(Chemical Equation Presented) 4,5,6-Trifluoropyridazin-3(2H)-one can be used as a scaffold for the synthesis of various 4,5- and 4,6-disubstituted and ring-fused pyridazinone systems by sequential nucleophilic aromatic substitution processes. Although the regioselectivity of nucleophilic substitution can be affected by the nature of the nucleophile and the substituent attached to the pyridazinone ring, a variety of polyfunctional systems can be readily accessed by sequential nucleophilic substitution methodology which may have applications in the drug discovery arena. For example, reaction of 4,5,6-trifluoropyridazin- 3(2H)-one with nitrogen nucleophiles leads to a mixture of aminated products arising from substitution of fluorine located at the 4- and 5-positions. The ratio of isomers obtained depends on the nucleophile where the 4-isomer is the major product for reaction with primary and secondary amines such as butylamine, morpholine, and aniline derivatives. Subsequent reaction of representative 4-aminated products gave 4,5-disubstituted systems and ring fused derivatives may be formed by reaction of 4,5,6-trifluoropyridazin-3(2H)-one or 4-substituted systems with N,N′-dimethylethylenediamine.