Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O.[I-].[Na+]>[CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCOC(=O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 82 %

Procedure:
0.546 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, 0.437 g of ethyl bromoacetate; 0.692 g of sodium carbonate and 0.016 g of sodium iodide were added to 20 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 16 hours. At the end of this time, the mixture was diluted with water and then extracted with ethyl acetate. The solvent was then removed by evaporation under reduced pressure. The resulting residue was then subjected to column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.602 g (yield 82%) of the title compound as a pale yellow oil. The hydrochloride of this compound, melting at 187°-190° C., may be prepared by similar means to Those described in Example 17.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(CNC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 3-(benzyloxycarbonylamino)-2,2-dimethylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.19 (s,6H), 1.90 (m,1H), 2.6-3.0 (m,3H), 3.26 (d,6 Hz,2H), 4.46 (m,1H), 5.07 (s,2H), 5.7 (br t,1H), 6.62 (d,7 Hz,1H), 6.97 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.3 (s,5H), 8.14 (br s,1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:16]=O)=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][O:14][CH3:15])[N:7]=1.[CH2:18]([NH:25][CH2:26][C@@H:27]([OH:31])[CH2:28][O:29][CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:18]([N:25]([CH2:16][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][O:14][CH3:15])=[CH:5][N:4]=1)[CH2:26][C@@H:27]([OH:31])[CH2:28][O:29][CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COCC1CCCN1c1cnc(C=O)c(Cl)n1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COCC1CCCN1c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 67.1 %

Procedure:
To a solution of 3-chloro-5-[2-(methoxymethyl)pyrrolidin-1-yl]pyrazine-2-carbaldehyde (511 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (469 mg) and acetic acid (343 μL) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (636 mg), and the mixture was stirred at room temperature for 14.5 hr. To the reaction mixture was added dropwise a saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (583 mg, 67%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([OH:32])[CH:31]=1>C1COCC1>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:27]=[CH:28][C:29]=1[O:33][CH3:34]
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(C)=O)c4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (prepared below, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (47.49 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 73% (100 mg, 0.22 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:13])[NH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1>Cl.O1CCOCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)[C:8]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:13]
Reactant: CC(C)NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)NC(=O)c1ccc(N2CCNCC2)c(F)c1
Reaction time: 0.5 h

Procedure:
tert-butyl 4-(2-fluoro-4-(isopropylcarbamoyl)phenyl)piperazine-1-carboxylate 303 (1.10 g, 3.01 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford the title compound as a white solid. ESI-MS: m/z 302 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]1[CH:40]=[C:41]([NH2:45])[CH:42]=[N:43][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:41]5[CH:42]=[N:43][CH:44]=[C:39]([F:38])[CH:40]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cncc(F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3cncc(F)c3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.5 %

Procedure:
A solution of the product of Example 19C (259 mg, 0.488 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with the product of Example 224C (60.2 mg, 0.537 mmol) and diisopropylethylamine (0.128 mL, 0.732 mmol), and stirred at room temperature under a nitrogen atmosphere for 15 hours. The solvent was removed by rotary evaporation in vacuo, and the residue was taken up in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 3% methanol/methylene chloride provided the title compound as a yellow solid (176 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][NH:42]5)=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9].[CH3:47][O:48][C:49]([NH:51][CH:52]([CH:56]([CH3:58])[CH3:57])[C:53](O)=[O:54])=[O:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][N:42]5[C:53](=[O:54])[CH:52]([NH:51][C:49]([O:48][CH3:47])=[O:50])[CH:56]([CH3:58])[CH3:57])=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:9])([F:11])[F:10]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
To a solution of crude [4,4,4-Trifluoro-1-(2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester (125 mg, 0.20 mmol) in dimethylformamide (0.6 mL) was added a solution of 2-methoxycarbonylamino-3-methyl-butyric acid (38 mg, 0.22 mmol) and HATU (82 mg, 0.22 mmol) in dimethylformamide (0.6 mL). Diisopropylethylamine (70 μL, 0.40 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The solution was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield (4,4,4-trifluoro-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester (73 mg, 47%). LCMS-ESI+: calculated for C40H47F3N8O6: 792.85; observed [M+1]+: 794.33. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82-7.70 (m, 4H), 7.68-7.63 (m, 4H), 7.32-7.31 (m, 2H), 5.20-5.16 (m, 2H), 4.56-4.51 (m, 1H), 4.26-4.22 (m, 1H), 4.04-3.96 (m, 1H), 3.91-3.84 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.51-3.46 (m, 1H), 2.38-1.96 (m, 12H), 1.90-1.78 (m, 1H), 1.01-0.89 (m, 6H) ppm.
Reaction SMILES: C([O:4][CH:5]1[CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:33])[O:19][C:20](=O)[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7][CH2:6]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=O)C.C[N:36](C)C=O>N>[OH:4][CH:5]1[CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:33])[NH:36][C:20](=[O:19])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7][CH2:6]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CC(=O)OC1CCc2c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc3n2C1
Reactant: CN(C)C=O
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC(O)CC4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 150 mg of 3-[7-acetoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 6 ml of dimethylformamide and 6 ml of 33% aqueous ammonia was heated to 150° C. for 6 hours. The mixture was extracted with ethyl acetate and the organic extracts were washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate gave 120 mg of 3-[6,7,8,9-tetrahydro-7-hydroxypyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 252°-255° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: CC(C)CN
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Product: CC(C)CNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (100 mg, 0.176 mmol) and isobutylamine (2 mL) the title compound was obtained as a yellow powder (90 mg, 0.149 mmol, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 7.86 (d, J=5.3 Hz, 1H), 7.67 (t, J=6.1 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.21-7.31 (m, 4H), 7.14 (bs, 1H), 5.62 (bs, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.45 (t, J=4.8 Hz, 4H), 3.02 (bs, 2H), 1.78-1.86 (m, 1H), 0.87 (d, J=6.6 Hz, 6H). MS (ESI): 603 [M−H]−.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=1
Reactant: Cc1ncc(Br)n1C
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.82 mL, 2.05 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (361.1 mg, 2.063 mmol) in dry THF (20 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.500 g, 1.03 mmol, Intermediate 12: step f) in dry THF (5 mL) was added dropwise. The reaction was stirred for 1.5 hours, then was removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=2.2 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.53-7.48 (m, 2H), 7.42-7.36 (m, 3H), 7.11 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 5.99 (s, 1H), 4.33 (s, 2H), 4.06 (s, 3H), 3.36 (s, 3H), 2.52 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H); MS m/e 581.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([C:25]#[N:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-:30].[K+].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:25]([NH2:26])=[O:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN(CCc1ccc(Cl)cc1)CCC(C#N)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN(CCc1ccc(Cl)cc1)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-[N-(4-chlorphenethyl)-N-methylamino]-1-cyano-1,1-diphenylpropane (0.2 g--Preparation 24) in 90% sulphuric acid (0.5 ml) was heated at 80°-85° c. for 3 hours. On cooling to room temperature, ice (10 g) was added and the mixture was basified (pH 10) by the addition of potassium carbonate. The mixture was extracted with dichloromethane (3×50 ml) and the combined dichloromethane extracts were washed with water (2×20 ml) then dried (Na2SO4) and concentrate in vacuo to give a gum. The gum was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) followed by dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.16 g.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13](F)[CH:12]=1.O>CS(C)=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]2[CH:15]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[S:3][C:13]=2[CH:12]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.73 g, 18.3 mmol) was suspended in DMSO (10 mL) and ethyl mercaptoacetate (1.111 mL, 10.1 mmol) was added potionwise using a water bath to moderate the exotherm. On complete addition, the water bath was removed and stirring continued for 15 minutes. A solution of 4-bromo-2-fluorobenzaldehyde (1.86 g, 9.16 mmol) in DMSO (2 mL) was added in one portion. The dark solution was stirred for 15 minutes before pouring into cold water (300 mL). The products were extracted into Et2O (2×200 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave 1.15 g of desired product (pale yellow solid, 44%). 1H NMR (DMSO-d6) δ 8.37 (d, J=1.8 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.60 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[C:9]=2[C:23]([NH2:25])=[O:24])=[CH:4][CH:3]=1>CO.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]2[C:9]([C:23]([NH2:25])=[O:24])=[C:8]([NH:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([OH:1])=[CH:3][CH:4]=3)[NH:12][N:11]=2)=[CH:19][CH:18]=1
Reactant: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1NCc1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(Nc2ccc(N)cc2)n[nH]c1NCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
5-((4-hydroxybenzyl)amino)-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide (4.80 g) was suspended in 300 mL of MeOH and palladium on carbon (50% wet with water) (480 mg, 0.10 eq.) was then added to the reaction vessel. The reaction was then purged and stirred under hydrogen pressure at room temperature for 18 hrs. or until no starting material is present and confirmed via HPLC. Once complete Celite was stirred into the reaction vessel, filtered through Celite and washed with additional MeOH. The MeOH was then evaporated off via vacuo and triturated with ethyl acetate and hexanes to yield 3-((4-aminophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide as a light purple powder collected via filtration (1.60 g, 36% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN([CH:10]=[O:11])C.C(Cl)Cl.[F:15][C:16]1[C:24]([F:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18](O)=[O:19]>CO>[F:15][C:16]1[C:24]([F:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18]([O:11][CH3:10])=[O:19]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(F)c1F
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (1 ml) and DMF (5 μl) were added to a CH2Cl2 (1.6 ml) solution containing 2,3-difluoro-5-nitrobenzoic acid (1.61 g) obtained in the 1st step, followed by stirring at room temperature for 15 minutes. The reaction solution was poured into a liquid mixture of MeOH/Py (100 ml/1.28 ml) and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A light yellow solid of methyl 2,3-difluoro-5-nitrobenzoate (1.71 g) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:12][CH2:13][CH3:14])[C:9](Cl)=[S:10].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:12][CH2:13][CH3:14])[C:9]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:10]
Reactant: CCCN(C(=S)Cl)c1ccccc1Cl
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCCN(C(=S)n1ccnc1)c1ccccc1Cl
Reaction time: 8 h

