Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Cl.O[N:9]1[CH2:12]C[CH2:10]1.[Cl:13][CH2:14][C:15](Cl)=[O:16]>O.C(Cl)Cl>[Cl:13][CH2:14][C:15]([N:9]1[CH2:12][CH:1]([OH:4])[CH2:10]1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: ON1CCC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)N1CC(O)C1
Temperature: 25 °C

Procedure:
To a suspension of potassium carbonate (13.9 g, 100 mmol, 2.2 eq.) in water (33.5 mL) was added hydroxyazetidine hydrochloride (5 g, 45.6 mmol, 1 eq.). The reaction mixture was stirred at r.t. until complete dissolution, then diluted with 33.5 mL of DCM and cooled to 0° C. prior to the dropwise introduction of chloroacetyl chloride (4.4 mL, 54.8 mmol, 1.2 eq.) over 30 min After 2 h stirring at r.t., the reaction mixture was filtered, the organic layer was separated, and the aqueous phase was extracted with a mixture EtOAc/nBuOH 1:1 (6×16 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was suspended in acetone (48 mL) and stirred vigorously for 20 min, filtered and the filtrate was concentrated in vacuo to afford Intermediate Gen-13-a.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13]([O:15][CH2:16][O:17][CH3:18])=[CH:12][CH:11]=[CH:10]2.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:18][O:17][CH2:16][O:15][C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2][O:1][CH3:21])[CH:10]=[CH:11][CH:12]=1
Reactant: CI
Reactant: COCOc1cccc2cccc(CCCO)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCc1cccc2cccc(OCOC)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.1 g of 8-(3-hydroxypropyl)-1-methoxymethoxy naphthalene was dissolved in 40 ml of N,N-dimethyl formamide, to which 1.4 g of 55% sodium hydride was added under ice cooling. Then, 1.93 ml of methyl iodide was added and stirred at a room temperature for 2 hours. After adding water to the reaction solution and extracting with ethyl acetate, the organic layer was washed with water and then with a saturated aqueous solution of sodium chloride successively and then dried over magnesium sulfate. After distilling off the solvent, when it was purified on silica gel column chromatography (10% ethyl acetate-hexane), 5.3 g of the above-captioned compound was obtained as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][CH:7]=[C:8]([CH2:9][P:10]([CH3:15])(=[O:14])[O:11][CH2:12][CH3:13])[C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:28](=[O:30])=[O:29].CC(OC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:10]([O:11][CH2:12][CH3:13])([CH3:15])=[O:14])[C:28]([OH:30])=[O:29])[C:4]=2[CH:3]=1
Reactant: O=C=O
Reactant: CCOP(C)(=O)Cc1csc2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOP(C)(=O)C(C(=O)O)c1csc2ccc(Cl)cc12
Temperature: -20 °C

Procedure:
To a dry 4N 300 ml flask equipped with magnetic stirrer, nitrogen inlet, temperature probe and addition port was added ethyl (5-chlorobenzo[b]thiophen-3-yl)methyl(methyl)phosphinate (12.7, 43.99 mmol) and dry THF (15 mL) under nitrogen. The resulting solution was cooled to −20° C. To the mixture was then added a 40% (2.2 M) NaHMDS solution in THF (25 mL), maintaining the temperature below 10° C. Following the base addition, CO2 was bubbled cautiously until no exotherm was observed, while maintaining the temperature of the reaction mixture below 15° C. The resulting mixture was then degassed with nitrogen and NaHMDS (10 mL) was added, followed by additional CO2 bubbling. The addition of NaHMDS ad CO2 was repeated 3 more times. The resulting solution was cooled to 0° C. and MTBE (80 mL) was added. To the resulting mixture was then added, slowly, 2N HCl (20 mL), followed by 6N HCl (40 mL), at which point the pH of the mixture was measured to be about 2. Throughout the addition of the acid, the temperature of the mixture was maintained between 0 and 15° C. Initial precipitation was observed upon acidification, while on completion of the acid addition, the mixture resolved in two clear layers. The layers were split, and the organic layer evaporated to yield an oil. The oil was digested overnight with MTBE (20 mL) to yield the title compound as a filterable solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24].C1C=CC=CC=1.O1CCOCC1CC(O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@H:12]([OH:13])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: O=C(O)CC1COCCO1
Solvent: c1ccccc1
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](O)C[C@H]1O

Procedure:
The 1.3-dinitroglycerol ester of prostaglandin F2β was prepared by the same procedure from the corresponding ester of prostaglandin E2 : a viscous, colorless oil, Rf 0.16 (benzene- dioxane-acetic acid, 20:10:1), mass spectrum (FAB) m/z 517 (M+H), 501 (M+H-H2O).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]1([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH2:19][CH2:18][CH:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)[CH2:16][CH2:15]1>O.C(OCC)(=O)C>[OH:13][C:14]1([CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH2:15][CH2:16][CH:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:32][CH:33]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)[CH2:18][CH2:19]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)(C3CCOCC3)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(O)(C3CCOCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogen carbonate (0.38 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-hydroxy-4-(tetrahydro-2H-pyran-4-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 24 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.045 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.042 mL) were added, and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.020 g, 14%).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:35]/[O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)/[C:32]([O-])=[O:33])[N:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na+].[NH2:57][C@@H:58]1[C:77](=[O:78])[N:60]2[C:61]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[C:62]([C@H:65]3[CH2:69][CH2:68][CH2:67][O:66]3)[CH2:63][S:64][C@H:59]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[O:66]1[CH2:67][CH2:68][CH2:69][C@@H:65]1[C:62]1[CH2:63][S:64][C@@H:59]2[C@H:58]([NH:57][C:32](=[O:33])/[C:31](/[C:29]3[N:30]=[C:26]([NH:25][C:6]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[S:27][CH:28]=3)=[N:35]\[O:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:77](=[O:78])[N:60]2[C:61]=1[C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71]
Reactant: CC(C)(C)OC(=O)C1=C([C@H]2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1=C([C@H]2CCCO2)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Yield: 67.8 %

Procedure:
Methanesulphonyl chloride (96μl, 1.25mmol) was added to sodium 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetate (852mg, 1.2mmol) in DMF (2ml) at <-40° C. The mixture was stirred 0.5h at -30±10° C. then t-butyl (6R,7R)-7-amino-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (326mg, 1mmol) in DMF (2ml), followed by pyridine (101μl, 1.25mmol), were added. The reaction was stirred for 1h without further cooling then diluted with ethyl acetate, washed twice with water and with brine, dried, concentrated in vacuo and flash chromatographed eluting with 25, 30% ethyl acetate in hexane to give the title compound as a colourless foam (665mg, 68%); vmax (CH2Cl2) 3395, 1787, 1722, 1687, 1527, 1449, 1156 and 1051cm-1 ; δH (CDCl3 /CD3OH) 1.55 (9H, s), 1.65-2.25 (4H, m), 3.32 and 3.40 (2H, ABq, J 17.6Hz), 3.8-4.0 (2H, m), 5.08 (1H, d, J 4.8Hz), 5.13 (1H, dd, J 7.0, 8.1Hz), 5.91 (1H, d, J 4.5Hz), 6.56 (1H, s), 7.2-7.5 (30H, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (1002)].
