Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:42][C:43]1[CH:44]=[C:45](I)[CH:46]=[CH:47][C:48]=1[F:49].[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:46]1[CH:45]=[CH:44][C:43]([F:42])=[C:48]([F:49])[CH:47]=1)=[CH:14]/[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)/C(I)=C\CC1CCCC1
Reactant: Fc1ccc(I)cc1F
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)/C(=C/CC1CCCC1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A mixture of zinc dust (0.98 g, 15 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.14 g, 0.75 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (82 mg, 0.75 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-4-cyclopentyl-2-iodo-but-2-enoic acid methyl ester (prepared in Example 21, 1.47 g, 5 mmol) in dry tetrahydrofuran (1.5 mL) over 3 min. After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (5 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min and then treated with 3,4-difluoro-iodobenzene (0.96 g, 4 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 25° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (50 mL), and the organic compound was extracted into diethyl ether (2×50 mL). The combined ether extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/diethyl ether) afforded (E)-4-cyclopentyl-2-(3,4-difluoro-phenyl)-but-2-enoic acid methyl ester (0.82 g, 73%) as a viscous oil: EI-HRMS m/e calcd for C16H18F2O2 (M+) 280.1275, found 280.1275.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([CH2:33][O:34][CH3:35])[CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:14]([CH:22]=[CH:23][CH:24]=1)[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[F:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[F:43].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:27]([CH2:26][CH2:25][C:13]1[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]2[CH:3]=[C:2]([C:40]3[CH:39]=[CH:38][C:37]([F:36])=[C:42]([F:43])[CH:41]=3)[CH:32]=[C:31]([CH2:33][O:34][CH3:35])[CH:30]=2)=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([OH:29])=[O:28]
Reactant: COCc1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COCc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Yield: 93.3 %

Procedure:
A similar procedure as described in step 3, method B was used, starting from 4-[3-[6-(3-bromo-5-methoxymethyl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (184 mg, 0.33 mmol), 3,4-difluorophenylboronic acid (106 mg, 0.66 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 0.06 mmol), and cesium carbonate (434 mg, 1.33 mmol) to obtain 4-[2-(2-carboxy-ethyl)-3-[6-(3′,4′-difluoro-5-methoxymethyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (180 mg, 93%) as a light yellow paste: ES(+)-HRMS m/e calcd for C33H38F2O7 (M+Na)+ 607.2478. found 607.2478.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]=[C:16]1[NH:20][CH2:19][C:18](=[O:21])[N:17]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[C:18](=[O:21])[CH2:19][NH:20][C:16]3=[O:15])=[CH:30][CH:29]=1)=[N:1]2
Reactant: O=Cc1ccc(CN2C(=O)CNC2=O)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4C(=O)CNC4=O)cc3)nc2c1
Temperature: 115 °C
Reaction time: 17 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.19 g, 0.98 mmol) in N,N-dimethylacetamide (4 mL) were added 4-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzaldehyde (0.19 g, 0.89 mmol), sodium hydrogen sulfite (58.5 wt %, 0.24 g, 1.30 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) and the reaction mixture was stirred at 115° C. for 17 hours under nitrogen, then cooled to room temperature. The precipitate was filtered, washed with methanol, water, then methanol, and dried in air. The solid was suspended in hot DMSO (approximately 3 mL); saturated aqueous NaHCO3 (approximately 3 mL) and water were added. The solid was filtered, washed with water, then methanol, and air dried to give the title compound as a light yellow solid. Yield: 0.16 g (46%). MP 317-318° C. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.17 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.74 (d, J=2.0 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 4.61 (s, 2H), 4.02 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H). MS (ES+) m/z: 395.09 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[OH-:28].[K+].O>C(O)(C)(C)C>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:24])=[O:28])=[CH:25][CH:26]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2CCN(c3ccc(C#N)cc3)CC2)c(C)c2c1OC(C)C2
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1c(C)c(N2CCN(c3ccc(C(N)=O)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 47.5 %

Procedure:
The mixture of 4-[4-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazin-1-yl]benzonitrile (70 mg, 0.194 mmol) synthesized in Reference example 29 and potassium hydroxide (33 mg, 0.582 mmol) was stirred in tert-butanol (2.0 mL) at 80° C. for 20 hours. After adding water, solids obtained were filtered and washed with ethanol to obtain the title compound 35 mg (yield 48%). Melting point was 240 to 245° C. (ethanol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.CC(C)([O-])C.[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Br)n1
Reactant: Cc1cccc(N)n1
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2cccc(C)n2)n1

