Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:5]([C:18]([O:20]CC)=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2>C(O)C.O>[OH:3][C:4]1[C:5]([C:18]([OH:20])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2
Reactant: CCOC(=O)c1nc2ccc(S(C)(=O)=O)cc2nc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc2nc(C(=O)O)c(O)nc2c1

Procedure:
Potassium hydroxide (1.0 mL, 1.8 mmol, 1.0 N solution) was added to a suspension of ethyl 3-hydroxy-6-(methylsulfonyl)quinoxaline-2-carboxylate (249 mg, 0.84 mmol) in ethanol (30 mL) and the resulting mixture was heated at reflux for 2 h. The cooled mixture was diluted with water (10 mL), acidified to pH 1 and the resulting solids were collected by filtration under reduced pressure to provide 3-hydroxy-6-(methylsulfonyl)quinoxaline-2-carboxylic acid as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.6 Hz, 1H), 7.87-7.84 (m, 2H), 3.31 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.Cl.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>C(#N)C>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:35]2[CH2:36][CH2:37][N:32]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH2:33][CH2:34]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(c1cccs1)N1CCNCC1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)cc1)C(F)(F)F
Temperature: 110 °C
Yield: 56.2 %

Procedure:
2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (2.6 g, 13 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (5.8 mL, 34 mmol), 1-(2-thiophenylsulfonyl)piperazine hydrochloride (3.0 g, 11 mmol, Example 29, step 1), and acetonitrile (22 mL) was added to a high-pressure reaction vessel. The vessel was sealed and heated at 110° C. for 19 h. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (50 mL) and the layers were separated. The organic material was washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated, hexanes (100 mL) was added to the residue and the slurry was filtered to give 2,2,2-trifluoro-1-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)ethanone (2.5 g) as a light tan solid. The material was used in the next step without purification
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[CH3:14][NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]([CH3:14])[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: CNCC1CCOCC1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N(C)CC2CCOCC2)cc1[N+](=O)[O-]
Yield: 62.4 %

Procedure:
To a stirred solution of 4.70 g (20.0 mmol) 4-bromo-2-nitro-anisole in 100 ml dioxane were added 4.03 g (24.3 mmol) methyl-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (1:1), 0.710 g (20.0 mmol) 2-(dicyclohexylphosphino)biphenyl, 16.5 g (50.65 mmol) cesium carbonate, and 227 mg (1.0 mmol) palladium (II) acetate. The mixture was heated at reflux for 24 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 hexane/ethyl acetate) afforded 3.5 g (62%) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-ylmethyl)-amine as a red oil. ES-MS m/e (%): 281 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:18]2[C:13](=[C:14]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[N:21]=[CH:20]3)[CH:15]=[CH:16][CH:17]=2)[C:12]([C:30]([F:33])([F:32])[F:31])=[N:11]1)[C:5]#[N:6].[OH-:34].[Na+].OO.[Cl-].[NH4+]>CS(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:18]2[C:13](=[C:14]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[N:21]=[CH:20]3)[CH:15]=[CH:16][CH:17]=2)[C:12]([C:30]([F:33])([F:32])[F:31])=[N:11]1)[C:5]([NH2:6])=[O:34]
Reactant: Cn1cc(-c2cn(-c3cccc4c3c(C(F)(F)F)nn4-c3ccc(C#N)cc3N)cn2)cn1
Reactant: [OH-]
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cn1cc(-c2cn(-c3cccc4c3c(C(F)(F)F)nn4-c3ccc(C(N)=O)cc3N)cn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of compound (20a) (50 mg) in DMSO (0.5 mL) were added 4N aqueous sodium hydroxide solution (56 μL) and aqueous hydrogen peroxide solution (25 μL), and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, an aqueous ammonium chloride solution was added to the reaction solution, and then the mixture was partitioned with ethyl acetate. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was subjected to slurry washing with acetonitrile. The precipitated solid was collected by filtration and dried to obtain compound (24) (33 mg, yield 63%) as a milky white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>C1COCC1.CCOC(C)=O>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[NH:1][C@@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3]1
Reactant: CN(C)C(=O)Cl
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
Commercial (3R,4R)-tert-butyl 3-amino-4-methylpiperidine-1-carboxylate (427, 250 mg, 1.16 mmol) was dissolved in 10 mL dry THF. To it were added DIEA (610 μL, 3.50 mmol) and dimethylcarbamoyl chloride (214 μL, 2.32 mmol). The mixture was stirred at RT for 2 hours, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to silica flash column using 0 to 5% MeOh in DCM to isolate (3R,4R)-tert-butyl 3-(3,3-dimethylureido)-4-methylpiperidine-1-carboxylate (428, 350 mg) in quantitative yield as a white solid. It was treated with 15 mL commercial 4N HCkl in dioxane at RT for 40 min to yield 1,1-dimethyl-3-((3R,4R)-4-methylpiperidin-3-yl)urea hydrochloride (429).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(C(C)=O)C.ClCCl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23])[CH:4]=1
Reactant: Oc1cc(Br)ccc1F
Reactant: FC(F)=CCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: FC(F)=CCCOc1cc(Br)ccc1F
Yield: 63 %

Procedure:
A mixture of 2-fluoro-5-bromophenol (2.40 g), potassium carbonate (2.31 m), Aliquat 336 (5 drops), sodium iodide (catalytic) and 4-bromo-1,1-difluoro-1-butene (1.79 mL) in methyl ethyl ketone was placed in a pressure vessel and heated in a 82° oil bath for 15 hours. The reaction mixture was cooled, diluted with dichloromethane, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica gel, eluant: 2.5% ethyl acetate/hexane to afford 4-bromo-2-(4,4-difluorobut-3-enyloxy)-1-fluorobenzene, 2.23 g (63% yield), identified by NMR analysis.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:46][CH3:47])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[NH:20][C:19]2=[O:45])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].Br[C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:46][CH3:47])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[C:19]2=[O:45])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)(OC)C(=O)Nc3ccccc32)C(C)C)cc1
Reactant: Brc1cccnc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)(OC)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 120 °C
Yield: 70.5 %

Procedure:
To a stirring suspension of 570 mg (0.90 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, and 172 mg (2.71 mmol, 3.0 equiv) of Cu0 powder in 10 mL of DMF is added 117 mg (1.80 mmol, 2.0 equiv of potassium acetate, followed by 285 mg (1.80 mmol, 2.0 equiv) of 3-bromopyridine). The resulting mixture is heated to 120° C. for 4 h, then an additional 285 mg of 3-bromopyridine is added and the reaction heated to 120° C. for an additional 15 h. The reaction mixture is then cooled to RT and filtered through a pad of Celite to remove the Cu0 powder. The reaction mixture is then poured into 100 mL of EtOAc-Et2O (1:1) and extracted with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 450 mg of the title compound as a light tan solid: mp 223°-224° C.; 1H NMR (CDCl3, 400 MHz) δ8.47 (d, 1H, J=3.8), 8.31 (s, br, 1H), 8.04 (d, 1H, J=8.2), 7.51 (d, 1H, J=7.3), 7.38 (d, 1H, J=7.7), 7.31-6.93 (m, 15H), 6.64 (d, 1H, J=7.5), 5.52 (s, 2H), 5.04 (m, 1H), 4.46 (d, 1H, J=15.9), 4.26 (d, 1H, J=15.8), 4.00 (m, 2H), 3.84 (s, 3H), 3.15 (s, 3H), 1.11 (2×d, 6H, J=6.7); low resolution MS (FAB)m/e 709 (MH+), 293, 265; Anal. (C42H40N6O5) Calcd. C, 71.17; H, 5.69; N, 11.86; Found C, 70.90; H, 5.74; N, 11.65.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[CH3:17][N:18]=[C:19]=[O:20].O>O1CCCC1>[CH3:17][NH:18][C:19]([N:3]1[CH2:4][C@@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[C@@H:2]1[CH3:1])=[O:20]
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Reactant: CN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1C[C@@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
A stirred solution of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of tetrahydrofuran was treated with 0.94 g (0.0165 mole) of methyl isocyanate added dropwise and stirred for 16 hr under a blanket of nitrogen. Dilution of the reaction mixture with water produced an oil which solidified. After decanting the aqueous tetrahydrofuran phase, the solid residue was recrystallized from ethanol-water to yield 3.95 g (91.4%) of fine white crystals, m.p. 104.5°-106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[OH:32])[CH2:27][CH2:26]1>CN(C)C=O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[OH:32])[CH2:27][CH2:26]2)=[CH:7][CH:6]=1)[CH3:13]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4.18 g (0.02 mole) of ethyl p-nitrophenylacetate in 200 mL of ethanol is subjected to catalytic hydrogenation. The mixture is filtered to remove the catalyst and the filtrate is concentrated to obtain quantitative yield of ethyl 4-aminophenylacetate. To an agitated solution of the ethyl 4-aminophenylacetate and 2.02 g (0.02 mole) of triethylamine in 50 ml of dimethylformamide is added dropwise a solution of 7.58 g (0.020 mole) of 1-(3-chloropropyl)-α,α-bis(4-fluorophenyl)-4-piperidinemethanol in 20 ml of dimethylformamide. After stirring at ambient temperature for 4 hr the reaction mixture is heated at 70° C. for 4 hr. The reaction mixture is concentrated and the crude product partitioned between methylene chloride and water. The methylene chloride solution is washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=O)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>N1CCCCC1.C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:23][C:19]1[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=1)[NH:14][CH:15]=[CH:16]3)[C:7](=[O:13])[NH:8]2
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccc2[nH]ccc2c1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (39 mg, 0.22 mmol), 1H-indole-5-carbaldehyde (32 mg, 0.22 mmol) and 1 drop of piperidine in ethanol was heated at 90° C. for overnight and cooled to room temperature. The reaction mixture was concentrated and the residue was purified on silica gel column to give 48 mg (72%) of 4-(2-hydroxy-ethyl)-3-(1H-indol-5-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=1I>COCCOC.O.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>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=1[C:17]1[CH:18]=[CH:19][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1nccc(Cl)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nccc(Cl)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 4-chloro-3-iodopyridin-2-amine (146 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (111 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH2:1]([O:8][C:9]1[C:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11][C:12]([C:18]([F:21])([F:19])[F:20])=[C:13]([CH:14]=1)[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(C2CCCCC2)cc1C(F)(F)F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1cc(OCc2ccccc2)c(C2CCCCC2)cc1C(F)(F)F
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a solution of 1-(benzyloxy)-2-cyclohexyl-5-nitro-4-(trifluoromethyl)benzene (250 mg, 0.66 mmol) and NiCl2 (170 mg, 1.31 mmol) in methanol (2.5 mL) was added NaBH4 (50 mg, 1.32 mmol) portionwise at 0° C. The reaction mixture turned black after 5 minutes. The reaction mixture was quenched with NaHCO3 and diluted with EtOAc. The reaction mixture was filtered through a plug of celite, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was then purified by silica gel column chromatography using 10% EtOAc/hexane gradient to give 5-benzyloxy-4-cyclohexyl-2-(trifluoromethyl)aniline (150 mg, 65%). LC/MS: m/z 350.3 (M+H)+ at 2.40 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)[C:5]([C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1COc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Br)cc1COc1ccc2c(c1)OCO2

Procedure:
Add 16.07 gm. (0.044 mole) of methyl 5-bromo-α-(3,4methylenedioxyphenoxy)-o-toluate to a solution of 3.52 gm. (0.088 mole) of sodium hydroxide in 24 ml. of water and 212 ml. of methanol. Heat the mixture under reflux for 1 hour. Remove the methanol under vacuum and dissolve the residue in 225 ml. of water. Acidify with concentrated hydrochloric acid to the congo red end point. Separate the solids by filtration and dry (yield 14.14 gm., m.p. 167°-177° C.). Recrystallize from ethanol-water to obtain pure product as tan needles (m.p. 177°-180° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc1)nn2-c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nccc2c1c(-c1ccc(N3CCNCC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-(4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)piperazine-1-carboxylate (920 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was diluted with dichloromethane, and the mixture was adjusted to pH=9 with saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (744 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[S:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH3:26][C:23]1[S:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: Cc1ccc(OB([O-])[O-])s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(C)s3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
In toluene/ethanol/water (10/1/1.2 ml) was dissolved methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (870 mg), and to the solution were added 5-methyl-2-thienyl borate (530 mg) and potassium carbonate (1.02 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (152 mg). The mixture was stirred at 100° C. for 16 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-(5-methyl-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (210 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=[O:2].CN(C(O[N:29]1N=N[C:31]2C=CC=[CH:35][C:30]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N)(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C.COCCOC>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:29][CH:30]([CH3:35])[CH3:31])=[O:16])=[CH:17][CH:18]=2)=[CH:19][CH:20]=1)=[O:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=Cc1ccc(OCCc2ccc(C(=O)O)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
4-[2-(4-Formylphenoxy)ethyl]benzoic acid (8.11 g; 30 mmole), TBTU (10.6 g; 33 mmole) and DMAP (8.1 g; 66 mmole) were dissolved in DMF (85 ml). The reaction mixture was cooled on an ice bath and isopropylamine (12 g; 200 mmole) dissolved in DME (100 ml) was added. The reaction mixture was stirred at room temperature over night. A large amount of water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with potassium hydogen sulfate (0.3 M), water and brine and dried with sodium sulfate. Evaporation gave 8 g (85.6% yield) of 4-[2-(4-formylphenoxy)ethyl]-N-isopropylbenzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:14]=[CH:15][N:16]=3)[CH2:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[N:10]([CH:14]=[CH:15][N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2=CCCn3ccnc32)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(-c2cccn3ccnc23)cc1

Procedure:
Combine 30 g (0.14 mole) of the product from Example 22 with 150 g of "activated" manganese dioxide in 500 ml of methylene chloride and heat to reflux for 6 hr. Filter the reaction mixture over celite, dry over magnesium sulfate, treat with charcoal, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.