Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:35][N:36]([CH3:47])[CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>C(O)(C)C.Cl>[CH3:35][N:36]([CH3:47])[CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42]([NH:43][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]5[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=5[F:33])[CH:21]=[CH:22][CH:23]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: O=C(Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4cccc(F)c34)n2)c1
Yield: 69.2 %

Procedure:
To the solution of N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (0.10 g) in isopropanol (6 mL) was added 3-{[2-(dimethylamino)ethyl]oxy}aniline (0.06 g) and 3 drops of concentrated hydrochloric acid. The reaction was microwaved in a sealed tube at 180° C. for 10 min. The isopropanol was removed by rotovaporation and the residue was treated with sat. NaHCO3 (5 mL), extracted with EtOAc (2×5 mL), and dried (Na2SO4). Concentration and purification with column chromatography afforded the title compound as a white solid (0.09 g, 70% yield). 1H NMR (400 MHz, CDCl3) 8 ppm 2.22 (s, 6H), 2.63 (t, J=5.6 Hz, 2H), 391 (t, J=5.6 Hz, 2H), 6.48 (dd, J=8.0, 1.7 Hz, 1H), 6.77 (td, J=7.2, 4.9 Hz, 1H), 6.82-6.85 (m, 1H), 6.86 (s, 1H), 6.89-6.94 (m, 3H), 7.00-7.07 (m, 1H), 7.21-7.32 (m, 4H), 7.43 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.90 (s, 1H), 8.33 (d, J=6.8 Hz, 1H), 8.35-8.38 (m, 1H), 8.45 (s, 1H); ESIMS (M+H)+=624.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Product: Cc1ccc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)cc1

Procedure:
6-Chloro-N-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and p-toluidine in a similar manner as described in Example 13 to give 59 mg (41% yield) of a yellow solid. 1H-NMR (CDCl3): δ 8.10 (s, 1H), 7.51 (m, 1H), 7.22 (d, 1H), 7.17-7.06 (m, 3H), 6.72 (d, 2H), 4.82 (m, 1H), 3.74 (s, 1H), 2.74 (m, 2H), 2.33 (s, 3H), 2.27 (m, 1H), 2.07 (m, 1H), 1.98-1.76 (m, 2H); MS m/z 309 (M−1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:30]([NH2:32])=[O:31])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=4)=[CH:7][C:6]=1[Cl:33].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:33][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[C:13]([C:30]([NH2:32])=[O:31])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=4)[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCCN3CCOCC3)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 75 °C
Yield: 86.8 %

Procedure:
3-(4-(2-Bromoethoxy)-3-chlorophenyl)-7-morpholino-9H-carbazole-1-carboxamide (110 mg, 0.146 mmol, Example 407A) was dissolved in DMF (5 ml). Morpholine (0.045 ml, 0.517 mmol) and K2CO3 (66 mg, 0.478 mmol) were added and the mixture heated to 75° C. for 1 hour. Additional morpholine (0.10 ml, 1.148 mmol) was added and the mixture heated for one additional hour. The mixture was concentrated to a volume of ˜1 ml, then diluted with 3 ml DMSO+3 ml MeOH, filtered through a 0.45 um Nylon filter and purified by prep HPLC. Product containing fractions were evaporated to dryness to give 67.8 mg 3-(3-chloro-4-(2-morpholinoethoxy)phenyl)-7-morpholino-9H-carbazole-1-carboxamide. MS (ESI) m/e+=535/537, m/e−=533/535 [1 Cl isotope pattern]. HPLC retention time 15.81 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (DMSO-d6) δ ppm 11.13 (s, 1H), 8.49 (d, 1H, J=1.5), 8.34 (b, 1H), 8.14 (d, 1H, J=1.5), 8.07 (d, 1H, J=8.5), 7.99 (d, 1H, J=2.3), 7.82 (dd, 1H, J=8.6, 2.4), 7.51 (b, 1H), 7.31 (d, 1H, J=8.8), 7.24 (d, 1H, J=2.0), 6.94 (dd, 1H, J=8.8, 2.0), 4.26 (t, 2H, J=5.8), 3.83-3.79 (m, 4H), 3.64-3.59 (m, 4H), 3.22-3.17 (m, 4H), 2.79 (t, 2H, J=5.8), 2.58-2.54 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([OH:18])[CH2:13][NH:14]CC=C)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(#N)C.O>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([OH:18])[CH2:13][NH2:14])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: C=CCNCC(O)c1cccc2c(C)c(C)oc12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: Cc1oc2c(C(O)CN)cccc2c1C
Yield: 43.1 %

