2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile

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

Procedure: To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (2.0 g, 8.3 mmol) in tetrahydrofuran (20 mL) under nitrogen was added 1 N solution of DIBAL-H in tetrahydrofuran (19 mL, 19 mmol) dropwise at −30° C. The resulting solution was stirred at ambient temperature for 3 hours before the addition of 2 N hydrochloric acid aqueous solution (10 mL) at 0° C. After stirred at ambient temperature for 10 minutes, the solution was basified with saturated aqueous sodium bicarbonate solution to pH 8-9, and then extracted with ethyl acetate (3×50 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 1-2% ethyl acetate in hexane to afford the title compound as a colorless oil. MS ESI: [M+H]+ m/z 245; 1H NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 7.32-7.21 (m, 1H), 7.18-7.03 (m, 2H), 1.41 (s, 6H). extracted with ethyl acetate (3×50 mL) All the organic solution was dried over sodium sulfate filtered concentrated in vacuo The crude residue was purified by flash column chromatography with 1-2% ethyl acetate in hexane

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A nitrogen-purged, 2-L, 3-neck flask containing 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (114.14 g, 0.4715 mol) was sequentially charged (while stirring) with LiCl (39.62 g, 0.9347 mol), LiOAc (15.41 g, 0.2334 mol), DMAc (283 mL), and H2O (28.3 mL). The solution was then purged (subsurface) with N2 for 1 h. The flask was then charged with 1-cyclopentyl-prop-2-en-1-ol (73.70 g, 0.5808 mol), Et3N (6.5 mL, 0.0466 mol, 10% of the total to be added), and Pd(OAc)2 (5.2487 g, 0.0234 mol) followed by a careful purge of the headspace. The reaction was heated towards 75° C. Once the internal temperature reached 60° C. the reaction may exotherm. It took a total of 20 minutes to heat the reaction to 75° C. Fifteen minutes after the internal temp had reached 60° C., an aliquot was removed and analyzed by HPLC, showing a 3:1 ratio of starting material to product. At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction. Each addition of TEA causes additional exotherms. Twenty minutes after the second NEt3 addition, an aliquot was removed and analyzed by HPLC, showing a 2:1 ratio of starting material to product. Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction. Thirty-five minutes after the final NEt3 addition, an aliquot was removed and analyzed by HPLC, showing >70:1 ratio of product to starting material. The reaction was heated for 30 min more, then cooled to <30° C. over 15 min. The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g). The solution stirred well for 2 hours then filtered over a cake of celite (28.5 g packed in a 4″ buchner funnel). This filtration of the bilayer through celite was slow, and the vacuum caused a significant portion of the organic solvent to boil away. The cake was washed with MTBE (250 mL followed by 125 mL). The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL), the phases mixed well, and the lower aqueous layer removed. The organic phase was extracted with H2O (200 mL) and the phases mixed well. The lower aqueous layer was removed. The organic layer was extracted with a 5% NaCl/H2O solution (200 mL). The phases were separated and the organic layer was added to a 1 L, 3-neck flask. The solution was concentrated by atmospheric distillation until the internal volume was ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K-F titration, showing 0.35% H2O. An additional portion of MTBE (150 mL) was added and distillation continued until the internal volume was again ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K—F titration, showing 0.14% H2O. The solution was cooled under nitrogen and held overnight at rt. The solution was used directly in the next reaction without further processing. 1H NMR (300 MHz, CDCl3): 1.52–1.72 (m, 9), 1.77 (s, 6), 2.73–2.92 (m, 4), 6.90–7.00 (m, 1), 7.33–7.39 (m, 1) A nitrogen-purged was sequentially charged The solution was then purged (subsurface) with N2 for 1 h a careful purge of the headspace reached 60° C. the reaction a total of 20 minutes to heat the reaction to 75° C Fifteen minutes had reached 60° C. an aliquot was removed At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction Each addition of TEA Twenty minutes after the second NEt3 addition an aliquot was removed Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction Thirty-five minutes after the final NEt3 addition an aliquot was removed The reaction was heated for 30 min more cooled to <30° C. over 15 min The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g) then filtered over a cake of celite (28.5 g This filtration of the bilayer through celite The cake was washed with MTBE (250 mL followed by 125 mL) The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL) the phases mixed well the lower aqueous layer removed The organic phase was extracted with H2O (200 mL) the phases mixed well The lower aqueous layer was removed The organic layer was extracted with a 5% NaCl/H2O solution (200 mL) The phases were separated the organic layer was added to a 1 L, 3-neck flask The solution was concentrated by atmospheric distillation until the internal volume After cooling below reflux an aliquot was removed An additional portion of MTBE (150 mL) was added distillation After cooling below reflux an aliquot was removed The solution was cooled under nitrogen held overnight at rt The solution was used directly in the next reaction without further processing