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([CH3:25])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH3:25][C:17]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
A suspension of sodium hydride (1150 mg of 60% in mineral oil, 3.7 mmol) was formed in THF (10 mL) and cooled in an ice bath. 2,2,2-Trifluoroethanol (0.34 mL, 4.7 mmol) was added dropwise, then the mixture was stirred at 0° C. for 5 mins. A solution of ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate (500 mg, 1.9 mmol) in THF (10 mL) was added and the mixture heated at reflux for 18 hours then cooled to room temperature. The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried over magnesium sulphate, filtered and evaporated to give an oil. Purification by flash column chromatography on silica gel using 40% hexane:60% DCM as eluent gave ethyl 4-methyl-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)nicotinate as a colourless oil (350 mg): 1H NMR (500 MHz, CDCl3): δ 7.24 (1H, s), 4.83-4.77 (2H, q, J 8.3), 4.43 (2H, q, J 7.1), 2.43 (3H, s), 1.38 (3H, t, J 7.1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[K+]>CN(C)C=O>[C:17]([O:20][CH2:2][C:3]1[N:4]=[C:5]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)c1cn2c(=O)cc(CCl)nc2s1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn2c(=O)cc(COC(C)=O)nc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
7-chloromethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (12.8 g), prepared according to Example 7, was dissolved in dimethylformamide and reacted with anhydrous potassium acetate (10 g) under stirring at room temperature for 20 hours. After dilution with ice water the precipitate was filtered and washed with water to give 7-acetoxymethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (12.7 g) which was hydrolysed by treatment with 37% HCl (20 ml) in dioxane (100 ml) under stirring at room temperature for 2 hours. The reaction mixture was diluted with acetone and the precipitate was filtered and then treated with aqueous Na2HPO4 : filtration and washings with water until neutral gave 7-hydroxymethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (7.1 g) which was reacted with dicyclohexylcarbodiimide (14.01 g) in benzene (90 ml) and dimethylsulphoxide (40 ml) in the presence of trifluoroacetic acid (1 ml) and pyridine (1.71 ml) under stirring at room temperature for 20 hours. After treatment with oxalic acid bihydrate (3.1 g) at room temperature, the precipitate of dicyclohexylurea was filtered off and the organic solution was concentrated in vacuo to dryness: the residue was purified over a SiO2 column using chloroform; methanol=95:5 as eluent. The 7-formyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester so obtained (2.7 g) was reacted with triphenylphosphoniumbenzyl chloride (2.94 g) under treatment with 50% NaH (0.43 g) in dimethylsulfoxide (10 ml) and dichloroethane (6 ml) at room temperature for 18 hours. After evaporation of the solvent in vacuo, the residue was diluted with ice water and the precipitate was filtered and washed with water: crystallization from isopropyl alcohol gave 1.9 g of 7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester, m.p. 183°-185° C., which was hydrolyzed by treatment with 0.5% KOH solution in 95% ethanol (80 ml) at reflux temperature for 1 hour. The precipitate was filtered and dissolved in dimethylformamide-formic acid: the solution was then diluted with ice water. The precipitate was filtered and washed with water until neutral: crystallization from CHCl3 -isopropyl alcohol gave 1.3 g of 7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 246°-248° C., N.M.R. (CF3COOD-CDCl3) δ p.p.m.: 6.84 (s) (1H, C-6 proton), 7.12 (d) (1H, β-ethenyl proton), 7.45-7.74 (m) (5H, phenyl protons), 7.85 (d) (1H, α-ethenyl proton), 8.97 (s) (1H, C-3 proton), JHαHβ =16 Hz.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[CH2:5][CH:6]1[NH:11][CH2:10][CH2:9][O:8][CH:7]1[CH2:12]2.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCOC(C)=O.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[CH2:28]([O:27][C:25]([N:11]1[CH2:10][CH2:9][O:8][CH:7]2[CH2:12][C:13]3[C:4]([CH2:5][CH:6]12)=[C:3]([O:2][CH3:1])[CH:16]=[CH:15][CH:14]=3)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cccc2c1CC1NCCOC1C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc2c1CC1C(C2)OCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of 6-methoxy-3,4,4a,5,10,10 a-hexahydro-2H-naphtho-[2,3-b][1,4]oxazine (0.62 g, 2.7 mmol) in 10 ml of CH2Cl2 was added triethylamine (1.0 ml, 7.2 mmol ) and benzyl chloroformate (0.6 ml, 4.1 mmol). The resulting mixture was stirred at 25° C. for 3 h. It was then diluted with 100 ml of EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oily residue which was subjected to column chromatography (20% EtOAc-CH2Cl2) to provide 0.46 g (48%) of the desired product. 1H NMR (300 MHz, CDCl3): δ 2.45 (dd, 1H, J=10.6, 16.6 Hz), 2.83 (dd, 1H, J=10.3, 16.0 Hz), 3.04 (dd, 1H, J=5.0, 16.0 Hz), 3.68-3.88 (m, 6H), 3.76 (s, 3H), 4.02(m, 1H), 5.16 (AB q, 2H, J=17.6 Hz), 6.66 (m, 2H), 7.09 (t, 1H,J=7.8 Hz).
Reaction SMILES: Br.Br[CH:3]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:4]1[CH:17]=[CH:16][C:7]2[NH:8][C:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[N:10][C:6]=2[CH:5]=1.[CH3:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1.CN(C)C=O>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:3]([N:27]2[CH:28]=[CH:29][N:30]=[C:26]2[CH3:25])[C:4]2[CH:17]=[CH:16][C:7]3[NH:8][C:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[N:10][C:6]=3[CH:5]=2)=[CH:19][CH:20]=1
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)Nc1nc2cc(C(Br)c3ccc(F)cc3)ccc2[nH]1
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2cc(C(c3ccc(F)cc3)n3ccnc3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.2 %

Procedure:
A mixture of 9.18 parts of methyl [5-[bromo(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]carbamate monohydrobromide, 12.3 parts of 2-methyl-1H-imidazole and 56.4 parts of N,N-dimethylformamide was stirred for 17 hours at room temperature. The reaction mixture was diluted with 300 parts of water. The precipitated product was filtered off and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 27 parts of ethyl acetate. The product was filtered off, washed with 1,1'-oxybisethane and dried, yielding 2.6 parts (34.2%) of methyl [5-[(4-fluorophenyl)(2-methyl-1H-imidazol-1-yl)methyl]-1H-benzimidazol-2-yl]carbamate; mp. >300° C. (compound 6).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+]>CO.C1COCC1.C(O)(=O)C.[Zn]>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-chloro-3-nitrobenzoate (2.1 g, 9.7 mmol) in methanol (100 mL) and THF (20 mL) was added zinc powder (1.9 g, 29 mmol), ammonium formate (3.1 g, 49 mmol), and a few drops of acetic acid. The mixture was allowed to stir at RT for 18 hours. Most of the volatiles were removed under reduced pressure. The residue was redissolved in EtOAc (200 mL), washed with brine, concentrated and purified by MPLC to provide methyl 3-amino-2-chlorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1Br.C([Li])CCC.[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC.O1CCCC1>[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: Clc1sccc1Br
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1NC(=O)C(c2ccsc2Cl)C(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Following the method of Gronowitz et al. [Chemica Scripta 15, p. 2 (1980)], 2-chloro-3-bromothiophene is reacted with n-butyl lithium in ether at -70° C. After 15 minutes, the organolithium reagent is poured into a solution of alloxan in tetrahydrofuran at -70° C. The reaction mixture is allowed to warm to room temperature for 2 hours, and 5-(2-chloro-3-thienyl)-2,4,6(1H,3H,5H)-pyrimidinetrione isolated according to Example 5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.Br.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccon1
Agent: Br
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
By the procedure of Example 8(i), 3-[(2-aminoethyl)thiomethyl]isoxazole (from the hydrobromide (3.7 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (3.5 g) to give 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene (3.6 g) which, on reaction with methylamine by the procedure of Example 8(ii) gives the title product (3.0 g).
Reaction SMILES: C1C=C2C=CC=C(/C=C/C3C=C[N+](C[CH2:20][OH:21])=CC=3)C2=CC=1.[Br-].[NH2:23][C:24]([NH2:26])=[S:25].O.CN1C[CH2:32][CH2:31][C:30]1=[O:34]>>[CH3:20][O:21][C:31]1[C:30](=[O:34])[NH:23][C:24](=[S:25])[NH:26][CH:32]=1
Reactant: OCC[n+]1ccc(/C=C/c2cccc3ccccc23)cc1
Reactant: NC(N)=S
Reactant: CN1CCCC1=O
Agent: [Br-]
Solvent: O
Product: COc1c[nH]c(=S)[nH]c1=O

Procedure:
Intermediate B111 (2.64 g, 1 equiv) and thiourea (2.42 g, 4 equiv) in 1-methyl-2-pyrrolidinone (40 ml) was heated to 180° C. for 2 hours. After cooling the mixture was treated with water and the resultant solid collected by filtration. This solid was applied to a column (silica, 2% methanol/dichloromethane) to afford the title compound as a colourless solid (0.169 g). 1H-NMR (CDCl3) δ 1.22 (3H, t), 4.21 (2H, q), 5.53 (2H,br s), 7.46 (1H, t), 7.53 (1H, d), 7.81 (1H, dt), 8.07 (1H, dd).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH2:5]([NH2:8])[CH:6]=[CH2:7].C([C:13]1C=C(C)C=C(C(C)(C)C)[C:14]=1[OH:24])(C)(C)C>O>[CH2:5]([N:8]1[C:1](=[O:4])[CH:2]=[CH:13][C:14]1=[O:24])[CH:6]=[CH2:7]
Reactant: C=CCN
Reactant: CC(=O)O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Product: C=CCN1C(=O)C=CC1=O

Procedure:
A mixture of 25 g of a commercial styrene/maleic anhydride copolymer (1/1 molar ratio, Mn 1600) and 250 mL of glacial acetic acid was stirred under nitrogen while 7.1 g of allylamine was added dropwise over a period of 10 min. The mixture was then heated at 114° for 2 hours. The clear solution was cooled, treated with 0.125 g of 2,6-di-tert-butyl-4-methylphenol, and added with stirring to about 2500 mL of water. The precipitated polymer was filtered, washed, re-dissolved in about 700 mL of acetone and again precipitated in excess water acidified with 10 mL of concentrated hydrochloric acid/liter. The resultant polymer was dried to constant weight under vacuum. The N-allylmaleimide copolymer was obtained as a white powder; weight 25.4 g. The infrared spectrum showed imide absorption at 1705 cm-1 and 1775 cm-1, and essentially no anhydride or amide absorption was seen. The nmr spectrum was also consistent with the styrene/N-allylmaleimide structure. The nitrogen analysis and nmr spectrum indicated about 75% conversion of anhydride groups to N-allylmaleimide groups, and complete hydrolysis was indicated for the remainder of the anhydride units. Found, N 4.38%.
Reaction SMILES: C([Cu])#N.[C:4]([Li])([CH3:7])([CH3:6])[CH3:5].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.C([C:18]([O:20][CH3:21])=[O:19])#N>CCOCC.CN(P(N(C)C)(N(C)C)=O)C>[CH3:5][C:4]([CH:11]1[CH2:12][CH2:13][CH2:14][C:9](=[O:15])[CH:10]1[C:18]([O:20][CH3:21])=[O:19])([CH3:7])[CH3:6]
Reactant: O=C1C=CCCC1
Reactant: COC(=O)C#N
Reactant: [Li]C(C)(C)C
Agent: N#C[Cu]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1C(=O)CCCC1C(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a suspension of anhydrous CuCN (2.16 g, 0.025 mol) in anhydrous ether (100 mL) at -78° C. was added tert butyllithium (29.0 mL of 1.7M solution in pentane, 0.05 mol). After being stirred at -78° C. for 1 hr and at -45° C. for 30 minutes, the reaction mixture was recooled to -78° C. A solution of cyclohexenone (2.4 g, 0.025 mol) in ether (25 mL) was added and stirring continued for 15 minutes at -78° C. and at -45° C. for 30 minutes The resulting mixture was recooled to -78° C. and HMPA (10 mL) in ether (25 mL) was added. After 5 min, methyl cyanoformate (2.55 g, 0.03 mol) in ether (25 mL) was added and the reaction warmed to 0° C. over a 2 hr period. The resulting mixture was quenched with 2N HCl (100 mL), the layers were separated, and the organic phase was washed with saturated NH4Cl solution (3×50 mL), water (2×50 mL), brine (1×50 mL) and dried (Na2SO4) . Removal of the solvent in vacuo and purification by Kugelrohr distillation (bath temperature 100°-115° C. at 0.6 mm) afforded 4.7 g (88%) of methyl 2-(1,1-dimethylethyl)cyclohexan-6-one-carboxylate.