Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N+:13]([O-])=O.[NH4+].[Cl-]>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[NH:13][CH:2]=[CH:1]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Vinylmagnesium bromide (1 M in THF, 681.5 mL) was added to a solution of 1-bromo-4-fluoro-2-nitrobenzene (D39) (52.0 g) in anhydrous THF (500 mL) dropwise at −78° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (3×200 mL). The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography on silica gel to afford 7-bromo-4-fluoro-1H-indole (D40) (20.0 g) as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1C(O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>Cl.O1CCOCC1.CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
(2S)-1-(tert-Butoxycarbonyl)-2-(1-hydroxy-2-phenoxyethyl)-pyrrolidine (1.93 g) was dissolved in 31 ml of 4N hydrochloric acid/1,4-dioxane, and the mixture was,stirred at room temperature for 0.5 hour. The reaction mixture was concentrated to dryness, and the residue obtained was dissolved in DMF (15 ml), after which N-(tert-butoxycarbonyl)-L-proline (1.36 g), N-methylmorpholine (0.69 ml), and HOBt (1.02g) were added thereto. After the reaction mixture was cooled to -25° C., DCC (1.30 g) was added thereto, and the mixture was stirred at -25° C. to 0° C. for 3 hours, and then at room temperature for 16 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, and saturated brine successively, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 2.10 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.CC1C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:31][CH2:32][F:33])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCF)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
1-tert-Butoxycarbonyl-3-oxopiperazine (21.6 g) was dissolved in dry DMF (500 ml) and poptassium tert-butoxide (24.2 g) was added. The mixture was stirred at ambient temperature for 30 minutes, then 1-(4-methylphenylsulfonyloxy)-2-fluoroethane (see J. Med. Chem. (1980), 23(9), 985-90 for outline of synthesis, 25.9 g) added, and stirring continued at the same temperature for 24 hours. Solvent was evaporated, and the residue partitioned between ethyl acetate and water. The organic layer was washed with water and evaporated. The residue was dissolved in isopropanol and diluted with iso-hexane, precipitating unchanged piperazinone starting material, which was removed by filtration. The solution was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 50% isopropanol in iso-hexane. Relevant fractions were combined and evaporated to give 1-tert-butoxycarbonyl-4-(2-fluoroethyl)-3-oxopiperazine (6.74 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.O>C(Cl)Cl>[CH3:21][O:22][CH2:23][O:11][C:5]1[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(Br)cc1C(C)=O

Procedure:
To a solution of 2-acetyl-4-bromophenol (3.63 g, 16.9 mmol) in methylene chloride (20 ml) on ice bath were added diisopropylethylamine (5.88 ml, 33.8 mmol) and chloromethyl methyl ether (1.92 ml, 25.3 mmol) with stirring. The mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give 4-(methoxymethyl) oxy-3-acetylbromobenzene (4.35 g, quantitatively).
Reaction SMILES: [Li]CCCC.C[N:7]([CH3:12])[CH2:8][CH2:9]NC.N1C=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])C=1.IC.[Na+].[Cl-]>C1COCC1>[CH3:17][C:16]1[CH:9]=[CH:8][N:7]=[CH:12][C:15]=1[CH:19]=[O:20]
Reactant: O=Cc1cccnc1
Reactant: CNCCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccncc1C=O
Reaction time: 0.25 h

Procedure:
n-BuLi (1.6M in hexanes) (2.2 mmol, 1.37 ml) was added dropwise to a stirred solution of N,N,N'-trimethylethylenediamine (2.4 mmol, 0.245 g) in THF at -78° C. A solution of 3-pyridinecarboxaldehyde (2 mmol, 0.214 g) in THF was added and the mixture stirred for 15 min before adding a further portion of n-BuLi (1.6M in hexanes) (4 mmol, 2.5 ml). After stirring for 2 h at -70° C., iodomethane was added, the mixture stirred at RT for 30 min, then poured into aqueous NaCl solution, extracted twice with Et2O, dried (MgSO4), filtered and concentrated in vacuo. The residue was subjected to chromatography (SiO2 ; Et2O) to afford the title compound as an oil.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](Cl)(Cl)=[O:7].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)O
Reactant: Cc1cccc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 89 %

Procedure:
14.8 g (200 millimoles) of t-butanol and 29 ml of ethyl acetate were added to a reaction system followed by blowing in 9.9 g (100 millimoles) of phosgene. A mixed solution containing 5.48 g (50.7 millimoles) of 2-amino-6-picoline, 12.5 g (97.0 millimoles) of N,N-diisopropylethylamine and 32 mL of ethyl acetate was dropped into this solution over the course of 1.5 hours while holding the internal temperature at −15° C. to −5° C. Following completion of dropping, the solution was stirred for 1 hour. Next, 50 mL of water and 5.1 g of 28% sodium hydroxide were sequentially added while holding the internal temperature at 0° C. or lower. After separating the liquid, the aqueous phase was extracted with ethyl acetate. The organic phases were combined and mixed, and a portion of the organic phase was sampled and subjected to quantitative analysis by HPLC. The target (6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained at a yield of 89%. The yield of 1,3-bis-(6-methyl-pyridin-2-yl)-urea (urea compound) was 8%. Furthermore, the yield of the urea compound was based on the raw material 2-amino-6-picoline and was calculated using 2 molecules of 2-amino-6-picoline for 1 molecule of the urea compound (and was similarly calculated in the subsequent examples and comparative examples).
Reaction SMILES: CS(O/[N:6]=[C:7]1\[CH2:8][CH2:9][C:10]2[C:15]\1=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)(=O)=O.B(F)(F)F.CS(Cl)(=O)=[O:24].C(Cl)Cl>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:6][C:7]2=[O:24])=[CH:11][CH:12]=1
Reactant: COc1ccc2c(c1)/C(=N/OS(C)(=O)=O)CC2
Reactant: CS(=O)(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: FB(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
To the solution of intermediate 17 (7.76 g, 30.4 mmol) in 1,2-dichloroethane (150 mL) was added BF3 (5.52 mL, 48.7 mmol, in MeOH), MsCl (3.8 mL, 48.7 mmol) and TiCl4 (5.35 mL, 48.7 mmol). The mixture was stirred at rt for 5 h. CH2Cl2 (150 mL) was then added to the reaction mixture. The solution was washed with water and brine. The water layer was neutralized by aqueous Na2CO3 to pH=7 and was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel column (elution with PE/EtOAc=4:1) to give 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (intermediate 18) (5.1 g, 95%) as a white solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(/C=C\C2C=CC=CC=2)C=CC=CC=1.C1(/C=C/C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Agent: C(=C/c1ccccc1)\c1ccccc1
Agent: C(=C\c1ccccc1)\c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(CCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.34 g (7.5 mmol) of diphenylacetylene (1), 4.01 mL (225 mmol) of distilled water and stainless steel balls (25 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 6 hours at 650 rpm (reversed every 30 minutes). After the lapse of 6 hours, 200 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The filtrate was concentrated, thereby providing reaction products. The confirmation by 1H-NMR thereof revealed that a mixture of cis-1,2-diphenylethylene (26), trans-1,2-diphenylethylene (27) and 1,2-diphenylethane (2) was obtained at a mixing ratio of 92/0/8. The yield was 92%. The reaction is expressed by the following scheme.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:3]1=2.S(Cl)([Cl:22])=O>>[Cl:22][C:17]([C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)=[O:19]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Heat a solution of 5 gm. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid and 40 ml. of thionyl chloride under reflux for 20 minutes. Evaporate the reaction mixture under vacuum to dryness. Repeat the evaporation with two 30 ml. portions of carbon tetrachloride. Crystallize the residue from diisopropyl ether to obtain the title product.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].O=O.C1(OC)C=CC=CC=1>[Cu]I.O>[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12]([C:1]#[N:2])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: [C-]#N
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: O=O
Agent: [Na+]
Solvent: O
Solvent: COc1ccccc1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 155 °C

Procedure:
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (1.47 g, 7.7 mmol), powdered sodium cyanide (1.87 g, 37.0 mmol, 97% purity), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (7.50 g, 30.9 mmol), oxygen-free 3,5-lutidine (1.98 g, 18.5 mmol) and oxygen-free anisole (15 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was heated at about 155° C. for 12 h and allowed to cool to room temperature overnight. The solid reaction mixture was heated at 155° C. for 2 h, and then more anisole (15 mL) and powdered sodium cyanide (0.779 g, 15.4 mmol) were added to the mixture. The reaction mixture was taken out of the glovebox, heated at about 115° C. and water (45 mL) was added over 5 minutes. After cooling to room temperature, the reaction mixture was filtered. The solid collected was washed with water (2×15 mL) and toluene (2×15 mL), and then dried in a vacuum-oven at 40° C. to give the title compound as an off-white solid (5.53 g).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C-:11]#[N:12].[Na+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[C:11]([CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:12]
Reactant: [C-]#N
Reactant: CCOC(=O)C[C@H](O)CCl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CC#N

Procedure:
To a well stirred solution of ethyl (S)-4-chloro-3-hydroxybutyrate (8.25 g, 50 mmoles) in 300 mM potassium phosphate buffer, 300 mM NaCN pH 8.0 (1 L) at 30° C. was added halohydrin dehalogenase SEQ ID NO: 14 (9 g) as a lyophilized powder. After fifty seven hours the mixture was washed with ethyl acetate (2 times 250 mL) and the combined organics dried over anhydrous sodium sulfate. The mixture was filtered and evaporated on a rotary evaporator to give essentially pure ethyl (R)-4-cyano-3-hydroxybutyrate, as determined using the gas chromatography method and elution time data described in Example 6, hereinbelow.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[I:11][C:12]1[C:16]([CH2:17][OH:18])=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:13]=1.C(N(CC)CC)C>ClCCl>[I:11][C:12]1[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:13]=1
Reactant: OCc1cn(C2CCCCO2)nc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cn(C2CCCCO2)nc1I
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and. To a stirred solution of oxalyl chloride (18.576 g, 146.35 mmol, 3.01 equiv) in anhydrous dichloromethane (300 mL) maintained under nitrogen at −78° C. was added DMSO (15.138 g, 193.75 mmol, 3.98 equiv) dropwise. The reaction mixture was stirred at −65° C. for 30 min. A solution of (3-iodo-1-(oxan-2-yl)-1H-pyrazol-4-yl)methanol (15.0 g, 48.68 mmol, 1.00 equiv) in dichloromethane (100 mL) was then added dropwise at −65° C. and the reaction was stirred for another 60 min at −65° C. Triethylamine (40.6 mL) was added dropwise at −65° C. and the reaction was stirred for 30 min at −65° C. The reaction was warmed to 0° C. then quenched by the addition of 100 mL of saturated NH4Cl solution. The resulting mixture was extracted with 3×400 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:20) to give 13.48 g (90%) of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde as a golden oil. 1H NMR (300 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.57 (s, 1H), 5.49 (dd, J=2.7 Hz, 9.9 Hz, 1H), 3.95-3.91 (m, 1H), 3.68-3.62 (m, 1H), 2.11-2.01 (m, 3H), 1.69-1.62 (m, 3H) ppm. LCMS (method A, ESI): RT=1.35 min, m/z=307.0 [M+H]+.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.[I-:17].[K+]>CN(C)C=O>[I:17][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(I)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-[(methylsulphonyl)oxy]-1-azetidinecarboxylate (Synlett; 1998; 379), (5.0 g, 19.9 mmol), and potassium iodide (16.5 g, 99.4 mmol) in N,N-dimethylformamide (25 ml), was heated at 100° C. for 42 hours. The cooled mixture was partitioned between water and ethyl acetate, and the layers separated. The organic phase was dried (MgSO4), concentrated under reduced pressure and the residue azeotroped with xylene. The crude product was purified by column chromatography on silica gel using dichloromethane as eluant, to give the title compound, 3.26 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.C([O-])(=O)C.[Na+].Cl.[NH2:20][OH:21]>C(O)C.O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:20][OH:21])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCCC2=NO

Procedure:
Dissolve 100 g (0.57 mol) of 6-methoxy-1-tetralone in 2.5 litres of a mixture of ethanol/water: 80/20. There are then added, at ambient temperature, 85 g (1.04 mol) of sodium acetate and 43 g (0.62 mol) of hydroxylamine hydrochloride. Heat the suspension at reflux for 4 hours. Dilute the mixture with 5 litres of water and extract with ethyl ether, wash with water, dry over magnesium sulphate and filter. After evaporating off the solvent, 99 g of a beige solid are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:26])[CH:14]3[NH:18]C(OC(C)(C)C)=O)[C:11]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:26])[CH:14]3[NH2:18])[C:11]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Yield: 85.9 %

Procedure:
3-(2-Acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.6 g) is dissolved in acetonitrile (190 cc) at 35° C. and treated with p-toluenesulphonic acid (monohydrate) (2.9 g) dissolved in acetonitrile (20 cc) for 3 hours at 35° C. and 16 hours at 25° C. and then for a further 6 hours at 35° C. after having added further p-toluenesulphonic acid (monohydrate) (0.95 g). The reaction mixture is partially concentrated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. and then diluted with methylene chloride (200 cc) and saturated sodium bicarbonate solution (200 cc). The aqueous layer is extracted with methylene chloride (100 cc) and the combined organic solutions are washed with water (200 cc) and then dried and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is dried under reduced pressure (10 mm Hg; 1.3 kPa) at 25° C. Crude 3-(2-acetamido-thiazol-5-yl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) is obtained in the form of a beige powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15]=O.[Na+].[Cl-].N>O.C1COCC1>[NH2:10][C@H:11]([C:12]([OH:14])=[O:13])[CH2:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=O
Reactant: NCC(=O)O
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 30 °C

Procedure:
A 100 g of the frozen cells of Escherichia coli K-12 SH1001 prepared in Preparation Example 2 and 100 g of the frozen cells of Escherichia coli K-12 YK2009 (FERM BP-3244) prepared in Preparation Example 3 were suspended in 500 ml of the reaction solution (adjusted to pH 9.5 with 25% ammonia) containing 0.1 g of indole, 7.5 g of glycine, 1.6 g of formalin (formaldehyde content: 37%), 100 mg of PLP, 1.0 g of THF and 2.3 g of NaCl, and then water was added to make the total amount of the suspension 1,000 ml. This suspension was poured into a 3-liter jar fermentor (mfd. by Able Inc.) and reacted with stirring at 30° C. The pH of the reaction solution was adjusted to maintain at 9.5 with 25% ammonia throughout the reaction. Also, indole was added continuously or intermittently so that the indole concentration wouldn't exceed 2 mmol/l while monitoring the indole concentration in the reaction solution by a high-performance liquid chromatograph (mfd. by Shimazu Corp.). Also, glycine and formaldehyde were added continuously or intermittently so that the L-serine concentration in the reaction solution wouldn't exceed the designated levels in the respective test sections shown in Table 1 while monitoring the L-serine concentration in the reaction solution by a high-performance liquid chromatograph (mfd. by Shimazu Corp.). Glycine was added in a total amount of 22.5 g. The L-tryptophan concentration in the reaction solution was monitored by a high-performance liquid chromatograph (mfd. by Shimazu Corp.). The yield (mol %) of L-tryptophan after the end of the reaction, based on the glycine added in the reaction solution, is shown in Table 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28]CC[Si](C)(C)C)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.CC1C(C)C=C(C2C=CC(C)=CC=2)C2C=C(C(OC3C=CC(C(OCC[Si](C)(C)C)=O)=CC=3)=O)C=CC1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:35][CH:36]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)OCC[Si](C)(C)C)cc4)cc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(C2=CC(C)C(C)c3ccc(C(=O)Oc4ccc(C(=O)OCC[Si](C)(C)C)cc4)cc32)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 110.0 mg (0.213 mmol) 2-trimethylsilylethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]oxy]benzoate (Compound 38) and 167.3 mg of tetrabutylammonium flouride (0.640 mmol, 0.64 ml of a 1M solution in THF) in 2.0 ml THF was stirred at room temperature for 22 hours. Ethyl acetate was added and the resulting solution washed with H2O and saturated aqueous NaCl then dried over MgSO4. Removal of the solvents under reduced pressure and washing of the residual solid with EtOAc and CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.10 (2H, d, J=8.8 Hz), 8.06 (1H, dd, J=2.0, 8.1 Hz), 7.82 (1H, d, J=1.9 Hz), 7.64 (1H, d, J=8.1 Hz), 7.35 (2H, d, J=8.6 Hz), 7.25 (4H, m), 6.08 (1H, t, J=4.7 Hz), 2.42 (2H, d, J=4.7 Hz), 2.35 (3H, s), 1.39 (6H, s).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])[C:7]([CH3:20])([CH3:19])[CH2:6]1)[CH:2]=[CH2:3].[CH3:21][SiH:22]([CH3:24])[CH3:23]>C(O)(C)C>[OH:18][C:15]([CH3:17])([CH3:16])[CH2:14][O:13][N:8]1[C:7]([CH3:20])([CH3:19])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH2:3][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:10][C:9]1([CH3:12])[CH3:11]
Reactant: C[SiH](C)C
Reactant: C=CCOC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Solvent: CC(C)O
Product: CC(C)(O)CON1C(C)(C)CC(OCCC[Si](C)(C)C)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound prepared in Example 17 with trimethylsilane and hydrogen hexachloroplatinate(lV) in isopropyl alcohol.