Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:40])([CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:39])([F:38])[F:37])([F:35])[F:34])([F:32])[F:31])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23])[CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4].[N:41]([CH2:44][CH2:45][CH2:46][Si:47]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])=[C:42]=[O:43]>C(C(C)=O)C>[CH:1]([O:40][C:42]([NH:41][CH2:44][CH2:45][CH2:46][Si:47]([O:48][CH2:49][CH3:50])([O:54][CH2:55][CH3:56])[O:51][CH2:52][CH3:53])=[O:43])([CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4])[CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:37])([F:39])[F:38])([F:34])[F:35])([F:31])[F:32])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23]
Reactant: CN(CC(O)CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Solvent: CCC(C)=O
Product: CCO[Si](CCCNC(=O)OC(CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(OCC)OCC
Temperature: 100 °C

Procedure:
Next, [C4F9SO2N(CH3)CH2]2CHOC(O)NH(CH2)3Si(OCH2CH3)3 was prepared as follows. A three-necked round bottom 500 ml flask fitted with a stirrer, heating mantle, condenser, nitrogen inlet, Dean-Stark trap and thermometer was charged with about 204.6 grams of the [C4F9SO2N(CH3)CH2]2CHOH (0.3 mol), and about 250 grams methyl ethyl ketone. The mixture was heated for about 1 hour at about 100° C. and about 50 grams of material was removed using the Dean-Stark trap. The mixture was cooled to about 30° C., and about 74.4 grams of OCN(CH2)3Si(OCH2CH3)3 (0.3 mol), and three drops of stannous octanoate were added. The resulting mixture was heated at about 75° C. under nitrogen for about 16 hours.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C[Si](C)(C)N[Si](C)(C)C>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1CONC(=O)N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: COc1ccc(NC2=NC(=O)NOC2)cc1
Yield: 58.8 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg ammonium sulfate, 1.47 g (0.012 mole) of p-methoxyaniline and 20 ml hexamethyldisilazane in 40 ml of freshly distilled dry dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to give a yield of 1.3 g (59 percent) of 5-((4-methoxyphenyl)amino)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]3([CH2:15][C:16]([CH3:21])([CH3:20])[C:17]=2C=O)[O:14][CH2:13][CH2:12][O:11]3)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(=NC1CCCCC1)C.[CH2:39]1C[O:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][C:10]3([CH2:15][C:16]([CH3:20])([CH3:21])[C:17]=2/[CH:39]=[CH:40]/[CH:41]=[O:42])[O:14][CH2:13][CH2:12][O:11]3)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC1(C)CC2(CC(c3ccc(F)cc3)=C1C=O)OCCO2
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Product: CC1(C)CC2(CC(c3ccc(F)cc3)=C1/C=C/C=O)OCCO2

Procedure:
In a manner similar to Scheme I, 26 (2.08 g, 7.17 mmol) was treated with the LDA-derived anion of ethylidenecyclohexylamine (1.36 g, 10.8 mmol) in anhydrous THF at 0°-5° C. and after workup and purification by SiO2 using 6:1 hexanes:EtOAc as eluent provided 1.25 g of orange solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Si:10](Cl)([C:13](C)(C)C)([CH3:12])[CH3:11]>C1COCC1>[CH3:11][Si:10]([CH3:13])([CH3:12])[O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7]
Reactant: OCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,5-pentandiol (44 mmol) in THF (15 mL) is cooled to 0° C. and treated with sodium hydride (44 mmol) followed by tert-butyldimethylsilyl chloride (44 mmol). The reaction mixture is stirred at room temperature overnight. Concentration in vacuo and flash chromatography affords 5-trimethylsiloxy-1-pentanol. To a solution of 5-trimethylsiloxy-1-pentanol (11.6 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 5-trimethylsiloxy-1-pentyl triflate (45) which is used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10](=O)[CH2:11][Cl:12])=[CH:7][CH:8]=[CH:9][C:2]1=2.[NH:14]1[CH2:18][CH2:17][NH:16][C:15]1=[S:19].C(O)C>C(O)(=O)C>[ClH:12].[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]3[N:16]4[CH2:17][CH2:18][N:14]=[C:15]4[S:19][CH:11]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C(CCl)c1cccc2sccc12
Reactant: S=C1NCCN1
Solvent: CCO
Solvent: CC(=O)O
Product: C1=C(c2cccc3sccc23)N2CCN=C2S1
Product: Cl
Temperature: 25 °C
Yield: 107.5 %

Procedure:
A mixture of 1-(benzo[b]thiophen-4-yl)-2-chloroethan-1-one (1.15 g), 2-imidazolidinethione (0.57 g), ethanol (10 ml) and acetic acid (6 ml) was heated under reflux for 18 hours then cooled to ambient temperature. The solvents were removed in vacuo and the residue was triturated with ether (30 ml). The resulting solid was collected by filtration, washed with ether (30 ml) and dried in vacuo at 40° C. to give 3-(benzo[b]thiophen-4-yl)-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (1.73 g) as a cream solid, m.p. 246-249° C.
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:27](=[O:29])=[O:28]>CN(C)C=O.[Zn].[Mn]>[C:1]([C:27]([OH:29])=[O:28])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=C=O
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Mn]
Agent: [Zn]
Solvent: CN(C)C=O
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 46 %

Procedure:
To a 50 ml round-bottomed flask, were added 1.0 g (15 mg-atom) of commercially available zinc powder, 1.9 g (15 mmol) of MnCL2 and 15 ml of dimethylformamide. Ultrasound generated in the same way as in Example 1 was applied for 1 hr to the solution to prepare zero-valent manganese. Next, a solution of 6 g (11 mmol) of C8F17I in 5 ml of dimethylformamide was added. As in Example 1, CO2 gas was introduced at a flow rate of 5 ml/min to the solution in a water bath for two hours under the irradiation of ultrasound by a ultrasonic cleaner (45 kHz, 35 W). The reaction was followed by the hydrolysis and then by the recrystallization such as in Example 1. 2.4 g (yield: 46%) of C8F17COOH was thus produced.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: CNS(=O)(=O)c1ccc(Cl)cn1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
5-Chloro-N-methylpyridine-2-sulfonamide (889 mg, 4.30 mmol) synthesized in Example (121a) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (172 mg, 4.30 mmol) was added. After ice cooling, p-methoxybenzyl chloride (0.70 mL, 5.16 mmol) was added, and the temperature was raised to room temperature, followed by stirring for 3 hours. Water (20 mL) was added to the reaction solution, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-20%) to afford the desired compound (817 mg, yield 58%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc2c1OCO2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc2c1OCO2)C(F)(F)F
Yield: 215.6 %

Procedure:
6.1 g (21.91 mmol) of 4-(1,3-benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ester, dissolved in 130 ml of tetrahydrofuran, is reacted with 9.5 ml (65.7 mmol) of (trifluoromethyl)trimethylsilane and 4.42 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. Carrying out and working up the reaction are carried out as described in Example 3. The crude product that is obtained is purified together with one batch of a similar order of magnitude [9.19 g (33.02 mmol) of 4-(1,3-benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ester as a starting material] by chromatography on silica gel (mobile solvent:ethyl acetate/hexane). 16.45 g (86%) of the desired product is isolated from the two batches together.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)[C:20]=1[CH3:36]>CN(C)C=O.ClCCl>[ClH:25].[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)[C:20]=1[CH3:36]
Reactant: Cc1ccccc1N
Reactant: COCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(Nc2ccccc2C)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Temperature: 130 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
o-Toluidine(0.48 ml, 4.5 mmol) and triethylamine were added to a solution of 6-methoxymethyl-5-methyl-2-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.9 g, 3 mmol) in dimethylformamide(5 ml) and stirred for 5 hours at 130° C. The reaction mixture was cooled to a room temperature, diluted with dichloromethane, and washed with aqueous sodium hydroxide and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the residual oil was purified by column chromatography. The purified compound was dissolved in ethyl ether. Ethyl ether saturated with hydrochloric acid was added to a mixture solution. The resulting solid was filtered and dried to give 400 mg of the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(S(=O)(=O)Cl)ccc32)cc1
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(S(=O)(=O)Nc4ccccc4)ccc32)cc1

