Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9](N)=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]1=[O:23])[CH:2]=[CH2:3].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[CH2:28]([O:27][C:25]([C:9]1[N:8]=[C:7]2[N:6]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:5](=[O:23])[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]2=[CH:11][CH:10]=1)=[O:26])[CH3:29]
Reactant: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(N)ccc21
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(C(=O)OCC)ccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 1 g. of amino product produced in Example 35 in 20 ml. of dry pyridine. Cool in an ice-bath and stir while slowly adding 300 mg. of ethyl chloroformate. Allow the reaction mixture to stand at room temperature overnight. Pour the reaction mixture into ice-water and collect the crude product by filration. Crystallize the crude product from dimethyl formamide-ether.
Reaction SMILES: [CH2:1]([O:5][CH:6]([CH3:9])[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[CH2:1]([O:5][CH:6]([CH3:9])[CH2:7][O:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOC(C)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h

Procedure:
40 g of dry pyridine and 15.3 g of 2-butoxypropanol were added into a four-necked flask and ice-cooled under stirring, and 35 g of p-toluenesulfonic acid chloride was added little by little to carry out the reaction for 2 hours. Then, the reaction mixture was returned to room temperature and the reaction was further carried out for 16 hours. The reaction product was added into ice-cooled 6% HCl aq. and the mixture was stirred. The mixture was then extracted with benzene and dried over anhydrous Na2SO4. Evaporation of benzene gave (2'-butoxypropyl)p-toluene sulfonate as an oily product. Yield: 33.2 g. The NMR data of this compound are shown below.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.F[C:24]1[CH:29]=[C:28]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][N:25]=1.[Cl-].[NH4+]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([CH:11]3[CH2:12][N:9]([C:26]4[CH:27]=[C:28]([CH:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH:29]=[CH:24][N:25]=4)[CH2:10]3)=[N:14][C:15]=2[CH:21]=1
Reactant: Fc1cc(C2CCOCC2)ccn1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Clc1ccc2[nH]c(C3CN(c4cc(C5CCOCC5)ccn4)C3)nc2c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
A mixture of cesium carbonate (1.08 g, 3.31 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.23 g, 0.83 mmol), and 2-fluoro-4-(tetrahydro-2H-pyran-4-yl)pyridine (0.15 g, 0.83 mmol) in DMA (1 mL) under argon was heated to 110° C. for 18 h. The mixture was then cooled to RT, ethyl acetate and saturated aqueous ammonium chloride were added and the layers were separated. The organic layer was washed with water (2×), brine, and dried over anhydrous magnesium sulfate. The aqueous layer was then extracted with ethyl acetate (2×) and the combined extracts were washed with water (2×), brine, and added to the original organic layer. The combined organic extracts were filtered and concentrated in vacuo to give an oil that was purified by reversed phase HPLC to give an oil. This oil was partitioned between ethyl acetate and saturated aqueous sodium carbonate solution. The biphasic mixture was stirred vigorously for 30 mins, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 5-chloro-2-(1-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.16 g, 0.43 mmol, 51% yield) as a white solid. [M+1] 369. IC50 (uM) 1.169.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17]
Reactant: O=C1CNC(=S)N1
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1=Cc1cc(O)c(O)c(Cl)c1
Temperature: 100 °C

Procedure:
A solution containing 1.16 g of thiohydantoin, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 0.2 ml of piperidine in 20 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 1.0 g, mp 303°-304° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:18][N:5]2[CH:6]=[CH:7][C:8]3[C:9]([CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=3)=[C:4]2[N:3]=1.[OH-].[K+].Cl>C1COCC1.C(O)C>[CH3:1][C:2]1[CH2:18][N:5]2[CH:6]=[CH:7][C:8]3[C:9]([CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=3)=[C:4]2[N:3]=1
Reactant: CCOC(=O)c1cc2c3n(ccc-2n1)CC(C)=N3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1=Nc2c3cc(C(=O)O)nc-3ccn2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.6 %

Procedure:
To a solution of compound 7b (240 mg, 0.99 mmol) in a mixture of THF (1 mL) and ethanol (1 mL) was added a 2N aqueous KOH solution (1 mL, 2 mmol). The solution was stirred at room temperature for 6 h. After cooling at 0° C., the reaction mixture was acidified at pH=1 by addition of concentrated hydrochloric acid. The solid was collected by filtration and dried at 60° C. under vacuum to give acid 15 (210 mg, 99%); mp 325-327° C.; IR (KBr) 3500-3300, 1714, 1669, 1251 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.52 (s, 3H), 7.51 (d, J=7.5 Hz), 7.67 (s, 1H), 8.04 (s, 1H), 8.54 (d, 1H, J=7.5 Hz), 13.18 (brs, 1H); 13C NMR (100 MHz, DMSO-d6) δ 10.1, 105.2, 106.8, 107.9, 112.2, 124.2, 129.8, 130.2, 135.4, 136.0, 161.5; MS m/z 215 (M+, 44), 197 (60), 171 (100), 170 (92), 143 (14), 117 (15). Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.71; H, 4.38; N, 19.61.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH:38]([N:41]([CH3:51])[C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([CH3:40])[CH3:39]>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][C:42]([N:41]([CH:38]([CH3:40])[CH3:39])[CH3:51])=[O:50])[CH2:49][CH2:48]3)=[O:28])[C@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CC(C)N(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-isopropyl-N-methyl-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 16c) in an analogous manner as described in example 25. LR-MS: 737.4 [(M+H)+]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-(2-fluoro-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=429.0 [M+H]+.
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)([OH:18])[CH2:16][CH:15]2[CH2:27][CH:12]1[CH2:13][CH2:14]2)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)([OH:18])[CH2:16][CH:15]2[CH2:27][CH:12]1[CH2:13][CH2:14]2)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: COc1cccc(C2(O)CC3CCC(C3)C2CN(C)C)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add H2O (100 mg, 5.56 mmol) and TMSCl (361 mg, 3.34 mmol) to a solution of 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol (877 mg, 3.03 mmol) in 2-butanone (60 mL). Stir the mixture at ambient temperature for 12 hours. Concentrate the mixture under vacuum to give 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol hydrochloride as white solid (986 mg, Yield: 100%). 1H NMR (400 MHz, D2O) δ 7.23-7.27 (t, J=16.4, 1H), 7.00-7.02 (d, J=8.0, 1H), 6.95-6.96 (t, J=4.0, 1H), 6.78-6.80 (d, J=10.4, 1H), 3.71 (s, 3H), 3.05-3.19 (m, 1H), 2.52-2.58 (m, 4H), 2.14-2.26 (m, 4H), 2.09-2.14 (m, 2H), 2.05-2.06 (d, J=2.4, 1H), 1.89-1.92 (m, 1H), 1.78-1.80 (m, 1H), 1.51-1.68 (m, 4H), 1.40-1.52 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:38][CH2:37][C:21]2([O:26][CH2:25][CH2:24][N:23]([C:27]([C:29]3[N:30]=[C:31]([CH:34]([CH3:36])[CH3:35])[S:32][CH:33]=3)=[O:28])[CH2:22]2)[CH2:20][CH2:19]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:34]([C:31]1[S:32][CH:33]=[C:29]([C:27]([N:23]2[CH2:22][C:21]3([CH2:37][CH2:38][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([CH3:40])([CH3:39])[CH:9]=[O:8])[CH2:19][CH2:20]3)[O:26][CH2:25][CH2:24]2)=[O:28])[N:30]=1)([CH3:36])[CH3:35]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCCC(C)(C)CO)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCCC(C)(C)C=O)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Trifluoroacetic acid (0.059 mL) was added to a solution of (9-(9-hydroxy-8,8-dimethylnonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 103, step c) (0.37 g) in DCM (20 mL) at 0° C. under argon and the mixture stirred for 5 min before addition of Dess-Martin periodinane (0.49 g). The reaction mixture was stirred at RT for 1.25 h then was quenched by addition of saturated sodium thiosulfate solution (20 mL) and saturated sodium bicarbonate solution (20 mL) then ethyl acetate was added and the mixture stirred for 5 min. The phases were separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organic solutions were washed with saturated sodium bicarbonate solution. Acetic acid (0.066 mL) was added to the organic phase which was then dried over sodium sulphate, filtered and evaporated in vacuo to afford the crude subtitled compound as a yellow oil. Yield 0.40 g.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[N+:16]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH3:13])([CH3:14])[C:11](=[O:12])[N:2]([CH3:1])[C:3]2=[O:15])=[CH:8][CH:7]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)c2ccccc2C(C)(C)C1=O
Agent: O=S(=O)(O)O
Product: CN1C(=O)c2cc([N+](=O)[O-])ccc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
2,4,4-Trimethyl-4H-isoquinoline-1,3-dione (5 g, 24.6 mmol) [prepared according to H. Takechi et al., Synthesis. 1992, 778] was dissolved in concentrated sulfuric acid (50 ml) at 0° C. Fuming nitric acid (2.5 ml) was added dropwise over 5 min and the reaction warmed to 25° C. After stirring for 30 min at 25° C. the reaction mixture was poured into ice water (100 ml) and the organics extracted into dichloromethane (3×50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound (5.31 g, 86%).
Reaction SMILES: [CH2:1]([O:4]N1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C(C)(C)C)(C)C)C=C.[CH2:24]([O:27][NH:28][C@@H:29]1[C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][C@@H:32]([CH2:39][O:40][CH3:41])[NH:31][CH2:30]1)[CH:25]=[CH2:26]>>[CH2:24]([O:27][N:28]1[C:1](=[O:4])[N:31]2[CH2:30][C@H:29]1[C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][C@H:32]2[CH2:39][O:40][CH3:41])[CH:25]=[CH2:26]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Reactant: C=CCON[C@H]1CN[C@H](COC)C=C1C(=O)NC
Product: C=CCON1C(=O)N2C[C@H]1C(C(=O)NC)=C[C@H]2COC
Yield: 68 %

Procedure:
The title compound (0.28 g, 68%) was prepared according to the procedure described for Intermediate 13, starting from (3R,6S)-3-(allyloxyamino)-6-(methoxymethyl)-N-methyl-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 258, 0.52 g)
Reaction SMILES: [CH2:1]([C:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.[O:14]=[O+][O-].O=O.CSC>CO.ClCCl>[O:14]=[CH:2][CH2:1][C:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]1
Reactant: C=CCC1(C(=O)OC(C)(C)C)CC1
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(CC=O)CC1
Temperature: 25 °C

Procedure:
4.0 g (21.9 mmol) of tert-butyl 1-(prop-2-en-1-yl)cyclopropanecarboxylate were dissolved in 70 ml of methanol and 30 ml of dichloromethane. At −78° C., ozone in a stream of O2 was passed through the reaction solution for 45 min using an ozone generator. Once the color of the solution had changed to light blue, the reaction solution was flushed with pure oxygen until the color had disappeared again. 6.5 ml (88.9 mmol) of dimethyl sulfide were then added, and the reaction solution was slowly warmed to RT. The mixture was concentrated on a rotary evaporator and the residue was purified by chromatography on silica gel (mobile phase gradient cyclohexane/ethyl acetate 50:1, 30:1, 20:1, 10:1). This gave 1.87 g (44.1% of theory) of the target compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([OH:12])=[O:11])(=O)[CH3:2].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O1CCOCC1>[CH3:2][C:1]1[O:12][C:10](=[O:11])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[N:4]=1
Reactant: CC(=O)Nc1ccsc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2ccsc2c(=O)o1
Temperature: 25 °C
Yield: 119.4 %

Procedure:
To a mixture of 3-acetamidothiophene-2-carboxylic acid (15.1 g, 75.67 mmol) and sodium acetate (6.45 g, 78.6 mmol) in dioxane (200 mL) was added acetic anhydride (71 mL, 75.7 mmol). The reaction was refluxed 2 hours, cooled to ambient temperature and partitioned between chloroform and water. Phases were separated and the aqueous layer was extracted with chloroform. The combined organic phase was washed with water and brine, dried over magnesiuym sulfate and concentrated to leave 15.1 g of 2-methyl-thieno[3,2-d][1,3]oxazin-4-one as a brown oil which slowly solidified.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3](O)(O)[CH:4]([O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[N:16]=[CH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[NH2:33][OH:34]>N1C=CC=CC=1>[F:1][C:2]([F:31])([F:30])[C:3](=[N:33][OH:34])[CH:4]([O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[N:16]=[CH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: OC(O)(C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C(F)(F)F
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropane-2,2-diol (147c) 1.22 g, 2.8 mmol) and hydroxylamine hydrochloride (3.32 g, 48 mmol) was mixed in pyridine (85 mL, dried over 4 Å MS). The mixture was stirred at 115° C. for 30 min, after which time HPLC analysis showed complete reaction. Solvent was evaporated and the residue partitioned between ethyl acetate and water. The phases were separated and the organic phase washed twice with water, followed by brine and then evaporated. The residue was subjected to chromatography (SiO2, gradient of 10-60% Ethyl acetate in Heptane) to afford somewhat impure 1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropan-2-one oxime as a 3:7 mixture of diastereomers (0.99 g, 82%).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH:5]([C:10]1[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[N:17]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:17]2[CH:18]([C:22]([F:24])([F:23])[F:25])[CH2:19][CH2:20][CH2:21][CH:16]2[C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:45])=[O:3])[CH:11]=[C:12]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:37][CH:36]=3)[CH:13]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccc(OC)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN2C(c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(CC(C)C)C(=O)O)c3)CCCC2C(F)(F)F)cc1
Temperature: 78 °C

