Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:11][CH3:12].[Br:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][C:21]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[C:20](I)[CH:19]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br-].[Zn+2].[Br-].O1CCCC1>[CH2:15]([O:14][C:10]([C:11]1[N:28]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[C:21]2[C:20]([CH:12]=1)=[CH:19][C:18]([Br:17])=[C:23]([C:24]([F:27])([F:25])[F:26])[CH:22]=2)=[O:13])[CH3:16]
Reactant: CCOC(=O)CC
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)c(Br)cc2I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Br)c(C(F)(F)F)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
N,N-diisopropylethyl amine (0.42 ml, 2.4 mmol), ethyl propionate (0.12 ml, 1.2 mmol), and tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol) were added to an anhydrous tetrahydrofuran (THF) solution (3.2 ml) containing N-(4-bromo-2-iodo-5-trifluoromethyl-phenyl)-4-methyl-benzenesulfonamide (208 mg, 0.4 mmol) and zinc bromide (270 mg, 1.2 mmol). Then, the mixture was evacuated, and backfilled with argon. This was stirred at 80° C. for 13 hours. After cooling it to room temperature, the reaction mixture was filtered through Celite, and washed with ethyl acetate. The wash solution was washed with an aqueous solution saturated with sodium bicarbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 5-bromo-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester was obtained as a pale brown solid (195 mg, 50%).
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9]Br)=[CH:6][CH:5]=1.[Br-].[CH2:14]([N+:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:21]1[CH:30]=[CH:29][C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:22]1[CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: c1ccc(C[n+]2ccc3ncccc3c2)cc1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(CCC2c3cccnc3C=CN2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a suspension of 581 mg (23.9 mmol) magnesium in 24 mL THF was added 5.3 g (23.9 mmol) 4-methoxyphenethyl bromide. The mixture was refluxed for 2 h and then cooled in an ice bath and 2.4 g (7.97 mmol) 6-benzyl-[1,6]naphthyridin-6-ium bromide (Chemical & Pharmaceutical Bulletin, 32(7), 2522-9; 1984) was added at once. The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and quenched with a 20% NH4Cl solution. The mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 2.57 g (90%) of the title compound was yielded as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[S:20][CH:19]=[CH:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[S:20][CH:19]=[CH:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[O:11])=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ncnc2ccsc12
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1ccc(CNC(=O)c2ncnc3ccsc23)cc1

Procedure:
Compound 7.3 (1.0 mmol) and Pd/C (10 w/w %, 60 mg) in MeOH—H2O (12 mL) is stirred under a hydrogen atmosphere at room temperature until the reaction is complete. The catalyst is removed by filtration and the filtrate is evaporated to dryness under reduced pressure to provide thieno[3,2-d]pyrimidine-4-carboxylic acid 4-amino-benzylamide (compound 7.4).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]1=[O:29].[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].[I-]>CN(C)C=O>[O:35]=[C:33]1[CH2:32][CH2:31][C:30](=[O:36])[N:34]1[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCCl)c1=O
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-(3-chloropropyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (24 mg, 0.057 mmol) in N,N-dimethylformamide (700 μL) was added succinimide (23 mg, 0.23 mmol), potassium carbonate (32 mg, 0.23 mmol), and possium iodide (38 mg, 0.23 mmol), respectively. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was cooled and quenched with cold 1 N aqueous hydrochloric acid and extracted with toluene. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 1-[3-(2,5-dioxo-1-pyrrolidinyl)propyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1 H), 7.31 (s, 1 H), 7.19 (dd, J=8.5, 5.3 Hz, 2 H), 7.04 (t, J=8.6 Hz, 2 H), 4.50 (q, J=7.1 Hz, 2 H), 4.17-4.12 (m, 4 H), 3.58 (t, J=7.1 Hz, 2 H), 2.71 (s, 4 H), 1.90 (m, 2 H), 1.47 (t, J=7.1 Hz, 3 H); MS m/z 504 (M+Na)+.
Reaction SMILES: [C:1]1([N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[CH2:16][CH2:17][OH:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:32]([N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:38](Cl)=[O:39])[CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1>[C:19]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:38](=[O:39])[N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:12][CH:11]2[CH2:16][CH2:17][OH:18])=[O:9])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(N(c1ccccc1)c1ccccc1)N1CCNCC1CCO
Reactant: CCCCCN(CCCCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(CCO)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 64.2 %

