BACKGROUND OF THE INVENTION A variety of small organic molecules are of interest since they can have potentially useful pharmacological activity. Among small organic molecules, nitrogen heterocycles hold a special place as historical pharmacophores.

Recent avances in combinatorial chemistry have significantly accelerated the process of drug discovery. In particular, combinatorial chemistry techniques have enabled synthesis of a large number of small organic molecules in a very expeditious manner.

Combinatorial library i. e., a library containing a large number of small organic molecules is useful as a research tool. In particular use of such libraries allows determination of biological binding properties of a large number of molecules. There is thus a need of an efficient process which will allow synthesis of small organic molecules, in particular nitrogen heterocycles, as well as a combinatorial library of such molecules.

SUMMARY OF THE INVENTION Keeping the above discussed needs in mind the present invention provides a process for the synthesis of dihydropyridone compound of Formula I. The process of the present invention can also be used to synthesize combinatorial libraries of dihydropyridone compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION The present invention thus provides a process for the synthesis of a compound of Formula I: ...... Formula I wherein: R1 represents H, an amino acid side chain, (CH2) 0 4-phenyl, (CH2) 1-6-NH-C (O)-O-alkyl, (CH2) s 4-phenoxy, (CH2) l 6-NH-C (O)-O-(CH2)-Ph, (CH2) 0 4-indole, C1 4 alkyl, or (CH2) 0- 4-S-alkyl; R² represents Cl 4-alkoxyphenyl, di-Cl 4-dialkylphenyl, Cl 8-alkylphenyl, halophenyl, halo-CI 4-alkyl phenyl, benzyl, cyanophenyl,-C5-lo-cycloalkyl, biphenyl, or C1-4-alkyl; R³ represents CI-14-alkyl, C2-14-alkenelene, aryl, substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalkyl, or -C1-8 alkyl-R5; R4 represents H or alkyl; R5 represents aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, Cl 8-alkylethers,-Cl 4-alkyltertiaryamines, or X represents O, NH or S; the process comprising the steps of: (i) reacting a compound of Formula A ........ Formula A, with a compound of Formula B ......... Formula B, to yield a compound of Formula C ....... Formula C, where SS represents a solid support, and Rl and R2 are as defined before; (ii) treating a compound of Formula C with a compound of Formula D R3_X-H.......... Formula D, where R3, and X are as defined before, to yield a compound of Formula I.

One preferred embodiment of the present invention provides a process wherein, step (i) comprises reacting a compound of Formula A with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP, DCC and EDC, and a dialkyl amino pyridine catalyst; and step (ii) comprises treating a compound of Formula C with a compound of Formula D in the presence of an amine base. A further preferred embodiment provides a process wherein the coupling agent in step (i) is DIC, the catalyst is dimethyl amino pyridine (DMAP); and the amine is triethyl amine.

Another preferred embodiment of the present invention provides a process wherein, R1 represents CH2-Ph, Ph, (CH2) 4-NH-C (O)-CI 4-alkyl, R 2 represents p-CI_4-alkoxy phenyl, 3,5-dialkyl phenyl, Cl 4-alkyl phenyl, p-halophenyl, 3,5-trifluoromethyl phenyl, benzyl, 4-cyanophenyl, 4-alkyl-phenyl, cyclohexyl, biphenyl, or alkyl; and R3 represents C2H5, A further preferred embodiment is one wherein R2 represents p-methoxy phenyl, 3,5-dimethyl phenyl, p-bromo phenyl or 4-methyl phenyl.

EXPERIMENTALDETAILS GeneralComments Discussed below are processes for the synthesis of compound of Formula B (Scheme I) and the novel process for the synthesis of dihydropyridone compound of Formula I (Scheme II).

