[acetyloxy(phenyl)-lambda3-iodanyl] acetate

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

Procedure: 2,4,6-Trichloro-N-(3-hydroxypropoxymethyl)-N-methylbenzenesulfonamide (363 mg, 1 mmol), 2,2,6,6-tetramethylpiperidin-1-yloxy radical (38 mg, 0.245 mmol) and [bis(acetoxy)iodo]benzene (705 mg, 2.19 mmol) were dissolved in acetonitrile/water (1:1; 8 ml) and the solution was stirred at RT for 30 min. The reaction soln. was then cooled with ice, and 2 N hydrochloric acid (4 ml) and EtOAc (40 ml) were added. The phases were separated and the organic phase was washed with water (3×20 ml) and saturated sodium chloride solution (2×20 ml), dried with Na2SO4 and concentrated i. vac. The compound was taken up in 1 N sodium carbonate soln. (30 ml) and the mixture was extracted with EtOAc (3×20 ml). The aqueous phase was then adjusted to pH 3 with 2 N hydrochloric acid and extracted with EtOAc (3×20 ml). The combined organic phases were washed with water (3×20 ml) and saturated sodium chloride solution (2×20 ml), dried with Na2SO4 and concentrated i. vac. Yield: 310 mg (82%) were added The phases were separated the organic phase was washed with water (3×20 ml) and saturated sodium chloride solution (2×20 ml) dried with Na2SO4 concentrated i (30 ml) and the mixture was extracted with EtOAc (3×20 ml) extracted with EtOAc (3×20 ml) The combined organic phases were washed with water (3×20 ml) and saturated sodium chloride solution (2×20 ml) dried with Na2SO4 concentrated i

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

Procedure: A solution of tert-butyl 5-((hydroxyimino)methyl)-1H-indole-1-carboxylate (260.3 mg, 1 mmol) in methanol (1 mL) was added slowly to a stirred solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (438.1 mg, 1.100 mmol) and (diacetoxyiodo)benzene (354.3 mg, 1.100 mmol) in methanol (2 mL) containing trifluoroacetic acid (15 μL, 0.1947 mmol) at ambient temperature. The reaction was stirred at this temperature for 17 hours then concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column) loaded with dichloromethane and eluted with 0 to 50% ethyl acetate/petroleum ether. Product fractions were combined and concentrate in vacuo to give the sub-title product as a white solid (108 mg, 16% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.22 (s, 18H), 1.57 (s, 9H), 6.73 (d, 1H), 7.69 (d, 1H), 7.80 (s, 1H), 7.89 (dd, 1H), 8.11 (d, 1H), 8.23 (d, 1H) and 8.94 (s, 1H) ppm. then concentrated in vacuo The residue was purified by column chromatography (ISCO Companion, 40 g column) eluted with 0 to 50% ethyl acetate/petroleum ether concentrate in vacuo

Conditions: temp:16.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A slurry of N-Boc-L-asparagine (5.00 g, 21.5 mmol), EtOAc (24 mL), acetonitrile (24 mL), water (12 mL), and PIDA (8.32 g, 25.8 mmol) was cooled and stirred at 16° C. for 30 min. The temperature was then allowed to reach 20° C., and the reaction was stirred until completion (ca. 4 h). The mixture was cooled to 0° C. and filtered. The filter cake was washed with EtOAc (10 mL) and dried in vacuo to give 1 (2.73 g, 62% yield). 1H NMR (CD3OD and a drop of TFA) δ4.05 (1H), 3.20-3.08 (2H), 1.45 (9H). to reach 20° C. the reaction was stirred until completion (ca. 4 h) The mixture was cooled to 0° C. filtered The filter cake was washed with EtOAc (10 mL) dried in vacuo

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

Procedure: A solution of crude (E)-ethyl 8-((hydroxyimino)methyl)indolizine-5-carboxylate (0.46 mmol) in THF (5 mL) was added slowly to a stirred solution of iodobenzene diacetate, (PhI(OAc)2, DIB, 296 mg, 0.92 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (222 mg, 0.92 mmol) in THF (10 mL) at rt. The mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then combiflash to give ethyl 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (50 mg, yield 23% over 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.66 (t, J=2.0 Hz, 1H), 7.84 (t, J=2.0 Hz, 1H), 7.68-7.71 (m, 3H), 7.25-7.27 (m, 2H), 7.06 (m, 1H), 4.43-4.56 (m, 4H), 1.41 (t, J=2.0 Hz, 3H) ppm; MS: m/z=471.7 (M+1, ESI+). The solvent was removed under reduced pressure the crude product was purified by prep-TLC and

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-(4-Chloro-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (50 mg, 0.13 mmol), PhI(OAc)2(60 mg, 0.19 mmol), and Pd(OAc)2(8.9 mg, 0.013 mmol) were dissolved in a mixture of acetic acid (0.6 mL) and acetic anhydride (0.6 mL). The mixture was stirred at 40° C. overnight. A solution of sodium thiosulfate was added and the mixture was stirred for 8 days at RT. A solution of potassium carbonate was added and the reaction pH was adjusted to 10. The aqueous phase was extracted (2×) with dichloromethane and methanol (9:1). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase preparative HPLC (10 to 30% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). The appropriate fractions containing product were free based by catch and release using SiliaBond Propylsulphonic Acid® (4 eq, CH3CN as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (3/1 mL). 1 M aqueous HCl (3 equivalents) was added, and the volatiles were concentrated in vacuo to afford the hydrochloride salt of 5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol as a yellow solid (19 mg, 33%). LCMS Rt=0.57 min [Method Q]; [M+H]: 393.2; 1H NMR (400 MHz, MeOD) δ 8.21 (d, J=10.0 Hz, 1H), 7.99 (d, J=10.0 Hz, 1H), 6.99 (dd, J=10.0, 2.0 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H), 5.09 (bs, 1H), 3.18 (s, 3H), 1.98-2.12 (m, 4H), 1.65 (s, 6H), 1.57 (s, 6H). the mixture was stirred for 8 days at RT The aqueous phase was extracted (2×) with dichloromethane and methanol (9:1) The combined organic phases were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The crude material was purified via reverse phase preparative HPLC (10 to 30% acetonitrile in water, 0.1% trifluoroacetic acid as modifier) The appropriate fractions containing product The solvent was concentrated in vacuo the volatiles were concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate (0.48 g, 1.01 mmol), PhI(OAc)2 (0.46 g, 1.41 mmol), and Pd(OAc)2(68 mg, 0.10 mmol) were dissolved in a mixture of acetic acid (4 mL) and acetic anhydride (4 mL). The mixture was stirred at 80° C. for 3 h. The crude reaction was purified by catch and release using SiliaBond Propylsulfonic Acid® (5 eq, CH3CN as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and 3-fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate was afforded as a green solid (0.50 g, 100%). [M+H]: 494.3; 1H NMR (400 MHz, MeOD) δ 8.09 (t, J=8.5 Hz, 1H), 7.99 (dd, J=9.5, 2.5 Hz, 1H), 7.50 (dd, J=10.5, 2.5 Hz, 1H), 7.45 (dd, J=8.5, 2.5 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 5.82 (tt, J=11.0, 4.0 Hz, 1H), 2.24 (dd, J=12.5, 4.0 Hz, 2H), 1.43 (t, J=12.0 Hz, 2H), 1.36 (s, 6H), 1.25 (s, 6H). The crude reaction was purified by catch and release The solvent was concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate (0.48 g, 1.01 mmol), PhI(OAc)2 (0.46 g, 1.41 mmol), and Pd(OAc)2(68 mg, 0.10 mmol) were dissolved in a mixture of acetic acid (4 mL) and acetic anhydride (4 mL). The mixture was stirred at 80° C. for 3 h. The crude reaction was purified by catch and release using SiliaBond Propylsulfonic Acid® (5 eq, CH3CN as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and 3-fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate was afforded as a green solid (0.50 g, 100%). [M+H]: 494.3; 1H NMR (400 MHz, MeOD) δ 8.09 (t, J=8.5 Hz, 1H), 7.99 (dd, J=9.5, 2.5 Hz, 1H), 7.50 (dd, J=10.5, 2.5 Hz, 1H), 7.45 (dd, J=8.5, 2.5 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 5.82 (tt, J=11.0, 4.0 Hz, 1H), 2.24 (dd, J=12.5, 4.0 Hz, 2H), 1.43 (t, J=12.0 Hz, 2H), 1.36 (s, 6H), 1.25 (s, 6H). The crude reaction was purified by catch and release The solvent was concentrated in vacuo

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-methylpentyl sulfamate from Step 1 (1.25 mmol) in 8 mL of dichloromethane was added sequentially MgO (116 mg, 30 mmol), PhI(OAc)2 (443 mg 1.4 mmol), and Rh2(oct)4 (20 mg, 0.025 mmol). The suspension was stirred vigorously and heated at 40° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with 20 mL of dichloromethane, and filtered through a pad of Celite then concentrated. The crude product was purified by multiple flash chromatographies (5% ethyl acetate/dichloromethane) to give 4-ethyl-4-methyltetrahydro-1,2,3-oxathiazine 2,2-dioxide. The reaction mixture was cooled to room temperature filtered through a pad of Celite then concentrated The crude product was purified by multiple flash chromatographies (5% ethyl acetate/dichloromethane)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-methylpentyl sulfamate from Step 1 (1.25 mmol) in 8 mL of dichloromethane was added sequentially MgO (116 mg, 30 mmol), PhI(OAc)2 (443 mg 1.4 mmol), and Rh2(oct)4 (20 mg, 0.025 mmol). The suspension was stirred vigorously and heated at 40° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with 20 mL of dichloromethane, and filtered through a pad of Celite then concentrated. The crude product was purified by multiple flash chromatographies (5% ethyl acetate/dichloromethane) to give 4-ethyl-4-methyltetrahydro-1,2,3-oxathiazine 2,2-dioxide. The reaction mixture was cooled to room temperature filtered through a pad of Celite then concentrated The crude product was purified by multiple flash chromatographies (5% ethyl acetate/dichloromethane)

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

Procedure: Based on a reported procedure: All manipulations were carried out in a dry box under a N2 atmosphere. To (diacetoxyiodo)benzene (3.00 g, 9.31 mmol, 1.00 equiv) dissolved in CH2C12 (100 mL) in a round-bottom flask was added TMSOTf (4.14 g, 18.6 mmol, 2.00 equiv) dropwise over 1 minute at 23 ° C. 4-Methoxypyridine (2.03 g, 18.6 mmol, 2.00 equiv) in CH2C12 (15 mL) was added to the solution dropwise over 5 minutes. The reaction mixture was concentrate until a white solid was observed. To the reaction mixture was added 100 mL of Et2O and the resulting solid was collected on a frit. The solid was washed with Et2O (3 x 10 mL) and subsequently dried under vacuum to afford 6.52 g of the title compound as a colorless solid (97%). NMR Spectroscopy: c 1H NMR (500 MHz, CD3CN, 23 ° C., δ): 8.77 (d, J=7.5 Hz, 4H), 8.60 (d, J=8.5 Hz, 2H), 7.79 (t, J=7.5 Hz, 1H), 7.64 (t, J=8.5 Hz, 2H), 7.19 (d, J=7.5 Hz, 4H), 3.99 (s, 3H). 13C NMR (125 MHz, CD3CN, 23 ° C., δ): 172.1, 149.9, 136.1, 135.7, 134.2, 121.9 (q, J=319 Hz, triflate), 115.3, 58.5. 19F NMR (375 MHz, CD3CN, 23 ° C., δ): −77.5. Anal: calcd for C20H19F6IN2O8S2: C, 33.34; H, 2.66; N, 3.89; found: C, 33.05; H, 2.59; N, 3.73. All manipulations were carried out in a dry box under a N2 atmosphere The reaction mixture was concentrate until a white solid To the reaction mixture was added 100 mL of Et2O the resulting solid was collected on a frit The solid was washed with Et2O (3 x 10 mL) subsequently dried under vacuum

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

Procedure: To a stirring solution of (Z)-4-bromo-2-(1-hydrazonoethyl)pyridine (2.53 g, 11.8 mmol) in DCM (40 mL) was added (diacetoxyiodo)benzene (3.8 g, 11.8 mmol) in small portions over several minutes and stirred at room temperature for 45 minutes. The reaction was quenched with saturated 1:1 Na2S2O3/NaHCO3 solution (40 mL) and stirred until gas evolution ceased. The aqueous layer was extracted with DCM, dried over MgSO4, and purified by column chromatography (gradient 0 to 45% EtOAc in hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=6.9 Hz, 2H), 7.79 (s, 2H), 6.97 (d, J=6.5 Hz, 2H), 2.57 (s, 7H). The reaction was quenched with saturated 1:1 Na2S2O3/NaHCO3 solution (40 mL) stirred until gas evolution The aqueous layer was extracted with DCM dried over MgSO4 purified by column chromatography (gradient 0 to 45% EtOAc in hexanes) to afford the product

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)picolinamide (0.4 g, 0.86 mmol) and PhI(OAc)2 (419 mg, 1.5 mmol) in a mixture of EtOAc (8 mL), MeCN (8 mL) and H2O (4 mL) was cooled to 0° C. and stirred for 30 minutes. The reaction was then allowed to warm to rt, and stirred for another 8 h. The mixture was diluted with NaHCO3 (aq., 60 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a white solid (0.21 g, 56%). to warm to rt stirred for another 8 h extracted with EtOAc (100 mL×3) The combined organic phases were washed with brine dried over Na2SO4 concentrated in vacuo The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=10/1)