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2-L, 3-neck flask was charged with (4-bromo-2-fluorophenyl)acetonitrile (100.91 g, 0.4715 mol), MeOTs (156 mL g, 1.034 mol), DMF (400 mL) and THF (400 mL). The headspace was purged with nitrogen and the solution was cooled to −10° C. The NaOtBu (96.58 g, 1.005 mol) was divided into 4 equal portions that were added separately to the reaction to control the exotherm. Five minutes after the fourth and final charge an aliquot was removed and analyzed by HPLC, verifying reaction completion. The cold bath was removed, and the reaction allowed to stir without cooling (internal temp=4° C.). The flask was then charged with DABCO (13.02 g, 0.116 mol) to consume the remaining MeOTs. After 30 min an aliquot was removed and analyzed by HPLC, showing no detectable MeOTs. The flask was charged with H2O (400 mL) and hexanes (400 mL) and the mixture added to a separatory funnel. The phases were mixed well and then separated. The aqueous phase was re-charged to the separatory funnel and re-extracted with hexanes (200 mL). The organic phases from the first two extractions were combined and transferred back to the separatory funnel and washed twice with H2O (200 mL). The phases were separated and the organic layer was added to a 2-L, 3-neck flask set up for distillation. The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation occurred. An aliquot of the solution was removed and analyzed by 1H NMR to record the amount of solvents present. The solution of product was held overnight and used without further processing in the next step. The headspace was purged with nitrogen were added separately to the reaction Five minutes after the fourth and final charge an aliquot was removed reaction completion The cold bath was removed without cooling (internal temp=4° C.) to consume the remaining MeOTs After 30 min an aliquot was removed The flask was charged with H2O (400 mL) and hexanes (400 mL) the mixture added to a separatory funnel The phases were mixed well separated The aqueous phase was re-charged to the separatory funnel re-extracted with hexanes (200 mL) The organic phases from the first two extractions washed twice with H2O (200 mL) The phases were separated the organic layer was added to a 2-L, 3-neck flask set up for distillation The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation An aliquot of the solution was removed

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2-L, 3-neck flask was charged with (4-bromo-2-fluorophenyl)acetonitrile (100.91 g, 0.4715 mol), MeOTs (156 mL g, 1.034 mol), DMF (400 mL) and THF (400 mL). The headspace was purged with nitrogen and the solution was cooled to −10° C. The NaOtBu (96.58 g, 1.005 mol) was divided into 4 equal portions that were added separately to the reaction to control the exotherm. Five minutes after the fourth and final charge an aliquot was removed and analyzed by HPLC, verifying reaction completion. The cold bath was removed, and the reaction allowed to stir without cooling (internal temp=4° C.). The flask was then charged with DABCO (13.02 g, 0.116 mol) to consume the remaining MeOTs. After 30 min an aliquot was removed and analyzed by HPLC, showing no detectable MeOTs. The flask was charged with H2O (400 mL) and hexanes (400 mL) and the mixture added to a separatory funnel. The phases were mixed well and then separated. The aqueous phase was re-charged to the separatory funnel and re-extracted with hexanes (200 mL). The organic phases from the first two extractions were combined and transferred back to the separatory funnel and washed twice with H2O (200 mL). The phases were separated and the organic layer was added to a 2-L, 3-neck flask set up for distillation. The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation occurred. An aliquot of the solution was removed and analyzed by 1H NMR to record the amount of solvents present. The solution of product was held overnight and used without further processing in the next step. The headspace was purged with nitrogen were added separately to the reaction Five minutes after the fourth and final charge an aliquot was removed reaction completion The cold bath was removed without cooling (internal temp=4° C.) to consume the remaining MeOTs After 30 min an aliquot was removed The flask was charged with H2O (400 mL) and hexanes (400 mL) the mixture added to a separatory funnel The phases were mixed well separated The aqueous phase was re-charged to the separatory funnel re-extracted with hexanes (200 mL) The organic phases from the first two extractions washed twice with H2O (200 mL) The phases were separated the organic layer was added to a 2-L, 3-neck flask set up for distillation The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation An aliquot of the solution was removed

