Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH:22]=[N:21][N:20]=[CH:19]3)[CH2:13]2)(=[O:10])=[O:9])=[C:4]([CH2:23][CH3:24])[CH:3]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=NO)C1C(=CC=CC=1)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.[Cu-]=O>[CH2:23]([C:4]1[CH:3]=[C:2]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)[CH2:13]1)(=[O:10])=[O:9])[CH3:24]
Reactant: CCc1cc(Br)ccc1S(=O)(=O)N[C@H]1CCC[C@@H](n2cnnc2)C1
Reactant: c1cn[nH]c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CCc1cc(-n2cccn2)ccc1S(=O)(=O)N[C@H]1CCC[C@@H](n2cnnc2)C1
Temperature: 120 °C

Procedure:
A mixture of 2a (39.6 mg, 0.096 mmol), pyrazole (49.0 mg, 0120 mmol), copper (1) oxide (16.0 mg, 0.112 mmol), salicylaldoxime (19.0 mg, 0.139 mmol) and cesium carbonate (255 mg, 0.783 mmol) in acetonitrile (500 μL) was placed in a sealed tube and heated in a microwave reactor at 120° C. for 30 min. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and brine. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were filtered through a short column of Celite®, eluting copiously with EtOAc, and concentrated in vacuo. The crude residue was purified by preparative thin layer chromatography on silica gel (10% MeOH/DCM as eluent) to afford the title compound, 6a. m/z (ES) 401 (MH); IC50=68 nM
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=1
Reactant: O=C1CCCN1CCn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnn(CCN2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrrolidin-2-one (0.21 g, 0.9 mmol) and Pd/C (50 mg) in ethanol (20 mL) was stirred overnight at room temperature under an atmosphere of hydrogen then filtered over Celite. The filtrate was concentrated in vacuo to afford 1-(2-(4-amino-1H-pyrazol-1-yl)ethyl)pyrrolidin-2-one V-5 (0.19 g, 100%) as a purple oil. LC-MS (Method C), RT=0.38 min. (ES+) 195.
Reaction SMILES: C([N:5]([CH:9]([CH2:23][C:24]([NH:26][CH2:27][C@@H:28]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:25])[CH2:10][CH2:11][NH:12][C:13](=[O:22])[O:14]CC1C=CC=CC=1)C(=O)[O-])(C)(C)C>[Pd].C(O)C>[C:36]([O:14][C:13](=[O:22])[NH:12][CH2:11][CH2:10][CH:9]([NH2:5])[CH2:23][C:24]([NH:26][CH2:27][C@@H:28]([NH:40][C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:25])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CC(CCNC(=O)OCc1ccccc1)N(C(=O)[O-])C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CC(N)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
35 mg of palladium on activated carbon (10%) are added to a mixture of 0.232 g (0.35 mmol) of the compound from Example 244A in 10 ml of ethanol, and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[C:18]=2[CH:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl>[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:26])=[O:25])[C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 1 h
Yield: 831.6 %

Procedure:
In 100 ml of chloroform was dissolved 5.0 g of 1-methylpiperazine, and to the solution was added 6.9 g of anhydrous potassium carbonate. To the mixture was added dropwise 200 ml of a chloroform solution containing 1.4 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred for one hour under cooling with ice, and then the reaction solution was washed with 50 ml of a 5N aqueous sodium hydroxide solution and extracted twice with 50 ml of a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted three times with 100 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, 50 ml of a 5N aqueous hydrochloric acid solution was added to the residue and the mixture was condensed to dryness under reduced pressure. The crystalline residue thus obtained was recrystallized from ethanol to give 14.9 g of 1-(5-isoquinolinesulfonyl)-4-methylpiperazine [i.e. Compound (36)] dihydrochloride in a yield of 82%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC(N)=O)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL), was added 2-bromo-acetamide (33 mg, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give 2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)acetamide as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.11 (s, 1H), 7.76 (d 1H), 7.09 (d, 1H), 6.27 (s, 1H), 4.0 (s, 2H), 3.75-3.73 (m, 2H), 3.22-3.13 (m, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.04-2.00 (m, 4H); ESMS m/z 473.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[CH:4][CH:3]=1.C1COCC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C([C@H]1C[C@@H]1c1ccc(Br)cc1)N1CCCCC1
Solvent: C1CCOC1
Product: Brc1ccc([C@H]2C[C@@H]2CN2CCCCC2)cc1