Procedure:
To a flask were added 0.76 g 6-methyl-2-aminopyridine, 1.0 g 2-bromo-6-methylpyridine, 0.95 g sodium tert-butoxide, 0.16 g 1,1′-bis(diphenylphosphino)ferrocene and 50 ml toluene. The mixture was purged thoroughly with nitrogen and 0.14 g of tris(dibenzylideneacetone)d2-propanollladium (0) was added and the mixture was heated to 80 C under nitrogen for 3 hours. After cooling to 22 C and quenching with 50 ml water, the product was extracted twice with ethyl acetate and washed twice with water. After filtration and solvent removal, the product was dissolved in 50 ml tert-butyl methyl ether and extracted into 60 ml 1M hydrochloric acid. Methanol was added and the mixture was heated to dissolve the solids and the organic layer was removed. The aqueous layer was basified with 3M sodium hydroxide solution, the product was extracted with tert-butyl methyl ether and washed with water. Following removal of solvent, an oil was obtained that was carried directly into the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH3:29][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:29])=[O:25])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1

Procedure:
4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoic acid from Step A (32 mg, 0.077 mmol) was dissolved in MeOH (0.5 mL) and DCM (0.5 mL). Trimethylsilyl diazomethane (2.0 M in ether) was slowly added at 0° C. until a yellow color persisted. The volatiles were evaporated to give methyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoate which was used without further purification. LCMS: m/z 421.1 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH:22]1([Mg]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=3)=[CH:9][CH:10]=2)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CON(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cc(C(F)(F)F)on2)cc1)C1CCCCC1
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A solution of N-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-benzamide (Preparative Example 15, 300 mg, 1.0 mmol) in THF (10 mL) was treated with a 1 N THF solution of cyclohexylmagnesium bromide (4 mL, 4 mmol) and stirred for 2 hr then quenched with a saturated ammonium chloride solution (2 mL) and diluted with EtOAc (10 mL). The organic layer was then washed with brine (2×10 mL), dried over MgSO4, filtered, evaporated in vacuo and the residue chromatographed on silica gel with EtOAc/hexanes (5 then 10%) as eluant to afford product as a colorless solid (81 mg, 25%). 1H NMR (CDCl3) 1.26-1.58 (m, 5H), 1.74-1.94 (m, 5H), 3.23-3.32 (m, 1H), 7.09 (s, 1H), 7.79 (d, J=8.3, 2H), 7.87 (d, J=8.3, 2H). 19F NMR −64.6. LC/MS 7.79 min, [M+1]+ 324.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26]>CN(C)C=O>[CH3:26][O:25][CH2:24][CH2:23][N:12]1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Temperature: 50 °C
Yield: 78.3 %

Procedure:
To a mixture of 8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (1.000 g, 4.850 mmol) and cesium carbonate (3.160 g, 9.699 mmol) in N,N-dimethylformamide (20 mL) was added, 1-bromo-2-methoxyethane (0.9 mL, 9.7 mol). The reaction was heated to at 50° C. O/N. The reaction mixture was filtered and the filtrate evaporated to afford a residue that was extracted into DCM and washed with water, brine and dried by passing through a funnel filled with MgSO4. The filtrate was evaporated and the residue purified by chromatography (silica gel eluted with 3:1 EtOAc:hexane) to provide 1-(2-methoxy-ethyl)-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.004 g, 78%) as pale yellow crystals that had the following properties: 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 8.05 (d, J=8.3, 1H), 7.38 (d, J=8.3, 1H), 4.05 (br s, 2H), 3.62 (m, 2H), 3.32 (s, 3H). 2.86 (br s, 2H), 2.35 2.10 (m, 4H).
Reaction SMILES: [CH3:1][PH:2](=[O:6])[O:3][CH2:4][CH3:5].C[Si](N[Si](C)(C)C)(C)C.[F:16][C:17](=[CH:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[CH2:4]([O:3][P:2]([CH:23]([CH3:24])[CH:17]([F:16])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:1])=[O:6])[CH3:5]
Reactant: CCO[PH](C)=O
Reactant: CC=C(F)C(=O)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: CCOC(=O)C(F)C(C)P(C)(=O)OCC
Temperature: 25 °C
Reaction time: 96 h
Yield: 40.2 %

Procedure:
A mixture of ethyl (methyl)phosphinate (3.2 g, 30 mmol) and 1, 1,1,3,3,3-hexamethyldisilazane (4.8 g, 30 mmol) was heated to reflux for 2 h under an argon atmosphere. The mixture was cooled to room temperature and a diastereomeric mixture of ethyl 2-fluorobut-2-enoate (4.0 g, 30 mmol) was added. The reagents were heated to 70° C. for three days and then at room temperature for 4 days under an argon atmosphere. The mixture was diluted with methylene chloride (200 mL). The solution was washed with 1 N HCl (200 mL) and the aqueous solution extracted with methylene chloride (200 mL). The combined organic solutions were washed with saturated sodium chloride, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride/methanol (99:1-97:3). The appropriate fractions were combined and evaporated to give 2.9 g (40%) of ethyl 3-[ethoxy(methyl)phosphoryl]-2-fluorobutanoate as a clear oil. 1H NMR (400 MHz, CDCl3) δ4.8-5.6 (m, 1H), 4.2-4.4 (m, 2H), 4.0-4.2 (m, 2H), 2.4-2.6 (m, 1H), 1.1-1.5 (m, 12H).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[H-].[Na+].[H-].[CH2:21]([NH:25][C:26](=[O:29])[CH2:27]Cl)[CH2:22][CH2:23][CH3:24].[I-].[K+].[Cl-].[Na+]>C1COCC1>[CH2:21]([NH:25][C:26](=[O:29])[CH2:27][CH:1]([P:2]([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:9])[P:10]([O:11][CH2:12][CH3:13])([O:14][CH2:15][CH3:16])=[O:17])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCNC(=O)CCl
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCCNC(=O)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 69.8 %

Procedure:
Tetraethyl methylenebisphosphonate (1.44 g, 5.0 mmol) in THF (1 mL) was added to a slurry of 80% sodium hydride (150 mg, 5.0 mmol) in THF (4 mL) at 0° C. The reaction was warmed to room temperature and stirred until all of the hydride was consumed. A solution of N-butyl-2-chloroacetamide (0.75 g, 5.0 mmol) in THF (1 ml) and potassium iodide (100 mg) were then added. The reaction mixture was then heated at 50° C. for 18 hours, during which time sodium chloride precipitated. Additional sodium hydride (20 mg) was added, and the reaction mixture was heated an additional 4 hours. After cooling, the mixture was poured into 1N HCl (10 mL) and diethyl ether (50 mL) was added. The diethyl ether layer was further extracted with water (3×10 mL). The combined aqueous fractions were extracted with dichloromethane (4×25 mL). The combined extracts were dried (Na2SO4) and concentrated to give the title compound (1.40 g, 70%) as an oil.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-])=O)=[C:8]([Br:17])[N:7]=1>C1COCC1>[Br:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]2[C:9](=[C:8]([Br:17])[N:7]=1)[NH:14][CH:2]=[CH:1]2
Reactant: COc1cc([N+](=O)[O-])c(Br)nc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: COc1c(Br)nc(Br)c2[nH]ccc12
Temperature: -20 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
Vinylmagnesium bromide (0.85 M in THF, 97.7 mL, 83.0 mmol) was added over 30 min. to a stirring solution of 2,6-dibromo-3-methoxy-5-nitropyridine (7.4 g, 23.7 mmol) in THF (160 mL) at −75° C. The sol tion was stirred 1 h at −75° C., overnight at −20° C. recooled to −75° C. and quenched with saturated aqueous NH4Cl (˜100 mL). The reaction mixture was allowed to warm to rt, washed with brine (˜100 mL) and extracted with Et2O (150 mL) and CH2Cl2 (2×100 mL). The combined organi were dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 3:1 hexanes/EtOAc) to yield 5,7-dibromo-4-methoxy-6-azaindole 36 (1.10 g, 3.60 mmol, 15%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:17])[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[I:18]Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:17])[C:11]3[N:12]([C:14]([I:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2ccnc12
Reactant: ClI
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Yield: 79 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 1) (6.65 g, 27 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as an off-white solid (8.0 g, 79%). MS (ISP) 369.0 [(M+H)+], 371 [(M+2+H)+].
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]C)=[O:32])[C:29]2([CH3:36])[CH3:35])=[C:4]([F:39])[CH:3]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[F:39][C:4]1[CH:3]=[C:2]([C:44]2[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:15][C:10]=2[N:9]=[C:8]1[C@@H:28]1[C@H:30]([C:31]([OH:33])=[O:32])[C:29]1([CH3:36])[CH3:35]
Reactant: COC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2F)C1(C)C
Reactant: OB(O)c1ccc(F)cc1
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccc(F)cc3)cc2F)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic methyl cis-3-[1-(4-bromo-2-fluorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]-2,2-dimethylcyclopropanecarboxylate and (4-fluorophenyl)boronic acid in Step A. MS (ESI): mass calcd. for C36H29F2N3O3, 589.22; m/z found, 590.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=8.5 Hz, 1H), 8.12-8.09 (m, 1H), 7.84-7.81 (m, 1H), 7.76-7.72 (m, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.58-7.53 (m, 1H), 7.51-7.46 (m, 2H), 7.34-7.30 (m, 2H), 7.28 (d, J=8.9 Hz, 1H), 7.25-7.23 (m, 1H), 7.16-7.10 (m, 3H), 6.92-6.88 (m, 1H), 5.49-5.38 (m, 4H), 2.34 (d, J=8.2 Hz, 1H), 2.14 (d, J=8.2 Hz, 1H), 1.31 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)C[Mg]Br
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 49 %