Preparation of Compound of Formula B SchemeI: 0 0 Me0 NH2 ZnCl2/Danishefsky's Diene StopA R1 1 2 Ru O R2 0 O O 4 NaOH Ra N Me0 N MeOH HO R1 Step B R 3 Formula B Step-A: General Procedure In a rection vessel was placed an amine ester 1, and from about 0.5 to about 1.6 mole equivalents of an aldehyde 2, both preferably as inert solvent solutions, for example THF solutions. To this mixture was added about 1.5 to about 2 mmol of magnesium sulfate, as a drying agent. This resulting mixture was mixed and was then combine with additional magnesium sulfate (0.8 to 2 equivalents). After cooling this mixture to low temperatures, preferably from about 10°C to about-78°C, one mole equivalent of zinc chloride was added, while maintaining the rection mixture at a temperature of about 0°C.

To this cold rection mixture was then added 1-methoxy-3-trimethylsilyl-oxy-1,3- butadiene (Danishefsky's Diene) in four equal portions over a period of four hours (once every hour). A total of about 1 to 2 mole equivalents of the Danishefsky's Diene was added. The rection mixture was maintained at a low temperature of about 0°C throughout the diene addition, and then stirred for 12-18 hours at about 0°C after the addition of the diene was completed.

The magnesium sulfate was separated from the rection mixture and the magnesium sulfate was washed with DCM. The DCM washings were mixed with the filtered rection mixture and this new rection mixture was extracted, in succession, with an inorganic acid, preferably 2N HCI, NaHC03 (x 2), dried (Na2S04) and concentrated under reduced pressure to yield a compound of Formula 3 as an oil.

Step-B: General Procedure The hydrolysis procedure, converting a compound of Formula 3 to Formula B, comprises combining an alcohol and an inert solvent, preferably a mixture of methanol- THF solution of a compound of Formula 3 with from about 2 to about 6 mole equivalents of NaOH and stirring this mixture for 8-16 h. This rection mixture was then diluted with ether and extracted with water (x2). The aqueous layers were combine and further washed with ether (xi), and acidifie (preferably with HCI) to a pH of about 0.5 to about 2.5. This acidic mixture was then extracted with DCM (x3), dried with sodium sulfate and concentrated to yield a compound of Formula B.

Amino Esters (Compounds of Formula 1): Most amino esters 1 with side chain protecting groups can be used in Scheme I, step A for the hetero-Diels Alder rection with Danishefsky's Diene. Hydrophobic aminoesters are preferred. Illustrative examples of the hydrophobic aminoesters are tryptophan methyl ester (Trp-OMe), lysine (epsilon Boc-amine) methyl ester (Lys (BOC)- OMe), and tyrosine (benzyl ether) methyl ester (Tyr (Bz) OMe). Listed in Table I are additional examples of the amino esters, compound of Formula 1 that can be used in Step A of Scheme I.

Table I Ex. Free amino ester R' 1 PheGlyOMe Ph 2 L-PheOMe CH2-Ph 3 TrpOMe 1 H-Indol-3-ylmethyl 4 Tyr (tau) 4-tert-Butoxy-benzyl 5 Lys (Boc) 4-tert- Butoxycarbonylamino- butyl 6 MetOMe (CH2)-S-CH3 7 D-PheOMe CH2-Ph 8 Lys (Z) 4- Benzyloxycarbonylarnino -butyl Aldehydes (Compounds of Formula 2) Aliphatic, aromatic, and heteroaromatic aldehydes, represented by Formula 2, were useful in Step A, Scheme I, to yield compound of Formula 3. Hydrophobic aldehydes were preferred since they seemed to enhance the solubility of the products during the extractive workup. Table 11 lists representative aldehydes, compound of Formula 2, that can be used in the novel process of the present invention.

Table II R'-CHO Table II (Continued) R²-CHO Synthesis of Compound of Formula I The following synthetic Scheme II outlines the novel process for synthesis of dihydropyridone compound of Formula I.

SchemeII R2 O O Ra SS S \/OH + Ri R1 Formula A Formula B R2 O 0 Ra N J R3-X-H (Formula D) 11 u SS S O Step (ii) R Formula C Formula I Step (i) Acylation of Thiophenol resin: Preparation of a compound of Formula C A solution of DIC and a compound of Formula B, (approx. 1 mole equivalent relative to the thiophenol resin (Formula A) in DCM was allowed to sit for about 15 to about 30 min. To this mixture was added a thiophenol resin of Formula A, and from about 0.08 to about 0.2 equivalents (relative to the thiophenol resin) of DMAP. This rection mixture was mixed for about 10 to 24 hours leading to the formation of a compound of Formula C, as a solid. The solid was collecte by filtration and washed in succession (up to five times each), with DCM, an inert solvent (preferably THF) MeOH, THF, and dried by conventional methods, preferably air dried, to yield a compound of Formula C.

Step (ii): Preparation of a compound of Formula I To a mixture of an inert solvent (preferably dioxane), an amine, and a cleaving nucleophile (R3-X-H, Formula D) was added a compound of Formula C. The ratio of dioxane/triethylamine/R3XH (Formula D), was preferably maintained at 8: 1: 1. Any amine, known to one skilled in the art, which is capable of acting as a base can be used instead of triethyl amine. Should the compound of Formula D be volatile, an excess amount of a compound of Formula D can be used in order to maintain the desired concentration. The resulting mixture was placed in a preheated oven at about 40 °C for 10 to 24 hours. This rection mixture was then filtered, by conventional means, and the filtered residue was washed with dioxane. The combine dioxane mixture was frozen and was then lyophilized. Lyophilization was generally accomplished, by conventional methods known to one skilled in the art, at about 5°C and over a period of about 10-18 hours. This process yielded compound of Formula I as a solid.

Cleaving Nucleophiles (R3-X-H, Formula D) A variety of primary, secondary, and tertiary alcools can be used as cleaving nucleophiles (R3-X-H, Formula D) in the novel process of the present invention.

Preferred cleaving nucleophiles are low boiling, low molecular weight primary alcools.

Table m, lists alcools (compound of Formula D) that are useful as cleaving nucleophiles in the novel process of the presently claimed invention.

Table IH R³-X-H Table M (Continued) R³-X-H Table M (Continued) R³-X-H Table IN (Continued) R³-X-H Table M (Continued)<BR> <BR> R3-X-H The process of the present invention can also be used to synthesize a library of compound of Formula I. The following experimental procedure outlines a general procedure for the synthesis of such a library.

ExperimentalProcedure: Dihydropyridone scaffolds (compound of Formula 3) were prepared in sets of 30, by rection between two free amino esters (compound 1) and fifteen different aldehydes (compound 2). In individual Pyrex jars, an amino ester 1 (50 mmol each, in its free base form following extraction with bicarbonate) and an aldehyde 2 (50 mmol each) were dissolve in 50 mL of dry THF. Approximately 9.0 g (75 mmol, 1.5 equiv) of magnesium sulfate was added to each rection mixture in the individual pyrex jars. After shaking for 10 minutes at ambient temperature the rection mixtures were transferred to fresh Pyrex jars containing fresh 6.0 g (50 mmol) of magnesium sulfate. These Pyrex jars were cooled in a freezer (to-78 °C) for 10 minutes and then zinc chloride (100 rnL, 50 mol, 1 equivalent) was added as a 0.5 M solution in THF (available from Aldrich Chemicals) to each jar. The jars were then placed in the freezer for 15 minutes at-78 °C.

Danishefsky's diene (1-methoxy-3-trimethylsilyl-oxy-1,3-butadiene) (1.2 equiv, 60 mmol, 12.5 mL total) was added to each rection mixture in four 3.15 mL portions over a four hour period (once/hour). In between additions the rection mixtures were stored at 0°C. After the addition of Danishefsky's diene was completed the resulting rection mixtures were maintained at 0°C for 8-16 hours.

These rection mixtures were then individually decanted in to a mixture of 100 mL 2N HCl and 25 mL DCM in separatory funnels leaving the magnesium sulfate behind. After extraction and separation, the aqueous layer was rinsed twice with 15 mL DCM. The combine organic layers were backwashed with about 100 mL (+ 10 mL) saturated aqueous sodium bicarbonate (NaHC03). After collecting the organic layer, approximately 2.5 g of sodium sulfate (NasSO4) was added as a drying agent, followed by 1.0 g of decolarizing carbon.

The resulting solutions were filtered through fritte syringes (catalog #2456, Applied Separations, ca. 1 inch diameter) packed with 0.75 inches of silica gel topped with 0.75 inches of Celite (the silica gel was primed with 10 mL DCM). The eluents were individually collecte in respective appropriately labeled 50 mL Falcon Tubes (two Falcon Tubes per product to keep the volume in each Falcon tube below 35 mL and avoid bumping in the Savant vacuum centrifuge). The solvent from the samples in the Falcon Tubes was concentrated in parallel with a commercially available Savant vacuum centrifuge fitted with an adapter for Falcon Tubes to yield an oily residue. Alternatively, the solutions can be individually concentrated in round-bottom flasks using a rotary evaporator.

After concentration the resulting oily residues were hydrolyse by individually redissolving/suspending in MeOH/THF (1: 3, total volume: 150 mL) and transferring in to 250 mL pyrex jars followed by addition of 50 mL of 3 N NaOH (3 equiv, 150 mmol).

These resulting individual mixtures were shaken for 8-12 hours.

The rection mixtures were individually added to a mixture of ether (150 mL) and water (100 mL) in separatory funnels. Following extraction, the aqueous layer was collecte in appropriately labeled containers and was washed two more times with ether (150 mol). The combine aqueous layer was acidifie to a pH of 1 using hydrochloric acid. The acidifie aqueous layer was extracted with 3 x 10 mL of DCM. The combine organic layers (ca. 30-35 mL) were backwashed with 50 mL saturated aqueous NaCl, dried (Na2SO4) and then concentrated either in pretared Falcon tubes with a commercially available Savant vacuum centrifuge (Savant Instrument Company, Holbrook, NY) or individually in round-bottom flasks via standard rotary evaporation, to yield compound of Formula 3.

Employing the above optimized procedure, scaffolds (compound of Formula 3) were reliably obtained in sufficient purity and quantity (as determined by in-process analysis) for further use. Specifically, every scaffold that was selected to load onto resin (compound of Formula A) was identifie by LC-MS and was present as greater than 50% AUC at 214 nm. The mass balance of each selected scaffold also correlated to greater than 0.8 molar equivalents relative to resin (loading 1.0 mmol/g). Enough resin was used with all scaffolds to provide 100 mg of resin (1.0 mmol/g)/well for a yield of 0.1 mmol/well of final products.

The selected scaffolds derived from each amino ester were acylated onto a thiophenol resin (Formula A) according to the following procedure. A 0.1 M solution of DIC and the appropriate scaffold, of Formula 3, (5-10 mmol, depending on the mass balance of the particular scaffold) in 50-100 mL in DCM was allowed to react for 15 min.

Then 5.0 g (5.55 mmol based on theoretical loading l. lu g/mol) thiophenol resin was added followed by 63 mg (0.5 mmol) of DMAP catalyst. The rection mixtures in the jars were sealed and shaken for 18 h.

After the acylation was complete, the resins were rinsed thoroughly with DCM (six), THF (Sx), MeOH (Sx), THF (Sx), and anhydrous dioxane (3x).

The derivatized thiophenol resin was transferred into clamped Polyfiltronics plates (2.7 p) either as slurries in dioxane or as dry samples with shallow well (<0.5 cm high) microtiter plates. With the Robbins Scientific Hydra (96 automate parallel syringes in a microtitor plate format, Robbins Scientific, Sunnyvale, CA) 1.0 mL of a 8: 1: 1 (v/v/v) mixture of dioxane/triethylamine/alcohols (#1-X) was added to each resin.

The top of the plates were clamped shut and the plates were placed in a preheated oven at 40°C for up to 12 h. The plates were removed from the oven and the products were collecte in a pretared 2 mL Beckman microtitor plate by gravity filtration followed by positive nitrogen pressure. The plates were rinsed in parallel with 0.7 mL of dioxane employing an ATR mouline apparats (ATR Biotech, Inc., Emeryville, CA). The resulting dioxane solutions were placed in a-78 °C freezer until frozen. The solvent was removed in parallel via lyophilization at 5°C with a tray lyophilizer (Virtis, Gardiner, NY). The plates were then removed from the tray lyophilizer and placed in a desiccater under high vacuum overnight prior to quality analysis of the resulting library products.

Library products were identifie by Mass Spectroscopy (MS).

SYNTHESIS OF SPECIFIC EXAMPLES Representative compound of Formula C (Standards 1-6) were prepared using the novel process of the present invention as discussed below.

Step (i): Acylation of Thiophenol resin: Preparation of a compound of Formula C.

A 0.1 M solution of DIC and a compound of Formula B (5-10 mmol) in 50-100 mL in DCM was allowed to react for 15 min. Then 5.0 g (5.55 mmol based on theoretical loading 1.11 g/mol) thiophenol resin (compound of Formula A) was added followed by 63 mg (0.5 mmol) of DMAP catalyst. The rection vessel was sealed and shaken for 18 h.

The resin was rinsed thoroughly with DCM (5x), THF (5x), MeOH (Sx), THF (six), and anhydrous dioxane (3x), and then air dried to yield a compound of Formula C.

Step (ii): Preparation of a compound of Formula I: The derivatized resin, compound of Formula C above, was mixed with 1.0 mL of a 8: 1: 1 (v/v/v) mixture of dioxane/triethylamine/alcohol. This rection mixture was maintained at about 40°C for 12 hours. The product formed was then collecte by filteration and diluted with about 1 mL dioxane. The dioxane solution was lyophilized at about 5°C over 12 hours. the product thus obtained was dried and identifie by mass spectroscopy <BR> <BR> <BR> <BR> <BR> N- [ (S)-1- (tert-Butoxyethoxycarbonyl)-2-phenylpropylJ- (6R) 2,3-didehydro-6-p- toluoylpiperidin-4-one (Standard 5) was prepared by the process of the present invention. This compound was obtained as a 9: 1 ratio of diastereomers. The major diastereomer was purifie by HPLC and characterized: 'H NMR (300 Mhz, CDCl3) O = 1.20 (s, 9 H; CH3), 2.34 (s, 3 H; CH3), 2.66 (dd, J = 6.3 Hz, 16.9 Hz, 1 H; CH2), 2.70 (dd, J = 13.3 Hz, 16.9 Hz, 1 H; CH2), 2.97 (dd, J = 10.4 Hz, 14.1 Hz, 1 H; CH2), 3.24 (dd, J = 5.1 Hz, 14.1 Hz, 1 H; CH2), 3.54 (t, J = 4.2 Hz, 2 H; CH2), 3.91 (dd, J = 5.1 Hz, 10.4 Hz, 1 H; CH), 4.23 (t, J = 4.2 Hz, 2 H; Chez), 4.71 (dd, J = 6.3 Hz, 13.3 Hz, 1 H; CH), 5.42 (d, J = 7.8 Hz, 1 H; CH), 6.71 (d, J = 7.8 Hz, 1 H; CH), 7.30 (b, m, 7 H; Ar), 7.52 (d, J = 7. 8 Hz, 2 H; CH); LC-MS: 436 for (M + H).

Standard 1 Standard 2 C25H27NO4 C25H27NO3 Exact Mass: 405.19 Exact Mass: 389.20 Mol. Wt.: 405.49 Mol. Wt.: 389.49 C, 74.05; H, 6.71; N, 3.45; O, 15.78 C, 77.09; H, 6.99; N, 3.60; O, 12.32 C25H35NO3 Exact Mass: 397.26 Mol. Wt.: 397.55 C, 75.53; H, 8.87; N, 3.52; O, 12.07 Standard 3 Standard 4 C29H35NO5 Exact Mass: 477.25 Mol. Wt.: 477.59 C, 72.93; H, 7.39; N, 2.93; O, 16.75 Standard 5 C29H35BrN205 Exact Mass: 570.19 Mol. Wt.: 571.50 C, 60.95; H, 6.17; Br, 13.98; N, 4.90; O, 14.00 Standard 6 C 29H30 F6 N25 Exact Mass: 600.21 Mol. Wt.: 600.55 C, 58.00; H, 5.04; F, 18.98; N, 4.66; O, 13.32 Analysis Methods: LC-MS: Mass Spectra data was obtained using the following instruments and conditions.

Sciex 150 MCA Sample: 10 zip injection Solvent A: 99% water + 1% methanol + 0.1 % acetic acid Solvent B: 99% methanol + 1% water + 0.1% acetic acid Flow rate: 0.5 mL/min UV detection at 214 and 254 nm Turbo ion spray source LC: Shimadzu LC-10 UV: Shimadzu SDD-10 Auto sampler: Gilson 215.

HPLC: HPLC data was obtained using the following instruments and conditions.

HPllOO with Zorbax SB-C18 4.6 mm x 7.5 cm column Solvent A: 99.9% water + 0.1% trifluoroacetic acid Solvent B: 99.9% méthanol+ 0.1% tiifluoroacetic acid Sample: 5tL injection Flow rate: 1.0 mL/min Ramp: 1-100% Solvent B over 9 min, then 100% Solvent B for 2 min LTV detection at 214 and 254 nm DEFINTTIONS As used in the present invention the following terms and abbreviations have the following meaning, unless otherwise indicated.

Library of compounds : This term indicates a collection of independent (individual) compound that are synthesized by the process of the present invention.

Generally the term library of compound indicates a collection of individual compound distinct from one another. Also included in the library of compound is a mixture of the individual compound.

"Alkyl", or"alkyl radical"is meant to indicate a hydrocarbon moiety of up to 8 carbon atoms. This hydrocarbon is generally attache to at least one other atom, and can be straight chain, or branche, or cyclic.

The term"alkylene"represents an alkyl group, as defined above, except that it has at least one center of unsaturation, i. e., a double bond. Illustrative examples are butene, butadiene, propene, and pentene.

The term"cycloalkyl","cycloalkyl ring", or"cycloalkyl radical"indicates a saturated or partially unsaturated three to ten carbon monocyclic or bicyclic hydrocarbon moiety which is optionally substituted with an alkyl group. The term straight chain alkyl is meant to represent an unbranched hydrocarbon moiety of up to 8 carbon atoms. An example of a straight chain alkyl is a n-pentyl group.

The term"hetero cycloalkyl"or"hetero cycloalkyl radical"means cycloalkyl, as defined above, except one or more of the carbon atoms indicated are replace by a hetero atom chosen from N, NRl2, O, S (O), S (O) 2 and S, wherein R12 is (Cl 6) alkyl, hetero (C2_6) alkyl or hydrogen. Illustrative examples of the term heterocyclo (C5_14) alkyl are morpholinyl, indolinyl, piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).

The term"aryl"means an aromatic monocyclic, bicyclic, or a fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated. Thus a C6-Cl4 aryl group inclues phenyl, naphthyl, anthracenyl, etc. The term"heteroaryl"means aryl, as defined above, wherein one or more of the carbon atoms is replace by a hetero atom chosen from N, O, and S. The hetero atoms can exist in their chemically allowed oxidation states. Thus Sulfur (s) can exist as a sulfide, sulfoxide, or sulfone. Each heteroaryl ring comprises from five (5) to fourteen (14) atoms. Illustrative examples of heteroaryl groups are thienyl, furyl, pyrrolyl, indolyl, pyrimidinyl, isoxazolyl, purinyl, imidazolyl, pyridyl, pyrazolyl, quinolyl, and pyrazinyl.

The term"amino acid side chain"as used herein represents a natural or unnatural amino acid. The term"natural amino acid", as used herein is intended to represent the twenty naturally occurring amino acids in their L'form, which are some times also referred as'common amino acids', a list of which can be found in Biochemistry, Harper & Row Publishers, Inc. (1983). The term"unnatural amino acid", as used herein, is intended to represent the'D'form of the twenty naturally occurring amino acids described above. It is further understood that the term unnatural amino acid inclues homologues of the natural amino acids, and synthetically modifie form of the natural amino acids. The synthetically modifie forms include amino acids having alkylene chains shortened or lengthened by up to two carbon atoms, amino acids comprising optionally substituted aryl groups, and amino acids comprise halogenated groups, preferably halogenated alkyl and aryl groups.

The term"natural amino acid side chain"is intended to represent a natural amino acid ("natural amino acid"as defined above) wherein a keto (C=O) group replaces the carboxylic acid group in the amino acid. Thus, for example, an alanine side chain is C (=O)-CH (NH2)-CH3; a valine side chain is C (=O)-CH (NH2)-CH (CH3) 2; and a cystine side chain is C (=O)-CH (NH2)-CH2-SH. The term"unnatural amino acid side chain"is intended to represent an unnatural amino acid ("unnatural amino acid"as defined above) wherein a keto (C=O) group replaces the carboxylic acid group forcing unnatural an-lino acid side chains similar to ones illustrated under the definition of "natural amino acid side chain"above.

"Optional substituents"for aryl, hetero aryl, and Ph groups are R7 and R8. These R7, and R8 substituents at each occurrence are independently selected from a group <BR> <BR> <BR> <BR> consisting of H, NH2, halo, O-C1 alkyl, NHC1-C4 alkyl, N (Cl-C4) 2 alkyl, and CF3; while R8 is selected from H and Cl 4 alkyl.

The term"amine base"as used herein is intended to represent a tertiary amine, preferably having a low boiling point. Illustrative examples of an amine base are tiiethyl amine and tiimethyl amine. The term"alkyl amine"is intended to represent an amino compound wherein the nitrogen atom is substituted with at least one alkyl group (alkyl as definedearlier).

The term"cleaving nucleophile"as used herein represents a molecule containing a hydroxy, thiol or a primary or secondary amine group capable of functioning as a nucleophile. Preferred cleaving nucleophiles are compound containing a hydroxy group, i. e., compound generally referred to as alcools.

As used in the present invention, the illustration: _ _ generally indicates the point of attachment of the group, comprising the illustration, to another group or atom. The term"Ph"represents an optionally substituted phenyl radical or group. The term."inert solvent"as used herein represents solvents which do not react with the reagents dissolve therein. Illustrative examples of inert solvents are tetrahydrofuran (THF), methylene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), diaoxane, chloroform, and DMSO.

ABBREVIATIONS AND COMMON NAMES ACD: Available Chemicals Directory ACN: acetonitrile AcOH: acetic acid AUC: area under the curve Danishefsky's Diene: 1-methoxy-3-trimethylsilyloxy-1,3-butadiene DCC: Dicyclo hexyl carbodimide DCM: dichloromethane DIC: diisopropylcarbodiimide DMAP: dimethylaminopyridine EDC: ethyl dimethyl amino propyl carbodimide HCI: hydrochloric acid HPLC: high performance liquid chromatography LC/MS: liquid chromatography/mass spectroscopy MeOH: methanol NaCl: sodium chloride NaOH: sodium hydroxide Na2SO4: sodium sulfate PyBOP: benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophossphate THF: tetrahydrofuran Yb (OTf) 3 : ytterbium triflate ZnCl2: zinc chloride