Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2OC(=O)[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:22]>ClC1C=CC=CC=1Cl>[CH2:26]([O:25][C:23]([C:21]1[S:17][N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[N:22]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C#N
Reactant: O=c1oc(-c2ccc(OCc3ccccc3)cc2)ns1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 150 °C
Yield: 68 %

Procedure:
To a solution of 5-(4-benzyloxyphenyl)-[1,3,4]oxathiazol-2-one (0.31 g, 1.08 mmol) in 1,2-dichlorobenzene (2 ml) was added ethyl cyanoformate (0.43 ml, 4.35 mmol). The resulting reaction mixture was refluxed overnight at 150° C. After the completion of the reaction (TLC monitoring), added ice-cold water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum, to get the product (0.250 g, 65%). MS ES+ (341.12).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([S:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].[OH-].[Ca+2].[OH-]>ClCCl>[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([S:33]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:6])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:20][CH:21]3[CH2:22][CH:23]([CH2:24][CH:25]([CH2:27]3)[CH2:26]1)[CH2:28]2)=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(SC2CCNCC2)ccc1Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(S(=O)C2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
m-Chloroperoxybenzoic acid (166 mg) was added to a solution of 2-chloro-5-(piperidin-4-ylsulfanyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.35 g, Example 55c) in dichloromethane (5 ml). After 2 h calcium hydroxide (0.20 g) was added and 30 min. later the salts removed by filtration. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 0-25% ethanol in dichloromethane). The residue was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the solution was concentrated under reduced pressure and triturated with diethyl ether to yield the title compound as the hydrochloride salt (0.030 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[CH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.I[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[C:29]2=[O:36]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30](=[O:35])[C:29]3=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: C#CCCN1CCC(Cc2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#CCCN3CCC(Cc4ccccc4)CC3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A mixture of 4-benzyl-1-(3-butynyl)piperidine (904 mg, 4 mmol), Et3N (4 mL), CuI (76 mg, 0.4 mmol) and Pd(PPh3)2Cl2 (41 mg, 0.1 mmol) in DMF (10 mL) is stirred at room temperature under N2 for 30 min. 5-Iodoisatin (546 mg, 2 mmol) is added and stirring continued overnight. The mixture is evaporated and the residue purified by medium-pressure column chromatography on silica gel eluting with 50% EtOAc/hexanes (+1% Et3N) to give an orange solid (238 mg). The solid is recrystallized from hot 90:10 isopropanol:water to give the title compound as orange crystals (152 mg): mp 140-141° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:16])=[C:8]([O:12][CH2:13][CH2:14]Cl)[C:9]=2[CH3:11])[S:4][C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC#N>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:16])=[C:8]([O:12][CH2:13][CH2:14][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:9]=2[CH3:11])[S:4][C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1OCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1OCCN1CCOCC1
Yield: 30 %

Procedure:
tert-Butyl 3-amino-5-(2-chloroethoxy)-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate, prepared above (50 mg, 0.22 mmol), was dissolved in CH3CN (5 mL), followed by the addition of K2CO3 (41 mg, 0.30 mmol), morpholine (26 mg, 0.30 mmol) and a catalytic amount of KI. The mixture was heated to reflux overnight, the solvent was removed under reduced pressure, water was added and the residue was extracted with ethyl acetate (10 mL), and the organic phases were washed with water (5 mL×3), brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC to furnish the title compound, tert-butyl 3-amino-4,6-dimethyl-5-(2-morpholin-4-yl-ethoxy)-thieno[2,3-b]pyridine-2-carboxylate (20 mg, 30%).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(Cl)Cl>[Si:9]([O:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
4-Hydroxymethylimidazole hydrochloride ACROS (5 g, 37.1 mmol) was suspended in CH2Cl2 (100 ml) and TEA (12.87 ml, 92.8 mmol) was added. The solution was cooled at 0° C. and tert-butyldiphenylsilylchloride (15.3 ml, 55.7 mmol) was added. The reaction mixture was stirred for 30 min at 0° C. and at room temperature for 3.5 h. Water was added, the organic extract was washed with water and brine, then died over MgSO4. The solvent was removed under reduced pressure and the resulting oil was crystallized from diisopropylether to afford a white solid (8.17 g, m.p.=135° C.).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[S:17]([N:20]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:19])=[O:18].[H-].[Na+]>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:13]=[CH:12][C:11]=1[S:17]([N:20]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])(=[O:19])=[O:18]
Reactant: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2Cl)c(C)c1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2Cl)c(C)c1
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a stirred solution of 4-(hydroxylmethyl)tetrahydro-2H-pyran (2.63 mg, 0.023 mmol) and 2-chloro-N-(3,5-dimethylpyridin-2-yl)-4-fluoro-N-isobutylbenzenesulfonamide (8.4 mg, 0.023 mmol) in dimethyl sulfoxide (200 μL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.906 mg, 0.023 mmol) and the reaction stirred for 2 hours. The reaction was quenched with methanol (2 mL) and water (2 mL), then the solvents evaporated in vacuo. The crude product was purified by flash silica (Si) chromatography (25% ethyl acetate-cyclohexane gradient) to give the title compound (5.2 mg). LCMS (2 min, High pH) Rt 1.48 min, m/z (ES+) 468 (M+H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:13]1[C:22]([Cl:23])=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>CS(C)=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:13]([CH:2]([C:1]#[N:5])[C:3]#[N:4])=[N:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: N#CCC#N
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CC(C#N)c1nc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Malononitrile B (0.66 g, 10 mmol) was dissolved in 20 ml DMSO. Cesium carbonate (4.87 g, 15 mmol) was added to the reaction mixture followed by addition of 2,3-dichloroquinoxaline (2.0 g, 10 mmol). The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was diluted with 50 ml ethyl acetate and washed with 1N HCl (2×50 mL). the mixture was extracted with ethyl acetate (2×80 mL). The combined organic layer was washed with brine solution (2×50 mL). The organic layer was collected and the solvent was removed under reduced pressure to yield the crude product C 2-(3-chloroquinoxalin-2-yl)malononitrile (2.0 g) which was used in the next step without further purification. Compound C (0.22 g, 1 mmol) was transferred to a microwave vessel containing 1 ml butyl amine. The reaction mixture was subjected to microwave irradiation at 70° C. for 30 min. The resultant crude reaction mixture was purified using column chromatography to yield compound D as shown in Scheme 3 (0.20 g, 86% yield). ESI (m/z): 266 (M+H+).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19](C(=O)C(F)(F)F)[CH2:18][CH2:17]3)(=[O:13])=[O:12])=[CH:6][CH:5]=1>C(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH2:20][NH:19][CH2:18][CH2:17]3)(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Nc3ccc(F)cc3)ccc2C1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(F)cc1)c1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
An aqueous solution (10 mL) of potassium hydroxide (2.24 g, 40.0 mmol) was added to a suspension of N-(4-fluorophenyl)-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (8.05 g, 20.0 mmol) in ethanol (40 mL), and the mixture was stirred at room temperature for 15 hr. The mixture was concentrated under reduced presesure and then diluted with water. While cooling in ice, 3 mol/L hydrochloric acid was added dropwise thereto to adjust the pH to 7 to 8. A precipitated solid was collected by filtration to afford the title compound as a colorless powder (6.04 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:7][C:6]=1[CH3:18])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:14]([O:13][C:11](=[O:12])[NH:10][C:8]1[S:9][C:5]([CH2:3][OH:2])=[C:6]([CH3:18])[N:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid methyl ester (0.5 g) was dissolved in anhydrous THF (7 mL) and cooled to 0° C. and 1 eq of Lithium aluminum hydride (2M solution in THF) was added and stirred 1 h. Reaction was slowly warmed to RT and stirred for 6 h. Reaction was cooled to 0° C. and quenched with min amount of sat. Na2SO4 soln. White solid was filtered and washed with ethyl acetate (5 mL), filtrate was concentrated by rotavap and residue was dried in vacuum gave (5-Hydroxymethyl-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.4 g). This was used in the next reaction without further purification. 1H NMR (400 MHz, Acetone-d6) 4.6 (s, 2H), 2.1 (s, 3H), 1.5 (s, 9H).
