Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@@H:7]2[C@H:2]1[CH2:3][C@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([C@@H:2]1[C@@H:7]([OH:1])[CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1CC[C@@H]2O[C@@H]2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CC[C@H](O)[C@@H](N=[N+]=[N-])C1
Temperature: 75 °C
Reaction time: 12 h
Yield: 92.7 %

Procedure:
Ethyl (1R*,3R*,4S*)-3,4-epoxycyclohexane-1-carboxylate (13.6 g) was dissolved in N,N-dimethyl-formamide (100 ml), ammonium chloride (6.45 g) and sodium azide (7.8 g) were successively added at room temperature, and the mixture was then stirred at 75° C. for 12 hours. The solvent was concentrated to about 1/3, and the residue was diluted with water and ethyl acetate to conduct stirring for 3 minutes. The resultant organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound (15.8 g) as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].Cl.[NH2:49][NH:50][C:51]([NH2:53])=[O:52].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.C1COCC1.O>[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:49][NH:50][C:51]([NH2:53])=[O:52])=[O:32])=[CH:34][CH:35]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(C(=O)O)cc2)cc1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(C(=O)NNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
836 mg (6.62 mmol) of oxalyl chloride are slowly added dropwise to a solution of 600 mg (1.10 mmol) of 4-{(3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoic acid from Example 105A in 6 ml of dry toluene with 4 drops of DMF while cooling in ice. The reaction mixture is stirred at RT for 10 minutes and then heated to reflux for 1 hour. After cooling, the mixture is concentrated in vacuo, and the residue is coevaporated twice with toluene and then taken up in 6 ml of THF. This solution is added dropwise to a previously prepared solution of 135.4 mg (1.21 mmol) of semicarbazide hydrochloride and 88.3 mg (2.21 mmol) of sodium hydroxide in 1 ml of THF and 0.25 ml of water at 0° C. The mixture is stirred at 0° C. for 2 hours and then at RT for 30 minutes, and the residue after concentration is reacted without further purification in the next stage.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:11]([C:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=1)[C:10]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(NC2=CC(=O)CC2)cc1OC1CCCCC1
Reactant: BrCc1ccccc1
Product: COc1ccc(N(Cc2ccccc2)C2=CC(=O)CC2)cc1OC1CCCCC1
Yield: 89.4 %

Procedure:
According to the same procedure as in Example 26, using 3-(3-cyclohexyloxy-4-methoxyanilino)-2-cyclopenten-1-one produced in Example 13(3) instead of 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one, and using benzyl bromide instead of methyl iodide, the title compound (yield 89.4%) was obtained as a yellow oil.
Reaction SMILES: O.C([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1>[Pd].CO>[C:21]1([CH2:20][CH2:19][CH2:18][CH2:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([OH:28])=[O:9])=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
10% Pd-C (1.40 g) was added to a 1% water-containing methanol solution (150 ml) of N-(5-phenylpentanoyl)-L-proline benzyl ester (13.87 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for two hours. After the catalyst was filtered off, the filtrate was concentrated to obtain N-(5-phenylpentanoyl)-L-proline (10.04 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>[Ni].CO>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(CO)cc1N

Procedure:
A mixture of 8.3 parts of 4-amino-3-nitrobenzaldehyde in 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 8.5 parts of 3,4-diaminobenzenemethanol as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C(Cl)Cl.[I:21]I>O>[I:21][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: II
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(I)c1
Reaction time: 72 h

