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ARChem on the National Chemical Database Service Portal

A description of the ARChem retrosynthetic analysis system under the CDS portal for UK academics. General approach, system design and access details.

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ARChem on the National Chemical Database Service Portal

  1. 1. ARChem – Synthesizing Ideas Bringing Computational Power to Organic Synthesis RSC Presentation - SimBioSys Inc. Orr Ravitz Chief Operating Officer
  2. 2. What is the value of a good synthetic idea?
  3. 3. The Motivation Goal: Synthesize quickly, efficiently, economically, ecologically. Intuition Knowledge Experience Literature Data: - 1000’s of high utility synthetic methods - 100,000’s of building blocks The value of a good idea:  Faster R&D turnaround – remain ahead of the curve  Synthetic efficiency – lower development, production costs  Better use of human time – increased productivity
  4. 4. Chemical data have been used in the same manner for over 100 years! Synthetic plan Thought process There is more than one way to synthesize a compound. Little in current approaches assists in finding the better ones. • Non-linear • Highly biased • Driven by intuition and knowledge • Gaps filled using literature searches
  5. 5. What is a synthetic idea? A full synthetic route, a key step, a critical sequence of reactions Not necessarily in your “comfort zone” Utilizing starting materials efficiently No obvious published precedent
  6. 6. Why Computer-Aided Synthesis Design? Cover more options, miss less opportunities Chemist Creativity Intuition Strategic perspective Knowledge (what works, what doesn’t) Computer Thoroughness Lack of bias Speed Low cost
  7. 7. The Approach • Comprehensive rule- and precedent-based retrosynthetic analysis back to available starting materials. • Automated rule generation with manual rule curation. • Generate many alternatives. • Provide supporting literature examples. • Allow user guidance and control.
  8. 8. Rule Generation Reactions MOS Reaction Rules
  9. 9. Reactions Reaction Rules Reaction Perception Source reaction: Extracted core Extended core Reaction file with atom mapping Atoms attached to bonds changed, made or broken in the reaction Include all structural motifs that are essential for the reaction to occur
  10. 10. Rule Extraction Similar extended cores Completed reaction rule Common extracted core Nucleofuge (NF) - a leaving group which carries away the bonding electron pair. Generalized rule Generalized group (NF) is replaced by the most common group. Reactions Reaction Rules
  11. 11. Source reactions Esterification examples Other examples ··· → ··· ··· → ··· ··· → ··· Esterification rule Other rule ··· → ··· Reactions Reaction Rules Rule Extraction
  12. 12. System Design Reactions MOS Reaction Rules Starting Materials Expert Knowledge- bases Target
  13. 13. Limitations Associated with Small Reaction Source Methods in Organic Synthesis (MOS) – 44,000 mapped reactions. • Partial coverage of synthetic methods • Small clusters – higher risk of over- and under-constrained rules • Not enough statistical power for supplementary information – yield, regioselectivity • Too few examples to determine functional group tolerance • Exact matches are rare Larger databases are available, but not as part of CDS: • Reaxys - Elsevier • ChemInform (CIRX) – Wiley & Sons
  14. 14. Solutions Ranking Prioritization of the alternatives – show best solutions first Transforms merit is evaluated using: • Reduction of target complexity (simplifying transforms before FGI/FGA). • Minimize wastage (atom efficient reactions). • Starting material coverage. • Prefer thoroughly explored chemistry (based on example count) . • Penalty for interference. • Yield.
  15. 15. Registering
  16. 16. Quota System • Each institution is assigned a search quota • Registration is open only when searches are available • For registered users – new search page deactivated when quota is filled • Old searches remain accessible even when quota is filled
  17. 17. ARChem – Synthesizing Ideas Bringing Computational Power to Organic Synthesis SimBioSys Inc. Thank you! For more information: Orr Ravitz, Ph.D. ravitz@simbiosys.com +1 (416) 741-4263
  18. 18. ARChem Transforming data into Knowledge. Generating ideas. Reactions Reaction Rules Starting Materials High Level Reasoning examples methods Reaction mechanisms Synthetic strategies Search strategies Solutions ranking Methods in Organic Synthesis
  19. 19. US Patent 6,211,244 NPS Pharm. 2001