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Abstract
An analysis of chemical reactions used in current medicinal chemistry (2014), three
decades ago (1984), and in natural product total synthesis has been conducted. The
analysis revealed that of the current most frequently used synthetic reactions, none
were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura
and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic
reactions in drug discovery. The most frequently used reactions were amide bond formation,
Suzuki-Miyaura coupling, and SNAr reactions, most likely due to commercial availability
of reagents, high chemoselectivity, and a pressure on delivery. We show that these
practices result in overpopulation of certain types of molecular shapes to the exclusion
of others using simple PMI plots. We hope that these results will help catalyze improvements
in integration of new synthetic methodologies as well as new library design.