Can easy chemistry produce complex, diverse, and novel molecules?

Statements, such as 'you need to break free from amide-formations to improve molecular properties' and 'novel chemistry leads to novel biology' are frequently encountered in the medicinal chemistry community. To verify whether truth lies in such preconceptions, we investigated whether complex, diverse, and novel molecules can be made by 'easy' chemistry. By analyzing the AstraZeneca screening collection, we conclude that novelty, diversity, and molecular complexity is currently not compromised by the use of the most popular reaction, amide bond formation, mainly because of a recent steady increase in unique amines available. Easy chemistry allows speedy access to a broad chemical space, facilitating progress in projects, and opens the possibility of synthesis automation and new technologies (e.g. DNA-encoded libraries).