Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:16](=[O:18])[CH3:17])[CH2:20][CH2:21]2)=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a stirred solution of trans-4-chloro-3-nitrocinnamic acid (1.50 g, 6.59 mmol) and 1-acetylpiperazine (0.89 g, 6.94 mmol) in 20 mL of DMF at room temperature was added EDAC (1.4 g, 7.30 mmol). The mixture was then stirred at room temperature for 2 hours. TLC indicated the complete consumption of the acid. Water was then added to quench the reaction and to precipitate out the product. Cinnamide was then collected through filtration and washed with cold water. The light yellow product was dried in a vacuum oven overnight at 40° C. to give 2.04 g (6.03 mmol, 91.6%) of the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:12]2[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([CH2:9][N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[N:15]=[C:14]3[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=23)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc(C)c(C)c2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
Sodium hydride (60% in oil, 0.158 g) was added to a solution of 1H-1,2,4-triazole (0.252 g) in N,N-dimethylformamide (DMF) (15 ml). The mixture was stirred for 15 minutes at room temperature, to which was added ethyl 6-chloromethyl-4-(4-chlorophenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.2 g). The mixture was stirred for 35 minutes at 80° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with dichloromethane-ethyl acetate (20:1, v/v), was obtained ethyl 4-(4-chlorophenyl)-2,3-dimethyl-6-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate (0.655 g, 50%). Recrystallization from ethanol gave colorless prisms, m.p.144°-145° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl.CO>[Cl:11][C:12]1[N:13]=[C:14]([N:3]2[C:4]3[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=3[N:1]=[CH:2]2)[CH:15]=[N:16][CH:17]=1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Temperature: 25 °C
Yield: 27 %

Procedure:
A mixture of 1H-benzimidazol-5-amine (0.8 g, 6 mmol), 2,6-dichloropyrazine (0.9 g, 6.0 mmol) and cesium carbonate (2.73 g, 8.4 mmol) in DMF (6 mL) was heated under N2 for 6 h. Upon cooling to RT the mixture was diluted with dichloromethane-methanol (6:1, 30 mL) and filtered and the filtrate concentrated in vacuo. The residue was chromatographed using CH2Cl2-MeOH (98:2-94:6) to give from the less polar fractions 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (398 mg):
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH2:8][CH2:9][N:10]([CH3:23])[C:11]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=O.O.[OH-].[Na+]>C1COCC1>[OH:7][CH2:8][CH2:9][N:10]([CH2:11][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[CH3:23]
Reactant: CN(CCO)C(=O)C1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCO)CC1CCCc2ccccc21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To an incomplete solution of 7.5 g (200 mmol) of LAH in 200 ml of THF was added a solution of 30.65 g (131.4 mmol) of 1-[N-(2-hydroxyethyl)-N-methylaminocarbonyl]-1,2,3,4-tetrahydronaphthalene, a compound of Formula 11 prepared, for example, as described in Preparation 11, dissolved in 100 ml of THF. The reaction was stirred at reflux for 30 minutes, cooled to ambient temperature, and treated with 7.5 ml of water, 7.5 ml of 15% NaOH, and finally with 22.5 ml of water. Insoluble inorganic materials were removed by filtration and the filtrate concentrated to give 27.31 g of 1-[N-(2-hydroxyethyl)-N-methylaminomethyl]-1,2,3,4-tetrahydronaphthalene, an intermediate of Formula 12, as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH2:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)[CH3:33]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]4[CH2:38][CH2:39][N:34]([CH2:32][CH3:33])[CH2:35][CH2:36]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CCN1CCC(N)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCC(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-ethylpiperidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.31 (m, 3H) 1.71-1.88 (m, 2H) 1.91-2.20 (m, 2H) 2.44 (s, 3H) 3.01-3.18 (m, 3H) 3.23-3.43 (m, 1H) 3.55 (d, J=12.13 Hz, 2H) 3.99-4.28 (m, 1H) 7.67 (d, J=7.83 Hz, 1H) 7.70-7.86 (m, 2H) 8.07-8.31 (m, 1H) 8.32-8.64 (m, 2H) 8.73 (d, J=6.32 Hz, 1H) 8.84-8.99 (m, 1H) 9.24 (br. s., 1H) 12.78-13.45 (m, 1H). MS m/z [M+H]+ 431.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=O>C1C=CC=CC=1>[CH:1]1[C:10]2[C:14](=[O:15])[C:2]3[C:3](=[CH:4][C:5]4[C:10]([CH:1]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:11](=[O:13])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)c2cc3ccccc3cc21

