Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Cl)nc1
Solvent: ClCCl
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 165 °C
Yield: 91.7 %

Procedure:
A mixture of 2,5-dichloropyridine (10.0 g, 67.6 mmol) and piperazine (58.1 g, 675 mmol) was stirred at 165° C. for 2 H. The mixture was allowed to cool, slurried with dichloromethane (200 ml) and the solid collected by filtration. The filtrate was concentrated in vacuo and the procedure repeated. The residue after concentration of the filtrate was purified by flash chromatography twice (eluting with 1% ammonia, 10% methanol in dichloromethane) to give 1-(5-chloro-2-pyridyl)piperazine (12.25 g, 92%) as a tan solid. A portion of this solid (0.484 g, 2.45 mmol) was added to a solution of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.392 g, 2.24 mmol) in toluene (10 ml) and the mixture heated at reflux under nitrogen for 6 h. The mixture was allowed to cool and the crystallised product filtered off. Recrystallisation from toluene gave the title compound (0.229 g, 31%), m.p. 196°-198° C.; (Found: C, 63.16; H, 5.60; N, 21.18. C17H18ClN5. 0.1PhMe requires C, 63.08; H, 5.62; N, 20.78%); δH (DMSO-d6) 2.46 (4H, t, J 5.0 Hz, 2×piperazinyl CH2), 3.45 (4H, t, J 5.0 Hz, 2×piperazinyl CH2), 3.67 (2H, s, CH2N), 6.82 (1H, d, J 9.1 Hz, 3'-H), 7.04 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.37 (1H, d, J 2.1 Hz, 2-H), 7.56 (1H, dd, J 9.1, 2.7 Hz, 4'-H), 8.05 (1H, dd, J 7.8, 1.4 Hz, 4-H), 8.08 (1H, d, J 2.7 Hz, 6'-H), 8.19 (1H, dd, J 4.6, 1.4 Hz, 6-H), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 328 [(M+H)+, ±Cl].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].CC([O-])(C)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([C:26]([F:25])([F:34])[F:35])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1coc(Nc2cccc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 7.6 %

Procedure:
In a 5 ml glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol), 3-trifluoromethyl aniline (170 mg, 1.05 mmol), t-BuOK (30 mg, 0.26 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 8.1 mg, 0.013 mmol), Pd(OAc)2 (2.9 mg, 0.013 mmol), DMF (1 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 130° C. for 4 min. The mixture was diluted with EtOAc and washed with 1N HCl and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (10 mg, 7.5%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C.C(O)C>[CH3:17][NH:18][C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution (ice bath) of N-Boc-2-morpholinecarboxylic acid (0.5 g, 2.16 mmol) in DMF (10 mL) was added HATU ((2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (0.98 g, 2.58 mmol), N,N diisopropylethylamine (2.2 g, 17.3 mmol), and 1 mL of 8 N solution of methylamine in ethanol. After the addition was finished the ice bath was removed, and the heterogeneous solution was stirred overnight at room temperature. The solution was dissolved in ethyl acetate (50 mL) and washed with a saturated solution of NaHCO3. Ethyl acetate layer was separated, dried (MgSO4) and concentrated under reduced pressure to give tert-butyl 2-(methylcarbamoyl)morpholine-4-carboxylate as an oil. MS (APCI) 245 (M+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:12]>CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH2:12])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: [NH4+]
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]ccc2c1
Yield: 63 %

Procedure:
5-bromo-1H-pyrrolo[2,3-b]pyridine (6.0 g, 30.45 mmol) in ammonium hydroxide (120 mL) was treated with copper sulphate pentahydrate (1.50 g, 6.09 mmol, 0.2 eq) and heated in a sealed tube overnight. The reaction was diluted with EtOAc and the insoluble black solid was filtered off. The filtrate was extracted (EtOAc/Water) and the organic layer washed with saturated aqueous ammonium chloride, followed by water and brine. The organics were dried over magnesium sulphate, filtered and evaporated to dryness to give the product as a pale brown solid (2.57 g, 63%)
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.C(OCC)(=O)C>[CH3:34][O:33][C:31]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:32]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(−)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg) and sodium bicarbonate (75 mg) in dry tetrahydrofuran (6 mL) at 0° C. under N2 is treated with methyl chloroformate (38 μL), and the resulting mixture is stirred at 0° C. for one hour. The reaction is then diluted with ethyl acetate (20 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 165-166° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16](F)[CH:15]=1>O1CCCC1>[CH2:1]([NH:5][C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[N+:20]([O-:22])=[O:21])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Add a solution of isobutylamine (14 mL, 0.138 mol), potassium carbonate (10.4 g, 0.075 mol) and water (50 mL) to a solution of 4-chloro-2-fluoro-nitrobenzene (11.0 g, 0.063 mol) in tetrahydrofuran (0.3 L) and stir at ambient temperature for 3 hours. Separate phases and wash organic layer with 1:1 solution of 1N HCl (aq)/saturated sodium chloride. Dry organic phase with solid magnesium sulfate, filter and concentrate under reduced pressure to give 14.5 g (0.063 mol) of the desired compound as an orange oil that solidifies upon standing.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1F

