6-bromo-3,4-dihydroisochromen-1-one

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

Procedure: A solution of DIPA (4 M, 270 mL, 1080 mmol) in THF (900 mL) was cooled to −65° C. and HexLi (2.1 M, 505 mL, 1061 mmol) was added dropwise over 15 minutes maintaining the internal temp <−55° C. Upon completion the reaction mixture was warmed up to −40° C. where it was stirred for 30 minutes. To the resulting solution of LDA was added 4-bromo-2-methylbenzoic acid (90 g, 419 mmol) slowly (over 15 minutes) as a solution in THF (400 mL) during which time the reaction mixture turned into a bright red suspension. The reaction mixture was stirred for 30 minutes at −40° C. and then warmed to 15° C. at which point paraformaldehyde (50.3 g, 1674 mmol) was added in 3 portions as a solid keeping the internal temperature (ice water bath) below <18° C. Stirring was then continued at room temperature for 1 hour during which time the mixture turned an orange-yellow color. After a second hour of stirring, the vessel was immersed in an ice water bath and 3N HCl (650 mL) was added at such a rate to keep the internal temperature less than 30° C. The contents of the reaction vessel were subsequently transferred to a separatory funnel where it was extracted 3×400 mL EtOAc and the combined organic phases were then concentrated to ˜800 mL total volume. To this was added Amberlyst® 15 ion exchange resin (12 g) and the resulting mixture stirred at 48° C. overnight (˜14 h). HPLC analysis the following morning indicated that cyclization to the desired halolactone was nearly complete. The resin was removed by filtration and the yellow solution concentrated to ˜200 mL total volume at which point the desired product began to crystallize as a yellow solid which was then collected by filtration. The cake was subsequently washed with MTBE (2×80 mL) to give the first crop of product. Additional material was salvaged by washing the collected supernatant 2× with 200 mL 10% K2CO3,aq followed by 200 mL 1M H3PO4. After concentration to −100 mL the crystallized material was collected by filtration, washed with MTBE and then combined with the first crop and dried to afford the title compound. maintaining the internal temp <−55° C The reaction mixture was stirred for 30 minutes at −40° C. was added in 3 portions as a solid below <18° C Stirring was then continued at room temperature for 1 hour during which time After a second hour of stirring the vessel was immersed in an ice water bath the internal temperature less than 30° C The contents of the reaction vessel were subsequently transferred to a separatory funnel where it was extracted 3×400 mL EtOAc the combined organic phases were then concentrated to ˜800 mL total volume To this was added Amberlyst® 15 ion exchange resin (12 g) the resulting mixture stirred at 48° C. overnight (˜14 h) The resin was removed by filtration the yellow solution concentrated to ˜200 mL total volume at which point the desired product to crystallize as a yellow solid which was then collected by filtration The cake was subsequently washed with MTBE (2×80 mL) to give the first crop of product by washing the collected supernatant 2× with 200 mL 10% K2CO3,aq After concentration to −100 mL the crystallized material was collected by filtration washed with MTBE dried

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

Procedure: A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (4.36 mL, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at −20° C. while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0° C. The resulting reaction mixture was stirred at 0° C. for 15 minutes. The reaction was then cooled at −40° C. while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 hour. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 minutes and then charged with DMF (ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 minutes. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.77 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH. H2SO4 (98%, 10.9 mL, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 hours. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, washed with brine, and solvent-switched to MTBE. Crystallization from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one. A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle was added dropwise via syringe the internal temperature below 0° C The resulting reaction mixture was added dropwise via syringe over 1 hour An internal temperature of ca. −40° C. was maintained during the addition The resulting reaction mixture was stirred at −40° C. for 30 minutes The reaction mixture was stirred at −40° C. for 15 minutes The reaction mixture was quenched with MeOH (5 vol., 20 mL) to warm to room temperature After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) The reaction mixture was extracted with EtOAc the resulting reaction mixture was stirred at reflux for 24 hours After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature The resulting organic layer was washed with water washed with brine, and solvent-switched to MTBE Crystallization from 1:1 MTBE

