MXPA00003681A - Coding combinatorial libraries with fluorine tags - Google Patents

Abstract

The present invention relates to coding combinatorial chemical libraries synthesized on a plurality of solid supports by attaching"tags"that comprise fluorine containing compounds in combinations and/or ratios. The tags can be decoded while attached to the solid support by fluorine nuclear magnetic resonance spectroscopy to follow the reaction history of individual beads, and to determine the particular member of the library that is attached on the bead.

Description

COMBINATION COLLECTIONS OF CODING WITH FLUOR MARKS TECHNICAL FIELD OF THE INVENTION The present invention relates to a process for encoding and identifying individual members of a combinatorial chemistry collection synthesized in a plurality of solid supports. The process provides binding of fluorine-containing labels to solid supports that are then encoded through fluorine nuclear magnetic resonance spectroscopy.

BACKGROUND OF THE INVENTION The combinatorial chemistry of mixing and division by splitting (CombiChem) is a synthetic tool that provides collections of numerous compounds that are structurally related. With this method, the collections are constructed on a solid support by assembling groups of chemically reactive building blocks (hereinafter "units" or "monomers") in many possible combinations. To understand the method of mixing and division by cleavage, one must first understand its predecessor, solid phase peptide synthesis. In solid phase peptide synthesis, a group of solid supports (e.g., beads) having reactive functionalities, is they react with an amino acid, followed by another amino acid, and so on. Once the desired polypeptide is formed, the peptide can be split from the bead. In this way, for example, if amino acids A, B and C are reacted in that sequence, an ABC tripeptide can be formed. In addition, amino acids A, B and C can also be reacted in five other sequences, ACB, BAC, BCA, CAB and CBA. If you allow duplicate each amino acid, for example, CHA, you can generate up to 27 tripeptides through this method. A disadvantage of this method is that each tripeptide is individually synthesized, so that synthesis is required to make all the permutations of tripeptides made from amino acids A, B and C. On the other hand, at the end of each synthesis, You can have the good idea that peptide was made, or you can easily unfold the product from the bead and identify the product through traditional analytical methods. The method of mixing and division by excision improves its predecessor by simultaneously adding different monomers to a mixture of pearls that already have several units. Using amino acids A, B and C as an example, three different bead deposits are reacted with A, B or C, respectively, and then mixed together. In this way, a third of these mixtures are beads carrying A, a third are beads carrying B and a third are beads carrying C. This mixture is then divided by splitting into three deposits. Each deposit is made react with A, B or C, respectively. In this way, a deposit will contain pearls that carry one of AA, BA or CA, another will contain pearls that bear one of AB, BB or CB, and the third will contain pearls that carry one of AC, BC or CC. The three deposits are then brought together again and divided by splitting again into three tanks and reacted with A, B or C, respectively. In this way, a deposit will now carry one of AAA, BAA, CAA, ABA, BAA, CBA, ACA, BCA or CCA, another will now carry one of AAB, BAB, CAB, ABB, BBB, CBB, ACB, BCB or CCB , and the third will now carry one from AAC, BAC, CAC, ABC, BBC, CBC, ACC, BCC or CCC. In nine reactions, the method of cleavage and division generates the 27 tripeptide permutations from A, B and C. In addition, the method of cleavage and division is no longer limited to peptide synthesis. Now many different chemical units and different types of reactions can be used to form collections of different kinds of compounds through combinatorial chemistry of mixing and cleavage. The chemical units, both natural and synthetic, can include compounds containing reactive functional groups such as nucleophiles, electrophiles, dienes, alkylating agents, acylating agents, diamines, nucleotides, amino acids, sugars, lipids or derivatives thereof, or organic monomers, synthons and combinations thereof. Alternatively, the reactions may include alkylation, acylation, nitration, halogenation, oxidation, reduction, hydrolysis, substitution, elimination, addition and the like. This method can produce non-oligomers, non-oligomers or combinations thereof in extremely small amounts. Non-oligomers include a wide variety of organic molecules, eg, heterocyclic, aromatic, alicyclic, aliphatic, and combinations thereof, such as steroids, antibiotics, enzyme inhibitors, ligands, hormones, drugs, alkaloids, opioids, terpenes, porphyrins, toxins, catalysts, as well as combinations thereof. The oligomers include oligopeptides, oligonucleotides, oligosaccharides, polyalipids, polyesters, polyamides, polyurethanes, polyethers, poly (phosphorus) derivatives, for example, phosphates, phosphonates, phosphoramides, phosphonamides, phosphites, phosphinamides, etc., poly (sulfur) derivatives ), for example, sulfones, sulfonates, sulphites, sulfinamides, sulfonamides, etc., where for the phosphorus and sulfur derivatives, the heterogeneous atom indicated, for the most part, will be bonded to C, H, N, O, and combinations thereof. Although the split division and rapid mixing method can generate a direct number of compounds, this diversity also generates its greatest challenge, identifying the individual compounds from the mixture. For example, if a pearl of a mixture of pearls bearing AAA, BAA, CAA, ABA, BBA, CBA, ACA, BCA or CCA is collected, how can the tripeptide be determined to be bound? Since each pearl generally has only a small amount of product, the reaction history and the Individual pearl composition are difficult to determine. Actually, the amounts of product in each bead are too small (depending on the size of the solid support, around 10 picomoles to 1 nanomole), and the structures in each bead are thus similar (eg, BAA vs. ABA), which Traditional analysis, such as proton or carbon nuclear magnetic resonance (NMR) spectroscopy and mass spectroscopy (MS) are generally insufficient to determine the structure of the compound in each bead. Other attempts to analyze the combinatorial constructs by marking the solid support require that the marks be separated for analysis (see, for example, International Patent Publication No. WO94 / 08051). However, the separation adds an extra reaction step to the entire construction, and the translation can become confusing during the separation process. In addition, there remains a need to have distinctive markings that are present in the bead in sufficient quantities for decoding. Various techniques and synthetic strategies are important factors in determining the success of combinatorial chemistry and are well known in the art. However, to refine the power of the splitting and mixing method as a synthetic tool, a method should be developed to easily identify the individual compounds attached to each bead of the generated composite collections. In other words, you must collect a pearl from a collection of many pearls of many different compounds and easily identify the specific member of the collection in that pearl. The patent application of E. U. A. No. 08 / 717,710, filed on September 13, 1996 by Hochlowski (pending), discloses that IR or Raman readable marks can be used to encode combinatorial collections without separating the mark or collection for analysis. However, the CombiChem industry continues to look for alternative coding schemes to expand the usefulness of the process.

COMPENDIUM OF THE INVENTION The present invention relates to the coding of CombiChem collections synthesized in a plurality of solid supports by joining "tags" comprising compounds containing fluorine. The codes are created by varying unique brands, combining different brands and / or varying the relationship of different brand combinations. With the application of appropriate marks at particular stages of the synthesis of a combinatorial collection, then it can be determined which compound was made in a particular bead through fluorine nuclear magnetic resonance spectroscopy (FNMR). The coding of combinatorial collections with fluorine labels has many advantages over the prior art. For the most part, fluorine is a robust portion that is not affected by the chemical reactions used to build the collection. Further, the solid support marked with fluorine can be read without separating the solid support mark. Actually, this method does not require the separation of either the brand or a member of the solid support collection to follow the reaction history of the individual pearls, or to determine the particular member of the collection that is attached to the pearl . In addition, the FNMR spectrum is sufficiently different to be read in small quantities, and peak areas are quantitative, so that coding through a tag relationship can be achieved.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1-15 illustrate the FNMR spectra of various brands or combination of marks.

DETAILED DESCRIPTION OF THE INVENTION Definitions The term "resin" as used herein, refers to resins of the type commonly used in the synthetic peptide preparation technique or in solid phase organic synthesis. Examples of such resins include, but are not limited to, methyl benzhydrylamine (MBHA) or benzhydrylamine (BHA) or Merrifield resin (i.e., chloromethylated polystyrene), Wang resin, Tentagel, Rink, etc.

Suitable protecting groups for amines include, but are not limited to, t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), biphenyloxycarbonyl (Bpoc), 1- (4,4-dimethyl-2,6-dioxocyclohex-1 -i I iden) et i lo (Dde) and triphenylmethyl (trityl). Common solvents include, but are not limited to, N, N-dimethylformamide (DMF), 1,2-dimethoxyethane (DME), dichloromethane (DCM), tetrahydrofuran (THF), and dimethylacetamide (DMA). Examples of common coupling agents for preparing amide bonds are N, N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), benzotriazole-1-yloxy-tris (dimethylammono) phosphonium hexafluorophosphate (BOP) ), bis (2-oxo-3-oxazolidinyl) -phosphine chloride (BOCPI), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP). Other common abbreviations include 4-dimethylaminopyridine (DMAP), trifluoroacetic acid (TFA), triethylamine (TEA), diaminopropionic acid (DAP), tosylate (Ts), mesylate (Ms, in contrast to MS for mass spectroscopy), 2,2'bis (diphenylphosphonyl) -1, 1'-biphenyl (BINAP), lysine (Lys), ornithine (Orn) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline ( EEDQ). All citations herein are incorporated herein by reference. As described above, the combinatorial synthesis of mixing and division by cleavage provides the simultaneous construction of many structurally related compounds on solid supports (without being so limited, hereinafter "pearls"). These groups of related compounds are called collections. After a particular group of reactions, each bead keeps multiple copies of individual chemical entities called members of the collection. The present invention provides a process for determining the individual members of a CombiChem collection in each bead. The process comprises covalently joining to each of the plurality of beads a separation code FNMR. The code is one or a group of compounds containing fluorine that can provide a single spectrum of FNMR. The presence or absence of a specific mark, or the relationship of two or more marks on the bead, identifies the unique chemical structure on the bead or the chemical steps used to generate that structure.

Solid Substrates Solid supports for use in CombiChem synthesis are well known in the art (see, for example, International Patent Publication No. WO94 / 08051). A common solid support is a polystyrene bead. Depending on the nature of the synthesis or the assay for the final product, a particular bead may be more or less desirable. Although pearls are especially convenient, other solid supports, such as glass capillaries, hollow fibers such as cotton, etc., are also useful. In some cases, the size of the solid support provides a desired variation in reaction histories. Any suitable composition can be used for the particles or beads. The usefulness of a composition depends on whether it maintains its mechanical integrity during the various stages of the process, it can be functionalized, it has functional groups or it allows the reaction with an active species, it allows the synthesis in series as well as the union of the identifiers, easily it can be mixed and separated, and / or allows convenient separation of brands and products. Illustrative beads used in this process include cellulose beads, pore glass beads, silica gel, polystyrene beads (particularly those entangled with divinylbenzene), grafted copolymer beads such as polyethylene glycol / polystyrene, polyacrylamide beads, pearls of latex, dimethyl acrylamide beads, particularly entangled with N, N'-bis-acryloyl ethylene diamine and comprising Nt-butoxycarbonyl-β-alanyl-N'-acryloyl hexamethylene diamine compounds, such as glass particles coated with a polymer hydrophobic such as entangled polystyrene or a fluorinated ethylene polymer, which is linear grafted polystyrene; and similar. General reviews of useful solid supports (particles) that include a covalently linked reactive functionality can be found in Atherton et al., Prospectives in Peptide Chemistry, Karger, 101-117 (1981); Amamath et al., Chem. Rev., 77: 183-217 (1977); and Fridkin, The Peptides, Vol. 2, Chapter 3, Academic Press, Inc., (1989), p. 333-363. Another preferred solid support is a polystyrene or polyethylene glycol resin. Said resins can be obtained from commercial sources (Wang, NovasSyn-PEG) or can be prepared according to standard procedures well known in the art. A process for preparing a polystyrene resin from Wang is described in the examples below. The beads can be functionalized in a variety of ways to allow the binding of an initial reagent depending on the nature of the synthesis. The functionalities present in the bead may include aldehyde, acid, ketone, hydroxy, aminohalogenide, amino, thio, active halogen (Cl or Br) or pseudohalogen (for example, -CN, toluenesulfonyl, methanesulfonyl, bromo sulfonyl, trifluorosulfonyl or the like). When selecting the functionality, some consideration should be given to the fact that the marks will usually also be attached to the pearl. The consideration will include whether the same functionality or a different one should be associated with the product and the brand, as well as whether two functionalities will be compatible with the product or brand union or the separation stages, as appropriate. Different linker groups can be used for the product, so that a specific amount of the product can be selectively released. In some cases, the support may have protected functionalities, which may be partially or totally unprotected before each stage, and in the latter case be re-protected. For example, a amino group can be protected with a carbobenzoxy group as in the synthesis of polypeptide, a hydroxy group with a benzyl ether, etc.

Marks The labels used according to a process of the present invention are any fluorine-containing compound capable of covalently binding to the solid support and can be easily detected through FNMR. Such compounds are well known in the art. Preferred labels include compounds that bind to a solid support through amide coupling of a carboxylic acid. In general, said mark is united in a site on the solid support that is different ("orthogonal" in CombiChem lingo) than the site where the combinatorial collection is attached. Without limiting the scope of the invention, preferred brands with their distinctive FNMR chemical shifts are listed below as trademarks 1-35.

(Mark 1, -117 ppm) (Mark 2, - 110 ppm) (Mark 3, -63 ppm) (Mark 4, -58 ppm) (Mark 5, -113 ppm) (Mark 6, -114 ppm) (Mark 7, -62 ppm) (Mark 8, - 104 ppm) (Mark 9, -134 ppm) (Mark 10, -122 ppm) (Mark 11, -120 ppm) (Mark 12, -116 ppm) (Mark 13, -63 ppm) (Mark 14, -63 ppm) (Mark 15, -124 ppm) (Mark 16, -114 ppm) (Mark 17, -113 ppm) (Mark 18, -109 ppm) (Mark 19, -82 ppm) (Mark 20, -78 ppm) (Mark 21, -72 ppm) (Mark 22, -71 ppm) (Mark 23, -69 ppm) (Mark 24, -67 ppm) (Mark 25, 59 &-66 ppm) (Mark 26, -63 ppm) (Mark 27, -63 ppm) (Mark 28, -63 &-109 ppm) (Mark 29, -62 &-111 ppm) (Mark 30, -61 &-117 ppm) (Mark 31, -60 &-109 ppm) (Mark 32, -59 ppm) (Mark 33, -59 &-115 ppm) (Mark 34, -42 ppm) (Mark 35, -82 &-122 ppm) In order to expand the applicability of this methodology to the coding of smaller beads and / or lower charge resins, the intensity of the fluorine mark signal marks can be improved through the use of compounds containing multiple fluorine. of "NMR equivalent". The marks 36-57 presented below provide additional examples of "loaded" marks.

(Mark 45) (Mark 46) (Mark 47) (Mark 48) (Mark 49) (Mark 50) (Mark 51) (Mark 52) (Mark 53) CF3 COCF3 • N. "COOH F3C .N. , COOH F3COC "(Mark 54) (Mark 55) Additional preferred embodiments of labels include acetylene portions containing a fluorine atom.

(Mark 58) (Mark 59) (Mark 60) (Mark 61) (Mark 62) Other preferred embodiments of marks are presented in the schemes and examples described below.

Codes A synthetic sequence can be encoded with individual marks, combinations of marks, or variable relationships of brand combinations. Table 1 provides examples of several codes and demonstrates that infinite numbers of codes can be generated from very few brands simply by varying the formulations or relationships. Relationship codes are created by simply mixing two or more marks together in the desired relationship and joining the mixture of marks to the incipient combinatorial collections. Those skilled in the art may know that although only one or two binding sites are generally shown for each bead, each bead actually contains numerous binding sites. Therefore, for a code based on a mixture of marks, each mark in the mixture will be attached to the pearl in a statistical distribution based on, in part, the ratio of marks in the mixture, and on the reactivity of the functionalities of Union.

TABLE 1 Code Mark (s) Marks in the Mix 1 1 2 2 3 3 4 4 5 1/2 (1 1) 6 1/2 (2 1) 7 1/2 (1 2) 8 1/3 (2 1) 9 1/3 (3 1) 10 1/4 (2 1) 11 1/4 (3 1) 12 2/3 d 1) 13 2/3 (2 1) 14 2/4 d 1) 15 2/4 ( 2 1) 16 1/2/3 (3 1: 1) 17 1/2/4 (3 2: 1) 18 1/3/4 (3 1: 1) 19 2/3/4 (3: 2: 2) 20 2/3/4 (3: 1: 1) Brands can also be used to generate a code by virtue of their presence or absence. For example, for a two-base or binary system (M = 2) with three identifiers (N = 3), they can be generated with 8 codes (MN = 23). Also, as the number of identifiers increases, the number of available copies increases exponentially (for example, a binary system (M = 2) with 4 identifiers (N = 4) can generate up to 24 or 16 different codes). As an example of a binary code with three identifiers, marks 1-3 can be selected from the above (mark 1, -117 ppm, mark 2, -110 ppm, mark 3, -63 ppm). In the binary system, the 8 available codes of the three marks are: 000, 100, 010, 001, 110, 101, 011 and 111, where the first position corresponds to the mark 1, and the second position corresponds to the mark 2 and the third position corresponds to the mark 3. In this way, if it is desired to collect a bead having a displacement of -117 and a displacement of -63, it can be concluded that the bead corresponds to the code 101. Without no FNMR displacement is observed, a code of 000 must be had. Finally, if a unique displacement of -110 is found, one must have a bead coded at 010. As shown above, the present invention can generate complicated codes. However, such codes are not necessary since large amounts of fluorine-containing compounds with different chemical shifts FNMR are readily available. In addition, large numbers of codes can be generated by simply making combinations of two labels with the available fluorine-containing compounds. For example, assuming that you can not distinguish marks in duplicate of singular marks, the three marks used in the previous binary example can generate 6 codes 1,2,3,1 / 2, 1/3, and 2/3. With five marks, 15 codes can be generated through this method.

Union of Marks to Pearls The precise means for covalently joining the identifiers to the pearl will depend, as is well known in the art, on the chemical structure of the brand and the nature of the solid support. In a preferred embodiment, a coded resin suitable for developing CombiChem collections can be synthesized by joining a "code linker" such as, for example, a lysine having different protecting groups on each of its amines to a suitable solid support such as, for example, example, aminomethyl-polystyrene as shown in Scheme 1. In addition, the term "orthogonal" in the CombiChem language refers to differentiated functionalities in the same portion. In this way, lysine having a different protecting group in each of its two amines is "orthogonally protected".

Scheme 1 The selective removal of a protecting group from a lysine-aminomethylpolystyrene site produces a material that can be targeted by cleavage in many reservoirs, as desired. Each deposit is differentially encoded through the union of one or more fluorine codes in the form of, for example, carboxylic acids containing fluorine. An example of a pearl marked with the mark 3 is shown in structure 1.

Structure 1 Each marked deposit is now ready to join a suitable combinatorial collection linker (e.g., a Wang linker) to produce a coded resin suitable for building a combinatorial collection. From Structure 1, one can simply check out the remaining amine and attach an appropriate linker. Structure 2 illustrates said coded resin.

Schemes 2-8 illustrate the direct incorporation of fluorine into the polystyrene resin as an alternative marking method. Scheme 2 illustrates an aryl halide coupling to an amine containing fluorine. Scheme 3 illustrates an aryl halide coupling to an acetylene containing fluorine. Scheme 4 illustrates a Friedel-Crafts coupling of the aromatic portion of polystyrene to the acid halide derivative of a fluorine-containing carboxylic acid (illustrated by the labels 1-57). Scheme 5 illustrates the coupling of the aromatic portion of polystyrene to an aryl borane containing fluorine through the Suzuki reaction. Scheme 6 illustrates a displacement reaction, wherein the nucleophile is the phenolic hydroxide, and the electrophile is a fluorine-containing portion having a leaving group. The expert in the art can understand that many other nucleophiles and electrophiles are available for displacement reactions (eg, amine nucleophiles, carbanion nucleophiles, enols, enamines, acetylene anions, etc., against carbonyl electrophiles, enones, etc.). Scheme 7 illustrates a coupling of amines and aldehydes through reductive amination. Scheme 8 illustrates a coupling of alkyl and aromatic hydroxides through the Mitsunobu reaction. The person skilled in the art can understand that, in addition to the phenolic hydroxides, the acid component can also include carboxylic acids, imides, oximes, etc.

Scheme 2 Scheme 3 Scheme 4 Scheme 5 l? n where X = Br, Cl, Ote, Oms Scheme 6 Reductive Animation Scheme 7 Mitsunobu Scheme 8 Other examples of methods for attaching labels to the solid support include, but are not limited to: carbene insertion into an aromatic portion; coupling of diaryldiasonium; and Mannich's reaction to through a portion of phenol or aniline with formaldehyde and a secondary amine. A potential labeling site can also be masked through the nitrilation of the aromatic group of a solid support comprising aromatic portions. At the desired point during the construction of the collection, the nitro portion can be reduced to the amine with tin chloride. The amine becomes a markable site. Those skilled in the art can understand that numerous methods for attaching labels to solid supports are appropriate for the different solid supports and different fluorine-containing labels that are available.

Coding of Combinatorial Collections Those skilled in the art understand that numerous permutations for combinatorial collection coding and binding exist. For example, a linker and a collection core can be attached first before the bead encoding. Scheme 9 illustrates three examples of pearl marking after the construction of the combinatorial collection has begun.

Scheme 9 From Scheme 9, one can obtain a bead that has a combinatorial linker attached to a combinatorial collection core, and an orthogonally joined (or code) mark. A core is any portion that has more than one site to join additional units. As shown in Scheme 9, a nucleus does not need to be a traditional amino acid. Actually, it does not have to be an amino acid at all. In Scheme 9, one of the functionalities can be checked out selectively. the nucleus, and join different monomers on each of the three combinatorial contributions marked to develop a diverse collection, as shown in structures 3-5.

Structure 3 Structure 4 Structure 5 Now Structures 3-5 can be mixed together, deprotect in the second functionality in the core, and react the three with a second monomer. To create even greater diversity, the mixture can be divided by splitting into deposits to react with several different groups of second monomers. For example, a reservoir containing structures 3, 4 and 5 can be deprotected in the second amine, and reacted with R4-X to complete the construction of the combinatorial collection. Another deposit can be deprotected and reacted with R5- (CO) -X. Structures 6-8 illustrate the deposit that reacts with R -X. Although the deposit now contains a blend of structure 6-8, any bead can be chosen for the mixture, and determining which member of the combinatorial collection is on that particular bead through FNMR.

Structure 6 Structure 7 Structure 8 In another preferred embodiment, each chemical step is coded by covalently bonding Lys, Orn or Dap orthogonally protected and labeled to the bead. As each step of the collection synthesis proceeds, a protective group of Lys, Orn or Dap is removed and linked to another brand or another Lys, Orn or Dap protected with another distinctive mark. Multiple reactions can be marked in the same way. Scheme 10 illustrates the binding of a lysine, premarked with a label 1, to a bead containing a lysine linker.

Collection Site of code Scheme 10 The protected amine with Boc or the amine protected with Alloc can now be deprotected. Any of the remaining protected amines can act as the collection site or the code site, although the Boc-protected amine is indicated as the collection site in Scheme 10. Now you can start the construction of a collection by joining a first monomer , followed by a second mark to encode the binding of a second monomer. Scheme 11 shows that the product of Scheme 10 with a first unit (amino acid A) linked through linker L can be encoded with a second tag 2, and reacted with a second unit (amino acid B) to produce a unique tag signature. FNMR representing the dipeptide AB.

Scheme 11 The protecting group may be a Dde, Fmoc, Bpoc, Alloc, or other common protecting group whose splitting is compatible with, and orthogonal to, the linker and collection. The FNMR signature of the pearl can be read either before or after this unfolding and, based on the observed signals, the reaction history of the pearl can be ascertained. Structure 9 illustrates a core wherein the functional groups at all orthogonal link sites are different. As an example, a bead having a free hydroxyl portion can be linked through the acid portion. After, the monomer is bound to the amine, followed by a second monomer in the aldehyde portion. Structures 10 and 11 illustrate the first unit, while Structures 12 and 13 illustrate the second unit. Those skilled in the art can recognize that the bound portion and the binding order may vary, and that protection and deprotection of the functional groups may be necessary. As a further example, if a bead is attached through the amine portion on the core, then diversification will occur in the acid portion.

Structure 9 Structure 10 Structure 11 Structure 12 Structure 12 The structures 14 and 15 illustrate the joining of the core to each of the two beads marked through a generic linker, L. In addition, they show the union of the structure 10 to the beads coded with the 1 mark and the Union of the Structure 11 to the pearls coded with the 2 mark.

Structure 14 Structure 15 Structures 14 and 15 are then mixed together, and split by splitting into two tanks (tanks 1 and 2) of the beads that are the mixtures of structures 14 and 15. The union of Structure 12 to tank 1 results in a mixture of structures 16 and 17.

Structure 17 Structure 17 From deposit 1, it can be determined which member of the collection is attached to any pearl simply by reading the FNMR mark. The mark 1 can imply the member corresponding to Structure 16, while the mark 2 can indicate the member corresponding to Structure 17. Similarly, the joining of Structure 13 to deposit 2, can result in a mixture of the structures 18 and 19. Again, the structure in each bead can be determined by reading the marks 1 or 2 through FNMR.

Structure 18 Structure 19 Structure 20 illustrates the use of a lysine code linker to join two tags to code the union of two monomer units to the collection core.

First unit of monomer already attached Structure 20 Scheme 12 illustrates another preferred embodiment wherein two different lysine linkers are used for the orthogonal linkage of different labels.

Scheme 12 Scheme 13 illustrates a multiple branding process, particularly elegant. The reductive amination of the product of Scheme 4 provides a coded resin that already has a linker for construction of the collection. After charging a core, a monomer can be selectively bound, then a second mark can be selectively bound. This product now is ready for the second monomer bond.

Load Core ad Scheme 13 Scheme 14 illustrates another method for modifying the product of Scheme 4 for the construction of the collection.

Scheme 14 Linkers of Collection Many functionalities and reagents can be used to facilitate partial selective separation of the pearl collection. Suitable examples of such spacers include ethers, such as substituted benzyl ether or derivatives thereof (eg, benzylhydric ether, indanyl ether, etc.) which can be split through reductive acidic or moderate conditions. Alternatively, ß-elimination may be employed, wherein a moderate base may serve to release the product. Acétals can also be used, including their thio analogs where the separation is achieved through moderate acid, particularly in the presence of a carbonyl capture compound. These can be formed by combining formaldehyde, HCl and a portion of alcohol to form an a-chloroether. Next, it is coupled with a hydroxy functionality in the bead to form the acetal. Various photolabile bonds can also be employed (for example, ethers or esters O-nitrobenzoyl, 7-nitroindanilic, 2- nitrobenzhydryl, etc.) Also the esters and amides can serve as linkers, when medium acid esters or amides are formed, particularly with cyclic anhydrides, followed by reaction with hydroxyl or amino functionalities in the bead, using a coupling agent such as DCC. In addition, the peptides are also potential linkers, wherein the sequence is subjected to enzymatic hydrolysis, particularly where the enzyme recognizes a specific sequence. Carbonates and carbamates can be prepared using carbonic acid derivatives, for example, phosgene, carbonyldiimidazole, etc., and a moderate base. The linker can be unfolded using an acid, base or strong reducing agent. When a linker is used, the functionalities in the solid support can be modified through a non-labile bond such as an ester bond, amide bond, amine bond, ether bond, or through a sulfur atom, silicon or carbon, depending on whether you want to remove the product from the bead or resin. Conveniently, the union of the bead or resin is permanent. Alternatively, the bond between the linker of the bead or resin may be labile or unfoldable. Depending on the nature of the linker group attached to the particle, reactive functionalities in the bead may not be necessary if the binding form allows insertion into single or double bonds, as is available with carbenes and nitrenes or other highly reactive species. In this case, the unlinkable link can be provided in the link group that links the product to the pearl. Preferred linkers are Lys, Orn, or Dap linkers protected with a photodefoldable protective group in the epsilon, gamma or delta amino group. The limited irradiation results in partial splitting of this photodegradable group, thereby releasing a site for the incorporation of one or more labels. An example of a collector linker is a protected 4-hydroxymethylphenoxyacetic acid (Wang linker) carrying a protecting group to mask the alcohol functionality. The following examples illustrate the preferred embodiment of the present invention, without limiting the claims or the specification. Those skilled in the art will readily appreciate that changes and modifications can be made to the specified embodiments without departing from the scope and spirit of the invention.

EXAMPLES Example 1 Manufacture of Marked Resin through Amide Coupling Diprotected Load Lysine on the Aminomethylpolystyrene Pearl (Scheme 1). Approximately 2.25 g (4.8 mmol) of N-α-BOC-N-e-FMOC lysine, approximately 1.69 ml (9.6 mmol) of N, N-diisopropylethylamine and approximately 2.24 g (4.8 mmol) PyBroP were successively added to a suspension of approximately 2.00 g (2.4 mmol capacity) of an aminomethyl polystyrene resin in approximately 30 ml of DCM. The suspensions were rotated at room temperature for approximately 1.5 hours and drained. The same amounts of reagent were added again to the resin, and the resulting suspension was rotated at room temperature for about 1.5 hours. The suspension was drained and the resin was washed successively with 5 portions of about 30 ml of DMF and 5 portions of about 30 ml of DCM and dried in vacuo.

FMOC deprotection Approximately 30 ml of 20% pyridine in DMF was added to approximately 2 g of the aminomethyl polystyrene of N-a-BOC-N-e-FMOC lysine prepared above. The suspension was rotated at room temperature for approximately 15 minutes, after which the solvent was drained. Approximately 30 ml of additional 20% pyridine in DMF was added and the suspension was rotated at room temperature for approximately 15 minutes, after which the solvent was drained. Then, the resin was washed sequentially with portions of about 30 ml of DMF, H2O, DMF, H2O, EtOH and MeOH.

Union of Fluorine Markers Deposit 1 (Mark 1) Approximately 2 ml of DMF was added to a 100 mg aminomethyl polystyrene deposit of N-a-Boc-lysine prepared above. The mixture was allowed to settle for about 30 minutes to allow the polystyrene to swell. Then, 3- (4-fluorophenyl) propionic acid (40 mg, 0.24 mM, 2 eq.) Was added to the mixture followed by 1,3-diisopropylcarbodiimide (56 ml, 0.36 mM, 3 eq.) And hydrate of 1 - hydroxybenzotriazole (16 mg, 0.12 mM, 1 eq.). This mixture was rotated for 16 hours at room temperature. Then, the resin was transferred to a frit funnel and washed sequentially with DMF, distilled water, ethanol, dichloromethane and methanol (aliquots of approximately 20 ml of each solvent, allowing 15 minutes of equilibration before the removal of each solvent). An individual bead FNMR spectrum of this deposit contained an individual peak at -118 ppm (see Figure 1). Note that minor variations, well known to those skilled in the art, can occur in the chemical shift of the fluorine peaks (label 1 listed as -117 ppm, but are shown as -117.71 ppm). However, these minor variations do not substantially change the effectiveness of fluorine labeling as a method for identifying collection member.

Deposits 2-4 (Marks 2-4) The method used to prepare tank 1 was used to bind 3,5-difluorophenylacetic acid (Trademark 2, 41 mg, 0.24 mM, 2 eq.). A single bead FNMR spectrum from reservoir 2 contained an individual peak at -110 ppm (see Figure 2). The method used to prepare tank 1 was used to bind 4-trifluoromethylbenzoic acid (Mark 3), 46 mg, 0.24 mM, 2 eq.). An individual bead FNMR spectrum from reservoir 3 contained an individual peak at -63 ppm. The method used to prepare tank 1 was used to bind 4- (trifluoromethoxy) benzoic acid (Trademark, 49 mg, 0.24 mM, 2 eq.). An individual bead FNMR spectrum from reservoir 4 contained an individual peak at -58 ppm.

Tank 5 (1: 1 Marks 1/2) Approximately 2 ml of DMF was added to a deposit of 100 mg of N-a-Boc aminomethyl polystyrene. lysine previously prepared. The mixture was allowed to settle for about 30 minutes to allow the polystyrene to swell. Then, a solution of pre-mixed 3- (4-fluorophenyl) propionic acid 20 mg, 0.12 mM) and 3,5-difluorophenylacetic acid (21 mg, 0.12 mM) in DMF was added to the mixture, followed by 1,3-diisopropylcarbodiimide. (56 ml, 0.36 mM, 3 eq.) And 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mM, 1 eq.). This mixture was rotated for 16 hours at room temperature. Afterwards, the resin was transferred to a frit funnel and washed sequentially with DMF, distilled water, ethanol, dichloromethane and methanol (aliquots of approximately 20 ml of each solvent, allowing 15 minutes of equilibration before the removal of each solvent). An individual bead FNMR spectrum of this deposit contained 2 fluorine peaks at .117 ppm and -110 ppm. The chemical shifts and the ratio of peak areas could be reproduced from pearl to pearl.

Deposits 6 (2: 1 Marks 1/2) and 7 (1: 2 Marks 1/2) The method used to prepare tank 5 was used to join a mixture of 3- / 4-fluorophenyl) -propionic acid (30 mg , 0.16 mM) and 3,5-difluorophenyl acetic acid (10 mg, 0.08 mM). The FNMR spectrum of individual deposit bead 6 contained 2 fluorine peaks at -117 ppm and -110 ppm. The chemical shifts and the ratio of peak areas could be reproduced from bead to bead, with a different relationship to bead from reservoir 5. The method used to prepare reservoir 5 was used to join a mixture of 3- (4-fluorophenyl) acid ) -propionic (10 mg, 0.08 mM) and 3,5-difluorophenylacetic acid (31 mg, 0.16 mM). The individual bead FNMR spectrum of reservoir 7 contained 2 fluorine peaks at -117 ppm and -110 ppm (see Figure 3). The chemical shifts and the ratio of peak areas could be reproduced from pearl to pearl, with a different relationship to the pearls of deposits 5 and 6. Note that mark 2, besides being twice as abundantly as mark 1, also has double the number of fluorine that mark 1. Accordingly, Figure 3 shows approximately 4 times the peak area for Mark 2 compared to Mark 1.

Additional Deposits The above methods were used to synthesize additional deposits using different carboxylic acid labels, and using them in combinations and ratios, as discussed in Table 2. Figures 4-9 are individual bead spectra for the 6, 9, brands 1/7, 2/7, 4/7 and 2/4/7, respectively. Figure 10 illustrates a spectrum of multiple beads for the mark 29. Figure 11 is a spectrum of multiple beads for a one-to-one ratio for Mark 3 (-63 ppm) to Mark 4 (-58 ppm). Note that the 3 mark joins the bead 2-3 times more easily than the 4 mark. Figure 12 shows a one to three relationship from Mark 3 to Mark 4. Figure 13 shows a two to one ratio of Mark 3 to Mark 4. Observe the highest signal to noise ratio for multiple bead cases (Figures 10-13).

BOC deprotection Approximately 3 ml of a 50% solution of trifluoroacetic acid in dichloromethane were added to each of the above deposits of labeled resin. The suspensions were rotated at room temperature for 30 minutes and drained. The procedure was repeated. After draining, the resin in each tank was washed with 5 portions of about 3 ml of dichloromethane, 5 portions of about 3 ml of 5% diisopropylethylamine in dichloromethane and 5 portions of about 3 ml of dichloromethane. Then, the resin was dried under vacuum. The coded pearl is now ready to join the desired collector link, core and first unit of the combinatorial collection.

EXAMPLE 2 Synthesizing and Decoding a Marked Combinatorial Collection General Synthetic reactions were performed in 8 ml reaction vessels on an Argonaut Nautilus 2400 multiple organic synthesizer. Washes were performed using the fast wash syringe pump cycle, and resulted in, in approximately 10 minutes, incubations for each wash of solvent. Fmoc and amino acid derivatives were used as received from commercial sources, such as ABI. The side chains were protected as indicated.

Addition of Linker (Illustrated by Structure 2) Samples of approximately 250 mg of each of the 10 BOC unprotected and labeled resins, as prepared in the Example 1, they were swollen in 2.6 ml of dichloromethane. Then, 1.2 ml of a solution of 1 M of 4- (4-hydroxymethylphenoxy) butyric acid (210 mg / ml, in 1: 1 dichloromethane: THF) was added, followed by 1.2 ml of a 1 M solution of EEDQ ( 247 mg / ml, dichloromethane). The reactions were incubated at 25 ° C for 18 hours, then drained and washed with dichloromethane (3x4.6 ml), methanol (2x46 ml), DMF (3x4.6 ml), methanol (2x4.6 ml), THF (3x4.6 ml), 1: 1 of 1 N of sodium hydroxide: dioxane (2x4.6 ml), THF (3x4.6 ml), and ethyl ether (2x4.6 ml), then dried in vacuo.

First Diversity Step Each bead deposit was washed with dichloromethane (1x4.6 ml).

Then, 2 ml of a 0.5 mm solution of the amino acids were added to each container according to the amino acid table. The vessels were cooled to 0 ° C and 0.4 ml of a 0.25 M solution of 4-dimethylaminopyridine (31 mg / ml, dichloromethane) combined with 0.8 ml of a solution of diisopropylcarbodiimide (0.195 ml / ml in dichloromethane) were added to each vessel. After 1 hour, the reactions were allowed to warm to 25 ° C, incubated for 3 hours, drained and the charge repeated, incubating for 7 hours at 25 ° C the second time. The vessels were emptied, washed with DMF (3x4.6 ml), methanol (2x4.6 ml), dichloromethane (3x4.6 ml), methanol (2x4.6 ml), THF (3x4.6 ml), and ethyl ether (2x4.6 ml), then dried under vacuum to obtain a bead coded with a linker and an amino acid corresponding to the code. The loads varied from 0.23-0.46 mmoles / g. The two lowest loads were manually re-performed through the same procedure to give the final results in the amino acid table.

Table of Amino Acids Amino acid, Code R-CH- (NHFmoc) -COOH Load 1 Val 0.37 2 Glu (Boc) 0.39 3 Leu 0.36 4 Phe 0.38 5 Gln (Trt) 0.33 6 Thr (t-Bu) 0.37 7 Tyr ( t-Bu) 0.38 8 Lys (Boc) 0.30 9 Trp (Boc) 0.39 10 Wing 0.33 First Mixture and Division by Excision A sample of 210 mg of each of the labeled resin deposits was added to a filter container, suspended in dichloromethane, mixed for about 1 hour, washed with diethyl ether (2x40 ml), and dried. This resulted in a mixture consisting of a statistical distribution of the 10 beads bound to the amino acid. Samples of approximately 180 mg of the mixture were charged to 8 ml reaction vessels.

Second Diversity Step The resins were Fmoc deprotected with pyridine (2x4.6 ml x 30 min incubation), drained and washed with DMF (3x4.6 ml), methanol (2x4.6 ml) and dichloromethane (4x4.6 ml). Approximately 1.16 ml of 2 M diisopropylethylamine in dichloromethane was added to each vessel, followed by 2 ml of a 0.55 M solution of the sulfonyl chlorides in dichloromethane according to the sulfonyl chloride box. The reactions were incubated for 12 hours at 25 ° C. The resins were washed with dichloromethane (2x4.6 ml), methanol (2x4.6 ml), DMF (3x4.6 ml), methanol (2x4.6 ml), dichloromethane (3x4.6). ml), THF (3x4.6 ml) and diethyl ether (2x4.6 ml), then dried in vacuo. A 15 mg sample of each reaction was removed and obtained.

Table of Sulfonyl Chloride Reaction Sulfonyl Chloride, R'-SO2-CI 1 8-Quinoline 2 alpha toluyl 3 Methane 4 Isopropyl 5 Trifluoroethane 6 Dansyl 7 Butane 8 Camphor 9 2-Thiophene 10 3-trifluoromethylphenyl Second Mixing and Division by Cleavage The resins not obtained from the second step of diversity were mixed in a filter vessel, suspended in dichloromethane, mixed for 2 hours, washed with methanol (2x40 ml), ethyl ether (2x40 ml), and dried. This resulted in a statistically distributed mixture with 100 beads bound to amino acid / sulfonamide. Samples of approximately 100 mg were loaded into 10 8 ml reaction vessels.

Third Step of Diversity Approximately 500 mg of powdered anhydrous potassium carbonate (desprotone hydrogen sulphonamide) and 4 ml of a 0.25 M solution of the alkyl bromides shown in the Table of alkyl bromide in NMP solution were added to each reaction vessel at room temperature. from the second step of mixing and division by splitting. The reactions were incubated at 25 ° C for 48 hours, washed with 1: 1 DMF: water (1x4.6 ml), water (2x4.6 ml), DMF (4x4.6 ml), methanol (2x4.6) ml), dichloromethane (3x4.6 ml), methanol (2x4.6 ml), THF (3x4.6 ml), and diethyl ether (2x4.6 ml), then dried under vacuum. The alkylation was carried out by adding about 3 ml of a 0.33 M solution of the alkyl bromides to each tube, cooling to 4 ° C and adding 1.2 ml of a 1 M solution of DBU in NMP. After 48 hours at 25 ° C, the resins were washed through the same procedure as the first alkylation and dried under vacuum.

Table of Alkyl Bromide Final Deposit Alkyl Bromide, R "-Br 1 Ethyl 2 t-butylacetyl 3 Tetrahydrofurfuryl 4 Decyl 5 a- (4-diethylamino) acetyl nonyl 6 Allyl 7 3-chlorobenzyl 8 Methylcyclohexyl 9 2-phenylethyl 10 6 -Hexanol "Classification" of Collection Observe that the three steps of diversity were marked only once with the fluorine marks, in the first step. In this case, the compound in each bead can be decoded with the following analysis. Since it is not necessary to mix and split the product of the last step of diversity, the binding of the alkyl bromide, it can be known exactly which alkyl bromide reacted with a particular deposit of bead. Then, the FNMR can be used to determine which monomer was added in the particular bead. Knowing the first and third units, the sulfonyl chloride units are sufficiently different to allow mass spectroscopy analysis.

In addition, the judicious selection of a diversity monomer can allow other types of combination analysis. For example, the dansylsulfonamide made by reacting the amino acid with dansyl chloride flowers under UV light. Accordingly, when a small portion of the reservoir 6 was placed under a long UV wave lamp, the pearls which bloomed the bright green color can be selected. In this manner, the compound that is bound to each of the selected beads must contain the allyl portion (as determined by deposit 6) and the dansylsulfonamide (as determined by UV fluorescence). Therefore, you only need to conduct an FNMR analysis to find out which amino acid is attached. Similarly, the judicious selection of monomers containing acetylenes or nitriles can result in a decoding analysis combining FNMR and IR / Raman spectroscopy.

EXAMPLE 3 Manufacture of Resin Made Through Friedel-Crafts Acylation Trifluoromethylbenzophenone resin (Scheme 4, Mark 3) A 500 ml flask was equipped with an overhead stirrer and charged with approximately 11.1 g of 1% interlaced polystyrene, approximately 150 ml of dichloromethane and approximately 1.0 g of iron chloride III. In one portion, 4-trifluoromethylbenzoyl chloride was added and the reaction (5.0 g, 24 mmol) and the reaction it was stirred for about 18 hours. The resin was collected, washed with dioxane (3x150 ml), 1: 1 dioxane: 2 N hydrochloric acid (3x150 ml), dioxane (3x150 ml), methanol (3x150 ml), and then dried under vacuum to give 12.4 g of resin. Elemental analysis indicated that approximately 0.74 mmoles of CF3 were loaded per gram of resin product. As shown in Figure 14, the chemical shift for the Friedel-Crafts junction of Mark 3 was not substantially different from that of the amide bound to Mark 3 (see Figures 11-13).

Trifluoromethylbenzhydrylamine resin (Reaction of Leukhart) A 250 ml three-necked flask was equipped with an overhead stirrer and a Dean-Stark trap and loaded with the above-prepared ketone resin (3.0 g, 2.22 mmoles ketone), ammonium formate (10 g, 159 mmoles) 88% formic acid (8 ml, 187 mmol, formamide (12 ml, 302 mmol), and 40 ml of nitrobenzene.The reaction mixture was heated to 165 ° C and the distillate was collected. resin was collected, washed with ethanol (3x30 ml), dioxane (3x30 ml), dichloromethane (3x30) ml), and ethanol (3x30 ml). The resin was suspended in 100 ml of 1: 1 concentrated hydrochloric acid: ethanol and heated to reflux for 1 hour, collected and washed with ethanol (3x30 ml), dichloromethane (3x30 ml), and methanol (3x30 ml). , then dried at 70 ° C under vacuum. Elemental analysis indicated that approximately 0.70 mmoles of CF3 and approximately 0.64 mmoles of N were loaded per gram of resin product. As shown through a FNMR spectrum of the partially complete reaction (Figure 15), the chemical shift of fluorine changed slightly (approximately 0.5 ppm) when the ketone was converted to benzhydrylamine.

EXAMPLE 4 Manufacture of Coded Resin through Acetylene Coupling Yodopolystyrene Synthesis Chromium trioxide (CrO3, 8.0 g, 80 mM) was placed in a round bottom flask under an argon atmosphere. During About 5 minutes, (CH3) 3SiCl (9.7 ml, 76 mM) was added through a syringe. The solution was stirred at about 35 ° C for about 30 minutes, followed by the addition of 200 ml of dichloromethane. Then, gas was bubbled vigorously through the suspension. After iodine (12.2 g, 48 mM) and polystyrene (10 g, 96 mM) were added in sequence, the suspension was stirred vigorously for 4 hours at room temperature. Then, a solution of saturated sodium bisulfite was added slowly until an orange-to-green color change was observed in the suspension, and the bubbling was no longer observed. The suspension was transferred to a frit glass filter funnel and washed sequentially with distilled water, DMF (dimethylformamide), water, 2N HCl, distilled water DMF, distilled water, methanol, dichloromethane and methanol (500 ml portions, about 5 minutes to balance each solvent). The p-iodopolystyrene product was dried and stored under vacuum.