Procedure:
Following the general procedure, reaction of 6b (3.70 g assayed, 12.0 mmol) with 1 M BH3 in THF (42.0 mL, 42.0 mmol) afforded 7b in an assay yield of 2.77 g (9.4 mmol, 78% assay yield, 99% peak area). A sample was concentrated in vacuo to an oil to provide the standard.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([NH:15][C@@H:16]([C:20]([F:23])([F:22])[F:21])[CH:17]([CH3:19])[CH3:18])=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12](Cl)[N:11]=[CH:10][CH:9]=3.C1C[O:29]CC1>Cl.CCOC(C)=O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([NH:15][C@@H:16]([C:20]([F:23])([F:22])[F:21])[CH:17]([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:29])[C:13]=3[C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)[C@@H](Nc1nc2ccnc(Cl)c2c2cc(Br)ccc12)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(F)(F)F

Procedure:
9-bromo-1-chloro-N-[(1R)-2-methyl-1-(trifluoromethyl)propyl]benzo[c]-1,6-naphthyridin-6-amine (1.0 g, 2.31 mmol) in 6 N HCl (4 mL) and THF (4 mL) was heated to 90° C. for 2 hr. The reaction was cooled and diluted with EtOAc and quenched with sat. NaHCO3. The mixture was extracted and the organic layers were separated, dried with MgSO4, filtered, and concentrated to give the crude product. Column chromatography on silica gel 100% Hex. to 100% EtOAc afforded 9-bromo-6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (600 MHz, CD3OD) δ 10.1 (d, 1H), 8.31 (d, 1H), 7.75 (d, 1H), 7.40 (d, 1H), 6.65, (d, 1H), 5.46 (m, 1H), 2.35 (m, 1H), 1.12 (d, 3H), 1.06 (d, 3H). LRMS (ESI) calc'd for (C17H16BrF3N3O) [M+H]+, 414.0; found 414.0.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[CH:30]=[CH:31][C:32]=1[N+:33]([O-])=O>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[CH:30]=[CH:31][C:32]=1[NH2:33]
Reactant: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1N

Procedure:
2-Methoxy-4-(4-pyrrolidin-1-yl-piperidin-1-yl)-phenylamine was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with 1-(3-Methoxy-4-nitro-phenyl)-4-pyrrolidin-1-yl-piperidine (280 mg, 89%). LC/MS (E/I+) 276.16 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8]O)[CH:7]=1.P(Br)(Br)[Br:12].C([O-])(O)=O.[Na+]>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][Br:12])[CH:7]=1
Reactant: OCc1cc(Br)ccc1F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(Br)cc1CBr
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To (5-bromo-2-fluoro-phenyl)-methanol (1.2 g, 5.9 mmol) in DME (20 mL) was added phosphorus tribromide (0.83 mL, 8.8 mmol), and the reaction was stirred at room temperature for 6 hours. The mixture was cooled to 0° C. and adjusted to pH 6 with saturated aqueous NaHCO3. The solution was extracted with EtOAc, and the combined organic layers were dried, concentrated, and purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(-c3ccc(F)cc3F)c2cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-6,7-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 397(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH:17][CH3:18].P(Cl)(Cl)Cl.ClC1C=CC=CC=1>CCCCCC>[F:12][C:13]([F:26])([F:27])[C:14]1[CH:15]=[C:16]([N:17]([CH3:18])[C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClP(Cl)Cl
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: CN(C(=O)c1cc(Cl)ccc1O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A mixture of 5-chlorosalicylic acid (173 mg, 1 mmol), 3,5-bis(trifluoromethyl)-N-methylaniline (243 mg, 1 mmol), phosphorus trichloride (44 μl, 0.5 mmol) and monochlorobenzene (5 mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, n-hexane (50 mL) was added, and the separated crude crystal was filtered and dissolved in ethyl acetate (50 mL). After the ethyl acetate solution was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (75 mg, 18.9%) as a white crystal.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].[Li+].CC([N-]C(C)C)C.[CH:22](OC)=[O:23]>O1CCCC1>[CH2:12]([O:11][P:6]([C:2]1[O:1][C:5]([CH:22]=[O:23])=[CH:4][CH:3]=1)([O:7][CH2:8][CH3:9])=[O:10])[CH3:13]
Reactant: COC=O
Reactant: CCOP(=O)(OCC)c1ccco1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C=O)o1
Reaction time: 1 h

