Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:26])=[CH:5][C:6]([N+:23]([O-])=O)=[C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:8]=1.O.NN>C(O)C.[Ni]>[NH2:23][C:6]1[CH:5]=[C:4]([Cl:26])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl 4-[(5-methoxy-4-chloro-2-nitrophenyl)amino]-piperidinecarboxylate (D47) (400 mg) was dissolved in ethanol (10 ml) and Raney nickel (50% aqueous suspension, 1.0 ml) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (0.5 ml) was added over 30 min. After 30 min more, the reaction mixture was cooled to room temperature, filtered through Celite evaporated and chromatographed on silica gel eluting with ethyl acetate-hexane mixtures to yield the title compound, 300 mg.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1)(=[O:4])=[O:3].[F:14][C:15]([F:36])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:36][C:15]([F:14])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](/[CH:25]=[C:12]2/[C:8]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:9][C:10](=[O:13])[S:11]/2)[CH2:21][CH2:20]1
Reactant: CS(=O)(=O)CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CS(=O)(=O)CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of 4-{[2-(methylsulfonyl)ethyl]amino}-1,3-thiazol-2(5H)-one (1.39 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.77 g) in 2-propanol (20 mL) was added piperidinium acetate (757 mg). The reaction mixture was stirred at 80° C. for 3 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (1.6 g).
Reaction SMILES: [OH:1][C:2]([C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][O:16][C:17]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:22][C:21]=2[Cl:37])=[O:18])[CH3:13])[CH2:8][CH2:7]1)=[O:4].Cl.C(=O)([O-])O.[Na+]>C1COCC1>[OH:1][C:2]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)([C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:14][CH2:15][O:16][C:17]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([CH2:28][OH:29])=[CH:22][C:21]=2[Cl:37])=[O:18])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: COc1cc(NC(=O)OCCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(NC(=O)OCCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of trans-4-[{2-[({[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-5-methoxyphenyl]amino}carbonyl)oxy]ethyl}(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 61; 315 mg; 0.44 mmol) in 6 ml THF were added 1.31 ml (1.31 mmol) of aqueous 1M HCl and the system was stirred at room temperature for 2.5 hrs. The solution was basified with aqueous 4% sodium hydrogen carbonate solution and extracted thrice with ethyl acetate. The organic extracts were washed with brine, dried and concentrated. The residue was purified by preparative reversed-phase HPLC (CH2Cl2/isopropanol 10:0 to 9:1) to give 78% of the title compound.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:58](=[O:60])[NH2:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:58]([NH2:59])=[O:60])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(C(N)=O)ccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC(=O)c1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1
Yield: 70 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7-carbamoyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a cream solid (26 mg, 70%). 1H NMR (400 MHz, DMSO-d6): δ 8.30-8.26 (br s, 1H), 8.21 (d, J=2 Hz, 1H), 8.17 (d, J=8 Hz, 1H), 7.98 (dd, J=2 and 8 Hz, 1H), 7.74-7.71 (br s, 1H), 7.47-7.33 (m, 7H), 7.19-7.15 (m, 2H), 2.44-2.36 (m, 2H), 2.19-2.11 (m, 2H), 2.07-1.96 (m, 1H), 1.72-1.62 (m, 1H). LCMS (Method F): RT=8.99 min, [M+H]+=434.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=O)[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18]>C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=2[C:5]2[CH2:14][CH2:13][C:12](=[N:19][C:16]#[C:17][CH3:18])[C:6]1=2
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Reactant: C#CCN
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC#N
Product: CC#CN=C1CCc2c1n(C)c1ccc(O)cc21
Reaction time: 16 h

Procedure:
To a stirred suspension of 7-hydroxy-4-methyl-1,4-dihydrocyclopent[b]indol-3(2H)-one (5.5 g) in acetonitrile (100 ml) was added propargyl amine (3.0 g), the solution was stirred at room temperature under a nitrogen atmosphere while titanium (IV) isopropoxide (15.6 g) was added in a dropwise manner. The mixture was stirred for 16 hours before quenching with ice water. The mixture was filtered, the solids were washed with CH2Cl2, the layers were separated and the organic portion was dried (Na2SO4). After concentration, the crude product was purified via flash chromatography eluting with hexane/acetone (2:1) to give 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-ol.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C(#N)C>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][NH:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)CCNCCNC(=O)OC(C)(C)C
Yield: 52.1 %

Procedure:
Mono-BOC-ethylenediamine (2) (16.28 g, 0.102 mol) was dissolved in acetonitrile (400 mL) and methyl acrylate (91.5 mL, 1.02 mol) was transferred to the mixture with acetonitrile (200 mL). The solution was refluxed overnight under nitrogen in the dark to avoid polymerization of methyl acrylate. After evaporation to dryness in vacuo, a mixture of water and ether (200 mL+200 mL) was added, and the solution was filtered and vigorously stirred. The aqueous phase was extracted one additional time with ether and then freeze dried to yield a yellow solid. Recrystallization from ethyl acetate yielded 13.09 g (46%) of the title compound. M.p. 138°-140° C. Anal. for C11H23 N2O4Cl, found (calc.) C: 46.49 (46.72) H: 8.38 (8.20) N: 9.83 (9.91) Cl: 12.45 (12.54). 1H-NMR (90 MHz; DMSO-d6) δ: 1.39 (s, 9H); 2.9 (m, 8H); 3.64 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12.CI.[CH3:21]N(C)C=O.[H-].[Na+]>O>[CH3:21][O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12
Reactant: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.1 g (4.5 mmol) of 4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 0.3 ml (5.0 mmol) of methyl iodide and 10 ml of dry dimethylformamide is treated with 0.2 g (4.5 mmol) of sodium hydride (55 percent oil dispersion, washed with n-hexane) and the mixture is stirred at room temperature for about 16 hours. The mixture is poured into 70 ml of water and extracted three times with chloroform. The chloroform solution is washed once with water, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with chloroform containing 5% of methanol. Recrystallization of the material obtained from ethyl acetate/hexane yields 4,5-dihydro-3-(methoxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 115°-116°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Cc1cccc(I)c1C
Product: Cc1cccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)c1C

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2,3-dimethylbenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 480.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][OH:14].[OH-].[Na+].O>C(Cl)Cl>[C:1]([O:14][CH2:13][CH2:12][N:11]([CH3:15])[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(C)CCOC(=O)c1ccccc1
Reaction time: 3.25 h
Yield: 61.6 %

Procedure:
A solution of 70.29 g (0.50 mol) of benzoyl chloride in 500 ml of methylene chloride was added to a solution of 44.57 g (0.50 mol) of 2-dimethylaminoethanol, 20.0 g (0.50 mol) of sodium hydroxide and 500 ml of water over 15 minutes with rapid stirring. Stirring was continued for 3.25 hours after which the organic layer was separated, washed with water, dried over MgSO4 and concentrated. Distillation of the residue gave 59.5 g of product; bp=102°-8° C./0.50 mm.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Br.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: NCCN1CCOCC1
Reactant: CC1(C)CC(n2ncc(Br)c(Br)c2=O)CC(C)(C)C1
Product: CC1(C)CC(n2ncc(NCCN3CCOCC3)c(Br)c2=O)CC(C)(C)C1

Procedure:
4-Bromo-5-(2-morpholinoethyl)amino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one was prepared from 4,5-Dibromo-2-(3,3,5,5-tetramethyl cyclohexyl)pyridazin-3-one in a similar manner using 2-Morpholinoethyl amine (4 equivalents). 1H NMR (300 MHz CDCl3) 7.51 (s, 1H), 5.67 (m, 1H), 5.33 (m, 1H), 3.78 (m, 4H), 3.38 (m, 2H), 2.70 (m, 2H), 2.52 (m, 4H), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(N2CCN(c3ccccn3)CC2)nn1
Yield: 45.3 %

Procedure:
A mixture of 3.3 parts of 3.6-dichloropyridazine, 3.3 parts of 1-(2-pyridinyl)piperazine. 1.5 parts of sodium hydrogencarbonate and 120 parts of ethanol was stirred and refluxed over weekend. The reaction mixture was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and tetrahydrofuran, yielding 2.5 parts (45.3%) of 3-chloro-6-[4-(2-pyridinyl)-1-piperazinyl]pyridazine; mp. 194.7° C. (compound 213).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.O.[OH:40]OS([O-])=O.[K+]>C1COCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[O:40])[CH:7]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(C2COc3cc(O)ccc3C2CCCCCCCCCSCCCC(F)(F)C(F)(F)F)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(CCCCCCCCCC1c2ccc(O)cc2OCC1c1ccc(O)cc1)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 73 %

Procedure:
To a solution of (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]chroman (140 mg, 0.250 mmol) and H2O (0.05 ml) in THF (1.2 ml) at 0° C. was added Oxone® (monopersulfate compound; DuPont product) (77 mg, 0.125 mmol). The resulting solution was stirred at 0° C. for 3.5 hr, and then poured into H2O. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel, 60% AcOEt/hexane) to afford (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman (105 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([O:17]CC)=O)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:21]([NH:34][NH2:35])(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([NH:35][NH:34][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:17])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(CC)c1=O
Reactant: CCCCCCCCCCCC(=O)NN
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(CC)c1=O

Procedure:
Reagents: Comp 40 (0.5 mmols, 0.15 g); dodecanoyl hydrazine (0.56 mmols, 0.124 g). Yield: 0.221 g (95%), white solid, m.p.=138° C.-139° C.
Reaction SMILES: C(OC(=O)[C:5]1[C:6](=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=1Cl)[N:7]([CH3:9])[CH3:8])C.[OH-:17].[K+]>O>[CH3:8][N:7]([CH3:9])[C:6]1[CH:5]=[C:13]([OH:17])[CH:12]=[C:11]([CH3:15])[CH:10]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1c(Cl)cc(C)cc1N(C)C
Agent: [K+]
Solvent: O
Product: Cc1cc(O)cc(N(C)C)c1

Procedure:
Ethyl-6-chloro-4,N,N-trimethylanthranilate (2.4 g) and KOH (powdered, 1.5 g) were heated together in a test-tube with a free flame. After the initial reaction (temp 200°-220°) had subsided, the temperature was raised to 240°-260°, whereupon a second vigorous reaction ensued and the mixture became dark. On cooling, the mixture was dissolved in water, extracted with ether to remove tarry byproducts, and acidified (pH 5) with acetic acid. The crude product was extracted into chloroform and after removal of solvent, was purified by sublimation at 0.1 mm. 3-Dimethylamino-5-methylphenol was obtained as a pale yellow solid, mp 67°-68°.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:14])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O.C(=O)(O)[O-].[Na+]>CCOCC>[N+:15]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:9]1[CH2:10][CH2:5][CH:18]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:7][CH2:8]1)[NH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]2=[O:14])([O-:17])=[O:16]
Reactant: CN1CCCC1=O
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: N#Cc1c[nH]c2cc(N3CCC(N4CCCC4)CC3)c([N+](=O)[O-])cc2c1=O
Temperature: 25 °C

Procedure:
A mixture of 1.3 g (5.21 mmol) of 7-chloro-4-hydroxy-6-nitro-3-quinolinecarbonitrile (U.S. Pat. No. 6,297,258) and 2.6 g (16.67 mmol) of 4-(1-pyrrolidine)piperidine 17.0 ml of 1-methyl 2-pyrrolidinone is heated at 120° C. for 5 hours. The mixture is cooled to room temperature and stirred with 15 mL of saturated solution of sodium bicarbonate. Following removal of solvents in vacuo, a residue is obtained, which is stirred with ether. The solid is collected by filtration and washed with ether. The crude product is dissolved in 9:1 methylene chloride/methanol, filtered through a pad of Celite (to remove inorganic material) and further washed with 9:1 methylene chloride/methanol. Evaporation of the filtrate to dryness yields a glassy residue. Purification by silica gel chromatography (gradient 9:1 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 1.3 g of 6-nitro-4-oxo-7-(4-pyrrolidin-1-ylpiperidin-1-yl)-1,4-dihydroquinoline-3-carbonitrile as an orange solid, mp 232-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]1[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:9]([O:11]C)=O)=[O:4].[O-:17][C:18]#[N:19].[K+]>C(O)(=O)C>[O:17]=[C:18]1[NH:19][C:9](=[O:11])[C:8]2[C:7](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]1[CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: N#C[O-]
Reactant: COC(=O)CNc1ccccc1C(=O)OC
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)Cn1c(=O)[nH]c(=O)c2ccccc21

