4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 42-(2-Iodo-3-trifluoromethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (A8) (500 mg, 1.10 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (400 mg, 2.20 mmol) in dioxane (20 mL) is added dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II) DCM adduct (71.8 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (1.65 mL, 3.30 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously overnight. Reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (396) as light brown oil (100 mg, 21%). The resulting reaction mixture Reaction mixture is filtered concentrated in vacuo the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 42-(2-Iodo-3-trifluoromethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (A8) (500 mg, 1.10 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (400 mg, 2.20 mmol) in dioxane (20 mL) is added dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II) DCM adduct (71.8 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (1.65 mL, 3.30 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously overnight. Reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (396) as light brown oil (100 mg, 21%). The resulting reaction mixture Reaction mixture is filtered concentrated in vacuo the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4,7-difluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (390) (451 mg, 1 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (364 mg, 2 mmol) in dioxane (20 mL) was added dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloromethane adduct (65 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (1.5 mL, 3 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously for 4 h. The reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (391) as light brown oil (150 mg, 36%). The resulting reaction mixture The reaction mixture is filtered concentrated in vacuo the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-(4,5-difluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (386) (2.55 g, 5.25 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (364 mg, 10.5 mmol) in dioxane (100 mL) is added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (350 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (7.87 mL, 15.75 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously for 6 h. Reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (387) as light brown solid (1.24 g, 57%). The resulting reaction mixture Reaction mixture is filtered concentrated in vacuo the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-(4,5-difluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (386) (2.55 g, 5.25 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (364 mg, 10.5 mmol) in dioxane (100 mL) is added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (350 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (7.87 mL, 15.75 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously for 6 h. Reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (387) as light brown solid (1.24 g, 57%). The resulting reaction mixture Reaction mixture is filtered concentrated in vacuo the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of the 2-iodo-3-methylbenzoic acid ethyl ester (289) (2.9 g-0.01 mol) and 2-methyl-1-propenylboronic acid pinacol ester (3.64 g-0.02 mol-2 eq) in dry DMF (50 mL) and saturated NaHCO3 (10 mL) is degassed for 10 minutes and then treated with tetrakis(triphenylphosphine)palladium(0) (400 mg). The mixture is stirred at 110° C. overnight. The reaction is cooled and the DMF removed in vacuo and the residue diluted with water (120 mL). The aqueous is filtered through hyflo and extracted with EtOAc (3×75 mL). The organic extracts are washed with water (2×50 mL) and brine (2×50 mL), and dried over MgSO4. The organic extracts are concentrated in vacuo and purified by flash chromatography (400 g silica gel, 5% EtOAc in heptane) to give the product as pale yellow oil (1.85 g, 85%). is degassed for 10 minutes treated with tetrakis(triphenylphosphine)palladium(0) (400 mg) The reaction is cooled the DMF removed in vacuo the residue diluted with water (120 mL) The aqueous is filtered through hyflo extracted with EtOAc (3×75 mL) The organic extracts are washed with water (2×50 mL) and brine (2×50 mL) dried over MgSO4 The organic extracts are concentrated in vacuo purified by flash chromatography (400 g silica gel, 5% EtOAc in heptane)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2-bromo-4-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (880 mg, 2.2 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-propenyl)-[1,3,2]dioxaborolane (903 μL, 4.4 mmol) and saturated NaHCO3 solution (4.4 mL) in anhydrous DMF (20 mL) is degassed with N2. While under N2 atmosphere, tetrakis(triphenylphosphine)palladium (196 mg, 10 mol %) is added and the reaction is heated in a 110° C. oil bath for 2 h. The reaction is cooled to room temperature, poured into water (40 mL) and extracted with EtOAc (2×30 mL). The combined organic layers are washed with water (15 mL) and brine (20 mL) then concentrated in vacuo. The residue is purified by flash column chromatography (24 g silica gel, gradient elution: 0-50% EtOAc in heptane) to give product (278) as a reddish-brown viscous oil (764 mg, 92%). is degassed with N2 While under N2 atmosphere, tetrakis(triphenylphosphine)palladium (196 mg, 10 mol %) is added The reaction is cooled to room temperature poured into water (40 mL) extracted with EtOAc (2×30 mL) The combined organic layers are washed with water (15 mL) and brine (20 mL) then concentrated in vacuo The residue is purified by flash column chromatography (24 g silica gel, gradient elution: 0-50% EtOAc in heptane)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-iodo-4-nitrobenzene (2.49 g, 10.0 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (1.82 g, 10.0 mmol), sodium bicarbonate (2.52 g, 30.0 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (816 mg, 1.0 mmol) in dioxane/water (5:1, 60 mL) was stirred at 90° C. for 20 h under N2. LCMS and TLC monitored the reaction was completed. The reaction mixture was cooled to RT and concentrated. The residue was dissolved in 100 mL of EtOAc, washed with water (150 mL×3) and brine, dried over Na2SO4, filtered and concentrated under vacuo. The crude product was purified by silica gel column, eluting with PE:EA (6:1), to obtain the desired product (1.9 g, 100% yield) as a yellow oil, 1H-NMR (400 MHz, CDCl3) δ ppm 8.17 (d, 2H, J=8.8 Hz), 7.35 (d, 2H, J=8.8 Hz), 6.36 (s, 1H), 1.96 (d, 3H, J=0.4 Hz), 1.90 (d, 3H, J=0.4 Hz). The reaction mixture was cooled to RT concentrated The residue was dissolved in 100 mL of EtOAc washed with water (150 mL×3) and brine dried over Na2SO4 filtered concentrated under vacuo The crude product was purified by silica gel column eluting with PE

