Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[CH:12](O)=O>O>[CH3:5][C:2]1([CH3:1])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[N:4][CH2:3]1
Reactant: CC(C)(CN)c1ccccc1
Reactant: O=CO
Solvent: O
Product: CC1(C)CN=Cc2ccccc21
Temperature: 200 °C
Yield: 79 %

Procedure:
A mixture of 2-methyl-2-phenylpropylamine (7 g, 0.047 mol) and 96% formic acid (11 ml) was slowly heated to 200° C. and kept at this temperature for 1.25 hours during which time excess formic acid and water was allowed to distil. This mixture was added at 160° C. to a mixture of polyphosphoric acid (51 g) and phosphorous pentoxide (10.5 g) that had previously been heated at 170-180° C. for 1 hour. The resultant mixture was heated at 175° C. for 2 hours, before being cooled slightly and poured into water (500 ml) with stirring. The mixture was washed with ethyl acetate and the aqueous layer basified with 40% aqueous sodium hydroxide and extracted with dichloromethane (3×200 ml). Combined halogenated organics were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a brown oil (5.95 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([O:32]CC)=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([OH:32])=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSc4ccccc4)CC3)c2c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 81.4 %

Procedure:
A mixture of 0.39 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 2.3 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 17 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and was then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 10 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and dried in a desiccator (10 kPa). 0.3 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:22]([C@H:21]([N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:15][CH:14]=1)[S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(CO)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(COS(C)(=O)=O)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R)-2-[N-(4-chloro-benzenesulfonyl)-N-(4-hydroxymethyl-benzyl)amino]-4-methyl-pentanoic acid amide (1.5 g, 3.5 mmol) in CH2Cl2 (15 mL) cooled to 0° C. was added Et3N (0.74 mL, 5.3 mmol). A solution of methanesulfonyl chloride (0.29 mL, 3.5 mmol) in 5 mL CH2Cl2 was added dropwise and the reaction was allowed to stir at 0° C. for 1 h. The reaction mixture was diluted with 25 mL CH2Cl2, quickly washed with 1 N HCl, brine, and dried by passing the organic phase through a cotton plug. The solvent was removed in vacuo affording the title compound in quantitative yield. The resulting foam was used as is in subsequent reactions. MS (ESI), (M+95)+, 409.15 1H NMR (CDCl3) δ 7.70 (d, 2H, J=8.0), 7.48 (d, 2H, J=8.0), 7.41 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 6.27 (br s, 1H), 5.32 (br s, 1H), 5.24 (s, 2H), 4.64 (d, 1H, Jab=16), 4.43 (d, 1H, Jab=16), 4.33 (t, 1H, J=6), 2.90 (s, 3H), 1.90 (m, 1H), 1.60 (m, 2H), 0.96 (d, 3H, J=7.0), 0.91 (d, 3H, J=7.0)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.FC(F)(F)C(O)=O.[OH-].[Na+].[Br:26][CH2:27][CH2:28]O>>[Br:26][CH2:27][CH2:28][O:16][CH:14]1[C:15]2[C:10](=[N:9][C:8]3[C:3]([C:2]=2[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][CH2:13]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Nc1c2c(nc3ccccc13)CCCC2OCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (7.55 g) in 40 ml of 2-bromoethanol was added 9.9 ml of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 18 hrs, added to iced sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (ethyl acetate→2% triethylamine/ethyl acetate) to give 7.6 g (67%) of a product. Recrystallization from methanol/water gave the analytical sample, mp 163.5°-164.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[N:17]=[CH:18][S:19][CH:20]=1>CN(C)C=O>[O:4]1[CH2:5][CH2:6][N:1]([CH2:15][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: BrCc1cscn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1nc(CN2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methylthiazole (1.98 g), N-bromosuccinimide (3.56 g) and α,α′-azobisisobutyronitrile (164 mg) were dissolved in carbon tetrachloride (200 ml), and the solution was heated under reflux for 2 hours. After completion of the reaction, insoluble matter was removed by filtration, N,N-dimethylformamide (20 ml) was added to the filtrate, and carbon tetrachloride was distilled off under reduced pressure to obtain an N,N-dimethylformamide solution (about 20 ml) of 4-(bromomethyl)thiazole. Morpholine (871 μl), triethylamine (2.79 ml) and N,N-dimethylformamide (10 ml) were successively added to this N,N-dimethyl-formamide solution (about 10 ml) of 4-(bromomethyl)-thiazole, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue and an organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:19) to obtain the title compound (700 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:27]([N:34]1[C:38](=[O:39])[C:37](=[C:40]2[N:44]([CH3:45])[C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[S:41]2)[S:36][CH2+:35]1SC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([N:13]=[C:35]2[N:34]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:38](=[O:39])[C:37](=[C:40]3[N:44]([CH3:45])[C:43]4[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=4[S:41]3)[S:36]2)[CH:6]=1)(=[O:12])[CH3:11]
Reactant: CCOc1ccc(C(C)=O)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCOc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethoxy-3′-nitroacetophenone was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.77 (1H, dd), 7.64–7.68 (2H, m), 7.61 (1H, d), 7.48 (1H, m), 7.25–7.36 (4H, m), 7.15 (1H, m), 6.99 (1H, d), 6.98 (1H, d), 5.20 (2H, s), 4.11 (2H, q), 3.69 (3H, s), 2.57 (3H, s), 1.43 (3H, t); MS(ESI): 516 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[I:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCc1ccc(I)cc1
Temperature: 0 °C
Yield: 85.5 %

Procedure:
A stirred, cooled (−78° C.) solution of ethyl-4-iodo-benzoate (available from Lancaster, 12.9 g, 45 mmol) in anhydrous dichloromethane (100 mL) under argon was treated with a 1M solution of di-isobutyl aluminum hydride in dichloromethane (100 mL, 100 mmol). The reaction mixture was allowed to warm to 0° C. in 1.5 h, quenched with saturated aqueous ammonium chloride solution and the resulting emulsion was filtered over a bed of celite. The phases in the filtrate were separated and the aqueous phase was extracted with dichloromethane (×1). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (9 g, 85%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([CH3:18])(O)[CH:13]([CH2:19][CH3:20])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH2:19]([C:13]1[CH2:12][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][C:14]=1[CH3:18])[CH3:20]
Reactant: CCC1CC(CCOCc2ccccc2)CCC1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Solvent: O
Product: CCC1=C(C)CCC(CCOCc2ccccc2)C1

Procedure:
A mixture of 5-(2-benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution (16.6 mL, 8.28 mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol) was added via syringe and the mixture was stored at rt for 48 h. Another portion of NaOMe (8.3 mmol) and EtI (35 mmol) was added and the mixture was allowed to react until the starting material was not present (by TLC). The solution was quenched with an aqueous work-up and the resultant residue was purified by chromatography to yield 5-(2-benzyloxy-ethyl)-1-ethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (Intermediate K2, 1.87 g (86%). The keto-ester (Intermediate K2) was heated at 90 EC in 10% KOH (100 mL) for 10 h, then 6 h at rt. The mixture was cooled to 0 EC and acidified with HCl. The solution was warmed to 40 EC for 15 min. and then stored at rt for 2 h. The mixture was neutralized to pH 7 with NaOH and the organic material was recovered by extraction with chloroform. The resulting 4-(2-benzyloxy-ethyl)-2-ethyl-cyclohexanone (Intermediate K3) was isolated by standard work-up and used without further purification (88%). Intermediate K3 (1.36 g, 5.24 mmol) was dissolved in THF (75 mL) and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0 EC and reacted at rt for 1 h. The organic material was isolated from an aqueous, acidic work-up and purified by chromatography to give 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol 1.36 g (94%). 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol (1.39 g, 5.04 mmol) and TsOH—H2O (0.48 g, 2.52 mmol) were heated to reflux in benzene (˜100 mL) for 18 h in the presence of MgSO4 (˜250 mg). After an aqueous work-up and chromatographic purification, the product [2-(3-ethyl-4-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate K4) was isolated as a pale yellow oil 0.912 g (71%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]1[C:14]([O:16][CH3:17])=[O:15].[CH3:18][C:19]1[CH:28]=[C:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](Cl)=[O:40])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:26]2[CH2:25][CH:24]=[CH:23][CH2:22][C:21]=2[N:20]=1>C(Cl)Cl.O>[CH3:18][C:19]1[CH:28]=[C:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39]([NH:1][CH:2]4[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]4[C:14]([O:16][CH3:17])=[O:15])=[O:40])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1N
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1NC(=O)c1ccc2c(ccn2Cc2cc(C)nc3ccccc23)c1
Reaction time: 3.5 h
Yield: 69.1 %

