(E)-N-cyclopropylhex-2-enamide

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask equipped with a stir bar, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with samarium (III) isopropoxide (Sm(O-i-Pr)3, 430 mg, 1.3 mmol), triphenyl arsine oxide (Ph3As═O; 420 mg, 1.3 mmol), S-(−)1,1′-bi-2-naphthol ((S)-BINOL), 370 mg, 1.3 mmol), 4 Å molecular sieves (13 g) and THF (20 mL) then stirred for 30 min at 25±5° C. Tert-butyl hydroperoxide (2.8 mL, 5.5 M, 16 mmol) was then added. The mixture stirred for 30 minutes at 25±5° C., the amide of Example 4 (2.0 g, 13 mmol) in THF (2.0 mL) was then added. The reaction was stirred for 14 hours after which time the reaction had reached 95% completion as determined by HPLC. A flask equipped with a stir bar thermometer and addition funnel The reaction was stirred for 14 hours after which time the reaction

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with tert-butyl hydrogen peroxide (TBHP; 95 mL, 5.5 M, 522 mmol) and tetrahydrofuran (THF; 200 mL). The reaction was cooled to −20±5° C. and n-butyl lithium (n-BuLi; 235 mL, 2.5 M, 587 mmol) was charged to the addition funnel and slowly added, keeping the reaction temperature below −5±5° C. Upon completion of addition the reaction was warmed to 0±5° C. and the amide of Example 4 (19.80 g, 130 mmol) in THF (20 mL) was added maintaining the temperature at 0±5° C. after which the temperature was increased to 25±5° C. and the reaction stirred for 12 hours. After this time IPAc (200 mL) and saturated aqueous sodium hydrosulfite (200 mL) were added and the reaction stirred for 60 min. The layers were separated and the aqueous layer extracted with IPAc (twice, 75 mL each). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound (21.87 g, 99%). A flask equipped with an overhead stirrer thermometer and addition funnel slowly added the reaction temperature below −5±5° C Upon completion of addition the reaction was warmed to 0±5° C. maintaining the temperature at 0±5° C. after which the temperature was increased to 25±5° C. the reaction stirred for 60 min The layers were separated the aqueous layer extracted with IPAc (twice, 75 mL each) The combined organic phases were dried over sodium sulfate (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%) as a fine white solid. A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slurry was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a three-neck 250 mL round bottom flask equipped with mechanical stirrer and containing compound 37 (10.0 g, 65.3 mmol) and urea hydrogen peroxide (UHP) (25.0 g, 4.0 eq.) in CH2Cl2 (100 mL, 10 vol) at 0° C., was added trifluoroacetic anhydride (41.1 g, 27.2 mL, 3.0 eq.). The reaction mixture was heated to 35±5° C. and stirred for 2 hours. After cooling the reaction mixture down to room temperature, another aliquot of trifluoroacetic anhydride (13.7 g, 9.0 mL, 1.0 eq.) was added. The reaction mixture was heated again to 35±5° C. and stirred for another 3 hours. The reaction mixture was then again cooled to 0° C. and quenched by adding saturated NaHCO3 (5 vol.) slowly and stirring for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL, 5 vol). The combined organic layer was dried and evaporated to afford the crude product, N-cyclopropyl-3-propyloxirane-2-carboxamide (38), as a pale yellow oil. The crude product was used for the next step without further purification. To a three-neck 250 mL round bottom flask equipped with mechanical stirrer After cooling the reaction mixture down to room temperature The reaction mixture was heated again to 35±5° C. stirred for another 3 hours The reaction mixture was then again cooled to 0° C. quenched by adding saturated NaHCO3 (5 vol.) slowly stirring for 30 minutes The organic layer was separated the aqueous layer was extracted with CH2Cl2 (50 mL, 5 vol) The combined organic layer was dried evaporated

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

Procedure: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipitate formed. The slimy was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide compound 37 as a fine white solid. 1H NMR (500 MHz, d6-DMSO) 7.89 (s, 1H), 6.58 (dt, J=15.2, 7.0 Hz, 1H), 5.80 (dt, J=15.2, 1.3 Hz, 1H), 2.70-2.65 (m, 1H), 2.12-2.06 (m, 2H), 1.44-1.37 (m, 2H), 0.88 (t, J=7.3 Hz, 3H), 0.64-0.60 (m, 2H), 0.42-0.38 (m, 2H). A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slimy was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask equipped with a stir bar, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with samarium (III) isopropoxide (Sm(O-i-Pr)3, 430 mg, 1.3 mmol), triphenyl arsine oxide (Ph3As═O; 420 mg, 1.3 mmol), S-(−)1,1′-bi-2-naphthol ((S)-BINOL), 370 mg, 1.3 mmol), 4 Å molecular sieves (13 g) and THF (20 mL) then stirred for 30 min at 25±5° C. Tert-butyl hydroperoxide (2.8 mL, 5.5 M, 16 mmol) was then added. The mixture stirred for 30 minutes at 25±5° C., the amide of Example 4 (2.0 g, 13 mmol) in THF (2.0 mL) was then added. The reaction was stirred for 14 hours after which time the reaction had reached 95% completion as determined by HPLC. A flask equipped with a stir bar thermometer and addition funnel The reaction was stirred for 14 hours after which time the reaction

