Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:22]1[CH2:32][CH2:31]N2[C:25](=NCCC2)[CH2:24][CH2:23]1.CCOC(C)=O>CC#N>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[NH:11][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:31][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1cc(Cl)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a mixture of 5-chloroisatoic anhydride (5.00 g, 25.3 mmol) and benzylbromide (78.83 g, 50.6 mmol) in 50 ml of CH3CN was added 7.57 ml of DBU (50.6 mmol) at rt under Ar. The resulting mixture was stirred at rt for 16 hr. Treated with 100 ml of EtOAc, the mixture was washed with H2O, brine and dried (Na2SO4). Removal of the solvent in vacuo followed by flash chromatography of the residue on silica gel (10% DCM/hexanes-5% EtOAc/hexanes) gave 6.50 g (73%) of product as a brown oil.: 1H-NMR (CDCl3; 400 MHz) 3 8.17 (t, 1H, J=5.2 Hz), 7.92 (d, 1H, J=2.8 Hz), 7.19-7.48 (m, 11H), 6.56 (d, 1H, J=9.2 Hz), 5.31 (s, 2H), 4.43 (d, 2H, J=5.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C21H18ClNO2, 352.1 (M+H), found 352.0.
Reaction SMILES: [O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18](O)O)[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22]([CH2:25][CH2:26][NH2:27])(=[O:24])=[O:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:21][S:22]([CH2:25][CH2:26][NH:27][CH2:18][CH2:17][N:16]1[C:9]2[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH:14]=[CH:15]1)(=[O:24])=[O:23]
Reactant: OC(O)Cn1ccc2ncnc(Oc3ccccc3)c21
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)CCNCCn1ccc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
2-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane-1,1-diol (500 mg) and 2-(methylsulfonyl)ethylamine (341 mg) were dissolved in N,N-dimethylformamide (29 mL)/acetic acid (2.9 mL), and the mixture was stirred at room temperature for 1.5 hrs. Sodium triacetoxyborohydride (579 mg) was added, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) to give the title compound (508 mg) as a candy-like substance.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=O)[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>N1C=CC=CC=1>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[S:36])[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
To a mixture of 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4-(1H,3H)-quinazolinedione (3.1 g) and phosphorus pentasulfide (6.1 g) was added pyridine (70 ml) and the mixture was stirred for 18 hours at 100° C. The reaction mixture was cooled and then concentrated in vacuo. To the residue was added water and the mixture was stirred and then resultant precipitates were collected by filtration and washed with water. To the precipitates was added chloroform and the mixture was stirred enough and then insoluble materials were filtered off. These insoluble materials were washed twice with chloroform and then whole chloroform layers were combined, washed with water and with saturated sodium chloride aqueous solution respectively, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by a column chromatography on silica gel (90 g) using 2% methanol in chloroform for elution to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-4-thioxo-3,4-dihydro-2(1H)-quinazolinone (1.2 g) as an amorphous material.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].Cl.[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])[C:23]([CH3:31])=[CH:22][C:21]=3[F:32])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34]>C(Cl)Cl.N1C=CC=CC=1>[F:32][C:21]1[CH:22]=[C:23]([CH3:31])[C:24]([O:26][C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([NH:8][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[C:10]([O:33][CH3:34])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COCC(=O)Cl
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(N)c(OC)cc23)c(F)cc1C
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc2ncnc(Nc3cc(OC(=O)OC)c(C)cc3F)c2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
Methoxyacetyl chloride (62 μl, 0.68 mmol) was added dropwise to a solution of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (215 mg, 0.52 mmol) in methylene chloride (5 ml) and pyridine (l.5 ml) at 0° C. and the mixture stirred for 2 hours at 0° C. Further methoxyacetyl chloride (14 μl, 0.15 mmol) was added and the mixture stirred for 20 minutes at 0° C. The reaction mixture was partitioned between ethyl acetate and water and the aqueous layer adjusted to pH9 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60138/2) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-methoxyacetamidoquinazoline (1 75 mg, 75%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=1)[C:5](O)=[O:6].C1C=CC(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=1)[C:5]([N:33]=[N+:34]=[N-:35])=[O:6]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C(=O)O)cc(/C=C/c2ccccc2)n1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N=[N+]=[N-])cc(/C=C/c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-6-(E)-styryl-isonicotinic acid (214 mg, 0.89 mmol) in DMF (5 mL) is added at 0° C. TEA (0.21 mL, 1.5 mmol) and slowly (30 min) DPPA (366 mg, 1.33 mmol). The reaction mixture is stirred for 0.5 h at 0° C. and 0.5 h at r.t. The reaction is quenched with ice (20 g) and extracted with Et2O (6×30 mL). The combined organic extracts are washed successively with saturated NaHCO3 (2×15 mL) and water (2×10 mL), and are evaporated in vacuo without heating. The residue is purified by FC (SiO2, EtOAc-heptane) to provide the title compound.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:38]=[CH:37][C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[N:28]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[S:25][CH:26]=[C:27]([C:29]4[CH:38]=[CH:37][C:32]5[NH:33][C:34](=[O:36])[O:35][C:31]=5[CH:30]=4)[N:28]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(-c2ccc3[nH]c(=O)oc3c2)cs1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: O=C(Nc1nc(-c2ccc3[nH]c(=O)oc3c2)cs1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (200 mg, 0.63 mmol) was treated with 6-(2-aminothiazol-4-yl)benzo[d]oxazol-2(3H)-one (198 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 0-70% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 73 mg (22%). 1H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.84-7.74 (m, 4H), 7.69 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.24-7.19 (m, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.13-7.07 (m, 2H), 3.85-3.78 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.67-1.58 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]([NH2:7])=O.B>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:5][NH2:7]
Reactant: NC(=O)c1ccc(Sc2ccc(Cl)cc2)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: Cl
Product: NCc1ccc(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 114.3 %

Procedure:
A solution of 3-chloro-4-(4-chlorophenylthio)benzamide (44.7 g, 150 mmol) in tetrahydrofuran (300 ml) was added dropwise over 30 minutes to a stirred 1.0M solution of borane in tetrahydrofuran (450 ml) under a nitrogen atmosphere at ambient temperature. The mixture was refluxed for 16 hours, cooled to 0° C., and quenched by addition of 2.0N hydrochloric acid. The solvent was evaporated under vacuum and the solid residue was slurried in water, filtered, and washed with water (4×300 ml). The solid was partially dried in the air, washed with diethyl ether (3×200 ml), and dried under vacuum at 50° C. for 3 hours and at ambient temperature for 16 hours. The crude product was suspended in diethyl ether (700 ml), vigorously stirred for 30 minutes, filtered, washed with diethyl ether, and dried to provide 27.5 g (57%) 3-chloro-4-(4-chlorophenylthio) benzylamine hydrochloride, m.p. 237°-240° C. The free base was liberated by slurrying the salt (6.77 g) in water (100 ml), basifying with 2.5N aqueous sodium hydroxide, adding diethyl ether (100 ml), and filtering. The biphasic filtrate was separated and the aqueous phase was extracted with diethyl ether. The combined diethyl ether phases were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The oily residue was kept under vacuum at ambient temperature for 16 hours to provide 5.80 g (97%) of 3-chloro-4-(4-chlorophenylthio)benzylamine as a colorless oil, 60 MHz 'H NMR (DMSO-d6): 2.22 broad s (2H), 3.37 s (2H), 7.1-7.5 complex m (7H); (DMSO-d6 /D2O/DCl) 4.05 s (2H), 7.03 d (J=9Hz, 1H), 7.3-7.6 broad m (6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)[S:5][C:6]=1[Br:7].O.[NH2:16]N>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][NH:11][N:16]=2)[S:5][C:6]=1[Br:7]
Reactant: NN
Reactant: CN(C)C=CC(=O)c1cc(Br)c(Br)s1
Solvent: O
Solvent: CCO
Product: Brc1cc(-c2cc[nH]n2)sc1Br
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A mixture of 1-(4,5-dibromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (9.6 mmol) and hydrazine hydrate (14.3 mmol) in 22 mL ethanol was refluxed for 15 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and dried in vacuum to afford 2.94 g (100% yield) 3-(4,5-dibromo-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][N:3]1[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].O.[OH-].[Li+].O.CO>O1CCCC1>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]1[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: COC(=O)c1ccn([C@H](C)c2ccccc2)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)n1ccc(C(=O)O)cc1=O
Temperature: 20 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
A mixture of (R)-methyl 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylate (451 mg, 1.75 mmol), lithium hydroxide monohydrate (369 mg, 8.77 mmol), water (4 mL) and methanol (4 mL) in tetrahydrofuran (12 mL) was stirred at 20° C. for 12 hours. The reaction mixture was concentrated. The residue was acidified with concentrated hydrochloride solution to pH=2. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:2) to give (R)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid as a white solid (336 mg, 80%). LRMS (M+H+) m/z: calcd 243.13. found 243.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][CH2:25]2)=[C:20](/[CH:34]=[CH:35]\[CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]1[C:41]2[CH:42]=[C:43]([C:46]3([CH3:53])[NH:50][C:49](=[O:51])[NH:48][C:47]3=[O:52])[CH:44]=[CH:45][C:40]=2[CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:48]3[C:47](=[O:52])[C:46]([C:43]4[CH:44]=[CH:45][C:40]5[CH2:39][CH2:38][O:37][C:41]=5[CH:42]=4)([CH3:53])[NH:50][C:49]3=[O:51])[CH2:26][CH2:25]2)=[C:20]([CH:34]=[CH:35][CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2ccc3c(c2)OCC3)NC(=O)NC1=O
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCC4)C2=O)CC1

Procedure:
(Z)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydrobenzofuran-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:8])[CH3:7].[N+:17]([O-])([O-:19])=[O:18].[K+]>>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (1 L) was cooled to −10° C. with a dry ice-isopropanol bath in a 2 L 3-necked round bottom flask fitted with a mechanical stirrer and temperature probe. The 2-t-butylaniline (109 g, 730 mmol) was added, giving a clumpy solid. Once the temperature of the mixture was stabilized at −10° C., the potassium nitrate (101 g, 1001 mmol) was added portion wise, as a solid, over a 4-hour period, maintaining the temperature between −20 and −5° C. Once all of the potassium nitrate was added, the reaction was left to stir overnight with gradual warming to RT. The reaction was quenched by diluting with water and then extracting three times with EtOAc. The EtOAc extracts were washed multiple times with saturated NaHCO3, until gas evolution ceased, then with brine. The EtOAc extracts were then combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure giving a black oil. The oil was eluted through a column of silica gel with EtOAc: hexanes gradient 5-50%. Solvent evaporation afforded 2-tert-butyl-5-nitrobenzenamine as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:33]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:34])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C5CCCCC5)c4)CC3)cccc2n1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and cyclohexanecarbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([C:43](Cl)=[O:44])[C:37]=2[N:36]=[CH:35]1>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:43]([C:42]2[C:37]3[N:36]=[CH:35][NH:34][C:38]=3[CH:39]=[CH:40][CH:41]=2)=[O:44])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2nccc3ccccc23)c(C)c1
Reactant: O=C(Cl)c1cccc2[nH]cnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCNC(=O)c2cccc3[nH]cnc23)Cc2nccc3ccccc23)c(C)c1
Reaction time: 48 h
Yield: 28.8 %

Procedure:
