Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[C:16]([F:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cr](O)(O)(=O)=[O:28].S(=O)(=O)(O)O>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:28])=[O:21])=[C:16]([F:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[Cr](=O)(O)O
Reactant: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Yield: 68.2 %

Procedure:
In a solution of 0.95 g of 5-(3,5-dichlorophenyl)-3-(3-fluoro-4-hydroxymethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 25 ml of acetone, Johnes' Reagent prepared from 1.50 g of chromic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of water was added dropwise under cooling with ice and with stirring, after the completion of the addition dropwise, continued to stir at room temperature for further 1.5 hour. After the completion of the reaction, the reaction mixture was poured in 50 ml of water and extracted with diethyl ether (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 0.67 g of the aimed product as beige crystal.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:12]([N:13]2[CH2:18][CH2:17][CH:16]3[NH:19][CH2:20][CH2:21][CH:15]3[CH2:14]2)=[CH:11][C:10]([C:22]#[N:23])=[CH:9][C:8]=1[NH:24][C:25]1[N:30]=[C:29]([N:31]([CH:41]2[CH2:43][CH2:42]2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[C:8]([NH:24][C:25]2[N:30]=[C:29]([N:31]([CH:41]3[CH2:42][CH2:43]3)[CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)[C:28]3=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]3[N:26]=2)=[CH:9][C:10]([C:22]#[N:23])=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]2[N:19]([C:2]([O:4][CH3:5])=[O:3])[CH2:20][CH2:21][CH:15]2[CH2:14]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC2CN(c3cc(C#N)cc(Nc4nc(N(Cc5ccc(OC)cc5)C5CC5)c5ncc(C#N)n5n4)c3Cl)CCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Methyl chloroformate (5.66 μl, 0.073 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 443F, 29 mg, 0.049 mmol) and triethylamine (0.020 ml, 0.146 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at room temperature overnight. Solvent was evaporated in vacuo and the crude intermediate was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-4% 2 N ammonia in methanol/dichloromethane) to give 28 mg of methyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)=[C:5]2[Cl:24].C[O-].[Na+].[C:28](=O)(O)[O-:29].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:29][CH3:28])[C:6]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)=[C:5]2[Cl:24]
Reactant: O=C([O-])O
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C

Procedure:
6-bromo-2,4-dichloro-3-(6-(trifluoromethyl)pyridin-3-yl)methyl)quinolone (1.0 g, 2.3 mmol, Intermediate 65: step b) and sodium methoxide (1.2 g, 22 mmol) in dry toluene (12 mL) were heated to 80° C. and refluxed under a positive pressure of nitrogen overnight. The mixture was allowed to cool to ambient temperature. Aqueous saturated sodium bicarbonate solution was added to the mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was purified by flash column chromatography (silica gel, 0-20% EtOAc-Hex) to provide the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)=[O:25]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)n1ncc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Yield: 78.4 %

Procedure:
A 4 L 3-neck round bottom flask fitted with a nitrogen inlet and mechanical stirrer was charged with a solution of 5-nitroindazole (80.0 g, 0.49 mol) in tetrahydrofuran (1 L). The mixture was cooled to 0° C. and triethylamine (85.4 mL, 0.61 mol) was added. To the mixture was added pivaloyl chloride (63.4 mL, 0.52 mol) dropwise over a period of 15 minutes. The reaction was allowed to warm to 20° C. over a period of 2 hours. The reaction was filtered and concentrated to a dark red oil. To the oil was added methylene chloride (60 mL). The resulting slurry was stirred vigorously, giving a white precipitate that was isolated by filtration. The solid was dried in a vacuum oven at 40° C. overnight to afford the title compound (95 g, 79%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH3:20]>C(C(C)=O)C(C)C>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([O:10][CH2:19][CH3:20])[CH:7]=[CH:8][CH:9]=1)[CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOc1cccc(N(CC)CC)c1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A 1 liter reactor is charged with 300 ml of methyl isobutyl ketone, 73.1 g of 3-diethylaminophenol and 153.3 g of ground potassium carbonate and the mixture is stirred for 30 minutes. Then 72.7 g of ethyl bromide are introduced into the autoclave, which is then closed and heated for 3 hours to 115°-120° C. The temperature is then kept for a further 5 hours at 140°-142° C. (pressure: 5 bar). The contents of the autoclave are cooled to c. 25° C. and potassium bromide is removed by filtration. After washing with a small amount of methyl isobutyl ketone, the combined filtrates are concentrated by evaporation, to give 75.6 g (91.1% yield) of 3-diethylaminophenetol with a titre of 96.9%.
Reaction SMILES: [N+:1](=[CH:3][CH2:4][CH3:5])=[N-].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[S:19][C:18](=[S:20])N[C:16](=[O:21])[N:15]=2)=[CH:9][CH:8]=1>CCOCC.O1CCCC1>[CH2:3]([N:1]1[C:16](=[O:21])[N:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[S:19][C:18]1=[S:20])[CH2:4][CH3:5]
Reactant: CCC=[N+]=[N-]
Reactant: O=c1nc(Sc2ccc(Cl)cc2)sc(=S)[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCn1c(=O)nc(Sc2ccc(Cl)cc2)sc1=S
Yield: 66.4 %