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

Procedure: To a slurry of sodium hydride (60% dispersion in mineral oil, 0.82 g, 20.6 mmol) in DMF (20 mL) cooled to 0° C. was added a solution of (4-bromo-2-fluoro-phenyl)-acetonitrile (2.0 g, 9.35 mmol) from Step 1 above, dissolved in THF (10 mL). The reaction was stirred till gas evolution ceased, and then iodomethane (1.3 mL, 20.6 mmol) was added slowly. The reaction was stirred for 30 minutes, and then diluted with 100 mL EtOAc. The solids were removed by filtration, and the organic layer was washed with 100 mL water. The organic layer was dried over MgSO4, and then filtered. The mother liquor was concentrated by rotary evaporation, and the product was distilled under high vacuum (0.3 torr, 45° C.). Yield: 2.25 g, 99%. %. 1H NMR (CDCl3) δ: 2.81 (s, 3H), 2.88 (s, 3H), 7.20–7.25 (m, 3H). The reaction was stirred for 30 minutes The solids were removed by filtration the organic layer was washed with 100 mL water The organic layer was dried over MgSO4 filtered The mother liquor was concentrated by rotary evaporation the product was distilled under high vacuum (0.3 torr, 45° C.)

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

Procedure: To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (3.0 g, 12.4 mmol) in diisopropylamine (32 mL) and DMF (16 mL) was added 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (3.2 g, 12.4 mmol), PdCl2(PPh3)2 (350 mg, 4 mol %), CuI (71 mg, 3 mol %). The mixture was heated to 90° C. for 30 min before it was cooled down to room temperature. The reaction was diluted with aqueous NH4Cl, extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (10–50% EtOAc in hexanes) to give the product (4.2 g, 79% yield). 1H NMR (300 MHz, CDCl3) δ: 1.65–1.76 (m, 14 H), 1.79 (s, 6 H), 1.82–1.85 (m, 1 H), 2.24 (s, 1 H), 2.59 (s, 1 H), 2.67 (m, 2 H), 5.46 (m, 1 H), 7.11 (dd, J=12.15, 1.60 Hz, 1 H), 7.18 (dd, J=8.10, 1.70 Hz, 1 H), 7.45 (t, J=8.10 Hz, 1 H). was cooled down to room temperature extracted with EtOAc (3×50 mL) The combined organic extracts were washed with brine dried with Na2SO4 evaporated to dryness The mixture was purified by flash column chromatography (10–50% EtOAc in hexanes)

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

Procedure: To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (3.0 g, 12.4 mmol) in diisopropylamine (32 mL) and DMF (16 mL) was added 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (3.2 g, 12.4 mmol), PdCl2(PPh3)2 (350 mg, 4 mol %), CuI (71 mg, 3 mol %). The mixture was heated to 90° C. for 30 min before it was cooled down to room temperature. The reaction was diluted with aqueous NH4Cl, extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (10–50% EtOAc in hexanes) to give the product (4.2 g, 79% yield). 1H NMR (300 MHz, CDCl3) δ: 1.65–1.76 (m, 14 H), 1.79 (s, 6 H), 1.82–1.85 (m, 1 H), 2.24 (s, 1 H), 2.59 (s, 1 H), 2.67 (m, 2 H), 5.46 (m, 1 H), 7.11 (dd, J=12.15, 1.60 Hz, 1 H), 7.18 (dd, J=8.10, 1.70 Hz, 1 H), 7.45 (t, J=8.10 Hz, 1 H). was cooled down to room temperature extracted with EtOAc (3×50 mL) The combined organic extracts were washed with brine dried with Na2SO4 evaporated to dryness The mixture was purified by flash column chromatography (10–50% EtOAc in hexanes)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A nitrogen-purged, 2-L, 3-neck flask containing 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (114.14 g, 0.4715 mol) was sequentially charged (while stirring) with LiCl (39.62 g, 0.9347 mol), LiOAc (15.41 g, 0.2334 mol), DMAc (283 mL), and H2O (28.3 mL). The solution was then purged (subsurface) with N2 for 1 h. The flask was then charged with 1-cyclopentyl-prop-2-en-1-ol (73.70 g, 0.5808 mol), Et3N (6.5 mL, 0.0466 mol, 10% of the total to be added), and Pd(OAc)2 (5.2487 g, 0.0234 mol) followed by a careful purge of the headspace. The reaction was heated towards 75° C. Once the internal temperature reached 60° C. the reaction may exotherm. It took a total of 20 minutes to heat the reaction to 75° C. Fifteen minutes after the internal temp had reached 60° C., an aliquot was removed and analyzed by HPLC, showing a 3:1 ratio of starting material to product. At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction. Each addition of TEA causes additional exotherms. Twenty minutes after the second NEt3 addition, an aliquot was removed and analyzed by HPLC, showing a 2:1 ratio of starting material to product. Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction. Thirty-five minutes after the final NEt3 addition, an aliquot was removed and analyzed by HPLC, showing >70:1 ratio of product to starting material. The reaction was heated for 30 min more, then cooled to <30° C. over 15 min. The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g). The solution stirred well for 2 hours then filtered over a cake of celite (28.5 g packed in a 4″ buchner funnel). This filtration of the bilayer through celite was slow, and the vacuum caused a significant portion of the organic solvent to boil away. The cake was washed with MTBE (250 mL followed by 125 mL). The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL), the phases mixed well, and the lower aqueous layer removed. The organic phase was extracted with H2O (200 mL) and the phases mixed well. The lower aqueous layer was removed. The organic layer was extracted with a 5% NaCl/H2O solution (200 mL). The phases were separated and the organic layer was added to a 1 L, 3-neck flask. The solution was concentrated by atmospheric distillation until the internal volume was ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K-F titration, showing 0.35% H2O. An additional portion of MTBE (150 mL) was added and distillation continued until the internal volume was again ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K-F titration, showing 0.14% H2O. The solution was cooled under nitrogen and held overnight at rt. The solution was used directly in the next reaction without further processing. 1H NMR (300 MHz, CDCl3): 1.52-1.72 (m, 9), 1.77 (s, 6), 2.73-2.92 (m, 4), 6.90-7.00 (m, 1), 7.33-7.39 (m, 1) A nitrogen-purged was sequentially charged The solution was then purged (subsurface) with N2 for 1 h a careful purge of the headspace reached 60° C. the reaction a total of 20 minutes to heat the reaction to 75° C Fifteen minutes had reached 60° C. an aliquot was removed At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction Each addition of TEA Twenty minutes after the second NEt3 addition an aliquot was removed Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction Thirty-five minutes after the final NEt3 addition an aliquot was removed The reaction was heated for 30 min more cooled to <30° C. over 15 min The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g) then filtered over a cake of celite (28.5 g This filtration of the bilayer through celite The cake was washed with MTBE (250 mL followed by 125 mL) The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL) the phases mixed well the lower aqueous layer removed The organic phase was extracted with H2O (200 mL) the phases mixed well The lower aqueous layer was removed The organic layer was extracted with a 5% NaCl/H2O solution (200 mL) The phases were separated the organic layer was added to a 1 L, 3-neck flask The solution was concentrated by atmospheric distillation until the internal volume After cooling below reflux an aliquot was removed An additional portion of MTBE (150 mL) was added distillation After cooling below reflux an aliquot was removed The solution was cooled under nitrogen held overnight at rt The solution was used directly in the next reaction without further processing

