Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14]CCCCCC=CCCC.CI>C1C=CC=CC=1>[CH3:14][O:12][C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9]
Reactant: CCCC=CCCCCCC
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: c1ccccc1
Solvent: CI
Product: COC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo 5.4.0!-undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution added 74.94 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and then cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, a saturated sodium bicarbonate solution, and then brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4%) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26]>CN(C)C=O>[CH3:26][O:25][CH2:24][CH2:23][N:12]1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2
Reactant: COCCBr
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Temperature: 50 °C
Yield: 78.3 %

Procedure:
To a mixture of 8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (1.000 g, 4.850 mmol) and cesium carbonate (3.160 g, 9.699 mmol) in N,N-dimethylformamide (20 mL) was added, 1-bromo-2-methoxyethane (0.9 mL, 9.7 mol). The reaction was heated to at 50° C., O/N. The reaction mixture was filtered and the filtrate evaporated to afford a residue that was extracted into DCM and washed with water, brine and dried by passing through a funnel filled with MgSO4. The filtrate was evaporated and the residue purified by chromatography (silica gel eluted with 3:1 EtOAc:hexane) to provide 1-(2-methoxy-ethyl)-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.004 g, 78%) as pale yellow crystals that had the following properties: 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 8.05 (d, J=8.3, 1H), 7.38 (d, J=8.3, 1H), 4.05 (br s, 2H), 3.62 (m, 2H), 3.32 (s, 3H). 2.86 (br s, 2H), 2.35 2.10 (m, 4H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].OS(O)(=O)=O.[CH3:19]O>>[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)[C:9]([O:11][CH3:19])=[O:10]
Reactant: CO
Reactant: NCc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(CN)ccc1Cl