Procedure:
In a similar manner as described for example B11, 81.7 mg of 1-(bromomethyl)-2-fluorobenzene, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, and 59.7 mg of potassium carbonate in 3 ml anhydrous DMF give methyl 3-[(2-fluorobenzyl)oxy]-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate as crude material that is used for step 2 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH2:30][C@H:31]([CH2:33][OH:34])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:30][C@@H:31]([CH3:32])[CH2:33][OH:34])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and L-alaninol gave 178. MS: (ESI+) 471.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[C:14]([CH:16]=O)[N:13]=[C:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[CH3:26][NH2:27].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[CH3:26][NH:27][CH2:16][C:14]1[N:13]=[C:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH:15]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2ccc(C)cc2)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
1-[(4-Methylphenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde (1.00 g) was dissolved in methanol (30 mL), 40% methylamine methanol solution (700 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (171 mg) was added at 5-10° C., and the mixture was stirred for 30 min. 1 mol/L Hydrochloric acid was added at the same temperature, and the mixture was further stirred for 30 min. The reaction mixture was alkalified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→0:1), dissolved in ethyl acetate (10 mL), and crystallized by adding a solution (5 mL) of anhydrous oxalic acid (53 mg) in ethyl acetate to give the title compound as colorless crystals (yield 197 mg, 17%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:6])[CH3:2]>CO.[H][H].[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.4 %

Procedure:
To a solution of 765 mg of 2-(1-tert-butoxycarbonylpiperidin-4-ylidene)propionic acid ethyl ester (prepared following the method of synthesis as described in International Publication WO 99/40070) in 4 ml of methanol, 100 mg of 10% palladium-on-carbon was added, and stirred for 4 hours at room temperature, in hydrogen atmosphere. Then the reaction liquid was filtered and the filtrate was concentrated to provide 743 mg of 2-(1-tert-butoxycarbonylpiperidin-4-yl)propionic acid ethyl ester as a slightly yellowish oil. Of said product, 306 mg was dissolved in 9 ml of tetrahydrofuran and cooled to 0° C. To said tetrahydrofuran solution 150 mg of lithium aluminium hydride was added portionwise. The reaction liquid was stirred at 0° C. for an hour, sodium sulfate decahydrate was added thereto and the temperature was restored to room temperature, followed by an overnight's stirring. The reaction liquid was filtered, and the filtrate was concentrated to provide 313 mg of 2-(1-tert-butoxycarbonylpiperidin-4-yl)propanol as a yellowish oil. Of said oil, 210 mg was dissolved in 2 ml of dichloromethane and the solution was added to another −78° C. solution of 188 μl of oxaryl chloride and 359 μl of dimethylsulfoxide in dichloromethane (4 ml) over a period of 5 minutes. After 30 minutes' stirring, a solution of 993 μl of triethylamine in 0.5 ml of dichloromethane was added to the reaction liquid and the temperature of the system was restored to room temperature, followed by 25 minutes' stirring. After addition of water, the reaction liquid was extracted with ethyl acetate and the ethyl acetate layer was washed twice with water, dried over anhydrous sodium sulfate and concentrated to provide 163 mg of a pale yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=3[F:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:33]1([CH2:38][CH2:39][C:40](Cl)=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C1C=CN=CC=1)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]([C:40](=[O:41])[CH2:39][CH2:38][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=3[F:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3cc(C(=O)OCC)ccc3F)cc2)cc1
Agent: CN(C)c1ccncc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3cc(C(=O)OCC)ccc3F)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using ethyl 3-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-4-fluorobenzoate and 3-cyclopentylpropionyl chloride in the presence of DMAP as a colorless oil (15%). M+ (ESI): 553.9. HPLC, Rt: 6.39 min (Purity: 93.6%).
Reaction SMILES: O[C@@H](CC)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]([CH2:30][C:31]1[CH:32]=[C:33]([CH:48]=[CH:49][CH:50]=1)[O:34][C@H:35]([CH2:46][CH3:47])[C:36]([O:38]CC1C=CC=CC=1)=[O:37])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]([CH2:30][C:31]1[CH:32]=[C:33]([CH:48]=[CH:49][CH:50]=1)[O:34][C@H:35]([CH2:46][CH3:47])[C:36]([OH:38])=[O:37])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1
Reactant: CC[C@@H](Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1)C(=O)OCc1ccccc1
Agent: CC[C@H](O)C(=O)O
Product: CC[C@@H](Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1)C(=O)O

