Patent Abstract:
The present invention provides an efficient and versatile method for the synthesis and screening of combinatorial libraries of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof. In order to expedite the synthesis of large arrays of compounds possessing these core structures, a general methodology for solid phase synthesis of these derivatives is provided. Arrays of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof useful as peptidomimetics and for the identification of agents having antifungal, antiviral, antimicrobial, anticoagulant, and antiulcer activity, or use in the treatment of inflammation, hypertension, cancer, and other conditions can be prepared by this method.

Full Description:
This application claims priority to U.S. Provisional Serial Application No. 60/085,465 filed May 4, 1998, the contents of which are incorporated herein by reference. 
    
    
     TECHNICAL FIELD 
     The present invention provides a method for the combinatorial synthesis and screening of libraries of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof. In order to expedite the synthesis of compound libraries possessing these core structures, the present invention also provides a general method for the solid phase synthesis of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof. The method involves a cyclization reaction between a 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol and an aldehyde or cyanogen bromide, respectively. Either the 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component, or the aldehyde component, may be covalently attached to the solid support. 
     BACKGROUND ART 
     The synthesis and screening of small molecule combinatorial libraries is an important tool in drug discovery. A convenient format for the generation of these libraries is the preparation of compounds on a solid support Solid-phase organic synthesis (SPOS) is especially useful for many synthetic transformations, since reagents can be used in large excess to drive reactions to completion, and any unreacted amount of reagents and soluble byproducts can be easily removed by filtration (see Thompson and Ellman 1996,  Chem. Rev.  96:555.; Herkens et al. 1996,  Tetrahedron  52:4527; Früchtel and Jung 1996,  Angew. Chem. Int. Ed. Engl.  35:17-42; Balkenhold et al. 1996,  Angew. Chem. Int Ed Engl.  35:2288-2337). 
     Substituted heterocyclic compounds offer a high degree of molecular diversity and have proven to be broadly useful as therapeutic agents. The benzimidazole, benzoxazole, and benzothiazole ring systems, in particular, are present in many known herbicides, fungicides, and drugs used in human as well as veterinary medicine. The generic structure and numbering system of these compounds are shown below.                           
     Benzimidazoles, benzoxazoles, and benzothiazoles have been shown to exhibit antiviral (Salluja et al. 1996,  J. Med. Chem.  39:881-891), antiulcer (Cereda et al. 1987,  Eur. J. Med. Chem.  22:527-537; Kugishima et al. 1994,  Heterocyclic Chem.  31:1557-1559.), antihistaminic (Jerchee et al. 1952,  Liebigs Annalen der Chemie  575:173; Janssens at al. 1981, Chem. Abstr. 94:30579), analgesic (Hunger at al. 1957,  Experientia  13:400), antihelmintic (Gyurik et al. 1981, U.S. Pat. No. 4,258,198; 1981,  Chem Abstr.  95:7284), antibacterial (Kusumi et al. 1988,  J. Am. Chem. Soc.  110:2954; Suto et al. 1995,  Tetrahedron Lett.  36:7213; Chaney et al. 1974,  J. Am. Chem. Soc.  96:1932; David et al. 1982,  J. Antibiotic.  35:1409; Westly et al. 1983,  J. Antibiotic.  36:1275), antiparasitic (Haugwitz et al. 1979,  J. Med. Chem.  22:1113; Haugwitz et al. 1982,  J. Med. Chem.  25:969), and antiinflammatory properties (Dunwell et al. 1975,  J. Med. Chem.  18:53; Dunwell et al. 1975,  J. Med. Chem.  18:1158; Evans et al. 1977,  J. Med. Chem.  20:169; Dunwell et al. 1977,  J. Med. Chem.  20:797), or other biologically relevant actions such as inhibition of elastase (Edwards et al. 1992,  J. Am. Chem. Soc.  114:1854; Edwards et al. 1995,  J. Med. Chem.  38:87; Edward et al. 1995,  J. Med. Chem.  38:3972), and H 2 -antagonist properties (Katsura et al. 1992,  Chem. Pharm. Bull.  40:371; Katsura et al. 1992,  Chem. Pharm. Bull.  40:1424). 
     In spite of their importance as phannacophoric scaffolds, there has been a lack of mild and efficient techniques for synthesizing benzimidazoles, benzoxazoles, and benzothiazoles on a solid support and, particularly, for producing libraries of derivatives for biological screening. Thus, the development of strategies for the solid phase synthesis of these heterocyclic systems and derivatives thereof is not only highly desirable, but also economically advantageous (see Nefzi et al. 1997,  Chem. Rev.  97:449-472). 
     Benzimidazoles, benzoxazoles, and benzothiazoles are usually prepared in solution by heating a 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol with carboxylic acids or their derivatives (chlorides, anhydrides, esters, amides, imino esters) at elevated temperatures and/or in the presence of strong acids (see Preston, P. N.  Benzimidazoles and Congeneric Tricyclic Compounds.  In  Heterocyclic Compounds;  Preston, P. N., Ed.; John Wiley &amp; Sons, NY, 1981, Vol. 40, pp 6-60). These conditions, however, are not always suitable for solid phase organic synthesis, particularly when thermally sensitive polymeric supports and/or acid-labile linkers are employed. In spite of this fact, the current methods for the solid phase synthesis of benzimidazoles and benzoxazoles are for the most part based on the above general approach and, therefore, subjected to its limitations. For example, Phillips and Wei ( Tetrahedron Lett.  37 (1996) pp.4887-4890) disclose a process for the solid phase synthesis of benzimidazoles that includes heating an immobilized 1,2-arylenediamine with an imino ester. Although the use of an imino ester allows one to carry out the reaction under essentially neutral conditions, a large excess of the reagent (ca. 30 eq.) and prolonged heating (ca. 55-90° C. for 24-40 h) are still needed to induce heterocycle ring formation. Imino esters, on the other hand, are not readily available reagents and must be individually prepared, isolated, and purified by conventional methods before they can be used in the synthesis of combinatorial libraries. 
     Wang and Hauske ( Tetrahedron Lett.  38 (1997) pp.6529-6532) disclose a method for the solid phase synthesis of benzoxazoles that involves a two-step reaction, in which a carboxylic acid is first amidated with a 2-aminophenol, and the resulting amidophenol is then cyclized intramolecularly. This method relies on the selective amidation of the resin-bound carboxylic acid with a 2-aminophenol without concomitant esterification, and in the intramolecular nature of the process. 
     Benzimidazoles have also been obtained in solution by treatment of a 1,2-arylenediamine with aldehydes and an oxidizing agent (see Chikashita et al. 1987,  Bull. Chem. Soc. Jpn.  60:737-746; Yadagiri and Lown 1990,  Synth. Commun.  20:955-963; Pätzold et al. 1992,  Synth. Commun.  22:281-288; Vanden Eynde et al. 1995,  Tetrahedron  51:5813-5818), or by treatment of a 1,2 arylenediamine with cyanogen bromide (see Rastogi and Sharma 1983,  Synthesis  861-882). Although not as widely publicized as the thermal cyclization of 1,2-arylenediamines with carboxylic acids or their derivatives, these alternative methods are known to afford benzimidazoles under very mild conditions. 
     A few of these methods have been applied to the solid phase synthesis of benzimidazoles from either immobilized aldehydes (see Sun et al. 1998,  Bioorg. Med. Chem. Lett.  8:361-364) or immobilized 1,2-arylenediamines (see Mayer et al. 1998,  Tetrahedron Left.  39:6655-6658), but not both. In the first case, the oxidizing agent used is nitrobenzene and the reaction is still performed at high temperature (ca. 130° C.); in the second case, the oxidizing agent is DDQ and the reaction is carried out at or near room temperature. 
     DESCRIPTION OF THE INVENTION 
     The description of the invention is provided according to the following outline. 
     OUTLINE 
     1. Terminology 
     2. Disclosure of the Invention 
     2.1. Overview 
     2.2. The 1,2-Arylenediamine, 2-Aminophenol and 2-Aminothiophenol Component 
     2.3. The Aldehyde Component 
     3. The Reaction Conditions 
     3.1. Immobilization of the Arylenediamine, Aminophenol, Aminothiophenol, or Aldehyde Component 
     3.2. Reaction of Solid-Supported 1,2-Arylenediamines, 2-Aminophenols, or 2-Aminothiophenols with Cyanogen bromide 
     3.3. Reaction of Solid-Supported 1,2-Arylenediamines, 2-Aminophenols, or 2-Aminothiophenol with Aldehydes 
     3.4. Reaction of Solid-Supported Aldehydes with 1,2-Arylenediamines, 2-Aminophenols, or 2-Aminothiophenols 
     4. Preparation of Derivatives of Benzimidazoles, Benzoxazoles, and Benzothiazoles 
     5. Cleavage and Analysis of Products 
     6. Preparation of Arrays of Benzimidazoles, Benzoxazoles, and Benzothiazoles 
     1. Terminology 
     Unless otherwise stated, the following terms, abbreviations, and pictorial representations used in the description, specifications, and claims of the invention have the meanings given below: 
     “Alkyl” refers to a straight chain, branched, or cyclic chemical group containing only carbon and hydrogen, such as methyl, —(CH 2 )—, tert-butyl, and cyclopentyl. Alkyl groups can be either unsubstituted or substituted with one or more substituents, e.g., halogen, hydroxy, alkoxy, amino, mercapto, acyloxy, carboxy, aryl, heteroaryl, or other functionality which may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Typically, alkyl groups will comprise 1 to 12 carbon atoms, preferably 1 to 10, and more preferably 1 to 8 carbon atoms. 
     “Alkoxy” refers to the group alkyl—O—. 
     “Aryl” or “Ar” refers to an aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl), which can be either unsubstituted or substituted with alkyl, halogen, hydroxy, alkoxy, mercapto, amino, nitro, cyano, carboxy, and carboalkoxy. Preferred aryl groups include phenyl, 1-naphthyl, 2-naphthyl, biphenyl, and the like. 
     “Aryloxy” refers to the group aryl—O—. 
     “Heteroaryl” or “HetAr” refers to a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g, furanyl, pyridyl, thiophenyl) or multiple condensed rings (e.g., benzimidazolyl, indolizinyl) and containing at least one heteroatom, such as N, O, or S, within the ring, which can optionally be unsubstituted or substituted with alkyl, halogen, hydroxy, alkoxy, mercapto, amino, nitro, cyano, carboxy, and other substituents. 
     “Arylalkyl” refers to the groups —R′—Ar and —R′—HetAr, where R′ is an alkyl group, Ar is an aryl group, and HetAr is a heteroaryl group. Examples of arylalkyl groups include benzyl (Bn) and furfuryl. 
     “Amino” or “amine” refers to the group —NR′R″, where R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, and heteroaryl. In a primary amino group, both R′ and R″ are hydrogen, whereas in a secondary amino group, either, but not both, R′ and R″ is hydrogen. 
     “Carboxy” or “carboxyl” refers to the group —COOH. 
     “Carboalkoxy” refers to the group —COOR′, where R′ is an alkyl group. 
     “Carboaryloxy” refers to the groups —COOAr and —CO—HetAr, where Ar is an aryl group and HetAr is a heteroaryl group. 
     “Carboalkyl” refers to the group —CO—R′, where R′ is an alkyl group. 
     “Carboaryl” refers to the groups —CO—Ar and —CO—HetAr, where Ar is an aryl group and HetAr is a heteroaryl group. 
     “Chemical library” or “combinatorial library” or “compound library” or “array” is an intentionally created collection of different compounds, usually prepared in parallel, and screened for biological activity in a variety of different formats (e.g., in solution or tethered to resin beads, silica chips, or other solid supports). 
     “Building block” refers to any molecule that can be covalently attached to other molecules to generate structurally different compounds. 
     “Combinatorial chemistry” or “combinatorial synthesis” refers to an ordered strategy for the parallel synthesis of diverse molecular entities which leads to the generation of chemical libraries. The strategy consists of the systematic and repetitive covalent connection of structurally different building blocks to each other to yield large arrays of compounds. 
     “Linker” refers to a molecule or group of molecules covalently attached to the solid support on one end and to the first building block on the other end. Linkers have different molecular structures and, therefore, different lengths, shapes, sizes, degree of hydrophobicity and hydrophilicity, steric bulk, and chemical reactivity. The selection of a linker in solid phase synthesis is dependent on both the synthetic scheme and the biological screening format. 
     “Solid support” refers to a material or group of materials having a rigid or semi-rigid surface, appropriate size, shape, and porosity, and high chemical resistance. Examples of solid supports are glass, silica, cellulose, polystyrene cross-linked with divinylbenzene, polystyrene-polyethyleneglycol copolymer, and other support materials commonly used in peptide, polymer, and small-molecule solid phase synthesis. 
     “Resin” refers to a solid support material which has been grafted with a linker for attachment of the first building block. Examples of preferred resins are Wang resin (a polystyrene-based resin with a 4-alkoxybenzyl alcohol linker), Rink amide resin (a polystyrene-based resin with a 4-(2′,4′-dimethoxyphenylaminomethyl)phenoxymethyl linker), and Sasrin resin (a polystyrene-based resin with a 2-methoxy4-alkoxybenzyl alcohol linker). Other preferred resins are described in the  Combinatorial Chemistry  &amp;  Solid Phase Organic Chemistry Handbook  published by NovaBiochem, La Jolla, Calif.; the  Solid Phase Sciences  catalog published by Solid Phase Sciences, San Rafael, Calif., or the  Rapp Polymere  catalog published by Rapp Polymere GmbH, Tubingen, Germany. 
     Resins are usually depicted as follows:                           
     Immobilization of a building block onto a resin is usually depicted as follows:                           
     wherein the type of functional group used for attachment will depend on the nature of both the compound to be synthesized and the resin employed. 
     “Protecting group” or “PG” refers to a chemical group that exhibits the following characteristics: (a) reacts selectively with the desired functionality to give a derivative that is stable to the ensuing reactions to which it will be subjected; (b) can be selectively removed from the derivative to afford the desired functionality in good yield, and (c) the conditions for its removal do not compromise the integrity of other functional groups. 
     Examples of protecting groups can be found in Greene et al. 1991,  Protective Groups in Organic Synthesis,  2nd. Ed., John Wiley &amp; Sons, Inc., New York. 
     Abbreviations: The following abbreviations are intended to have the following meaning: 
     API=Atmospheric Pressure Ionization 
     DCC=Dicyclohexylcarbodide 
     DCM=Dichloromethane 
     DIC=Diisopropylcarbodiimide 
     DIEA=Diisopropylethylamine 
     DMA=Dimethylacetamide 
     DMAP=4-Dimethylaminopyridine 
     DMF=Dimethylformamide 
     DMSO=Dimethylsulfoxide 
     ES=Electrospray 
     EtOH=Ethanol 
     Fmoc=Fluorenylmethoxycarbonyl 
     HBTU=O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate 
     HOBt=1-Hydroxybenzotriazole 
     HPLC=High-Performance Liquid Chromatography 
     MeCN=Acetonitrile 
     MeOH=Methanol 
     MS=Mass Spectrum 
     MSNT=1-(Mesitylene-2-sulfonyl)3-nitro-1,2,4-triazole 
     NMI=1-Methylimidazole 
     NMR=Nuclear Magnetic Resonance 
     PG=Protecting group 
     SPOS=Solid Phase Organic Synthesis 
     TBTU=O-Benzotriazol-l-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 
     TCNE=Tetracyanoethylene 
     TEA=Triethylamine 
     TFA=Trifluoroacetic acid 
     THF=Tetrahydrofuran 
     2. Disclosure of the Invention 
     2.1. Overview 
     The present invention discloses an efficient and versatile approach for the combinatorial synthesis and screening of libraries of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof. In order to expediently synthesize a combinatorial library of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, a generalized methodology for the solid phase synthesis of these compounds is also provided. This methodology overcomes the limitations of previous approaches for the solid phase synthesis of benzimidazoles and benzoxazoles, and provides the first example of a solid phase synthesis of benzothiazoles. 
     In one aspect of the invention, the method of synthesizing benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, comprises the steps of first immobilizing a 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or a synthetic precursor thereof, onto a solid support; removing any protecting groups or performing other operations upon said synthetic precursor to unmask the amino, hydroxy, and mercapto functionalities, and fretting the resulting 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol with cyanogen bromide to form the corresponding heterocycles, which is depicted below:                           
     In another aspect of the invention, the method of synthesizing benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, comprises the steps of first immobilizing a 1,2-arylenediamine, 2-aminophenol, 2-aminothiophenol, or a synthetic precursor thereof, onto a solid support; removing any protecting groups or performing other operations upon said synthetic precursor to unmask the amino, hydroxy, and mercapto functional groups, and treating the resulting 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol, either sequentially or simultaneously, with an aldehyde and an oxidizing agent to form the corresponding heterocycles, which is depicted as follows:                           
     In “Reaction 2”, the resin-bound 1,2-arylene diamine can be attached to the solid support through a linker off the aromatic ring as shown in the scheme (first reaction), or through a substituent off one of the nitrogens as shown below:                           
     In yet another aspect, the method of synthesizing benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, comprises the steps of first immobilizing an aldehyde, or a synthetic precursor thereof, onto a solid support, removing any protecting groups or performing other operations upon said synthetic precursor to unmask the aldehyde functional group, and treating the resulting aldehyde, either sequentially or simultaneously, with an 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol and an oxidizing agent to form the corresponding heterocycles, which is depicted as follows:                           
     2.2. The 1,2-Arylenediamine, 2-Aminophenol, and 2-Aminothiophenol Component 
     According to the above embodiments, the 1,2-arylenediamine, 2-aminophenol, and 2-aminothiophenol component preferably comprises compounds of formula I, II, and III, respectively:                           
     wherein R 1  is selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, aryloxy, amino, carboxy, carboalkoxy, cyano, and nitro, and R 2  is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl, or substituted arylalkyl. 
     Depending on the combinatorial or synthetic scheme, the 1,2-arylenediamine, 2-aminophenol, and 2-aminothiophenol component may contain additional substituents on the phenyl ring. If necessary, these substituents can be protected with an appropriate protecting group. 
     In a more preferred embodiment, the 1,2-arylenediamine, 2-aminophenol, and 2-aminothiophenol component is selected from the group consisting of, but not limited to, 1,2-phenylenediamine; N-methyl-1,2-phenylenediamine; 2,3-diaminonitrobenzene; 3,4-diaminobenzoic acid; 3-amino4N-benzylamino)benzoic acid; 2,3-diaminophenol; 3,4-diaminophenol; 2-aminophenol; 3-amino4hydroxybenzoic acid; 4-amino-3-hydroxy-benzoic acid; 2-aminothiophenol; 3-amino mercaptobenzoic acid; 4-amino-3-mercapto-benzoic acid. The 1,2-arylenediamine, 2-aminophenol, and 2-aminothiophenol component, if not commercially available, can be prepared by standard chemical procedures. 
     2.3. The Aldehyde Component 
     According to the above embodiments, the aldehyde component preferably comprises a compound of formula IV, V, or VI:                           
     wherein R 3  is an alkyl or arylalkyl group, Ar is an aryl group, and HetAr is a heteroaryl group, either unsubstituted or preferably substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, mercapto, amino, nitro, cyano, carboxy, and carboalkoxy. If necessary, these substituents can be protected with an appropriate protecting group. 
     In a more preferred embodiment, the aldehyde component is selected from the group consisting of, but not limited to, benzaldehyde; 2-formylbenzenesulfonic acid; 5-formyl-2-furansulfonic acid; 4-fluorobenzaldehyde; 2-hydroxybenzaldehyde; 3-hydroxybenzaldehyde; 4-hydroxybenzaldehyde; 3,4dihydroxybenzaldehyde; 3,5-dihydroxybenzaldehyde; 2-nitrobenzaldehyde; 4-nitrobenzaldehyde; 4-dimethyl-aminobenzaldehyde; 4-hydroxy-3-nitrobenzaldehyde; 5-nitro-2-furaldehyde; 5-nitro-2-thiophenecarboxaldehyde; 2-carboxybenzaldehyde; 3-carboxybenzaldehyde; 4-carboxy-benzaldehyde; 4-formylcinnamic acid. The aldehyde component, if not commercially available, can be prepared by standard chemical procedures. 
     3. The Reaction Conditions 
     3.1. Immobilization of the Arylenediamine, Aminophenol, Aminothiophenol, or Aldehyde Component 
     According to the present invention, a 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component is reacted with either cyanogen bromide or an aldehyde component and an oxidant component, to yield a benzimidazole, benzoxazole, benzothiazole, or a derivative thereof. The 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component, or the aldehyde component, can be utilized in a soluble format or can be attached to a solid support. 
     According to the latter embodiment, the 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component, or the aldehyde component, will include a functionality which can covalently bind the molecule to the solid support. This functionality will be present in the molecule in addition to the 1,2-diamino, 2-amino-1-hydroxy, or 2-amino-1-mercapto groups, or to the aldehyde group, or protected derivatives or synthetic precursors thereof. 
     The choice of functionality used for attaching the 1,2-arylenediamine, 2-amino-phenol, or 2-aminothiophenol component, or the aldehyde component, to the solid support will depend on the nature of the compound to be synthesized and the type of resin employed. Preferred functionalities include, but are not limited to, halogen, hydroxy, amino, and carboxy. Conditions for coupling monomers and polymers to solid supports through these functional groups are known in the art; illustrative examples are given in reaction scheme 4.                           
     3.2. Reaction of Solid-Supported 1,2-Arylenediamines, 2-Aminophenols, or 2-Aminothiophenols with Cyanogen bromide 
     In a preferred embodiment, an immobilized 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component is treated with a solution of cyanogen bromide, usually at ambient temperature, and for a period of 2 to 24 h. However, depending on the nature of the components, those skilled in the art will recognize that it may be necessary to perform the reaction at temperatures other than ambient and for periods of time longer than 24 h. 
     The reaction is typically performed in an organic solvent, such as acetonitrile, dichloromethane, tetrahydrofuran, methanol, aqueous methanol, dimethylformamide, or dimethylacetamide. Most preferably, acetonitrile and dichloromethane are used. The ratio of 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component to cyanogen bromide component will typically range from about 1:1.1 to about 1:100, preferably from about 1:1.1 to about 1:25. 
     Hydrogen bromide is formed as a secondary product of the reaction. In some instances, it may be necessary to neutralize the hydrogen bromide formed by addition of an exogenous base. In a preferred embodiment, the exogenous base will be soluble in the reaction solvent. Particularly preferred exogenous bases include tri(lower alkyl)amines, such as diisopropylethylamine (DIEA) or triethylamine (TEA). 
     3.3. Reaction of Solid-Supported 1,2-Arylenediamines, 2-Aminophenols, or 2-Aminothiophenols with Aldehydes 
     In a preferred embodiment, an immobilized, 2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component is treated, either sequentially or simultaneously, with an aldehyde component and an oxidant component, usually at ambient temperature, and for a period of 2 to 24 h. However, depending on the nature of the components, those skilled in the art will recognize that it may be necessary to perform the reaction at temperatures other than ambient and for periods of time longer than 24 h. 
     The oxidant employed in the reaction is selected from a group consisting of p-chloranil (CA); 7,7,8,8-tetracyanoquinodimethane (TCNQ); benzylidenemalononitrile (BMCN); tetracyanoethylene (TCNE); 2,3-dicyano-1,4-benzoquinone (DCBQ), or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Most preferably, TCNE is used. 
     The ratio of 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component to aldehyde component and to oxidant component will typically range from about 1:1.1:1.1 to about 1:100:100, preferably from about 1:1.1:1.1 to about 1:25:25, and most preferably from about 1:1.1:1.1 to about 1:10:10. 
     The reaction is typically performed in an organic solvent, such as tetrahydrofuran, dichloromethane, methanol, , acetonitrile, dimethylformamide, dimethylacetamide, or combinations thereof Most preferably, dichloromethane and dimethylacetamide are used. 
     In some instances, the reaction is performed in the presence of a dehydrating agent which is some embodiments may serve to catalyze the condensation reaction. Preferred dehydrating agents include molecular sieves, magnesium sulfate, trimethyl orthoformate, and the like. 
     3.4. Reaction of Solid-Supported Aldehydes with 1,2-Arylenediamines, 2-Aminophenols, or 2-Aminothiophenols 
     In a preferred embodiment, an immobilized aldehyde is treated, either sequentially or simultaneously, with a 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component and an oxidant component, usually at ambient temperature, and for a period of 2 to 24 h. However, depending on the nature of the components, those skilled in the art will recognize that it may be necessary to perform the reaction at temperatures other than ambient and for periods of time longer than 24 h. 
     The oxidant employed in the reaction is selected from a group consisting of p-chloranil (CA); 7,7,8,8-tetracyanoquinodimethane (TCNQ); benzylidenemalononitrile (BMCN); tetracyanoethylene (TCNE); 2,3-dicyano-1,4-benzoquinone (DCBQ), or 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ). Most preferably, TCNE is used. 
     The ratio of aldehyde component to 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component and to oxidant component will typically range from about 1:1.1:1.1 to about 1:100:100, preferably from about 1:1.1:1.1 to about 1:25:25, and most preferably from about 1:1.1:1.1 to about 1:10:10. 
     The reaction is typically performed in an organic solvent, such as tetrahydrofuran, dichloromethane, methanol, ethanol, acetonitrile, dimethylformamide, dimethylacetamide, or combinations thereof. Most preferably, dichloromethane and dimethylacetamide are used. 
     In some instances, the reaction is performed in the presence of a dehydrating agent which is some embodiments may serve to catalyze the condensation reaction. Preferred dehydrating agents include molecular sieves, magnesium sulfate, trimethyl orthoformate, and the like. 
     4. Preparation of Derivatives of Benzimidazoles, Benzoxazoles, and Benzothiazoles 
     The benzimidazoles, benzoxazoles, or benzothiazoles prepared according to the method described in the present invention can be further manipulated using any one or more of a variety of transformations to increase the molecular diversity of the final products. 
     For example, the 2-amino group of the benzimidazoles, benzoxazoles, or benzothiazoles formed in the reaction of 1,2-arylenediamines, 2-aminophenols, or 2-aminothiophenols with cyanogen bromide, respectively, can be acylated with carboxylic acids or their acyl derivatives (e.g., chlorides or anhydrides) to form amides; sulfonylated with sulfonyl chlorides to form sulfonamides; reacted with isocyanates or isothiocyanates to form ureas or thioureas; condensed with α,β-unsaturated carboxylic acid chlorides or esters to yield fused 2-oxo-pyrimidyl derivatives, or alkylated with aldehydes in the presence of a reducing agent (e.g., NaBH 4 , NaCN(BH 3 ), Na(OAc) 3 BH), to give secondary amines. These examples are illustrated in FIG.  1 . Other preferred transformations of 2-aminobenzimidazoles, which may be applied to their congeneric heterocyclic compounds, are described in Rastogi and Sharma 1983, Synthesis 861-882. 
     The above examples are illustrative; other transformations, such as oxidation of the sulfur atom of benzothiazoles, alkylation of the heterocyclic nitrogens of benzimidazoles, and the like, will be apparent to those skilled in the art. 
     For purposes of simplicity, FIG. 1 shows benzimidazoles, benzoxazoles, and benzothiazoles obtained from resin-bound 1,2-arylenediamines, 2-aminophenols, or 2-aminothiophenols and cyanogen bromide; however, the corresponding benzimidazoles, benzoxazoles, or benzothiazoles obtained from resin-bound 1,2-arylenediamines, 2-aminophenols, or 2-aminothiophenols and aldehydes, or from resin-bound aldehydes and 1,2-arylenediamines, 2-aminophenols, or 2-aminothiophenols can also be further derivatized. 
     5. Cleavage and Analysis of Products 
     For some applications, it may desirable to have a “support-free” or “soluble” library of molecules. Soluble molecules can be useful for a variety of purposes, including structural analysis and screening for activity in a particular assay. The generation of support-free molecular libraries and the solubilization of compounds synthesized on a solid support can be accomplished by techniques known in the art. 
     Typically, the linkers employed to immobilize a molecule to a solid support can be cleaved under a variety of conditions, including treatment with acid, base, nucleophiles (ie., groups capable of donating electrons), oxidants, reducing agents, and light. Examples of resins with cleavable linkers are described in the  Combinatorial Chemistry  &amp;  Solid Phase Organic Chemistry Handbook  published by NovaBiochem, La Jolla, Calif. 
     In a preferred embodiment, acid-sensitive linkers such as those present in Wang resin, Sasrin resin, and Rink amide resin can be employed in the solid phase synthesis of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, described in the present invention. Thus, if desired, the immobilized products can be cleaved from the solid support by treatment with an acid, and the support-free benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, released into solution. 
     The nature and amount of acid used in the cleavage step will depend on the specific resin employed in the solid phase synthesis, and on the chemical stability of the products. Preferably, the acid will be selected from the group consisting of acetic acid (AcOH), trifluoroacetic acid (TFA), hydrochloric acid (HCl), and hydrofluoric acid (HF). Most preferably, trifluoroacetic acid is used. 
     The acid is usually employed in solution, with water and dichloromethane being the preferred solvents. The amount of acid in the solution will typically range from about 1% (v/v) to about 95% (v/v), preferably from about 1% (v/v) to about 50% (v/v), and most preferably from about 1% (v/v) to about 25% (v/v). 
     The support-free benzimidazoles, benzoxazoles, and benzothiazoles, or derivatives thereof, can be analyzed by standard analytical methods, such as thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), and mass spectrometry (MS). Combinatorial libraries are preferably analyzed by a combination of HPLC and MS, herein referred to as “LC/MS,” which provides information on the identity as well as the purity of the cleaved products. 
     6. Preparation of Arrays of Benzimidazoles, Benzoxazoles, and Benzothiazoles 
     The method for the solid phase synthesis of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, disclosed in the present invention can be used to prepare and screen large numbers of compounds, in the hundreds, the thousands, and even in the ten thousands in a reasonable period of time. Synthesis may be coordinated with screening in various different ways to assay compounds from unusually large libraries in a timely manner. 
     Accordingly, the method of synthesis described above is preferably used to prepare more than 2, preferably more than 10, preferably more than 40, and more preferably more than 90 different compounds simultaneously. Moreover, the method described herein can be utilized in a stepwise fashion as well as in a one step condensation reaction, thereby decreasing significantly the number of reactions required for the preparation of a combinatorial library. For example, a 288-component library can be readily prepared in one step by condensing a solid supported 1,2-arylenediamine, a 2-aminophenol, and a 2-aminothiophenol each with a set of 96 different aldehydes under the conditions described in this invention. Alternatively, a 288-component combinatorial library can be prepared in two steps by condensing a solid supported 1,2-arylenediamine, a 2-aminophenol, and a 2-aminothiophenol each with cyanogen bromide under the conditions described in this invention, and then reacting the 2-aminobenzimidazole, 2-aminobenzoxazole, or 2-aminobenzothiazole with 96 different carboxylic acids or their acyl derivatives. The 2-aminobenzimidazole, 2-amino-benzoxazole, or 2-aminobenzo- thiazole prepared in the first step can also be reacted with different sulfonyl chlorides, isocyanates, thioisocyanates, or aldehydes and a reducing agent, to increase the total number of library components. 
     Those skilled in the art will recognize the above format as one that can be performed on any array, e.g. 96-well filtration plate, preferably with but also without the aid of automated liquid dispensing equipment. 
     The method of synthesis of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, described in the present invention is particularly suitable for the generation of combinatorial libraries because of the following attributes: (a) the synthesis of benzimidazoles, benzoxazoles, benzothiazoles, and derivatives thereof, takes place at room temperature and under neutral conditions; (b) reaction times are usually 1 day or less; (c) most reagents are commercially available; (d) chemical yield and purity of the products are very high, thereby requiring small amounts of solid supported starting material; (e) the oxidative cyclization reaction between 1,2-arylenediamines, 2-amino-phenols, or 2-aminothiophenols and aldehydes is highly chemoselective and tolerates a wide range of substituents on either component, which enhances the structural diversity of the compounds that can be prepared by this method; (f) in the oxidative cyclization process, either the 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol component, or the aldehyde component, can be immobilized onto the solid support, which also contributes to increase the structural diversity of the compounds that can be prepared by this approach; (g) the method provides a general and uniform protocol for the synthesis of all three classes of heterocycles, ie., benzimidazoles, benzoxazoles, and benzothiazoles. Furthermore, compound libraries possessing these core structures can be prepared from a common resin-bound aldehyde, thereby maximizing the value and efficiency of the synthetic process 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 illustrates the versatility of our approach towards benzimidazoles, in particular, the preparation from either resin-bound diamines or resin-bound aldehydes. This enhances molecular diversity of the combinatorial libraries that may be prepared. 
     FIG. 2 illustrates the possible reactions associated with a multi-step process for creating diverse libraries. 
    