To a solution of N1-(3,5-dimethyl-pyridin-2-ylmethyl)-N1isoquinolin-1-ylmethyl-butane-1,4-diamine (83 mg, 0.24 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.96 mmol) and 1H-benzoimidazole-4-carbonyl chloride (86 mg, 0.48 mmol) and the mixture was stirred for 2 d. Then it was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 (3×15 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1) afforded the product as a yellow oil (34 mg, 29%). 1H NMR (CDCl3) δ 1.48-1.53 (m, 2H), 1.66 (s, 6H), 1.72 (br m, 2H), 2.03 and 2.07 (s, total 3H), 2.25 and 2.27 (s, total 3H), 2.64 (t, 2H, J=7.5 Hz), 3.30 (br m, 1H), 3.40 (br m, 1H), 3.81 and 3.87 (s, total 2H), 4.21 and 4.25 (s, total 2H), 7.37-7.42 (m, 2H), 7.55-7.57 (m, 2H), 8.04-8.07 (m, 2H), 8.13-8.17 (m, 2H), 8.38 and 8.40 (s, total 1H), 9.79 (br s, 1H). 13C NMR (CDCl3) δ 18.32, 18.43, 24.42, 26.61, 27.88, 30.10, 39.57, 53.83, 54.90, 58.23, 59.54, 115.20, 121.06, 123.26, 123.88, 126.80, 127.01, 127.27, 128.13, 130.33, 132.48, 133.33, 136.67, 139.37, 141.47, 146.47, 146.58, 154.16, 159.19. ES-MS m/z 493 [M+H]+. Anal. Calcd. for C30H32N6O.1.4CH2Cl2: C, 61.67; H, 5.74; N, 13.74. Found: C, 62.01; H, 5.79; N, 13.67.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.Br[CH2:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[F:27].CCOC(C)=O>C1COCC1>[F:27][C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[CH2:17][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(CN2CCOCC2)c1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A −20° C. mixture of DIEA (552 mg, 4.27 mmol) and morpholine (242 mg, 2.78 mmol) in THF (5 mL) was treated drop-wise with a solution of 2-(bromomethyl)-1-fluoro-4-nitrobenzene (500 mg, 2.137 mmol) in THF (5 mL) and stirred overnight as the cooling bath expired. The mixture was treated with EtOAc, washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 4-(2-fluoro-5-nitrobenzyl)morpholine (414 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (dd, J=6.2, 3.0 Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.48 (t, J=9.1 Hz, 1H), 3.61 (s, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.40 (t, J=4.4 Hz, 4H); MS (ESI) m/z: 241.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35].NC1C=C(O)C(C)=CC=1.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(Cl)=O)=NC=NC=2N=1)(C)C>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([C:31]([F:30])([F:39])[F:40])[CH:33]=3)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3ncccc23)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 260B was reacted with 3-(trifluoromethyl)aniline according to the procedure from Example 137C substituting 3-(trifluoromethyl)aniline for 5-amino-o-cresol and substituting the product from Example 260B for the product from Example 137B to provide the title compound as an off white solid after trituration of the reaction product from methanol (43 mg, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-])=O.C(O)C.[H][H]>CCOCC.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: Nc1cccc(C(=O)O)c1C(=O)O
Yield: 84 %

Procedure:
After a mixture of 10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) was charged to a 2.5 L Parr hydrogenator under nitrogen, hydrogen was charged to the reaction vessel for up to 55 psi (379 kPa). The mixture was shaken for 13 hours while the hydrogen pressure was maintained at between 50 psi (245 kPa) and 55 psi (379 kPa). Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuum to yield a solid. The solid was suspended in ether and isolated by vacuum filtration. The solid was dried in vacuum to a constant weight to afford 54 g (84% yield) of 3-aminopthalic acid as a yellow product. The product in DMSO-d6 was characterized by a 1H NMR spectrum showing the following chemical shifts (δ in ppm): 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (brs, 2H). The product in DMSO-d6 was characterized by a 13C-NMR spectrum showing the following chemical shifts (δ in ppm): 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
Reaction SMILES: CO[CH:3](O)[C:4]([O:6][CH3:7])=[O:5].[CH:9](=[O:12])[CH2:10][CH3:11]>C(NCCCC)CCC>[CH:9](/[C:10](/[CH3:11])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:12]
Reactant: CCC=O
Reactant: COC(=O)C(O)OC
Solvent: CCCCNCCCC
Product: COC(=O)/C=C(/C)C=O
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
3 g (0.025 mol) of di-n-butylamine were added at 20° C. to a stirred mixture of 120 g (1 mol) of methyl 2-methoxy-2-hydroxyacetate and 58 g (1 mol) of propionaldehyde. An exothermic reaction started immediately and the temperature of the reaction mixture rose to about 90° C., and it boiled vigorously. After about 10 min the temperature started to fall again and reached room temperature after about 1.5 h. Distillation of the reaction mixture yielded 66.4 g of methyl 3-formylcrotonate of b.p. 45°-58° C./8-9 mbar, corresponding to a yield of 52%. The trans/cis ratio was determined by gas chromatography to be 91/9.