Procedure:
Substituted tetracenes also can be prepared by any known method, including for example, the following sequence of reactions: 1) the condensation of naphthalene-2,3-dicarboxylic anhydride and benzene derivatives, 2) dehydration to form the corresponding tetracene-5,12-quinone, 3) and reduction of the quinone to give the corresponding tetracene derivative. Such methods are taught, e.g., in Waldmann, H. and Mathiowetz, H., Ber. dtsch. Chem. Ges. 64, 1713 (1931), Weizmann, C., Haskelberg, L. and Berlin, T., J. Chem. Soc. 398 (1939); Waldemann, H. and Plak, G., J. prakt. Chem. (2) 150, 113, 121 (1938), which are herein incorporated by reference. Other examples of synthesis of alkyl homologues of tetracene include: 2-methyltetracene (Coulson, E. A., J. Chem. Soc. 1406 (1934)), 5-methyltetracene (Clar, E. and Wright, J. W., Nature, Lond. 63, 921 (1949)), 2-isopropyltetracene (Cook, J. W., J. Chem. Soc. 1412 (1934)), 1,6-dimethyltetracene (Fieser, L. F. and Hershberg, E. B. J. Amer. Chem. Soc. 62, 49 (1940)), 2,8-dimethyltetracene (Fieser, L. F. and Hershberg, E. B. J. Amer. Chem. Soc. 62, 49 (1940) and Coulson, E. A., J. Chem. Soc. 1406 (1934)), 2,9-dimethyltetracene (Coulson, E. A., J. Chem. Soc. 1406 (1934)), and 5,12-dimethyltetracene (Wolf, J., J. Chem. Soc. 75, 2673 (1953)), which are herein incorporated by reference.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2=[O:15])=[C:4]([CH3:16])[CH:3]=1.[N+:17]([C:20](=[CH2:26])[CH2:21][C:22](OC)=[O:23])([O-:19])=[O:18].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:16][C:4]1[CH:3]=[C:2]([N:1]2[CH2:26][CH:20]([N+:17]([O-:19])=[O:18])[CH2:21][C:22]2=[O:23])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]1=[O:15]
Reactant: C=C(CC(=O)OC)[N+](=O)[O-]
Reactant: Cc1cc(N)ccc1N1CCCCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(N2CC([N+](=O)[O-])CC2=O)ccc1N1CCCCOC1=O
Reaction time: 0.83 h

Procedure:
1.52 g (6.89 mmol) 3-(4-amino-2-methyl-phenyl)-[1,3]oxazepan-2-one and 1.0 g (6.89 mmol) methyl 3-nitro-but-3-enoate (prepared analogously to M. Mühlstädt, B. Schulze J. Prakt. Chem. 1971, 313(4), 745-753) are melted together at 130° C. for 50 minutes. The mixture is allowed to cool and dissolved in DMF. The solution is acidified with TFA and purified by chromatography using reversed phase HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][C:7]=1[NH2:8].[CH2:19](N(CCO)CCO)[CH2:20]O.[OH-].[NH4+]>C(O)(=O)C>[CH3:19][C:20]1[N:8]=[C:7]2[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=[C:2]2[N:1]=1
Reactant: CCOC(=O)c1cc(N)c(N)nc1C(=O)OCC
Reactant: OCCN(CCO)CCO
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2nc(C)nc-2[nH]c1C(=O)OCC
Temperature: 0 °C