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]([CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([Br:15])=[CH:10][C:9]=3[N:8]=[C:7](Cl)[C:6]=2[N:17]=1.[NH3:23]>CO>[NH2:2][C:3]1[N:4]([CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([Br:15])=[CH:10][C:9]=3[N:8]=[C:7]([NH2:23])[C:6]=2[N:17]=1
Reactant: N
Reactant: CC(C)(O)Cn1c(N)nc2c(Cl)nc3cc(Br)ccc3c21
Agent: Br
Solvent: CO
Product: CC(C)(O)Cn1c(N)nc2c(N)nc3cc(Br)ccc3c21
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
1-(2-Amino-7-bromo-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol hydrobromide (1.18 g, 3.19 mmol) and ammonia (50 mL of a 7 N solution in methanol) were added to a pressure vessel, which was sealed and heated at 140° C. for five days. Additional ammonia in methanol was added after two days. When the reaction was complete, the volatiles were removed under reduced pressure, and the residue was stirred with aqueous sodium hydroxide (100 mL of 2 N) for 15 minutes. A solid was present and was isolated by filtration, washed with water and diethyl ether, and dried under vacuum to provide 681 mg of 1-(2,4-diamino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a gray solid.
Reaction SMILES: [OH-].[Na+].C([O:10][C:11]1[CH:47]=[CH:46][C:45]([O:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)=[CH:44][C:12]=1[C:13]([NH:15][C:16]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:34][C:17]=1[C:18]([O:20]C1CCN(C(OC(C)(C)C)=O)CC1)=[O:19])=[O:14])C1C=CC=CC=1>CO.O1CCOCC1>[C:58]([O:57][C:55]([N:52]1[CH2:53][CH2:54][CH:49]([O:48][C:45]2[CH:46]=[CH:47][C:11]([OH:10])=[C:12]([CH:44]=2)[C:13]([NH:15][C:16]2[CH:37]=[C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:35]=[CH:34][C:17]=2[C:18]([OH:20])=[O:19])=[O:14])[CH2:50][CH2:51]1)=[O:56])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccc(-c3ccccc3)cc2NC(=O)c2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc2OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.13 mL) was added to a solution mixture of the obtained tert-butyl 4-(2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzamido)-4-phenylbenzoyloxy)piperidine-1-carboxylate (0.072 g) in methanol (1 mL) and dioxane (1 mL), followed by stirring at room temperature for 1 hour. A 2 mol/L aqueous solution of sodium hydroxide (0.089 mL) was added to the reaction mixture, followed by heating to reflux for 20 minutes. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 3.5 with a 10% aqueous solution of citric acid, ethyl acetate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution mixture of the obtained residue, 10% palladium-carbon (0.039 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.024 g of 2-(5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a light yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9]([OH:11])=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](O)[CH3:22]>O>[NH:5]1[C:9](=[O:11])[CH2:8][CH2:7][C@H:6]1[C:12]([O:14][CH2:21][CH3:22])=[O:13]
Reactant: CCO
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)[C@@H]1CCC(=O)N1
Temperature: 160 °C

Procedure:
Thionyl chloride (217 ml) is slowly added to a stirred suspension of L-glutamic acid (417 g) in dry ethanol (1 L), and the mixture is refluxed for 5 hours. Ethanol is removed under vaccum to give a residue, which is dissolved in water (500 ml). The water solution is made alkaline with saturated sodium carbonate solution and extracted with chloroform (4×200 ml). The chloroform extract is dried (Na2SO4) and evaporated to give crude product (178 g). This material is heated (160° C.) under vaccum (10 mm Hg) for 3 hours. Subsequent distillation gives pure ethyl L-pyroglutamate (126.6 g; b.p. 126° C./0.07 mm Hg; [α]D =-2.15°±0.01 (H2O, c=17.8).
