We have created a pipeline of recently enhanced open source components for extracting chemical reactions from full text chemical literature. OSCAR4 is used to recognise chemical entities and resolve to structures where appropriate. OPSIN is used to resolve systematic chemical names to structures. Chemical Tagger performs part of speech tagging allowing the interpretation of phrases in chemical syntheses. The final output is a semantic representation (chemical components and their roles, reaction conditions, actions including workup, yield and properties of the product). We then attempt to map all atoms in the product(s) to reactants. If successful we also attempt to calculate the stoichiometry of the reaction. The system has been deployed on over 56,000 USPTO patents published since 2008. The level of recall is useful and most extracted reactions make chemical sense. The pipeline is generally applicable to reactions in chemical literature including journals and theses.

1. Automated Extraction of Reactions from the
Patent Literature
Daniel Lowe
Unilever Centre for Molecular Science Informatics
University of Cambridge
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2. Chemistry patent applications
• 100,000s applications each year
400000
350000
Chemistry patent applications per year
300000
250000
200000
150000
100000
50000
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
World Intellectual Property Indicators, 2011 edition
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3. 3

4. The idea
XML patents
Reaction
Extraction
System
Extracted Reactions
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5. Steps involved
• Identifying experimental sections
• Identifying chemical entities
• Chemical name to structure conversion
• Associating chemical entities with quantities
• Assigning chemical roles
• Atom-atom mapping
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6. Building on existing projects
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7. Archetypal experimental section
Section heading
Section target
compound
Step identifier
Step target
compound
Paragraph number
Synthesis
Workup
Characterisation
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8. Jessop, D. M.; Adams, S. E.; Murray-Rust, P.
Mining Chemical Information from Open
Patents. Journal of Cheminformatics 2011, 3, 40.
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9. ChemicalTagger
• Tags words of text
• Parses tags to identify phrases
• Generate XML parse tree
– http://chemicaltagger.ch.cam.ac.uk/
– Hawizy, L.; Jessop, D. M.; Adams, N.; Murray-Rust, P. ChemicalTagger: A tool for
semantic text-mining in chemistry. J Cheminf 2011, 3, 17.
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10. Tagging
• Regex tagger: tags keywords e.g. “yield”, “mL”
• OSCAR4 tagger: Finds names OSCAR4 believes to be chemical
e.g. “2-methylpyridine”
• OpenNLP: Tags parts of speech
Additional taggers:
• OPSIN tagger: Finds names OPSIN can parse
• Trivial chemical name tagger: Tags a few chemicals missed by
the other taggers and cases that are partially matched by
the regex tagger e.g. Dess-martin reagent
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11. Sample ChemicalTagger Output
<MOLECULE>
<OSCARCM>
<OSCAR-CM>methyl</OSCAR-CM>
<OSCAR-CM>4-(chlorosulfonyl)benzoate</OSCAR-CM>
</OSCARCM>
<QUANTITY>
<_-LRB->(</_-LRB->
<MASS>
<CD>606</CD>
<NN-MASS>mg</NN-MASS>
</MASS>
<COMMA>,</COMMA>
<AMOUNT>
<CD>2.1</CD>
<NN-AMOUNT>mmol</NN-AMOUNT>
</AMOUNT>
<COMMA>,</COMMA>
<EQUIVALENT>
<CD>1</CD>
<NN-EQ>eq</NN-EQ>
</EQUIVALENT>
<_-RRB->)</_-RRB->
</QUANTITY>
</MOLECULE>
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12. Phrase Identification
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13. Quantity Identification
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14. Section/Step Parsing
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15. Pyridine, pyridines and pyridine rings
The pyridine / Pyridines / Pyridine ring /
Entity Pyridine
Pyridine from step 1 A pyridine Pyridyl
Type Exact DefiniteReference ChemicalClass Fragment
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16. Section/Step Parsing
Workup phrase types : Concentrate, Degass,
Dry, Extract, Filter, Partition, Precipitate,
Purify, Recover, Remove, Wash, Quench
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17. Atom-mapping
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18. Example
Methyl 4-[(pentafluorophenoxy)sulfonyl]benzoate
To a solution of methyl 4-(chlorosulfonyl)benzoate (606
mg, 2.1 mmol, 1 eq) in DCM (35 ml) was added
pentafluorophenol (412 mg, 2.2 mmol, 1.1 eq) and Et3N
(540 mg, 5.4 mmol, 2.5 eq) and the reaction mixture stirred
at room temperature until all of the starting material was
consumed. The solvent was evaporated in vacuo and the
residue redissolved in ethyl acetate (10 ml), washed with
water (10 ml), saturated sodium hydrogen carbonate (10
ml), dried over sodium sulphate, filtered and evaporated to
yield the title compound as a white solid (690 mg, 1.8
mmol, 85%).
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19. Graphical Output
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20. CML output
<reaction xmlns="http://www.xml-cml.org/schema" xmlns:cmlDict="http://www.xml-cml.org/dictionary/cml/" xmlns:nameDict="http://www.xml-..
<dl:reactionSmiles>Cl[S:2]([c:5]1[cH:14][cH:13][c:8]([C:9]([O:11][CH3:12])=[O:10])[cH:7][cH:6]1)(=[O:4])=[O:3].[F:15][c:16]1[c:21]([OH:22])[c:20]([..
<productList>
<product role="product"> Reaction SMILES
<molecule id="m0">
<name dictRef="nameDict:unknown">title compound</name>
</molecule>
<amount units="unit:mmol">1.8</amount>
<amount units="unit:mg">690</amount> Quantities including yield are extracted
<amount units="unit:percentYield">85.0</amount>
<identifier dictRef="cml:smiles" value="FC1=C(C(=C(C(=C1OS(=O)(=O)C1=CC=C(C(=O)OC)C=C1)F)F)F)F"/>
<identifier dictRef="cml:inchi" value="InChI=1/C14H7F5O5S/c1-23-14(20)6-2-4-7(5-3-6)25(21,22)24-13-11(18)9(16)8(15)10(17)12(13)19/h2-5H..
<dl:entityType>definiteReference</dl:entityType>
<dl:state>solid</dl:state> SMILES and InChIs for every structure
</product> resolvable reagent/product
</productList>
<reactantList> Entity is classified as an exact compound,
<reactant role="reactant" count="1">
<molecule id="m1">
definite reference, chemical class or polymer
<name dictRef="nameDict:unknown">methyl 4-(chlorosulfonyl)benzoate</name>
</molecule>
<amount units="unit:mmol">2.1</amount>
<amount units="unit:mg">606</amount>
<amount units="unit:eq">1.0</amount>
<identifier dictRef="cml:smiles" value="ClS(=O)(=O)C1=CC=C(C(=O)OC)C=C1"/>
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21. Evaluation
• 2008-2011 USPTO patent applications classified as containing
organic chemistry  65,034 documents.
• 484,259 reactions atom mapped reactions extracted
• Adding the additional requirements that all the identified
product molecules were resolvable to structures and that all
reagents were believed to describe exact compounds
 424,621 reactions.
• 100 of these were selected for manual evaluation of quality
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22. Reactions found
100,000
10,000
Patents with given number of reactions
1,000
100
10
1
0 200 400 600 800 1000
Number of extracted reactions
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23. Results
• 96% correctly identified the primary starting material and product
whilst not misidentifying reagents that could be confused with the
starting material
• As compared to the 495 expected chemical entities there were 61 false
positives and 16 false negatives
• Only 4 of the 321 reagents (with quantities) did not have these
quantities recognised and associated with the reagent
• Association of quantities/yields with products was less successful, 48
out of the 74 cases where such data was present were handled
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24. Use Cases
• Reaction searching
• Analysing trends in reactions over time
• Reaction outcome prediction
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25. Example of reaction searching
C[CH:1]=[CH2:2].ICI>>C([CH:1]1[CH2:2][CH2]1)
6 reactions found in 5 patents
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26. Name I20110224.tarUS20110046406A1-20110224.ZIP0066
Text from US 2011/0046406 A1
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27. Most lexical variants
1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride
EDCI hydrochloride
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride
N-ethyl-N'-(3-dimethylamino-propyl)-carbodiimide hydrochloride
And 127 more!
N-[3-(Dimethylamino) propyl]-N'-ethylcarbodiimide hydrochloride
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl
675 chemicals had over
1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
1-(-3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride 10 lexical variants!
N-(3-Dimethylamino-1-propyl)-N'-ethylcarbodiimide hydrochloride
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride
1-(3-(Dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride
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28. Most common solvents
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29. Known Limitations
• The first workup reagent is often erroneously classified as a
reactant
• Atom mapping produces mappings that are not necessarily
representative of reaction mechanism and occasionally
involve clearly incorrect atoms
• Conditions from analogous reactions are not resolved
• Temperature/time for reactions to occur not captured
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30. Conclusions
• 424,621 exact atom-mapped reactions were
extracted from 4 years of USPTO patent
applications
• Evaluation indicates the reactions to be of
generally good quality especially if the
misidentification of workup reagents as
reactants is not considered important
• All the code to extract reactions is open source:
https://bitbucket.org/dan2097/patent-reaction-extraction
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31. Acknowledgements
Unilever centre: Indigo toolkit:
Robert Glen Mikhail Rybalkin
Peter Murray-Rust Savelyev Alexander
Lezan Hawizy Dmitry Pavlov
David Jessop
Matthew Grayson
Boehringer Ingelheim for funding SMARTS searching:
Roger Sayle
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32. Any Questions?
Email: daniel@nextmovesoftware.com
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