3). Use of n-propanephosphonic acid anhydride (T3P) as the coupling agent with triethylamine (TEA) as the base also yielded a 60:40 ratio of 1 and 2, as did N,N′-diisopropylcarbodiimide (DIC) with 4-dimethylaminopyridine (DMAP) (entries 4 and 5). Each of these amide coupling reactions (entries 1-5) occurred in the presence of strongly basic amines with pKa 9.7-10.9. Switching to 1ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in combination with hydroxybenzotriazole (HOBt), where amide coupling occurs without the addition of an amine base resulted in an improved 70:30 ratio of 1 and 2 (entry 6). This result prompted us to trial the amide synthesis with the original benzotriazole tetramethyl uronium coupling agent but as a tetrafluoroborate salt (TBTU) in pyridine as a solvent. Under these less basic conditions (entry 7) exclusive formation of 1 was observed by UPLC analysis. An alternate synthesis of b-amidomethyl-vinyl sulfone 1 was also developed to avoid the liability of cyclization during the amide bond formation (Scheme 3). MOM-protection of pyrazole 3 occurred exclusively at the N1 position as expected and was confirmed by 1 H-13 C HMBC NMR analysis. Coupling of MOM-protected pyrazole 5 using the TBTU-pyridine protocol gave exclusively amide 6 with no byproducts resulting from cyclization. Acid mediated cleavage of the MOM protecting group yielded pure 1 as an HCl salt without the need for chromatography. The HCl salt of 1 was stable upon storage as a solid or as a 10 mM DMSO stock solution. pyrazin-4(5H)-one Conditions for controlled cyclization of the HCl salt of b-amidomethyl-vinyl sulfone 1 to dihydropyrazolo pyrazin-4(5H)-one 2 by intramolecular aza-Michael reaction were explored (Table ). Reactions were performed at room temperature for 2h in the presence of different bases with the conversion to 2 monitored by UPLC. K2CO3 in ethanol gave efficient cyclization (entry 1). However, no cyclization occurred with K2CO3 in water due to the limited aqueous solubility of 1 (entry 2). Na2CO3 in an aqueous dioxane mixture resulted in clean cyclization to 2 (entry 3). The less basic NaHCO3 in methanol or water was not as effective as K2CO3 (entries 4 and 5) within the 2h reaction time. The amine base TEA in methanol was also less effective (entry 6). The stronger amine bases DIPEA or DBU showed faster conversion to 2 but were still not as rapid as the inorganic bases (entries 7 and 8). Na2CO3 in an aqueous dioxane (entry 3) was chosen as the optimal cyclization conditions for synthesis of 2 since it was fast, resulted in a simple work-up, and avoided the need for chromatography.