Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)([CH3:9])[CH2:5]CC#N.Cl.[CH2:18]([OH:21])[CH2:19]O>[Cu]>[CH3:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)([CH3:9])[CH2:5][CH2:19][C:18]([OH:21])=[O:1]
Reactant: [OH-]
Reactant: OCCO
Reactant: Cc1ccc(C(C)(C)CCC#N)cc1
Agent: [Cu]
Agent: Cl
Agent: [K+]
Product: Cc1ccc(C(C)(C)CCC(=O)O)cc1
Temperature: 10 °C
Yield: 89.6 %

Procedure:
Potassium hydroxide (112 g) is slowly dissolved (heat evolved) in ethylene glycol (400 ml) in a 2 liter copper (or stainless steel) flask. The 4-methyl-4-p-tolylpentanenitrile (94 g, 0.5 mol) was then added, the mixture refluxed for 6 hours, cooled to 10° C and diluted with 400 ml ice cold water. Hydrochloric acid (conc., 180 ml) was added slowly (heat evolved, cooling required) until the reaction mixture was acid to congo test paper. The resulting mixture was extracted with benzene, washed with water, concentrated and distilled to yield 92.8 g (89.6%) of the 4-methyl-4-p-tolylpentanoic acid: bp 178° (2 mm); nD20 1.5147;
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[N:10]=[C:1]=[O:2])=[O:15]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1N=C=O
Yield: 100 %

Procedure:
Phosgene was bubbled through a solution of 10 g (66 mmol) of methylanthranilate in 15 ml of anhydrous toluene for 2 hours at reflux. Then the solvent was distilled off under reduced pressure to give 11.7 g (100%) of 2-methoxycarbonylphenylisocyanate; NMR (CDCl3) 3.89 (s, 3H, CH3); 7.0-7.63 (m, 3H, phenyl H-3,-4,-5); 8.0 (dd, 1 H, phenyl H-6). This was converted to the title compound, in 34% overall yield, by condensation with an equimolar amount of 2-pyridylcarbinol followed by saponification of the resulting ester with 1N sodium hydroxide and acidification of the reaction mixture to pH 4. The crude product was purified by crystallization from ethyl acetate; melting point =172°-175° C.; NMR (DMSO-d6) 5.2 (s, 2H, methoxy CH2); 6.8-8.8 (m, 9H, aromatic, NH); 10.8 (broad s, 1H, OH).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:23][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([O:21]C)=[O:20])=[CH:11][C:12]=3[C:13]3([O:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:4][CH2:3]1.CCO.[OH-].[Na+].O>C1COCC1>[CH3:1][C:2]1([CH3:24])[CH2:23][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([OH:21])=[O:20])=[CH:11][C:12]=3[C:13]3([O:14][CH2:15][CH2:16][CH2:17][O:18]3)[C:5]2=[N:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)C1(OCCCO1)C1=NCC(C)(C)CN12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC1(C)CN=C2N(C1)c1ccc(C(=O)O)cc1C21OCCCO1
Yield: 50.3 %

Procedure:
To a solution of methyl 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carboxylate (0.200 g, 0.610 mmol) in THF (4 mL)/EtOH (4 mL) was added 1N NaOH (2 mL) and H2O (2 mL) and the reaction was refluxed for 1 hr. The reaction was quenched with 1 N HCl and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound as white solid (0.097 g, 50%). NMR (400 Mz, DMSO-d6): consistent. MS (ES+) m/z 317.3 [M+H]. m.p.: 151.1-153.3° C.
Reaction SMILES: OCC[CH:4]([OH:6])[CH3:5].C=O.C(O)[C:10]([NH2:15])(CO)[CH2:11][OH:12].[CH3:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]#[C:27][I:28])=[O:23]>O>[OH:12][CH2:11][CH:10]1[NH:15][CH2:5][CH2:4][O:6]1.[CH2:20]([NH:21][C:22](=[O:23])[O:24][C:25]#[C:26][CH2:27][I:28])[CH2:19][CH2:18][CH3:17]
Reactant: CCCCNC(=O)OCC#CI
Reactant: CC(O)CCO
Reactant: NC(CO)(CO)CO
Agent: C=O
Solvent: O
Product: CCCCNC(=O)OC#CCI
Product: OCC1NCCO1
Temperature: 60 °C

Procedure:
A closed vessel is charged with 102 g of 1,3-dihydroxybutane and 62 g of prilled paraformaldehyde is added and mixed at room temperature until a uniform slurry is formed. The slurry is then heated to 60° C. and a 2% molar (or 1–5%) molar excess of tris(hydroxymethyl)aminomethane (THAM) is introduced. A total of 124 g of 99% pure tris(hydroxymethyl)aminomethane is gradually added in increasing increments until a 2% molar excess is obtained. The ensuing condensation reaction takes place over a period of 3 hours. During the reaction, soluble bicyclic hydroxymethyl oxazolidine is continuously formed. Since paraformaldehyde and tris(hydroxymethyl)-aminomethane are of low solubility in the reaction medium, completion of the reaction is indicated when a clear solution is formed with water by-product. When the mixture becomes clear, insuring that all of the formaldehyde has reacted, the resulting solution is allowed to cool to ambient temperature and 4.42 g of powdered IPBC (weight ratio of bicyclic hydroxymethyl oxazolidine HMBO to IPBC is 33:1) is added and stirred until a clear solution is obtained. No crystallization of IPBC is noted in the substantially colorless product and a pure clear, liquid composition containing less than 1000 ppm of formaldehyde is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>P(=O)(O)(O)O>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CC(C)=CCO
Reactant: CCOC(C)([O-])[O-]
Agent: O=P(O)(O)O
Product: C=CC(C)(C)CC(=O)OCC
Yield: 78.9 %

Procedure:
A mixture of 4.3 g of 3-methyl-2-buten-1-ol, 16.2 g of ethyl orthoacetate and 3 drops of phosphoric acid was reacted as described in Example V A to give 6.15 g (79% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 87°-88°/ 58 mm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9](F)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>COCCOC>[CH3:22][C:18]1[CH:17]=[C:16]([NH:15][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([NH:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(N)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: NCc1cccnc1
Solvent: COCCOC
Product: Cc1cccc(Nc2c(C#N)cnc3cnc(NCc4cccnc4)cc23)c1
Temperature: 140 °C
Yield: 2.1 %

Procedure:
In a microwave vial, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.200 g, 0.963 mmol) and m-toluidine (0.11 mL, 0.11 g, 1.1 mmol) were taken up in 5 mL DME. The vial was crimp-sealed and heated in a microwave reactor at 140° C. for 10 minutes. 3-(aminomethyl)pyridine (2.0 mL, 2.1 g, 19 mmol) was then added, and the reaction was heated at 200° C. for 30 minutes. To work up the reaction, the vial contents were partitioned between EtOAc and brine. The aqueous layer was extracted with additional EtOAc, and the combined organic extracts washed with water and evaporated. The crude product was purified twice by preparative HPLC, and lyophilized to give a fluffy, bright yellow solid (7.5 mg, 2.1% yield): 1H NMR (400 MHz, DMSO-D6) δ 2.31 (s, 3 H) 4.55 (d, J=4.0 Hz, 2 H) 7.06 (s, 3 H) 7.16 (s, 1 H) 7.21-7.39 (m, 2 H) 7.44 (s, 1 H) 7.75 (d, J=7.6 Hz, 1 H) 8.22 (s, 1 H) 8.43 (s, 1 H) 8.59 (s, 1 H) 8.82 (s, 1 H) 9.61 (br s, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]([N:12]([CH:27]([C:34]1[O:42][C:38]2=[CH:39][CH:40]=[CH:41][C:37]2=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O[Li].O>C1COCC1.CO.O>[O:42]1[C:38]2=[CH:39][CH:40]=[CH:41][C:37]2=[CH:36][CH:35]=[C:34]1[CH:27]([N:12]([S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:14])=[O:15])[CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:43])=[O:2])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C(Cc1ccccc1)N(C(c1ccccc1)c1ccc2cccc-2o1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C(Cc2ccccc2)C(=O)O)C(c2ccccc2)c2ccc3cccc-3o2)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (40 mg, 0.067 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1) and then added 1N aqueous solution of LiOH.H2O (0.40 mL, 0.40 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and methanol (9:1) to obtain 2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid. (29 mg, 75%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ7.59 (d, 2H), 7.48 (d, 2H), 7.42 (d, 2H), 7.19 (m, 4H), 7.06, 6.88 (2m, 6H), 6.37 (s, 1H), 4.55 (m, 3H), 3.70 (s, 3H), 3.19, 2.85 (2m, 2H), 2.56, 2.00, 1.98 (3s, 9H). ESI− (M−H): 582.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1)C=O.[N+:15]([CH3:18])([O-:17])=[O:16].[C:19]([O-])(=O)C.[NH4+]>CC(O)=O>[Br:1][C:2]1[C:3]([CH:19]=[CH:18][N+:15]([O-:17])=[O:16])=[CH:4][CH:5]=[CH:6][C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: O=Cc1cccc(Br)c1OCC1CC1
Reactant: CC(=O)[O-]
Reactant: C[N+](=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1cccc(OCC2CC2)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
380 mg (1.49 mmol) 5-Bromo-6-cyclopropylmethoxy-benzaldehyde (example XIX), 239 μL (4.47 mmol) nitromethane and 115 mg (1.49 mmol) ammonium acetate in 1.2 mL AcOH are stirred at 100° C. for 2 h. The reaction mixture is cooled to r.t. and quenched by the addition of 4 mL MeOH and 0.9 mL water. After stirring at r.t. for 1 h the precipitate is filtered off and dried at 40° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH2:20][CH3:21])[CH:14]=1.C(Cl)Cl.[OH2:25]>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:20][CH3:21])(=[O:9])=[O:25])[CH:14]=1
Reactant: CCSc1cccc(Br)c1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
The MCPBA (2.37 g, 10.6 mmol) was added to a solution of 1-bromo-3-(ethylthio)benzene (1.00 g, 4.80 mmol) in DCM (10 ml, 156 mmol) cooled to 0° C. The reaction was stirred for 1 h and then was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude residue was purified by flash column chromatography with a hexane:ethyl acetate gradient to give 1-bromo-3-(ethylsulfonyl)benzene as a colorless oil 1.1 gm 92%, 1H NMR (300 MHz, CDCl3): δ□8.09(m, 1H), 7.85(d,1H), 7.78(d, 1H) 7.45(t,1H), 3.14(q, 2H), 1.25(t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[S:16]>O1CCOCC1>[ClH:11].[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:15]1[S:16][CH2:12][CH2:13][N:14]=1
Reactant: S=C=NCCCl
Reactant: Cc1cccc(CN)c1C
Solvent: C1COCCO1
Product: Cc1cccc(CNC2=NCCS2)c1C
Product: Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
Under a dry nitrogen atmosphere, a stirred mixture of 5.56 grams (0.041 mole) of 2,3-dimethylbenzylamine and 5.0 grams (0.041 mole) of 2-chloroethylisothiocyanate in 100 mL of 1,4-dioxane was heated to 80° C. where it stirred for about 18 hours. The reaction mixture was allowed to cool and a solid precipitate that had formed was collected by filtration. The solid was rinsed with diethyl ether and was dried under reduced pressure to yield 8.0 grams of the title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].N12CCN(CC1)CC2>C(OC)(C)(C)C>[C:14](=[O:15])([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: C1CN2CCN1CC2
Solvent: COC(C)(C)C
Product: CN1C(C)(C)CC(OC(=O)Oc2ccccc2)CC1(C)C
Reaction time: 2 h

Procedure:
Into a 500 ml 3-neck flask was added 17.1 grams (0.1 mole) 1,2,2,6,6-pentamethyl-4-piperidinol and 300 mls of methyl t-butyl ether (MtBE). The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 15.6 grams (0.1 mole) phenyl chloroformate. The phenyl chloroformate was slowly added to the 1,2,2,6,6-pentamethyl-4-piperidinol solution without any appreciable exotherm. Then 11.2 grams (0.1 mole) of 1,4-diazabicyclo(2.2.2)octane (DABCO) was added at room temperature. The temperature rose to 50° C. and a precipitate formed. The reaction was stirred for 2 hours, an additional 2 grams of DABCO and 1.25 grams of phenyl chloroformate was added, the reaction heated to reflux and refluxed 2 hours. The reaction mixture was cooled, transferred to a separatory funnel and washed with water to remove DABCO, DABCO hydrochloride and a small amount of 1,2,2,6,6-pentamethyl-4-piperidinol. The product was then extracted out of the MtBE layer with 100 mls of 5% HC1 diluted with water to 400 mls. The MtBE layer which contained diphenyl carbonate was discarded. The acid layer was made basic with 100 ml of 10% NaOH. The product was extracted out of the aqueous layer with 200 ml MtBE. The MtBE extract was washed with 100 ml 5% NaHCO3, dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue was a white solid weighing 20.4 grams (70.1% crude yield) which had a melting point of 63°-67° C. Liquid chromatography indicated the product was essentially one component. The infrared spectrum contained a strong carbonyl peak at 1755 cm-1.