Procedure:
To 2-{5-[1-(4-Methoxy-benzyl)-6-trifluoromethyl-piperidin-2-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester, compound 7c (21.3 mg, 0.034 mmol) in EtOH (2 mL) was added 2M KOH (67 μl, 0.134 mmol). The reaction was heated to 78° C. for 5 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, followed by salt exchange with aqueous 1N HCl and subsequent lyophilization, gave the title compound as a white solid. (13 mg, 61%) 1H NMR (300 MHz, MeOD) δ ppm 0.89-0.99 (m, 6 H) 1.53 (dd, J=13.38, 6.59 Hz, 1 H) 1.68 (ddd, J=13.75, 7.16, 6.97 Hz, 1 H) 1.74-1.89 (m, 4 H) 1.92-2.07 (m, 3 H) 3.50-3.58 (m, 1H) 3.68 (s, 3 H) 3.67-3.82 (m, 4 H) 6.70 (d, J=8.67 Hz, 2 H) 7.01 (d, J=7.16 Hz, 2 H) 7.41-7.54 (m, 3 H) 7.68-7.77 (m, 4 H) Calcd for C33H35F6NO3 (M+H) 607.63, Found 608.4.
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH2:8][C:9]([O:11][CH3:12])=[O:10].[C:13]1([CH:19]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:20][CH2:21][CH2:22][N:23]2[C:31]3[C:26](=[C:27]([OH:32])[CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CN(C=O)C>[C:33]1([CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:20][CH2:21][CH2:22][N:23]2[C:31]3[C:26](=[C:27]([O:32][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc2c1CCN2CCOC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1CCN2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Under argon atmosphere, potassium t-butoxide (586 mg) and methyl bromoacetate (2.50 ml) were added to 1-(2-(diphenylmethoxy)ethyl)-4-hydroxyindoline (855 mg) in DMF (15 ml), and the obtained mixture was stirred at room temperature for 2 hours. To the reaction mixture, saturated aqueous ammonium chloride solution (5 ml) was added to stop the reaction and the resultant was extracted with ethyl acetate. The obtained organic layer was washed and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (571 mg, yield: 55%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Product: COc1cc2nc(NC(=O)N3CCN(c4cc(C)cc(C)c4)CC3)c(OC)nc2cc1OC
Yield: 56 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 56%). 1H NMR (300 MHz, CDCl3) δ 2.28 (s, 3H), 2.30 (s, 3H), 3.26 (m, 4H), 3.77 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 4.13 (s, 3H), 6.59 (s, 3H), 7.14 (s, 1H), 7.27 (s, 1H).
Reaction SMILES: [CH3:1][O:2][P:3]([O:7]/[C:8](/[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[C:13]([Cl:19])[CH:12]=1)=[CH:9]\[Cl:10])([O:5][CH3:6])=[O:4].[CH2:20]([OH:25])[CH2:21][CH:22]([OH:24])[CH3:23]>>[CH2:20]([OH:25])[CH2:21][C@H:22]([OH:24])[CH3:23].[CH3:6][O:5][P:3]([O:7]/[C:8](/[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[C:13]([Cl:19])[CH:12]=1)=[CH:9]\[Cl:10])([O:2][CH3:1])=[O:4]
Reactant: CC(O)CCO
Agent: COP(=O)(OC)O/C(=C\Cl)c1cc(Cl)c(Cl)cc1Cl
Product: C[C@@H](O)CCO

Procedure:
The microorganisms usable in the present invention include those belonging to the genera Rhodococcus, Gordona and Streptomyces and capable of acting on an enantiomorphic mixture of 1,3-butanediol so as to leave (R)-1,3-butanediol as such and those belonging to the genera Rhodococcus and Gordona capable of acting on an enantiomorphic mixture of 1,3-butanediol so as to leave (S)-1,3-butanediol as such.