2-trimethylsilylacetonitrile

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

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

Procedure: To a mixture of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.7 g, 0.012 mol), tris(dibenzylideneacetone)dipalladium(0) (10.0 g, 0.012 mol), 6-bromoquinoline (120.0 g, 0.577 mol) in DMF (360 mL) in a 3-neck round bottom flask with stirring under an atmosphere of nitrogen was added (trimethylsilyl)acetonitrile (98.7 mL, 0.721 mol), followed by zinc difluoride (42 g, 0.40 mol). The flask was sealed under an atmosphere of nitrogen. The reaction was stirred at 105° C. for 20 h. After cooling the solution to RT, the reaction mixture was quenched with aqueous ammonia solution and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%) to afford the desired product quinolin-6-ylacetonitrile (70 g, 72.1%). Analytical LCMS: (M+H)+=168.9. The flask was sealed under an atmosphere of nitrogen The reaction was stirred at 105° C. for 20 h the reaction mixture was quenched with aqueous ammonia solution extracted with ethyl acetate (3×500 mL) The combined organic layers were washed with brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%)

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

Procedure: To a mixture of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.7 g, 0.012 mol), tris(dibenzylideneacetone)dipalladium(0) (10.0 g, 0.012 mol), 6-bromoquinoline (120.0 g, 0.577 mol) in DMF (360 mL) in a 3-neck round bottom flask with stirring under an atmosphere of nitrogen was added (trimethylsilyl)acetonitrile (98.7 mL, 0.721 mol), followed by zinc difluoride (42 g, 0.40 mol). The flask was sealed under an atmosphere of nitrogen. The reaction was stirred at 105° C. for 20 h. After cooling the solution to RT, the reaction mixture was quenched with aqueous ammonia solution and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%) to afford the desired product quinolin-6-ylacetonitrile (70 g, 72.1%). Analytical LCMS: (M+H)+=168.9. The flask was sealed under an atmosphere of nitrogen The reaction was stirred at 105° C. for 20 h the reaction mixture was quenched with aqueous ammonia solution extracted with ethyl acetate (3×500 mL) The combined organic layers were washed with brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%)

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

Procedure: A mixture of 3-chloropyridine-N-oxide (2.12 g, 16.30 mmol), trimethylsilyl(acetonitrile) (3.25 g, 32.80 mmol), triethylamine (3.30 g, 32.60 mmol) and acetonitrile (10 mL) was heated at reflux for 6 h. After concentration under reduced pressure, the resulting residue was basified with aqueous sodium carbonate (3N) and extracted with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloropicolinonitrile (1.90 g). The crude product was carried forward without further purification. MW=139 confirmed by LC-MS, tr=2.33 min (Method E) MH+=140. was heated at reflux for 6 h After concentration under reduced pressure extracted with methylene chloride The combined organic layers were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

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

Procedure: To a mixture of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.7 g, 12 mmol), tris(dibenzylideneacetone)dipalladium(0) (10 g, 12 mmol), 6-bromoquinoline (120 g, 577 mmol) in N,N-dimethylformamide (360 mL) in a 3-neck round bottom flask with stirring under positive nitrogen pressure was added (trimethylsilyl)acetonitrile (98.7 mL, 721 mmol), followed by zinc difluoride (42 g, 400 mmol). The flask was sealed under an atmosphere of nitrogen. The reaction mixture was stirred at 105° C. for 20 h. After cooling the solution to RT, the reaction mixture was quenched with an aqueous ammonia solution and extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified under flash chromatography eluting with ethyl acetate in hexanes (0-65%) to afford the desired product. (70 g, 72.1%) LCMS: (M+H)=168.9. The flask was sealed under an atmosphere of nitrogen The reaction mixture was stirred at 105° C. for 20 h the reaction mixture was quenched with an aqueous ammonia solution extracted with ethyl acetate (3×500 mL) The combined organic extracts were washed with brine dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified under flash chromatography eluting with ethyl acetate in hexanes (0-65%)

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

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

Procedure: To a mixture of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.7 g, 0.012 mol), tris(dibenzylideneacetone)dipalladium(0) (10.0 g, 0.012 mol), 6-bromoquinoline (120.0 g, 0.577 mol) in DMF (360 mL) in a 3-neck round bottom flask with stirring under an atmosphere of nitrogen was added (trimethylsilyl)acetonitrile (98.7 mL, 0.721 mol), followed by zinc difluoride (42 g, 0.40 mol). The flask was sealed under an atmosphere of nitrogen. The reaction was stirred at 105° C. for 20 h. After cooling the solution to RT, the reaction mixture was quenched with aqueous ammonia solution and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%) to afford the desired product quinolin-6-ylacetonitrile (70 g, 72.1%). Analytical LCMS: (M+H)+=168.9. The flask was sealed under an atmosphere of nitrogen The reaction was stirred at 105° C. for 20 h the reaction mixture was quenched with aqueous ammonia solution extracted with ethyl acetate (3×500 mL) The combined organic layers were washed with brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%)

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

Procedure: To a mixture of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.7 g, 0.012 mol), tris(dibenzylideneacetone)dipalladium(0) (10.0 g, 0.012 mol), 6-bromoquinoline (120.0 g, 0.577 mol) in DMF (360 mL) in a 3-neck round bottom flask with stirring under an atmosphere of nitrogen was added (trimethylsilyl)acetonitrile (98.7 mL, 0.721 mol), followed by zinc difluoride (42 g, 0.40 mol). The flask was sealed under an atmosphere of nitrogen. The reaction was stirred at 105° C. for 20 h. After cooling the solution to RT, the reaction mixture was quenched with aqueous ammonia solution and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%) to afford the desired product quinolin-6-ylacetonitrile (70 g, 72.1%). Analytical LCMS: (M+H)+=168.9. The flask was sealed under an atmosphere of nitrogen The reaction was stirred at 105° C. for 20 h the reaction mixture was quenched with aqueous ammonia solution extracted with ethyl acetate (3×500 mL) The combined organic layers were washed with brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was chromatographed on a silica gel column (ethyl acetate in hexanes: 0-65%)

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

Procedure: In a glass tube with screw-on lid, 2 g (7.43 mmol) of 4-bromo-2,6-dichloro-N,N-dimethylaniline (known from European Journal of Organic Chemistry (2006), (19), 4398-4404) are initially charged with 86 mg (0.14 mmol) of xantphos and 136 mg (0.14 mmol) of tris(dibenzylideneacetone)-dipalladium in 10 ml of DMF. 1.01 g (8.92 mmol) of trimethylsilylacetonitrile and 0.46 g (4.46 mmol) of zinc fluoride are then added, and in the closed vessel the reaction is heated at 90° C. for 16 hours. The reaction mixture is cooled, water and ethyl acetate are added and the mixture is filtered through silica gel. The reaction mixture is cooled the mixture is filtered through silica gel

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

Procedure: To a stirred solution of AcOLi (27 mg, 0.41 mmol) in DMF (1 mL) were added successively a solution of 8-bromo-2-formylquinolin-7-yl benzenesulfonate (1.60 g, 4.08 mmol) in anhydrous DMF (10 mL) and TMSCH2CN (465 mg, 4.11 mmol) at 0° C. And the reaction mixture was slowly warmed to room temperature. The mixture was stirred for 12 h at the same temperature and quenched with 15% citric acid (5.0 mL) and MeOH (5.0 mL). After the removal of MeOH in vacuo, the mixture was extracted with AcOEt and organic layer was washed with brine and dried over anhydrous Na2SO4, and evaporated. Purification by silica gel chromatography (Hexanes/EtOAc=2/1) gave S0187 as a yellow gum (0.89 g, 2.05 mmol, 50% yield). 13CNMR (ppm, 500 MHz, CDCl3, 298 K) δ: 159.989, 148.716, 144.388, 138.493, 135.675, 135.042, 129.556, 128.819, 128.189, 127.380, 123.481, 119.173, 118.419, 117.117, 68.926, 26.812. 1HNMR (ppm, 500 MHz, CDCl3, 298 K) δ: 8.262 (d, 1H, J=8.5 Hz), 7.968 (d, 2H, J=8.0 Hz), 7.836 (d, 1H, J=9.0 Hz), 7.716 (t, 1H, J=7.0 Hz), 7.633 (d, 1H, J=9.0 Hz), 7.588-7.545 (m, 3H), 5.224−5.188 (m, 1H), 5.126 (d, 1H, J=6.0 Hz), 3.031−2.929 (m, 2H). MS-ESI (m/z): [M+H]+ calculated for C18H14BrN2O4S, 433.0 (79Br) and 435.0 (81Br); found 432.9 (79Br) and 434.9 (81Br). quenched with 15% citric acid (5.0 mL) and MeOH (5.0 mL) After the removal of MeOH in vacuo the mixture was extracted with AcOEt and organic layer was washed with brine dried over anhydrous Na2SO4 evaporated Purification by silica gel chromatography (Hexanes/EtOAc=2/1)

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

Procedure: To a screw-capped vial containing 2-(3,5-dibromophenyl)-1,3-dioxolane (4.g, 12.99 mmol), Xantphos (0.15 g, 0.26 mmol), Pd2(dba)3 in anhydrous DMF (5.0 mL) was added trimethylsilyl acetonitrile (2.20 mL, 16.07 mmol) and the reaction mixture was degassed with nitrogen for 15 min to give an orange-red suspension. To the above mixture was added ZnF2 under nitrogen atmosphere and the vial sealed with a cap containing a PTFE/silicone septum under nitrogen. The heterogeneous mixture was heated with stirring at 90° C. in an oil bath to give an olive green suspension. The reaction mixture was let stirred at 90° C. for 22 h to give a dark brown suspension/solution. The reaction mixture cooled to room temperature and diluted with diethyl ether (100 mL). The resulting solution was washed with water (2×75 mL). The organic layer was removed and evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford an orange-red viscous liquid (3.65 g). Purification of the crude product by Silica-gel flash chromatography on silica gel column and elution with 10-80% ethyl acetate in hexanes afforded the desired product as a pale yellow viscous liquid (1.95 g). LC-MS analysis of the liquid shows the desired product's mass: m/z 268 (79BrM+H), m/z 270 (81BrM+H), m/z 290 (79BrM+Na), and m/z 292 (81BrM+Na); GC-MS (EI mode) analysis also shows the desired product's mass: m/z 266 (79BrM+) and m/z 268 (81BrM+), Calcd for C11H10BrNO2: 268.11. 1H NMR (400 MHz, CDCl3): δ 3.72 (s, 2H, —CH2CN), 3.98-4.05 (M, 2H, —CH2—O—), 4.06-4.13 (M, 2H, —CH2—O—), 5.75 (s, 1H, O—CH—O), 7.36 (s, 1H), 7.47 (s, 1H), 7.58 (s, 1H). 1H NMR spectrum of the liquid was consistent with the suggested structure of the product. the reaction mixture was degassed with nitrogen for 15 min to give an orange-red suspension the vial sealed with a cap The heterogeneous mixture was heated to give an olive green suspension The reaction mixture was let stirred at 90° C. for 22 h to give a dark brown suspension/solution The reaction mixture cooled to room temperature The resulting solution was washed with water (2×75 mL) The organic layer was removed evaporated in vacuo the residue was dissolved in ethyl acetate (50 mL) dried over anhydrous Na2SO4 filtered evaporated in vacuo

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

Procedure: To a mixture of Xantphos (0.049 g, 0.084 mmol), Pd2(dba)3 (0.077 g, 0.084 mmol) and 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500 g, 0.838 mmol) in N,N-dimethylformamide (0.838 ml) was added (trimethylsilyl)acetonitrile (0.138 ml, 1.006 mmol) followed by zinc difluoride (0.061 g, 0.587 mmol). The flask was sealed under an atmosphere of nitrogen and heated at 100° C. overnight. The reaction was diluted with water and extracted with DCM (×2). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was taken up in DCM and purified via MPLC, eluting with 0-100% ethyl acetate in heptanes with a 5% DCM additive, followed by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19×100 mm), 0.1% TFA in CH3CN/H2O, gradient 25% to 95% over 12 min to provide 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.092 g, 0.165 mmol, 19.72% yield) as a light-yellow solid. 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (92 mg) was taken up in 2.5 mL of DCM and 2.5 mL of TFA and was heated under microwave irradiation for 1 h at 70° C. until complete deprotection. The reaction mixture was concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19×100 mm), 0.1% TFA in CH3CN/H2O, gradient 25% to 70% over 12 min to provide 1-(5-(cyanomethyl)-2-methoxyphenyl))-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.011 g, 0.025 mmol, 3.01% yield) as a white solid. MS (ESI, pos. ion) m/z: [M+1] 437.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.68 (s, 3 H) 4.03 (s, 2 H) 6.44 (d, J=1.76 Hz, 1 H) 6.71 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.64 Hz, 1 H) 7.30 (d, J=2.28 Hz, 1 H) 7.34 (d, J=8.60 Hz, 1 H) 7.55 (dd, J=8.60, 2.28 Hz, 1 H) 7.84 (dd, J=8.97, 2.23 Hz, 1 H) 8.22 (d, J=9.74 Hz, 1 H) 8.36 (d, J=2.18 Hz, 1 H) 8.73 (d, J=1.87 Hz, 1 H) 11.64 (s, 1 H). The flask was sealed under an atmosphere of nitrogen extracted with DCM (×2) The combined organics were washed with brine dried over sodium sulfate filtered concentrated in vacuo purified via MPLC eluting with 0-100% ethyl acetate in heptanes with a 5% DCM additive