2-(4-iodophenyl)-2-methylpropanenitrile

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Part D. To a DMSO (4 mL, degassed) solution of ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.6 g, 1.9 mmol), and 2-(4-iodophenyl) 2-methylproprionitrile (0.6 g, 2.2 mmol), and K2CO3 (0.66 g, 4.8 mmol) and was added CuI (73 mg, 0.3 mmol). The reaction was heated to 130° C. for 18 h. The reaction was cooled, extracted with EtOAc, washed with H2O, and dried (MgSO4). Purification by chromatography on silica gel (1:1 hexanes/ethyl acetate) afforded the title compound 0.4 g (45.9%) of a pale yellow solid; Mass Spec (M+H)+ 459.3. The reaction was cooled extracted with EtOAc washed with H2O dried (MgSO4) Purification by chromatography on silica gel (1:1 hexanes/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-(4-iodophenyl)-2-methylpropanenitrile. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofurane is used instead of isopropylmagnesium chloride. Obtained

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2 L flat bottomed flask fitted with an argon inlet and condenser was charged with (4-(bis(4-chlorophenyl)amino)phenyl)boronic acid (39.3 g), 2-(4-iodophenyl)-2-methylpropanenitrile, compound from Example 5 (c) (27.1 g) and tetrahydrofuran (591 mL). Sodium carbonate (33.9 g) was dissolved in water (393 mL) and this was added to the tetrahydrofuran mixture. The reaction mixture was then heated to 75° C. for 16 hours. Ethyl acetate (200 mL) and water (200 mL) were added and the mixture filtered through a celite pad. The layers were split, the organic layers washed with brine (600 mL), dried over MgSO4 and concentrated. The resulting material was purified by flash column chromatography eluting with ethyl acetate/heptane mixtures. The fractions were concentrated to a thick slurry and the solid filtered off, washed with heptane and dried under vacuum to give an off-white solid. Yield: 27 g. 1H NMR (400 MHz, CDCl3): δ 7.56-7.42 (6H, m, Ar—H), 7.21 (4H, m, Ar—H), 7.15-7.02 (6H, m, Ar—H), 1.77 (6H, s, CH3). A 2 L flat bottomed flask fitted with an argon inlet and condenser the mixture filtered through a celite pad The layers were split the organic layers washed with brine (600 mL) dried over MgSO4 concentrated The resulting material was purified by flash column chromatography eluting with ethyl acetate/heptane mixtures The fractions were concentrated to a thick slurry the solid filtered off washed with heptane dried under vacuum to give an off-white solid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NMP (197 mL, Sigma-Aldrich) was added to a suspension of sodium tert-butoxide (124.0 g, Alfa-Aesar) in THF (197 mL, Univar) under argon. The mixture was cooled to 0° C. and a solution of iodomethane (87.9 mL, Sigma-Aldrich) and 4-iodophenylacetonitrile (78.4 g) in a 50:50 mixture of NMP/THF (173 mL) was added dropwise keeping the internal temperature below 10° C. The mixture was warmed to room temperature and stirred overnight. 2M HCl (930 mL) and toluene (930 mL) were added then the aqueous layer was separated and extracted with toluene (2×465 mL). The combined organics were washed with saturated sodium bicarbonate (930 mL), brine (930 mL), 2M sodium thiosulfate (930 mL), dried (magnesium sulphate) and concentrated in vacuo to a yellow/orange solid. Purification by column chromatography eluting with EtOAc/heptane mixtures gave the title compound as a pale yellow oil. Yield 4.55 g, 1H NMR (400 MHz, CDCl3): δ 7.71 (2H, d, Ar—H), 7.23 (2H, d, Ar—H), 1.70 (6H, s, CH3). was added dropwise the internal temperature below 10° C The mixture was warmed to room temperature the aqueous layer was separated extracted with toluene (2×465 mL) The combined organics were washed with saturated sodium bicarbonate (930 mL), brine (930 mL), 2M sodium thiosulfate (930 mL) dried (magnesium sulphate) concentrated in vacuo to a yellow/orange solid Purification by column chromatography eluting with EtOAc/heptane mixtures

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NMP (197 mL, Sigma-Aldrich) was added to a suspension of sodium tert-butoxide (124.0 g, Alfa-Aesar) in THF (197 mL, Univar) under argon. The mixture was cooled to 0° C. and a solution of iodomethane (87.9 mL, Sigma-Aldrich) and 4-iodophenylacetonitrile (78.4 g) in a 50:50 mixture of NMP/THF (173 mL) was added dropwise keeping the internal temperature below 10° C. The mixture was warmed to room temperature and stirred overnight. 2M HCl (930 mL) and toluene (930 mL) were added then the aqueous layer was separated and extracted with toluene (2×465 mL). The combined organics were washed with saturated sodium bicarbonate (930 mL), brine (930 mL), 2M sodium thiosulfate (930 mL), dried (magnesium sulphate) and concentrated in vacuo to a yellow/orange solid. Purification by column chromatography eluting with EtOAc/heptane mixtures gave the title compound as a pale yellow oil. Yield 4.55 g, 1H NMR (400 MHz, CDCl3): δ 7.71 (2H, d, Ar—H), 7.23 (2H, d, Ar—H), 1.70 (6H, s, CH3). was added dropwise the internal temperature below 10° C The mixture was warmed to room temperature the aqueous layer was separated extracted with toluene (2×465 mL) The combined organics were washed with saturated sodium bicarbonate (930 mL), brine (930 mL), 2M sodium thiosulfate (930 mL) dried (magnesium sulphate) concentrated in vacuo to a yellow/orange solid Purification by column chromatography eluting with EtOAc/heptane mixtures

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Part D. To a DMSO (4 mL, degassed) solution of ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.6 g, 1.9 mmol), and 2-(4-iodophenyl) 2-methylproprionitrile (0.6 g, 2.2 mmol), and K2CO3 (0.66 g, 4.8 mmol) and was added CuI (73 mg, 0.3 mmol). The reaction was heated to 130° C. for 18 h. The reaction was cooled, extracted with EtOAc, washed with H2O, and dried (MgSO4). Purification by chromatography on silica gel (1:1 hexanes/ethyl acetate) afforded the title compound 0.4 g (45.9%) of a pale yellow solid; Mass Spec (M+H)+ 459.3. The reaction was cooled extracted with EtOAc washed with H2O dried (MgSO4) Purification by chromatography on silica gel (1:1 hexanes/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-(4-iodophenyl)-2-methylpropanenitrile. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofurane is used instead of isopropylmagnesium chloride. Obtained