Procedure:
Diethyl 5,6-diamino-2,3-pyridinedicarboxylate (10.38 g, 0.041 mol) is stirred under an N2 atmosphere in 100 mL glacial acetic acid, to give a clear orange solution. Triethylortboacetate (TEOA), (0.19 mol) is then added and the mixture is heated to reflux for 15 hours. The cooled solution is poured into ice water and neutralized with ammonium hydroxide. The solution is extracted with ethyl acetate, the combined organic layers washed with brine. dried over Na2SO4, filtered and concentrated to an oil. The oil is taken up in ethyl acetate and the desired product is precipitated by the addition of hexanes in two crops of beige solid, totalling 8.11 g (71.3%), having a melting point of 164°-165° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][S:12][CH2:13][CH2:14][OH:15])=[CH:4][N:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:16]([O:15][CH2:14][CH2:13][S:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][CH:4]=2)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc2ncn(CSCCO)c2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCSCn1cnc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 100 ml flask equipped with a magnetic stirring bar and a CaCl2 drying tube was charged with 1.0 g (4.4 mM) 2-amino-9-(2-hydroxyethylthiomethyl)-9H-purine, 0.054 g (0.44 mM) 4-dimethylaminopyridine, 0.9 ml (8.8 mM) acetic anhydride, and 200 ml of dry DMF. The solution was stirred for 24 hrs at room temperature and then quenched with 5 ml of MeOH. The solution was evaporated in vacuo (bath temp 40° C.) and the brown oil so obtained chromatographed using the "flash" method. Elution of the column with 1.5% methanol in ethyl acetate provided a yellow oil which crystallized on standing. The light yellow crystals were dissolved in a solution of 2% MeOH in toluene and treated with 0.05 g Darco G-60. The methanol was evaporated from the toluene solution resulting in the precipitation of light yellow crystals. The product was dried for 16 hrs at 78° C. to yield the title compound, mpt. 119°-120.5° C.
Reaction SMILES: [N+]([O-])(O)=O.[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH2:19])=[NH:18])[CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:6].CN(C)[CH:22]=[CH:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[CH:27]=1)=O.[OH-].[Na+]>C(O)C(C)C>[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17]2[N:19]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[CH:27]=3)[CH:23]=[CH:22][N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:6]
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Reactant: CCOC(=O)c1cccc(NC(=N)N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1

Procedure:
14.5 g (53.7 mmol) of 3-ethoxycarbonyl-phenyl-guanidine nitrate, 11.3 g (53.7 mmol) of 3-dimethylamino-1-(2-chloro4-pyridyl)-2-propen-1-one and 2.4 g (60 mmol) of sodium hydroxide are stirred in 150 ml of isobutanol for 14 hours at 110°. After cooling, washing twice with 100 ml of ethanol each time and crystallising (tetra-hydrofuran/ethanol), N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro4-pyridyl)-2-pyrimidineamine is obtained; m.p. 149°-150°, FAB-MS: 355 (M+ +H).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[C:25]([Cl:37])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)(C)(C)C.[OH-].[Na+]>O1CCCC1>[Cl:37][C:25]1[CH:24]=[C:23]([S:20]([NH:19][C@@H:14]2[CH2:15][CH2:16][CH2:17][C:18]3[C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])=[CH:10][CH:11]=[CH:12][C:13]2=3)(=[O:21])=[O:22])[CH:28]=[CH:27][C:26]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of (R)-{5-[3-chloro-4-(4-chloro-phenoxy)benzenesulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (160 mg, 0.277 mmol) in tetrahydrofuran (3 mL) was added 1N sodium hydroxide (3 mL). The reaction mixture was stirred at room temperature for 2 hours, and then extracted with diethyl ether (10 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and stirred with diethyl ether (3 mL) and petroleum ether (9 mL) at room temperature for 2 hours. The precipitate was collected by filtering through a glass funnel to afford (R)-{5-[3-chloro-4-(4-chloro-phenoxy)-benzenesulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid (114 mg, 79%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (d, J=8.59 Hz, 1H), 8.02 (d, J=2.27 Hz, 1H), 7.82 (dd, J=8.59, 2.27 Hz, 1H), 7.53 (d, J=8.84 Hz, 2H), 7.13-7.23 (m, 2H), 7.05 (t, J=8.08 Hz, 1H), 6.67 (dd, J=11.75, 7.96 Hz, 2H), 4.65 (s, 2H), 4.39 (d, J=8.08 Hz, 1H), 1.78 (m, 2H), 1.59 (m, 4H); MS cald. For C24H21Cl2NO6S 521, obsd. 522 (ESI+) [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[Mg].C(O)(=O)C>CO>[CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc2ccc(=O)[nH]c2c1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a solution of 1.0 g (5.7 mmol) of 7-dimethylamino-2-quinolone [A. Rice, Ann. Chim. 48: 958-996 (1958)] in 40 mL of MeOH was added 1.3 g (5.7 mmol) of magnesium. The reaction was warmed gently on a steam bath, and then was allowed to stir for two hours at room temperature. Acetic acid (8 mL) was then added and the solution filtered. The filtrate was concentrated and the residue chromatographed on 220 g of silica gel, eluting with 97.5:2.5 (v/v) CH2Cl2 :MeOH. Fractions 50-60 (12 mL/fraction) were combined and concentrated to yield 0.4 g of the dihydroquinolone as a white solid, m.p. 154°-156° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[O:15][CH:16]([CH3:19])[CH2:17]Cl>O.CO>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:17][CH:16]([CH3:19])[O:15][C:14]1=[O:20]
Reactant: CC(CCl)OC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CN(c2ccc([N+](=O)[O-])cc2Cl)C(=O)O1

