This study presents a method for late-stage saturation (LSS) of drug molecules using mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed hydrogenation conditions. These methods convert aromatic carbon atoms (sp²) into sp³ carbon atoms, leading to saturated molecules with improved medicinal properties. The approach is effective for a wide range of chemical space, producing complex saturated pharmaceuticals with various functional groups and three-dimensional architectures. The rhodium-catalyzed method is compatible with traces of dimethyl sulfoxide (DMSO) or water, enabling the use of pharmaceutical compound collections stored in wet DMSO as substrates for chemical synthesis. The study demonstrates the LSS of 768 complex and densely functionalized small-molecule drugs. The research highlights the importance of increasing the fraction of sp³ carbon atoms (Fsp³) in drug molecules to improve solubility, selectivity, and metabolic stability. LSS allows for the modification of complex molecular structures at a late stage, enabling the exploration of chemical space and property space. The study shows that LSS can significantly enhance drug properties, such as solubility, stability, and potency, as demonstrated by examples like the saturation of SARS-CoV M pro inhibitor and TNKS1 inhibitors. The method is also effective for various drug candidates, including those with multiple stereocenters and complex functional groups. The study also demonstrates the scalability and versatility of LSS, with the ability to process a large number of drug-like molecules in a high-throughput format. The LSS protocol was tested on a library of 768 drugs stored in wet DMSO, and the results showed a high conversion rate to saturated products. The method is tolerant of various reaction conditions, including different solvents, temperatures, and concentrations, making it suitable for both traditional and miniaturized scales. The study also highlights the potential of LSS to improve the synthetic efficiency and complement retrosynthetic strategies, as demonstrated by the synthesis of several drug candidates in a single step. Overall, the study demonstrates the potential of LSS as a valuable tool in drug discovery, enabling the rapid exploration of three-dimensional chemical space and the development of safer, more effective, and metabolically stable drugs. The method is user-friendly, efficient, and compatible with a wide range of substrates, making it a promising approach for the future of pharmaceutical research.This study presents a method for late-stage saturation (LSS) of drug molecules using mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed hydrogenation conditions. These methods convert aromatic carbon atoms (sp²) into sp³ carbon atoms, leading to saturated molecules with improved medicinal properties. The approach is effective for a wide range of chemical space, producing complex saturated pharmaceuticals with various functional groups and three-dimensional architectures. The rhodium-catalyzed method is compatible with traces of dimethyl sulfoxide (DMSO) or water, enabling the use of pharmaceutical compound collections stored in wet DMSO as substrates for chemical synthesis. The study demonstrates the LSS of 768 complex and densely functionalized small-molecule drugs. The research highlights the importance of increasing the fraction of sp³ carbon atoms (Fsp³) in drug molecules to improve solubility, selectivity, and metabolic stability. LSS allows for the modification of complex molecular structures at a late stage, enabling the exploration of chemical space and property space. The study shows that LSS can significantly enhance drug properties, such as solubility, stability, and potency, as demonstrated by examples like the saturation of SARS-CoV M pro inhibitor and TNKS1 inhibitors. The method is also effective for various drug candidates, including those with multiple stereocenters and complex functional groups. The study also demonstrates the scalability and versatility of LSS, with the ability to process a large number of drug-like molecules in a high-throughput format. The LSS protocol was tested on a library of 768 drugs stored in wet DMSO, and the results showed a high conversion rate to saturated products. The method is tolerant of various reaction conditions, including different solvents, temperatures, and concentrations, making it suitable for both traditional and miniaturized scales. The study also highlights the potential of LSS to improve the synthetic efficiency and complement retrosynthetic strategies, as demonstrated by the synthesis of several drug candidates in a single step. Overall, the study demonstrates the potential of LSS as a valuable tool in drug discovery, enabling the rapid exploration of three-dimensional chemical space and the development of safer, more effective, and metabolically stable drugs. The method is user-friendly, efficient, and compatible with a wide range of substrates, making it a promising approach for the future of pharmaceutical research.