Scientific & technical presentation Virtual Synthesis - Reactor

1. Scientific & technical presentation Virtual Synthesis - Reactor

2. Why do Virtual Synthesis? • 33.5 million compounds are registered in CAS (January 2008) • The estimated number of „realizable” molecules is 10120-10200 • There are 1079 atoms in the Universe Most compounds can not be synthesized! http://www.cas.org www.swisseduc.ch/chemie/vsn/veranst/ethkolloq/docs/carreira.ppt http://www.nso.edu/PR/answerbook/universe.html

3. Elements of the Virtual Synthesis Technology • Chemical properties predictions • Calculator Plugins • A language for describing chemical rules • Chemical Terms • A library of selective reactions „knowing” chemistry • Chemaxon Reaction Library • A reaction engine with high capacity and performance • Reactor • Virtual synthesis applications • Synthesizer (combinatorial, random, exhaustive)

4. Chemical Terms, a Language for Cheminformatics Elements of the language • structure matching functions (describing functional groups, reaction sites, similarity…) • property calculations (partial charge distribution, pKa, logP, localization energy…) • arithmetic and logic-operators Chemical Terms examples

5. Calculator Plugins acceptor acceptorCount acceptorSiteCount acidicpKa acidicpKaLargeModel aliphaticAtom aliphaticAtomCount aliphaticBondCount aliphaticRingCount angle aromaticAtom aromaticAtomCount aromaticBondCount aromaticElectrophilicityOrder aromaticNucleophilicityOrder aromaticRingCount array asymmetricAtom asymmetricAtomCount atno atomCount atomicPolarizability averagePolarizability balabanIndex basicpKa basicpKaLargeModel BCUT bond bondCount bondType canonicalResonant canonicalTautomer carboaromaticRingCount carboRingCount chainAtom chainAtomCount chainBond chainBondCount charge chiralCenter chiralCenterCount composition conformer conformerCount conformers connected connectedGraph connections count cxsmarts cxsmiles cyclomaticNumber dihedral dissimilarity distance distanceDegree donor donorCount donorSiteCount dotDisconnectedFormula doubleBondStereoisomer doubleBondStereoisomerCount doubleBondStereoisomers dreidingEnergy eccentricity electrophilicLocalizationEnergy enumeration enumerationCount enumerations exactMass field filter formalCharge formula fusedAliphaticRingCount fusedAromaticRingCount fusedRingCount hararyIndex hasValidConformer hydrogenCount heavy heteroaromaticRingCount heteroRingCount hyperWienerIndex isoelectricPoint isotopeComposition isotopeFormula largestAtomRingSize largestRingSize logD logP logPIncrement logS logSMicro logSNeutral logSTrue lowestEnergyConformer majorMicrospecies majorMs map mass match matchCount max maxAtom maxValue microspecies microspeciesCount microspeciesDistribution min minAtom minValue molBinFormat molecularPolarizability molFormat molImage name nucleophilicLocalizationEnergy pair piChargeDensity piEnergy piOrbitalElctronegativity pKa plattIndex polarizability property randicIndex refractivity refractivityIncrements resonant resonantCount resonants ringAtom ringAtomCount ringBond ringBondCount ringCount ringCountOfAtom rotatableBond rotatableBondCount shortestPath sigmaOrbitalElectronegativity smallestAtomRingSize smallestRingSize smarts smiles solubility solubilityAtIsoelectricPoint solubilityOfMicroSpecies solubilityOfNeutral solventAccessibleSurfaceArea sortAsc sortDesc stereoisomer stereoisomerCount stereoisomers stericEffectIndex stericHindrance sum szegedIndex tautomer tautomerCount tautomers tetrahedralStereoisomer tetrahedralStereoisomerCount tetrahedralStereoisomers topologicalPolarSurfaceArea totalChargeDensity traditionalName uniqueSmiles valence vanDerWaalsSurfaceArea wienerIndex wienerPolarity

6. Applications of Chemical Terms virtual synthesis reaction and synthesis rules CT pharmacophore analysis pharmacophore definitions drug design goal functions structure searching advanced query expressions

7. Charles Friedel 1832-1899 James Mason Crafts 1839-1917 Encoding Synthetic Knowledge in ReactionsThe Friedel-Crafts acylation

8. Encoding Synthetic Knowledge in ReactionsThe Friedel-Crafts acylation: generic scheme The hydrogen of an aromatic carbon atom is substituted with an acyl group of an acid halide during hydrogen halide elimination. C(a) aromatic carbon atom L[O, S] oxygen or sulfur atom L[Cl, Br, I] chlorine, bromine or iodine atom

9. Encoding Synthetic Knowledge in ReactionsThe Friedel-Crafts acylation: finding reactive sites REACTIVITY:charge(ratom(1), "aromaticsystem") < -0.2 Friedel-Crafts acylation occurs only if the aromatic system is at least as activated as mono-halobenzenes.

10. Encoding Synthetic Knowledge in ReactionsThe Friedel-Crafts acylation: finding the most reactive sites SELECTIVITY:-energyE(ratom(1)) TOLERANCE:0.02 Directing rule: the electrophilic substitution takes place on the aromatic carbon atom with the lowest localization energy having an attached electrophile in the transition state.Aromatic carbon with the lowest localization energy provides the main product. Other aromatic carbons having similar localization energies (with less difference than 0.02) are also considered to lead to main products.

11. Encoding Synthetic Knowledge in ReactionsThe Friedel-Crafts acylation: excluding compounds giving side reactions,destroying the catalyst EXCLUDE: match(reactant(1), "[Cl,Br,I]C(=[O,S])C=C") || match(reactant(0), "[H][O,S]C=[O,S]") || match(reactant(0), "[P][H]") || (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) || (max(pka(reactant(0), filter(reactant(0), "match('[#7:1][H]', 1)"), "basic")) > 0) Exclude aromatic compounds containing nucleophilic groupsand acrylic halides. For example, phenols and indols are processed, but benzylalcohols or anilines are not.

12. Encoding Synthetic Knowledge in ReactionsThe Friedel-Crafts acylation as a smart reaction REACTIVITY:charge(ratom(1), "aromaticsystem") < -0.2 SELECTIVITY:-energyE(ratom(1)) TOLERANCE:0.02 EXCLUDE:match(reactant(1), "[Cl,Br,I]C(=[O,S])C=C") || match(reactant(0), "[H][O,S]C=[O,S]") || match(reactant(0), "[P][H]") || (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) || (max(pka(reactant(0), filter(reactant(0), "match('[#7:1][H]', 1)"), "basic")) > 0

13. Reactants Products Reactor, the engine ChemAxon Reaction Library Baeyer-Villiger ketone oxidation Baylis-Hillman vinyl alkylation Beckmann rearrangement Bischler-Napieralski isoquinoline synthesis Friedel-Crafts reaction Friedlander quinoline synthesis Gabriel synthesis Grignard reaction Hell-Volhardt-Zelinski halogenation REACTOR

14. Reactor the Application

15. The Reaction Editor

16. Reactor, key features Effective • millions of compounds in a combinatorial reaction • up to 500,000 compounds / hour (P4 1.8 GHz) Compatible • reactions: MRV, RXN, RDF, SMARTS/SMIRKS • compounds: MRV, MOL, SDF, SMILES • mapping: MDL, Daylight, automapper Flexible • memory, file and database operations (via Oracle Cartridge) • sequential or combinatorial mode • compound or reaction output type • reverse direction Smart • chemo-, regio- and stereospecific • customizable Available • Java API, command line tool, JSP, GUI • premade reaction library • documentation and examples • free for the Academic community

17. Visit othertechnical presentations MarvinSketch/Viewhttp://www.chemaxon.com/MarvinSketch_View.ppt MarvinSpacehttp://www.chemaxon.com/MarvinSpace.ppt Calculator Pluginshttp://www.chemaxon.com/Calculator_Plugins.ppt JChem Basehttp://www.chemaxon.com/JChem_Base.ppt JChem Cartridgehttp://www.chemaxon.com/JChem_Cartridge.ppt Standardizerhttp://www.chemaxon.com/Standardizer.ppt Screenhttp://www.chemaxon.com/Screen.ppt JKlustorhttp://www.chemaxon.com/JKlustor.ppt Fragmenterhttp://www.chemaxon.com/Fragmenter.ppt Reactor http://www.chemaxon.com/Reactor.ppt