Procedure:
1 g (4 mmol) of 2,3-dimethyl-7-(2-allylamino-1-hydroxyethyl)benzofuran, 85 mg (0.092 mmol) of Wilkinson's catalyst (tris(triphenylphosphine)rhodium(I)) and 25 ml of an acetonitrile/water (84/16) mixture are introduced into a 100 ml three-necked flask equipped with a distillation system and a 50 ml dropping funnel. 30 ml of the same acetonitrile/water (84/16) mixture are placed in the dropping funnel. The solution is stirred at reflux, under a nitrogen stream, for 1 h 30, small amounts of acetonitrile/water (84/16) mixture being added regularly in order to replace the solvent distilled off. The mixture is subsequently concentrated under vacuum and the residue is purified by column chromatography (elution solvent: 90/10 dichloromethane/methanol) and then dried in a desiccator under vacuum over phosphorus pentoxide. 354 mg of 2,3-dimethyl-7-(2-amino-1-hydroxyethyl)benzofuran are obtained--M.p.: 73° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][CH:23]=[C:18]4[CH:17]=[N:16]3)=[CH:11][CH:10]=2)O1.[OH-:25].[Na+].OO>C1COCC1>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([OH:25])=[CH:10][CH:11]=2)[C:19]2=[N:20][CH:21]=[N:22][CH:23]=[C:18]2[CH:17]=[N:16]1
Reactant: [OH-]
Reactant: CC1(C)OB(c2ccc(-n3ncc4cncnc43)cc2)OC1(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc(-n2ncc3cncnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 21C (100 mg, 0.31 mmol) in THF (5 mL) was added NaOH (0.248 mL, 0.621 mmol) and hydrogen peroxide (0.048 mL, 0.466 mmol). The mixture was stirred at 0° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure and the concentrate was dissolved in 8 mL of water. The aqueous solution was acidified with diluted HCl. A white precipitate was collected, washed with water, and dried to provide the desired product 21D: 1H NMR (400 MHz, DMSO-D6) δ ppm 9.75 (1H, s), 9.44 (1H, s), 9.09 (1H, s), 8.59 (1H, s), 7.82-7.99 (2H, m), 6.83-7.05 (2H, m).
Reaction SMILES: [CH:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(Cl)(Cl)Cl.C(C(C)=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
1-Indanol (2.3 g, 17 mmol) was dissolved in chloroform (25 ml), and the solution was mixed with thionyl chloride (1.4 ml, 19 mmol) and stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the thus obtained residue was mixed with t-butoxycarbonylpiperazine (3.1 g, 17 mmol), potassium carbonate (6.0 g, 48 mmol) and potassium iodide (2.8 g, 17 mmol) and stirred overnight at 100° C. in methyl ethyl ketone (100 ml). The reaction solution was mixed with water, the reaction product was extracted with ethyl acetate, washed with water and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 3.6 g (12 mmol, 72%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzoyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid; Rf : 0.61 (SiO2, hexane:acetone=95:5).
Reaction SMILES: Br[C:2]1[C:3]([CH2:20][OH:21])=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.CO.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)CC.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:3]([CH2:20][OH:21])=[C:4]3[N:10]=[CH:9]2)=[CH:13][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cn2cnc3c(CO)c(Br)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CCC#N
Product: COc1ccc(Cn2cnc3c(CO)c(-c4ccccc4)cnc32)cc1
Temperature: 110 °C
Reaction time: 26 h
Yield: 85 %

Procedure:
A reactor containing [6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x211 (0.55 g, 1.58 mmol) in propionitrile (4 ml) and methanol (1 ml) is charged sequentially with phenylboronic acid (0.24 g, 1.25 eq, 1.98 mmol), sodium carbonate (0.34 g) in water (1.6 ml, 2 eq as a 2 M aqueous solution, 3.16 mmol), and tetrabutylammonium bromide (0.1 g, 0.2 eq, 0.32 mmol). The content of the reactor is evacuated several times and subsequently flushed with argon. Then tetrakis(triphenylphosphine)palladium(0) (0.09 g, 5 mol %, 0.08 mmol) is added. The reactor is equipped with a reflux condenser. The whole apparatus is evacuated twice and subsequently flushed with argon. The reaction mixture is kept for 26 h in a flow of argon under vigorous stirring at a bath temperature of 110° C. In the process, the strongly heterogeneous reaction mixture transforms into a solution. When the reaction is complete, the obtained solution is partitioned in 10% aqueous NaH2PO4/ethyl acetate mixture. The organic layer is additionally washed with saturated aqueous NaHCO3, dried with anhydrous sodium sulfate and evaporated in vacuum. The obtained compound is purified by chromatography on silicagel (chloroform/isopropanol) to afford 0.46 g of [3-(4-methoxybenzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methanol x214.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[C:11](=[O:12])[CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)=[CH:4][C:3]=1[F:22].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[C@@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:8]2)=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(Oc2ccc(Cl)c(F)c2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](Oc2ccc(Cl)c(F)c2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
To a solution of 416 (1.6 g, 4.9 mmol) and anhydrous THF (50 mL) cooled to −78° C. was added dropwise L-selectride (1.0 M, 15 mL) and then the reaction was stirred at −78° C. for 3 h. The reaction was quenched with H2O (30 mL). The mixture was extracted with EtOAc (3×100 mL) and the extract was washed with brine (3×30 mL). The organic phases were dried (Na2SO4), filtered and concentrated. LC-MS indicated about 9:1 of two isomers. The residue was purified by reverse phase column chromatography using a MeCN/5% aqueous NH4OH (0 to 35%) to afford 0.56 g (35%) of cis-(±)-tert-butyl 3-(4-chloro-3-fluorophenoxy)-4-hydroxy-pyrrolidine-1-carboxylate (418). LC-MS (ESI) m/z 276 (M+H-56).
Reaction SMILES: [C:1]([CH:3]([CH:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:9])C(OC)=O)#[N:2].[Cl-].[Na+].CS(C)=O>O>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:8]([CH3:9])[CH2:3][C:1]#[N:2])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1
Reactant: COC(=O)C(C#N)C(C)c1ccc(N2CCN(C)CC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(CC#N)c1ccc(N2CCN(C)CC2)cc1
Temperature: 162.5 °C
Yield: 79.7 %

Procedure:
A mixture of methyl 2-cyano-3-(4-(4-methylpiperazin-1-yl)phenyl)butanoate (700 mg, 2.32 mmol), sodium chloride (405 mg, 6.90 mmol), DMSO (5 ml) and water (2 ml, 3 vol %) and heated at 160-165° C. for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 450 mg (79.6%) of 3-(4-(4-methylpiperazin-1-yl)phenyl)butanenitrile as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([C:25]#[N:26])=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.ClC1C=CC=CC=1C1N=C(NCC(C)C)C(C#N)=CC=1C1C=CC(Cl)=CC=1.COCC(Cl)=O.[H-].[Na+].NC1C2[C:74](=NC(C3C=CC(Cl)=CC=3Cl)=C(C3C=CC(Cl)=CC=3)C=2)[N:73]([CH2:95]C(C)C)[C:72](=O)C=1OC>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:10]2[CH:11]=[C:12]3[C:13](=[N:14][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16](=[O:20])[C:17]([O:18][CH3:19])=[C:25]3[N:26]=[CH:72][N:73]([CH3:95])[CH3:74])=[CH:32][CH:31]=1
Reactant: COc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(CC(C)C)c1=O
Reactant: COCC(=O)N(CC(C)C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: CC(C)CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: COCC(=O)Cl
Agent: [H-]
Product: COc1c(N=CN(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(CC(C)C)c1=O

Procedure:
N-(6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-3-cyanopyridin-2-yl)-N-isobutyl-2-methoxyacetamide (prepared by the reaction of the product of Step A EXAMPLE 27 with 2-methoxyacetyl chloride using the conditions of EXAMPLE 62 Step A) was reacted with NaH using the conditions of EXAMPLE 80 affording 4-amino-7-(2,4-dichlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-3-methoxy-1,8-naphthyridin-2(1H)-one which was treated to the conditions of EXAMPLE 85 to afford the title compound (E/Z mixture of isomers). HPLC/MS: 557.0 (M+1), 558.9 (M+3); Rt=3.70 min.
Reaction SMILES: C1C=C2[N:7]=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.O.N.[NH:26]([C:33]([C:36]1[N:37]([CH3:50])[C:38]([C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=2)=[N:39][N:40]=1)([CH3:35])[CH3:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C1COCC1>[NH:26]([C:33]([C:36]1[N:37]([CH3:50])[C:38]([C:41]2[CH:42]=[CH:43][C:44]([C:45]([NH2:7])=[O:46])=[CH:48][CH:49]=2)=[N:39][N:40]=1)([CH3:35])[CH3:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cn1c(-c2ccc(C(=O)O)cc2)nnc1C(C)(C)Nc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(C(N)=O)cc2)nnc1C(C)(C)Nc1ccccc1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
HOBt hydrate (82 mg), WSC hydrochloride (103 mg), and ammonia water (33 μl) were added to a THF (1 ml) and DMF (1 ml) solution of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl]benzoic acid (150 mg) at room temperature, followed by stirring at the same temperature overnight. After most of the solvent was removed by evaporation under reduced pressure, water was added thereto and the whole was extracted four times with ethyl acetate. The organic layer washed with brine, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was removed by evaporation. Ethyl acetate was added to the resulting white crystals, which was filtered and washed with ethyl acetate to obtain 120 mg of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl]benzamide (white crystals).
Reaction SMILES: Cl.C(O)(C)C.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C@H:16]1[CH2:19][C@@H:18]([O:20]CC2C=CC=CC=2)[CH2:17]1.C([O-])(O)=O.[Na+]>CCO.[Pd]>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C@@H:16]1[CH2:17][C@H:18]([OH:20])[CH2:19]1
Reactant: c1ccc(CO[C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: CCO
Product: O[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Temperature: 70 °C
Yield: 113.5 %

Procedure:
A mixture of hydrogen chloride (5-6 N) in isopropyl alcohol (5 mL, 25 mmol), cis-benzothiazol-2-yl-(3-benzyloxy-cyclobutyl)-amine (500 mg, 1.6 mmol), and palladium black (250 mg, 50% wt percent) in EtOH (20 mL) under hydrogen atmosphere (balloon) was heated to 70° C. for 20 h. Then it was cooled to RT and solid NaHCO3 (500 mg) was added. The mixture was stirred until gas evolution ceased. The palladium was filtered off using Celite® and the filtrate was concentrated in vacuo to give oil (400 mg), which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:14][CH2:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(Cl)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(Cl)ccc1CBr
Temperature: 75 °C
Yield: 69.2 %

Procedure:
A mixture of ethyl 5-chloro-2-methylbenzoate (3.20 g, 16.1 mmol), N-bromosuccinimide (3.15 g, 17.7 mmol) and benzoyl peroxide (0.39 g, 1.61 mmol) in 1,2-dichloroethane (90 mL) was heated to 75° C. in an oil bath for 4 h. After this time, the mixture was cooled to room temperature and the organic layer was washed with water (45 mL) and brine (45 mL). The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica, 1:20 ethyl acetate/hexanes) afforded ethyl 2-(bromomethyl)-5-chlorobenzoate (3.09 g, 68%) as a clear oil: 1H NMR (500 MHz, CDC13) 7.94 (d, J=2.5 Hz, 1H), 7.46 (dd, J=8.5, 2.5 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.91 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H); ESI MS m/z 279 [(M+2)+H]+.
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[NH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.N1C=CN=C1>ClCCl>[Si:2]([O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[NH2:9])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
Chloro t-butyldimethylsilane (11 g, 72.98 mmol), 3-aminophenol (6.64 g, 60.81 mmol) and imidazole (5.38 g, 79.10 mmol) were added into 200 ml of dichloromethane. The mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted using 200 ml of saturated ammonium chloride and 200 m of dichloromethane and the organic layer was washed twice using 200 ml of water. After concentrated under vacuum, the title compound (13.5 g, 99%) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:3]=1.[CH2:23]([O:27]C=C)[CH2:24]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:3]=1)(=[O:27])[CH3:24]
Reactant: C=COCCCC
Reactant: COC(=O)c1ccc2c(Br)nn(CC(=O)OC(C)(C)C)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C(C)=O)nn(CC(=O)OC(C)(C)C)c2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A solution of methyl 3-bromo-1-(2-tert-butoxy-2-oxoethyl)-1H-indazole-6-carboxylate (1.00 g, 2.71 mmol), n-butyl vinylether (1.75 mL, 13.5 mmol), palladium acetate (61 mg, 0.27 mmol), triphenylphosphine (142 mg, 0.54 mmol) and triethylamine (0.45 mL, 3.25 mmol) in dry CH3CN (10 mL) was heated at 100° C. under microwave irradiation for 7 h. Then, the mixture was further heated at 120° C. for 5 h under microwave irradiation. The solvent was evaporated, and the residue was then treated with 4N HCl/dioxane with stirring at RT for 16 h. Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the pure fractions the title compound. MS (LC-MS): 333 [M+H]+, 355 [M+Na]; tR (HPLC conditions k): 3.83 min.