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ABSTRACT The overall goal of a process chemistry department within the pharmaceutical industry is to identify and develop a commercially viable approach to a drug candidate. However, the

high chemical complexity of many modern pharmaceuticals presents a challenge to process scientists. Delivering disruptive, rather than incremental, change is critical to maximizing synthetic

efficiency in complex settings. In this Review, we focus on the importance of synthetic strategy in delivering ‘disruptive innovation’ — innovation that delivers a step change in synthetic

efficiency using new chemistry, displacing any prior synthetic route. We argue that achieving this goal requires visionary retrosynthetic strategy and is tightly linked to the discovery and

development of new reactions and novel processes. Investing in high-risk innovation during the route design process can ultimately lead to safer, more robust and more efficient manufacturing

processes capable of addressing the challenge of high molecular complexity. Routinely delivering such innovation in a time-bound environment requires organizational focus and can be enabled

by the concepts of expansive ideation, strategy aggregation and strategy selection. Access through your institution Buy or subscribe This is a preview of subscription content, access via

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SOLID-PHASE SYNTHESIS Article 19 April 2021 THE LANDSCAPE OF SMALL-MOLECULE PRODRUGS Article 02 April 2024 MOLECULAR CHAMELEONS IN DRUG DISCOVERY Article 20 December 2023 REFERENCES *

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1162–1168 (2010). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank all of the collaborators and researchers who have worked on these fascinating molecules

during their development. M.D.E. and M.A.S. are especially grateful to P. Baran for insightful discussions and inspiration, along with S. Tummala, R. Waltermire, A. Ortiz and C. Guerrero

for helpful discussions. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, 08901, New Jersey, USA Martin

D. Eastgate & Michael A. Schmidt * Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, 06877, Connecticut, USA Keith R. Fandrick Authors *

Martin D. Eastgate View author publications You can also search for this author inPubMed Google Scholar * Michael A. Schmidt View author publications You can also search for this author

inPubMed Google Scholar * Keith R. Fandrick View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Martin D. Eastgate.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3

POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5 POWERPOINT SLIDE FOR FIG. 6 POWERPOINT SLIDE FOR FIG. 7 POWERPOINT SLIDE FOR FIG. 8 GLOSSARY * Ideation Ensuring the robust and

expansive evaluation of all key strategic bonds, developing a much fuller retrosynthetic analysis before entering the lab, and using the collective wisdom of multiple researchers to raise

and address concerns. * Strategy aggregation Taking the multiple synthetic proposals, or proposed disconnections, and collating them into clusters of aligned core disconnection strategies or

reactivities, not focusing on any individual technology or precedent. Key experiments can rapidly be explored in the lab to assist in the triaging of strategies. * Strategy selection

Aligning the team on selecting a strategy, not an individual synthesis proposal. The selected strategy should have multiple related synthetic options (for example, shared reactivity patterns

or common intermediates) such that high-risk disruptive approaches can be investigated, while data gained from the exploration can be applied to lower-risk proposals. Appropriate selection

can also lead to a more effective staged approach to synthesis development, which is often crucial in aligning work to the risk of the drug progressing to market. RIGHTS AND PERMISSIONS

Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Eastgate, M., Schmidt, M. & Fandrick, K. On the design of complex drug candidate syntheses in the pharmaceutical industry.

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