Tri-tert-butylphosphoniumtetrafluoroborate

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

Procedure: 1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(pyridin-2-ylmethyl)methanesulfonamide (31.0 g, 72.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (22.72 g, 109 mmol), potassium fluoride (13.96 g, 240 mmol), tri-t-butylphosphonium tetrafluoroborate (2.112 g, 7.28 mmol), and Pd2(dba)3 (3.33 g, 3.64 mmol) were placed in a flask under an atmosphere of argon. DMF (364 ml) was added and argon was bubbled through the solution for several minutes. The solution was then heated at 130° C. for 6 h. The mixture was then cooled to room temperature, aqueous sodium hydrogen carbonate (saturated, 2000 mL) was added and the mixture was extracted with ethyl acetate (10×500 mL). The combined organic fractions were dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA to afford the title compound as a pale yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 9.21 (d, 1H); 8.53 (d, 1H); 8.47 (m, 1H); 8.46 (m, 1H); 8.15 (d, 1H); 8.14 (s, 1H); 7.78 (m, 4H); 7.39 (m, 2H); 7.32 (d, 1H); 7.24 (m, 1H); 4.63 (s, 2H); 4.22 (d, 1H); 3.88 (s, 3H). LRMS (APCI) calculated for C25H21N5O3S [M+H]+, 472.1; found 472.1. argon was bubbled through the solution for several minutes The mixture was then cooled to room temperature aqueous sodium hydrogen carbonate (saturated, 2000 mL) was added the mixture was extracted with ethyl acetate (10×500 mL) The combined organic fractions were dried (anhydrous Na2SO4) filtered concentrated under reduced pressure The residue was purified by preparative HPLC Reverse phase (C-18) eluting with Acetonitrile/Water+0.05% TFA

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

Procedure: 1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-phenylmethanesulfonamide (4.4 g, 10.36 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (2.59 g, 12.43 mmol), potassium fluoride (1.985 g, 34.2 mmol), tri-t-butylphosphonium tetrafluoroborate (0.270 g, 0.932 mmol), and Pd2(dba)3 (0.379 g, 0.414 mmol) were combined as solids and placed under a nitrogen atmosphere. DMF (104 ml) was added, the mixture was degassed, and then the reaction was heated to 130° C. with stirring for 2 h. After cooling to room temperature, the mixture was poured into aqueous sodium hydrogen carbonate (saturated, 250 mL) and extracted with dichloromethane (4×250 mL). The organic extracts were combined, dried over Na2 SO4, and concentrated under reduced pressure. The residue was then dissolved in hot dioxane (500 mL). Hexanes were added until a precipitate formed. After standing at room temperature overnight, the precipitate was collected to afford the title compound as a gray solid. 1H NMR (600 MHz, DMSO-D6) δ 9.22 (d, 1H); 8.53 (d, 1H); 8.47 (s, 1H); 8.15 (s, 1H); 8.14 (d, 1H); 7.78 (m, 2H); 7.39 (d, 1H); 7.32 (m, 5H); 7.20 (m, 1H); 4.75 (s, 2H); 3.88 (s, 3H); 3.23 (s, 3H). LRMS (APCI) calculated for C21H21N4O3S [M+H]+, 409.1; found 409.1. the mixture was degassed After cooling to room temperature the mixture was poured into aqueous sodium hydrogen carbonate (saturated, 250 mL) extracted with dichloromethane (4×250 mL) dried over Na2 SO4 concentrated under reduced pressure The residue was then dissolved in hot dioxane (500 mL) Hexanes were added until a precipitate formed After standing at room temperature overnight the precipitate was collected

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

Procedure: Sodium tert-butoxide (47.4 g, 493 mmol) was added in one portion to a 1 L flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (40.0 g, 164 mmol) and dissolved in dioxane (658 ml) at 0° C. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (52.7 g, 164 mmol) was added followed by palladium(II) acetate (1.846 g, 8.22 mmol) and tri-t-butylphosphonium tetrafluoroborate (7.16 g, 24.66 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction flask was cooled to 50° C., 1M NaOH (500 mL) was added and the solution was stirred for 1 h. Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) and extracted with dichloromethane (3×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/Hexanes gradient) to afford the title compound as a pale yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.47 (m, 1H); 8.17 (s, 1H); 7.81 (s, 2H); 7.47 (d, 1H); 7.32 (m, 5H); 7.21 (m, 1H); 4.75 (s, 2H); 3.24 (s, 3H). LRMS (APCI) calculated for C22H18ClN2O3S [M+H]+, 425.1; found 425.0. The resulting suspension was degassed by sparging with nitrogen for 30 min left Then, the reaction flask was cooled to 50° C. 1M NaOH (500 mL) was added the solution was stirred for 1 h Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) extracted with dichloromethane (3×500 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography (EtOAc/Hexanes gradient)

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

Procedure: Sodium tert-butoxide (8.99 g, 94 mmol) was added in one portion to a 250 mL flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (7.59 g, 31.2 mmol) and dioxane (125 ml) at room temperature. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10.00 g, 31.2 mmol) was added followed by palladium(II) acetate (0.350 g, 1.560 mmol) and tri-t-butylphosphonium tetrafluoroborate (1.358 g, 4.68 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction mixture was cooled to room temperature, acidified with 1N HCl (100 mL), basified with saturated aqueous sodium hydrogen carbonate (400 mL) and extracted with dichloromethane (3×250 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow foam. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.46 (d, 1H); 8.42 (d, 1H); 8.03 (dd, 1H); 7.81 (d, 1H); 7.44 (d, 1H); 7.33 (d, 1H); 7.22 (m, 2H); 7.17 (m, 2H); 7.11 (m, 1H); 6.10 (s, 1H); 3.71 (s, 3H); 3.20 (s, 3H). LRMS (APCI) calculated for C24H20ClN2O5S [M+H]+, 483.1; found 483.0. The resulting suspension was degassed by sparging with nitrogen for 30 min left Then, the reaction mixture was cooled to room temperature extracted with dichloromethane (3×250 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient)

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

Procedure: 1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylmethanesulfonamide (1.44 g, 3.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (1.239 g, 5.95 mmol), tri-t-butylphosphonium tetrafluoroborate (0.104 g, 0.357 mmol), Pd2(dba)3 (0.145 g, 0.159 mmol), and potassium fluoride (0.761 g, 13.10 mmol) were combined as solids and then placed under a nitrogen atmosphere. DMF (39.7 ml) was added and the resulting suspension was heated to 130° C. and left to stir for 1 h. Then, the reaction was cooled to room temperature and partitioned between saturated aqueous sodium hydrogen carbonate (250 mL) and dichloromethane (250 mL). The organic layer was dried over anhydrous Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc+10% MeOH/Hexanes gradient) to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 9.21 (d, 1H); 8.54 (d, 1H); 8.47 (s, 1H); 8.19 (s, 1H); 8.14 (s, 1H); 7.81 (m, 2H); 7.40 (d, 1H); 7.32 (d, 1H); 4.63 (s, 2H); 3.88 (s, 3H); 2.74 (s, 6H). LRMS (APCI) calculated for C21H21N4O3S [M+H]+, 409.1; found 409.1. left Then, the reaction was cooled to room temperature partitioned between saturated aqueous sodium hydrogen carbonate (250 mL) and dichloromethane (250 mL) The organic layer was dried over anhydrous Na2 SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography on silica (EtOAc+10% MeOH/Hexanes gradient)

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

Procedure: To a degassed solution of (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (example 1k) (0.60 g, 1 mmol) in anhydrous dioxane (4 mL) was added under argon Cs2CO3 (0.665 g, 2.0 mmol), 2,4,6-trivinyl-cyclotriboroxane pyridine complex (0.365 g, 1.5 mmol) and tri-tert-butyl-phosphonium tetrafluoroborate (0.044 g, 0.15 mmol) in dioxane was added under argon the Pd2(dba)3 (0.028 g, 0.03 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after flash-chromatography on silica gel (hexane-EtOAc 3:1 to 2:1) and crystallization from CH2Cl2-hexane as white crystals: HPLC RtA=2.22 min; ESIMS [M+NH4]+=504. the reaction mixture was heated at reflux for 2 h the organic layer was washed with water and brine dried over MgSO4 filtered evaporated

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

Procedure: To a −78° C. solution of tert-butyl piperidine-1-carboxylate (1.0 mL, 5.20 mmol), dry ether (20 mL) and TMEDA (0.82 mL, 5.47 mmol) was added sec-butyllithium, 1.4M in cyclohexane (3.90 mL, 5.46 mmol) dropwise over 5 minutes. After 2 hours, a solution of zinc chloride, 0.5M in ether (6.8 mL, 6.80 mmol) was added over 7 minutes. After 30 minutes, the mixture was warmed to ambient temperature and stirred for a further 30 minutes then 2-fluoro-3-iodopyridine (1511 mg, 6.78 mmol), palladium(ii) acetate (127 mg, 0.566 mmol), tri-t-butylphosphonium tetrafluoroborate (268 mg, 0.924 mmol) was added in one portion. After 18 hours, NH4OH (10 mL, 10% aqueous solution) was added dropwise, followed by Et2O (10 mL). The organic layer was extracted, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 0% to 40% EtOAc in hexane, to provide tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.250 mmol) as a colorless oil. [M+Na]=303.2. After 30 minutes After 18 hours The organic layer was extracted washed with brine dried (MgSO4) concentrated in vacuo chromatographed through a Redi-Sep® pre-packed silica gel column (40 g) eluting with 0% to 40% EtOAc in hexane

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

Procedure: A solution of 20.00 g of 1-(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene in 200 mL of toluene was sonicated under reduced pressure, and then to the solution were added 975 mg of palladium acetate, 1009 mg of tri-tert-butylphosphonium tetrafluoroborate, 13.72 g of (4S)-4-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydroquinoline and 6.26 g of sodium tert-butoxide at room temperature. After nitrogen substitution, the mixture was stirred at 100° C. for 4 hours. After radiation, to the reaction solution were added 100 mL of saturated aqueous ammonium chloride solution, 100 mL of water and 100 mL of ethyl acetate, and the mixture was filtered through Celite®. Celite® was washed with 100 mL of ethyl acetate, and then the organic layer was separated. The organic layer was washed with 100 g of 20% saline, dried over magnesium sulfate, and then concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexan/ethyl acetate=5/1 to 4/1) to give 22.31 g of 1-[2-[(4S)-4-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydroquinolin-1-yl]-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (yield: 80%). the mixture was filtered through Celite® Celite® was washed with 100 mL of ethyl acetate the organic layer was separated The organic layer was washed with 100 g of 20% saline dried over magnesium sulfate concentrated The resulting residue was purified by column chromatography on silica gel (n-hexan/ethyl acetate=5/1 to 4/1)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (500 mg, 1.86 mmol), tert-butyl acrylate (408 uL, 2.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (51 mg, 0.056 mmol), [(t-Bu)3PH]BF4 (27 mg, 0.093 mmol) and N,N-dicyclohexylmethylamine (738 uL, 3.48 mmol) in anhydrous 1,4-dioxane (5 mL) was heated at 95° C. overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated and the crude product was purified by silica chromatography to yield ethyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (70). MS m/z 317.14 (M+1)+. The reaction was cooled to room temperature filtered The solvent was concentrated the crude product was purified by silica chromatography

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (500 mg, 1.86 mmol), allyl cyanide (224 uL, 2.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (26 mg, 0.028 mmol), [(t-Bu)3PH]BF4 (16 mg, 0.056 mmol), and N,N-dicyclohexylmethylamine (433 μL, 2.04 mmol) in anhydrous 1,4-dioxane (6 mL) was heated at 95° C. overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated. The crude product was purified by silica chromatography to give ethyl 6-(3-cyanoprop-1-enyl)imidazo[1,2-a]pyridine-3-carboxylate (24v). MS m/z 256.4 (M+1)+. The reaction was cooled to room temperature filtered The solvent was concentrated The crude product was purified by silica chromatography

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

Procedure: To a sealed tube were added (S)-2-((3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-N-(1-(p-tolyl)ethyl)acetamide (50 mg, 0.13 mmol), Pd[P(tBu)3)]2 (3.4 mg, 6.7 μmol), CsF (45 mg, 0.30 mmol), [(t-Bu)3PH]BF4 (3.9 mg, 0.013 mmol) and Pd2(dba)3 (6.1 mg, 6.7 μmol). The tube was evacuated and flushed 3 times with argon and then 3-fluoro-2-tributylstannyl-pyridine (104 mg, 0.27 mmol) in dioxane (1 ml) was added and the suspension heated at 100° C. for 16 h. After cooling to rt, CH2Cl2 and NaHCO3 solution were added and the phases separated. The organic layers were washed with water, dried over Na2SO4 and the solvents removed under reduced pressure. Purification using preparative reverse phase chromatography (LC SunFire C18 OBD column) followed by liberation of the free base (SPE cartridge SCX-1, eluent 7M NH3 in methanol) yielded the title compound (3.7 mg, 6%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.59 (d, 1H), 8.54 (d, 1H), 7.91 (t, 1H), 7.62-7.58 (m, 1H), 7.18 (d, 2H), 7.08 (d, 2H), 6.64 (s, 1H), 4.96 (q, 1H), 4.87 (d, 1H), 4.84 (d, 1H), 3.89 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 1.37 (d, 3H); HPLC-MS RtJ=1.08 min; [M+H]+=434.1] The tube was evacuated flushed 3 times with argon After cooling to rt the phases separated The organic layers were washed with water dried over Na2SO4 the solvents removed under reduced pressure Purification

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with (racemic)-2′-Chloro-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (100 mg, 274 μmol), cesium carbonate (134 mg, 411 μmol), bis(triphenylphosphine)palladium(II) chloride (19 mg, 27 μmol) and tri-tert-butylphosphonium tetrafluoroborate (16 mg, 55 DMF (1 ml), DBU (21 μl, 137 μmol) and 3,3-dimethylbut-1-yne (167 μl, 1371 μmol) were added. The vial was sealed and heated at 150° C. in Biotage microwave oven for 60 min. The mixture was diluted with 5 ml of EtOAc, filtered through Celite and concentrated in vacuo to give brown oil, which was re-dissolved in 7 ml of EtOAc and shaken with 10 ml of 2N HCl. Acidic aqueous layer was basified with 30% ammonium hydroxide and precipitated brown oil was extracted twice with EtOAc. The organic layers were washed with brine, concentrated, dissolved in 1.5 ml of DMF, filtered through Nalgene PTFE 0.2 mkm filter and subjected to preparative reverse phase HPLC (15-90% ACN in 0.1% aq TFA). The fractions containing product were concentrated in vacuo in order to remove ACN, saturated NaHCO3 was added and the mixture was extracted with EtOAc (15 ml). The organic layer was washed with brine, dried over MgSO4 and concentrated to give (rac)-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (49% yield). were added The vial was sealed filtered through Celite concentrated in vacuo to give brown oil, which precipitated brown oil was extracted twice with EtOAc The organic layers were washed with brine concentrated dissolved in 1.5 ml of DMF filtered through Nalgene PTFE 0.2 mkm filter The fractions containing product were concentrated in vacuo in order to remove ACN, saturated NaHCO3 was added the mixture was extracted with EtOAc (15 ml) The organic layer was washed with brine dried over MgSO4 concentrated