Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]=O>CO.C(O)(=O)C>[CH3:14][CH:10]1[N:11]([CH3:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: C=O
Solvent: CO
Solvent: CC(=O)O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C
Temperature: 80 °C

Procedure:
tert-Butyl-3-methylpiperazine carboxylate (1.49 g, 7.45 mmol) and paraformaldehyde (1.12 g, 37.2 mmol) were dissolved in a mixture of MeOH and acetic acid (5:1) on molecular sieves. NaBCNH3 (1.88 g, 29.8 mmol) was added to the suspension at 25° C. The slurry was subsequently heated to 80° C. for 10 hr. Then the mixture was cooled, filtered, and concentrated. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The organic solution was dried over Na2SO4, and concentrated to give a white oily (1.2 g, 90%). LC-MS (ESI) m/z: 215 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.CCCCCC.[CH3:19][C:20]([S:23]([N:25]=[C:26]1[CH2:29][O:28][CH2:27]1)=[O:24])([CH3:22])[CH3:21].C[Al](C)C>C1COCC1.C1(C)C=CC=CC=1>[CH3:22][C:20]([S:23]([NH:25][C:26]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:29][O:28][CH2:27]1)=[O:24])([CH3:19])[CH3:21]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: Brc1ccccn1
Agent: C[Al](C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2ccccn2)COC1
Temperature: -100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromopyridine (0.16 g, 1.02 mmol, 1.0 eq) in dry THF at −100° C. was slowly added a solution of n-BuLi in hexane (2.5M, 0.41 ml, 1.03 mmol, 1 eq), and reaction mixture was then kept in same temperature for 30 minute. A mixture of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (0.18 g, 1.02 mmol, 1 eq) and a 2M solution of Me3Al (0.5 ml, 1 mmol, 1 eq) in toluene was stirred at −78° C. for 10 minutes, and then added to the above reaction mixture slowly. The reaction temperature was maintained at −100° C. for another 1 h, after which the reaction mixture warmed to 0° C. slowly. The reaction mixture was quenched with a saturated solution of Na2SO4 and extracted with ethyl acetate. The organic layer was separated and washed with a saturated brine solution, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified through a neutral alumina column using 0.5% MeOH/DCM. Yield: 0.1 g (38.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=O)[CH3:15])=[C:4]([F:17])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([NH2:24])[CH3:15])=[C:4]([F:17])[CH:3]=1
Reactant: CC(=O)c1ccccc1-c1ccc(Cl)cc1F
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethanone (3.2 g, 12.9 mmol) in anhydrous methanol (200 mL) was added solid ammonium acetate (19.8 g, 257 mmol). The reaction mixture was heated at 60° C. for one hour, followed by the addition of a methanolic solution of sodium cyanoborohydride (1.62 g, 25.8 mmol). After 16 hours, the methanol was removed in vacuo and aqueous ammonium hydroxide was added. The aqueous phase was extracted with diethyl ether (3×200 mL) until the amine was no longer present in the aqueous phase. The organic phase was then washed with 2 N aqueous hydrochloric acid (3×100 mL) and the aqueous phases combined. The solid formed during the acid wash was determined to be the dialkyated amine and was segregated from the aqueous phase. Aqueous sodium hydroxide was added to the acidic aqueous phase until the solution was neutralized to pH 8 to 9. The basic aqueous phase was extracted with diethyl ether until the primary amine was no longer detected in the aqueous phase. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford a clear oil that was used without further purification;
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:43]1[N:44]=[C:45]([NH:48]C=O)[S:46][CH:47]=1)[C:12]([NH:14][CH:15]1[C:41](=[O:42])[N:17]2[C:18]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:19](/[CH:22]=[CH:23]/[Cl:24])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:12]([NH:14][CH:15]1[C:41](=[O:42])[N:17]2[C:18]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])=[C:19](/[CH:22]=[CH:23]/[Cl:24])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (3.0 g) in a mixed solvent of methanol (30 ml) and tetrahydrofuran (5 ml) was added concentrated hydrochloric acid (1.67 ml) at room temperature, and the mixture was stirred for two hours at the same temperature. The reaction mixture was diluted with water (40 ml), adjusted to pH 6.0 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried and evaporated under reduced pressure. The residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (2.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].Cl.N[CH:18]([CH3:23])[CH2:19][N:20]([CH3:22])[CH3:21].N1C=CN=C1.CCN(CC)CC>O1CCOCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH:18]([CH3:23])[CH2:19][N:20]([CH3:22])[CH3:21])[C:5]2=[O:15]
Reactant: CC(N)CN(C)C
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(CN(C)C)N1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Temperature: 130 °C
Yield: 64 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (1.66 g, 8.0 mmol), HCl salt of 2-amino-N,N-dimethyl-propylamine (5.3 g, crude, <30 mmol), imidazole (1.36 g, 20 mmol) and Et3N (8.4 mL, 6.07 g, 60 mmol) in dioxane (80 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 130° C. for 72 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (240:10:1) afforded the title compound (1.49 g, 64%). 1H NMR (DMSO-d6) δ 1.32 (d, J=6 Hz, 3H, CH3), 2.09 (s, 6H, 2CH3), 2.25 (m, 1H), 2.95 (m, 1H), 4.35 (m, 1H), 7.43 (s, 1H), 8.29 (s, 1H), 8.39 (br s, 2H, NH). ESI-MS m/z 293.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:16]=[CH:15][C:11](C=NO)=[CH:10][CH:9]=2)[CH:3]=1.Cl.[NH2:18][C:19]([NH2:21])=[S:20].C(N(CC)CC)C>CN(C)C=O.O1CCOCC1.S([O-])(O[O-])(=O)=O.[K+].[K+].O1CCCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([NH:18][C:19]([NH2:21])=[S:20])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: NC(N)=S
Reactant: Cc1ccnc(-c2ccc(C=NO)cc2)c1
Agent: Cl
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(-c2ccc(NC(N)=S)cc2)c1
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
To a solution of 4-(4-methylpyridin-2-yl)benzaldehyde oxime (0.41 g) in N,N-dimethylformamide (2 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 1.06 ml) and potassium peroxymonosulfate (OXONE, 0.712 g). The reaction mixture was stirred for 1.5 hours, and to the mixture were added tetrahydrofuran (10 ml) and thiourea (0.176 g). Then to the resultant suspension was added a solution of triethylamine (0.673 ml) in tetrahydrofuran (2 ml) dropwise, and the mixture was stirred for 1 hour. The mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml), and to the solution was added aqueous ammonia (28%, 3 ml) dropwise. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. To the residue was added dichloromethane and diisopropyl ether, and the precipitate was collected by filtration and dried to give N-(4-(4-methylpyridin-2-yl)-phenyl)thiourea (206 mg).
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[N:5][N:4]=[C:3]1[SH:10].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[C:21]2[N:25]([C:26]=1[C:27](O)=O)[CH:24]=[CH:23][O:22]2.O=P(Cl)(Cl)Cl>C(Cl)Cl>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[C:21]2[N:25]([C:26]=1[C:27]1[S:10][C:3]3=[N:4][N:5]=[C:6]([CH:7]([CH3:9])[CH3:8])[N:2]3[N:1]=1)[CH:24]=[CH:23][O:22]2
Reactant: CC(C)c1nnc(S)n1N
Reactant: O=C(O)c1c(-c2ccc(F)cc2F)nc2occn12
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc2sc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: 0 °C
Yield: 15 %

Procedure:
A 5 mL round-bottomed flask equipped with a reflux condenser outfitted with a nitrogen inlet adapter was charged with 4-amino-5-isopropyl-4H-1,2,4-triazole-3-thiol (0.15 g, 0.95 mmol, Enamine) and 6-(2,4-difluorophenyl)imidazo[2,1-b]oxazole-5-carboxylic acid (0.25 g, 0.95 mmol) in POCl3 (3.5 mL, 38 mmol) to give a tan suspension. The reaction mixture was heated at about reflux for about 18 h, allowed to cool, and then poured over stirring ice water. The mixture was diluted with DCM and the layers were separated. The organic layer was concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to provide a white solid (0.055 g) which was dissolved in a minimal amount of hot ACN and left to cool to ambient temperature for about 2 h. The resulting crystals were isolated by filtration, washed with ACN, and dried under vacuum to give the title compound (0.020 g, 5%): LC/MS (Table 1, Method b) Rt=1.95 min; MS m/z: 387.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH3:25])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[N:14](C(OC(C)(C)C)=O)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH3:25])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[NH:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 17 g (0.0466 mole) of Boc-N-methyl-L-alanyl-L-alanine benzyl ester in 150 ml of dry dichloromethane, cooled at -10° C., was added 100 ml trifluoroacetic acid, which was previously cooled at -10° C. The reaction mixture was stirred for 16 hours at -5° C., then poured carefully with good stirring into a mixture of 177 g of sodium bicarbonate, ice, and 150 ml of dichloromethane. The organic layer was separated and the aqueous layer was further extracted with another 60 ml of dichloromethane. The combined organic layers were washed with 3×50 ml of saturated sodium bicarbonate solution, dried over manesium sulfate, and evaporated to give 11.6 g (91% of theory) of crude product which was used in step 3 without further purification.
Reaction SMILES: C([N:8]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][CH:41]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>O1CCCC1.CO.[OH-].[OH-].[Pd+2].O>[CH3:34][C:32]1[CH:33]=[C:28]([C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10][CH2:9][NH:8][CH2:36][CH2:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][CH:41]=2)=[CH:18][C:17]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:22])=[CH:16][CH:15]=3)[CH:29]=[C:30]([CH3:35])[CH:31]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N4CCCC4)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N4CCCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of pyrrolidine-1-carboxylic acid [3-(2-{benzyl-[4-(4-methanesulfonylaminophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-amide (16 mg in a mixture of 1 mL tetrahydrofuran and 3 mL methanol) was added 15 mg of 10% palladium hydroxide on carbon catalyst followed by acetic acid (0.015 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 25 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:8:1) gave the title compound (14 mg). m/e=602 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[N:16]([CH:17]=2)[C:15]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=2[S:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[N:27]1([CH2:26][CH2:25][O:22][C:20]2[CH:19]=[CH:18][C:15]3[N:16]4[CH:17]=[C:10]([C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=5)[N:11]=[C:12]4[S:13][C:14]=3[CH:21]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1