Procedure:
To a solution of 5-(aminomethyl)-2-chlorobenzoic acid hydrochloride (17.0 g, 76.5 mmol) in methanol (200 mL) was added conc. H2SO4 (15 mL). The reaction mixture was refluxed for 15 h. The reaction mixture was concentrated and water was added. The aq. solution was basified with sodium bicarbonate. The reaction mixture was extracted with 10% MeOH:DCM and concentrated to afford 15.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.1 (br s, 2H), 3.73 (s, 2H), 3.85 (s, 3H), 7.50 (s, 2H), 7.77 (s, 1H); MS (m/z): 200.05 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:21]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=1)N>>[CH3:29][C:25]1[CH:24]=[C:23]([N:21]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:28]=[CH:27][N:26]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: Cc1cc(NN)ccn1
Product: Cc1cc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)ccn1
Yield: 37 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 4-hydrazino-2-methylpyridine according to the method described for Example 1 in 37% yield. MS: M=330.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[NH2:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[S:22])=[CH:11][C:6]=2[N:7]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccc2sc(N)nc2c1
Solvent: C1CCOC1
Product: Nc1nc2cc(NC(=S)NC(=O)c3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of anhydrous THF (6.7 mL) was added 5-amino-benzothiazol-2-ylamine (Example 16, 100 mg, 0.61 mmol) and benzoyl isothiocyanate (0.08 mL, 1 equiv). The resulting mixture was stirred at room temperature for 2 hours, after which the solvent was evaporated and the residue was washed with a 1:1 mixture of ether/hexanes (0.164 g, 83%). 1H NMR (DMSO d6) δ: 12.61 (s, 1H), 11.53 (s, 1H), 7.99 (d, 1H, J=3.9 Hz), 7.76 (s, 1H), 7.69–7.65 (m, 2H), 7.59–7.53 (m, 4H), 7.25–7.23 (d, 1H, J=3.9 Hz); MS (ESI) 328.8 (M+1, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[CH:12]=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[C:4]([F:21])[CH:3]=1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[C:12]([Cl:22])=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[C:4]([F:21])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate in DMF was added N-chlorosuccinimide. The reaction mixture was stirred at room temperature for 25 minutes and then quenched with saturated sodium bisulfite. The reaction mixture was diluted with H2O and partitioned between EtOAc/diethyl ether and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave the desired product as a white solid. MS ESI (+) m/z 389, 391, 393 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.13 (s, 1H), 7.34 (d, 1H), 7.24 (d, 1H), 6.69 (t, 1H), 3.87 (s, 3H), 3.29 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:25]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
DIEA (137.5 mL, 0.766 mol) was added to a suspension of (5)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (75.0 g, 0.357 mol) in THF (900 mL), and the mixture was cooled to 0° C. (ice/water bath). Methyl chloroformate (29.0 mL, 0.375 mol) was added dropwise over 45 min, the cooling bath was removed and the heterogeneous mixture was stirred at ambient temperature for 3 h. The solvent was removed under diminished pressure and the residue partitioned between EtOAc and water (1 L each). The organic layer was washed with H2O (1 L) and brine (1 L), dried (MgSO4), filtered and concentrated under diminished pressure. The crude material was passed through a plug of silica gel (1 kg), eluting with hexanes (4 L) and 15:85 EtOAc/hexanes (4 L) to afford (S)-tert-butyl 2-(methoxycarbonylamino)-3-methylbutanoate as a clear oil (82.0 g, 99% yield). 1H-NMR (500 MHz, DMSO-d6, δ=2.5 ppm) 7.34 (d, J=8.6, 1 H), 3.77 (dd, J=8.6, 6.1, 1 H), 3.53 (s, 3 H), 1.94-2.05 (m, 1 H), 1.39 (s, 9 H), 0.83-0.92 (m, 6 H). 13C-NMR (126 MHz, DMSO-d6, δ=39.2 ppm) 170.92, 156.84, 80.38, 60.00, 51.34, 29.76, 27.62, 18.92, 17.95. LC/MS: [M+Na]+ 254.17.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(OCC)(=O)C>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[CH3:29]
Reactant: CC1(C)OC(c2ccc(O)cc2)OC1(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol (10.0 g, 45.5 mmol) and Cs2CO3 (23.5 g, 68.25 mmol) in DMF (60 mL) was added ethyl α-bromoacetate (11.6 g, 68.25 mmol). The mixture was stirred at room temperature for 24 hours, then diluted with-ethyl acetate, washed with water, dried over Na2SO4. After filtration and evaporation, the residue was dried under high vacuum to provide [4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-acetic acid ethyl ester (12.52 g, 90% yield) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)c1cncnc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cncnc3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
0.1 g of pyrimidine-5-carboxylic acid (0.805 mmol) and 0.28 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (0.805 mmol) were dissolved in 10 ml of dichloromethane. 0.46 g of diisopropylethylamine (3.17 mmol), 0.054 g of hydroxybenzotriazole (HOBt, 0.4 mmol), and 0.17 g of N-ethyl-N′-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDCl, 0.88 mmol) were added at 0° C. The reaction mixture was stirred for 16 h at room temperature. Then, 0.085 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred for 4 h. The solvent was evaporated and the residue partitioned between and ethyl acetate and saturated aqueous sodium chloride. 4 ml of acetone were added to improve phase separation. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5-10%). Evaporation of the solvent yielded 0.16 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].[OH-].[K+].Cl[CH:18]([F:20])[F:19].O>CC(O)C>[F:19][CH:18]([F:20])[O:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14]
Reactant: Cc1c(C(F)(F)F)nn(C(C)C)c1O
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(C(F)(F)F)nn(C(C)C)c1OC(F)F
Reaction time: 2 h
Yield: 75 %

Procedure:
Into 17.1 g (82.1 mmol) of 5-hydroxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole in 100 ml of 2-propanol was added 23.0 g (410.7 mmol) of powdery potassium hydroxide at room temperature, followed stirring. Furthermore, stirring was continued while an excess amount of chlorodifluoromethane was introduced into the reaction solution. Thereafter, the reaction temperature once rose to 70° C. by exothermic heat and then returned to room temperature after 2 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled to obtain 15.9 g (yield: 75.0%) of 5-difluoromethoxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[N:23]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[CH2:22][CH2:21][N:20]=1
Reactant: Clc1ccccc1CC1=NCCN1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)N1CCN=C1Cc1ccccc1Cl
Reaction time: 2 h

Procedure:
Dissolve 2-chloro-3-pyridinylcarbonyl chloride (4.69g) in dichloromethane (25 ml), and add the solution to a stirred, cooled (ice bath) solution of 2-(2-chlorophenyl)methyl-imidazoline (4.30g) and diisopropylethylamine (7.69 ml) and dichloromethane (25 ml). Allow the resulting solution to stir 2 hours, then wash it with water, 1 M sodium bicarbonate solution, and with water. Dry the dichloromethane solution, using sodium sulfate, then filter and evaporate the solvent. Crystallize the residue from ethyl acetate to obtain 2-[(2-chlorophenyl)methyl]-1-[(2-chloro-3-pyridinyl) carbonyl]-4,5-dihydro-1H-imidazole, mp 128.5°-130° C.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH:19]2[O:21][CH2:20]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:25][CH:22]2[CH2:24][CH2:23]2)[O:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C=Cc2ccccc2OCC2CO2)on1
Reactant: NC1CC1
Product: CC(C)c1cc(C=Cc2ccccc2OCC(O)CNC2CC2)on1

Procedure:
7 g (0.025 mole) of 3-isopropyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 3 g (0.05 mole) of cyclopropylamine are reacted by the method described in Example 5. 3.0 g (30% of theory) of colorless crystals are obtained as the fumurate. Melting point 148°-152° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH2:10])[C:8]#[N:9].[OH-:11].[K+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH2:10])[C:8]([NH2:9])=[O:11]
Reactant: C=C(C#N)c1ccccn1
Reactant: [OH-]
Agent: [K+]
Product: C=C(C(N)=O)c1ccccn1

Procedure:
The Scheme 18 shows a proposed process for synthesizing pyridinyl acrylamide (76). Diketone (72) is reacted with compound (35) to yield pyridinyl ketone compound (73), which is transformed to the pyridinyl acrylonitrile compound (74) by reacting with cyanomethylphosphonic acid diethyl ester and NaH. 3-(2-Alkyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (75) obtained by hydrolyzing the pyridinyl acrylonitrile compound (74) with KOH is reacted with the amine compound (1) to yield pyridinyl acrylamide (76).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:13]=[CH2:12]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
The reaction mixture of 4-hydroxybenzoic acid, methyl ester (20.0 g, 131.0 mmol), allyl bromide (17.0 g, 138.0 mmol) and potassium carbonate (45.0 g, 329.0 mmol) in DMSO (30.0 mL) was stirred at room temperature for 8 hours. EtOAc (150 mL) was added, and the organic phase was washed with water (30×3 mL). The organic layer was dried over MgSO4. The solvent was removed. The product thus obtained was of sufficient quality for use in the next step without further purification, (25.0 g, yield 99%). 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (2H, m), 6.86 (2H, m), 5.98 (1H, dt, J=17.2, 5.3 Hz), 5.35 (1H, dd, J=17.2, 1.6 Hz), 5.24 (1H, dd, J=10.6, 1.6 Hz), 4.52 (2H, d, J=5.5 Hz), 3.81 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)=[O:16]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:21][CH:22]=3)=[O:16])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: c1cncc(N2CCNCC2)c1
Product: CS(=O)(=O)Nc1ccc(C(=O)CN2CCN(c3cccnc3)CC2)cc1
Yield: 60.4 %

Procedure:
Treatment of 1-(3-pyridinyl)piperazine (0.65 g) with N-[4-(bromoacetyl)phenyl]methanesulphonamide (1.17 g) according to the method of Example 1 gave the title compound, (0.90 g), m.p. 197°-198° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[H-].[Na+].[CH3:14][N:15]1[C:20]([CH3:21])=[CH:19]C(=O)[O:17][C:16]1=O>O1CCCC1>[CH3:14][N:15]1[C:20]([CH3:21])=[CH:19][C:3]([OH:5])=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:16]1=[O:17]
Reactant: Cc1cc(=O)oc(=O)n1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
At room temperature, 1 ml of a solution of 0.71 g of diethyl malonate in tetrahydrofuran was added to a mixture of 0.19 g of sodium hydride and 4 ml of tetrahydrofuran, and the mixture was stirred for 20 minutes. At room temperature, 3 ml of a solution of 0.59 g of 3,4-dimethyl-2H-1,3-oxazine-2,6(3H)-dione in tetrahydrofuran was added to the mixture, followed by stirring for 2 hours under heat refluxing condition. The reaction mixture was concentrated under reduced pressure. To the residue were added 10 ml of water and 12 ml of 2 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to obtain 0.57 g of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate represented by the formula:
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][C:33](=[O:34])[N:32]([CH3:36])[CH3:31])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OC(=O)N(C)C)cc4)cc3)n(C)c(=O)c12

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (478 mg), dimethylcarbamoyl chloride (0.15 ml) and potassium carbonate (315 mg) in DMF (7 ml) was stirred at 50° C. for 48 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate to provide the title compound as colorless solid (346 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[NH:10][C@H:11]([CH2:36][OH:37])[CH2:12][CH2:13][C:14](=[O:35])[NH:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>CN(C=O)C.CC(OC)(C)C>[CH2:1]([O:8][C:9](=[O:38])[NH:10][C@H:11]([CH2:36][O:37][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:12][CH2:13][C:14](=[O:35])[NH:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CC[C@@H](CO)NC(=O)OCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H](CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
Intermediate B1, prepared above, was dissolved in DMF (10 mL). Imidazole (2.69 g, 39.5 mmol, 2.3 equiv) and tert-butyldimethylsilyl chloride (2.86 g, 19.0 mmol, 1.1 equiv) were added. The reaction mixture was stirred overnight, then diluted with MTBE (500 mL) and washed sequentially with 2.5% KHSO4, H2O, NaHCO3, H2O, and brine (100 mL each). The organic phase was dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (gradient elution, 25→40% EtOAc in hexanes) to provide the title intermediate (7.6 g, 71%) as a white amorphous solid: IR (cm−1) 3307, 1708, 1660, 1496, 1249; 1H NMR (CDCl3) δ-0.01-0.05 (m, 6H), 0.89 (s, 9H), 1.76-1.93 (m. 2H), 2.29-2.40 (m, 2H), 3.56-3.77 (m, 3H), 5.03-5.16 (m, 3H), 7.00 (s, 1H), 7.18-7.39 (m, 20 H); Anal. C38H46N2O4Si: C, H, N.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:19])[C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:20].[CH2:21]([NH:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>CS(C)=O>[CH2:21]([N:25]([CH2:26][CH3:27])[C:2]1[C:3]([CH3:20])=[C:4]([N:9]([CH3:19])[C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Cc1cc(C)c(N(C)c2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CCCCNCC
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc(N(C)c2c(C)cc(C)cc2C)c1C
Temperature: 160 °C

Procedure:
A mixture of (6-chloro-2,5-dimethyl-pyrimidin-4-yl)-methyl-(2,4,6-trimethylphenyl)-amine (200 mg) and N-butyl-ethylamine (0.3 ml) in 1 ml of DMSO was heated in oil bath of 160° C. for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give the crude material. After silica gel column purification using chloroform as eluent, the title compound was obtained as an oil. 1H NMR (CDCl3) δ 6.83 (s, 2H), 3.22 (s, 3H), 3.12 (m, 4H), 2.44 (s, 3H), 2.26 (s, 3H), 2.01 (s, 6H), 1.35-1.42 (m, 2H), 1.1-1.25 (m, 2H), 1.00 (t, 3H), 0.90 (t, 3H) ppm.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl>[CH2:19]([O:18][C:16]([NH:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a stirred solution of valinol (13.96 g, 0.14 mol) and triethylamine (18.87 mL, 0.14 mol) in 250 mL of dry methylene chloride cooled to 0° C. under a nitrogen atmosphere was added 19.3 mL (0.14 mol) of benzyl chloroformate dropwise over 20 min. After warming to RT overnight, the mixture was diluted with methylene chloride (100 mL) and washed with 1 N HCl (2×), brine and dried with anhydrous magnesium sulfate. The resulting mixture was filtered and evaporated to give 30.70 g (95.6%) of N-benzyloxycarbonyl-valinol as a white solid: Rf =0.27 (silica gel; 1:1 hexane:ethyl acetate). Used without further purification.