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

1. ARChem – Synthesizing Ideas
Bringing Computational Power to Organic Synthesis
RSC Presentation - SimBioSys Inc.
Orr Ravitz
Chief Operating Officer

2. What is the value of a good
synthetic idea?

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. 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. 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. 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. 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. Rule Generation
Reactions
MOS
Reaction Rules

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. 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. Source reactions
Esterification examples
Other examples
··· → ···
··· → ···
··· → ···
Esterification rule
Other rule
··· → ···
Reactions
Reaction Rules
Rule Extraction

12. System Design
Reactions
MOS
Reaction Rules
Starting Materials
Expert Knowledge-
bases
Target

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. 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. Registering

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. 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. 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

20. US Patent 6,211,244
NPS Pharm. 2001