Procedure:
In the same manner as in Examples 1 and 2, a phenyl etherification reaction (step-1) and hydrolysis (step-2) were performed under the conditions indicated in the following Table 1. Also, phenethyl (S)-2-trifluoromethanesulfonyloxybutyrate (Example 11) and phenethyl (S)-2-para-toluenesulfonyloxybutyrate (Comparative Example 7) were produced using (S)-2-hydroxybutyric acid, n-butyl (S)-2-methanesulfonyloxybutrate (Comparative Examples 1 to 3) and n-butyl (S)-2-para-toluenesulfonyloxybutyrate (Comparative Examples 4 to 6) were produced using n-butyl (S)-2-hydroxybutrate, and methyl (S)-2-chlorobutyrate (Comparative Example 8) was produced using (S)-2-chlorobutyric acid, according to standard methods. The yields and optical purities are presented together in Table 1.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](Cl)=[C:11]([C:16]2[C:17](Cl)=[N:18][S:19][N:20]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[SH2:23].[Na].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]2[S:23][C:17]3[C:16](=[N:20][S:19][N:18]=3)[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S
Reactant: O=C(c1ccccc1)N1CCC(Cl)=C(c2nsnc2Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCc2sc3nsnc3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-benzoyl-4-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine (3.4 g, 10 mmol) in dimethylformamide was added sodiumhydrogensulfide monohydrate (1.5 g, 20 mmol) and potassium carbonate (2.0 g). The reaction mixture was stirred at room temperature for 3 h. Water (500 ml) was added and the water phase was extracted with diethylether (2×15 ml). The organic extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography, eluent: methylene chloride/ethyl acetate: 10/1, giving the title compound in 2.1 g yield.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
1.00 gram (2.21 mmol) of (−)-2-amino-2′-diphenylphosphino-1,1′-binaphthyl (the formula (1-1a)) was dissolved in 44 ml of methylene chloride, followed by the addition of 0.21 ml (2.65 mmol) of pyridine and 0.28 ml (2.43 mmol) of benzoyl chloride under 0° C. The reaction mixture was stirred at room temperature for 5 hours. To the reaction solution, 30 ml of saturated aqueous solution of ammonium chloride was added and extracted with 100 ml of methylene chloride. The extract was washed with 70 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:6 mixture of ethyl acetate and hexane) to obtain 1.16 gram of the titled compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:25]NC(=O)CCC(N)=O.[OH-].[Na+]>CN(C)C=O.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3[Br:25])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)CCC(=O)NBr
Reactant: c1ncc(-c2ccc3c(c2)OCO3)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Brc1ncoc1-c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a −78° C. solution of 5-benzo[1,3]dioxol-5-yl-oxazole (670 mg, 3.54 mmol) in dimethylformamide (5 mL) was slowly added lithium bis(trimethylsilyl)amide(3.54 mL, 1 M in THF, 3.54 mmol, 1 equiv). The reaction mixture was stirred under nitrogen atmosphere for 1 hour at −78° C., and then treated slowly with a solution of N-bromosuccinamide (630 mg, 3.54 mmol, 1 equiv) in dimethylformamide (2 mL). The resulting reaction mixture was stirred at −78° C. for 1 hour, warmed to ambient temperature and poured into a mixture methylene chloride and 1 N aqueous sodium hydroxide. The aqueous layer was exctracted with methylene chloride, and the combined organics were washed with 1 N aqueous sodium hydroxide and brine, then dried over magnesium sulfate and concentrated in vacuo to provide 5-benzo[1,3]dioxol-5-yl-4-bromo-oxazole (853 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17](OC)=[O:18])([C:13](OC)=[O:14])[CH2:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:17][OH:18])([CH2:13][OH:14])[CH2:10][C:9]=2[C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(=O)OC)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC(CO)(CO)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
Under nitrogen, a solution of 1.01 g (2.34 mmol) of 1-[2-(4-fluorophenyl)-4,4-dicarbomethoxycyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared in Step 8) in 1.5 mL of THF at -78° C. was treated with 11.6 mL (11.6 mmol) of DIBAL (1.0M in THF). The reaction was stirred at ambient temperature for 1.5 hours, quenched with acetone and aqueous NaOH, extracted with ethyl acetate, dried MgSO4), and concentrated in vacuo to give 840 mg of crude 1-[2-(4-fluorophenyl)-4,4-di(hydroxymethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene as a colorless oil: NMR (CDCl3) δ 2.82 (d, J=5 Hz, 4H), 3.04 (s, 3H), 3.86 (d, J=5 Hz, 4H), 6.94 (t, J=9 Hz, 2H), 7.11 (dd, J=5 and 9 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.77 (d, J=9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:26]=1
Reactant: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reaction time: 0.67 h
Yield: 77 %

Procedure:
To a mixture of 1-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (269) (358.2 mg, 0.87 mmol) and NH4Cl (39.4 mg, 0.74 mmol) in EtOH (8.7 mL)/water (4.3 mL) at 100° C. was added Fe (411.3 mg, 7.36 mmol) in one portion and the mixture heated to reflux with vigorous stirring for 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was dissolved in DCM, extracted with water, dried aver anhydrous Na2SO4 and concentrated under reduced pressure affording 270 (256.5 mg, 0.67 mmol, 77% yield) as a white solid. MS (m/z): (M+1) 384.2 (100%).