    
     EXAMPLES 
     The following examples are included for the purpose of illustrating the invention and are not intended to limit its scope in any matter. 
     Example 1 
     Preparation of Resin-Bound 4-Carboxybenzaldehyde 
     
       
                 
         
             
             
         
      
     
     4-Carboxybenzaldehyde (2.61 g, 17.4 mmol), DCC (2.19 g, 17.4 mmol), HOBt (1.17 g, 8.7 mmol), and DMAP (1.06 g, 8.7 mmol) were dissolved in dry DMA (8.1 mL). The solution was added to Wang resin (15.0 g, subn. 0.58 mmol/g, 8.7 mmol), and the resulting suspension was shaken at room temperature for 24 h. The resin was filtered, washed successively with DMA, DCM, and dried under high vacuum. The loading of the resin was determined by direct cleavage of an aliquot with 20% (v/v) TFA in DCM, and subsequent analysis of the product by HPLC. 
     Example 2 
     Preparation of Resin-Bound N,N′-Fmoc-3,4-Diaminobenzoic Acid 
     
       
                 
         
             
             
         
      
     
     A solution of N,N′-Fmoc-3,4-diaminobenzoic acid (3.76 g, 6.3 mmol), MSNT (1.40 g, 4.7 mmol), and NMI (1.03 g, 12.6 mmol) in 6:1 DMA-DCM (35 mL) was added to Wang resin (5.00 g, subn. 0.63 mmol/g, 3.2 mmol), and the suspension was shaken at room temperature for 24 h. The resin was filtered, washed successively with DMA and DCM, and dried under high vacuum. The substitution of the resin was determined by direct cleavage of an aliquot with 20% (v/v) TFA in DCM, and subsequent analysis of the product by HPLC. 
     Example 3 
     2-(4-Carboxyphenyl)benzimidazole 
     
       
                 
         
             
             
         
      
     
     Resin-bound 4-carboxybenzaldehyde (subn. 0.65 mmol/g, 400 mg, 0.26 mmol) was suspended in DMA (3 mL) and treated with 1,2-phenylenediamine (2.6 mmol) and TCNE (2.6 mmol). The suspension was sonicated for 1 h and shaken at 25° C. for an additional 22 h. The resin was filtered, washed with DMA, DCM, and dried under high vacuum. The benzimidazole was cleaved from the solid support with 20% (v/v) TFA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound.  1 H NMR (d 6 -DMSO) δ 7.35-7.43 (m, 2H), 7.69-7.78 (m, 2H), 8.19 (d, 2H, J=8.3 Hz), 8.26-8.34 (m, 2H), 12.50-14.20 (br s, CO 2 H). MS (API-ES + ) m/z 239 (M+H). 
     Example 4 
     2-(4-Carboxyphenyl) methylbenzimidazole 
     
       
                 
         
             
             
         
      
     
     This compound was prepared according to the procedure described in Example 3.  1 H NMR (d 6 -DMSO) δ 2.64 (s, 3H, CH3), 7.15-7.37 (m, 2H), 7.50-7.62 (m, 1H), 8.12-8.25 (m, 2H), 8.30-8.43 (m, 2H), 12.30-14.10 (br s, 1H, CO 2 H). MS (API-ES + ) m/z 253 (M+H). 
     Example 5 
     2-(4-Carboxyphenyl)-4-hydroxybenzimidazole 
     
       
                 
         
             
             
         
      
     
     This compound was prepared according to the procedure described in Example 3.  1 H NMR (d 6 -DMSO) δ 6.81 (d, 1H, J=7.7 Hz), 7.10-7.30 (m, 2H), 8.17 (d, 2H, J=8.3 Hz), 8.34 (d, 2H, J=7.8 Hz), 10.2-10.9 (br s, 1H, OH), 12.40-13.80 (br s, 1H, CO 2 H). MS (API-ES + ) m/z 255 (M+H) 
     Example 6 
     2-(4-Carboxyphenyl)4-nitrobenzimidazole 
     
       
                 
         
             
             
         
      
     
     This compound was prepared according to the procedure described in Example 3.  1 H NMR (d 6 -DMSO) δ 7.47 (t, 1H, J=8.1 Hz), 8.10-8.15 (m, 3H), 8.16 (d, 1H, J=8.1 Hz), 8.48 (d, 2H, J=8.4 Hz), 12.40-14.00 (br s, 1H, CO 2 H). MS (API-ES + ) mz 284 (M+H). 
     Example 7 
     2-(4-Carboxyphenyl)-5-benzimidazolylcarboxylic acid 
     
       
                 
         
             
             
         
      
     
     This compound was prepared according to the procedure described in Example 3.  1 H NMR (d 6 -DMSO) δ 7.72 (d, 1H, J=8.4 Hz), 7.89 (dd, 1H, J=8.5, 1.6 Hz), 8.14 (d, 2H, J=8.4 Hz), 8.23 (br. s, 1H), 8.32 (d, 2H, J=8A Hz), 12.20-13.80 (br. s, 2H, C0 2 ”). MS (API-ES + ) m/z 283 (M+H). 
     Example 8 
     2-Phenyl-4-benzimidazolylcarboxylic acid 
     
       
                 
         
             
             
         
      
     
     Resin-bound N,N′-Fmoc-3,4-diaminobenzoic acid (subn.0.23 mmol/g, 350 mg, 0.081 mmol) was treated with 20% (v/v) piperidine in DMA (3×2 mL×5 min.) to remove the Fmoc protecting groups. After the third treatment, the resin was washed with DMA and DCM, and then treated with a suspension of benzaldehyde (17.4 mg, 0.164 mmol) and TCNE (21.0 mg, 0.164 mmol) in DMA (3 mL). The mixture was sonicated for 1 h, and shaken at room temperature for an additional 23 h. The resin was filtered, washed with DMA, DCM, and dried under high vacuum. The benzimidazole was cleaved from the solid support with 20% (v/v) TEA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound.  1 H NMR (CD 3 OD) δ 7.50-7.80 (m, 3H), 7.64 (d, 2H, J=8.4 Hz), 7.97 (d, 2H, J=8.4 Hz), 8.05-8.20 (m, 2H), 8.38 (s, 1H). MS (API-ES − ) m/z 237 (M−H). 
     Example 9 
     2-(4-Carboxyphenyl)benzoxazole 
     
       
                 
         
             
             
         
      
     
     Resin-bound 4-carboxybenzaldehyde (subn. 0.60 mmol/g, 400 mg, 0.24 mmol) was treated with a solution of 2-aminophenol (262 mg, 2.4 mmol) in DMA (3 mL). The suspension was shaken at room temperature for 24 h. Tetracyanoethylene (307 mg, 2.4 mmol) was added, and the mixture stirred at room temperature for an additional 24 h. The resin was filtered, washed with DMA and DCM, and dried under high vacuum. The benzoxazole was cleaved from the solid support with 20% (v/v) TFA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound.  1 H NMR (CD 3 OD) δ 7.36-7.45 (m, 2H), 7.62-7,67 (m, 111), 7.72-7.77 (m, 1H), 8.17 (d, 2H, J=8.3 Hz), 8.29 (d, 2H, J=8.3 Hz). MS (API-ES + ) m/z 240 (M+H). 
     Example 10 
     2-(4-Carboxyphenyl)benzothiazole 
     
       
                 
         
             
             
         
      
     
     A solution of 2-aminothiophenol (300 mg, 2.4 mmol) in DMA (3 mL) was added to resin-bound 4-carboxybenzaldehyde (subn. 0.60 mmol/g, 400 mg, 0.24 mmol), followed by TCNE (307 mg, 2.4 mmol). The suspension was shaken at 25° C. for 24h. The resin was filtered, washed with DMA and DCM, and dried under high vacuum. The resin-bound benzothiazole was cleaved from the solid support with 20% (v/v) TFA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound.  1 H NMR (d 6 -DMSO) δ 7.52 (t, 1H, J=7.6 Hz), 7.60 (t, 1H, J=7.0 Hz), 8.12 (d, 2H, J=8.4 Hz), 8.23 (d, 2H, J=8.4 Hz), 8.00-8.40 (m, 2H). MS (API-ES + ) m/z 256 (M+H). 
     Representative structures, yields, and purities of cleaved products obtained from the condensation of resin-bound 1,2-arylenediamines, 2-aminophenols, or 2-aminothio-phenols with aldehydes or cyanogen bromide, or from the condensation of resin-bound aldehydes with 1,2-arylenediamines, 2-aminophenols, or 2-aminothiophenols, are given in Table 1. 
     
       
         
               
             
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Structure, Yield, and Purity of Benzimidazoles, Benzoxazoles, 
               
               
                 and Benzothiazoles Prepared on Solid phase a,b   
               
             
          
           
               
                 Structure 
                 Yield 
                 Purity 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 99 
                 81 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 95 
                 93 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 99 
                 78 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 85 
                 91 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 81 
                 60 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 47 
                 84 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 90 
                 91 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 63 
                 74 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 94 
                 79 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 77 
                 81 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 88 
                 74 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 61 
                 80 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 99 
                 65 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 79 
                 78 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 66 
                 91 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 85 
                 88 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 99 
                 74 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 88 
                 85 
               
               
                   
               
               
                   a Purity refers to percent of product in the cleaved material, determined by HPLC.  
               
               
                   b Yield refers to percent amount of product relative to the substitution level of the resin, corrected for purity.  
               
             
          
         
       
     
     The above description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this disclosure. Merely by way of example a range of suitable process times, reaction temperatures, and other reaction conditions may be utilized, as well as additional reaction types for creating a diverse array of compounds. The scope of the invention should therefore be determined not merely with reference to the above description, but instead with reference to the appended claims along with a full scope of equivalents. 
     Synthesis of Combinatorial Libraries 
     A number of techniques for the creation of combinatorial libraries having desired degrees of molecular diversity exist, one of which involves the use of combinatorial techniques. Suitable combinatorial techniques include those described in U.S. Pat. Nos. 5,840,500, 5,847,150, 5,852,028, 5,856,107, 5,856,496, 5,859,027 and 5,861,532. These techniques can be performed on solid or in solution phase. 
     The preferred process of the present invention is a solid phase synthesis (SPS) based approach. The reaction is carried out on macroscopic particles made of material insoluble in the reaction medium. The scaffold is generally linked to the surface of the support to form the scaffold-support reagent. This link is selected so that it places the compound in the reaction medium. The chemistry of the link is selected so that it can be selectively cleaved in a subsequent step, thereby releasing the synthesized product. Suitable SPS supports can be selected form commercially available resins. The scaffold-support reagent can be prepared batch wise prior to placement in the array, if desired. Each synthetic modification of the scaffold compound is prepared in sufficient quantity to permit its screening and analysis using conventional methodology, e.g., HPLC, mass spectral analysis and the assays described in the references cited in the background section. 
     The array of synthesized compounds is screened using conventional methodology and scored. The compounds can be chemically characterized using conventional techniques, e.g. mass spec and HPLC, before or after the screening process. The assay and individual synthetic steps can be automated. Adjustments in the synthetic approach are possible on a real-time basis. 
     Typically, synthesis in a 96-well plate (an 8 by 12 array) permits eight or twelve distinct scaffold resins to be distributed across the rows or down the columns, respectfully. These resins can then be reacted sequentially with any desired series of reactants. The diversity of the molecular array can be controlled to achieve any desired degree of diversity. 
     Typically, synthesis in a 96-well plate (an 8 by 12 array) permits eight or twelve distinct scaffold resins to be distributed across the rows or down the columns, respectfully (see Meyers et al. 1995,  Molecular Diversity  1:13-20). These resins can then be reacted sequentially with any desired series of reactants. The diversity of the molecular array can be controlled to achieve any desired degree of diversity. 
     The reactions can be monitored and products characterized at each synthetic step, if desired. Reaction conditions can also be varied. Appropriate blocking groups can be added and removed to direct a desired synthesis route. These methods are capable of constructing, tens of thousands of molecules in a relatively short time span. 
     Incorporation by reference 
     To the extent necessary to understand or complete the disclosure of the present invention, all publications, patents, and patent applications mentioned herein are expressly incorporated by reference therein to the same extent as though each were individually so incorporated.

Technology Classification (CPC): 2