Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:13]([N+:24]([O-])=O)[CH:12]=1)[CH2:2][CH2:3][CH3:4].[ClH:35]>C(O)(=O)C.O.CCOC(C)=O.C([O-])(O)=O.[Na+].C(Cl)Cl.CCOCC.[Fe]>[ClH:35].[ClH:35].[ClH:35].[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:13]([NH2:24])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(N)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-3-nitro-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine (5 mmol, 2.34 g) in acetic acid (10 mL) was added iron powder (˜325 mesh, 50 mmol, 2.80 g). And the mixture was stirred at 100° C. for 0.5 hour. It was then diluted with water/EtOAc and neutralized slowly with NaHCO3 powder. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (10 mL), 2N HCl in ether (10 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine trihydrochloride (2.06 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:23])=[C:13]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH3:23])[CH:11]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2
Agent: O=C[O-]
Agent: [NH4+]
Product: Cc1cc2c(cc1C1CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran-4-yl)-6-methyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Yellow solid. MS (m/e): 262.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9](Br)[CH:10]=1)=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([C:20]2[CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=[CH:24][C:19]=2[Cl:18])[CH:10]=1)=[O:4]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1cnc(OC2CCCC2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 61.4 %

Procedure:
5-Bromo-6-cyclopentyloxy-3-pyridinecarboxylic acid methyl ester (0.33 g, 1.1 mmol) was dissolved in DMF (3.5 mL). To this solution was added [2-chloro-5-(trifluoromethyl)phenyl]-boronic acid (370 mg, 1.6 mmol), palladium(II)acetate (7 mg), triphenylphosphine (18 mg) and triethylamine (0.46 mL). The whole mixture was heated with stirring at 100° C. for 20 h, cooled to room temperature and partitioned between dichloromethane and a mixture of water and concentrated ammonium hydroxide solution (water/ammonia 4:1 v/v). Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 6:1) to yield 0.27 g of the title compound as a light yellow oil, MS (ISP) 400.4 (M+H)+.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.1 %

Procedure:
To a stirred suspension of 1.37 g (10.0 mmol) of 3-hydroxypiperidine hydrochloride and 2.53 g (3.5 mL) of triethylamine in 30 mL of dichloromethane at 0° C. was added dropwise 2.93 g (10.5 mmol) of trityl chloride. The mixture was stirred at ambient temperature overnight, diluted with 100 mL of dichloromethane, washed sequentially with water, 5% aqueous citric acid solution, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, and concentrated to give 3.85 g of the title compound as a white foam.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:1][NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(CCc1cccnc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCc1cccnc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of benzyl-methyl-(2-pyridine-3-yl-ethyl-)amine (4.3 g) in methanol was added 10% palladium-carbon, and was stirred at 50° C. under hydrogen atmosphere for 1 hour. After filtrating with Celite, the filtrate was concentrated, and the title compound (2.39 g) was obtained as a colorless oily matter.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(O)C.[Pd]>[CH2:32]([O:31][P:30]([C:9]([P:4](=[O:8])([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:37])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: [H][H]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CCCCCCCCCCC/C=C\c1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reaction time: 3 h
Yield: 30.5 %

Procedure:
Tetraethyl[2-[2-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (1.5 g, 2.7 mmol) prepared according to Example 9 was dissolved in ethanol (17 ml), and quinoline (0.043 ml) and 5% palladium on calcium carbonate poisoned with lead (13 mg) was added. A balloon filled with hydrogen was attached to the flask after purging with hydrogen. After stirring for 3 hours the hydrogen pressure was released, and the reaction mixture was filtered through Celite. The filtrate was stripped. 1H NMR showed that only small amount of starting material had been converted to product. The hydrogenation was repeated using twice the amount of catalyst and quinoline for 4.5 hours, then workup as before. 1H NMR showed that a considerable amount of starting material remained. Three additional hydrogenations totaling 47 hours were done before the conversion was greater than 90%. Chromatography on silica eluting with 5% ethanol in petroleum ether (90°-110° C. boiling range) gave the product, 0.459 g, 0.825 mmol, 30.5 % yield; 1H NMR (CDCl3) ∂ 0.88 (t, J=6.7 Hz, 3H), 1.03 to 1.45 (several m, 30H), 2.09 (m, 2H), 3.96 (m, 4H), 4.20 (m, 4H), 5.79 (dt, J=11.5, 7.4 Hz, 1H), 6.37 (d, J =11.4 Hz, 1H), 7.28 (m, 3H), 7.78 (d, J=7.3 Hz, 1H), 8.31 (dd, J=47.8, 28.4 Hz, 1H); CI mass spectrum m/z 557 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]1[C:40]([NH2:41])=[CH:39][CH:38]=[C:37]([NH2:42])[CH:36]=1.O>CN(C)C=O>[NH2:41][C:40]1[CH:35]=[CH:36][C:37]([NH:42][C:25](=[O:26])[CH2:24][C@@H:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)=[CH:38][CH:39]=1
Reactant: Nc1ccc(N)cc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)Nc1ccc(N)cc1)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
(S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (3.0 g), triethylamine (1.56 ml) and p-phenylenediamine (0.97 g) are dissolved in dimethylformamide (30 ml). Benzotriazol-1-yl-oxy-tris(dimethyl)phosphonium hexafluorophosphate (3.6 g) is added, and the mixture is stirred at room temperature for 12 hours. After the completion of the reaction, water (200 ml) is added, and the mixture is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent is distilled away under reduced pressure, the residue is subjected to silica gel column chromatography and obtained crystals are recrystallized from toluene to give 0.56 g of (S)-N-(4-aminophenyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4, 3-a][1,4]diazepine-6-acetamide, melting point 169°-173° C.
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@H:5]([C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[CH2:4]1)#[N:2]>Cl>[C:1]([C@H:3]1[CH2:7][NH:6][C@H:5]([C:15]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[CH:21][CH:22]=2)=[O:31])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: N#C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
The crude (2S,4R)-tert-butyl 4-cyano-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidine-1-carboxylate was combined with hydrogen chloride (4N in dioxane, 20 mL). The mixture was stirred at ambient temperature for 1 hour and then quenched with saturated sodium bicarbonate (aq., 100 mL). The mixture was extracted with ethyl acetate (30 mL) and the extract was washed with deionized water (30 mL) and then brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate to give (2S,4R)-4-cyano-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.88 g, 2.69 mmol, 65% yield over 2 steps) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>CCCCCC>[C:1]1([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:18][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[O:36])=[CH:19][CH:20]=3)[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(-c3ccccc3)c2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc(-c3ccccc3)c2)cc1
Reaction time: 0.5 h

Procedure:
4-(2-Phenylpyridin-4-yl)oxyaniline (110 mg, 0.42 mM) was added to ethyl acetate (10 ml), and then parafluorophenyl isocyanate (0.56 ml, 4.9 mM) was added while stirring, which was continued for 30 minutes. After adding n-hexane (20 ml) to the reaction solution, the solvent was partially distilled off under reduced pressure and the precipitating solid was filtered out to obtain the target substance (98 mg) as a gray solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[Cl-].[Li+].[CH3:31][N:32]1[C:40]2[C:35](=[CH:36][C:37]([C:41]3[N:46]=[C:45]([Sn](CCCC)(CCCC)CCCC)[CH:44]=[CH:43][N:42]=3)=[CH:38][CH:39]=2)[CH:34]=[N:33]1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:43]3[CH:44]=[CH:45][N:46]=[C:41]([C:37]4[CH:36]=[C:35]5[C:40](=[CH:39][CH:38]=4)[N:32]([CH3:31])[N:33]=[CH:34]5)[N:42]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(-c2ccc3c(cnn3C)c2)n1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C)c4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
(S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (17.4 mg, 0.036 mmol), Pd(PPh3)4 (2.1 mg, 0.002 mmol), lithium chloride (2.3 mg, 0.054 mmol), and copper(I) iodide (1.0 mg, 0.005 mmol) were taken in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added 1-methyl-5-(4-(tributylstannyl)pyrimidin-2-yl)-1H-indazole (9.0 mg, 0.018 mmol) in degassed 1,4-dioxane (0.5 mL). The reaction mixture was heated at 100° C. for 5 h, cooled, filtered through celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+: calc'd for C33H31ClN5O3S: 612.2 (M+H+); Found: 611.9 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:5]=1)[CH3:2].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=1[C:28](Cl)=[O:29]>C1COCC1>[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=1[C:28]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:5]=1)=[O:29]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CCNc1cccc(OC2CCN(C)CC2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(=O)c1c(F)cc(F)cc1F)c1cccc(OC2CCN(C)CC2)n1
Temperature: 55 °C
Yield: 81.7 %

Procedure:
Dissolve ethyl-[6-(1-methyl-piperidin-4-yloxy)-pyridin-2-yl]-amine (preparation 74, 110 mg, 0.47 mmol) in THF (6 mL), add triethylamine (95 mg, 0.94 mmol) and 2,4,6-trifluorobenzoyl chloride (136 mg, 0.70 mmol) sequentially, heat at 55° C. overnight. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3.5% 2M NH3-methanol in methylene dichloride provides 151 mg (82%) of the title compound as an oil: mass spectrum (ion spray): m/z=394.1 (M+1); 1H NMR (CDCl3, ppm): 7.43 (t, 1H), 6.52 (m, 4H), 4.82 (m, 1H), 4.03 (q, 2H), 2.73 (m, 2H), 2.33 (s, 3H), 2.26 (m, 2H), 1.95 (m, 2H), 1.75 (m, 2H), 1.31 (t, 3H). Mono-hydrochloride salt: Anal calcd for C20H22F3N3O2.HCl.H2O: C, 53.63; H, 5.63; N, 9.38. Found: C, 53.66; H, 5.12; N, 9.29.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)=[C:41]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)=[C:41]([S:52]([CH3:55])(=[O:53])=[O:54])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccc(Cl)cc1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(-c2ccc(Cl)cc2)c(S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-4′-chloro-2-(methylsulfonyl)biphenyl (Intermediate 211), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[CH3:43])[NH2:39]>CN(C=O)C.O>[CH3:35][C:36]1[CH:37]=[C:38]([NH:39][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:40]=[CH:41][C:42]=1[CH3:43]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(O)c([N+](=O)[O-])c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4-hydroxy-3-nitrobenzoic acid (732 mg), EDCI (768 mg) and HOBt (540 mg) in DMF (8 mL) was added 3,4-dimethylaniline (484 mg) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was concentrated until crystallization occurred. The mixture was cooled to room temperature and the solid filtered, washed with EtOAc and dried under reduced pressure to give N-(3,4-dimethyl-phenyl)-4-hydroxy-3-nitrobenzamide as a pale-yellow solid, mp=209-212° C.; MS (m/z) 285 (M−1).
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27]C(OC(C)(C)C)=O)[CH:22]=2)=[O:20])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=2)=[O:20])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)c2ccc(NC(=O)OC(C)(C)C)c3ccccc23)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(=O)c2ccc(N)c3ccccc23)ccn1
Temperature: 0 °C

Procedure:
To a solution of (4-(tert-butoxycarbonyl)aminonaphthalen-1-yl)(2-(tert-butoxycarbonyl)amino pyridin-4-yl)methanone (378 mg, 0.815 mmol) in DCM (20 mL) under N2 at 0° C. was added TFA (4.0 mL, 50 mmol). After 30 min at 0° C. the reaction mixture was warmed to RT for 4.5 hr and was then evaporated in vacuo. The residue was subjected to purification by SCX capture and release to afford the title compound, Intermediate G1, as a yellow solid (200 mg, 93%); Rt 1.01 min (Method 2); m/z 264 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(F)c(Cl)c1)C(=O)OCC

Procedure:
3-Chloro-4-fluoroaniline (I) and diethyl ethoxymethylenemalonate were heated at 120°-130° C. to give diethyl (3-chloro-4-fluorophenyl)aminomethylenepropanedioate (II). The latter was cyclized by heating it at reflux in diphenyl ether to give the quinoline III.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29](O)=[O:30])(=[O:12])=[O:11].[CH3:33][C@@H:34]1[CH2:39][NH:38][CH2:37][C@H:36]([CH3:40])[NH:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29]([N:38]1[CH2:37][C@H:36]([CH3:40])[NH:35][C@H:34]([CH3:33])[CH2:39]1)=[O:30])(=[O:11])=[O:12]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol), (2R,6S)-2,6-dimethyl-piperazine (32 mg, 1.2 eq.), HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated and purified on s silica gel column to give the titled compound.
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[CH:34]=1>[Cu]I.CS(C)=O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][CH:19]=2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: COc1cc(Br)ccc1Cl
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: COc1cc(Oc2ccc(-c3cccnc3N)cc2)ccc1Cl
Temperature: 130 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 4-bromo-1-chloro-2-methoxybenzene (714 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (359 mg) as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:29][CH:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:27]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[NH:26]1[CH2:29][CH:28]([N:30]2[CH2:35][CH2:34][N:33]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]4[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:4][CH:3]=3)[CH2:32][CH2:31]2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(C4CNC4)CC3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 3-piperazin-1-yl-azetidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)(=[O:7])=[O:6])[CH3:3]>C(O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:5]([NH:4][CH:2]([CH3:3])[CH3:1])(=[O:7])=[O:6])=[CH:10][CH:11]=1
Reactant: CC(C)NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CC(C)NS(=O)(=O)Cc1ccc(N)cc1

Procedure:
By a procedure similar to that described in example 9(b) the product of stage (a) was hydrogenated in ethanol to give the title compound (2.45 g) m.p. 105°-107° (from isopropanol)