Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH2:11][CH2:12][N:13](C(OCC(Cl)(Cl)Cl)=O)[CH2:14][CH:15]=1>C(O)(=O)C.O.[Zn]>[NH:13]1[CH2:14][CH:15]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:11][CH2:12]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC=C(c2nc3ccccc3o2)CC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: C1=C(c2nc3ccccc3o2)CCNC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 52.6 g of 4-(2-benzoxazolyl)-3,6-dihydro-1(2H)-pyridinecarboxylic acid, 2,2,2-trichloroethyl ester in 1250 ml of glacial acetic acid is gradually added 92.5 g of zinc dust and the reaction mixture stirred at room temperature under nitrogen for 6 hours. The reaction mixture is filtered and concentrated on the rotary evaporator to give a viscous gum. This material is suspended in 500 ml of water, the pH adjusted to 2-3, and the suspension extracted with 500 ml of ether in two portions. These are combined, dried and concentrated to give 11.32 g of unreacted starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[C:5]2[CH3:14].[Cl:15][C:16]1[C:26]([Cl:27])=[C:25]([Cl:28])[C:24]([Cl:29])=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>ClC1C=CC=CC=1Cl>[CH3:14][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([N:1]3[C:22](=[O:21])[C:17]4=[C:16]([Cl:15])[C:26]([Cl:27])=[C:25]([Cl:28])[C:24]([Cl:29])=[C:18]4[C:19]3=[O:20])[CH:3]=2)[N:8]=[C:7]([CH3:13])[CH:6]=1
Reactant: Cc1cc(C)c2cc(N)cc(C)c2n1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C)c2cc(N3C(=O)c4c(Cl)c(Cl)c(Cl)c(Cl)c4C3=O)cc(C)c2n1
Yield: 87 %

Procedure:
350 g of o-dichlorobenzene was added to 186 g (1.0 mole) of 6-amino-4,8-dimethylquinaldine and 286 g (1.0 mole) of 3,4,5,6-tetrachlorophthalic anhydride, and the mixture was refluxed at the boiling point for 4 hours. The reaction mixture was then cooled. The crystals precipitated were collected by filtration, and dried to afford 394 g (0.87 mole) of 4,8-dimethyl-6-(3,4,5,6-tetrachlorophthalimido)-quinaldine. Then, 372 g (1.30 moles) of 3,4,5,6-tetrachlorophthalic anhydride, 2,000 g of 1,2,4-trichlorobenzene and 40 g of anhydrous zinc chloride were added, and the mixture was heated under reflux for 3 hours. Then, 500 g of dimethylformamide was added, and the mixture was stirred under reflux for 1 hour. The product was treated in the same way as in paragraph (C) of Example 1 to afford 571 g (0.79 mole) of a yellow compound. Since the compound obtained was scarcely soluble in dimethylformamide, its visible spectrum could not be measured. In its infrared spectrum (KBr), absorptions ascribable to --CO--N--CO-- were observed at 1730 cm-1 and 1790 cm-1, and absorptions ascribable to --CO--C--CO--, at 1645 cm-1 and 1695 cm-1. The elemental analysis values of this product were as follows:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl.O>[CH2:49]([O:56][C:57]([N:59]1[CH2:64][CH2:63][N:62]([C:6](=[O:8])[C@@H:2]([NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]([CH3:4])[CH3:5])[CH2:61][CH2:60]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Boc-(L)-Val-OH (2 g) in DCM (5 mL) was added DIPEA (4.7 mL) and HATU (5.2 g). After stirring at RT for 10 min, a solution of piperazine-1-carboxylic acid benzyl ester in DCM (5 mL) was added and the resulting reaction mixture was stirred at RT for 2 h. Water was added and the phases were separated. The org. phase was washed with brine, dried (MgSO4) and evaporated off to give 9.3 g of the desired compound as beige oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][O:9][C:10](Cl)=[O:11]>CCCCCC.C(OCC)(=O)C>[Cl:7][CH2:8][O:9][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:11]
