2-[(E)-3-methoxyprop-1-enyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

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

Procedure: A solution of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate (Synthesis 170-B) (0.100 g, 0.22 mmol), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.044 g, 0.22 mmol), sodium carbonate (0.5 M, 0.66 mL) and tetrakis(triphenylphosphine) palladium(0) (0.013 g, 0.01 mmol) in acetonitrile (2.00 mL) was heated under microwave irradiation for 20 min at 100° C. The solvent was removed in vacuo and the crude product was purified by silica column chromatography, eluting with ethyl acetate and hexane (1/1). to give the title compound as a colourless oil (0.057 g, 65%). The solvent was removed in vacuo the crude product was purified by silica column chromatography eluting with ethyl acetate and hexane (1/1)

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

Procedure: A solution of 3,5-dichloropicolinonitrile (1.0 eq.), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 100° C. for 2 hours, then 80° C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-3-chloro-5-(3-methoxyprop-1-enyl)picolinonitrile as a white solid. The two phases were separated the aqueous layer was extracted twice with ethyl acetate The combined organic layers were washed with brine dried over anhydrous MgSO4 concentrated en vacuo The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO)

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

Procedure: To a solution of methyl 3,5-dibromo-4-methylbenzoate (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.1 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.02 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 100° C. for 2 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil. The vessel was repeatedly evacuated back-filled with nitrogen The now black suspension was cooled to RT extracted with ether The combined organic extracts were washed further with water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→→1:1 (v/v) Hex:EtOAc)

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

Procedure: To a solution of 6-bromoindan-1-one (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.3 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a beige solid. The vessel was repeatedly evacuated back-filled with nitrogen The now black suspension was cooled to RT extracted with ethyl acetate The combined organic extracts were washed with water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc)

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

Procedure: To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) in DMF (0.2 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 2 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil. The vessel was repeatedly evacuated back-filled with nitrogen The now black suspension was cooled to RT extracted with ethyl acetate The combined organic extracts were washed with water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc)

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

Procedure: To a solution of tert-butyl (3-bromo-5-formylbenzyl)cyclopropylcarbamate (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1 eq.) in DMF (0.2 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 90° C. for 6 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were washed further with 10% aq. HCl, 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil. The vessel was repeatedly evacuated back-filled with nitrogen The now black suspension was cooled to RT extracted with ether The combined organic extracts were washed further with 10% aq. HCl, 1 N aq. NaOH, water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc)

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

Procedure: To a solution of 3,5-dibromo-N-cyclopropyl-4-methylbenzamide (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.1 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow-orange oil. The vessel was repeatedly evacuated back-filled with nitrogen The now black suspension was cooled to RT extracted with ethyl acetate The combined organic extracts were washed further with water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc)

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

Procedure: 5-Bromo-N-cyclopropyl-2,3-dimethylbenzamide (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) were combined in a 5:1 (v/v) mixture of DMF:n-PrOH (0.1 M). To this solution was then added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.) and the vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting biphasic suspension was heated at 100° C. for 18 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a white solid. back-filled with nitrogen The now black suspension was cooled to RT extracted with ether The combined organic extracts were then washed with water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc)

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

Procedure: To a 4:1 (v/v) DMF:n-propanol solution (0.15 M) of N-[(3-bromo-5-chlorophenyl)methyl]cyclopropanamine (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (2 eq.) was added trans-dibromobis(triphenylphosphine) palladium(II) (0.05 eq.) followed by sodium carbonate (2 M aqueous solution, 3 eq.). The reaction vessel was evacuated and purged with nitrogen five times and then heated at 100° C. for 2 h. The cooled reaction mixture was poured into aq. sat. NH4Cl and then extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:7 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as an oil. The reaction vessel was evacuated purged with nitrogen five times The cooled reaction mixture extracted with EtOAc The combined organic extracts were washed further with water and brine dried over MgSO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:7 (v/v) Hex:EtOAc→EtOAc)

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

Procedure: Methyl 3-bromo-1-naphthalenecarboxylate (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) were combined in a 5:1 (v/v) mixture of DMF:n-PrOH (0.2 M). To this solution was then added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.) and the vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 N aq. Na2CO3 (2 eq.) was added and the resulting biphasic suspension was heated at 90° C. for 8 h. The now black suspension was cooled to RT, diluted with water and extracted with 1:1 (v/v) hexanes:ether. The combined organic extracts were then washed further with 1 N aq. NaOH, 1 N aq. HCl, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a red oil. back-filled with nitrogen The now black suspension was cooled to RT extracted with 1:1 (v/v) hexanes The combined organic extracts were then washed further with 1 N aq. NaOH, 1 N aq. HCl, water and brine This was then dried over Na2SO4 filtered the filtrate concentrated in vacuo

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

Procedure: 1,1-Dimethylethyl[(5-chloro-2-methylphenyl)methyl]cyclopropylcarbamate (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1 eq.) were combined in n-BuOH (0.48 M). To this solution was then added tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.02 eq.), [2′,6′-bis(methyloxy)-2-biphenylyl](dicyclohexyl)phosphane (0.08 eq.) and powdered potassium phosphate (2 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen before the resulting suspension was heated at 100° C. for 16 h. The now black suspension was cooled to RT, diluted with EtOAc and filtered through a pad of SiO2. The filtrate was then concentrated in vacuo and the crude product thus obtained was directly subjected to purification by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc). The title compound was isolated as a pale yellow oil. The vessel was repeatedly evacuated back-filled with nitrogen before the resulting suspension The now black suspension was cooled to RT diluted with EtOAc filtered through a pad of SiO2 The filtrate was then concentrated in vacuo the crude product thus obtained was directly subjected to purification by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-((3-Bromo-5-chlorobenzylamino)(amino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-4-carboxamide TFA salt (˜10-15 mg) (Prepared by analogy to Example 1), (E)-2-(3-methoxypropenyl)-4,4,5,5,-tetramethyl-(1,3,2)-dioxaborolane (20 mg), tetrakis-(triphenylphosphine)-palladium (5 mg) and aqueous tripotassium phosphate (2M, 100 μl) in DMF (1 mL) was heated at 85° C. under nitrogen overnight. Product was obtained by HPLC purification. 1H NMR (CD3OD): δ 2.69 (s, 3H), 3.40 (s, 3H), 3.86(s, 3H), 4.11, 4.13(d, 2H), 4.58(s, 2H), 6.44(m, 1H), 6.64, 6.67(d, 1H), 7.05, 7.07(d, 2H), 7.29 (s, 1H), 7.37(s,1H), 7.46 (s, 1H), 7.62, 7.64(d, 2H). MH+=469.23 Product was obtained by HPLC purification