Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[SH2:9]>C(N(CC)CC)C>[NH2:6][C:5](=[S:9])[CH2:4][C:3]([N:2]([CH3:8])[CH3:1])=[O:7]
Reactant: CN(C)C(=O)CC#N
Reactant: S
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CC(N)=S
Temperature: 55 °C
Reaction time: 12 h

Procedure:
A reaction mixture was prepared from 22.4 g. of N,N-dimethylcyanoacetamide, 21 ml. of liquid hydrogen sulfide and 1 ml. of triethylamine. The reaction mixture was placed in an autoclave and the autoclave shaken at about 55° C. for about 12 hours. The reaction mixture was taken from the autoclave and the volatile constituents removed by evaporation. Ethanol was added to the residue, thus producing a crystalline solid. The solid was filtered and the filter cake washed with cold ethanol. Twenty-one grams of 3-amino-3-thioxo-N,N-dimethylpropanamide were obtained melting at 111°-114° C. The compound had the following nmr (CDCl3 +DMSOd6):δ3.07 (doublet, 6H); 3.82 (singlet, 2H); 9.1 (very broad, 1H).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:27])=[O:26])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), benzene-sulfonyl chloride (12 μL, 0.094 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH:12]=[CH2:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]([CH:12]=[CH2:13])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:17]
Reactant: C1COCCN1
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: CS(C)=O
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOCC3)cc21

Procedure:
2.6 g of 7-chloro-6-fluoro-4-oxo-1-vinyl-1,4-dihydro-quinoline-3-carboxylic acid, 3.5 cm 3 of morpholine and 30 cm3 of dimethylsulphoxide were heated for 15 hours under reflux. The solvent was removed by distillation under reduced pressure and the residue was taken up in 20 cm3 of ethanol. The insoluble solid was separated and recrystallised from 8 cm3 of a 1:1 (by volume) mixture of methylcellosolve and ethanol. 0.4 g of 6-fluoro-7-morpholino-4-oxo-1-vinyl-1,4-dihydroquinoline-3-carboxylic acid, m.p. 218°-220° C., was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13].N1C=CC=CC=1>C(Cl)Cl>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:12](=[O:13])[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
The title compound 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) was prepared by the following procedure: To 2-aminobenzothiazole (5.0 g, 30 mmol) was added DCM (36 mL) and the reaction mixture was stirred at 0° C. for 15 minutes. Then, p-nitrophenyl chloroformate (6.64 g, 33 mmol) in DCM (60 mL) was added, followed by pyridine (2.66 mL, 33 mmol) in DCM (36 mL). The reaction mixture was stirred and allowed to warm to rt overnight. The reaction mixture was filtered, washed with DCM, and dried to provide 9.22 g (90%) of the desired product 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19): LC/MS (APCI): m/z 316.0 (M+H).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH:11]=[CH:10]1)(C(C)(C)C)(C)C.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[OH:28][CH:11]1[CH:10]2[CH:9]([O:8]2)[CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]1
Reactant: CCOC(=O)N1CC=CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)N1CC(O)C2OC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a solution of Compound 239D (25.2 g, 88.3 mmol) in 250 mL of CH2Cl2 at 0° C. was added solid m-CPBA (39.6 g, 176.6 mmol, 77% max) in small portions while the internal temperature was kept below 0° C. during the addition. The mixture was stirred at 0° C. for 30 min and then room temperature for 4.0 hrs. More solid m-CPBA (39.6 g, 176.6 mmol, 77% max) was added in small portions and the mixture was stirred at room temperature for three days. The precipitate was removed by filtration and the filtrate was washed with 20% Na2S2O3 (500 mL×3), sat'd NaHCO3 (500 mL×3) and brine (250 mL), dried over anhydrous Na2SO4. Purification by flash chromatography (hexane-EtOAc: 9.5:0.5 to 9:1) on silica gel afforded 4.33 g of 239E (lower Rf) as an oil.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([CH:33]=[O:34])[CH2:25][C:26](=NNC(N)=O)[OH:27])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=[O:37])C.CO>C=O.O>[C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([CH:33]=[O:34])[CH2:25][C:26]([OH:27])=[O:37])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(O)=NNC(N)=O
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=O)O
Yield: 79 %

Procedure:
A solution of (3S)-3-[N-((1-naphthyloxy)acetyl)leucinyl]amino-4-oxobutanoic acid semicarbazone (0.320 g, 0.68 mmol) in 37% aqueous formaldehyde(1.0 mL)-acetic acid(1.0 mL)-methanol(3.0 mL) was stirred at room temperature under nitrogen for 3.5 hrs. The resulting solution was diluted with water and extracted with EtOAc. The extract was washed with water and saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was taken up in EtOAc, filtered through Celite and evaporated to dryness. The product was taken up in a small amount of dioxane, diluted with water, frozen and lyophilized to give the title compound (0.222 g, 79%) as a fluffy white solid. TLC(EtOAc-pyridine-AcOH—H2O; 60:20:5:10) Rf=0.65.
Reaction SMILES: ClC[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][NH:38][CH2:37][CH2:36]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][N:38]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)([S:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1)[CH2:37][CH2:36]2
Reactant: COc1ccc(C(C#N)(Cc2cccc(CCl)c2)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C#N)(Cc2cccc(N3CCc4cc(OC)c(OC)cc4C3)c2)Sc2ccc(C)cc2)cc1OC
Temperature: 85 °C
Yield: 65.8 %

Procedure:
A mixture of 0.21 g of 3-(chloromethyl)-α-(3,4-dimethoxyphenyl)-α-[(4-methylphenyl)thio]benzene propane nitrile, 0.091 g of 6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline and 0.3 g of anhydrous potassium carbonate in 2.0 mL of N,N-dimethylformamide is heated at 85° C. for 4 hours, cooled, poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried and filtered. The filtrate is evaporated in vacuo to yield an oil. This oil is purified by flash chromatography with 1.5% methyl alcohol in chloroform to yield 0.18 g of the desired product as a yellow glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([C@H:23]2[CH2:27][S:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[S:24]2)[CH:20]=[C:19]([O:40][CH3:41])[C:4]=1[O:5][CH2:6][CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:10].[C:42](Cl)(=[O:44])[CH3:43].C(N(CC)CC)C>ClCCl>[C:42]([N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9]([O:8][CH2:7][CH2:6][O:5][C:4]1[C:19]([O:40][CH3:41])=[CH:20][C:21]([C@H:23]2[CH2:27][S:26][C@H:25]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[S:24]2)=[CH:22][C:3]=1[O:2][CH3:1])=[O:10])(=[O:44])[CH3:43]
Reactant: COc1cc([C@H]2SC[C@H](c3cc(OC)c(OCCOC(=O)NCc4ccccn4)c(OC)c3)S2)cc(OC)c1OC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc([C@H]2SC[C@H](c3cc(OC)c(OCCOC(=O)N(Cc4ccccn4)C(C)=O)c(OC)c3)S2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans-2-[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonylaminomethyl]pyridine (31) (FIG. 26) (0.313 g,0.520 mmole) was dissolved in 20 ml dry dichloromethane. The reaction was cooled to 0° C. under an argon atmosphere and 44 μl of acetyl chloride was added. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was recooled to 0° C. and 87 μl triethyl amine and 44 μl acetyl chloride was added. The reaction was then allowed to warm to room temperature and was stirred for an additional 12 hours. The reaction was then quenched with 10% NaHCO3 and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated to a brown oil which was purified by flash column chromatography using 1:1 hexane/ethyl acetate--1:2 hexane/ethyl acetate as eluent. The column yields 293 mg (88%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9](N)=[O:10])=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1.[OH-:18].[Na+]>O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([OH:18])=[O:10])=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1
Reactant: [OH-]
Reactant: Cc1nc(-c2cc(C(N)=O)c(=O)[nH]c2C)cs1
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2cc(C(=O)O)c(=O)[nH]c2C)cs1

Procedure:
C-4. 1,2-Dihydro-6-methyl-5-(2-methyl-4-thiazolyl)2-oxo-3-pyridinecarboxylic acid--A mixture containing 32 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxamide, 50 ml of 35% aqueous sodium hydroxide solution and 300 ml of water was heated on a steam bath for 15 hours and cooled. The reaction mixture was filtered to remove a small quantity of insoluble material and the filtrate was acidified with concentrated hydrochloric acid. The resulting precipitate was collected, washed with water and dried in an oven at 80° C. to produce 30.2 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxylic acid, m.p. 297°-299° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1.[C:40]([C:43]1[CH:44]=[C:45]([N:49]2[C:53]([SH:54])=[N:52][N:51]=[N:50]2)[CH:46]=[CH:47][CH:48]=1)([OH:42])=[O:41].O>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:3]=1[NH:4][C:5]1[CH:9]([S:54][C:53]2[N:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:40]([OH:42])=[O:41])[CH:44]=3)[N:50]=[N:51][N:52]=2)[C:8](=[O:10])[N:7]([C:11]2[C:12]([Cl:19])=[CH:13][C:14]([Cl:18])=[CH:15][C:16]=2[Cl:17])[N:6]=1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Sc2nnnn2-c2cccc(C(=O)O)c2)c1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of 15.4 g of 3-(2-chloro-5-tetradecaneamidoanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one and 5.4 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole was dissolved in 100 ml of dimethylformamide (DMF), and a solution of 4.9 g of N-glucosuccinic acid imide in 20 ml of DMF was added dropwise thereto at room temperature. The resulting mixture was stirred for 30 minutes, and 500 ml of water was added thereto. The mixture was then extracted with ethyl acetate. The ethyl acetate was distilled away under reduced pressure, and the residue was precipitated from a mixed solvent of ethyl acetate and acetonitrile to obtain 14 g of 3-(2-chloro-5-tetradecaneamidoanilino)-1-(2,4,6-trichlorophenyl)-4-[1-(3-carboxyphenyl)-5-tetrazolylthio]-2-pyrazolin-5-one, m.p., 155°-165° C. Yield was 68%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[CH3:22][N:23]([CH3:39])[CH:24]1[CH2:28][CH2:27][N:26]([C:29]2[S:30][C:31]3[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=3[N:33]=2)[CH2:25]1>>[CH3:22][N:23]([CH3:39])[CH:24]1[CH2:28][CH2:27][N:26]([C:29]2[S:30][C:31]3[CH:37]=[C:36]([NH:38][C:13](=[O:15])[CH:12]=[CH:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH:35]=[CH:34][C:32]=3[N:33]=2)[CH2:25]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)C=Cc1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4ccc5ccccc5c4)cc3s2)C1
Yield: 95.7 %

Procedure:
Prepare according to Method C (Example 9), using 3-(2-naphthyl)acrylic acid (69 mg, 0.348 mmol), oxalyl chloride (150 μL, 1.72 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (60 mg, 0.229 mmol) to afford the title compound (97 mg, 96%). mass spectrum (m/e): 442.0 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.30 (d, 1H, J=1.3 Hz), 8.14 (s, 1H), 8.00-7.92 (m, 3H), 7.78 (dd, 1H, J=8.5, 1.6 Hz), 7.71 (d, 1H, J=15.6), 7.59-7.54 (m, 2H), 7.45-7.42 (m, 2H), 6.97 (d, 1H, J=15.4 Hz), 3.71 (t, 1H, J=8.1 Hz), 3.62 (t, 1H, J=7.9 Hz), 3.47 (m, 1H), 3.26 (m, 1H), 2.89 (m, 1H), 2.21-2.17 (m, 7H), 1.94-1.86 (m, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[CH:4]=1.[C:11](=[O:13])=[O:12]>C1COCC1>[CH2:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:11]([OH:13])=[O:12])[CH3:10]
Reactant: CCc1cccc(Br)c1
Reactant: O=C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cccc(C(=O)O)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Magnesium turnings (829 mg, 34.1 mmol) were placed in an oven-dried 50 mL RBF and heated three times under high vacuum, then filled with nitrogen. The flask was sealed with a rubber septum and a pressure release system. Anhydrous THF (6.0 mL) and 1-bromo-3-ethylbenzene (297 mg, 1.6 mmol) were added. The reaction mixture was heated to 50-60° C. for 5 min. 1-Bromo-3-ethylbenzene (5.812 g, 31.4 mmol) was dissolved in anhydrous THF (12.0 mL) and added drop-wise via syringe maintaining 50-60° C. The reaction mixture was stirred for 2 h cooling to room temperature. The septum was replaced by a balloon with carbon dioxide and stirred for 16 h at room temperature. The reaction was quenched with a few grams of dry ice, acidified with hydrochloric acid (2M, 50 mL) and extracted with diethylether (2×100 mL). The combined organic layers were washed with a solution of sodium hydroxide (1M, 100 mL). The organic layer was disposed. The aqueous layer was acidified with hydrochloric acid (2M, 100 mL) and extracted with diethylether (2×100 mL). The combined organic of this extraction were dried (MgSO4), filtered and concentrated in vacuo. The title compound was obtained as pale pink crystalline solid (2.698 g, 54%).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a stirred solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (Ark Pharm, 5.387 g, 20.40 mmol) in DMF (80.0 mL) at 0° C. was added potassium carbonate (5.870 g, 42.47 mmol), followed by methyl iodide (8.789 g, 61.92 mmol). After stirring at 0° C. for 15 min., the reaction was heated to 40° C. for 2 h. The mixture was filtered and concentrated. The residue was dissolved in EtOAc (150 mL), washed with water (2×100 mL), brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as a pale yellow oil (5.348 g, 94%). LCMS calc. for C8H6BrFNO4 (M+H)+: m/z=277.9. found no ionization.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14]>C(Cl)Cl.N1C=CC=CC=1>[C:12]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)=CCC/C(C)=C/COC(=O)C(C)C
Yield: 31.2 %

Procedure:
A mixture of geraniol (355 mg, 2.3 mmol) and isobutyryl chloride (407 mg, 3.8 mmol) was refluxed for 4.5 hours in 9.5 ml of methylene chloride (CH2Cl2) and 2 ml of pyridine. After the reflux, the reaction mixture was quenched over ice/water, extracted with hexane, washed, and dried over magnesium sulfate. The reaction mixture was concentrated under vacuum at 32° C. to yield 161 mg of oil, which was then purified by open column chromatography using ethyl acetate/hexane (5/95) as an eluant to afford 119 mg (yield: 33%) of a pale yellow oil having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[NH:15][C:14](=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[N:13]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([CH3:1])[CH:3]=2)[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=1
Reactant: Cc1cc(-c2cc(C(F)(F)F)[nH]c(=O)n2)ccc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (4.31 g, 13.4 mmol) and phosphoroxychloride (40 mL) according to the general procedure I. Obtained as a light yellow solid (4.47 g, 98%). MS (EI) 340.1 [(M)+]; Mp 53° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].CCN(CC)CC.[CH2:17](N)[CH2:18][CH2:19][CH3:20]>CCCCO>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]=1[NH2:1]
Reactant: CCCCN
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCCCc1ncnc(Cl)c1N
Reaction time: 16 h