Procedure:
The 1-tert-butyl 3-methyl 4-amino-1,3-pyrrolidinedicarboxylate (0.10 g, 0.41 mmol) was combined with the acid chloride from step (501b) (0.10 g, 0.32 mmol) in methylene chloride (15 mL) and water saturated sodium bicarbonate (15 mL). The reaction was stirred for 3.5 h, partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a solid. This was purified by flash chromatography on silica gel eluting hexane: ethyl acetate (30:60, v:v) to give the 1-tert-butyl 3-methyl 4-[({1-[(2-methyl-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]-1,3-pyrrolidinedicarboxylate (0.120 g, 70%) as a solid, MS (M+H)+=543.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[C-:9]#[N:10].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:9]([CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1)#[N:10]
Reactant: [C-]#N
Reactant: BrCCC1OCCO1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCC1OCCO1
Temperature: 23 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
A mixture of 2-(2-bromoethyl)-1,3-dioxolane (8.14 g, 45 mmol), potassium cyanide (5.85 g, 90 mmol), and 18-crown-6 (30 mg) in 30 mL of dimethylformamide was stirred for 72 hours at 23° C. The reaction mixture was filtered, diluted with 70 mL of dichloromethane and washed twice with 10 mL of water. The organic phase was dried over magnesium sulfate and distilled under vacuum to yield 3.2 g of 2-(2-cyanoethyl)-1,3-dioxolane. This was stirred in 20 mL of 1M HCl for 40 hours. The mixture was neutralized with sodium bicarbonate and extracted with 100 mL of dichloromethane. The dichloromethane extract was dried over magnesium sulfate and evaporated to yield 2.5 g of the desired aldehyde as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[CH3:1][N:2]1[C:6]([Sn:12]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][N:4]=[N:3]1
Reactant: Cn1ccnn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.8 %

Procedure:
To a solution of 1-methyl-1H-[1,2,3]triazole (1.33 g, 16 mmol) in THF (20 mL) at −78° C., was added dropwise n-BuLi (11 mL, 1.6M, 18 mmol). The mixture was stirred at −78° C. for 2 h before addition of Bu3SnCl (4.75 mL, 17.6 mmol). The mixture was stirred at this temperature for 1 h and at r.t. for 1 h. The mixture was concentrated in vacuo and hexanes was added. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo to afford 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (6.12 g, 82% yield) as a yellow syrup.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([F:16])[CH:7]=1.[CH2:17](O)[CH3:18]>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])=[C:8]([F:16])[CH:7]=1
Reactant: CCO
Reactant: Nc1ccc(CC(=O)O)c(F)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(N)cc1F
Temperature: 40 °C

Procedure:
Thionyl chloride (986 mL, 8.51 mol) was added dropwise to a stirred suspension of 2-(4-amino-2-fluorophenyl)acetic acid (960 g, 5.68 mol) in ethanol (10 L) at 0° C. under a nitrogen atmosphere. The reaction mixture was then heated to 40° C. for 48 hours, with the reaction progress monitored by 1H-nmr spectroscopy. The reaction mixture was evaporated to dryness and the residue redissolved in a mixture of dichloromethane (8 L) and saturated sodium hydrogen carbonate solution (5 L). Further sodium hydrogen carbonate solution was added (˜8 L) until the aqueous phase was basic. The layers were separated and the organic phase washed with saturated sodium hydrogen carbonate solution (4 L), dried over magnesium sulphate and the solvent removed under reduced pressure gave the desired product, ethyl (4-amino-2-fluorophenyl)acetate, as an orange oil (1042 g, 93% yield), that may crystallise upon standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([OH:13])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:15](OCC)=[O:16].O>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:11])[NH:12][C:15](=[O:16])[O:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC(=O)N(O)c1ccc(F)c(F)c1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2ccc(F)c(F)c2)o1
Reaction time: 1 h

Procedure:
1-(3,4-Difluorophenyl)-1-hydroxyurea (0.2 mole) dissolved in aqueous sodium hydroxide (200 ml; 2N) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10°C and ethyl chloroformate (0.21 mole) is slowly added with stirring. After the addition is completed stirring is continued for a period of about one hour. The reaction mixture is then poured into 2 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The dried product is then dissolved in a methylene chloride-tetrahydrofuran mixture and the resulting solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3,4-difluorophenyl)-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:20])[C@H:14]([C@H:16]([CH2:18][CH3:19])[CH3:17])[NH2:15])([CH3:11])[CH3:10]>>[CH3:11][Si:9]([O:12][C:13](=[O:20])[C@H:14]([C@H:16]([CH2:18][CH3:19])[CH3:17])[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:8])[CH3:10]
Reactant: CC[C@H](C)[C@H](N)C(=O)O[Si](C)(C)C
Reactant: CC(=O)C(=O)Cl
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)C(C)=O)C(=O)O[Si](C)(C)C

Procedure:
A method of synthesizing pyruvyl-isoleucine according to the invention the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting the pyruvyl chloride with a suspension of isoleucine trimethylsilyl ester hydrochloride to yield pyruvyl-isoleucine trimethylsilyl ester and then subjecting the pyruvyl-isoleucine trimethylsilyl ester to hydrolysis to yield pyruvyl-isoleucine. The pyruvyl-isoleucine synthesized via the method set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: [Sb:1].[H-].[Li+].[CH3:4][Si:5]([CH3:8])([CH3:7])Cl>O1CCCC1>[CH3:4][Si:5]([Sb:1]([Si:5]([CH3:8])([CH3:7])[CH3:4])[Si:5]([CH3:8])([CH3:7])[CH3:4])([CH3:8])[CH3:7]
Reactant: [Sb]
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)[Sb]([Si](C)(C)C)[Si](C)(C)C
Temperature: -20 °C

Procedure:
1.22 g (0.01 mol) of 200 mesh antimony powder, 0.72 g (0.03 mol) of lithium hydride, and 40 ml of tetrahydrofuran (THF) were placed in a 100 ml flask. With stirring, the mixture was refluxed for 4 hours. All of the black powder constituting antimony disappeared, and a muddy colored precipitate was formed. Then, the mixture was cooled down to −20° C.; 3.3 g (0.03 mol) of trimethylchlorosilane was added. The mixture was allowed to warm up to room temperature. After stirring for 4 hours, the mixture was filtered under inert atmosphere. The solvent was removed by distillation. Tris(trimethylsilyl)antimony was purified by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28](B(O)O)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O.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>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:28]4[C:29]([O:31][CH3:32])=[N:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ncc(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c(OC)n1
Temperature: 125 °C

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (4.1, 48 mg, 0.11 mmol, synthesized by procedures similar to those that were used to make compound 1.5 described in SCHEME 1), 2,4-dimethoxypyrimidin-5-ylboronic acid (4.2, 24 mg, 0.13 mmol), PdCl2(PPh3)2 (38 mg, 0.05 mmol), K2CO3 (23 mg, 0.16 mmol) in 1 mL acetonitrile and 1 mL water was degassed using argon stream and heated in microwave reactor at 125° C. for 15 min. The mixture was filtered and directly subjected to reverse phase prep HPLC to isolate the title compound. MS found for C20H17ClN6O3S (M+H)+ 457.1, 459.1 (Cl pattern).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C[CH2:7][O:8][CH2:9][CH3:10]>>[CH2:10]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH:9]1[O:8][CH2:7]1
Reactant: c1cc[nH]c1
Reactant: CCOCC
Product: c1ccn(CC2CO2)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A reaction mixture formed from 200 g of sodium hydroxide NaOH, 8.4 g of tetrabutylammonium hydrogensulfate, 200 ml of water and 125 ml of epichlorohydrin is stirred very vigorously at room temperature in a one liter reactor. 40 g of freshly distilled pyrrole are added dropwise while cooling the solution with a bath of ice-cold water in order to keep the temperature of the mixture between 15° and 20° C. The mixture is left stirring with a stream of nitrogen for 3 hours, 100 ml of ether are added in order to cause an aqueous phase and an organic phase to settle which are separated from each other. The aqueous phase is extracted twice with 100 ml of ether. The whole of the organic phase is washed with aqueous salt solution until neutrality, dried over a molecular sieve, filtered and distilled under vacuum. 58 g of N-glycidylpyrrole ##STR4## or a yield of 80%, are obtained. The product is characterized by 1H NMR and 13C NMR. Its purity is 93%; it is determined by liquid phase chromatography.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5]([NH:7][C@@H:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5]([NH:7][C@@H:8]1[O:16][CH2:15][C@@H:13]([O:14][C:23](=[O:25])[CH3:24])[C@H:11]([O:12][C:11](=[O:12])[CH3:13])[C@H:9]1[O:10][C:9](=[O:10])[CH3:8])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=NN(CCCl)C(=O)N[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1NC(=O)N(CCCl)N=O
Yield: 29.4 %

Procedure:
1-(2-chloroethyl)-1-nitroso-3-(β-D-xylopyranosyl) urea (99mg) was acetylated with acetic anhydride and pyridine in the same manner as that used in Example 1(b). Crystallization from a mixture of chloroform and n-propanol yielded the titled compound (42 mg). Yield 29.4%. mp. 124.5°-125° C. (with decomposition). [α]D17 -19.0° (c 0.9, chloroform).