(2-BOC-AMINOPHENYL)BORONIC ACID, PINACOL ESTER

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 2-(Mesitylethynyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 3-chloro-5-(mesitylethynyl)picolinonitrile (Example 77/Step 1) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (commercially available) following the procedures described for Example 45/Step 1.

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

Procedure: To a round bottom flask with refluxing condenser were added 5-((1H-indol-5-yl)ethynyl)-3-chloropicolinonitrile (from the previous step) (1 eq.), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.25 eq.), K3PO4 (2 eq.), tris(dibenzylideneacetone)dipalladium(0) (0.05 eq.), and 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.1 eq.). n-Butanol and water (5:2, 0.2 M) were added, and the content were degassed (vacuum followed by nitrogen flush) for three times. The reaction mixture was stirred vigorously under nitrogen at 100° C. overnight in an oil bath. The content were cooled down and were taken up in 200 mL of water followed by extraction with methylene chloride. Combined organic layers were dried (Na2SO4) and concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product 2-((1H-indol-5-yl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. To a round bottom flask with refluxing condenser the content were degassed (vacuum followed by nitrogen flush) for three times The content were cooled down followed by extraction with methylene chloride Combined organic layers were dried (Na2SO4) concentrated

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

Procedure: A solution (0.15 M) of methyl 5-bromo-4-(2-tert-butoxy-2-oxoethyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (from Step 2) in dioxane was treated with tert-butyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.5 eq.) and 2 N Na2CO3 solution (6 eq.) and degassed. PdCl2(PPh3)2 (0.2 eq.) was added and the suspension refluxed for 30 mins. After cooling, EtOAc was added and the solution was washed with water, brine, dried over sodium sulfate and evaporated in vacuo to give a residue which was purified by flash chromatography (PE:EtOAc, 95:5) to afford the title compound (89%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 8.00 (s, 1H), 7.73 (m, 2H), 7.47-7.43 (t, J 8.6, 1H), 7.27-7.23 (m, 2H), 4.73-4.49 (dd, J 20, 2H), 3.82 (s, 3H), 2.17-2.11 (m, 1H), 1.82-1.21 (m, 10H), 1.37 (s, 9H), 1.28 (s, 9H). MS (ES+) m/z: 569 [M+H]+. degassed the suspension refluxed for 30 mins After cooling the solution was washed with water, brine dried over sodium sulfate evaporated in vacuo to give a residue which was purified by flash chromatography (PE:EtOAc, 95:5)

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

Procedure: Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester gives “A81”; method 1: HPLC/MS: 1.38 min, [M+H]=406; gives “A81” 1.38 min, [M+H]=406

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

Procedure: A slurry of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (1.75 g, 5.22 mmol), LiCl (880 mg, 21.0 mmol), 1M aqueous Na2CO3 (13 mL, 13.0 mmol), Pd(PPh3)4 (600 mg, 0.52 mmol) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (2.5 g, 7.8 mmol) in toluene (19 mL) and EtOH (19 mL) was heated at relfux for 2 h. The reaction mixture was cooled and concentrated to dryness under vacuum. The residue was treated with H2O (120 mL) and extracted with EtOAc(2×200 mL). The combined organics were washed with brine (2×20 mL), dried (MgSO4), filtered, concentrated and purified by SiO2 chromatography (5–25% EtOAc/hexanes) to yield methyl 2-(2-(tert-butoxycarbonyl)phenyl)-3-cyclohexyl-1H-indole-6-carboxylate (1.8 g, 4.0 mmol, 77%) as a yellow-pink solid. 1HNMR (500 MHz, CDCl3) δ. 8.26 (d, J=8.5 Hz, 1H), 8.14 (s, 1H), 8.11 (s, 1 H), 7.86 (d, J=8.2 Hz, 1H), 7.82 (dd, J=8.2, 1.5 Hz, 1H), 7.43 (ddd, J=8.5, 7.3, 1.5 Hz, 1H), 7.28 (d, J=7.6, 1.5 Hz, 1H), 7.11 (ddd, J=7.6, 7.3, 1.2 Hz, 1H), 6.67 (br s, 1H), 3.94 (s, 3H), 2.56 (tt, J=12.1, 3.5 Hz, 1H), 1.97–1.22 (m, 10H), 1.45 (s, 9H). LCMS: m/e 449 (M+H)+, ret time 2.39 min, column C, 2 minute gradient, start at 0% B. The reaction mixture was cooled concentrated to dryness under vacuum The residue was treated with H2O (120 mL) extracted with EtOAc(2×200 mL) The combined organics were washed with brine (2×20 mL) dried (MgSO4) filtered concentrated purified by SiO2 chromatography (5–25% EtOAc/hexanes)

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

Procedure: Water (3.0 mL), sodium carbonate (1.1 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.5 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (30 mg) were added to an ethylene glycol dimethyl ether (10 mL) solution of methyl 4-chloro-2-nitrobenzoate (0.90 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 1.5 g of methyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a light yellow solid. by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes The organic layer was separated washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate]

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

Procedure: Water (0.6 mL), sodium carbonate (0.16 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenylcarbamate (0.19 g), and tetrakis(triphenylphosphine)palladium(0) (29 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 4-bromo-2-nitrobenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 91-80% hexane/ethyl acetate] to obtain 0.21 g of tert-butyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a yellow solid. by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes The organic layer was separated washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography [eluent: 91-80% hexane/ethyl acetate]

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

Procedure: Water (3.0 mL), sodium carbonate (1.1 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.5 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (30 mg) were added to an ethylene glycol dimethyl ether (10 mL) solution of methyl 4-chloro-2-nitrobenzoate (0.90 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 1.5 g of methyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a light yellow solid. by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes The organic layer was separated washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate]