Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[H][H]>[Pd].C(O)C>[CH:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)=[CH2:2]
Reactant: [H][H]
Reactant: C#CC1(O)CN2CCC1CC2
Agent: [Pd]
Solvent: CCO
Product: C=CC1(O)CN2CCC1CC2
Yield: 98.7 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (5.0 g), palladium on calcium carbonate (5 % w/w, 0.5 g) and ethanol (200 ml) was stirred under an atmosphere of hydrogen until 900 ml of hydrogen has been consumed. The mixture was filtered and evaporated to give 3-ethenyl-3-hydroxyquinuclidine (5.0 g) as an oil which gave a solid on standing and was used without further purification, m.p. 76°-80° C.; NMR(DMSO-d6): 1.2(1H, m), 1.4-1.6(3H, m), 2.0(1H, m), 2.45-2.85(6H, m), 4.55(1H, s), 5.0(1H, d of d), 5.25(1H, d of d), 6.1(1H, d of d); m/z 154 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[CH3:12][CH:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:13]
Reactant: CC(C)I
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
Into a 1000-mL 3-necked round-bottom flask was placed 2-hydroxybenzaldehyde (36 g, 294.79 mmol, 1.00 equiv), 2-iodopropane (100 g, 588.26 mmol, 2.00 equiv), potassium carbonate (122 g, 882.71 mmol, 2.99 equiv) and N,N-dimethylformamide (500 g, 6.84 mol, 23.21 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 1000 mL of water. The resulting solution was extracted with 3×500 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 50 g (crude) of 2-(propan-2-yloxy)benzaldehyde as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([C:10]#[N:11])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH3:13].[H][H]>O1CCCC1>[CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([CH2:10][NH2:11])([CH3:9])[CH2:6][CH:4]([NH2:13])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Reactant: N
Reactant: [H][H]
Solvent: C1CCOC1
Product: CC1(C)CC(N)CC(C)(CN)C1
Yield: 95.1 %

