The general structure of the pyrimidinone hit cluster was a 3-ring aromatic scaffold comprised of a pyrimidinone, pyrazole, and an amide-coupled phenyl for which a 5-step linear synthetic sequence was designed. The pyrimidinone portion of the scaffold (Scheme 1) was synthesized via initial cyclocondensation of thiourea and ethyl 3-oxopentanoate to produce 6-ethyl thiouracil intermediate (2). Intermediate 2 was selectively S-methylated with a slight excess of methyl iodide starting at 3 °C and was allowed to warm to room temperature producing intermediate 3. Nucleophilic substitution of 3 with hydrazine produced intermediate 4. This intermediate was then heated with 3-aminocrotonitrile and underwent a regioselective cyclization creating the pyrazolo-pyrimidinone intermediate 5. Finally, after extensive troubleshooting with numerous amide coupling protocols including benzoyl chloride and standard amide coupling, a procedure adapted from literature 46 using fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH) to produce sterically minimal benzoyl fluoride intermediates was able furnish low to moderate yields for the final amide products 1, 6, 9-32, 36-40. The methoxymethyl containing analog 32 was deprotected to yield the phenol 33. Yields for analogs with electron-rich benzoic acids (e.g. 21-26) were below the quantity necessary for biological testing, thus further optimization led to a final reaction using lithium bis(trimethylsilyl)amide (LiHMDS) pre-activation of the primary amine alongside in situ benzoyl fluoride activation of benzoic acids to provide yields sufficient for testing for these more synthetically-challenging analogs.