Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:40])[C:8]1[N:12]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:14]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:40][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:22]3[CH2:27][CH2:26][N:25]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:24][CH2:23]3)=[C:15]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:14]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCNCC3)c2n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
Methanesulfonyl chloride (0.08 mL, 1.03 mmol) was added dropwise to a mixture of the above amine (102 mg, 0.211 mmol) and powdered K2CO3 (263 mg, 1.90 mmol) in CH2Cl2 (10 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 5 hrs. Water was added, the phases were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent was removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-9H-purine (105 mg, 88%): mp 236-239° C.; 1H NMR (CDCl3) δ 7.84 (s, 1H), 7.76 (dd, J=8.4, 0.5 Hz, 1H), 7.42 (t, JHF=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.57 (tt, J=11.7, 4.4 Hz, 1H), 4.38 (br s, 4H), 4.09 (m, 2H), 4.06 (s, 3H), 3.88 (t, J=4.8 Hz, 4H), 2.96 (dt, J=12.5, 2.8 Hz, 2H), 2.88 (s, 3H), 2.35-2.20 (m, 4H); Anal. Calcd. for C24H28F2N8O4S: C, 51.2; H, 5.0; N, 19.9. Found: C, 51.0; H, 4.9; N, 19.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[C:10]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:9]2[Cl:32])[CH:5]=[CH:6][CH:7]=1.C=O.[BH3-][C:36]#N.[Na+]>C1COCC1>[Cl:32][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH3:36])[CH:3]=2)[C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11]=2[C:10]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(-c1ccc(Cl)cc1)c(Cl)n2-c1cccc(N)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cccc(-n2c(Cl)c(-c3ccc(Cl)cc3)c3c(NC(=O)OC(C)(C)C)ncnc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of tert-butyl 7-(3-aminophenyl)-6-chloro-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbamate (21) (421 mg, 0.89 mmol), aqueous HCHO (109 mg, 1.34 mmol) and 4 Å MS (3.0 g) in dry THF (5.0 mL) was stirred at r.t. overnight. NaBH3CN (56 mg, 0.89 mmol) was added and stirred at r.t. for 1 hr before the reaction was quenched with sat. NaHCO3 solution (10.0 mL), and was extracted with DCM (20.0 mL×2). The combined organic phases was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatographic (silica gel, 0 to 40% EA in PE) to afford tert-butyl 6-chloro-5-(4-chlorophenyl)-7-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbamate (22) (82 mg, 19% yield) as a yellow solid. LC-MS (ESI): m/z (M/M+2) 483.1/485.8.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]5)=[CH:39][CH:40]=4)[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Yield: 78 %

Procedure:
A suspension of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.91 g, 11.2 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 3.43 g, 11.2 mmol), and Hunig's Base (2.55 mL, 14.6 mmol) in acetonitrile (20 mL) was stirred at room temperature over the weekend. The reaction mixture had completely solidified (pinkish-tan in color), but was judged complete by HPLC and LCMS. The reaction mixture was partitioned between a saturated aqueous of sodium bicarbonate (150 mL) and dichloromethane (150 mL). The aqueous layer was extracted with dichloromethane (2×100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a tan solid which was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (0-50%) to afford tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl) isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (4.60 g; 78%) as a white, crystalline solid. The material was suspended in methanol (−75 mL) and was sonicated for 5 minutes. The MeOH was removed under reduce pressure, and the residue was re-suspended in methanol (−50 mL) with sonication. Vacuum filtration and drying afforded tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (4.04 g, 7.67 mmol, 68% yield) as a white, crystalline solid. The methanol filtrate was concentrated to afford additional tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (570 mg; 10%) as a slightly off-white solid. The compound had an HPLC retention time=3.12 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=527.1. 1H NMR (500 MHz, CDCl3) δ ppm 1.47 (s, 9H) 3.28-3.37 (m, 3H), 3.60 (br. s., 2H), 3.74 (br. s., 2H), 7.49 (d, J=7.70 Hz, 2H), 7.53-7.62 (m, 3H), 7.69 (d, J=7.15 Hz, 2H), and 8.16 (d, J=7.70 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32](=[O:38])[O:33][CH2:34][CH2:35][O:36][CH3:37]>CC(C)=O>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:32]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[CH2:23][O:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:38]
Reactant: COCCOC(=O)Nc1cccc(C)c1CCl
Reactant: Cc1nc2c(O)cccn2c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOC(=O)Nc1cccc(C)c1COc1cccn2c(C=O)c(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
A mixture of 2.0 g (11.35 mmol) of 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde, 1.2 g of anhydrous sodium carbonate, 0.17 g (1.14 mmol) of sodium iodide and 3.3 g (12.8 mmol) of 2-methoxyethyl 2-chloromethyl-3-methylphenylcarbamate in 30 ml of acetone is stirred at RT for 24 h and poured onto 200 ml of ice-water. The precipitate is filtered off, dried and recrystallized from toluene/diisopropyl ether. 3.9 g (86.5%) of the title compound of m.p. 119°-120° C. are obtained.
Reaction SMILES: [C:1]([CH:5]([OH:35])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[C:14]([C:15]([N:17]=[CH:18][N:19]=3)=[NH:16])=[N:13][C:12]2=[SiH2:21])[C@H:8]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:7]1[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([CH:5]([OH:35])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[C:14]([C:15]([N:17]=[CH:18][N:19]=3)=[N:16][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:13][C:12]2=[SiH2:21])[C@H:8]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:7]1[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=N)O[C@@H]1C(O)C(C)(C)C
Product: CC(C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=NC(=O)c2ccccc2)O[C@@H]1C(O)C(C)(C)C

Procedure:
introducing an acyl group at the N6 position of the product from step (2) with an acylating agent, for example, using benzoyl chloride under conditions suitable for obtaining 5′,3′-O-di-tert-butylsilanediyl-2′-O-tert-butyldimethylsilyl-N6-benzoyl adenosine,
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[F:21])=[O:4].Cl.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)CC)C>O>[C:23]([NH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:8][C:7]=1[F:21])=[O:4])(=[O:25])[CH3:24]
Reactant: NCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Yield: 99 %

Procedure:
A solution of 2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide (1:1) hydrochloride (50 mg, 0.15 mmol), acetyl chloride (14.4 mg, 0.18 mmol), triethylamine (31 mg, 0.30 mmol) was stirred at 0° C. for 4 h. Then the mixture was diluted with water and the mixture extracted with DCM. The organic layer was then washed with brine, dried, filtered and evaporated to leave the title compound (50 mg, 99%) as a white solid. MS: m/e=335.2 (M++H).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].ClCCl.C(N(S(F)(F)[F:39])CC)C>O>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:39])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(OCc2ccc(C(F)c3cccc(C#N)c3)cc2)c(C)c1O
Temperature: -78 °C
Yield: 79.6 %

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (0.5 g, 1.29 mmol) and dichloromethane (15 mL) is stirred at −78° C. Diethylaminosulfur trifluoride (0.2 mL, 1.48 mmol) is added and the reaction is warmed to room temperature and stirred 30 min. The mixture is cooled to 0° C. and diluted with water (50 mL). The layers are separated, and the aqueous layer is extracted with dichloromethane (3×50 mL). The organic layers are combined, dried on magnesium sulfate, filtered, and concentrated. The residue is purified via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to give the title compound (400 mg, 80%) as a white solid. LCMS M+1 390.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:13])/[CH2:11][OH:12])=[CH:5][CH:4]=1)[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.ClCCl>[C:14]([O:12][CH2:11]/[C:10](/[CH3:13])=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(/C=C(\C)CO)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(/C=C(\C)COC(C)=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1790 %