Procedure:
Monatsh. Chem. (1987) 118; pages 71-79 describes the reaction of methyl N-(methoxycarbonylmethyl)anthranilate with potassium cyanate in glacial acetic acid to give methyl 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetate. Although 10 equivalents of potassium cyanate are employed, the yield is only 19%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[O:19]C)[N:3]=1.NC1N=C(N)N=[C:24]([C:29]2[CH:38]=[CH:37][C:36]3C(=CC=CC=3)[C:30]=2[O:39]CC2C=CC=CC=2)[N:23]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:30](=[O:39])[C:29]2[CH:38]=[CH:37][CH:36]=[N:23][CH:24]=2)[N:5]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[OH:19])[N:3]=1
Reactant: Nc1nc(N)nc(-c2ccc3ccccc3c2OCc2ccccc2)n1
Reactant: COc1c(-c2nc(N)nc(N)n2)ccc2ccccc12
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2ccc3ccccc3c2O)n1

Procedure:
The same methods as in the preceding examples were conducted using 2,4-diamino-6-(1-methoxy-2-naphthyl)-s-triazine or 2,4-diamino-6-(1-benzyloxy-2-naphthyl)-s-triazine to afford 2-amino-4-nicotinamido-6-(1-hydroxy-2-naphthyl)-s-triazine, pale yellow needles, melting point 301° to 302° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20]CC)=O)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:23][NH2:24].C(OC(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]([NH:24][CH3:23])=[O:20])=[O:15])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CNC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.4.). Starting with 2.20 g (5.91 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 3.3. of Example 3, and 14.80 ml (29.55 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after crystallization from diisopropyl ether, 1.974 g of pure product are obtained in the form of a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[C:21]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:20]=2[OH:38])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:38][C:20]1[C:21]([CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: CC(C)=CCc1c(OCc2ccccc2)ccc(C(=O)C=Cc2ccc(OCc3ccccc3)cc2)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(O)ccc(C(=O)CCc2ccc(O)cc2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
Then, 21.03 g of the so-obtained 4,4'-dibenzyloxy2'-hydroxy-3'-(3-methyl-2-butenyl)chalcone was added to 200 ml of an ethyl acetate suspension of 7.01 g of 5% palladium/carbon, in which hydrogen had been adsorbed in advance, and the mixture was stirred at room temperature for 6 hours and hydrogen was absorbed. After the reaction, the suspension was filtered to remove the palladium/carbon, and the solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from benzene to obtain 11.85 g (yield=86.6%) of 1-(2,4-dihydroxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless needle.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:4]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:33])=O>ClCCl>[Cl:33][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc(OC2CCN(C)CC2)c2c(=O)[nH]cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 7-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one (3.00 g, 10.4 mmol) and diisopropyl ethylamine (5 ml) in dichloromethane (300 ml) was stirred at ambient temperature under an atmosphere of nitrogen. Phosphoryl chloride (10 ml) was added, and the resultant orange solution was heated at reflux for 20 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. Residual phosphoryl chloride was then removed by azeotrope with toluene to give the crude product as an orange oil. Purification by chromatography on silica gel, eluting with 5% triethylamine in dichloromethane, gave an orange solid, which was further purified by trituration under acetonitrile, and then dried in vacuo to yield 4-chloro-5-(N-methylpiperidin-4-yloxy)-7-methoxyquinazoline (2.4 g, 75% yield) as a pale yellow amorphous solid: