Warfarin is the most globally prescribed anti-coagulant/blood thinner for treatment of stroke and heart attack. The drug is a known potent rodenticide whose therapeutic and toxicol. mechanism is due to its activity as a vitamin-K antagonist that disrupts the reductive recycling of vitamin-K at the enzyme vitamin-K epoxide reductase (VKOR). As a therapeutic, warfarin activity in the patient is highly sensitive to the metabolome of blood especially in individuals whose diets contain variable amounts of vitamin-K and other plant-based coumarin ring functional groups. Warfarin, in contrast to its toxicity in rats and mice, is not poisonous in humans owing, in part, to its ability to bind to the transporter human serum albumin (SA) which buffers its free concentration in blood. SA′s are largely alpha helical proteins with a mol. weight of 66kDa and are known to bind to warfarin at the Type-I binding pocket. Although only the S-Warfarin enantiomer is thought to be therapeutically active at VKOR, the R- enantiomer is found to be relatively benign owing to its ability to also bind to SA whose Type-I binding pocket is only mildly chirally-selective. To date we have determined that the differential binding of R- and S-warfarin to SA is only about 2 kcal/mol. To continue these studies we plan to extend our synthetic approaches to include addnl. fluorinated warfarin derivatives Such modifications will result in new compounds which likely still exhibit anticoagulant activity but with modified binding to the Type-I site on SA and hence affect the absorption, distribution, metabolism, and elimination (ADME) properties of the drug in vivo. Here we introduce the synthesis, purification, and characterization of phenyl-substituted fluorinated warfarin derivatives by the macroscale Michael Addition method in combination with the classic quinidine resolution of R- and S-enantiomers and present our initial attempts to explore the syntheses of the fluorinated derivatives with microscale combinatorial methods in conjunction with LC-MS/MS for purification and anal. and sym. and asym. conditions.