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask equipped with a stir bar, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with samarium (III) isopropoxide (Sm(O-i-Pr)3, 430 mg, 1.3 mmol), triphenyl arsine oxide (Ph3As═O; 420 mg, 1.3 mmol), S-(−)1,1′-bi-2-naphthol ((S)-BINOL), 370 mg, 1.3 mmol), 4 Å molecular sieves (13 g) and THF (20 mL) then stirred for 30 min at 25±5° C. Tert-butyl hydroperoxide (2.8 mL, 5.5 M, 16 mmol) was then added. The mixture stirred for 30 minutes at 25±5° C., the amide of Example 4 (2.0 g, 13 mmol) in THF (2.0 mL) was then added. The reaction was stirred for 14 hours after which time the reaction had reached 95% completion as determined by HPLC. A flask equipped with a stir bar thermometer and addition funnel The reaction was stirred for 14 hours after which time the reaction

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with tert-butyl hydrogen peroxide (TBHP; 95 mL, 5.5 M, 522 mmol) and tetrahydrofuran (THF; 200 mL). The reaction was cooled to −20±5° C. and n-butyl lithium (n-BuLi; 235 mL, 2.5 M, 587 mmol) was charged to the addition funnel and slowly added, keeping the reaction temperature below −5±5° C. Upon completion of addition the reaction was warmed to 0±5° C. and the amide of Example 4 (19.80 g, 130 mmol) in THF (20 mL) was added maintaining the temperature at 0±5° C. after which the temperature was increased to 25±5° C. and the reaction stirred for 12 hours. After this time IPAc (200 mL) and saturated aqueous sodium hydrosulfite (200 mL) were added and the reaction stirred for 60 min. The layers were separated and the aqueous layer extracted with IPAc (twice, 75 mL each). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound (21.87 g, 99%). A flask equipped with an overhead stirrer thermometer and addition funnel slowly added the reaction temperature below −5±5° C Upon completion of addition the reaction was warmed to 0±5° C. maintaining the temperature at 0±5° C. after which the temperature was increased to 25±5° C. the reaction stirred for 60 min The layers were separated the aqueous layer extracted with IPAc (twice, 75 mL each) The combined organic phases were dried over sodium sulfate (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%) as a fine white solid. A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slurry was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried

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

Procedure: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%) as a fine white solid. A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slurry was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a three-neck 250 mL round bottom flask equipped with mechanical stirrer and containing compound 37 (10.0 g, 65.3 mmol) and urea hydrogen peroxide (UHP) (25.0 g, 4.0 eq.) in CH2Cl2 (100 mL, 10 vol) at 0° C., was added trifluoroacetic anhydride (41.1 g, 27.2 mL, 3.0 eq.). The reaction mixture was heated to 35±5° C. and stirred for 2 hours. After cooling the reaction mixture down to room temperature, another aliquot of trifluoroacetic anhydride (13.7 g, 9.0 mL, 1.0 eq.) was added. The reaction mixture was heated again to 35±5° C. and stirred for another 3 hours. The reaction mixture was then again cooled to 0° C. and quenched by adding saturated NaHCO3 (5 vol.) slowly and stirring for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL, 5 vol). The combined organic layer was dried and evaporated to afford the crude product, N-cyclopropyl-3-propyloxirane-2-carboxamide (38), as a pale yellow oil. The crude product was used for the next step without further purification. To a three-neck 250 mL round bottom flask equipped with mechanical stirrer After cooling the reaction mixture down to room temperature The reaction mixture was heated again to 35±5° C. stirred for another 3 hours The reaction mixture was then again cooled to 0° C. quenched by adding saturated NaHCO3 (5 vol.) slowly stirring for 30 minutes The organic layer was separated the aqueous layer was extracted with CH2Cl2 (50 mL, 5 vol) The combined organic layer was dried evaporated

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

Procedure: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipitate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide compound 37 as a fine white solid. 1H NMR (500 MHz, d6-DMSO) 7.89 (s, 1H), 6.58 (dt, J=15.2, 7.0 Hz, 1H), 5.80 (dt, J=15.2, 1.3 Hz, 1H), 2.70-2.65 (m, 1H), 2.12-2.06 (m, 2H), 1.44-1.37 (m, 2H), 0.88 (t, J=7.3 Hz, 3H), 0.64-0.60 (m, 2H), 0.42-0.38 (m, 2H). A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slurry was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried