Tips and Tricks Chemistry November 2005

2006 Edition CAS... we are scientists, creating and delivering the most complete and effective digital information environment for scientific research and discovery CAS is a self-sustaining division of the American Chemical Society CAS employs 1250 staff members in Columbus, Ohio Chemical Abstracts Service, CAS

2006 Edition CAS Content... the world’s largest collection of chemical and related scientific information for the research community including: Most authoritative collection of substance information available Worldwide coverage of current and comprehensive journals and patents Chemical Abstracts Service, CAS

2006 Edition SciFinder content CAplus from CAS with 25.6 mil references, abstracts and detailed indexing from –Sources: 9,500 journals, patents from 50 offices, internet journals and preprint servers, conferences, theses and report –Citations from journals and patents Registry from CAS with ~83.5 mil substances –Small molecules, biosequences, polymers, inorganics, alloys, complexes –Single compounds have experimental data from InfoChem and CAS and have calculated data from ACDlabs

2006 Edition SciFinder content CASREACT from CAS with 9.2 mil single and multi-step reactions –From journals and patents, ChemCats from CAS with supplier data from 914 catalogues –Screening compounds, fine chemicals and some bulk for 8 mil compounds Chemlist from CAS with regulatory information Medline from NLM with 15.5 mil records from –Sources: 3200 journals

2006 Edition Unique and comprehensive databases: Creating Content

2006 Edition SciFinder benefits Easy access to largest database covering chemistry and related sciences relevant to drug discovery –Solid look at IP status for substances and biosequences –Advanced analysis tools to handle larger answer sets in a creative way –Powerful alerting due to high currency of the information –Content and interface designed by scientists for scientists –Big time save not having to run experiments that are well documented in the literature –Big money save not having to continue projects that have already received patent protection by competition

2006 Edition Agenda Structure searching features Substance viewer features Get related feature Reaction searching in SF2006 Novel compound or freedom to operate?

2006 Edition Structures in SciFinder The CAS Registry file contains over 26.4 million small molecules or small sequences At present over 6.2 mil structures have defined stereochemistry in the structure Stereochemistry is not available for certain classes of compounds –Coordination compounds, allenes and cumulenes (not searchable), stereo bond between two ring systems

2006 Edition Structure searching in SF SciFinder and Scholar use a broader structure search, which includes tautomers and related compounds –Double bond geometry may be impacted by a tautomer –Carbohydrates and hemiacetals may have different configurations (included as hits)

2006 Edition Searching a stereo structure

2006 Edition Automatic analyze by stereo

2006 Edition Absolute stereo answers These answers will have the R-stereoisomers pictured either with the bond into the plane or out of the plane. The author must have provided complete configuration of the stereo node.

2006 Edition Absolute stereo mirror image answers These answers will have the S-stereoisomers pictured either with the bond into the plane or out of the plane. It is also called the “meso” compound of our structure.

2006 Edition Relative stereo answers These answers will have the stereochemistry defined relative to another chiral center. The stereochemistry could be shown as R,S or S,R being identical for relative stereoisomers. Relative stereo answers can be useful for structure searches with multiple chiral centers.

2006 Edition Stereo answers not matching These answers do not have the desired stereochemistry at the node we searched, but there is stereochemistry elsewhere in the molecule. In this case it is the Z double bond geometry. If we had searched a compound with R,R bonds, we would also see the R,S and S,R answers in this set.

2006 Edition No stereo in answer structure These answers will be completely flat structures (or racemic mixtures) with no other stereochemistry in the structure that was searched. Some compounds with stereochemistry in the name may still be found in this set.