Procedure:
A solution of 5 g of potassium hydroxide in 10 ml of water was added to a stirred solution of 21.5 g of 2A in 300 ml of methanol. The mixture was heated for 0.5 hour by a steam bath and concentrated to dryness under reduced pressure. The residue was diluted with water; the mixture was acidified with hydrochloric acid and extracted with ether. The extract was dried and the solvent was evaporated under reduced pressure. Trituration of the residue with hexane gave 3-(2-chloro-4-nitrophenyl)-5-methyl-2-oxazolidinone (2B), as a solid, mp: 73°-75° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH2:12]>CCCCCC.ClCCl>[C:1]([N:9]([CH2:10][CH2:11][NH2:12])[CH2:8][CH2:7][NH2:6])(=[O:4])[CH:2]=[CH2:3]
Reactant: NCCNCCN
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CC(=O)N(CCN)CCN
Temperature: 105 °C
Reaction time: 0.01 h

Procedure:
4-N-acryloyl-diethylenetriamine was prepared by slowly adding, at 23° C., 200 ml of a solution of acryloyl chloride in a mixture of hexane and dichloromethane (C6H14 :C2Cl2 =3:1) at a concentration of 3.6 wt% (0.4 mEq/ml) to 600 ml of 1.4 wt% (0.4 mEq/ml) diethylenetriamine which had been purified by vacuum distillation. The reaction product was oligomerized by the addition of 200 ml of a 4.1 wt% solution of isophthaloyl chloride in dichloromethane at 20° C. with mechanical stirring. An asymmetric microporous polysulfone support flat sheet membrane 4 mils thick was immersed in a 2 wt% aqueous solution of 4-N-acryloyl-diethylenetriamine oligomer, drained of excess solution, then immersed in a 0.5 wt% solution of trimesoyl chloride at 20° C. for 30 seconds. The composite membrane was then air-dried at room temperature for 30 minutes and subjected to heat treatment at 105° C. for 10 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15]Br)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[N:23][CH:24]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][CH2:13][C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[NH:9][CH:8]=3)[CH2:27][CH2:26]2)=[N:21][CH:22]=[N:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCBr)c2c1
Reactant: COc1cncnc1N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 69.4 %