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

Procedure: A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (4.36 mL, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at −20° C. while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0° C. The resulting reaction mixture was stirred at 0° C. for 15 minutes. The reaction was then cooled at −40° C. while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 hour. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 minutes and then charged with DMF (ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 minutes. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.77 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH. H2SO4 (98%, 10.9 mL, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 hours. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, washed with brine, and solvent-switched to MTBE. Crystallization from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one. A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle was added dropwise via syringe the internal temperature below 0° C The resulting reaction mixture was added dropwise via syringe over 1 hour An internal temperature of ca. −40° C. was maintained during the addition The resulting reaction mixture was stirred at −40° C. for 30 minutes The reaction mixture was stirred at −40° C. for 15 minutes The reaction mixture was quenched with MeOH (5 vol., 20 mL) to warm to room temperature After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) The reaction mixture was extracted with EtOAc the resulting reaction mixture was stirred at reflux for 24 hours After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature The resulting organic layer was washed with water washed with brine, and solvent-switched to MTBE Crystallization from 1:1 MTBE

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

Procedure: 6-Bromo-3,4-dihydro-1H-isochromen-1-one (6.90 g, 30.4 mmol), tributyl(1-ethoxyethenyl)stannane (10.8 mL, 31.9 mmol, 1.05 equiv), and PdCl2(PPh3)2 (1.07 g, 1.52 mmol, 0.05 equiv) were weighed into a 250 mL round bottom flask. To this was added dioxane (70 mL) and the resulting mixture stirred at 80° C. for 4 h. The reaction was not complete by HPLC, therefore another 0.1 equiv of tin reagent was added. After 30 min 6-bromo-3,4-dihydro-1H-isochromen-1-one had been fully consumed as indicated by HPLC. The reaction mixture was cooled to 0° C. and 35 mL THF followed by 14 mL H2O were added. To this was introduced solid N-bromosuccinimide (5.68 g, 31.9 mmol, 1.05 equiv), added in portions over 5 min. After stirring for 30 min there was still evidence of remaining enol ether, therefore NBS was added in small portions (˜300 additional mg added) until it was consumed as evidenced by HPLC. Water was then added and the mixture extracted with EtOAc. The aqueous layer was extracted 2 additional times with EtOAc, the combined organics dried with MgSO4, filtered and concentrated in vacuo. This was transferred with EtOAc to a 100 mL round bottom flask, the resulting solution concentrated to ˜25 mL total volume, at which point hexane (50 mL) was added dropwise. When complete the heterogeneous mixture was stirred for 30 min, then cooled to 0° C. and stirred for 10 min, then filtered and washed twice with hexanes. The desired product was dried under a nitrogen bag, then purified by flash chromatography (12 to 100% EtOAc/Hex) to provide the title compound. After 30 min 6-bromo-3,4-dihydro-1H-isochromen-1-one had been fully consumed The reaction mixture was cooled to 0° C. were added added in portions over 5 min After stirring for 30 min there was consumed Water was then added the mixture extracted with EtOAc The aqueous layer was extracted 2 additional times with EtOAc the combined organics dried with MgSO4 filtered concentrated in vacuo This was transferred with EtOAc to a 100 mL round bottom flask the resulting solution concentrated to ˜25 mL total volume, at which point hexane (50 mL) was added dropwise When complete the heterogeneous mixture was stirred for 30 min cooled to 0° C. stirred for 10 min filtered washed twice with hexanes The desired product was dried under a nitrogen bag purified by flash chromatography (12 to 100% EtOAc/Hex)

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

Procedure: A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (3.10 g, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at −20° C. while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0° C. The resulting reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was then cooled at −40° C. while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 h. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 min and then charged with DMF (2.98 g, 40.8 mmol, ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 min. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.770 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH (40 mL). H2SO4 (98%, 20.0 g, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, brine, and solvent-switched to MTBE. Precipitation from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one. A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle was added dropwise via syringe the internal temperature below 0° C The resulting reaction mixture was added dropwise via syringe over 1 h An internal temperature of ca. −40° C. was maintained during the addition The resulting reaction mixture was stirred at −40° C. for 30 min The reaction mixture was stirred at −40° C. for 15 min The reaction mixture was quenched with MeOH (5 vol., 20 mL) to warm to room temperature After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) The reaction mixture was extracted with EtOAc the resulting reaction mixture was stirred at reflux for 24 h After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature The resulting organic layer was washed with water, brine, and solvent-switched to MTBE Precipitation from 1:1 MTBE

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

Procedure: To a 100 mL round bottom flask was added 6-bromo-3,4-dihydro-1H-isochromen-1-one (20 g, 88 mmol, 1.0 eq), potassium trifluoro(vinyl)borate (23.6 g, 176 mmol, 2.0 eq), [1,1′-bis(diphenylposphino)-ferrocene]dichloropalladium(II) complex with dichloromethane(1:1) (7.2 g, 8.8 mmol, 0.1 eq) and triethylamine (24.5 mL, 2.0 eq). To above mixture was added ethanol (400 mL). The flask was degassed and filled with nitrogen. The reaction was heated to reflux under N2 for 10 hr, then cooled and stirred at r.t. for 5 hr. The mixture was then diluted with EtOAc, filtered through a pad of Celite® and washed with brine. The organic phase was dried over Na2SO4, filtered and purified by flash column chromatography using Biotage and the solvent systems (0-50% EtOAc/Hexane). The fractions containing desired product were collected and concentrated to give 6-vinyl-3,4-dihydro-1H-isochromen-1-one. The flask was degassed filled with nitrogen The reaction was heated to reflux under N2 for 10 hr cooled The mixture was then diluted with EtOAc filtered through a pad of Celite® washed with brine The organic phase was dried over Na2SO4 filtered purified by flash column chromatography The fractions containing desired product were collected concentrated

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

Procedure: 6-Bromo-3,4-dihydro-1H-isochromen-1-one (3.00 g, 13.2 mmol) was dissolved in CCl4 (150 mL) then added N-bromosuccinimide (2.352 g, 13.21 mmol) followed by benzoyl peroxide (0.0960 g, 0.396 mmol) and refluxed for 3 hrs. Filtered and concentrated then chromatographed through a 120 g ISCO Redi-sep. column and eluted with 0-25% ETOAc/Hexane to yield 4,6-dibromo-3,4-dihydro-1H-isochromen-1-one. LC-MS (IE, m/z): 306.9 [M+1]+; 1H-NMR (500 MHz, CDCL3) δ ppm 8.03 (d, J=8.9 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.68 (s, 1H), 5.32 (t, J=3 Hz, 1H), 4.72-4.81 (q, 1H). refluxed for 3 hrs Filtered concentrated then chromatographed through a 120 g ISCO Redi-sep column and eluted with 0-25% ETOAc/Hexane