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[Br:13][CH2:14][CH2:15][CH2:16][NH2:17].CCN(CC)CC>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][NH:17][S:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Cc1ccccc1)NCCCBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
A solution of phenylmethanesulfonyl chloride (2.19 g, 10 mmol) was added into a suspension of 3-bromopropan-1-amine hydrobromide (2.19 g, 10 mmol) and Et3N (2.02 g, 20 mmol) in THF (50 mL) at 0° C. The mixture was stirred at 0° C. for 5 min. TLC confirmed the completion of reaction. Solid was filtered out with suction, and the filtrate was concentrated to provide compound N-(3-bromopropyl)(phenyl)methanesulfonamide (2.7 g, quant.) as a pale yellow solid which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 4.48 (m, 1H), 4.27 (s, 2H), 3.41 (t, J=6.6 Hz, 2H), 3.16 (q, 2H), 2.01 (m, 2H). LCMS (ESI), m/z, 314 and 316 [M+Na]+, Br pattern found.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2].Cl[C:33](OC1C=CC=CC=1)=[O:34].[CH2:42]([CH2:44][NH2:45])[OH:43]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][O:18][C:33](=[O:34])[NH:45][CH2:44][CH2:42][OH:43])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2]
Reactant: NCCO
Reactant: CCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc2nc(COC(=O)NCCO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2-hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester (800 mg, 1.79 mmol), in anhydrous pyridine (20 mL) under a nitrogen atmosphere is added phenyl chloroformate (0.566 mL, 4.5 mmol) in one lot. A gelatinous, white precipitate is formed. The stirred reaction mixture is heated to 80° C. After 45 minutes TLC/LCMS analysis indicates completion of the reaction. The reaction is allowed to cool and evaporated in vacuo to dryness. The residue is partitioned between ethyl acetate and 2 M HCl. The organic phase is separated, dried over anhydrous Na2SO4, and evaporated to give an off-white foam which is dried at high vacuum. The foam is dissolved in anhydrous THF (10 mL) and ethanolamine (2 mL, 33 mmol) is added. The reaction mixture is stirred overnight at room temperature under argon. TLC/LCMS analysis indicates completion of the reaction. The reaction mixture is evaporated in vacuo to dryness and the residue is partitioned between dichloromethane and 2 M HCl. The organic phase is separated, dried over anhydrous Na2SO4 and evaporated in vacuo to give an orange oil. Purification by flash chromatography on silica (gradient elution with ethyl acetate, 50% to 70% to 90%, in cyclohexane) provides the title compound as colourless crystals after drying at high vacuum (872 mg, 1.64 mmol, 91%). Mp 122-125° C.; 1H NMR (400 MHz, CDCl3) 1.41 (3 H, t, J=7 Hz), 2.30 (1 H, bm), 2.43 (3 H, s), 2.67 (3 H, d, J=5 Hz), 2.74 (3 H, s), 3.27 (2 H, m), 3.66 (2 H, bm), 4.45 (2 H, q, J=7 Hz), 4.73 (2 H, m), 4.97 (1 H, bm), 5.31 (1 H, bm), 7.45 (1 H, d, J=8 Hz), 7.49 (1 H, s), 7.71 (1 H, t, J=8 Hz), 7.79 (1 H, m), 8.10 (1 H, d, J=8 Hz); MS m/z (ES+) 533.2 (M+1, 100%); HPLC: retention time=4.313 min, >99%, column Phenomex-Kingsorb C18, 3 cm×4.6 mm ID, solvent system MeCN/H2O (0.1% TFA), gradient 10 to 90% MeCN, 10 min; Detection 254 nm.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[O:12]=[C:13]1[NH:17][C:16](=O)[CH2:15][N:14]1[CH2:19][C@@H:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27].CO>O1CCCC1>[OH:25][C@H:23]1[CH2:22][N:21]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)=[O:27])[C@H:20]([CH2:19][N:14]2[CH2:15][CH2:16][NH:17][C:13]2=[O:12])[CH2:24]1
Reactant: O=C1CN(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1NCCN1C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a suspension of sodium borohydride (0.42 g) in tetrahydrofuran (20 ml) was dropwise added boron trifluoride etherate (5.25 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. To this solution was added a solution of (2S,4R)-2-(2,4-dioxoimidazolidin-1-yl)methyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.1 g) in tetrahydrofuran (10 ml) under ice-cooling and the mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was dropwise added methanol (5 ml) and the mixture was filtered off. The filtrate was evaporated in vacuo. The resulting residue was dissolved in methanol (30 ml) and 1.7 -1 hydrogen chloride-methanol solution (6 ml) and the solution was allowed to stand overnight at ambient temperature. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (60 ml). The solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give precipitates. The precipitates were washed with ethyl acetate (20 ml) and air-dried to give (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methyl pyrrolidine (1.39 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]=O.[C:11]([CH:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19])(=[O:13])[CH3:12]>O>[C:11]([C:14]1([CH2:9][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17][O:16][C:15]1=[O:19])(=[O:13])[CH3:12]
Reactant: C=O
Reactant: CC(=O)C1CCOC1=O
Reactant: NCc1ccccc1
Solvent: O
Product: CC(=O)C1(CNCc2ccccc2)CCOC1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 59.4 g of water, 21.4 g of benzylamine was added, and the resulting mixture was stirred with 17.8 g of 37% by weight formaldehyde aqueous solution at room temperature for 1 hour. To the mixture, 25.6 g of 3-acetyltetrahydrofuran-2-one was added dropwise, followed by stirring at 60° C. for 1 hour. After the completion of reaction, the resulting mixture was cooled to room temperature, followed by removal of water from the resulting oily matter, and thereby yielded 23.6 g of 3-acetyl-N-benzyl-3-aminomethyltetrahydrofuran-2-one as a yellow oily matter.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].O1[CH:12](CC)[CH2:11]1.[OH-].[Na+].O>C(O)(=O)C.C(O)C>[C:6]([CH:5]1[CH2:2][CH:1]([CH2:11][CH3:12])[O:3][C:4]1=[O:9])(=[O:7])[CH3:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCC1CC(C(C)=O)C(=O)O1
Reaction time: 48 h
Yield: 45 %

Procedure:
2-acetyl-4-ethyl butyrolactone was prepared from ethylacetoacetate and 1,2-epoxybutane according to the method described in Johnson U.S. Pat. No. 2,443,827. A mixture of 40 g sodium hydroxide (1.0 mole), 270 ml water and 90 ml ethanol was cooled to 0°, stirred, and 130 g ethylacetoacetate (1.0 mole) and 72 g 1,2-epoxybutane (1.0 mole) added. Stirring was continued at 0°, and the mixture was thereafter left at 4° C. for 48 hours. The reaction mixture was neutralized with 80 ml acetic acid, extracted with toluene, washed with water, sodium bicarbonate and finally with water. The mixture was then dried (magnesium sulfate), filtered and the solvent removed, leaving a product, bp 86°-96°-/0.1 mm, in 45% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:18])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.C(Cl)(Cl)Cl.C(=O)([O-])[OH:28].[Na+].[CH2:32]([O:34][C:35]([CH2:37][N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[C:39]1[C:47](Cl)=[O:48])=[O:36])[CH3:33]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH3:18])[S:17][C:13]=1[N:12]1[C:19]([CH3:22])=[N:20][N:21]=[C:11]1[CH2:10][NH:9][C:47]([C:39]1[N:38]([CH2:37][C:35]([O:34][CH2:32][CH3:33])=[O:36])[C:46]2[C:41]([CH:40]=1)=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:48])=[O:28]
Reactant: CCOC(=O)Cn1c(C(=O)Cl)cc2ccccc21
Reactant: Cc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc(C)n2-c2sc(C)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
4-(2-Chlorophenyl)-2,9-dimethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (4.15 g) was dissolved in 5% hydrochloric acid (50 ml), and the solution was stirred at 60° C. for 4 hours. The reaction mixture was cooled in a water bath, and chloroform (60 ml) and sodium hydrogencarbonate (12.6 g) were added with vigorous stirring. Then, 1-ethoxycarbonylmethylindole-2-carbonyl chloride (3.52 g) was added, and the mixture was stirred for 1 hour. The chloroform layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as eluent and crystallized from a mixed solvent of ethyl acetate and hexane to give 6.23 g of ethyl 2-(4-(3-(2-chlorobenzoyl)-5-methylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate.