Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH3:32][NH:33][C@H:34]([C:36]([OH:38])=[O:37])[CH3:35].Cl>C1COCC1.O>[CH3:32][N:33]([C:14](=[O:16])[CH2:13][CH2:12][S:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C@H:34]([C:36]([OH:38])=[O:37])[CH3:35]
Reactant: O=C(O)CCSSc1ccc([N+](=O)[O-])cc1
Reactant: CN[C@@H](C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)N(C)C(=O)CCSSc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a stirred solution of 3-(4-nitrophenyldithio)-propanoic acid (5b) (0.100 g, 0.386 mmol) in dry THF (10 mL) at −40° C. under argon was added isobutyl chloroformate (0.053 g, 0.386 mmol) and triethylamine (0.039 g, 0.38 mmol) and the reaction stirred at 0° C. for one hour. An aqueous solution (5 mL) of N-methyl-L-alanine (0.040 g, 0.386 mmol) and triethylamine (0.039 g, 0.386 mmol) was then added and the mixture stirred at 0° C. for five hours. The mixture was diluted with water (50 mL), acidified (aqueous HCl), and extracted with ethyl ether (3×25 mL). The combined organic layers were dried (Na2SO4), and the solvent evaporated under reduced pressure. The residue was chromatographed over silica gel eluting with methylene chloride/ethyl acetate to yield 0.048 g (36%) yellow crystals: mp 74-77° C. 1H NMR (CDCl3) δ1.4 (3H, d), 2.6-3.4 (4H, m), 2.9 (3H, s), 5.1 (1H, q), 7.6-8.3 (4H, 2d).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:28])=S.[Na+].[Na+].O>C(O)(=O)C>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S([O-])([O-])=S
Reactant: COCCOc1ccc(Sc2ccccc2)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1ccc(S(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 86 %

Procedure:
In 85 g of acetic acid was dissolved 12 g of 4-(2-methoxyethoxy)phenyl phenyl sulfide obtained in Synthesis Example 1-29. While the solution was maintained at an internal temperature of 30° C., 4.5 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 1.2 g sodium thiosulfate pentahydrate and 15 g water was added dropwise to quench the reaction. The solution was combined with 80 g of methylene chloride and 40 g of water for extraction. The organic layer was separated, washed with water, and concentrated in vacuum. On subsequent crystallization from ethyl acetate/hexane, 11 g of the target compound, 4-(2-methoxyethoxy)phenyl phenyl sulfoxide was obtained as white crystals. Yield 86%.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:30])[NH:24]2>>[Cl:19][C:20]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:30])[N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CC1Cc2c(ccc(F)c2Cl)N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2c(ccc(F)c2Cl)N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 44.8 %

Procedure:
The product is prepared according to the procedure described in example 1c, step 3c, using 248 mg of sodium (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and 160 mg of 4-chloro-5-fluoro-2-methyl-2,3-dihydro-1H-indole (reference example 10c). After silica column purification: eluent 99/01 then 98/02 dichloromethane/methanol, 157 mg of 2-[2-(4-chloro-5-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid which will be separated into its two enantiomers on a chiral column.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
7-Benzyloxy-4-chloro-3-nitroquinoline (66.4 g, 0.21 mol) was dissolved in a mixture of dichloromethane (1.5 L) and triethylamine (59 mL, 0.422 mol). A solution of 1-amino-2-methyl-2-propanol (22.5 g, 0.25 mol) in dichloromethane (100 mL) was added dropwise. The reaction was stirred at ambient temperature for 3 hours and then quenched with 1% aqueous sodium carbonate solution. A precipitate formed which was filtered to provide 60 g of crude 1-(7-benzyloxy-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a yellow-brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[O:10]1[CH2:14][CH2:13][CH:12]([CH:15]=O)[CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:15][CH:12]2[CH2:13][CH2:14][O:10][CH2:11]2)=[CH:4][N:3]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: O=CC1CCOC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ncc(NCC2CCOC2)c(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To 2,4-dichloropyrimidin-5-amine (6.22 g, 38.0 mmol) in 16.5 mL of dichloromethane was added dry tetrahydrofuran-3-carbaldehyde (3.8 g, 38.0 mmol). The solution was cooled to 0° C. A solution of titanium tetrachloride (41.8 ml, 41.8 mmol) in 10 mL of dichloromethane was added slowly. The reaction mixture was stirred at for 2 hours. Sodium triacetoxyborohydride (24.13 g, 114 mmol) was added in 4 equal portions over about 10 minutes and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with water and extracted twice with methyl-t-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 8.2 g of 2,4-dichloro-N-((tetrahydrofuran-3-yl)methyl)pyrimidin-5-amine as a tan solid which was used without further purification. [M+H] found 249.
Reaction SMILES: C([C:3]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=O.[BH4-].[Na+].Cl.[CH3:20][OH:21]>C[O-].[Na+]>[OH:21][C:20]1[C:15]([CH3:3])=[CH:14][C:13]([CH3:16])=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1C=O
Reactant: CO
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Product: COC(=O)C(C)Oc1cc(C)cc(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7.89 g (0.0355 mole) of methyl 2-(2-formyl-5-methyl-phenoxy)propionate in 20 mL of methanol, cooled to 5° C., was added a solution of 0.10 g (0.0018 mole) of sodium methoxide in 20 mL of methanol. While the temperature was maintained between 0° C. and 5° C., 0.36 g (0.0094 mole) of sodium borohydride was added to the reaction during a period of about 10 minutes. The reaction mixture was allowed to warm to ambient temperature, where it was stirred for two hours. At the end of this period, the reaction mixture was poured into 75 mL of 0.25N hydrochloric acid. This mixture was extracted twice with methylene chloride. The combined extracts were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving a colorless oil as a residue. This oil was placed on a silica gel column and eluted first with methylene chloride/ethyl acetate (95/5) and then with the same solvents (90/10). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 5.76 g of methyl 2-(2-hydroxy-methyl-5-methylphenoxy)propionate was isolated as a colorless oil. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:17][CH:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCNCc1ccc(F)cc1

Procedure:
Tert-butyl 4-bromobutylcarbamate (0.735 g, 2.91 mmoles), (4-fluorophenyl)methanamine (0.333 g, 2.91 mmoles) and potassium carbonate (0.806 g, 5.83 mmoles) were stirred in acetonitrile (15 mL) at 100° C. for 1 hour. The reaction mixture was cooled, the solvent waqs concentrated and the residue was taken into dichloromethane and washed with water twice. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to provide the title compound which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:31]CC2C=CC(OC)=CC=2)=[C:4]([C:8]([CH2:27][CH:28]([CH3:30])[CH3:29])([CH3:26])[C:9]([NH:11][CH:12]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:25])=[O:10])[CH:5]=[CH:6][CH:7]=1>CCCCCC>[Cl:1][C:2]1[C:3]([SH:31])=[C:4]([C:8]([CH2:27][CH:28]([CH3:29])[CH3:30])([CH3:26])[C:9]([NH:11][CH:12]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:25])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CSc2c(Cl)cccc2C(C)(CC(C)C)C(=O)NC2CCCCCCCCCCNC2=O)cc1
Solvent: CCCCCC
Product: CC(C)CC(C)(C(=O)NC1CCCCCCCCCCNC1=O)c1cccc(Cl)c1S

Procedure:
The title compound was prepared as a 1:1 mixture of diastereoisomers from 3-chloro-2-(4-methoxybenzylthio)-α-(2-methylpropyl)-N-(2-oxo-3-azacylotridecyl)phenylpropanamide in a similar manner to that described in Example 4, mp 143°-148° C. (after trituration with hexane).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]1[C:22]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([C:22]2[C:21]([F:20])=[CH:26][CH:25]=[CH:24][N:23]=2)([OH:31])[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1ncccc1F
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ncccc1F
Yield: 18 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(3-fluoropyridin-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (27 mg, 18%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]3[CH2:24][O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]([OH:23])[CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCNCC1
Reactant: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CC2CO2)CC1
Product: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CC(O)CN2CCCCC2)CC1

Procedure:
In analogy to the procedure described for example 166B, (rac)-1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one and piperidine gave the title compound as light yellow viscous oil. MS: 422.2 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[C:16]2[N:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.CN1CCOCC1.[CH3:40][CH:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1>CN(C)C=O.ClCCl.C(OCC)(=O)C.CCCCCC>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:47][CH:44]3[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]3)=[O:24])=[CH:20][N:21]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CC1CCC(N)CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC1CCC(NC(=O)c2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
Thionyl chloride (1.00 ml) and N,N-dimethylformamide (one drop) were added to a suspension of the [6-[(4-chlorophenylsulfonyl)(2, 5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 ing, 0.236 minol), which had been obtained in Example 338, in dichloromethane (4 ml). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness. The residue was then dissolved in dichioromethane (6 ml), followed by the addition of N-methylmorpholine (51.8 μl, 0.472 mmol) and 4-methylcyclohexylamine (37.4 μl, 0.283 mmol). After the reaction mixture was stirred at room temperature for 18 hours, the mixture was diluted with dichloromethane. The solution was washed successively with 1N hydrochloric acid, water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography on a silica gel column. A fraction obtained from the elution portion with hexane:ethyl acetate=3:1 was concentrated, whereby a white solid was obtained. The resulting solid was recrystallized from ethyl acetate-hexane, whereby the title compound (70.3 mg, 0.135 mmol, 57%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][S:5]2.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.O>[Br:27][CH2:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][S:5]2
Reactant: CCOC(=O)c1c(C)nc2sccn12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c(CBr)nc2sccn12
Temperature: 25 °C

Procedure:
To a stirred solution of Step 1 intermediate (2.60 g, 12.366 mmol) and azobisisobutyronitrile (AIBN) (0.041 g, 0.247 mmol) in carbon tetrachloride (40 mL) at reflux temperature was added N-bromosuccinimide (2.40 g, 13.602 mmol). After refluxing for 18 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated. Aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to obtain 1.95 g of the product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.6 Hz, 3H), 4.36 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.52 (d, J=4.5 Hz, 1H), 8.10 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 291.58 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:14]([C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([CH3:25])[C:17]=1[CH2:18]Br)[CH3:15].[I-].[K+].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC>[CH2:14]([C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([CH3:25])[C:17]=1[CH2:18][NH:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH3:15]
Reactant: CCc1cc(F)cc(C)c1CBr
Reactant: Cc1cc(N)c2nc(C)c(C)n2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1cc(F)cc(C)c1CNc1cc(C)cn2c(C)c(C)nc12
Yield: 28.9 %

Procedure:
8-Amino-2,3,6-trimethylimidazo[1,2-a]pyridine (0.38 g, 2.16 mmol) and 2-ethyl-4-fluoro-6-methylbenzylbromide (0.50 g, 2.16 mmol) were dissolved in 10 ml dimethoxyethane. Potassium iodide (0.2 g, 1.2 mmol) and Na2CO3 (0.4 g, 3.8 mmol) were added and the mixture was refluxed for 6 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (60:40) as eluent. 203 mg (29%) of the title compound was obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[CH3:25][N:26]=[C:27]=S.C(O)C>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:25]([NH:26][CH3:27])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: CN=C=S
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Yield: 32 %

Procedure:
A solution of 3-butyl-6-hydrazino-1-(4-nitrobenzyl)uracil (1.7 g, 5 mM) and methyl isothiocyanate (0.7 ml, 10 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. To the solution was added ethanol (20 ml) and the mixture was cooled to give crystalline product. Recrystallization from DMF/ethanol gave pale yellow crystals (0.61 g, 32%), m.p. 277°-279° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.CO>C(OCC)C>[N+:9]([C:5]1[C:6]([OH:8])=[N:7][C:2](/[CH:1]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3][C:4]=1[OH:12])([O-:11])=[O:10]
Reactant: Cc1nc(O)c([N+](=O)[O-])c(O)n1
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1c(O)nc(/C=C/c2ccccc2)nc1O
Temperature: 90 °C
Yield: 63.1 %