Procedure:
12.4 g. N-2-chlorophenyl-N-propyl(thiocarbamoyl) chloride and 6.8 g. imidazole were refluxed in 75 ml. dry tetrahydrofuran for 16 hours. A further 2 g. imidazole was then added and the heating continued for 8 hours. After separating the solid formed evaporation of the tetrahydrofuran left an oil which was dissolved in methylene chloride. The resulting organic phase was washed with water, dried with soldium sulphate and the solvent evaporated to leave an oil which crystallised on treatment with light petroleum and chilling to give the product, 1-[N-2-chlorophenyl-N-propyl (thiocarbamoyl)]imidazole, m.p. 59°-61° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(O)c2ccc(C)cc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
7-methyl-4-hydroxy-2-methoxycarbonylquinoline (6.45 g, 30.14 mmol) was suspended in MeOH (150 mL) and water (100 mL), and LiOH (3.08 g, 75.5 mmol) was added and stirred at ambient temperature for 2 hours. The methanol was evaporated in vacuo and residue was crystallized by addition of 2N hydrochloric acid. The resulting solid was filtered, washed with water and dried to afford 7-methyl-4-hydroxy-2-carboxyquinoline (6.0 g, 98%), NMR (DMSO-d6) 2.40 (s, 3), 6.68 (s, 1), 7.22 (d, 1), 7.68 (s, 1), 7.96 (d, 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14](Cl)=[O:15])[CH:7]=[CH:6]2.[NH3:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([NH2:18])=[O:15])[CH:7]=[CH:6]2
Reactant: N
Reactant: COc1ccc2cc(C(C)C(=O)Cl)ccc2c1
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(C)C(N)=O)ccc2c1
Reaction time: 3 h

Procedure:
Into 300 ml of dry toluene, were dissolved 10.8 g of oa (6-methoxy-2-naphthyl)-propanoic acid chloride, followed by introducing dry ammonia at a temperature not more than 15° C. for 30 minutes. Stirring was continued at room temperature for 3 hours, and then precipitated while solid was filtered off. The resulting white solid was washed with toluene and then water, followed by recrystallizing with ethanol to obtain 10.0 g of oa (6-methoxy-2-naphthyl)-propanamide.