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

Procedure: A solution of DIPA (4 M, 270 mL, 1080 mmol) in THF (900 mL) was cooled to −65° C. and HexLi (2.1 M, 505 mL, 1061 mmol) was added dropwise over 15 min maintaining the internal temp <−55° C. Upon completion the reaction mixture was warmed up to −40° C. where it was stirred 30 min. To the resulting solution of LDA was added 4-bromo-2-methylbenzoic acid (90 g, 419 mmol) slowly (over 15 min) as a solution in THF (400 mL) during which time the reaction mixture turned into a bright red suspension. The reaction mixture was stirred for 30 min at −40° C. and then warmed to 15° C. at which point paraformaldehyde (50.3 g, 1674 mmol) was added in 3 portions as a solid keeping the internal temperature (ice water bath) below <18° C. Stirring was then continued at room temperature for 1 hour during which time the mixture turned an orange-yellow colour. After a second hour of stirring, the vessel was immersed in an ice water bath and 3N HCl (650 mL) was added at such a rate to keep the internal temperature less than 30° C. The contents of the reaction vessel was subsequently transferred to a separatory funnel where it was extracted 3× 400 mL EtOAc and the combined organic phases were then concentrated to ˜800 mL total volume. To this was added Amberlyst 15 resin (12 g) and the resulting mixture stirred at 48° C. overnight (˜14 h). HPLC analysis the following morning indicated that cyclization to the desired halolactone was nearly complete. The resin was removed by filtration and the yellow solution concentrated to ˜200 mL total volume at which point the desired product began to crystallize as a yellow solid which was then collected by filtration. The cake was subsequently washed with MTBE (2× 80 mL) to give the first crop of product. Additional material was salvaged by washing the collected supernatant 2× with 200 mL 10% K2CO3,aq followed by 200 mL 1M H3PO4. After concentration to ˜100 mL the crystallized material was collected by filtration, washed with MTBE and then combined with the first crop of and dried to afford the title compound. LCMS: m/z 227, 229 (M+1)+; maintaining the internal temp <−55° C The reaction mixture was stirred for 30 min at −40° C. was added in 3 portions as a solid below <18° C Stirring was then continued at room temperature for 1 hour during which time After a second hour of stirring the vessel was immersed in an ice water bath the internal temperature less than 30° C The contents of the reaction vessel was subsequently transferred to a separatory funnel where it was extracted 3× 400 mL EtOAc the combined organic phases were then concentrated to ˜800 mL total volume To this was added Amberlyst 15 resin (12 g) the resulting mixture stirred at 48° C. overnight (˜14 h) The resin was removed by filtration the yellow solution concentrated to ˜200 mL total volume at which point the desired product to crystallize as a yellow solid which was then collected by filtration The cake was subsequently washed with MTBE (2× 80 mL) to give the first crop of product by washing the collected supernatant 2× with 200 mL 10% K2CO3,aq After concentration to ˜100 mL the crystallized material was collected by filtration washed with MTBE dried

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

Procedure: A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (4.36 mL, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at −20° C. while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0° C. The resulting reaction mixture was stirred at 0° C. for 15 min. The reaction was then cooled at −40° C. while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 h. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 min and then charged with DMF (ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 min. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.77 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH. H2SO4 (98%, 10.9 mL, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, washed with brine, and solvent-switched to MTBE. Crystallization from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one. A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle was added dropwise via syringe the internal temperature below 0° C The resulting reaction mixture was added dropwise via syringe over 1 h An internal temperature of ca. −40° C. was maintained during the addition The resulting reaction mixture was stirred at −40° C. for 30 min The reaction mixture was stirred at −40° C. for 15 min The reaction mixture was quenched with MeOH (5 vol., 20 mL) to warm to room temperature After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) The reaction mixture was extracted with EtOAc the resulting reaction mixture was stirred at reflux for 24 h After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature The resulting organic layer was washed with water washed with brine, and solvent-switched to MTBE Crystallization from 1:1 MTBE

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

Procedure: 6-Bromo-3,4-dihydro-1H-isochromen-1-one (6.90 g, 30.4 mmol), tributyl(1-ethoxyethenyl)stannane (10.8 mL, 31.9 mmol, 1.05 equiv), and PdCl2(PPh3)2(1.07 g, 1.52 mmol, 0.05 equiv) were weighed into a 250 mL round bottom flask. To this was added dioxane (70 mL) and the resulting mixture stirred at 80° C. for 4 h. The reaction was not complete by HPLC, therefore another 0.1 equiv of tin reagent was added. After 30 min 6-bromo-3,4-dihydro-1H-isochromen-1-one had been fully consumed as indicated by HPLC. The reaction mixture was cooled to 0° C. and 35 mL THF followed by 14 mL H2O were added. To this was introduced solid N-bromosuccinimide (5.68 g, 31.9 mmol, 1.05 equiv), added in portions over 5 min. After stirring for 30 min there was still evidence of remaining enol ether, therefore NBS was added in small portions (˜300 additional mg added) until it was consumed as evidenced by HPLC. Water was then added and the mixture extracted with EtOAc. The aqueous layer was extracted 2 additional times with EtOAc, the combined organics dried with MgSO4, filtered and concentrated in vacuo. This was transferred with EtOAc to a 100 mL round bottom flask, the resulting solution concentrated to ˜25 mL total volume, at which point hexane (50 mL) was added dropwise. When complete the heterogeneous mixture was stirred for 30 min, then cooled to 0° C. and stirred for 10 min, then filtered and washed twice with hexanes. The desired product was dried under a nitrogen bag, then purified by flash chromatography (12 to 100% EtOAc/Hex) to provide the title compound. After 30 min 6-bromo-3,4-dihydro-1H-isochromen-1-one had been fully consumed The reaction mixture was cooled to 0° C. were added added in portions over 5 min After stirring for 30 min there was consumed Water was then added the mixture extracted with EtOAc The aqueous layer was extracted 2 additional times with EtOAc the combined organics dried with MgSO4 filtered concentrated in vacuo This was transferred with EtOAc to a 100 mL round bottom flask the resulting solution concentrated to ˜25 mL total volume, at which point hexane (50 mL) was added dropwise When complete the heterogeneous mixture was stirred for 30 min cooled to 0° C. stirred for 10 min filtered washed twice with hexanes The desired product was dried under a nitrogen bag purified by flash chromatography (12 to 100% EtOAc/Hex)

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

Procedure: A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (3.10 g, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at −20° C. while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0° C. The resulting reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was then cooled at −40° C. while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 h. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 min and then charged with DMF (2.98 g, 40.8 mmol, ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 min. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.770 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH (40 mL). H2SO4 (98%, 20.0 g, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, brine, and solvent-switched to MTBE. Precipitation from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one. A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle was added dropwise via syringe the internal temperature below 0° C The resulting reaction mixture was added dropwise via syringe over 1 h An internal temperature of ca. −40° C. was maintained during the addition The resulting reaction mixture was stirred at −40° C. for 30 min The reaction mixture was stirred at −40° C. for 15 min The reaction mixture was quenched with MeOH (5 vol., 20 mL) to warm to room temperature After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) The reaction mixture was extracted with EtOAc the resulting reaction mixture was stirred at reflux for 24 h After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature The resulting organic layer was washed with water, brine, and solvent-switched to MTBE Precipitation from 1:1 MTBE

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

Procedure: 6-bromo-3,4-dihydro-1H-isochromen-1-one (10 g, 44 mmol) was combined with tri-t-butyl phosphonium tetrafluoroborate (256 mg, 0.881 mmol), palladium (II) acetate (99 mg, 0.44 mmol) and commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc solution (0.5 M, 97 mL, 48 mmol) in DMF (100 mL), and the mixture was degassed three times by alternating vacuum and nitrogen purge. The mixture was then heated at 85° C. for 6 h, then was stirred at RT overnight. Ethyl acetate and ether were added and the mixture was washed with water. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, and washed twice with water and once with brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by MPLC (silica) eluting with ethyl acetate in hexanes to afford the title compound. LCMS: m/z 235 (M+1)+. the mixture was degassed three times purge Ethyl acetate and ether were added the mixture was washed with water The aqueous layer was extracted with ethyl acetate washed twice with water and once with brine The organic layer was dried over MgSO4 filtered concentrated The crude product was purified by MPLC (silica) eluting with ethyl acetate in hexanes