The study by Liu et al. explores the late-stage saturation (LSS) of drug molecules, particularly aromatic and heteroaromatic drugs, to improve their medicinal properties. The authors demonstrate that these molecules can be readily saturated under mild conditions using rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation. This process converts sp³ carbon atoms into sp³ carbon atoms, leading to saturated molecules with enhanced solubility, selectivity, and metabolic stability. The methods are effective in a wide range of chemical spaces, producing complex pharmaceuticals with various functional groups and three-dimensional structures. Notably, the rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, making it suitable for reforming pharmaceutical compound collections stored in wet DMSO. The study also highlights the potential of LSS to improve the synthetic efficiency and expand the three-dimensional chemical space of drugs, offering a valuable tool for drug discovery and optimization.The study by Liu et al. explores the late-stage saturation (LSS) of drug molecules, particularly aromatic and heteroaromatic drugs, to improve their medicinal properties. The authors demonstrate that these molecules can be readily saturated under mild conditions using rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation. This process converts sp³ carbon atoms into sp³ carbon atoms, leading to saturated molecules with enhanced solubility, selectivity, and metabolic stability. The methods are effective in a wide range of chemical spaces, producing complex pharmaceuticals with various functional groups and three-dimensional structures. Notably, the rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, making it suitable for reforming pharmaceutical compound collections stored in wet DMSO. The study also highlights the potential of LSS to improve the synthetic efficiency and expand the three-dimensional chemical space of drugs, offering a valuable tool for drug discovery and optimization.