Reactant: O=C(Cl)OCCl
Reactant: C1CCNCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(OCCl)N1CCCCC1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Piperidine(1.06 g, 12.5 mmol) was added to a solution of chloroformic acid chloromethyl ester(645 mg, 5 mmol) in n-hexane (15 mL) at 0° C. under argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. After the ethyl acetate solution was washed successively with 1N hydrochloric acid(20 mL), water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound(796 mg, 89.6%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]([CH:23]=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].OO.[OH:28]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>C(#N)C.O>[C:1]([O:4][C:5]1[C:22]([C:23]([OH:28])=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CC(=O)Oc1cc2c(cc1C=O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)Oc1cc2c(cc1C(=O)O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of 3-acetoxyestra-1,3,5(10)-trien-17-one-2-carboxaldehyde (61, 1.20 g, 3.5 mmol) in acetonitrile (17 mL) and H2O (2.1 mL) were added 30% hydrogen peroxide (0.53 mL) and sodium phosphate monobasic (1.79 g) at room temperature. Sodium chlorite (0.935 g in a H2O (7.0 mL) solution) was added dropwise to the reaction mixture over a 1 h period, and stirring continued for an additional 2 h at room temperature. The reaction mixture was quenched with sodium sulfite, acidified with 10% HCl, and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was washed with Et2O to afford 1.06 g of 62 (85% yield) mp: 180-181° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21](O)=[O:22])=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([NH:33]O)=[NH:32])=[CH:27][N:26]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:22][N:33]=[C:31]([C:28]4[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=4)[N:32]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1cnc(N)nc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4cnc(N)nc4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a white solid (60 mg, 27%). MS (ISP) 438.3 [(M+H)+]; mp 302° C.
Reaction SMILES: [F:1][C:2]([F:19])([S:15]([O-:18])(=[O:17])=[O:16])[CH:3]([O:8]C(=O)C(C)(C)C)[C:4]([F:7])([F:6])[F:5].[CH2:20]([N+:27]([CH3:30])([CH3:29])[CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CO.O>[F:19][C:2]([F:1])([S:15]([O-:18])(=[O:16])=[O:17])[CH:3]([OH:8])[C:4]([F:5])([F:7])[F:6].[CH2:20]([N+:27]([CH3:30])([CH3:29])[CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
In 139 g of methanol was dissolved 46.3 g (0.1 mole) of benzyltrimethylammonium 1,1,3,3,3-pentafluoro-2-pivaloyloxypropane-1-sulfonate in Synthesis Example 2. The solution was stirred under ice cooling, to which a solution of 8.0 g (0.2 mole) of sodium hydroxide in 24 g of water was added dropwise at a temperature below 20° C. The solution was stirred overnight at room temperature, after which 21 g of conc. hydrochloric acid and 60 g of water were added to quench the reaction. Methanol was removed in vacuum from the reaction solution, dichloromethane and water were added to the residue, and the organic layer was separated and concentrated again. To the residue containing some white crystals, 150 g of diisopropyl ether was added for crystallization. Filtration and drying gave the target compound. White crystals, 37 g, yield 98%.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[Br-].O.Cl>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:10][CH2:11][CH:6]([C:4](=[O:5])[CH2:8][CH2:7][CH:6]=[CH2:4])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CON(C)C(=O)C1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 183.2 %

