Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1.II>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:9])[CH:2]=[CH2:3]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C=CCOCc1c(OC)cccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: II
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCOCc1c(OC)cccc1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 110 %

Procedure:
Into a 200 mL round bottom flask was added 6.6 g (0.0297 mol) of 2-allyloxymethyl-3-methoxy benzoic acid and 40 mL of ethyl acetate. 24.05 g of a 25% pentafluorophenol (6.01 g, 0.0327 mol) solution in ethyl acetate was added while stirring. The reaction flask was placed into a water bath and while stirring small portions of DCC (6.2 g, 0.030 mol) were added. The stirring continued overnight at room temperature. The reaction was filtered through two Whatman #541 filters to remove the DCU precipitate. The ethyl acetate solution was concentrated to yield 12.8 g (110% yield), indicating presence of DCC and DCU. This was confirmed by TLC (1:1 ethyl acetate:hexane), which indicated a Rf of 0.72 plus other less polar compounds (I2 stain indicates about 85% purity). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.7 (d, 1H), 7.45 (t, 1H), 7.15 (d, 1H), 6.0-5.9 (m, 1H), 5.3-5.1 (2d, 2H), 4.88-4.83 (d, 21-H), 4.06 (d, 2H), 3.90 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH2:14]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 66.6E (53.2 g, 230 mmol) in DMSO (45.0 mL) was added 1-(bromomethyl)benzene (35.6 mL, 299 mmol). After cooling in an ice water bath, cesium carbonate (128 g, 391 mmol) was carefully added to the mixture, and the mixture was allowed to warm to room temperature. After overnight stirring, the mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined and then washed with brine. After drying over anhydrous magnesium sulfate and filtration, the organic solvent was removed under reduced pressure to yield 66.11C as a white solid.
Reaction SMILES: C([NH:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12])(=O)C.Cl.O.[OH-].[Na+]>CO>[NH2:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12]
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=NNC(=O)N(N)C1
Temperature: 5 °C

Procedure:
85 g of 4-acetylamino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine in 250 ml of methanol are stirred together with 63 ml of hydrochloric acid(37%) for 4 hours at 50° C. After cooling to 5° C., 250 ml ofice cold water and 125 ml of sodium hydroxide solution (50%) are added. Thesolvent is removed by evaporation in vacuo. The residue is taken up in 100 ml of ethanol, and the solvent is removed again in vacuo. The residue is taken up in 1200 ml of acetonitrile, undissolved salt precipitates are removed by filtration, the filtrate is concentrated to a small volume, theresidue is caused to crystallise by adding 100 ml of acetic acid ethyl ester at 0° C., and the colourless crystals are filtered off and dried yielding 60.4 g (92% of the theoretical amount) of the title compound having a melting point of 118°-120° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([OH:19])=O.CN(C)C=O.S(Cl)([Cl:27])=O>>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([Cl:27])=[O:19]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
30 g (0.12 mol) of 2-anthraquinonecarboxylic acid are suspended in 100 ml of thionyl chloride at 0° C., with exclusion of moisture. After 2 ml of N,N-dimethylformamide (DMF) have been added, the mixture is heated slowly to the reflux temperature. A clear solution is formed. Excess thionyl chloride is removed by distillation in vacuo, and the residue is recrystallised from toluene. 27 g of 2-anthraquinonecarboxylic acid chloride are obtained. A mixture of 17 g (0.15 mol) of hydroxyethyl methacrylate, 30 ml (0.2 mol) of triethylamine and 50 ml of methylene chloride is added dropwise to a solution of 27 g (0.1 mol) of 2-anthraquinonecarboxylic acid chloride in 200 ml of methylene chloride such that the temperature of the reaction mixture does not exceed 10° C. Acidified ice-water is then added and the organic phase is washed several times with water and sodium bicarbonate solution and dried over sodium sulfate. After the methylene chloride has been stripped off and the residue has been recrystallised from ethanol, the hydroxyethyl methacrylate of 2-anthraquinonecarboxylic acid is obtained in a yield of 72% of theory, melting point: 119°-120° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][CH:28]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:7]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Place N-(6-aminopyridin-2-yl)-4-fluorobenzamide (Preparation 37) (2 g, 8.3 mmol) and 1-boc-4-piperidone (15.0 g, 83 mmol) in 1,2-dichloroethane (20 mL). Stir for 1 hr. then add sodium triacetoxyborohydride (4.38 g, 20.8 mmol). After stirring for 36 hr., quench with 1 N NaOH and dilute with CH2Cl2. Separate and extract the aqueous layer twice with CH2Cl2, combine organics, dry over MgSO4, and concentrate. Take up the residue in CH2Cl2, and place on two 10 g SCX columns. Wash the columns successively with CH2Cl2 and then with methanol. Elute the product with 2M NH3 in methanol. Concentrate and chromatograph on silica gel, eluting with a gradient of 0-10% (2M NH3 in methanol) in CH2Cl2) to give the title intermediate 3.11 g (90%): mass spectrum (ion spray): m/z 415.4 (M+1); mp 82.7° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCO)nc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-ethyl-2-pyridyl)ethanol (12 g) and 4-fluoronitrobenzene (11.2 g) in dimethylformamide (80 ml) sodium hydride (3.9 g) is added portionwise under ice cooling. This mixture is agitated under ice cooling for one hour, at room temperature for thirty minutes, poured into ice water and extracted with ethyl acetate. Drying the organic layer and evaporating the solvent gives a yellow solid (4-(2-(5-ethyl-2-pyridyl)ethoxy)nitrobenzene, 21.4 g, 98.2%). Recrystallizing from a mixture of ether and hexane yields pale yellow crystals (m.p. 45–47° C.). NMR δ (ppm) in CDCl3: 1.25 (3H, t, J=7.6), 2.65 (2H, q, J=7.6), 3.28 (2H, t, J=6.7), 4.47 (2H, t, J=6.7), 6.95 (2H, m), 7.19 (1H, d, J=7.9), 7.49 (1H, dd, J=2.4; 8.0), 8.17 (2H, m), 8.41 (1H, d, J=2.2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17](O)=[O:18])=[N:15][CH:16]=1)=[O:10]>C(OCC)(=O)C>[N:1]1([C:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([O:8][CH3:7])=[O:10])=[CH:16][N:15]=2)=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)N2CCOCC2)nc1

Procedure:
63 mg of morpholine was coupled to 120 mg of 5-(methoxycarbonyl)pyridine-2-carboxylic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried (MgSO4) and evaporated to afford methyl 6-(morpholine-4-carbonyl)nicotinate. 180 mg of methyl 6-(morpholine-4-carbonyl)nicotinate was hydrolyzed via Procedure M to give 6-(morpholine-4-carbonyl)nicotinic acid. 100 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 6-(morpholine-4-carbonyl)nicotinic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholine-4-carbonyl)nicotinamide. MS (Q1) 423.4 (M)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[Li]CCCC.[I:18]I>O1CCCC1>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([I:18])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: II
Reactant: Clc1nccc2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1nccc2ccc(I)cc12
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
Into a 50 mL round-bottom flask, was placed 7-bromo-1-chloroisoquinoline (as prepared in the previous step, 520 mg, 2.15 mmol, 1.00 equiv) and tetrahydrofuran (10 mL). This was followed by the addition of n-BuLi (0.85 mL, 1.25 equiv) dropwise with stirring at −78° C. in 2 min. The resulting solution was allowed to react, with stirring, for an additional 40 min at −80° C. To this was added a solution of I2 (541 mg, 2.14 mmol, 1.25 equiv) in tetrahydrofuran (3 mL) dropwise with stirring at −78° C. in 1 min. The reaction mixture was allowed to react, with stirring, overnight at 25° C. The reaction was then quenched by the addition of 1 mL of water.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(=S)=S>[C:5]([C:17]1[CH:16]=[CH:15][C:14]2[O:9][C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][O:12][C:13]=2[CH:18]=1)(=[O:7])[CH3:6]
Reactant: CCOC(=O)C1=COc2ccccc2O1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C1=COc2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Slowly add 8.1 g (60.7 mmol) of aluminium chloride to a solution of 2.85 g (36.3 mmol) of acetyl chloride and 5 g (24.7 mmol) of ethyl 1,4-benzodioxin-2-carboxylate in 120 cm3 of carbon disulfide at 0° C. Stir for 4 hours at room temperature and then, after acid hydrolysis with 20 cm3 of 2N hydrochloric acid, extract the reaction mixture with methylene chloride. After drying the methylene chloride phase over magnesium sulfate, concentrating to dryness and washing with ethanol, ethyl 6-acetyl-1,4-benzodioxin-2-carboxylate is obtained in a yield of 95%.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].I[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccnc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 2-bromo-pyridin-3-ol (10.0 g, 57.8 mmol) in DMF (100 ml) was added NaH (4.2 g, 110 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 0.5 h. Then iodomethane (4.0 mL, 64 mmol) was added dropwise at 0° C. and the resulting solution was stirred at ambient temperature for 2 h. The mixture was poured into water. The organic layer was separated. The aqueous phase was extracted with EtOAc (80×3 mL). The combined organic layers were dried over anhydrous Na2SO4 and distilled under reduced pressure to give a residue, which was purified by chromatography on silica gel (5% ethyl acetate in petroleum ether) to give 2-bromo-3-methoxypyridine (7.0 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J=4.8, 1.6, 1H), 7.23 (dd, J=8.0, 4.8, 1H), 7.16 (d, 1H, J=4.8, 1.6), 3.92 (s, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=[CH2:1])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: COC(=O)CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Product: C=C(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
330 mg (0.92 mmole) of methyltriphenylphosphonium bromide and 105 mg (0.94 mmole) of potassium t-butoxide were suspended in 4 ml of dried benzene, and the mixture was stirred under a stream of nitrogen at room temperature for 4 hours. A solution prepared by dissolving 200 mg of methyl 4-(3,4-dichlorophenyl)-4-oxobutanoate [prepared as described in step (a) above] in 1 ml of benzene was added to the reaction mixture, and the mixture was then stirred for 18 hours. At the end of this time, the reaction mixture was filtered through a Celite (trade mark) filter aid and washed with diethyl ether. The filtrate was then concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a 23:2 by volume mixture of hexane and diethyl ether as the eluent, to give 95 mg (yield 64%) of the title compound as a pale yellow oil.
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][CH:10]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1csc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Sodium cyanoborohydride (2 g) was added portionwise to a stirred mixture of 4-bromo-2-thiophenecarbaldehyde (4.78 g), morpholine (2.1 g), glacial acetic acid (1.8 g) and ethanol (125 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic phase was washed with brine and evaporated. The resultant oil was partitioned between a dilute (10%) aqueous hydrochloric acid solution and methylene chloride. The aqueous phase was basified by the addition of a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated to give 4-bromo-2-morpholinomethylthiophene (3.2 g);
Reaction SMILES: [CH2:1]([N:5]1[CH2:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]1=O)[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:5]1[CH2:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1Cc2c([nH]c3ccccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCN1Cc2[nH]c3ccccc3c2C1

