disruption fluid, there were added 2 g of glucose, 1 mg of NAD and 1 g of N-benzyl-3-pyrrolidinone. This reaction mixture was stirred at 30° C. for 18 hours under a nitrogen atmosphere while adjusting the pH to 6.5 by adding 5 M hydrochloric acid and sodium hydroxide solution. After completion of the reaction, 2 ml of 5 M sodium hydroxide solution was added, and this reaction mixture was extracted with toluene. The solvent was then removed from the extract by an evaporator, and the extract was analyzed. Then, N-benzyl-3-pyrrolidinol was obtained in 96% yield. The N-benzyl-3-pyrrolidinol formed on that occasion was the R form with an optical purity of 99.9% ee.