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pyl)-3-ethylcarbodiimide.HCl (EDC.HCl) (1940 g) was added portionwise over 15-30 min. The reaction temperature was kept below 35° C. When the reaction appeared complete (approx. two hours, <5% pyrazine 2-carboxylic acid by LC assay), the reaction mixture (yellow/white slurry) was diluted with 10% ~CO$_{3 }$ in water (24 L, 20 mL/g acid) and the reaction slurry was kept below 35° C. The slurry was cooled to 10° C., aged for two hours and filtered (mother liquor assay=3-4 mg/mL). The wet cake was washed with deionized water (12 L, 10 mL/g acid) and dried under vacuum (22" Hg) at 40° C. with a nitrogen purge. Theoreti› cal yield of 1816 g . Actual yield 1533 g (84%). 

[0399] $^{1}$H NMR: (CD$_{3}$ CN, 400 MHz): o9.29(d, 1=1.5 Hz, lH), 8.82 (d, 1=2.5 Hz, lH), 8.63 (dd, 1=2.6,1.4 Hz, lH), 8.40 (bs, lH), 4.14 (dq, 1=9.4, 6.8 Hz, 2H). 

[0400] HPLC Assay conditions: Waters Xterra RPS col› umn, elution with acetonitrile and 5 mM K phosphate adjusted to pH=8, detection at 220 nm. 

[0401] Step Two: 

[0402] Preparation of the piperazine amide 

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[0403] Pyrazine amide (60.2 g 0.268 mol, not corrected for water content) was suspended in absolute ethanol (550 mL) in a 1.0 L autoclave hydrogenation vessel and cooled to 15° C. Wet 20% Pd(OH)iC 11.0 g (20 wt %, S0wt % wet) was added and reaction was purged with N$_{2 }$ three times. H$_{2 }$ (5 psig) was introduced with stirring and the temperature maintained at 15° C. for 60 minutes. The temperature was then increased to 60° C. and the hydrogen pressure increased to 40 psig and the reaction mixture stirred for 18 additional hours. The reaction was considered complete when conver› sion is >99% by LC assay. The reaction mixture was filtered through Solka-Floc and the catalyst solids were washed with ethanol 2x110 mL. Assay of the combined filtrate and washes gave 53.5 g of racemic piperazine amide (Yield= 86%) 

[0404] $^{1}$H NMR (CD$_{3}$ CN, 400 MHz): 07.58 (bs, lH), 3.90 (dq, 1=9.5,6.7 Hz, 2H), 3.24(dd, 1=7.9, 5.5 Hz, lH), 2.96 (dd, 1=12.1, 3.6 Hz, lH), 2.84-2.78 (m, lH), 2.77-2.67 (m, 3H), 2.66-2.56 (m, lH), 1.90 (s, 2 H). 

[0405] HPLC Assay conditions: YMC Basic column, elu› tion with acetonitrile and 0.1 % aqueous H$_{3}$PO$_{4}$, detection at 210 nm. 

[0406] Step Three: 

[0407] Resolution of the piperazine amide 

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[0408] The pip amide ethanol filtrate (116.37 g containing 10.3 g of racemic pip amide by LC assay) was concentrated in vacuo to a final volume of 40.2 mL (3.9 mL per gram of pip amide) and the slurry is diluted with 82.4 mL (8 mL per gram pip amide) of acetonitrile (ACN) and stirred until homogenous. Separately (S)-camphorsulfonic acid ((S)› CSA) (19.26 g, MW=232.30, 1.7 eq) was dissolved in 185 mL of ACN (18 mL per gram of pip amide). The water content of the two solutions was then determined by Karl Fisher titration. The CSA solution was added to the pip amide solution giving a small exotherm to approx. 31-32° C. Water (11.02 mL, 1.118 mL per gram of pip amide minus the total water content of the two solutions) was then added, such that the acetonitrile:ethanol:water ratio was 26:2.9:1.1 (v/v/v). Solids began to form after 15-30 min. The solution/ slurry was heated to 72° C. to completely dissolve all solids. The yellow solution was recooled to 62° C. and seeded with a slurry of 10.3 mg of pip amide salt in 1 mL of acetonitrile. After a two hour age at 62° C. the slurry was allowed to cool to room temperature overnight ( crystallization was complete when loss to mother liquors was <21 mg pip amide/mL by LC assay. The slurry was filtered then washed with 2x30 mL of ACN:EtOH:H$_{2}$O [(26:2.9:1.1), (v:v:v)] solution. The wet cake (-13 g, white solid) was dried at 40° C. in a vacuum oven (24 in Hg, nitrogen sweep) to give 11.16 g of product (yield=33%). Assay method (Pip Amide) as above. Chiral assay gives an enantiomeric excess (ee) of 98.0%. 

[0409] $^{1}$H NMR (CD$_{3}$OD, 400 MHz): d4.84(bs, SH), 4.64 (dd, 1=12.0, 3.6 Hz, lH), 4.13-3.9 (m, 3H), 3.77 (m, 2H), 3.66 (m, lH), 3.54-3.43 (m, 2H), 3.28(d, 1=14.7 Hz, 2H), 2.82 (d, 14.7 Hz, 2H), 2.55 (m, 2H), 2.36 (m, 2H), 2.12- 1.998 (m, 4H), 1.92 (d, 1=18.4 Hz, 2H), 1.72 (m, 2H), 1.45 (m, 2H), 1.09 (s, 6H), 0.87 (s, 6H). 

[0410] Enantiomeric excess determined by chiral HPLC of the mono BOC piperazine amide. HPLC assay condi› tions: Chiral AGP column, elution with acetonitrile and 10 mM Kphospate, pH=6.5, detection at 210 nm. 