Procedure:
2-(4-Nitrophenyl)imidazo[2,1-b]benzothiazol-7-ol, 4-(2-chloroethyl)-morpholine hydrochloride, potassium carbonate, and tetrabutylammonium iodide were added to N,N-dimethylformamide forming a yellow suspension that was heated at a temperature of >50° C. for over 3 hours. The reaction was cooled and the solids were collected, slurried into water, filtered, slurried into acetone, filtered and washed with acetone to give yellow solids that were dried under vacuum to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:15][C@@H:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:9]=1)[CH3:14])(=[O:18])[CH3:17]
Reactant: C=COC(C)=O
Reactant: Cc1cccc(-n2nnc(C(C)O)n2)c1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1nnn(-c2cccc(C)c2)n1
Yield: 42.3 %

Procedure:
A mixture of 1-[2-(3-methylphenyl)-2H-tetrazol-5-yl]ethanol (93 g, 460 mmol) and Novozyme 435® (10 g) in dry toluene (4800 mL) was stirred slowly. Vinyl acetate (39.2 g, 460 mmol) was added and the mixture was stirred at room temperature for 5 hours. Novozyme 435® was filtrated and washed with toluene (100 mL). The filtrate was concentrated and purified on silica using petroleum ether/ethyl acetate (6:1) as eluent giving the title product (47.92 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C([Li])(C)(C)C.C1([O:30][C:31]([C:33]2[N:34]([CH3:45])[C:35]([CH2:38][N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])=[N:36][CH:37]=2)=O)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.CCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:31]([C:33]3[N:34]([CH3:45])[C:35]([CH2:38][N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])=[N:36][CH:37]=3)=[O:30])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: COCCN(C)Cc1ncc(C(=O)Oc2ccccc2)n1C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCCN(C)Cc1ncc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)n1C
Temperature: -30 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (220 mg, 0.83 mmol) in dry tetrahydrofurane (10 ml) at −70° C. is slowly added a solution of tert.butyllithium (1.1 ml of a 1.5 M solution in pentane corresponding to 1.65 mmol) and the remaining suspension slowly warmed to about −30° C. At this time, a solution of 2-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester (252 mg, 0.83 mmol) in tetrahydrofurane (4 ml) was added and the mixture stirred for 1 h at room temperature. The reaction mixture was treated with saturated aqueous ammonium chloride solution (10 ml) followed by ethyl acetate (20 ml) and the formed precipitate collected. The phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, dried with magnesium sulfate and evaporated to dryness to yield another batch of raw product. Flash-chromatography on silica (eluent trichloromethane containing 30% of ethyl acetate) yielded the title compound as white solid (31% yield). MS: m/e=475(M+H+), mp 176-178° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C@H:9]1[CH2:13][NH:12][C@@H:11]2[C@@H:14]([OH:17])[CH2:15][O:16][C@H:10]12.[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33](Cl)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>O.O1CCOCC1>[OH:17][C@@H:14]1[C@H:11]2[N:12]([C:33]([O:32][CH2:31][CH:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]4[C:30]3=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:34])[CH2:13][C@H:9]([O:8][CH3:7])[C@H:10]2[O:16][CH2:15]1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CO[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 0.67 h
Yield: 66 %

Procedure:
A solution of sodium carbonate (239 mg, 2.26 mmol) in water (10 mL) was added whilst stirring to a solution of (3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol in 1,4-dioxane (7 mL). A solution of 9-fluorenylmethoxycarbonyl chloride (319 mg, 1.23 mmol) in 1,4-dioxane (3 mL) was added then the mixture stirred for 40 minutes then water (30 mL) was added and the product extracted into dichloromethane (1×40 mL then 2×30 mL). The organic layer was washed with brine (50 mL), then dried (MgSO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 7:93 to 45:55 gave bicyclic alcohol (6b) (270 mg, 66%) as a white solid. TLC (Rf=0.34, EtOAc:heptane 3:2), analytical HPLC single main peak, Rt=15.990 min., HPLC-MS 382.1 [M+H]+, 404.1 [M+Na]+, 785.3 [2M+Na]+; [α]D18.5 −35.4° (c=2.758, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 3:2; 1.02 (0.6H, d, J=3.55 Hz, OH major), 2.59 (0.40H, d, J=3.19 Hz, OH minor), 3.10 (0.6H, dd, J=12.54 and 3.89 Hz, FmocNCH2 major), 3.26 (1.8H, s, OCH3 major), 3.30 (0.4H, dd, J=12.21 and 4.19 Hz, FmocNCH2 minor), 3.35 (1.2H, s, OCH3 minor), 3.49 (0.6H, m, OCH2CHOH major), 3.52 (0.6H, dd, J=10.04 and 1.81 Hz, OCH2CHOH major), 3.55-3.59 (1.2H, m, OCH2CHOH major and FmocNCH major), 3.64 (0.6H, d, J=3.69 Hz, CHOCH3 major), 3.65-3.70 (1H, m, FmocNCH2), 3.75-3.79 (0.8H, m, OCH2CHOH minor and CHOCH3 minor), 3.85 (0.4H, dd, J=9.85 and 4.46 Hz, OCH2CHOH minor), 4.22-4.26 (1.4H, m, FmocNCH minor and Fmoc CH), 4.37 (0.6H, d, J=4.64 Hz, OCHCHOCH3 major), 4.40-4.44 (1.2H, m, Fmoc CH2 minor and OCH2CHOH minor), 4.60 (0.4H, d, J=4.94 Hz, OCHCHOCH3 minor), 4.70 (0.6H, dd, J=10.80 and 3.96 Hz, Fmoc CH2 major), 4.82 (0.6H, dd, J=10.80 and 4.25 Hz, Fmoc CH2 major), 7.29-7.80 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3) 47.248/47.378 (Fmoc CH), 49.754/50.177 (FmocNCH2), 56.868/56.996 (OCH3), 65.736/67.270 (Fmoc CH2), 68.262/69.085 (FmocNCH), 73.760/74.008 (OCH2CHOH), 75.812/76.145 (OCH2CHOH), 81.509/82.286 (OCHCHOCH3), 83.496/84.166 (OCHCHOCH3), 119.805, 119.982, 120.003, 124.494, 124.576, 124.958, 124.975, 127.019, 127.034, 127.404, 127.488, 127.637, 127.726, 127.754 and 127.865 (Fmoc aromatic CH), 143.633, 143.909, 143.943 and 144.037 (Fmoc quaternary), 154.255/155.025 (Fmoc C═O).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3]O.S([O-])([O-])=O.[Na+].[Na+].CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.[OH-].[K+].[F:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[CH:36]2>CO>[F:32][C:33]1[CH:34]=[C:35]2[C:39]([NH:38][CH:37]=[C:36]2[CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])=[CH:40][CH:41]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: N[C@@H](CO)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N[C@@H](Cc1c[nH]c2ccc(F)cc12)C(=O)O
Reaction time: 0.08 h

Procedure:
In the same manner as in Example 1, the cell suspension of Proteus vulgaris ATCC 13315 was prepared. Subsequently, 50 ml of a solution containing 120 mg/ml L-serine, 8 mg/ml sodium sulfite and 0.2 mg/ml pyridoxal 5′-phosphate were adjusted to pH 8.8, using potassium hydroxide solution, to adjust the final volume to 80 ml (substrate solution B). Subsequently, 1 ml of cell suspension was added to the 8 ml of substrate solution B, to which was added 1 ml of a solution containing 200 mg/ml 5-fluoroindole dissolved in methanol, and was incubated at 37° C. After the reaction had proceeded for the times indicated in Table 2, the reaction was stopped with boiling for 5 minutes. The amount of 5-fluoro-L-tryptophan produced in the reaction solution for 2, 6, 18 and 30 hours of reaction is shown in Table 2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][S-:12].[Na+]>C(O)C>[CH3:11][S:12][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])nc1

Procedure:
5-Chloro-2-nitropyridine (8.0 grams) was added to a solution of 2.5 grams of sodium methanethiolate in 100 milliliters of ethanol at a temperature of 0° C. to which solution excess sodium methanethiolate was added portionwise. The resulting reaction mixture was then heated to reflux and refluxed for 15 hours with constant stirring. At the end of the 15 hours, the reaction mixture was filtered and allowed to concentrate to 75 milliliters. The reaction mixture was then permitted to cool and filtered again, yielding the desired 5-(methylthio)-2-nitropyridine; it was recrystallized from ethanol, m.p., 100.5°-02.5° C.