Reaction SMILES: [CH2:1]([S:4][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:44]>C(OCC)(=O)C>[CH2:1]([S:4]([CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)=[O:44])[CH:2]=[CH2:3]
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(F)cc1)C(=O)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: C=CCS(=O)C1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(F)cc1)C(=O)C(C)(C)C
Yield: 58.3 %

Procedure:
To a solution of 4.0 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-fluorophenoxy)-3-trimethylacetylthio-propenate in ethyl acetate at -78° was added a solution of 1.5 g of 80% m-chloroperoxybenzoic acid in ethyl acetate over 10 minutes. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over MgSO4, and evaporated in vacuo to dryness. Chromatography over silica gel and elution with ethyl acetate-hexane mixtures afforded 2.4 g of the title compound as a yellow oil (58% of the theoretical yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[C:10](Cl)[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1>>[Cl:7][C:8]1[N:9]=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: C1COCCN1
Product: Clc1nc(N2CCOCC2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Morpholine (87 ml, 1.00 mol, 2.2 equiv.) was added to a solution of 2,4-dichloro-thieno[3,2-d]pyrimidine 3 (93.4 g, 0.456 mol, 1.0 equiv.). The reaction mixture was stirred at ambient temperature for 1 h and the resulting slurry was filtered, rinsed with water (500 ml). The cake was dried in a vacuum oven at 40° C. for 24 hours to give 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 as an off-white solid (109 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.74 (t, J=4.9 Hz, 4H), 3.90 (t, J=4.9 Hz, 4H), 7.40 (d, J=5.6 Hz, 1H), 8.30 (d, J=5.6 Hz, 1H). LCMS (ESI pos) m/e 257 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11](CO)[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[O-]S([O-])(=O)=O.[Mg+2]>O>[C:1]([O:9][CH2:10][CH:11]=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC(O)CO)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Product: O=CCOC(=O)c1ccccc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
This known intermediate was prepared by portionwise addition of NaIO4 (80 g) to a mixture of 1-benzoyl glycerol (50 g), CH2Cl2 (500 ml), and H2O (25 ml) under vigorous stirring at room temperature. The resulting solution was stirred for 2 hours, MgSO4 (100 g) was added and the solution stirred for an additional 30 minutes. The mixture was filtered, the filtrate evaporated in vacuo and the residue distilled in vacuo to yield 26 g of pure product.
Reaction SMILES: C(O[C:4]([C:6]1[O:15][C:9]2=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]=1[NH2:16])=[O:5])C.[NH2:17][C:18](N)=[O:19].N>O>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]2[C:7]3[NH:16][C:18](=[O:19])[NH:17][C:4](=[O:5])[C:6]=3[O:15][C:13]=2[N:12]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)c1oc2cc(C)ncc2c1N
Agent: N
Solvent: O
Product: Cc1ccc2c(n1)oc1c(=O)[nH]c(=O)[nH]c12
Reaction time: 0.5 h

Procedure:
A round-bottomed flask was loaded up with 3-amino-6-methyl-furo[2,3-d]pyridine-2-carboxylic acid ethyl ester, 16 (926 mg, 4.20 mmol, 1 eq) and urea (2.52 g, 42.0mmol, 10 eq). The mixture was heated up at 190° C. for 3 h until no more ammonia release was observed. H2O (10 mL) was added, and the reaction mixture was stirred for 30 min vigorously; it was then filtered, and the solid was washed with H2O (3×10 mL) before drying to furnish the product as a pale brown solid (1.60 g, quant.)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:11]([NH2:13])[CH3:12]>C1COCC1.O>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:13][CH2:11][CH3:12])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ncc(Br)c(OC)n1
Temperature: 60 °C
Yield: 86.5 %

Procedure:
A solution of 5-bromo-2-chloro-4-methoxypyrimidine (0.6 g, 2.69 mmol) in THF (10 mL) was treated with ethylamine (2.0M in THF, 6.71 mL, 13.43 mmol) was heated at 60° C. for 1 h, cooled to RT and diluted with water. The mixture was extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by column chromatography (EtOAc/Hex) to afford 5-bromo-N-ethyl-4-methoxypyrimidin-2-amine as a white solid (0.54 g, 87%). MS (ESI) m/z: 232.03 (M+H+).
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10]CC)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:10])=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCON=C(C(=O)OCC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
Ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetate (mixture of syn isomer and anti isomer, 1 g.) was added to a mixture of methanol (10 ml.) and 1 N aqueous solution of sodium hydroxide (6 ml.), and stirred at room temperature for 18 hours. After distilling off the methanol from the resultant solution in vacuo, a saturated aqueous solution of sodium bicarbonate (15 ml.) and ethyl acetate (15 ml.) were added to the residue and shaken sufficiently. The aqueous layer was separated, adjusted to pH 1.0 with 10% hydrochloric acid and extracted with ethyl acetate (20 ml.). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with a mixture of n-hexane and diethyl ether (1:1). The precipitates were collected by filtration and washed with the same mixture to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer, 0.30 g.).