Procedure:
(E)-3-(4-Ethylphenyl)-2-methyl-2-propen-1-ol (4.6 g, 26 1 mmol, obtained by LiAlH4 reduction of (E)-3-(4-ethylphenyl)-2-methyl-2-propenal as described for (E)-2-Ethyl-3-(4-methylphenyl)-2-propen-1-ol) was added to a mixture of acetic anhydride (4.0 g, 39 mmol), pyridine (3.5 g, 44 mmol) and DMAP (0.46 g, 3.7 mmol) in 50 ml of dichloromethane. The mixture was stirred for 20 hours at room temperature. The dichloromethane was removed on a rotary evaporator, and the residue dissolved in EtOAc. This solution was washed with aqueous 10% HCl, aqueous 10% NaOH, and saturated aqueous NaCl. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by silica gel flash chromatography (hexane/EtOAc=80:20) followed by Kugelrohr distillation (140-160° C., 0.05 mbar) yielding 3.9 g (17.9 mmol, 69% yield) of the product as a colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(O)=O.[O-:28][C:29]#[N:30].[Na+]>O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][C:29]([NH2:30])=[O:28])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccccc1C=C1c2ccccc2CCc2ccccc21
Yield: 48 %

Procedure:
According to the procedure of F. Kurzer, Org. Syn. Coll. Vol (IV) 49 (1963), mix 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine ((133 mg, 0.54 mmol) with HOAc (4 mL) and water (2 mL). Dissolve sodium cyanate (80 mg, 1.2 mmol) in water (1 mL) and add this solution to the amine derivative. Stir the reaction at room temperature for 2 h. and then pour into water (100 mL). Extract the title compound into EtOAc, dry (MgSO4) and concentrate to give 240 mg crude product. Purify on silica gel using EtOAc/hexane to give 150 mg (48%) product as a colorless oil. MS (ES) 341 (M+1), 339 (M−1). HPLC shows 96.6% purity.
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([N:13]1[CH2:25][CH2:24][CH2:23][C@H:14]1[C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH:8]([CH3:10])[CH3:9].[C:33](Cl)([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34]>C1COCC1.CCOC(C)=O>[NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([N:13]1[CH2:25][CH2:24][CH2:23][C@H:14]1[C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:33]([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34])[CH:8]([CH3:10])[CH3:9]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N(CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 79.3 %

Procedure:
A solution of Boc-Lys(iPr)-Pro-D-Ala-NH2 (9.11 gm) in 10% Na2 CO3 (25 mL) and THF (30 mL) was cooled to 0° C. and treated with a solution of Fmoc-Cl (6.46 gm) in THF. After 1 hour at 0° C. the mixture was partitioned between EtOAc (200 mL) and water (100 mL) and the layers were separated. The organic layer was washed with water (100 mL), 10% citric acid (2×100 mL) and water (100 mL), then dried over Na2SO4 and evaporated to dryness to yield an oil. The residue was dissolved in EtOAc and precipitated from heptane to yield 11.66 gm of crude product. This material was dissolved in a small in EtOAc and loaded onto a silica gel (200 gm) column which was eluted with an EtOAc/heptane mixture (2/1), followed by EtOAc and finally by ethanol. The product-containing fractions were combined and evaporated in vacuo to dryness to yield an oil. The residue was dissolved in a small amount of EtOAc and precipitated from heptane to yield 10.75 gm of Boc-Lys(iPr,Fmoc)-Pro-D-Ala-NH2. HPLC: 98.1%, MS: (M+H)+ =678, (M+NH4)+ =695, [a]D=-12.2 (c=1, HOAc)
Reaction SMILES: P([O-])([O-])([O-])=O.[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]2[CH:8]1[CH:9]2[C:13]([O:15]CC)=[O:14]>CCCCCC>[O:6]=[C:7]1[CH2:12][CH2:11][C@H:10]2[C@@H:8]1[C@@H:9]2[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Product: O=C(O)[C@@H]1[C@H]2CCC(=O)[C@H]21
Temperature: 40 °C
Reaction time: 13 h
Yield: 14.8 %