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-iodo-4-nitrobenzene (2.49 g, 10.0 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (1.82 g, 10.0 mmol), sodium bicarbonate (2.52 g, 30.0 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (816 mg, 1.0 mmol) in dioxane/water (5:1, 60 mL) was stirred at 90° C. for 20 h under N2. LCMS and TLC monitored the reaction was completed. The reaction mixture was cooled to RT and concentrated. The residue was dissolved in 100 mL of EtOAc, washed with water (150 mL×3) and brine, dried over Na2SO4, filtered and concentrated under vacuo. The crude product was purified by silica gel column, eluting with PE:EA (6:1), to obtain the desired product (1.9 g, 100% yield) as a yellow oil, 1H-NMR (400 MHz, CDCl3) δ ppm 8.17 (d, 2H, J=8.8 Hz), 7.35 (d, 2H, J=8.8 Hz), 6.36 (s, 1H), 1.96 (d, 3H, J=0.4 Hz), 1.90 (d, 3H, J=0.4 Hz). The reaction mixture was cooled to RT concentrated The residue was dissolved in 100 mL of EtOAc washed with water (150 mL×3) and brine dried over Na2SO4 filtered concentrated under vacuo The crude product was purified by silica gel column eluting with PE

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

Procedure: 2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(2-methylprop-1-enyl)naphthalen-2-yl)acetic acid (77) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane and K2CO3 instead of triethylamine, and toluene, ethanol, water as a solvent mixture. 1H-NMR: 400 MHz, (CD3OD) δ: 7.69 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.54 (m, 3H), 7.27 (m, 2H), 7.02 (s, 1H), 6.23 (s, 1H), 5.18 (s, 1H), 2.57 (s, 3H), 1.83 (s, 3H), 1.68 (s, 3H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.98.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (121.6 mg, 0.4177 mmol, 2-methyl-1-propenylboronic acid pinacol ester (129 uL, 0.629 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (15.9 mg, 0.0224 mmol), and potassium carbonate (150.5 mg, 1.089 mmol) was added 1,4-dioxane (2 mL, 20 mmol) and water (0.2 mL, 10 mmol). The reaction mixture was stirred at 90° C. for 3 hours. The reaction mixture was then poured into ethyl acetate, which was washed with two portions water, dried with brine and MgSO4, filtered, and evaporated in vacuo to yield 144.5 mg of crude product. 44 mg of this crude material was purified via reverse phase HPLC and lyophilized to yield 28.2 mg N-(7-(2-methylprop-1-enyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.919, M+H=267.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.10 (s, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.57 (dd, J=8.6, 1.4 Hz, 1H), 6.41 (s, 1H), 2.12-1.99 (m, 1H), 1.93 (d, J=7.7 Hz, 6H), 0.83 (m, 4H). was washed with two portions water dried with brine and MgSO4 filtered evaporated in vacuo to yield 144.5 mg of crude product 44 mg of this crude material was purified via reverse phase HPLC

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (121.6 mg, 0.4177 mmol, 2-methyl-1-propenylboronic acid pinacol ester (129 uL, 0.629 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (15.9 mg, 0.0224 mmol), and potassium carbonate (150.5 mg, 1.089 mmol) was added 1,4-dioxane (2 mL, 20 mmol) and water (0.2 mL, 10 mmol). The reaction mixture was stirred at 90° C. for 3 hours. The reaction mixture was then poured into ethyl acetate, which was washed with two portions water, dried with brine and MgSO4, filtered, and evaporated in vacuo to yield 144.5 mg of crude product. 44 mg of this crude material was purified via reverse phase HPLC and lyophilized to yield 28.2 mg N-(7-(2-methylprop-1-enyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.919, M+H=267.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.10 (s, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.57 (dd, J=8.6, 1.4 Hz, 1H), 6.41 (s, 1H), 2.12-1.99 (m, 1H), 1.93 (d, J=7.7 Hz, 6H), 0.83 (m, 4H). was washed with two portions water dried with brine and MgSO4 filtered evaporated in vacuo to yield 144.5 mg of crude product 44 mg of this crude material was purified via reverse phase HPLC