Procedure:
A mixture of 5-nitro-3-(3-bromopropyl)indole (0.57 g, 2.0 mmol), 1-(5-methoxy-4-pyrimidyl)piperazine (0.47 g, 2.4 mmol), KI (0.40 g, 2.4 mmol) and diisopropylethylamine (1.75 mL, 10.0 mmol) in 20 mL of acetonitrile was refluxed under Ar for 6 h. The cooled reaction mixture was diluted with ethyl acetate and washed (H2O, brine). The aqueous wash was back-extracted with CH2Cl2 and the organic phase was washed (H2O, brine). The combined organic phases were dried (Na2SO4) and evaporated, and the residue was chromatographed (SiO2 /CH2Cl2 -MeOH, 95:5) to give a solid. This material was triturated with CH2Cl2 -hexane to give the title compound (0.55 g, 70%) as a yellow solid, m.p. 163°-166° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH:20]2[O:22][CH:17]([CH2:18][CH2:19]2)[CH2:16]1>>[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[S:26][CH:27]=2)[CH2:21][CH:20]2[O:22][CH:17]([CH2:18][CH2:19]2)[CH2:16]1
Reactant: CN1C(=O)CCc2cc(I)ccc21
Reactant: OC1(c2csc(S)c2)CC2CCC(C1)O2
Product: CN1C(=O)CCc2cc(Sc3cc(C4(O)CC5CCC(C4)O5)cs3)ccc21
Yield: 28 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 3-hydroxy-3-(2-mercaptothien-4-yl)-8-oxabicyclo[3,2,1]octane to give 3-hydroxy-3-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]-8-oxabicyclo[3,2,1]octane in 28% yield.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)CCc2ccccc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.8 %

Procedure:
Triethylsilane (0.776 mL, 4.87 mmol) was added to a stirring, room temperature solution of 43 (0.5266 g, 1.57 mmol) in trifluoroacetic acid (TFA) (3.74 mL, 0.42 M) under N2. After stirring at room temperature for 4 hours, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 0 to 11 min, 35:65 H2O:CH3CN. 11.5-20 min, 35:65 to 0:100 H2O:CH3CN; 20 mL/min.; λ=254 nM; 200 mg/mL, 0.7 mL/injection. 0.2455 g (48.7%) of 44 was obtained as a fluffy white solid. (Note: An undesired impurity has a retention time of 12.062 min by HPLC.) 1H (CDCl3, 400 MHz): δ 9.27 (1H, broad s), 7.34-7.26 (2H, m), 7.24-7.17 (3H, m), 6.81 (1H, s), 6.75 (1H, s), 4.33 (2H, q, J=7.1 Hz), 2.67 (2H, t, J=7.8 Hz), 2.53 (2H, t, J=7.8 Hz), 1.93 (2H, quint, J=7.8 Hz), 1.37 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 161.34, 142.31, 128.40, 128.22, 125.99, 125.64, 122.47, 120.73, 114.82, 60.17, 35.33, 32.47, 26.17, 14.41 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.41; CH2 carbons: 60.17, 35.33, 32.47, 26.17; CH carbons: 128.40, 128.22, 125.64, 120.73, 114.82 ppm. HPLC: 11.140 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:15]=1.[Br:23]N1C(=O)CCC1=O>CC(C)=O>[Br:23][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cn1
Solvent: CC(C)=O
Product: Cn1cc(-c2cc(-c3[nH]c4ccccc4c3Br)c(=O)[nH]n2)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
30 mg of 4-(1H-Indol-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one is dissolved in 4 ml of acetone and 22 mg of N-bromosuccinimide is added. The solution is stirred at RT for 20 min and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 14 mg. LC-MS (ES+) 370/372 (M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4]([NH2:6])=[NH:5])#[N:2].[C:7]1([CH:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[NH2:5][C:4]1[N:3]=[C:1]([NH2:2])[C:15]2[CH2:14][CH:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:18][CH2:17][C:16]=2[N:6]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: N#CNC(=N)N
Product: Nc1nc(N)c2c(n1)CCC(c1ccccc1)C2

Procedure:
This compound was prepared in a manner analogous to that of Example 1, using 4.2 grams (0.05 mole) of cyanoguanidine and 13.1 grams (0.08 mole) of 4-phenylcyclohexanone. The crude product was recrystallized from ethanol, yielding 2,4-diamino-6-phenyl-5,6,7,8-tetrahydroquinazoline, mp 223°-226° C. The NMR spectrum was consistent with the proposed structure.