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in n-BuOH was treated with Et3N (1.2 mmol) and n-Butylamine (1.0 mmol) at 80 C. After 16 h, solvent was removed under reduced pressure. The residue was dissolved in EtOAc, the organic layer washed with water and then dried (MgSO4). Filtration and removal of solvent gave 6-chloro-5-amino-4-butyl pyrimidine as a brown solid. Rf=0.5 in 1:1 EtOAc:hexane. 1H NMR (CDCl3) δ 8.07 (s, 1H), 4.88 (br s, 1H), 3.49 (m, 2H), 3.35 (br s, 2H), 1.6 (m, 2H), 1.44 (m, 2), 0.95 (t, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[CH:8]2)[CH:2]=[CH2:3].[H-].[Na+].[CH2:18](Br)[CH:19]=[C:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([O:15][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:9]=[CH:8]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc2[nH]c(=O)ccc2c1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2nc(OCC=C(C)C)ccc2c1
Yield: 34.9 %

Procedure:
10.2 Grams of 6-allyloxy-2(1H)-quinolinone was dissolved in 100 ml of dimethylformamide, then 2.2 g of 60% oily sodium hydride and 9.1 g of prenyl bromide were added thereto by the procedures similar to those employed in Reference example 7 and reacted. Then, thus obtained reaction mixture was treated and oily mixture was obtained. This mixture was subjected to separation and refining by means of a silica gel flush column chromatography in which a mixture of ethyl acetate:n-hexane (1:10 to 1:2) was used as an eluent. Colorless to light yellow oily product, which was obtained by concentrating the second eluate portion under reduced pressure, was allowed to stand at room temperature, then it was crystallized. There was obtained 4.7 g (34.9%) of 6-allyloxy-2-prenyloxy-quinoline by recrystallization from n-hexane. Colorless needle-like crystals (recrystallized from n-hexane)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH2:17])[C:6](=[O:16])[NH:7]2.Cl.N[OH:20].O>C(O)CCC>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[N:17][OH:20])[C:6](=[O:16])[NH:7]2
Reactant: Nc1nc2c(Cl)cc(C(F)(F)F)cc2[nH]c1=O
Reactant: NO
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Cl)c2[nH]c1=NO
Temperature: 25 °C
Yield: 68.8 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973), was used. A mixture of 5-chloro-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (35 mg, 0.13 mmol) and hydroxylamine hydrochloride (20 mg, 0.29 mmol; Aldrich Co.) in 2 mL of 1-butanol was heated to reflux. The resulting suspension was stirred under reflux for 12 h. The resulting suspension was cool to 25° C., and added H2O (5 mL). A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 25 mg (69%) of 5-chloro-7-trifluoromethyl-3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid of a new compound: mp dec.>235° C. 1H NMR (300 MHz, DMSO-d6) δ 11.199 (br s, 1H, NH), 10.932 (br s, 1H, NOH), 10.411 (br s, 1H, NH), 7.604 (s, 1H, H-7), 7.317 (s, 1H, H-5). LRMS: 279 (M+, 100%), 249 (50%).
Reaction SMILES: [F:1][C:2]([CH:5]=[CH:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([F:4])[F:3].C1C(C(OO)=[O:21])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]([CH:5]=[CH:6][CH2:7][C:8]1[CH:13]2[O:21][CH:12]2[CH:11]=[CH:10][CH:9]=1)([F:3])[F:4]
Reactant: O=C(OO)c1ccccc1
Reactant: FC(F)(F)C=CCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)C=CCC1=CC=CC2OC12
Reaction time: 168 h
Yield: 77 %

Procedure:
7.4 g of m-trifluoromethylallylbenzene was added to chloroform solution containing perbenzoic acid prepared from 29.3 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 7 days. After the completion of reaction, the resulting mixture was washed with sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the concentrated was distilled under reduced pressure, there was obtained 6.2 g (yield 77%) of m-trifluoromethylallylbenzene oxide having a boiling point of 110° - 111° C/23 mmHg as colourless liquid.