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2-L, 3-neck flask was charged with (4-bromo-2-fluorophenyl)acetonitrile (100.91 g, 0.4715 mol), MeOTs (156 mL g, 1.034 mol), DMF (400 mL) and THF (400 mL). The headspace was purged with nitrogen and the solution was cooled to −10° C. The NaOtBu (96.58 g, 1.005 mol) was divided into 4 equal portions that were added separately to the reaction to control the exotherm. Five minutes after the fourth and final charge an aliquot was removed and analyzed by HPLC, verifying reaction completion. The cold bath was removed, and the reaction allowed to stir without cooling (internal temp=4° C.). The flask was then charged with DABCO (13.02 g, 0.116 mol) to consume the remaining MeOTs. After 30 min an aliquot was removed and analyzed by HPLC, showing no detectable MeOTs. The flask was charged with H2O (400 mL) and hexanes (400 mL) and the mixture added to a separatory funnel. The phases were mixed well and then separated. The aqueous phase was re-charged to the separatory funnel and re-extracted with hexanes (200 mL). The organic phases from the first two extractions were combined and transferred back to the separatory funnel and washed twice with H2O (200 mL). The phases were separated and the organic layer was added to a 2-L, 3-neck flask set up for distillation. The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation occurred. An aliquot of the solution was removed and analyzed by 1H NMR to record the amount of solvents present. The solution of product was held overnight and used without further processing in the next step. The headspace was purged with nitrogen were added separately to the reaction Five minutes after the fourth and final charge an aliquot was removed reaction completion The cold bath was removed without cooling (internal temp=4° C.) to consume the remaining MeOTs After 30 min an aliquot was removed The flask was charged with H2O (400 mL) and hexanes (400 mL) the mixture added to a separatory funnel The phases were mixed well separated The aqueous phase was re-charged to the separatory funnel re-extracted with hexanes (200 mL) The organic phases from the first two extractions washed twice with H2O (200 mL) The phases were separated the organic layer was added to a 2-L, 3-neck flask set up for distillation The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation An aliquot of the solution was removed

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2-L, 3-neck flask was charged with (4-bromo-2-fluorophenyl)acetonitrile (100.91 g, 0.4715 mol), MeOTs (156 mL g, 1.034 mol), DMF (400 mL) and THF (400 mL). The headspace was purged with nitrogen and the solution was cooled to −10° C. The NaOtBu (96.58 g, 1.005 mol) was divided into 4 equal portions that were added separately to the reaction to control the exotherm. Five minutes after the fourth and final charge an aliquot was removed and analyzed by HPLC, verifying reaction completion. The cold bath was removed, and the reaction allowed to stir without cooling (internal temp=4° C.). The flask was then charged with DABCO (13.02 g, 0.116 mol) to consume the remaining MeOTs. After 30 min an aliquot was removed and analyzed by HPLC, showing no detectable MeOTs. The flask was charged with H2O (400 mL) and hexanes (400 mL) and the mixture added to a separatory funnel. The phases were mixed well and then separated. The aqueous phase was re-charged to the separatory funnel and re-extracted with hexanes (200 mL). The organic phases from the first two extractions were combined and transferred back to the separatory funnel and washed twice with H2O (200 mL). The phases were separated and the organic layer was added to a 2-L, 3-neck flask set up for distillation. The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation occurred. An aliquot of the solution was removed and analyzed by 1H NMR to record the amount of solvents present. The solution of product was held overnight and used without further processing in the next step. The headspace was purged with nitrogen were added separately to the reaction Five minutes after the fourth and final charge an aliquot was removed reaction completion The cold bath was removed without cooling (internal temp=4° C.) to consume the remaining MeOTs After 30 min an aliquot was removed The flask was charged with H2O (400 mL) and hexanes (400 mL) the mixture added to a separatory funnel The phases were mixed well separated The aqueous phase was re-charged to the separatory funnel re-extracted with hexanes (200 mL) The organic phases from the first two extractions washed twice with H2O (200 mL) The phases were separated the organic layer was added to a 2-L, 3-neck flask set up for distillation The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation An aliquot of the solution was removed

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2-L, 3-neck flask was charged with (4-bromo-2-fluorophenyl)acetonitrile (100.91 g, 0.4715 mol), MeOTs (156 mL g, 1.034 mol), DMF (400 mL) and THF (400 mL). The headspace was purged with nitrogen and the solution was cooled to −10° C. The NaOtBu (96.58 g, 1.005 mol) was divided into 4 equal portions that were added separately to the reaction to control the exotherm. Five minutes after the fourth and final charge an aliquot was removed and analyzed by HPLC, verifying reaction completion. The cold bath was removed, and the reaction allowed to stir without cooling (internal temp=4° C.). The flask was then charged with DABCO (13.02 g, 0.116 mol) to consume the remaining MeOTs. After 30 min an aliquot was removed and analyzed by HPLC, showing no detectable MeOTs. The flask was charged with H2O (400 mL) and hexanes (400 mL) and the mixture added to a separatory funnel. The phases were mixed well and then separated. The aqueous phase was re-charged to the separatory funnel and re-extracted with hexanes (200 mL). The organic phases from the first two extractions were combined and transferred back to the separatory funnel and washed twice with H2O (200 mL). The phases were separated and the organic layer was added to a 2-L, 3-neck flask set up for distillation. The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation occurred. An aliquot of the solution was removed and analyzed by 1H NMR to record the amount of solvents present. The solution of product was held overnight and used without further processing in the next step. The headspace was purged with nitrogen were added separately to the reaction Five minutes after the fourth and final charge an aliquot was removed reaction completion The cold bath was removed without cooling (internal temp=4° C.) to consume the remaining MeOTs After 30 min an aliquot was removed The flask was charged with H2O (400 mL) and hexanes (400 mL) the mixture added to a separatory funnel The phases were mixed well separated The aqueous phase was re-charged to the separatory funnel re-extracted with hexanes (200 mL) The organic phases from the first two extractions washed twice with H2O (200 mL) The phases were separated the organic layer was added to a 2-L, 3-neck flask set up for distillation The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation An aliquot of the solution was removed

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

Procedure: To a slurry of sodium hydride (60% dispersion in mineral oil, 0.82 g, 20.6 mmol) in DMF (20 mL) cooled to 0° C. was added a solution of (4-bromo-2-fluoro-phenyl)-acetonitrile (2.0 g, 9.35 mmol) from Step 1 above, dissolved in THF (10 mL). The reaction was stirred till gas evolution ceased, and then iodomethane (1.3 mL, 20.6 mmol) was added slowly. The reaction was stirred for 30 minutes, and then diluted with 100 mL EtOAc. The solids were removed by filtration, and the organic layer was washed with 100 mL water. The organic layer was dried over MgSO4, and then filtered. The mother liquor was concentrated by rotary evaporation, and the product was distilled under high vacuum (0.3 torr, 45° C.). Yield: 2.25 g, 99%. %. 1H NMR (CDCl3) δ: 2.81 (s, 3H), 2.88 (s, 3H), 7.20-7.25 (m, 3H). The reaction was stirred for 30 minutes The solids were removed by filtration the organic layer was washed with 100 mL water The organic layer was dried over MgSO4 filtered The mother liquor was concentrated by rotary evaporation the product was distilled under high vacuum (0.3 torr, 45° C.)