Procedure:
A solution of 7.7 g of diazopropane in ether is added in portions to a solution of 28.8 g of 2,3-dihydro-6-(4-chlorophenylthio)-2-thioxo-4H-1,3,5-thiadiazin-4-one in 250 ml of tetrahydrofuran at 22° C. The solvent is distilled off, the residue is taken up in a small amount of methanol, and the precipitate is filtered off under suction, washed with methanol and dried. 21.9 g of 3-propyl-6-(4-chlorophenylthio)-2-thioxo-1,3,5-thiadiazin-4-one are obtained in the form of yellow crystals of melting point 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:30])[O:28][CH3:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:27]([O:28][CH3:29])=[O:30])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCNC(c2ccc(Cl)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
Methyl 2-(4-chlorophenyl)piperidine-4-carboxylate (3.13 g, 12.34 mmol) was dissolved in DCM (50 mL), then DIPEA (5.39 mL, 30.84 mmol) was added. Methyl carbonochloridate (1.360 mL, 17.27 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 3 h. The mixture was washed with 0.1 M HCl (2*100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(4-chlorophenyl)piperidine-1,4-dicarboxylate (3.97 g, quant.) as an orange oil. MS m/z 312 (M+H)+
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([SH:20])=[N:18][N:17]=[N:16]2)[CH:12]=[CH:13][CH:14]=1)(=O)CCCCC.[ClH:21]>C(O)C>[ClH:21].[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([SH:20])=[N:18][N:17]=[N:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCC(=O)Nc1cccc(-n2nnnc2S)c1
Agent: Cl
Solvent: CCO
Product: Nc1cccc(-n2nnnc2S)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
150 g (0.51M) of 1-(3-hexanamidophenyl)-5-mercaptotetrazole was dispersed in 450 ml of ethanol, and 300 ml of concentrated hydrochloric acid was added thereto with stirring at room temperature. After the reaction was carried out at room temperature for 3 hours, the mixture was cooled with ice, and the precipitated crystals were separated by filtration and washed with acetone to obtain 110 g of 1-(3-aminophenyl)-5-mercaptotetrazole hydrochloride. The resulting amine hydrochloride was dispersed in 750 ml of acetonitrile. After adding 485 ml of triethylamine, 125 g of butyl isocyanate was added dropwise at room temperature. After the reaction was carried out at room temperature for 6 hours, 2.2 liters of water were added and the pH was adjusted to 2 with hydrochloric acid. The precipitated crystals were separated by filtration and recrystallized from ethanol to obtain 69 g (yield: 46%) of the desired product having a melting point of 171°-172° C. (decomposition).
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])[CH:7]=[CH2:8].[CH3:21]O>>[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20][CH3:21])=[O:19])=[O:11])[CH:7]=[CH2:8]
Reactant: CO
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Yield: 43 %

Procedure:
A catalytic amount of concentrated H2SO4 (4.5 mL) was added to a solution of Alloc-hydroxyproline (2) (43 g, 200 mmol) in MeOH (300 mL) at 10° C. (ice) and the reaction mixture was then heated at reflux for 2 h. After cooling to room temperature the reaction mixture was treated with TEA (43 mL) and the MeOH evaporated in vacuo. The residue was dissolved in EtOAc (300 mL), washed with brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo to give a viscous oil. Purification by flash chromatography (40% EtOAc/Petroleum Ether) removed the high Rf impurity to provide the pure ester 3 as a transparent yellow oil (19.6 g, 43%): [α]23D=−79.0° (c=0.35, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ 5.98-5.78 (m, 1H, NCO2CH2CH═CH2), 5.35-5.16 (m, 2H, NCO2CH2CH═CH2), 4.65-4.45 (m, 4H, NCO2CH2CH═CH2, NCH2CHOHCH2 and NCHCO2CH3), 3.75 and 3.72 (s×2, 3H, OCH3), 3.70-3.54 (m, 2H, NCH2CHOHCH2), 3.13 and 3.01 (br s×2, 1H, OH), 2.39-2.03 (m, 2H, NCH2CHOHCH2); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ 173.4 and 173.2 (CO2CH3), 155.0 and 154.6 (NC═O), 132.6 and 132.4 (NCO2CH2CH═CH2), 117.6 and 117.3 (NCO2CH2CH═CH2), 70.0 and 69.2 (NCH2CHOH), 66.2 (NCO2CH2CH═CH2), 57.9 and 57.7 (NCHCO2CH3), 55.2 and 54.6 (NCH2CHOH), 52.4 (OCH3), 39.1 and 38.4 (NCH2CHOHCH2); MS (EI), m/z (relative intensity) 229 (M+, 7), 170 (M-CO2Me, 100), 144 (M-CO2C3H5, 12), 126 (26), 108 (20), 68 (7), 56 (8); IR (Neat) 3438 (br, OH), 2954, 1750 and 1694 (br, C═O), 1435, 1413, 1345, 1278, 1206, 1130, 1086, 994, 771 cm−1; exact mass calcd for C10H15NO5 m/e 229.0950, obsd m/e 229.0940.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[N-:28]=[C:29]=[O:30].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])[NH2:28])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [N-]=C=O
Reactant: Cc1c(C(=O)c2ccc(N)cc2)c2ccccc2n1CCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C(=O)c2ccc(NC(N)=O)cc2)c2ccccc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a stirred suspension of 12.0 g. (0.03 mole) of 2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]- 1H-indole (Example 4B) in 15 ml of glacial acetic acid and 30 ml. of water was added a solution of 4.5 g. (0.06 mole) of sodium isocyanate in 30 ml of water. The mixture was stirred at room temperature for two hours, then diluted with water and made alkaline with 10% sodium hydroxide The solid which separated was collected and recrystallized from DMF to give 5.9 g (48%) of 2-methyl3-(4-carbamylaminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole, m p. 192°-202° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].O.S(=O)(=O)(O)[OH:20]>C([O-])(=O)C>[C:16]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:14][C:13]2=[O:15])(=[O:20])[CH3:17]
Reactant: C#Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Reactant: O=S(=O)(O)O
Agent: CC(=O)[O-]
Solvent: O
Product: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1.20 g of 2-butyl-6-ethynyl-4(1H)-quinazolinone in 90 ml of acetate acid is added 0.45 g of mercuric sulfate, 0.9 ml of water and 0.3 ml of sulfuric acid. The reaction mixture is heated at reflux for 5 hours, cooled to room temperature and quenched with 150 ml of water. The resulting mixture is concentrated in vacuo, diluted with 150 ml of water and extracted with 6:1 chloroform-methanol. The combined organics are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.67 g of the desired product as a white solid. CI MASS SPEC 245(MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[C:5]([CH3:18])([CH3:17])[CH2:4][CH2:3]1)[NH:13][C:12](=O)[CH2:11][CH2:10]3.[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>C1COCC1>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:24]([CH2:23][N:13]2[C:14]3[C:9](=[CH:8][C:7]4[C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:18])([CH3:17])[C:6]=4[CH:15]=3)[CH2:10][CH2:11][CH2:12]2)=[CH:25][CH:26]=1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCC(=O)N3
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCc3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Temperature: 60 °C
Yield: 61.3 %

Procedure:
To a solution of 6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-1H-benzo[g]quinolin-2-one (130 mg, 0.50 mmol) in THF (4 mL) was added NaH (18 mg, 0.76 mmol) in one portion at ambient temperature. To this solution was added methyl 4-(bromomethyl)-benzoate (229 mg, 1.01 mmol) in THF (8 mL). The mixture was then heated at 60° C. for 8 h, cooled to ambient temperature, quenched with aqueous saturated NH4Cl (20 mL), extracted with EtOAc (100 mL), dried with (MgSO4), concentrated, and purified by column chromatography (10% ether in hexane) to afford 4-(6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-1H-benzo[g]quinolin-1-ylmethyl)benzoic acid methyl ester (120 mg, 58%): 1H NMR (400 MHz, CDCl3) δ 8.10 (½ ABq, 2H, J=8.0 Hz, ArH), 7.48 (½ ABq, 2H, J=8.0 Hz, ArH), 7.08 (s, 1H, ArH), 6.70 (s, 1H, ArH), 5.20 (s, 2H, CH2), 4.51 (s, 3H, CH3), 2.91 (t, 2H, J=7.0 Hz, ring CH2), 2.81 (broad m, 2H, ring CH2), 1.60 (s, 4H, 2CH2), 1.23 (s, 12H, 4CH3).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][N:6]1[CH:14]=[C:12]([CH3:13])[C:10](=[O:11])[NH:9][C:7]1=[O:8].Cl>[OH-].[Na+]>[N:6]1([CH2:5][CH2:4][C:3]([OH:15])=[O:2])[CH:14]=[C:12]([CH3:13])[C:10](=[O:11])[NH:9][C:7]1=[O:8]
Reactant: COC(=O)CCn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cn(CCC(=O)O)c(=O)[nH]c1=O
Yield: 70.9 %

Procedure:
3-(1-Thyminyl)propanoic acid methyl ester (1 g, 0.0047 mol) was suspended in 2M sodium hydroxide (15 mL), refluxed for 10 minutes. The pH was adjusted to 0.3 with conc. hydrochloric acid. The solution was extracted with ethyl acetate (10×25 mL). The organic phase was extracted with saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated to dryness in vacuo, to give the title compound as a white solid (0.66 g, 71%). M.p. 118°-121° C. Anal. for C8 H10N2O4, found (calc.) C: 48.38 (48.49) H: 5.09 (5.09) N: 13.93 (14.14). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14][CH2:15]C)=[O:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:29])C>>[C:1]1([C@H:7]([N:9]2[C:10]3[N:20]=[CH:19][CH:18]=[CH:17][C:11]=3[C:12](=[O:13])[O:14][C:15]2=[O:29])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cccnc1N[C@H](C)c1ccccc1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: C[C@H](c1ccccc1)n1c(=O)oc(=O)c2cccnc21

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 57A for the product of Example 3A (0.250 g, 62%). 1H NMR (300 MHz, DMSO-d6) δ 1.86 (d, J=6.99 Hz, 3H), 6.65 (q, J=6.99 Hz, 1H), 7.27 (m, 3H), 7.40 (m, 3H), 8.43 (dd, J=7.72, 1.84 Hz, 1H), 8.73 (dd, J=4.96, 2.02 Hz, 1H).
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[N:13]=[C:14]([NH:18][CH2:19][CH3:20])[N:15]=[C:16]([CH3:17])[C:11]=3[CH:10]=[CH:9][C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br>CC(O)=O.C(Cl)Cl>[Br:22][C:9]1[C:8](=[O:21])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]2[N:13]=[C:14]([NH:18][CH2:19][CH3:20])[N:15]=[C:16]([CH3:17])[C:11]=2[CH:10]=1
Reactant: CCNc1nc(C)c2ccc(=O)n(C3CCCCC3)c2n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNc1nc(C)c2cc(Br)c(=O)n(C3CCCCC3)c2n1
Yield: 80 %

Procedure:
To 8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one in AcOH and CH2Cl2 was added Br2 (22 uL, 0.42 mmol) at 80° C. Standard workup and purification by column chromatography gave 65 mg (0.17 mmol, 80% yield) of 6-bromo-8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:12][CH3:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][CH2:20][N:14]([CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCN1CCCNCC1
Product: CCCN1CCCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
In a manner similar to Preparation 2, react 1-fluoro-4-nitrobenzene with hexahydro-1-propyl-1H-1,4-diazepine to obtain the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:36][C:35]1[CH:34]=[CH:33][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=2)=[O:19])=[CH:16][C:15]=1[NH:14][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:12]
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1ccc2ncccc2c1
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc2ncccc2c1

Procedure:
Using an analogous procedure to that described in Example 1, 6-quinolylcarbonyl chloride was reacted with 3-amino-4-methyl-N-(3-morpholinophenyl)benzamide to give the title compound; NMR Spectrum: (DMSOd6) 2.35 (s, 3H), 3.0-3.1 (m, 4H), 3.65-3.75 (m, 4H), 6.65-6.7 (m, 1H), 7.17 (t, 1H), 7.3-7.35 (m, 1H), 7.38-7.48 (m, 2H), 7.6-7.7 (m, 1H), 7.8-7.85 (m, 1H), 8.0 (s, 1H), 8.1-8.15 (m, 1H), 8.3-8.35 (m, 1H), 8.5-8.55 (m, 1H), 8.7 (s, 1H), 8.98-9.02 (m, 1H), 10.0-10.1 (br s, 1H), 10.25-10.35 (br s, 1H); Mass Spectrum: M+H+ 467.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:9]([C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)([CH3:22])[CH3:23]
Reactant: CN(C)c1ccc(CNc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Yield: 44.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-dimethylaminophenyl)[(4-dimethylaminophenyl)methyl]amine (1.05 g) and 2,6-diisopropylphenyl isocyanate (1.03 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-dimethylaminophenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.815 g) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])(C)(C)C.[ClH:24].O1CCOCC1>>[ClH:24].[NH2:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:12][CH:13]([OH:15])[CH2:14]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(1S)-Benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (515 mg, 1.6 mmol) was dissolved in cold 4N HCl-dioxane, the mixture stirred 2 h at 25° C., concentrated, and the residue coevaporated with ether giving a colorless solid (415 mg, 100%).