Synthesis of Chloromethyl-polystyrene Approximately 5 g of the p-iodo-polystyrene synthesized above were placed in distilled dichloromethane from (CaH2 (200 ml) and allowed to swell for about 1 hour at room temperature, then the mixture was brought to 0 ° C in an ice bath. under an argon atmosphere With stirring, chloromethyl-methyl ether (10 ml, 130 mM) and 90.5 ml, 4.3 mM SnCl4) were added slowly via separate syringes to the suspension. Then, the suspension was stirred for about 1 hour at about 0 ° C under an argon atmosphere, then transferred to a frit filter funnel and washed sequentially with dioxane / distilled water (1: 1), 2N dioxane. HCl (1: 1), distilled water, dioxane, distilled water, methanol, dichloromethane and methanol (500 ml portions, about 5 minutes to balance each solvent). The product was dried and stored under vacuum. Elemental analysis of the product p-iodo-p-chloromethylpolystyrene indicated: Cl: 11.61% by weight and 24: 93% by weight.

Synthesis of Yodopolstyireno de Wang The yodoclorometilpolstyireno anterior (3.22 g) was dissolved in 100 ml of DMA and allowed to swell at room temperature for about 30 minutes. About 7.7 grams of 4-hydroxybenzyl alcohol (62 mM) were added to the suspension, followed by sodium methoxide (1.7 g, 31 mM). Then, the reaction mixture was heated to reflux under an argon atmosphere for about 48 hours. At that time, the suspension was allowed to cool to room temperature and transferred to a frit funnel and washed sequentially with dioxane / distilled water (1: 1), dioxane / 2 N HCl (1: 1), distilled water, dioxane , distilled water, DMF, distilled water, DMF, distilled water, methanol, dichloromethane and methanol (500 ml portions, about 5 minutes to balance each solvent). The product was dried under vacuum and stored.

Synthesis of Wang's Polystyrene Marking The iodo polystyrene from Wang synthesized above (100 mg) was added to a solvent mixture composed of trimethylformamide / distilled water / triethylamine (9: 1: 1) (5 ml. volume of total solvent) and allowed to cool for about 30 minutes at room temperature. A premixed solution of DMF (0.5 ml) containing "labels" (eg, 3,3,3-trifluoropropin and 1-ethylinyl-4-fluorobenzene) (50 mg each) was added to the bead suspension of the polymer followed by potassium carbonate (50 mg, 0.36 mM), tetrabutylammonium bromide (50 mg, 0.16 mM). After the suspension was stirred under argon for about 30 minutes, at that time tetrakis (triphenyl phosphine) palladium (O) (25 mg, 0.02 mM) was added quickly. The reaction mixture was heated to 80 ° C and stirred at that temperature under an argon atmosphere for 16 hours. Then, the mixture was allowed to cool to room temperature, then a saturated solution of ammonium acetate (5 ml) was added and the mixture was stirred at room temperature for about 30 minutes. At that time, 5 ml of dimethoxyethane was added, and the mixture was stirred for an additional 30 minutes. The mixture was then transferred to a frit filter funnel and washed sequentially with distilled water, dimethyl formamide, distilled water, 2 N HCl, distilled water, dimethyl formamide, distilled water, methanol, dichloromethane and methanol (50% portions). ml, about 10 minutes between washes to balance). The mixture of two marks was used to create a code.

Claims (32)

1. - A process for encoding individual members of a combinatorial chemistry collection synthesized into a plurality of solid supports comprising covalently linking at least one readable label of FNMR to each of the plurality of solid supports.

2. The process according to claim 1, wherein each bead is coded by a mark.

3. The process according to claim 1, wherein each bead is coded by two or more marks.

4. The process according to claim 1, wherein the code corresponds to a unique number of the collection.

5. The process according to claim 1, wherein the code corresponds to a specific chemical reaction.

6. The process according to claim 1, wherein the label is linked through coupling an aryl halide to a fluorine-containing amine moiety.

7. The process according to claim 1, wherein the label is attached by coupling an aryl halide to an acetylene containing fluorine.

8. The process according to claim 1, wherein the label is linked through Friedel-Crafts coupling and an aryl portion to a halogenide of fluorine-containing acid.

9. The process according to claim 1, wherein the mark is linked through Suzuki coupling of an aryl halide to an aryl borane containing fluorine.

10. The process according to claim 1, wherein the label is linked via displacement coupling of a fluorine-containing nucleophile with an electrophilic or a nucleophilic with an fluorophonic-containing electrophile.

11. The process according to claim 1, wherein the label is linked through reductive amination of an aldehyde with an amine.

12. The process according to claim 1, wherein the label is attached via Mitsunobu coupling of an alkyl hydroxide with acid portions selected from the group consisting of phenols, carboxylic acids, imides and oximes.

13. The process according to claim 1, wherein a site for joining the mark is masked as a nitro portion.

14. - The process according to claim 1, wherein the mark is joined after the collection synthesis has begun.

15. The process according to claim 1, wherein the mark is attached to the solid support before beginning the collection synthesis.

16. The process according to claim 1, wherein the brand is covalently linked to a solid support through a linker.

17. The process according to claim 16, wherein the brand is pre-attached to a linker and the brand is attached to the solid support by attaching the linker to the solid support.

18. The process according to claim 16, wherein the coding linker is selected from the group consisting of lysine, ornithine and diaminopropionic acid and protected derivatives thereof.

19. The process according to claim 16, wherein the coding linker is selected from the group consisting of lysine and protected derivatives thereof.

20. The process according to claim 16, wherein the lysine or its protected derivative is attached to the solid supports through its alpha amino group and is marked in its epsilon amino group.

21. The process according to claim 16, wherein the lysine or its protected derivative is attached to the solid supports through its carboxyl portion and is labeled at its amino epsilon group.

22. The process according to claim 16, wherein the lysine or its protected derivative is attached to the solid supports through its carboxyl portion and is labeled at its alpha and epsilon amino groups.

23. The process according to claim 1, wherein the mark is selected from the group consisting of marks 1-62 and combinations thereof.

24. The process according to claim 23, wherein the mark is selected from the group consisting of marks 1-35 and combinations thereof.

25. The process according to claim 23, wherein the mark is selected from the group consisting of marks 36-57 and combinations thereof.

26. The process according to claim 22, wherein the mark is selected from the group consisting of marks 58-62 and combinations thereof.

27. The process according to claim 1, further comprising decoding the individual members through the analysis selected from the group consisting of UV, fluorescence, mass spectroscopy, IR, Raman or a combination thereof.

28.- A solid combinatorial chemical support comprising a solid support and at least one readable label by means of FNMR joined to the solid support.

29. The solid chemical combinatorial support according to claim 28, wherein the mark is selected from the group consisting of marks 1-62 and combinations thereof.

30. The solid combinatorial chemical support according to claim 28, wherein the mark is selected from the group consisting of 1-35 labels and combinations thereof.

31. The solid chemical combinatorial support according to claim 28, wherein the mark is selected from the group consisting of marks 36-57 and combinations thereof.

32. - The solid chemical combinatorial support according to claim 28, wherein the mark is selected from the group consisting of marks 58-62 and combinations thereof.