Procedure:
2-n-Butyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one, 20 g., in dry tetrahydrofuran, 400 ml., is added slowly to a slurry of LiAlH4, 14 g., in tetrahydrofuran, 250 ml. After refluxing twenty hours, the reaction mixture is hydrolyzed with 30 ml. of water, and filtered. After the solvent is removed, one obtains 20.1 g. of a reddish-brown solid. Recrystallization from methanol, 200 ml., gives 11 g. of the title compound, m.p. 151°-2°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:16]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:11])[NH2:16])[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
To a solution of (S)-2-tertbutoxycarbonylamino butyric acid (1.2 g, 5.8 mmol) in anhydrous THF (20 mL) cooled to −15° C. was added N-methylmorpholine (0.64 mL, 5.8 mmol) and isobutylchloroformate (0.75 mL, 5.8 mmol) under an atmosphere of nitrogen. After 2 minutes, 33% aqueous ammonia (0.5 mL, 8.7 mmol) was added and the resulting mixture stirred at this −15° C. for 2 h. The reaction mixture was left to warm to RT then partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic fractions were washed with aqueous 5% NaHCO3, water, dried (MgSO4) and concentrated in vacuo. The resulting white solid was used without further purification (1.0 g, 85%). 1H NMR (CDCl3, 300 MHz): δ 6.15 (1H, br s), 5.63 (1H, br s), 5.08 (1H, br s), 4.05 (1H, br s), 1.95-1.80 (1H, m), 1.70-1.53 (1H, m), 1.40 (9H, s), 0.95 (3H, d, J=6.71 Hz). 327997
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:8][C:9]1C=CC=C[CH:10]=1.C=O>>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:10]=[CH:9][NH:8]1
Reactant: Oc1ccccc1
Reactant: Nc1ccccc1
Agent: C=O
Product: C1=Cc2ccccc2ON1
Yield: 73.7 %

Procedure:
At room temperature, phenol, aniline and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:1:2. After being homogeneously stirred, the mixture was heated to a molten state, reacted for 4 h and placed in a cooling unit to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 73.7%.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1[C:29]([F:30])=[CH:28][C:10]([O:11][C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:27])=[C:9]([O:31]C)[CH:8]=1)[CH3:6].O>ClCCl>[CH2:5]([C:7]1[C:29]([F:30])=[CH:28][C:10]([O:11][C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:27])=[C:9]([OH:31])[CH:8]=1)[CH3:6]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A commercial solution of boron tribromide (1N in DCM, 3.5 mL, 3.46 mmol) was added to a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoy] piperazin-2-one (which may be prepared in accordance with the experimental described in Example 5, step 1; 500 mg, 1.28 mmol) in dichloromethane (4.3 mL) placed under argon at −30° C. The reaction mixture was stirred at room temperature for 36 hours then diluted by addition of dichloromethane (20 mL) and water (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/acetone (80:20) as eluent. The title product was obtained as a beige solid (440 mg, 92%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][CH:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][CH:24]([O:26][C:27](Cl)=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>ClCCl>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][C@H:24]([O:26][C:27]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CN(C)CCN
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 25 %

Procedure:
Cholesteryl chloroformate (3 g, 6.7 mmoles) in 5 mL dry dichloromethane was added dropwise to a solution of N,N-dimethylethylene diamine (24 mmoles) in 4 mL dry dichloromethane at 0° C. The reaction was allowed to stir overnight. The solvent was then evaporated on a rotary evaporator and the residue was purified by recrystallisation from absolute ethanol to give a white solid (0.84 g, 25% yield, Rf=0.5 in 30% methanol in chloroform).
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC>CN(C1C=CN=CC=1)C>[S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)([O:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Yield: 95 %

Procedure:
This compound was synthesized as a colorless oil from cyclopentylmethanol (235.0 mg, 2.35 mmol), TsCl (581.5 mg, 3.05 mmol), Et3N (473.2 mg, 4.70 mmol), and DMAP (287.1 mg, 2.35 mmol) in 95% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.77 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 3.88 (d, J=7.1 Hz, 2H), 2.44 (s, 3H), 2.18 (dt, J=15.0, 7.5 Hz, 1H), 1.80-1.62 (m, 2H), 1.62-1.41 (m, 4H), 1.25-1.09 (m, 2H); 13C NMR (100 MHz, CDCl3, δC) 144.83, 133.40, 130.02, 128.07, 74.51, 38.79, 29.19, 25.45, 21.86. ESI-MS: 255.1 (M+H+), 277.1 (M+Na+).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[NH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])=[CH:3][CH:2]=1.[OH:15]P(O)(O)=O>[O-]S([O-])(=O)=O.[Cu+2]>[C:12]([NH:14][C@H:8]([C:9]([OH:15])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:13])[NH2:11]
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Reactant: O=P(O)(O)O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: NC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
The assay of the D-hydantoinase activity was conducted by incubating a reaction mixture containing 120 mg/dl D-5-benzylhydantoin (BH), 50 mM KPB (pH 8.0) and an enzyme solution at 37° C. for 30 minutes, adding 9 volumes of 1.1 mM CuSO4, 11.1 mM H3PO4, centrifuging at 20,000 G for 10 minutes to remove the pellet, and then quantifying the resultant N-carbamylphenylalanine (N-Car-Phe) by HPLC. One unit of the enzyme activity was defined as an enzymatic activity capable of producing 1 μmol of N-carbamylphenylalanine per 1 minute under the condition described above.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=O)[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].CO>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 6-nitro-4-H-benzo[1,4]oxazin-3-one (7.84 g, 40.38 mmol) in tetrahydrofuran (100 mL) was added a solution of 2.0M borane-methyl sulfide complex in tetrahydrofuran (91 mL, 181 mmol). The mixture was heated to reflux for 4.5 hours then allowed to stir overnight at room temperature. Methanol was added slowly to react with unreacted borane-methyl sulfide complex, which resulted a violent evolution of gas. When this subsided, excess methanol was added and the solution heated to reflux. After 2 hours the solution was cooled, the solvent evaporated under vacuum, and the residue triturated with ethyl acetate/hexane. An orange solid was filtered off which was rinsed with hexane, to yield 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a solid product. More of the solid was recovered as a second crop from the filtrate.