Procedure:
A solution of diethyl 2-furanphosphonate (1 mmol) in THF (tetrahydrofuran) was treated with LDA (1.12 mmol, lithium N,N-diisopropylamide) at −78° C. for 20 min. Methyl formate (1.5 mmol) was added and the reaction was stirred for 1 h. Extraction. and chromatography gave compound 1 as a clear yellow oil.
Reaction SMILES: COC1C=C(OC)C=C[C:4]=1[CH2:5][NH:6][C:7]1[N+:8]([O-:17])=[CH:9][C:10]([CH3:16])=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1.C(OC(=O)C)(=[O:26])C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:16][C:10]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]([NH:6][C:5](=[O:26])[CH3:4])=[N+:8]([O-:17])[CH:9]=1
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])c(C)c[n+]2[O-])c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc([N+](=O)[O-])c(C)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-5-methyl-4-nitropyridin-2-amine 1-oxide (1.1 g, 3.5 mmol) in DCM (20 mL) and TFA (3 mL) was allowed to stir at rt for 4 h. The reaction mixture was concentrated and the residue was dissolved in DCM (20 mL). To this solution were added TEA (2.5 mL, 17.7 mmol) and acetic anhydride (0.4 g, 4.3 mmol). The reaction mixture was allowed to stir at rt overnight and then filtered to give N-(5-methyl-4-nitro-1-oxidopyridin-2-yl)acetamide (0.73 g, 98%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:3]=1.C(O)C.[ClH:20].C1(C)C=CC=CC=1>O>[ClH:20].[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16]
Reactant: N#Cc1ccc(F)cc1N1CCCCC1=O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: NCc1ccc(F)cc1N1CCCCC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of intermediate 112, 4-fluoro-2-(2-oxopiperidin-1-yl)benzonitrile (150 mg, 0.69 mmol) in H2O (10 mL) was added ethanol (10 mL) 10% palladium on charcoal (50 mg) and 1N HCl (2.1 mL, 20.6 mmol). The reaction was shaken in a Parr system under H2 (40 psi) for 1 h. Then the Pd/C catalyst was removed by filtration on Celite and the filtrate was concentrated in vacuo to yield a solid. Toluene (2×50 mL) was added to the solid and the solution was evaporated in vacuo. LCMS (M+H)+ m/z 170.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[NH:15][C:16]([CH3:24])=[C:17]2[C:22]=1[CH:21]=[N:20][NH:19][C:18]2=[O:23].[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=2[F:1])=[C:6]([C:14]2[NH:15][C:16]([CH3:24])=[C:17]3[C:22]=2[CH:21]=[N:20][NH:19][C:18]3=[O:23])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1[nH]c(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2F)c2cn[nH]c(=O)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1[nH]c(-c2cc(N)ccc2Oc2ccc(F)cc2F)c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73302.5 %

Procedure:
A mixture of Example 78b (80 mg, 0.20 mmol) and 10% palladium on carbon (42.7 mg, 0.040 mmol) in ethyl acetate (20 mL) was treated with a balloon of hydrogen gas. The reaction mixture was stirred at ambient temperature for 16 hours. The solid was removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 2-6% methanol in dichloromethane) to afford the title compound (54 g, 73%). 1 H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1 H) 11.34 (s, 1 H) 8.00 (s, 1 H) 7.20-7.37 (m, 1 H) 6.85-6.97 (m, 1 H) 6.71-6.83 (m, 3 H) 6.59 (dd, J=8.73, 2.78 Hz, 1 H) 5.18 (s, 2 H) 2.56 (s, 3 H). MS (ESI+) m/z 369 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>N1C=CC=CC=1>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)#[N:5]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: c1ccncc1
Product: N#Cc1cc([N+](=O)[O-])ccc1NC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 8.16 gm. (0.05 mole) of 2-amino-5-nitrobenzonitrile and 9.28 gm. (0.05 mole) of m-nitro benzoyl chloride in 50 ml. of dry pyridine is refluxed for three hours. The pyridine is removed by distillation in vacuo and the solid residue triturated with water. There is obtained 15.3 gm. (95%) of a yellow solid that melts at 203°-205°. Recrystallization from aqueous ethanol (2:1) gives material melting at 205°-206°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I.[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(F)cc21
Temperature: 0 °C
Yield: 113.6 %

Procedure:
In DMF (65 ml) was dissolved 6-fluoroindole (6.10 g, 45.1 mmol). Under stirring at 0° C., sodium hydride (60% in oil, 1.45 g, 36.3 mmol) was added in portions. After stirring at 0° C. for 30 minutes, methyl iodide (2.46 ml, 39.6 mmol) was added to the reaction mixture. The reaction mixture was stirred further at the same temperature for 2.5 hours. A saturated aqueous solution of ammonium chloride was added, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (5:1, v/v) eluate fractions, 6-fluoro-1-methylindole (6.71 g, 99%) was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH3:30])[C:25]([OH:29])=[C:26]([Cl:28])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:28][C:26]1[CH:27]=[C:22]([Cl:21])[CH:23]=[C:24]([CH3:30])[C:25]=1[O:29][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:4]=2[N:3]=1
Reactant: CCC(CC)c1ccc(C(F)(F)F)c2nc(Cl)n(C)c12
Reactant: Cc1cc(Cl)cc(Cl)c1O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(C(F)(F)F)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 110 °C
Yield: 65 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole (304 mg, 1.00 mmol), 4,6-dichloro-o-cresol (531 mg, 3.00 mmol), potassium carbonate (553 mg, 4.0 mmol) and N,N-dimethylformamide (5 ml) was heated at 110° C. for 48 h. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 10% ethyl acetate/n-hexane and recrystallization from diisopropylether/n-hexane to give 290 mg (0.65 mmol, 65%) of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH:13](I)([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:5]([O:8][CH:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(O)ncc1Br
Reactant: CC(C)I
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC(C)C)ncc1Br
Yield: 99 %

Procedure:
A solution of methyl 5-bromo-2-hydroxypyridine-4-carboxylate (3.00 g, 12.9 mmol), isopropyl iodide (3.30 g, 19.4 mmol) and Ag2CO3 (4.66 g, 16.8 mmol) in toluene (40 mL) was heated at 100° C. for 2 hours. The solid was filtered through CELITE® and the filtrate was concentrated under vacuum and purified by column chromatography (0-20% ethyl acetate/heptanes) to give methyl 5-bromo-2-(propan-2-yloxy)pyridine-4-carboxylate (112a, 3.5 g, 99%) as a colorless oil.
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)[CH:13]=1>C(OCC)(=O)C.O>[NH2:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[C:12]([C:6]3[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[O:16][N:15]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1
Temperature: 25 °C

Procedure:
Tin (II) chloride (135 mg, 0.6 mmol) was added to a solution of 5-(2,6-dichlorophenyl)-3-(3-nitrophenyl)isoxazole compound (100 mg, 0.3 mmnol) in ethyl acetate (20 mL). The resulting solution was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate twice. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was concentrated under reduced pressure to give the title compound as an off-white solid, 71 mg.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[NH:17][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:15][C:14]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[C:13]1[CH:31]([CH2:36][CH2:37][CH3:38])[C:32]([O:34][CH3:35])=[O:33].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[Cl-].[NH4+]>CN(C=O)C>[CH2:39]([N:17]1[C:12](=[O:11])[C:13]([CH:31]([CH2:36][CH2:37][CH3:38])[C:32]([O:34][CH3:35])=[O:33])=[C:14]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[N:15]=[C:16]1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)[nH]c1=O
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)n(Cc2ccccc2)c1=O
Reaction time: 0.08 h

Procedure:
LHMDS (1M in THF; 2 eq) is added to a cold (−-10° C.) stirred solution of methyl 2-(6-oxo-2-(piperidin-1-yl)-4-p-tolyl-1,6-dihydropyrimidin-5-yl)pentanoate (1 eq) in dry DMF (2 mL/mmol of the limiting reagent). After stirring for 5 minutes, benzyl bromide (2 eq) is added and the reaction mixture is stirred at room temperature for 18 hours. A saturated solution of ammonium chloride is then added and the aqueous layer is extracted with ethyl acetate. The organic layer is dried over magnesium sulphate, filtered and evaporated to dryness. The crude material is purified by flash chromatography on silica gel to provide the methyl 2-(1-benzyl-6-oxo-2-(piperidin-1-yl)-4-p-tolyl-1,6-dihydropyrimidin-5-yl)pentanoate which is deprotected following general method D yielding to the title compound.