Table 1.

Summary of activity‐directed synthesis case studies.

	Biological target (assay type)	Underpinning chemistry	Medicinal chemistry strategy	Number of rounds and reactions	Discoveries
1 (Figure 2, 9)	Androgen receptor (FRET)	Metal carbenoid	Scaffold discovery	3 rounds (36, 192 and 108 reactions)	Agonists and partial agonists with sub‐micromolar activity Scaffolds with no previously annotated AR activity
2 (Figure 3, 11)	Androgen receptor (FRET)	Metal carbenoid	Fragment growth	3 rounds (192, 86 and 48 reactions)	Four distinct chemotypes Elaborated fragments with low micromolar (or better) activity
3 (Figure 4, 12)	S. aureus (cell‐based bacterial)	Pd‐catalysed carbonylation	SAR expansion	1 round (220 reactions)	Expanded series of antibacterial quinazolinones
4 (Figure 5, 14)	p53/hDM2 PPI (fluorescence anisotropy)	Metal carbenoid	Scaffold hopping	2 rounds (154 and 192 reactions)	Experimental scaffold hopping to yield low micromolar PPI inhibitors Ligands for a binding site not evolved to bind small molecules