2006 Edition Three types of structure searches Exact search Substructure search Similarity search Additional filters

2006 Edition Example: Warfarin ( )

2006 Edition Exact structure search Retrieves 135 answers –47 single compound substances 14 unlabelled compounds 33 radio-labelled compounds –88 salts and mixtures Of these there are 26 tautomers

2006 Edition Substructure search Retrieves 613 answers –424 single compound substances 375 unlabelled compounds 49 radio-labelled compounds –189 salts and mixtures There are 57 tautomers There are 38 compounds with a mol weight of >500 All 135 answers of the exact search are included in this answer

2006 Edition Similarity search Ranks the compounds according to their Tanimoto similarity score based on structural attributes The 109 compounds with a score of ≥ 99 are the same as the 135 exact compounds minus the 26 tautomers

2006 Edition Substructure is very different from similarity search Unique answer for similarity search Unique answer for substructure search

2006 Edition Additional analyze features Analyze by real-atom attachment –Useful to see a breakdown of the types of substitution at different nodes of your query Analyze by ring skeleton –Beware this only analyzes the rings that are part of the query structure, not any ring Analyze by precision –Separates out the exact structure, close and loose tautomer answers

2006 Edition Example query structure X = any Halogen R1=O/N You may define an R-group as the VAP node; you may define multiple VAP nodes to the same ring system

2006 Edition Classes of substances Substance class or the type of study can be selected using the additional options before the search

2006 Edition Analyze your answers

2006 Edition Real atom attachment Makes a distinction between C and Ak and Cb Select option to refine your search

2006 Edition Real atom attachment (2) Cannot analyze a node that is part of a repeating group. Halogen attachments are in addition to the X drawn at a variable position

2006 Edition Variable node analyze Compounds may have additional halogen substitution on the phenyl ring, so numbers may be higher

2006 Edition Precision analyze Conventional structure match exactly Closely assoc. tautomers have 1 bond shifted or created Loosely assoc. tautomers have bigger variation Make a selection to remove unwanted answers

2006 Edition Precision analyze: close tautomer This compound is considered a close tautomer, because the second double bond in the ring, could also be drawn as a keto substituent, which would have matched the query.

2006 Edition Ring skeleton analyze Option to analyze only the shape, the shape and atoms, the shape, atoms and bonds or rings that have at least one atom in common with the query structure

2006 Edition Refine substances

2006 Edition Refine: want a maximum of 2 halogens anywhere on the phenyl Replaced the specific phenyl with a generic Cb node. One X is drawn; second optional halogen is defined as R2=H,X. The tool “lock substitution” prevents additional substituents

2006 Edition Agenda Structure searching features Substance viewer features Get related feature Reaction searching in SF2004 Novel compound or freedom to operate?

2006 Edition Search options from substance viewer = Same as Get References = View 3D (Accelrys software) = Commercial suppliers = Search exact compound in a reaction explore = Regulatory information

2006 Edition Exact reaction link: specify the role in the reaction Could work very well for reactions in water or reactions with a specific catalyst

2006 Edition Exact reaction link results Leads to 871 reactions from 258 documents

2006 Edition Get Reference Link Records from are not associated to any roles

2006 Edition Get Reference link Not all publications in Chemical Abstracts are selected for CASREACT !! (only 258 out of 480 with reaction indexing)

2006 Edition Agenda Structure searching features Substance viewer features Get related feature Reaction searching in SF2004 Novel compound or freedom to operate?

2006 Edition Get related feature Starting your search from a text explore Obtain all the substances indexed in the reference list –Answer set must be <1000 references –Refine with structure fragments or calculated properties Obtain all reactions indexed from the listed references Obtain the older cited references or forward citing references –Answer set must be <500 references

2006 Edition RC metathesis ( )

2006 Edition Limit the related substances that are indexed as products

2006 Edition All indexed products We are interested in compounds with a ring atoms

2006 Edition All indexed products

2006 Edition 411 large rings as products

2006 Edition Get References again SciFinder didn’t remember the original search at this point

2006 Edition Hard to do this search starting with all large ring compounds

2006 Edition Agenda Structure searching features Substance viewer features Get related feature Reaction searching in SF2004 Novel compound or freedom to operate?

2006 Edition Reaction Searching in SF/SFS CASREACT database offers full reaction searching –Reactions from CAS cover 1985-present –Reactions from InfoChem –Common enzymatic reactions –Reactions from INPI Contains new/novel reactions not all reactions Details of solvents, catalysts, reagents not routinely indexed in CAplus

2006 Edition Searching in CASREACT By structure fragments for products, reactant/reagents –Indicate reacting bond (reaction site) –Indicate reaction map (identical atom in reactant and product) –Compounds indexed as solvents or catalysts cannot be searched by structure By functional groups –Indicate role: product, reactant, reagent, or non-reacting

2006 Edition Searching by Functional Groups Non-reacting role allows for searching reactions “in the presence of” a group

2006 Edition Reaction Searching in SF/SFS Registry and CAplus –All preparative literature with most reaction participants indexed with CASRN –Solvents, catalysts only indexed if novel or emphasized by the author –Pre-1967 literature partially indexed by CAS RNs Use older names or formulas for the substance

2006 Edition Coupling reaction of dialkylphenols

2006 Edition Reaction example Run a closed or open structure search New up front limitation options

2006 Edition Reaction example As soon as you move over any substance in the reaction display the formula or the structure becomes a button to request more information Click substance

2006 Edition Reaction example Information from patents and journals Single step and multi-step reactions; click the microscope for intermediate reaction steps

2006 Edition Reaction example Scroll down for all steps; the mouse wheel is now enabled for power-scrolling

2006 Edition View options Get only one sample reaction per document Hypertext link to other query hit reactions from that document

2006 Edition Analyze Reactions

2006 Edition Click on a substance for more info Commercial availability or retrosynthetic steps

2006 Edition Reaction example Reactions will search the compound itself as a reaction participant References will show the list of references limited by the usual roles Substance details for the Registry record Commercial sources from Chemcats Regulatory info from Chemlist

2006 Edition No commercial availability

2006 Edition Reaction example Retrieves new reactions with this substance as the reaction product

2006 Edition Reaction Information Creates an infinite path of reaction browsing Can use the [BACK] button to go to the previous reaction answers Is only available to SF subscription users and SciFinder Scholar users

2006 Edition Getting references and abstracts

2006 Edition References from the reactions

2006 Edition Reaction searching Remember, CASREACT has a focus on novel reactions For a more comprehensive preparative answer, search the substance in Registry and refine by the preparation role If necessary search by names or by CAS number without roles for information from

2006 Edition Reactions in Registry/CAplus

2006 Edition

Compare to 8 documents from our reaction search !! More comprehensive answers

2006 Edition Searching for specific catalysts Catalysts and solvents are not structure searchable in the reaction explore Possibility to search them via the exact, substructure or similarity search and select “Get Reactions” with the appropriate reaction role Example: finding reactions catalyzed by similar compounds to Proline, a well known organocatalyst

2006 Edition Running a similarity search on Proline

2006 Edition Selecting similar compounds, but not Proline itself

2006 Edition Selecting similar compounds, but not Proline itself

2006 Edition Catalysts may be given as a CAS RN

2006 Edition Agenda Structure searching features Substance viewer features Get related feature Reaction searching in SF2004 Novel compound or freedom to operate?

2006 Edition Chemical patent protection can be very complex SciFinder provides access to 85 mil chemical compounds Specific substances from patent claims and examples have been registered Broad “Markush” claims in patents can describe thousands of compounds For freedom-to-operate searching you need to have a search done for prophetic compounds hidden in large Markush claims

2006 Edition Markush answers A search in CAS’ Marpat database revealed compound theoretically matches the Markush definition in 7 patents –e.g., WO by AstraZeneca

2006 Edition Markush answers If these are answers you need to know, contact your information professional, a patent office, or CAS’ Science IP

Tips and Tricks Chemistry