Dedicated to Professor Dr. Andrea Vasella on the occasion of his 65th birthday By attaching (methyl)-or (difluoromethyl)-phosphonate groups to the 1-positions of ethene, cyclopentene or benzene, and attaching 1-(methyl)-5-chlorouracil or 1-(methyl)thymine groups to the corresponding 2-positions, compounds 1 -5 were prepared as potential inhibitors of recombinant human thymidine phosphorylase (TP). The products were designed to mimic the interatomic distance (ca. 3.41 ) between the incoming phosphate and leaving pyrimidine groups at the transition state for the putative S N 2 mechanism of TP. Free rotation around the (unsaturated-CH 2 ) -pyrimidine bonds in 1 -5 enabled a span of ca. 2.40 -4.40 between the CH 2 or CF 2 C-atoms in the phosphonates and N(1) of the pyrimidines to be covered. The products were found to be ineffective inhibitors, and some reasons for this are given.