Procedure:
Part A: Ethyl 4-aminobenzoate (5.0 gr, 30.27 mmol) and sodium bicarbonate (3.81 g, 45.40 mmol, 1.5 eq.) were added to a 50:50 mixture of methylene chloride and water. The mixture was chilled to 0 degree and I2 (11.53 g, 45.40 mmol, 1.5 eq.) was added slowly. The reaction mixture was allowed to come to room temperature and was stirred for 72 hours. The layers were then separated and the aqueous layer washed with methylene chloride. All organics were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on silica using 30% ethyl acetate in hexanes as solvent to afford ethyl 3-iodo-4-aminobenzoate. C9H10NO2I MS 292 (M+H)+ 309 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([O:4][C:5]([NH:7][C@H:8]([C:28]([OH:30])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:6])[CH3:3].[C:32](=O)([O-])O.[K+].IC.O>CN(C)C=O>[CH3:3][C:2]([CH3:31])([O:4][C:5]([NH:7][C@H:8]([C:28]([O:30][CH3:32])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[O:6])[CH3:1]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine (5.00 g, 11.7 mmol) in N,N-dimethylformamide (10 mL) was treated with potassium hydrogen carbonate (1.4 g, 14.1 mmol) and iodomethane (0.8 ml, 12.9 mmol). The reaction mixture was stirred at room temperature for 2 h. Then water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), concentrated and chromatographed (10-40% ethyl acetate/hexanes) to give N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (4.20 g, 81%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:23]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:23])[C:14]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CI
Reactant: COC(=O)c1cc(Cl)cc(NC(=O)C2CCCC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(N(C)C(=O)C2CCCC2)c1C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclopentanecarboxamido)-2-methylbenzoate (0.3 g, 1.01 mmol) in DMF, sodium hydride (0.060 g, 0.0015 mmol) was added at 0° C. and reaction mixture was allowed to stir for 15 min. Methyl iodide (0.32 mL, 0.50 mmol) was added and reaction mixture and was stirred at room temperature. After complete consumption of starting material, the reaction was quenched with addition of water and extracted with ethyl acetate. The combined organic layer was the washed with brine, dried (Na2SO4) and concentrated. The crude compound was used for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:38][C:39]1[C:43]([S:44](Cl)(=[O:46])=[O:45])=[C:42]([CH3:48])[O:41][N:40]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:44]([C:43]2[C:39]([CH3:38])=[N:40][O:41][C:42]=2[CH3:48])(=[O:46])=[O:45])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1S(=O)(=O)N(Cc1ccc(-c2ncccn2)cc1)Cc1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
To a solution of {3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (83.3 mg, 0.2054 mmol), prepared in Step A of Example 13o, in CH2Cl2 was added triethylamine (0.94 mL, 0.68 mmol) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride (44.2 mg, 0.226 mmol) and the reaction was heated at reflux overnight. After cooling to room temperature, additional triethylamine (0.94 mL) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride (44 mg) was added. The reaction was heated at reflux for 72 h and was cooled to room temperature. The organic solution was washed sequentially with 5.5% aqueous HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provide the title compound of Step A (61 mg). MS 565 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]5[O:28][CH2:29][O:30][C:23]=45)=[N:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:31][CH3:32])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:33]=O.[OH-].[Na+]>C(O)=O>[OH:1][C:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]5[O:28][CH2:29][O:30][C:23]=45)=[N:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:31][CH3:32])[CH2:7][CH2:6][N:5]([CH3:33])[CH2:4][CH2:3]1
Reactant: C=O
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCN(C)CC1
Temperature: 100 °C

Procedure:
A mixture of 7-[2-(4-hydroxypiperidin-4-yl)ethoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline (0.065 g), formaldehyde (40% aqueous solution; 0.2 ml) and formic acid (2 ml) was stirred and heated to 100° C. for 1.5 hours. The mixture was basified to pH9.5 by the addition of 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using an 80:17:3 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.021 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.8 (m, 4H), 2.05 (m, 2H), 2.8 (s, 3H), 3.15 (m, 2H), 3.3 (m, 2H), 4 (s, 3H), 4.35 (m, 2H), 6.05 (s, 2H), 6.95 (m, 3H), 7.4 (s, 1H), 8.1 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 453.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([OH:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([O:24][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH2:21][CH2:22][CH3:23]
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Reactant: CCCCO
Product: CCCCOC(=O)NC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p.=83° C. and MS: m/e=325.4 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and butan-1-ol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:16]/[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:7]=[N:8]NC1C=CC=CC=1>O.O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[N:8][N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=1
Reactant: C(=NNc1ccccc1)/C(=N\Nc1ccccc1)c1ccco1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-n2ncc(-c3ccco3)n2)cc1
Reaction time: 2 h
Yield: 57.6 %

Procedure:
An aqueous solution of hydrated copper sulphate (421 mg, 1.68 mmol) in 2 mL of demineralized water was added portion-wise to a solution of (2E)-2,2′-(1-(furan-2-yl)ethane-1,2-diylidene)bis(1-phenylhydrazine) (150 mg, 0.493 mmol) in dioxane (3.3 ml) while heating under reflux. After complete addition, heating was continued further for 2 hours. The solvent was then evaporated to dryness. The resulting crude material was subjected to flash column chromatography using an ethyl acetate/hexane solvent system (1-1.5%) to yield the desired compound 4-(furan-2-yl)-2-phenyl-2H-1,2,3-triazole as a yellow solid (60 mg, 57.7%). The HPLC purity of the final product was 96.03%. LC-MS [M+1] (C12H9N3O+H expected 212.07). The melting point of the final compound was observed to be 80° C. The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].CCN(C(C)C)C(C)C.[CH2:16]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([N:20]([C:1](=[O:5])[C:2]([Cl:4])=[O:3])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNCCCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)C(=O)Cl
Reaction time: 0.08 h

Procedure:
To a 0° solution of oxalyl chloride (479 mL, 5.49 mmol) in THF (10 mL) under nitrogen was added DIPEA (2.28 mL, 13.07 mmol) and dibutylamine (925 mL, 5.49 mmol). The resulting mixture was stirred at 0° for 5 min, whereby (dibutylamino)oxoacetyl chloride is formed, then transferred via syringe to a solution of 4-(4-aminophenyl)-2-aminothiazole (corresponding to the deprotected title compound of either Example 1 (a) or 1 (b)). The resulting mixture was stirred under nitrogen for 4 h, after which time another batch of freshly prepared (N,N-dibutylamino)oxalylchloride (prepared in the same manner and with the same amounts as above) was added to the reaction mixture. The stirring was continued for 1 h. The mixture was then diluted with EtOAc and extracted with 10% aqueous HCl. This aqueous extract was washed with EtOAc:Hex (1:1), then filtered. The collected solid, containing the desired product as its hydrochloride salt, was treated with 2N aqueous NaOH and extracted with EtOAc. This latter extract was washed with H2O, dried (MgSO4) and concentrated under reduced pressure to give a solid (398 mg) which was further purified by crystallization from EtOAc/MeOH to give the title compound (240 mg, 12% yield) as a beige solid: M.p. 178-179° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.75 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=9.0 Hz), 7.02 (s, 2H), 6.92 (s, 1H), 3.33 (m, 4H), 1.50-1.60 (m, 4H), 1.33 (sixt., 4H, J=7.5 Hz), 1.25 (sixt., 4H, J=7.5 Hz), 0.92 (t, 3H, J=7.5 Hz), 0.82 (t, 3H, J=7.5 Hz); MS (FAB) m/z 375 (MH)+. Anal. Calcd for C19H26N4O2S: C, 60.94; H, 7.00; N, 14.96. Found: C, 60.82; H, 6.85; N, 14.95.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@@H:3]1[OH:16].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]([OH:16])[C@@H:2]([NH:1][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CCOC(=O)C=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H](N)[C@H]1O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CN[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Reaction time: 0.5 h

Procedure:
To a solution of (3R-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title A compound) and ethyl glyoxylate (2.5 g) in methanol (30 mL) and acetic acid (2 mL) at 0° C. under argon atmosphere was added sodium cyanoborohydride (1.5 g). The reaction mixture was stirred at 0 C. for 30 minutes, poured into saturated sodium bicarbonate (150 mL) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography to give an oil, which solidified upon standing (1.8 g, 48%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].Cl>CO.[Pd]>[CH3:14][C:11]1([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(C2(C)CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2(C)CCNCC2)CC1
Reaction time: 3 h

Procedure:
A suspension of 2.28 g (5.62 mmol) tert-butyl 4-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine-1-carboxylate and 300 mg 10% Pd/C in 50 mL MeOH was hydrogenated for 3 h at 50° C. and 3447 hPa hydrogen pressure. To complete the reaction 0.47 mL conc. HCl were added and the mixture was hydrogenated for another 3 h at 50° C. and 3447 hPa hydrogen pressure. The catalyst was filtered off, the filtrate was evaporated down i. vac., the residue was stirred with diethyl ether, suction filtered and dried.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: CNc1cc(Cl)ccc1C(C)=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1ccc(Cl)cc1N(C)C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of acetic anhydride (12 ml) and formic acid (8 ml) was heated at 55° for 3 hours and then cooled to ambient temperature. 4'-Chloro-2'-(methylamino)acetophenone (9.7 g) was then added and the mixture stirred at ambient temperature overnight. Water (40 ml) was added and the mixture stirred in an ice/salt bath and neutralised by adding aqueous sodium hydroxide (specific gravity 1.5, 22 ml) whilst maintaining the temperature below 30°. The reaction mixture was extracted with dichloromethane (3×50 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-5'-chloro-N-methylformanilide.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[CH:6][C:7]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:8][CH:9]=2)[N:4]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:11]1[C:10]2[C:5](=[CH:6][C:7]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:8][CH:9]=2)[N:4]=[C:3]([CH2:2][Cl:1])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(CCl)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Product: FC(F)(F)c1cccnc1-c1ccc2c(Cl)nc(CCl)nc2c1

Procedure:
Reflux a mixture of 2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one and POCl3 for 16 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline.
Reaction SMILES: C([CH:3]([C:43](N)=[O:44])[C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:42])[NH:12][C:13](=[O:41])[N:14]2[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)=[CH:9][CH:8]=1)=[O:5])C.C([OH:48])C.[OH-].[Na+]>O1CCCC1>[O:41]=[C:13]1[NH:12][C:11](=[O:42])[C:10]2[C:15](=[CH:16][C:7]([NH:6][C:4]([CH2:3][C:43]([OH:48])=[O:44])=[O:5])=[CH:8][CH:9]=2)[N:14]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1
Reactant: CCO
Reactant: CCC(C(N)=O)C(=O)Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
Ethyl N-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydro-7-quinazolinyl]malonamide (690 mg) obtained in Example 43 was dissolved in tetrahydrofuran (10.0 ml) and ethanol (10.0 ml) and then a 1N aqueous solution of sodium hydroxide (5.0 ml) was added. The reaction mixture was stirred at room temperature for 16 hours and the solvent was distilled off under reduced pressure, and the residue was made acidic with 1N hydrochloric acid, and then extracted with ethyl acetate. After the extract was washed with water and dried (Na2SO4), the solvent was distilled off under reduced pressure to give the title compound (126 mg, 19%). Recrystallization from ethyl acetate-methanol-tetrahydrofuran yielded a colorless crystal having a melting point of 230 to 232° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>C(O)C>[OH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[N:17][OH:18]
Reactant: NO
Reactant: O=Cc1ccc(-c2ccccc2)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(-c2ccccc2)cc1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
2-Hydroxy-4-phenylbenzaldehyde (3.7 g), hydroxylamine hydrochloride (1.4 g), sodium acetate (3.1 g) and water (10 mL) were suspended in ethanol (50 mL), and the mixture was stirred at 80° C. for 3 hours. To the reaction mixture was added water (50 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (3.0 g).