Reaction libraries

Cheminform RX, nowadays called the Cheminform Reaction Library, is distributed as an in-house version in a client-seiwer architecture by M DL Information Systems, Inc., San Leandro, CA, USA [22]. 

Observe that to generate the reactions of Fig. 9 no information was necessary on whether such a reaction is known no database of reactions is necessary. The problems in building, updating and maintaining a reaction library are thus avoided. The formal treatment of reactions as bond and electron-shifting processes allows the generation, in principle, of all conceivable reactions, and can be seen as a method to deal freely with molecular architecture. The program s result could be a known reaction, but equally a new, as yet undiscovered reaction which could be realised in the laboratory. 

In a 1998 publication, the concept of microwave-assisted parallel synthesis in plate format was introduced for the first time. Using the three-component Hantzsch pyridine synthesis as a model reaction, libraries of substituted pyridines were pre-... 

In a recent example, Mironov used the rational replacement of starting materials for oligomerization reactions to discover new MCRs in a systematic way [31]. A reaction library of six alkenes/alkynes, two isonitriles, two nitriles and isoquinoline was set up, giving (n1 — n)/2 different reactions products. A minimum peak height of 30% of the total reaction product was used as a criterion for identifying an efficient MCR. In this way, a novel MCR that yields pyrrolo[2,l-a]isoquinolin-1-ones from electron-deficient olefins, isonitriles and isoquinoline was found (Scheme 10.6). 

Beilstein, Crossfire, SPORE, Chemlnform Reaction Library, ORGSYN, etc. MDL 175 http //www.mdli.com... 

By analyzing an input molecule, substructures are found which point to chapters in the reaction library. There, descriptions of changes in these substructures are contained which will occur in the course of a certain reaction. Implementing these changes leads to synthetic precursors. Thus, the recognition of the substructure of a /3-hydroxy-carbonyl group would point to the chapter aldol condensation in the reaction library. There the structural changes of a retro-aldol condensation are contained and result in the two carbonyl compounds as precursors (see Fig. 1). As the reac-... 

Figure 9.30 Parallel reaction libraries for the optimization of the nucleophilic displacement (L18 and of the t-butyl ester hydrolysis (L19).

TABLE 9.2 Yields and Purity of 9.73 from Parallel Reaction Library L18 Selected Entries... 

KF as the best basic reagents and towards DMF as the best solvent. An accurate determination of yields and purity of 9.73 in all reaction vessels selected entry 43 (TEA-DMF) as the best compromise for step a, Fig. 9.29. A similar optimization was performed for the f-butyl ester hydrolysis (step b, Fig. 9.29), creating the 39-member reaction library L19 by permutations of acidic reagents and solvents, and addition of adjuvants (Fig. 9.30). The screening outcome (Table 9.3) highlighted the poor performances of ion-exchange resins (no reaction) and TFA (unclean product) to prepare 9.74, and selected entry 7 (HCl/EtOAc) as the best reaction conditions to obtain clean 9.74 (CSA (camphor sulfonic acid) actually performed slightly better, but the reaction work-up was less automation friendly). The whole manual optimization process required three to four days, and the best reaction conditions were used directly to produce a 590-member discrete library, which met the >75% purity cutoff (78). 

Among other similar reports, Bray et al. (122) optimized the SP reductive amination of a model ketone with three primary amines using a 56-member reaction library with simultaneous variation of amines, reducing agent concentrations, pH, and solvents. Gayo and Suto (123) optimized the coupling of an acyl chloride with benzylamine in solution using a 30-member reaction library with simultaneous variation of the... 

These files serve several other functions. Each reaction stored in CHESS needs to know structures of products and reactants. This is accomplished using reference numbers that point to the molecular reaction files of CHESS. Other knowledge must be placed into these reaction libraries. All of the information must be represented in such a way as to permit CHESS to reason on the stored reaction mechanisms. 

There are several different levels of reaction libraries, separated according to the level of reasoning that needs to take place. The first level of the library contains specific methods of analysis. If a match occurs here, the system would be acting simply as a methods reference book. The information needed at this level includes such parameters as the procedure, reactants and their concentrations, expected products, reaction conditions, procedural notes and a literature reference where the method was obtained. 

We now turn our attention to the terminating synthesis routes discovered by SYNCHEM after a total of approximately twenty minutes of search time (Fig. 6). The twistane ring system was first prepared by Whitlock in 1962 and other syntheses have since been published. Conceptually, the computer discovered all of these approaches, but due to presently severe limitations on our reaction library, they differ in details. SYNCHEM s syntheses need to be further refined by a knowledgeable chemist before they could be considered useful. 

As we remarked above, it is certainly not always the case that every reaction schema in a chapter of the reaction library passes the A-test for that chapter and is accepted for further processing. Fig. 7 illustrates the elimination of schema by A-test and, it so happened here, by N-test as well. The arrows... 

Another likely trend is the availability of new chemical databases for in-house use. We are already seeing this. Examples are additional reaction libraries, chemical structure, biological response, and bibliographic databases tailored to particular areas of interest, as well as additional collections of physico- chemical property data such as log P,pKa, and spectra libraries. ... 

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