Procedure:
To solution of 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (1.0 g, 4.1 mmol) in 10 mL of THF was added 2.0 M isobutylmagnesium bromide in ether. The reaction mixture was stirred 2 h and then quenched with MeOH. Poured into sat. KH2PO4 and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with 5% EtOAc/DCM. Obtained 650 mg (49% yield) of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol. MS found: (M+H)+=299.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH2:5]1>C(O)=O>[CH3:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6](=[O:1])[CH2:5]1
Reactant: CC1(C)CC=Cc2ccccc21
Reactant: OO
Solvent: O=CO
Product: CC1(C)CC(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred mixture of 30% hydrogen peroxide (5 ml) and 97% formic acid (20 ml) in a round bottom flask equipped with an additional funnel, thermometer, and an ice water bath was added 1,2-dihydro-1,1-dimethylnaphthalene (4.5 g, 28 mmoles) dropwise at 5° C. under a nitrogen atmosphere. When the addition was complete, the reaction vessel was raised above the cooling bath to allow the reaction temperature to rise to just between 35° C. at which point the flask was immersed again. In this manner the temperature of the reaction was maintained between 30 and 35° C. for 45 minutes. After this time the exothermic phase of the reaction ended and the mixture was allowed to cool to room temperature. A solution of 10% aqueous ferric sulfate was added in portions of a few milliliters each until cloudiness persisted in the stirred mixture and then all solvent was removed under reduced pressure. The viscous brown residue was refluxed with 20% H2SO4 (20 ml) for 4 hours and then cooled, extracted three times with ether (75 ml each), dried over magnesium sulfate, filtered and evaporated to leave a brown oil. This was purified using silica gel column chromatography eluting with ethyl acetate:hexane (7:93) to give 4,4-dimethyl-2-tetralone. (3.4 g, 74%). Overall yield=40%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[C:27](O)(=[O:29])[CH3:28]>C(Cl)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:27](=[O:29])[CH3:28])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:24])([F:26])[F:25])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Solvent: CC(=O)Cl
Product: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C)cc2)cc1

Procedure:
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (0.60 g, 1.57 mmol) was heated in 2 mL acetyl chloride and 2 mL acetic acid at reflux for 2 h. An additional 2 mL acetyl chloride was added and the mixture was heated to reflux for an additional 5 h. The mixture was cooled and concentrated. Recrystallization from ether/hexane furnished the product as a white solid: Anal. Calc'd for C19H16N3O3SF3: C, 53.90; H, 3.81; N, 9.92; S, 7.57. Found: C, 54.04; H, 3.80; N, 9.93; S, 7.66.