Procedure:
Through a tubular reactor (diameter 16 mm, packing height 50 cm, oil-heated double jacket), installed up-stream of the hydrogenation reactor and packed with 70.0 g (100 ml) of γ-aluminum oxide in the form of 1.5 mm extrudates there were passed upwardly, per hour, 40.4 g of a 50% solution of isophoronenitrile (purity 99.0%) in tetrahydrofuran and 303.0 g of liquid ammonia at a pressure of 250 bar and a temperature of 80° C. Hydrogen was then added to the stream at a rate of 60 standard liters (2.7 moles) per hour, and the effluent from the in-line imination reactor was passed upwardly through the hydrogenation reactor at a pressure of 250 bar and a temperature of 130° C. The effluent was depressurized to standard pressure, and the ammonia was distilled off. The hydrogenation product contained, apart from tetrahydrofuran, 96.4% of isophoronediamine and 0.6% of 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane, as determined by gas-chromatographic analysis. The product obtained over an on-stream period of 121 hours was collected and separated by fractional distillation. There were obtained 2,371 g of isophoronediamine, corresponding to a yield of 95.1%.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: ClCc1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a stirred solution of N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (500 mg, 1.61 mmol) in DMF (2.5 mL) was added potassium carbonate (446 mg, 3.22 mmol). The resulting mixture was stirred at room temperature for 15 minutes. 2-Chloromethyl-pyridine hydrochloride (291 mg, 1.78 mmol) was added and the resulting mixture stirred and heated to 50° C. for 18 h. The mixture was cooled to room temperature and saturated aqueous potassium carbonate solution (15 mL) and ethyl acetate (5 mL) were added. The resulting mixture was stirred for 20 minutes. The solid was collected by filtration, washed with saturated aqueous potassium carbonate solution, ethyl acetate and isohexane and dried giving the title compound as a solid (425 mg, 60%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.29 (s, 3H), 2.86 (m, 1H), 5.33 (s, 2H), 7.16 (m, 2H), 7.34 (m, 2H), 7.55 (m, 1H), 7.62 (m, 1H), 7.81 (s, 1H), 7.86 (m, 1H), 7.98 (m, 2H), 8.36 (s, 1H), 8.60 (m, 1H), 10.00 (s, 1H); Mass Spectrum: M+H+ 401.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O)=[O:15])[CH3:12].C([O-])(=O)C.[Na+]>O>[Cl:3][C:19]1[CH2:20][CH2:21][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:17][C:18]=1[CH:9]=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1CCCCC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N1CCC(Cl)=C(C=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
POCl3 (2.18 g, 23.4 mmol) was added very slowly to dry DMF (2.7 ml) at 0° C. and the resulting mixture was stirred at 25° C. for 15 min. The reaction mixture was again cooled to 0° C., and N-ethoxycarbonyl piperidone (11.7 mmol) was added. The resulting reaction mixture was stirred at 25° C. for 3 h. It was then stirred with sodium acetate (7 g) and water (8.5 ml) and extracted with benzene. The organic layer was successively washed with water, sodium hydrogencarbonate an brine and was finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product, which was used directly in the next step without further purification. Yield: 63%.
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14]CC)=[O:13].N1P(Cl)(Cl)=NP(Cl)(Cl)=NP=1(Cl)Cl.[Br:32][C:33]1[C:34]([CH3:51])=[N:35][O:36][C:37]=1[NH:38][S:39]([C:42]1[CH:46]=[CH:45][S:44][C:43]=1[C:47](OC)=[O:48])(=[O:41])=[O:40]>C1COCC1.O>[Br:32][C:33]1[C:34]([CH3:51])=[N:35][O:36][C:37]=1[NH:38][S:39]([C:42]1[CH:46]=[CH:45][S:44][C:43]=1[C:47]([NH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]([C:12]([OH:14])=[O:13])[CH:10]=1)=[O:48])(=[O:40])=[O:41]
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Reactant: CCOC(=O)c1cccc(N)c1
Agent: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)Nc2cccc(C(=O)O)c2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
Et3N (2.27 mL, 16 mmol), ethyl 3-aminobenzoate (836 mL, 5.44 mmol) and phosphonitrilic chloride trimer (1.89 g, 5.44 mmol) were sequentially added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbonyl)thiophene-3-sulfonamide (Example 12) (1 g, 2.27 mmol) in dry THF (20 mL). The reaction was stirred at room temperature for 1 hour and cooled. Water (5 mL) was added to quench the reaction. The resulting solution was concentrated on a rotavap. The residue was diluted with EtOAc and washed with 2 N HCl (2×150 mL). The organic layer was dried (MgSO4). The solid was filtered off and the filtrate was concentrated. The residue was treated with 1 N NaOH (200 mL) and stirred at 0° C. for 15 minutes. The mixture was then acidified with conc. HCl to pH ˜1. The resulting yellow precipitate was filtered off and recrystallized from CH3CN/H2O to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (153 mg, 11.6%) as a yellowish powder, m.p. 183-185° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(O)[CH2:10][CH2:9]1)=O)(C)(C)C.COCCN(S(F)(F)[F:36])CCOC.S(=O)(=O)(O)O.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([F:36])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][C:17]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cc(C2(F)CCNCC2)ccc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid tert-butyl ester (2.8 g) was dissolved in methylene chloride (20 ml) and the mixture was cooled to −78° C. DEOXO-FLUOR (trademark) (APOLLO CO., 1.8 g) was added, and the mixture was stirred for 2 hr. Then, after stirring at room temperature for 2 hr, water was added, and the mixture was extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate(10:1-5:1)) to give a solid. 1,4-Dioxane (20 ml) and 10% aqueous sulfuric acid (5 ml) were added to the solid, and the mixture was stirred with heating at 70° C. for 1.5 hr. After completion of the reaction, the reaction system was basified (pH=9) with a 1N aqueous sodium hydroxide solution, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-fluoropiperidine (655 mg, yield 31%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)[N:5]=[N:6][CH:7]=1.[I:17]NC(=O)CCC(N)=O.C(OCC)C>CN(C)C=O>[I:17][C:14]1[N:11]2[CH:12]=[CH:13][C:8]([C:4]3[N:5]=[N:6][CH:7]=[C:2]([CH3:1])[N:3]=3)=[CH:9][C:10]2=[N:16][CH:15]=1
Reactant: NC(=O)CCC(=O)NI
Reactant: Cc1cnnc(-c2ccn3ccnc3c2)n1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cnnc(-c2ccn3c(I)cnc3c2)n1
Yield: 39.6 %

Procedure:
7-(5-Methyl-[1,2,4]triazin-3-yl)-imidazo[1,2-a]pyridine (200 mg, 0.9 mmol, 1 equiv) and N-iodosuccinamide (300 mg, 1.3 mmol, 1.4 equiv) in dimethylformamide (5 ml) was stirred at room temperature. After 3 hours diethyl ether was added and the resultant solid was isolated by vacuum filtration furnishing 120 mg of a yellow solid. MS: [M+H]+338
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Reaction time: 4 h
Yield: 65 %

Procedure:
A solution of 2-amino-3-chlorobenzoic acid (7.0 g, 0.041 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was cooled to 0° C. in a 250 mL 3-necked flask which was fitted with a magnetic stirring bar and a constant additional funnel. Bromoacetyl bromide was added dropwise over a 27 min period while keeping the internal temperature between 0° C. and 2° C. After the addition was complete, the ice-bath was removed and stirring was continued for 4 h. The reaction mixture was cooled using an ice-bath, water (100 mL) was added, and then the yellow precipitate which formed was filtered. The filtered solid was washed with water and then dried in a vacuum oven for 2 days, yielding 7.7 g (65%) of the title compound as a light yellow crystals: mp 173°-175° C.; 1H NMR (CD3OD) δ7.88 (dd, 1H, J=1.6, J=6), 7.68 (dd, 1H, J=1.2, J=6.8), 7.39 (t, 1H, J=8), 6.6 (bs, 1H, NH), 4.06 (s, 2H); 13C NMR (CD3OD) δ176.57, 168.38, 134.84, 134.40, 131.95, 130.53, 129.15, 129.05, 28.66; MS (EI, m/z) 293 (M+).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]([O-:34])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.[CH3:35][C:36]([CH3:39])([O-])[CH3:37].[K+]>>[C:36]([O:34][C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:21][CH:22]=1)=[O:33])([CH3:39])([CH3:37])[CH3:35]
Reactant: O=C([O-])c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 74.1 %

Procedure:
Following a procedure similar to that described in Example 68(a), but using 4.80 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9), 6.94 g of t-buryl 4'-bromomethylbiphenyl-2-carboxylate and 2.28 g of potassium t-butoxide, 7.50 g of the title compound were obtained as crystals, melting at 90°-91° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:24]=[S:23]1(=[O:25])[CH2:26][CH2:27][CH2:28][N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:5]([CH2:14][CH3:15])[C:6]3[C:11]([C:3]=2[C:1]#[N:2])=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)=[CH:17][CH:18]=1
Reactant: CCn1c(-c2ccc(NS(=O)(=O)CCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 70 °C
Yield: 68 %

Procedure:
A solution of 3-chloropropane-1-sulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, prepared above (3.65 g, 2.33 mmol) in DMF (100 mL) is treated with K2CO3 and heated at 70° C. for 2 h. After cooling to room temperature, the reaction mixture is diluted with H2O and extracted 3× with hot EtOAc. The hot organic layers are washed with warm H2O (3×) and saturated NaCl and dried and concentrated to a solid. Trituration (CH2Cl2/hexanes) gives 2.27 g (68%) of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:11])[CH2:9][Cl:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-].[Na+].[OH-].[K+:15].C(C1OC1)Cl>O>[C:1]([O:6][CH2:7][CH:8]1[O:11][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl-:10].[K+:15]
Reactant: C=C(C)C(=O)OCC(O)CCl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCC1CO1
Product: C=C(C)C(=O)OCC1CO1
Product: [Cl-]

Procedure:
A feed with 3-chloro-2-hydroxypropyl methacrylate (CHPMA), epichlorohydrln, and minor amounts of by-products (GMA and heavies such as polymer by-product materials) flows into an epoxidation reactor to which aqueous alkali metal hydroxides such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) and additional epichlorohydrin are added. KOH reacts with CHPMA to form glycidyl methacrylate to (GMA), water, and potassium chloride (KCl). Sodium hydroxide may be used in place of KOH, but a higher GMA yield is obtained using KOH. Preferable reaction conditions are: starting molar epichlorohydrin/CHPMA ratio of 6.0 or higher (most preferably 9.0), molar KOH/CHPMA ratio of 0.8-1.5 (most preferably 1.1, temperature of 40-80 degrees centigrade (most preferably 60-65 degrees Centigrade), and a pressure of less than atmospheric (typically 150-200 mm Hg absolute). Preferably, KOH is added as a 40-60 weight per cent solution in water. A vapor stream removed from the epoxidation reactor is fractionated and the overhead epichlorohydrin/water stream is condensed and allowed to separate into two liquid phases. The heavier (organic) phase is returned to the fractionation tower as reflux and from the bottom of the fractionation tower to the epoxidation reactor. (See FIG. 7 and previous description thereof). The aqueous phase is sent forward in the process in the same manner as previously described for the epoxy process to serve as wash water which removes the last traces of KCl from the GMA product before the epichlorohydrin is stripped and the product recovered.
Reaction SMILES: [Na+].[Cl-].[CH:3]([CH:5]([CH2:11][C:12]1C=CC2OCOC=2C=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].[CH:21]1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=[CH:70][C@@H:71]([C@H:73]([C@@H:75]([C@@H:77]([CH2:79]O)[OH:78])[OH:76])O)O>>[OH:4][CH2:3][C@H:5]([CH2:11][CH2:12][C:71]1[CH:70]=[CH:79][C:77]2[O:78][CH2:21][O:76][C:75]=2[CH:73]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: 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](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Reactant: CCOC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)[C@H](CO)CCc1ccc2c(c1)OCO2
Temperature: 37 °C
Reaction time: 18 h

Procedure:
Recombinant Escherichia coli HB101 (pTSBG1) (Accession Number: FERM BP-7119) was inoculated in 50 ml of 2× YT medium (containing 1.6% of tripeptone, 1.0% of yeast extract, and 0.5% of NaCl, pH=7.0) sterilized in a 500-ml Sakaguchi Flask and incubated while shaking at 37° C. for 18 hours. To 50 ml of the resultant culture solution, 0.5 g of the ethyl 2-formyl-3-(3,4-methylenedioxyphenyl)-propionate obtained in Example 1, 2.5 mg of NADP, and 0.5 g of glucose were added, and the reaction mixture was stirred at 30° C. for 24 hours. After completion of the reaction, the reaction solution was extracted with toluene and the extract was concentrated to obtain 0.49 g of a blown oily substance. The chemical purity and optical purity of the product were analyzed in the same manner as in Example 9. The chemical purity was 96.8% and the optical purity was 43.0% ee. The product had an (S) configuration.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([O:22][CH3:23])=[CH:20]C=[CH:18][N:17]=3)[CH2:12][CH:11]2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.COC1C(N2CCNCC2)=[N:44]C=NC=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:21]([O:22][CH3:23])=[CH:20][N:44]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Reactant: COc1cncnc1N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCCc2csc3ccccc23)CC1

Procedure:
The title compound was prepared (1.03 g, 74%, mp 209°-212° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thienepropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:18]4[CH:19]=[C:20]([C@H:23]([N:28]5[CH2:32][CH2:31][C@@:30]([NH:34]C(=O)OC(C)(C)C)([CH3:33])[CH2:29]5)[C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:42])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:18]4[CH:19]=[C:20]([C@H:23]([N:28]5[CH2:32][CH2:31][C@:30]([CH3:33])([NH2:34])[CH2:29]5)[C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:42])[CH3:2]
Reactant: CCOc1cc2nc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc2nc(-c3nnc4ccc([C@H](N5CC[C@](C)(N)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of tert-butyl (S)-1-((S)-1-(3-(7-ethoxy-6-fluoro quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ylcarbamate (5.406 g, 9.185 mmol) in DCM (40 mL) was added 4M HCl in dioxane (22.96 mL, 91.85 mmol) and stirred at ambient temperature for 1.5 h. The filtered precipitate was dissolved in water and basified (1N NaOH), extracted with ethyl acetate (3×200 mL), washed with brine (200 mL), dried (MgSO4), filtered concentrated under reduced pressure and the residue purified by flash chromatography (1 column volume DCM, increasing to 10% methanol/DCM over 2 column volumes, holding for 3 column volumes, then switching to 10% [10% NH4OH/Methanol]/DCM for 7 column volumes) to give (S)-1-((S)-1-(3-(7-ethoxy-6-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-amine (4.13 g, 8.45 mmol, 92.05% yield). MS APCI (+) m/z 489 (M+1) detected. Specific rotation: [α]20D=−0.87° (c=1.02, MeOH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:13]=[O:14])=[CH:3][CH:4]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(-c2ccccc2C=O)cc1

Procedure:
Methyl (4-bromophenyl)acetate (5.9 g), (2-formylphenyl)boronic acid (5.0 g) and potassium carbonate (10.8 g) were combined in a mixture of toluene and methanol [9:1] (50 mL). The resulting mixture was degassed by bubbling nitrogen though for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (1.5 g) was added and the reaction heated to reflux for 12 hours, under nitrogen. The reaction mixture was filtered through a pad of Celite, the filter pad was washed with ethyl acetate and the combined filtrates evaporated. Purification on silica, eluting with a gradient 0 to 10% ethyl acetate in iso-hexane.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:33]([O-:35])=[O:34])=[C:17]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[N:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:20]2=[O:32])[CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:9][C:10]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:33]([O-:35])=[O:34])=[C:17]([N:19]2[C:24](=[O:25])[N:23]([CH3:3])[C:22](=[O:26])[N:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:20]2=[O:32])[CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (0.15 mL, 2.41 mmol) and potassium carbonate (0.19 g, 1.34 mmol) are added to a solution of methyl 3-[5-(2,4-dichlorophenoxy)-2-nitrophenyl]tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.40 g, 0.83 mmol) in N,N-dimethylformamide. The reaction mixture is stirred overnight at room temperature and poured into a saturated ammonium chloride solution. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and an ethyl acetate/hexanes (1:3) solution gives the title product as a yellows foam which is identified by NMR spectral analysis.