Overall, the crystallographic results identify which vectors can be elaborated, with what type of chemical group and to what extent, thereby providing an estimate of the crystallographic SAR landscape around fragment F709 (Fig. ). Several modifications, including replacing the piperazine a with diazepane moiety or dimethyl-piperazine, replacing the furan with a 6-membered ring or tri-heterocyclic ring, and adding a sulphonamide to the furan, in Iter 4.2 (Fig. ), consistently resulted in non-binding events despite positive quality control confirming that their synthesis has been successful. We also recognize that there might be a high proportion of false negatives as soaking of crude reaction mixtures and high-throughput methodologies, in general, maximises data quantity over quality. However, our sampling of the chemical space was thorough enough to cause a change of binding pose paired with protein conformational changes that would not have been identified by classical or guided docking methods. It is also interesting to note that such chemical exploration would not have been possible without the use of multi-step chemistry thus highlighting the importance of those more laborious routes.