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Virtual Synthesis - Reactor

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1 Virtual Synthesis - Reactor
Scientific & technical presentation Virtual Synthesis - Reactor

2 Elements of the Virtual Synthesis Technology
Chemical property predictions Calculator Plugins A language for describing chemical rules Chemical Terms A library of selective reactions Chemaxon Reaction Library A high performance reaction engine Reactor Virtual reaction applications Reactor (wizard, JChem for Excel, Instant Jchem) Metabolizer Our goal was to design and develop a high performace software system able to process virtual reactions in a synthetically feasible way. In-silico libraries of synthetic reactions can be used with no or minimal preparations, since the correspoding chemical knowledge base is built in each reaction definition.

3 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 structure search match("olefine.mol") and !match("c1ccncc1") and (atomCount("16") == 0) or (mass() < 300); goal function inhibitor = inhibitor.mol; similarity(inhibitor, chemical_tanimoto) - similarity(inhibitor, pharmacophore_tanimoto); drug likeness filter (mass() <= 500) and (logP() <= 5) and (donorCount() <= 5) and (acceptorCount() <= 10); Complex chemical expressions can be described in Chemical Terms.

4 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 Since the Chemical Terms language supports an open plugin system, the list of available functions can be extended.

5 Applications of Chemical Terms
virtual synthesis reaction and synthesis rules CT pharmacophore analysis pharmacophore definitions drug design goal functions Chemical Terms is the key customization component in various cheminformatics areas, from pharmacophore analysis to virtual synthesis. structure searching advanced query expressions

6 Encoding Synthetic Knowledge in Reactions The Friedel-Crafts acylation
James Mason Crafts Charles Friedel The technology behind the ChemAxon Reaction Library is introduced by the modelling of the Friedel-Crafts reaction.

7 Encoding Synthetic Knowledge in Reactions The 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 The generic reaction scheme describes the transformation only. This keeps the equation relatively simple. Stereospecific transformations can be marked on the scheme (i.e. inversion/retentions, cis-trans modifications)

8 Encoding Synthetic Knowledge in Reactions The 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 monohalobenzenes. The REACTIVITY rule refines the generic scheme by describing reactive and inactive functional groups (chemospecificity).

9 Encoding Synthetic Knowledge in Reactions The 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 carbons having the lowest electrophilic localization energies provide the main product. Aromatic carbons having similar localization energies to the lowest one (within 0.02 tolerance range) are included. When more than one reactive sites are found in a reactant, the main product is determined the SELECTIVITY rule (regiospecificity). A TOLERANCE value for the SELECTIVITY rule allows the generation of more than one main products.

10 Encoding Synthetic Knowledge in Reactions The Friedel-Crafts acylation: excluding compounds giving side reactions, destroying the catalyst EXCLUDE: match(reactant(1), "[Cl,Br,I]C(=[O,S])C=C") or match(reactant(0), "[H][O,S]C=[O,S]") or match(reactant(0), "[P][H]") or (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) or "match('[#7:1][H]', 1)"), "basic")) > 0) The EXCLUDE field defines those functional groups, which can cause side reactions or can lead to unexpected results. Exclude aromatic compounds containing nucleophilic groups and acrylic halides. For example, phenols and indols are processed, but benzylalcohols or anilines are not.

11 Encoding Synthetic Knowledge in Reactions The Friedel-Crafts acylation as a smart reaction
REACTIVITY: charge(ratom(1), "aromaticsystem") < -0.2 SELECTIVITY: -energyE(ratom(1)) TOLERANCE: 0.02 The complete definition of a "smart" virtual Friedel-Crafts reaction. The effect of steric issues and simpler nucleophility calculations will be introduced later. EXCLUDE: match(reactant(1), "[Cl,Br,I]C(=[O,S])C=C") or match(reactant(0), "[H][O,S]C=[O,S]") or match(reactant(0), "[P][H]") or (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) or "match('[#7:1][H]', 1)"), "basic")) > 0

12 ChemAxon Reaction Library
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 Reactants Products REACTOR

13 Reactor the Application

14 The Reaction Editor

15 Reactor Module in Instant JChem
The Reactor module of Instant JChem provides an easy to use virtual synthesis application for the scientists working in local or corporate database environments.

16 Reactor in JChem for Excel
JChem for Excel is a new application bringing ChemAxon’s cheminformatics toolkit to Microsoft Excel. Reactor is integrated as one of the first features.

17 Reactor, key features Effective Compatible Flexible Smart Available
millions of compounds in a combinatorial reaction high performance (speed depends on the complexity of the reaction) Compatible reactions: MRV, RXN, RDF, SMARTS/SMIRKS, CDX, SKC compounds: MRV, MOL, SDF, SMILES, CDX, SKC mapping: changing atoms, matching atoms, all atoms Flexible memory, file and database operations sequential and combinatorial modes compound, reaction and fused reaction output types reverse direction Smart chemo-, regio- and stereospecific customizable behaviour reactant ratio to specify excess Available Java and .NET API, command line tool, wizard, Jchem for Excel, Instant JChem premade reaction library documentation and examples free for the Academic community

18 Visit other technical presentations
MarvinSketch/View MarvinSpace Calculator Plugins JChem Base JChem Cartridge Standardizer Screen JKlustor Fragmenter Reactor

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