Procedure:
While under a nitrogen atmosphere, a solution of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid, methoxy-methyl amide (1.8 g, 6.39 mmol), in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with 4-butenylmagnesiun bromide (0.5 M in THF, 31.95 mL, 15.98 mmol) dropwise. After stirring for 1 hour at 0° C. the reaction mixture was warmed to room temperature overnight, poured into water, acidified to pH 3-4 with 1 N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-20% ethyl acetate in heptane) gave 1-[4-(4-chlorophenyl)-cyclohexyl]pent-4-en-1-one as a colorless oil (1.62 g, 92%); 1H NMR (CDCl3, 300 MHz) δ 7.26 (m, 2H), 7.12 (d, J=8 Hz, 2H), 5.81 (m, 1H), 5.02 (m, 2H), 2.58 (t, J=7 Hz, 2H), 2.44 (m, 2H), 2.34 (m, 2H), 1.99 (m, 4H) and 1.47 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21]C)[C:8]=2[Cl:13])[N:3]=1.B(Br)(Br)Br.[OH-].[NH4+]>C(Cl)Cl>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[OH:21])[C:8]=2[Cl:13])[N:3]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2nc(N)nc(N)c2c1Cl
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)ccc3O)ccc2n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 8.9 %

Procedure:
A solution of 2.8 grams (0.084 mole) of 2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline (prepared in Example 2) in 300 mL of methylene chloride was stirred, and 35 mL of 1.0M boron tribromide in methylene chloride was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 21 hours. Thin layer chromatographic analysis of the reaction mixture indicated that the reaction was not complete. The reaction mixture was heated at reflux for about 6 hours, then it was allowed to cool to ambient temperature where it was stirred for about 60 hours. After this time, the reaction mixture was poured into 500 mL of ice containing 100 mL of concentrated ammonium hydroxide. The mixture was filtered to collect a solid. The solid was washed with water and dried at 70° C. under reduced pressure, yielding 2.4 grams of 2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: N1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:12])=[CH:9][N:8]=2)CCOCC1.[OH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.[OH-].[K+]>CS(C)=O.C(Cl)Cl.O>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:7]2[CH:30]=[CH:29][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:12])=[CH:9][N:8]=2)[CH2:33][CH2:34]1
Reactant: CN1CCC(O)CC1
Reactant: O=C(NCCc1ccc(Oc2ccccc2)cc1)c1ccc(N2CCOCC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CN1CCC(Oc2ccc(C(=O)NCCc3ccc(Oc4ccccc4)cc3)cn2)CC1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A solution of 6-chloro-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide (130 mg, intermediate from example 23) in DMSO (1.4 ml) was treated with 4-hydroxy-N-methylpiperidine (68 mg) and KOH (93 mg). The reaction mixture was heated for 20 min at 100° C. in the microwave oven. Then it was cooled to r.t. and diluted with CH2Cl2 and water. The aqueous layer was washed with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 98:2) to give 6-(1-methyl-piperidin-4-yloxy)-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide (29 mg) as off-white solid. MS (ISP): 432.2 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11](F)=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:5]2[CH:23]=[CH:24][N:25]=[C:4]2[N:3]=1.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][OH:31].[H-].[Na+].[Cl-].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9]([F:16])=[CH:10][C:11]([O:31][CH2:30][CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])=[CH:12][C:13]=2[F:14])=[C:6]([NH:17][CH2:18][C:19]([F:21])([F:20])[F:22])[N:5]2[CH:23]=[CH:24][N:25]=[C:4]2[N:3]=1
Reactant: CN(C)CCCO
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2NCC(F)(F)F)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc3nccn3c2NCC(F)(F)F)c(F)c1
Temperature: 50 °C
Yield: 51.7 %

Procedure:
To a solution of 7-chloro-N-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidin-5-amine (19 mg, 0.05 mmol) and 3-dimethylamino-1-propanol (51 m g, 0.5 mmol) in 0.5 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 20 mg, 0.5 mmol). The mixture is heated at 50° C. for 30 minutes, and cooled to room temperature. A saturated sodium chloride solution is added, and the product is extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 30% methyl alcohol in ethyl acetate. Concentration provides 7-chloro-6-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrimidin-5-amine as a tan solid (12 mg, mp 52-55° C.). MS: m/z 464.3 (M+H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][Si:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:4][CH2:5][CH2:6][CH2:7][Si:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 95.3 %

Procedure:
32.9 g (91.4 mmol) of compound (C) was added to a 1 N solution of sodium carbonate in ethanol and the mixture was heated at 70° to 80° C. for 3 h to conduct the hydrolysis. 27.7 g (87.1 mmol) of 3-hydroxypropyltriphenylsilane (D) was thus obtained (yield: 95.4%). 250 ml of dry benzene was placed in a flask after replacing air in the flask with a dry inert gas (argon). 5.0 g (15.7 mmol) of compound (D) and 1.9 g of triethylamine were dissolved therein. 50 ml of a solution of 1.6 g (17.7 mmol) of acryloyl chloride in benzene was added slowly thereto. After the completion of the addition, the mixture was stirred at room temperature for 6 h. The reaction solution was washed with a 0.5 N hydrochloric acid, water, a 1 N sodium carbonate solution and water successively and then dried over magnesium sulfate. Benzene was distilled off and the residue was purified according to column chromatography (silica gel/benzene) to obtain 5.1 g (13.7 mmol) of 3-acryloyloxypropyltriphenylsilane in the form of white crystals (yield: 87.3%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[OH:14][C:15]1[CH:19]=[C:18]([N:20]2[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[S:17][C:16]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:22]1[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N:20]([C:18]2[S:17][C:16]([C:29]([O:31][CH3:32])=[O:30])=[C:15]([O:14][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]([F:13])([F:12])[F:1])[CH:19]=2)[CH:21]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: FC(F)(F)Oc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
110 mg of 2-(trifluoromethoxy)benzyl bromide is added to a mixture of 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 59.7 mg of potassium carbonate in 3 ml anhydrous DMF. The mixture is stirred for 14 h at room temperature. Ice water is added and the organic phase is extracted with dichloromethane. The organic phase is poured on a phase separator and the solvent is removed under vacuum. The residue is dissolved in ethyl acetate and filtered through a short plug of silica gel (eluent: ethyl acetate) to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1.[C:16]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[N:38]3[C:33]([CH:34]=[N:35][C:36](S(C)=O)=[N:37]3)=[CH:32][CH:31]=2)[CH:25]=1)(=[O:23])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[N:38]3[C:33]([CH:34]=[N:35][C:36]([NH:15][C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])[CH:10]=4)=[N:37]3)=[CH:32][CH:31]=2)[CH:25]=1)(=[O:22])=[O:23])([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: CN1CCCC1COc1cccc(N)c1
Product: CN1CCCC1COc1cccc(Nc2ncc3ccc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)n3n2)c1

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(1-Methyl-pyrrolidin-2-ylmethoxy)-phenylamine and N-tert-Butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide. 1H-NMR (DMSO) 6 , 9.8 (brs, 1H), 9.4 (9.6, 1H), 9.1 (s, 1H), 8.4 (m, 2H), 7.9 (d, J=7.9 Hz, 1H), 7.7 (t, 1H), 7.6 (s, 1H), 7.5 (d, J=7.9 Hz, 1H), 7.4 (s, 1H), 7.3 (t, 1H), 7.2 (d, J=4.8 Hz, 1H), 7 (d, J=4.8 Hz, 1H), 6.6 (d, 1H), 4.2 (m, 1H), 4.1 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 3.0 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.8 (m, 1H), 1.1 (s, 9H); LC/MS (ESI+): 535 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>C(O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: CCOc1nc(Cl)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
12 gm (0.037 mol) of 6-ethoxy-2-chloro-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine were stirred together with 22 gm (0.28 mol) of piperazine in ethanol at 40°C for 2 hours. Then, the reaction mixture was poured into water, and the precipitate formed thereby was suction-filtered off and recrystallized from ethanol. Yield: 13 gm (93.8% of theory); m.p. 223°-224°C.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([CH:12]([CH2:16][C:17](=[O:19])[CH3:18])[C:13](=O)[CH3:14])([O:9]CC)=[O:8].[OH-].[K+]>CO>[CH3:14][C:13]1[O:19][C:17]([CH3:18])=[CH:16][C:12]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(CC(C)=O)C(C)=O
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)c(C)o1

Procedure:
To a stirred and refluxing solution of ethyl sodioacetoacetate (0.5 mole, 78g.) and sodium iodide (1g.) in dry acetone (250 ml.) was added chloroactone (0.54 mol. 50g.) over a period of ten minutes. After one hour the acetone was distilled from the reaction mixture and the residue was diluted with 400 ml. water. The preciptated oil was extracted with ether and the ether removed to yield the intermediate 3-carbethoxy-2,5-hexanedione (75g.). The intermediate (26.4g.) was cyclized by heating under reflux over 5 g. anhydrous oxalic acid for 11/4 hours. The crude ester was saponified by heating under reflux for 45 minutes with potassium hydroxide (26g.) in methanol (200 ml.). The methanol was removed, the residue dissolved in water and the solution acidified to yield 2,5-dimethyl-3-furoic acid (18g.), m.p. 130°-133°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28]Cl.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:28][C:27]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:25]([Cl:24])[CH:26]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg (0.067 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 3 mg (0.08 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 16 mg (0.08 mmol) of 3,4-dichlorobenzyl chloride was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][C:4]([N+:7]([O-:9])=[O:8])=[N:3]1.ClOC(C)(C)C>C(#N)C>[N:1]([N:2]1[CH:6]=[N:5][C:4]([N+:7]([O-:9])=[O:8])=[N:3]1)=[N:1][N:2]1[CH:6]=[N:5][C:4]([N+:7]([O-:9])=[O:8])=[N:3]1
Reactant: Nn1cnc([N+](=O)[O-])n1
Agent: CC(C)(C)OCl
Solvent: CC#N
Product: O=[N+]([O-])c1ncn(N=Nn2cnc([N+](=O)[O-])n2)n1
Temperature: 0 °C
Yield: 31.5 %

Procedure:
1-Amino-3-nitro-1,2,4-triazole (1.3 g, 10 mmol) was dissolved in 10 mL of dry acetonitrile, cooled to 0° C. with stirring under argon, and treated with t-butyl hypochlorite (1.1 g, 10 mmol) over 10 minutes. The resulting solution was stirred for 24 h, at room temperature, concentrated in vacuo, and triturated with isopropyl alcohol (3 mL). The undissolved solid was collected by filtration to give 400 mg (30%) of 1,1'-azobis-(3-nitro-1,2,4-triazole). The identity of the product was confirmed using NMR spectroscopy and X-ray diffraction.