Procedure:
To a solution of 174 mg (0.53 mmol) of (RS)-1-(N,N-diphenylcarbamoyl)-2-(2-hydroxyethyl) piperazine in 10 mL of dry tetrahydrofuran was added 450ml (3.23 mmol) of triethylamine in one portion and 176 mg (0.80 mmol) of dipentylcarbamyl chloride (dissolved in 2 mL of dry tetrahydrofuran) and the mixture was stirred under nitrogen at 60° C. for two days. The solution was cooled and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 75:25 v/v ethyl acetate/hexane as the eluant afforded 173 mg (64%) of a yellow oil.
Reaction SMILES: Cl.C(N(CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])#[N:14]>CN1CCCC1=O>[NH:9]1[C:13]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])=[N:14][N:11]=[N:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(C=O)c1
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=Cc1cccc(-c2nnn[nH]2)c1
Temperature: 110 °C

Procedure:
5.8 g (42.1 mmol) of triethylamine hydrochloride and 6.0 g (92.3 mmol) of sodium azide are added to a solution of 4.0 g (30.5 mmol) of 3cyano-benzaldehyde in 100 ml of 1-methyl-2-pyrrolidone and heated at 110° C. for 1.5 hours (argon atmosphere). When cool the reaction mixture is poured into 0.6 liter of ice/37% HCl (20:1) and stirred thoroughly to complete the reaction. Extraction with 3 portions of ethyl acetate, washing the organic phases with 3× water and brine, drying (Na2SO4), concentration by evaporation and stirring in diethyl ether yield 3-(tetrazol-5-yl)-benzaldehyde; m.p. 185-189° C.; TLC: Rf=0.13 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1.N1C=C(C(O)=O)C=C(C(O)=O)C=1.C1(C)C=C(C)C=C(C)C=1.C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)c2sccc12
Agent: O=C(O)c1cncc(C(=O)O)c1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: Cc1cc(C)cc(C)c1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Temperature: 167 °C
Yield: 87.1 %

Procedure:
A 2.5 l, 4-necked glass flask equipped with a mechanical stirrer, a thermometer, a cooler, a dropping funnel and an argon inlet was charged under argon in sequence with 118.2 g (250 mmol) of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione, 98.3 g (375 mmol) of 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-, diethyl ester, 563 ml of mesitylene and 17.4 ml (125 mmol) of triethylamine. The suspension was stirred at reflux (ca. 167° C.) for 6 h, then the resulting solution was cooled to 90° C. within 50 min, finally 1560 ml of ethanol were added within 10 min whereas the temperature dropped to 40° C. The suspension was cooled to 0° C. and stirred at this temperature for 5 h. Finally the precipitate was isolated by filtration, the filter cake was washed with 700 ml of ethanol and dried over night at 60° C./10 mbar, to afford 101.1 g (92.3%) of 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione as off-white crystalline material with a m.p. of 208° C.
Reaction SMILES: [OH-].[Na+:2].[F:3][CH:4]([F:43])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[N:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[N:25][C:26]([N:29]4[CH2:34][CH2:33][C:32]([CH2:40][OH:41])([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]4)=[N:27][CH:28]=3)[C:20]([F:22])=[CH:21][C:16]2=[N:15][C:14]=1[CH3:42]>C1COCC1.CO.O>[F:43][CH:4]([F:3])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[N:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[N:25][C:26]([N:29]4[CH2:30][CH2:31][C:32]([CH2:40][OH:41])([C:35]([O-:37])=[O:36])[CH2:33][CH2:34]4)=[N:27][CH:28]=3)[C:20]([F:22])=[CH:21][C:16]2=[N:15][C:14]=1[CH3:42].[Na+:2]
Reactant: CCOC(=O)C1(CO)CCN(c2ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(C)nc4cc3F)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc2cc(F)c(-c3cnc(N4CCC(CO)(C(=O)[O-])CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
Sodium hydroxide (7 mg, 0.175 mmol) was added to a solution of Example 174 (0.1 g, 0.176 mmol) in THF-MeOH-water, 1:1:1 (4 mL). The mixture was stirred at 70° C. for 2 h. The mixture was concentrated and diluted with water, then washed with EtOAc. The aqueous layer was freeze-dried. The resulting material (95 mg) was purified by HPLC to give the title compound (30 mg, 30%) as a white lyophilised solid. δH (400 MHz, DMSO-d6) 8.48 (m, 2H), 8.34 (d, J 7.5 Hz, 1H), 7.46 (m, 1H), 7.30 (m, 1H), 7.26 (t, J 72 Hz, 1H), 7.19 (m, 1H), 7.14 (td, J 7.5, 1.1 Hz, 1H), 7.02 (m, 1H), 4.39 (m, 2H), 4.34 (s, 2H), 3.43 (s, 2H), 3.23 (m, 2H), 2.28 (s, 3H), 1.98 (m, 2H), 1.40 (m, 2H). LCMS (pH 10): MH+ 542, RT 1.44 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16]I.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH3:16][O:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
(4′-Bromobiphenyl-4-yl)methanol (1.2 g, 4.6 mmol) was dissolved in tetrahydrofuran (20 mL), and methyl iodide (0.97 g, 6.8 mmol), and then sodium hydride (63%, 0.26 g, 6.8 mmol) were added under a nitrogen atmosphere at 4° C., followed by stirring at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/dichloromethane), and a fraction corresponding to the Rf value=0.50 (hexane/dichloromethane=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (1.2 g, 4.3 mmol) as a white solid (yield 95%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[CH2:4][OH:5].[OH-].[K+].C1C[O:18][CH2:17]C1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O.CCOC(C)=O>[Cl:12][C:8]1[CH:7]=[C:6]([C@H:3]2[CH2:4][O:5][C:17](=[O:18])[NH:2]2)[CH:11]=[CH:10][CH:9]=1
Reactant: C1CCOC1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1N[C@@H](c2cccc(Cl)c2)CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.5 %

Procedure:
To a solution of (S)-2-amino-2-(3-chlorophenyl)ethanol hydrochloride (500 mg, 2.40 mmol) in water (12 mL) at 0° C. was added potassium hydroxide (809 mg, 14.4 mmol) followed by THF (12 mL) and the reaction was stirred at 0° C. for 20 minutes. Triphosgene (713 mg, 2.40 mmol) was added and the reaction was stirred at 0° C. for 2 hours. The reaction was poured into EtOAc and the organic phase washed with 1N HCl, 1N NaOH and brine. After drying over MgSO4, concentration yielded (S)-4-(3-chlorophenyl)oxazolidin-2-one (278 mg, 58.5% yield) as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][C@@H:43]([CH3:56])[CH2:44][O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH:41]=1)[C:36]([OH:38])=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH2:57][C:58]1[CH:62]=[CH:61][N:60]([CH3:63])[N:59]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][C@@H:43]([CH3:56])[CH2:44][O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:47]([CH3:49])[CH3:48])[CH:50]([CH3:52])[CH3:51])[CH:41]=1)[C:36]([NH:57][C:58]1[CH:62]=[CH:61][N:60]([CH3:63])[N:59]=1)=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1)(C(C)C)C(C)C
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
HATU (23.5 g, 61.8 mmol) was added to 3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoic acid (23.6 g, 51.5 mmol), followed by addition of DMF (140 mL), and cooled to 0° C. 3-Amino-1-methylpyrazole (6.00 g, 61.8 mmol) was added followed by DIPEA (21.3 mL) and the reaction was stirred under argon at 0° C. for 3 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (500 mL) and washed with citric acid solution (200 mL), sodium hydrogen carbonate solution (150 mL), and saturated brine solution (2×150 mL). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (21.7 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+:30]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.N[C@@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
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](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: C[C@@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: NC1CCN(Cc2ccccc2)C1

Procedure:
To a flask containing 0.6 g of a substrate N-benzyl-3-pyrrolidinone, 1.85 g of D-glucose, 2.3 mg of NAD+, 1.83 g of D-alanine, and 4.0 mg of pyridoxal phosphate, 30 ml of a culture fluid of the E. coli HB101 (pNTASPAG), obtained in Example 11, which expresses TAS, PALDH, and GDH were added. The resultant product was stirred at 30° C. while being adjusted to a pH of 6.8 by drippage of 5 N aqueous solution of sodium hydroxide. During the reaction, the reaction liquid was sampled. From the sample, N-benzyl-3-aminopyrrolidine was extracted by the addition of ethyl acetate after basifying the sample with 6 N aqueous solution of sodium hydroxide. The amount of N-benzyl-3-aminopyrrolidine produced was measured by analyzing N-benzyl-3-aminopyrrolidine under the following HPLC conditions. Further, by the law of the art, N-benzyl-3-aminopyrrolidine thus obtained was acted on by 3,5-dinitrobenzyl chloride to form a dinitrobenzyl derivative. After that, the dinitrobenzyl derivative was analyzed under the following HPLC conditions, whereby the optical purity thereof was measured.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=C)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:14]=[O+][O-].CSC>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=Cc1cccc(F)c1C(=O)OC
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)c1c(F)cccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Into a solution of methyl 2-fluoro-6-vinylbenzoate (31 g, 0.172 mol) in dry dichloromethane (300 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until it turned colorless. Dimethylsulfane (84.13 g, 1.36 mol) was added dropwise to the solution, which was subsequently warmed to RT and stirred for 2 hours. The mixture was then washed with water (30 mL) and extracted with DCM (3×300 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (10-100%) and PE to give the title compound (21 g, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 10.01 (s, 1H), 7.65-7.63 (d, J=7.6 Hz, 1H), 7.56-7.53 (dd, J1=5.2 Hz, J2=8.0 Hz, 1H), 7.35-7.30 (t, J=8.4 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:32]=C)=[C:4]([CH:15]=[C:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=2)[C:17]=1[O:18][CH3:19])[C:5]([NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14])=[O:6].CC(C)=[O:36].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>S([O-])([O-])(=O)=S.[Na+].[Na+].O.O.[O-][Os]([O-])(=O)=O.[K+].[K+].O>[Cl:1][C:2]1[C:17]([O:18][CH3:19])=[C:16]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:26]=2)[CH:15]=[C:4]2[C:3]=1[CH:32]([OH:36])[N:7]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14])[C:5]2=[O:6]
Reactant: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1Cl
Reactant: CC(C)=O
Agent: O=[Os](=O)([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1Cl)C(O)N([C@@H]1CCCC[C@H]1O)C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of rac-3-chloro-2-ethenyl-N-(trans-2-hydroxycyclohexyl)-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzamide (0.08 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 mL) were added potassium osmate(VI) dihydrate (5.00 mg) and sodium periodate (0.12 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.07 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:19]([Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])([CH3:22])([CH3:21])[CH3:20].[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:33])[CH3:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
A catalytic amount of benzoylperoxide (0.5 g) was added to a refluxing solution of an equimolar mixture of Example 1d (30 g, 0.134 mol) and N-bromosuccinimide (24 g, 0.134 mol) in dry CCl4 (175 mL) for 1.5 h. The reaction mixture was filtered, concentrated and purified using flash chromatography (silica gel, PE60-80° C.) to obtain the title compound as an oil. Yield: 36 g, (90%); 1H NMR (CDCl3): δ 0.30 (s, 6H, 2CH3), 1.10 (s, 9H, 3CH3), 4.5 (s, 2H, CH2), 6.8-7.5 (m, 4H, Ar).
Reaction SMILES: [K+].[CH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[S:7][C:6]=2[CH:5]=[C:4]([C:15]([O-:17])=O)[CH:3]=1.C(Cl)(=O)C([Cl:21])=O>C1C=CC=CC=1>[Cl:21][C:15]([C:4]1[CH:3]=[CH:2][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[S:7][C:6]=2[CH:5]=1)=[O:17]
Reactant: O=C([O-])c1ccc2c(c1)sc1ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc2c(c1)sc1ccccc12
Reaction time: 0.5 h

Procedure:
To a suspension of 8.9 g. of dibenzothiophene-3-carboxylic acid potassium salt in 200 ml. of benzene was added dropwise with stirring over a period of 30 minutes, a solution of 6.4 g. of oxalyl chloride in 50 ml. of benzene. The mixture was stirred and refluxed for two hours. The mixture was filtered and the solvent was removed in vacuo on the steam bath. The residue, 3-chlorocarbonyldibenzothiphene (7.9 g.) was used directly in the next step.