Procedure:
2.33 g (6 mmol) of crude 1-[3-(4-cyano-phenyl)-propionyl]-1,2,3,4-tetrahydro-quinoline-6-sulphonylchloride are added dropwise, whilst cooling with ice, to a solution of 0.56 g of aniline in 15 ml of pyridine. Then the mixture is heated for 30 minutes to 100° C. and evaporated to dryness. The residue is chromatographed over a silica gel column with methylene chloride:ethyl acetate.
Reaction SMILES: [CH3:1][O:2][P:3]([N:7]=[C:8]=O)([O:5][CH3:6])=[O:4].[C:10]([CH:12]1[CH2:14][NH:13]1)#[N:11].C([O:17]CC)C>>[CH3:6][O:5][P:3]([N:7]1[CH2:8][C:12]1([C:14](=[O:17])[NH2:13])[C:10]#[N:11])([O:2][CH3:1])=[O:4]
Reactant: N#CC1CN1
Reactant: COP(=O)(N=C=O)OC
Reactant: CCOCC
Product: COP(=O)(OC)N1CC1(C#N)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.6 g. dimethoxyphosphoryl isocyanate in 18 ml. anhydrous diethyl ether is added dropwise at 5°-10° C. to a solution of 1.62 g. 2-cyanoaziridine in 36 ml. anhydrous diethyl ether. After stirring for 2 hours in an ice bath, the reaction mixture is allowed to warm to ambient temperature. The precipitated crystals are filtered off with suction and washed with diethyl ether. There is thus obtained 1.85 g. 1-N-dimethoxyphosphoryl-carbamoyl-2-cyanoaziridine; m.p. 72°-76° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]#[C:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: CN1CCN(CCCc2cc(Cl)c3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)CC1
Yield: 27 %

Procedure:
A mixture of 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.125 g, 0.27 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.034 g, 30%). 1H NMR (300 MHz, CDCl3): 5 (ppm) 1.79 (m, 2H), 2.23-2.60 (m, 13H), 2.64 (t, 2H), 4.18 (s, 2H), 4.80 (s, 2H), 7.08 (s, 1H), 7.24 (s, 1H), 7.42 (d, 2H), 7.59 (d, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:26]([N:17]1[CH2:18][CH2:19][N:14]([C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][NH:11][C:10](=[O:13])[CH:9]=2)[CH2:15][CH2:16]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1cc(N2CCNCC2)c(-c2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCN(c2cc(=O)[nH]nc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A 100 ml three necked round bottom flask was charged with 6-phenyl-5-(piperazin-1-yl)pyridazin-3(2H)-one (2.0 g), dry potassium carbonate (2.1 g) and dry DMF (150 ml) under nitrogen atmosphere. The reaction mixture was stirred at room temperature and benzoylchloride (1.5 g) was added into the reaction mixture very slowly. The reaction mixture was heated 120° C. for 4 hrs. The progress of reaction was monitored by TLC. After consumption of starting material reaction mixture was cooled to 0° C., ice-cold water (20.0 ml) was added to reaction mixture and the organic compound was extracted into ethylacetate (4×20 ml). Combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography using MeOH/CHCl3 (1:9) as eluent to afford 5-(4-benzoylpiperazin-1-yl)-6-phenylpyridazin-3 (2H)-one.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:29]2[CH:47]=[CH:46][C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]([C:42]([F:45])([F:44])[F:43])=[C:38]([CH:41]=3)[C:39]#[N:40])=[CH:31][CH:30]=2)O1>CN(C=O)C.O>[C:39]([C:38]1[CH:41]=[C:34]([CH:35]=[CH:36][C:37]=1[C:42]([F:43])([F:44])[F:45])[O:33][C:32]1[CH:46]=[CH:47][C:29]([C:2]2[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)#[N:40]
Reactant: CCOC(=O)/C=C/c1cccc(Br)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C(F)(F)F)c(C#N)c3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(-c2ccc(Oc3ccc(C(F)(F)F)c(C#N)c3)cc2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
(E)-Ethyl 3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)acrylate (13) was prepared as follows: A mixture of compound 11 (0.6 g, 1.0 eq), K2CO3 (2 eq), 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(trifluoromethyl)benzonitrile (12) (1.05 eq) and Pd[(o-toly)3P]2Cl2 (0.2 eq) in 10 mL of DMF and water (0.1 mL) was flushed with argon and then shaken at 90° C. for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), and extracted with EtOAc. The organic layer was washed with brine, concentrated, and purified by column (EtOAc/hexanes 10/1) to afford compound 13 as a colorless oil (0.8 g): 1H-NMR (400 MHz, CDCl3) δ 8.07 (d, 2H, 8.9 Hz), 7.74-7.84 (m, 4H), 7.39-7.43 (m, 2H), 7.3-7.33 (m, 1H), 7.21 (d, 2H, 8.8 Hz), 7.12 (d, 1H, 15.8 Hz), 4.32 (q, 2H, 7.2 Hz), 1.38 (t, 3H, 7.0 Hz).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(N([CH2:14][CH3:15])CC)C.CN(C=[O:20])C>>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH2:15][C:14]1=[O:20]
Reactant: Nc1ccccc1N
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Product: O=C1CNc2ccccc2N1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of o-phenylenediamine (4 g, 37.03 mmol) in DMF (30 mL) was added triethylamine (10.3 mL, 74.06) followed by ethyl-2-bromo acetate (4.53 mL, 40.73 mmol). The reaction was stirred at RT for 16 h and at 80° C. for 3 h. The reaction was monitored by TLC. After completion of reaction, the DMF was removed under vacuum. Water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (300 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum, and the product recrystallized with DCM/hexane in 1:1 ratio to obtain 2.2 g of desired compound.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:10](=O)([OH:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([O:11][C:10]([N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)O
Reactant: c1cc2c(s1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine (1.3 g, 9.0 mmol) was dissolved in dichloromethane (25 ml), and the solution was mixed with t-butyl bicarbonate (3.1 ml, 13 mmol) and triethylamine (1.3 ml, 9. 0 mmol) and stirred at room temperature for 13 hours. The reaction solution was mixed with dichloromethane, washed with water and saturated brined and dried with anhydrous sodium sulfate. When the solvent was removed by evaporation from the organic layer under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography, it was able to isolate a part of the title compound, but the most part was obtained as its mixture with t-butyl bicarbonate (total yield, 2.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH2:17]([O:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:18].C(N(CC)CC)C.Cl>C(O)CCC.C(O)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:26]2[CH2:27][CH2:28][CH:23]([O:22][CH2:21][CH2:20][O:19][CH2:17][CH3:18])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CCOCCOC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: CCO
Product: CCOCCOC1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Yield: 45.9 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (4.3 g.), 4-(2-ethoxyethoxy)piperidine (3.2 g.) and triethylamine (10 ml.) in n-butanol (400 ml.) were heated at reflux overnight under an atmosphere of nitrogen. The mixture was then cooled, evaporated in vacuo, and the residue basified (aqueous Na2CO3) and extracted 3 times with chloroform. The combined chloroform extracts were evaporated and the residue chromatographed on neutral alumina (150 g., Grade I, deactivated with 5 ml water). Elution with chloroform gave the crude product (3.6 g.) which was converted to the hydrochloride salt by treatment with hydrogen chloride in ethanol. The hydrochloride was then recrystallized from ethanol/isopropanol to give 4-amino-6,7-dimethoxy-2-[4-(2-ethoxyethoxy)piperidino]quinazoline hydrochloride (3.4 g.), m.p. 219°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([NH:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N([CH2:31][CH3:32])CC)C.[CH2:33]([O:40][CH2:41][C:42](Cl)=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:25])[CH:4]([NH:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:42](=[O:43])[CH2:41][O:40][CH2:33][C:32]2[CH:31]=[CH:36][CH:35]=[CH:34][CH:39]=2)=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:42](=[O:43])[CH2:41][O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:10][CH:11]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CCc1ccc(O)cc1
Reactant: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)C(Cc1ccc(OC(=O)COCc2ccccc2)cc1)NC(=O)CCc1ccc(OC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 3-(4-hydroxy-phenyl)-2-[3-(4-hydroxy-phenyl)-propionylamino]-propionic acid methyl ester 23 (10 grams, 29.15 mmol) and triethylamine (7.4 grams, 73.12 mmol) in anhydrous acetone (100 mL) at 0° C. is added dropwise benzyloxy acetyl chloride (11.8 grams, 63.95 mmol). The reaction mixture is stirred at room temperature for 10 hours. The resulting solids are filtered off. Acetone is distilled off, and water (100 mL) is added. The crude 25 is extracted into chloroform (2×100 mL), washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 25, which can be purified from appropriate solvent.