Procedure:
2.0 mg of the crude enzyme powder of the present enzyme obtained in Reference Example 14 from Burkholderia cepacia SC-20 was added to, and suspended in, 1 ml of 100 mM phosphate buffer (pH 7.0). 10 mg of racemic ethyl(1SR,5RS,6SR)-2-oxobicyclo[3.1.0]hexane-6-carboxylate was dissolved in 1 ml n-hexane, added to the enzyme solution, and heated to 40° C., and the mixture was stirred. After 13 hours, an aliquot of the reaction solution was removed and analyzed in the same manner as in Examples 1 to 8, and the formed 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid was measured for optical purity and reaction yield. As a result, (+)-(1R,5S,6R)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid was obtained with 62.9% optical purity in 14.8% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH2:15][CH2:14]1>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH2:15][CH2:14]1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: Clc1ccccc1OCC1CO1
Solvent: CCO
Product: O=C1NCCCN1C1CCN(CC(O)COc2ccccc2Cl)CC1

Procedure:
A solution of 9.2 g of 1-(o-chloro-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from chloroform/petroleum ether to yield the 1-[3-(o-chloro-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 150°-153° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+:26]([C:29]1[CH:42]=[CH:41][C:32]([O:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([O:40][C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]4[CH:41]=[CH:42][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=4)=[CH:39][CH:38]=3)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 93.2 %

Procedure:
2-(4-(3-Chloro-5-trifluoromethyl-2-pyridyloxy)phenoxypropionic acid chloride hydrochloride (0.7 g) and 4-(4-nitrophenoxy)phenol (0.5 g) were dissolved in dry tetrahydrofuran (10 ml), and stirred with an addition of triethylamine (0.5 ml) at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure and the residue was dissolved in methylene chloride (20 ml), followed by washing with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure and the residue obtained was purified by medium pressure column chromatography by using silica gel, to obtain 4-(4-nitrophenoxy)phenyl 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionate (0.9 g) (oily product).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]3[C:18]4[NH:17][C:16](=[O:19])[NH:15][C:14]=4[CH:13]=[C:12]([C:20]4[C:21]([CH3:26])=[N:22][O:23][C:24]=4[CH3:25])[CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>CO.C(Cl)Cl>[CH:1]1([C:4]2[C:9]([C:10]3[C:18]4[NH:17][C:16](=[O:19])[NH:15][C:14]=4[CH:13]=[C:12]([C:20]4[C:21]([CH3:26])=[N:22][O:23][C:24]=4[CH3:25])[CH:11]=3)=[CH:8][CH:7]=[CH:6][N+:5]=2[O-:32])[CH2:3][CH2:2]1
Reactant: Cc1noc(C)c1-c1cc(-c2cccnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc(-c2ccc[n+]([O-])c2C2CC2)c2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (35 mg, 0.1 mmol) was dissolved in MeOH/DCM (1/1 mL). To the solution was added 3-Chloroperoxybenzoic acid (69.75 mg, 0.4 mol) and the mixture stirred at RT overnight. The organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 2-cyclopropyl-3-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridine 1-oxide.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:14])[C:9]([O:11]CC)=[O:10])[CH:4]=[CH:3][C:2]=1[NH:15][C:16](=[O:22])[C:17]([O:19]CC)=[O:18].Cl>[OH-].[Na+].O>[N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:14])[C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[NH:15][C:16](=[O:22])[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)C(=O)Nc1ccc(NC(=O)C(=O)OCC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)Nc1ccc(NC(=O)C(=O)O)nc1

Procedure:
Diethyl N,N'-2,5-pyridinediyldioxamate (1.0 g., 0.0032 mole) is stirred in 1.0N sodium hydroxide (25 ml.) at 70°-85° until solution is complete. The reaction mixture is diluted with water (25 ml.) and acidified (pH=3) with concentrated hydrochloric acid. The desired product is collected by filtration (0.35 g., 43%, m.p. 290°-295° dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 7-(benzyloxy)-6-methoxyquinolin-4-ol (24.60 g, 87.45 mmol) in toluene (75 mL) was added phosphorus oxychloride (90 mL) slowly. The reaction was heated to reflux for 2 hours, and then cooled to room temperature, diluted with EtOAc (200 mL). The resulted solution was poured into a mixture of ice and 3 N NaOH in portions. The pH of the mixture was adjusted with 3 N NaOH to 7˜8. The organic phase was separated, washed with water (200 mL) followed by brine (100 mL) and concentration in vacuo. The title compound was obtained as a white solid (22.1 g, 84.5%).