Procedure:
A mixture of 2-methyl-5-nitropyrimidine-4,6-diol (4.7 g, 27.5 mmol) and benzaldehyde (42 mL, 414 mmol) was treated with piperidine (21.3 mL, 215.3 mmol). The reaction mixture was heated to 90° C. for 2 hrs. The temperature was then increased to 120° C. for 30 min. After cooling the reaction mixture to ambient, methanol (10 mL) and diethyl ether (200 mL) were added sequentially. The resulting solid was collected by filtration and washed with 5% aqueous hydrochloric acid to give 5-nitro-2-[(E)-2-phenylvinyl]pyrimidine-4,6-diol (4.5 g). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, 1H, J=16.4 Hz), 7.15 (m, 2H), 7.54 (m, 3H), 6.81 (d, 1H, J=16.4 Hz). MS (m/z) 260 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:12][CH2:13][F:14])[CH2:7][NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:12][CH2:13][F:14])[CH2:7][N:8]([C:27]([NH:26][CH2:24][CH3:25])=[O:28])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)NCN(CCF)c2ccc(Cl)cc21
Reactant: CCN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CN(CCF)c2ccc(Cl)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 500 mg of the compound of Example 1 dissolved in 2.5 ml of acetonitrile there are added 0.5 ml of triethylamine and 2.5 ml of ethyl isocyanate. The reaction mixture is stirred at ambient temperature for 5 hours. The solvent is then removed under reduced pressure. The residue is taken up in 10 ml of acetone; charcoal is added to the resulting solution, which is then filtered; water is then added to the filtrate. The precipitate obtained is collected by filtration, washed with water and dried.
Reaction SMILES: [H-].[Na+].[CH3:3]CCCC.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([CH:27]=[CH2:28])[CH2:17][NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].CCCCCC.CCOC(C)=O>CCCCCC.C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([CH:27]=[CH2:28])[CH2:17][N:18]([CH3:3])[C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: C=CC(CNC(=O)c1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: CCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(CN(C)C(=O)c1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Wash a suspension of NaH (312 mg of 60% in mineral oil, 7.81 mmol, 1.25 eq) in hexane with dry pentane (2×100 mL), suspend in dry THF (30 mL) and treat with the product of step 7 (2.0 g, 6.25 mmol) at 23° C. Stir the resulting yellow suspension for 20 min at 23° C., then add CH3 l (777 μL, 12.5 mmol, 2.0 eq). After 1 h, pour the mixture onto a pad of silica gel packed with hexane:EtOAc (1:1) (500 mL) and concentrate the filtrate to give 2.1 g (6.25 mmol, >99%) of N-[2-(3,4-dichlorophenyl)-3-butenyl]-N-methyl benzamide as a light yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:12][OH:13])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.1 %

Procedure:
To a solution of 4-methoxybenzaldehyde (5.0 g, 36.8 mmol) in methanol (300 mL) was added hydroxylamine hydrochloride (7.6 g, 110.4 mmol) and 2N NaOH (37 mL, 73.6 mmol). The mixture was stirred at room temperature for 6 hours. The mixture was neutralized to pH 4 by using 1N HCl. Excess methanol was removed in vacuo to precipitate out the oxime. The precipitations were filtered and washed with water. The product was dried under vacuum and yield a white solid (4.9 g, 88%): 1H NMR (270 MHz, acetone-d6) δ 8.07 (s, 1H), 7.55 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](O)=[O:20])[CH:14]=1)[C:9](=[O:22])[NH:8][C:7]2=[O:23].ClC1C=CC=C2C=1N(CC1C=CC=C(C(OC)=O)C=1)C(=O)NC2=O.[OH-].[Na+].C(C1C=C(C=CC=1)CN1C2C(=CC=CC=2)C(=O)NC1=O)(O)=O.[N:72]1([C:78]2[N:83]=[CH:82][CH:81]=[CH:80][N:79]=2)[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([N:75]3[CH2:76][CH2:77][N:72]([C:78]4[N:79]=[CH:80][CH:81]=[CH:82][N:83]=4)[CH2:73][CH2:74]3)=[O:20])[CH:14]=1)[C:9](=[O:22])[NH:8][C:7]2=[O:23]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3cccc(Cl)c32)c1
Agent: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3cccc(Cl)c32)c1
Agent: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: [Na+]
Product: O=C(c1cccc(Cn2c(=O)[nH]c(=O)c3cccc(Cl)c32)c1)N1CCN(c2ncccn2)CC1

Procedure:
The compound was prepared from 8-chloro-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from 8-chloro-1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione and NaOH using a procedure similar to those of compound of Examples 2), and 2-(piperazin-1-yl)pyrimidine using a procedure similar to those described for the synthesis of compound of Example 3. 1H NMR (DMSO-d6): 11.94 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 8.05 (d, J=6.6 Hz, 1H), 7.77 (d, J=6.6 Hz, 1H), 7.50-7.20 (m, 5H), 6.66 (t, J=4.8 Hz, 1H), 5.53 (s, 2H), 3.90-3.50 (m, 8H). MS: m/z 477.1 [M+H]+.