Triester compounds and methods of use thereof

Abstract

The application provides a novel triester compound and the pharmaceutical composition and formulation thereof, as well as a method of using the triester compound for the treatment of, inter alia, an inflammatory-related disease or disorder.

Description

TRIESTER COMPOUNDS AND METHODS OF USE THEREOFRELATED APPLICATIONSThis application claims the benefit of U.S. Provisional Application No. 63 / 697,733, filed on September 23. 2024; U.S. Provisional Application No. 63 / 693.282, filed on September 11, 2024; U.S. Provisional Application No. 63 / 549,036, filed on February 2, 2024; and U.S. Provisional Application No. 63 / 611,392, filed on December 18, 2023. The entire teachings of the above applications are incorporated herein by reference.FIELD OF THE APPLICATIONThis application relates to new compositions of biologically active compounds that are useful for treating diseases and methods of making such compositions.BACKGROUNDInflammator -related diseases and disorders represent a significant healthcare challenge, impacting the well-being of individuals across the globe. These conditions encompass a broad spectrum of ailments, ranging from pulmonary disorders to skin conditions, and ocular diseases. Calcineurin plays a pivotal role in the immune system and the pathogenesis of inflammatory -related diseases and disorders. It serves as a crucial catalyst in T-cell activation by promoting the activation of Nuclear Factor of Activated T-cells (NFAT). consequently leading to the upregulation of interleukin 2 (IL-2) and the fostering of T-cell growth and differentiation in immune responses. As a result, calcineurin has emerged as a primary target for immunosuppressive drugs, which include cyclosporine, voclosporin, pimecrolimus, and tacrolimus. Nevertheless, these calcineurin inhibitors (CNIs) are associated with a range of potential side effects, such as elevated blood pressure, renal complications, an increased susceptibility to infections, and in the case of topical applications like pimecrolimus and tacrolimus, localized skin irritation.Also, CNIs have been a cornerstone in the immunosuppressive regimens for organ transplantation, notably exemplified by tacrolimus for kidney transplant. Lentine et al.. "OPTN SRTR 2021 Annual Data Report: Kidney”, American Journal of Transplantation, Volume 23, Issue 2, Supplement 1, 2023, Pages S21-S120, ISSN 1600-6135, https: / / doi.Org / 10.1016 / j.ajt.2023.02.004. How ever, the standard of care for CNIs has beenassociated with several areas of safety concern, notably impacting renal function, blood pressure, glucose tolerance, hyperlipidemia, and neurotoxicity’.One of the predominant challenges associated with CNI therapy, particularly tacrolimus, is nephrotoxicity. Despite advancements in patient selection and dosing strategies, nephrotoxicity remains a significant concern, often necessitating substantial dose reduction or discontinuation of CNIs. The impact on renal function not only poses a clinical challenge but also contributes to patient nonadherence, reflecting a key dose-limiting issue for tacrolimus. Naesens et al., "Calcineurin inhibitor nephrotoxicity". Clinical Journal of the American Society of Nephrology. (February 2009) 4 (2): 481-508.Another major concern is tacrolimus-induced CNS toxicity, with common side effects such as headache, insomnia, and tremor. More severe manifestations, including psychosis, visual changes, and seizures, further compound the challenges associated with this class of immunosuppressants.The cumulative impact of these side effects on patient compliance is profound. Nonadherence rates have surged, reaching up to 65% in young adults and a notable increase from 17% at baseline to 31% at 18% post-transplantation in adult kidney transplant recipients.This trend underscores the imperative need for novel CNIs that provide improved safety profiles and enhance patient adherence to post-transplantation regimens.SUMMARY OF THE INVENTIONThe invention is based on the discovery of the unexpected therapeutic effect of novel compounds on treating inflammatory-related conditions such as organ transplant rejection, pulmonary diseases including chronic pulmonary inflammation, SARS. and respiratory’ tract inflammation; skin conditions including psoriasis, dermatitis, and eczema; or other topical or systemic inflammations. The compounds comprise a plurality’ of ring moieties such as substituted phenyl and at least three ester moieties. The compound can be represented by Formula (I):Formula (I), wherein all the variables are as defined below7.DETAILED DESCRIPTION CompoundsThe extensive range of side effects and prevalent patient nonadherence associated with current calcineurin inhibitors (CNIs) necessitates an urgent exploration into the development of new CNIs with improved safety profiles. In pursuit of this objective, this invention introduces novel compounds designed to minimize or prevent central nervous system (CNS) exposure to avoid neurotoxicity. The compounds exhibit optimal properties to be used as Long- Acting Injectables which, when applied subcutaneously, result in sustained exposure in the circulation to target the relevant immune cells peripherally, offering a potential reduction in side effects and an opportunity to overcome the limitations inherent in existing immunosuppressive treatment regimens. The compounds of the invention comprise at least three ester groups and are represented by Formula (I):or a pharmaceutically acceptable salt, a stereoisomer and a mixture of stereoisomers, or a prodrug thereof; wherein X is selected from -COORA, -CONRBRC, -NHCONRBRC, -C(O)NHORA, - C(O)SRA, -S(O)2ORA, -S(O)2NRBRC, -S(O)2NHC(O)RA, -NHC(O)NHS(O)2RA, and -Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11, RI2, R13, and R14 are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORA, CN, NRBRC, NRAC(O)RA, S(O)RA (racemic ore enantiomerically pure), S(O)2RA, SOZNRBRC, S(O)2ORA, COORA, C(O)RA, and C(O)NRBRC; or each pair of Ri and R2, R3 and R4, Rs and Re. R7 and Rs. R9 and Rio. and R11 and RI2independently, together with the phenyl to which they are attached to, form a substituted or unsubstituted fused bicyclic ring system comprising zero, one, two, or more heteroatoms selected from -N-, -S-, and -O- (preferably one or two heteroatoms selected from -N-, -S-, and -O-); or R13 and R14 together form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl; the ring systems can be mono-, di-, or trisubstituted, preferably with alkyl, alky oxy, more preferably methyl and methoxy;R15 is selected from absent, H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORA, CN, NRBRC, NRAC(O) A, S(O)RA (racemic or enantiomerically pure), S(O)2RA, SChNRnRc, S(O)2ORA, COORA, C(O)RA, and C(O)NRBRC; each RA, RB, and Rc is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or RB and Rc can be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5, 6, 7, or 8 membered ring;Ri6 and Ri? are each independently selected from substituted or unsubstituted alkyl; or Ri6 and R17 together form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl (such as a substituted or unsubstituted cycloalkadienyl), substituted or unsubstituted heterocycloalkyl, wherein these ring systems can be optionally fused or bridged; alternatively. Ris, Ri6 and R17 form a substituted or unsubstituted 5- to 10-membered bridged ring system that has zero, one, two, or more heteroatoms;Z is carbon or nitrogen; and n is 0 or 1.In some preferred embodiments. Ri6 and Ru together with the Z to which they are attached form a substituted or unsubstituted 5- to 10-membered cycloalkyl, preferably a cycloalkenyl, or more preferably a cycloalkadienyl.In some preferred embodiments, R15 is H, hydroxyl, or a Ci-6 alkyl.For example, the compound is not a naturally occurring product. For example, the compound is not:In some embodiments, n is 0, Ri6 and R17 form a substituted or unsubstituted cyclohexadiene, resulting in Formula (II):Formula (II), wherein X, Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11, R12, R13, R14, and R15 are as defined above;R19, R20, R21, R22, R23, and R25 are each independently selected from absent, H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORA, CN, NRBRC. NRAC(O)RA, S(O)RA, S(O)2RA, SO2NRBRC, SO3RA, COORA, C(O)RA, and C(O)NRBRC; each RA, RB, and Rc is independently as defined above; or each pair of R19 and R20, R20 and R21 or R22, R21 or R22 and R23, R23 and R25 together with the ring to which they are attached independently form a fused ring system; or any two or three of R15, R19, R20, R21, R22, R23, and R25 together with the ring to which they are attached form a bridged ring structure; or R21 and R22 together form an oxy (=0).In some embodiments, n is 0, Ri6 and R17 form a substituted or unsubstituted 2.5- cyclohexadienone, resulting in Formula (III):Formula (III); wherein X. Ri. R2. R3, R4, Rs, Re, R7, Rs, R9, Rio, R11. R12, R13. R14. and Ris, R19. R20, R23, and R25 are as defined above.In some cases, R19, R20, R23, and R25 are each independently selected from H, D, halogen, -OH, a substituted or unsubstituted C1-6 alkyl, -O-C1-6 alkyl, CN; or R19 and R20 together with the ring to which they are attached to form a fused bicyclic ring system; or R23 and R25 together with the ring to which they are attached to form a fused bicyclic ring system; or any two of R19, R20, R23, and R25 together with the ring to which they are attached to form a bridged ring system.In some cases, R19. R20, and R23 are each independently selected from H, D, halogen. - OH, a substituted or unsubstituted C1-6 alkyl; R25 is a -O-C1-6 alkyl.In some cases, R19 is a C1-3 alkyl; R25 is a -O-C1-3 alkyl; and R20, and R23 are each independently selected from H, D, halogen, -OH, a substituted or unsubstituted C1-6 alky l.In some embodiments, X is -COOH, -COOCH3, -CONH2, -C(O)NHOH, - NHC(O)NH2, -S(O)3H, -S(O)2NH2, -S(O)2NHC(O)CH3, -NHC(O)NHS(O)2CH3. and - COCH3.Preferably, X is -COOH.In some embodiments, Ri, R2, R3, R4, Rs, R7, Rs, R9, Rio, R11, and R12 are each independently selected from H, F, Cl, Br, -OH, a substituted or unsubstituted C1-6 alkyl (including but not limited to -CH3, -CH2CH3, isopropyl, cyclopropyl), -CF3, -CHF2, or -CH2F. -CN, -O-Ci-6 alkyl (including but not limited to -OCH3, -OCH2CH3, -O-isopropyl, or -O-cyclopropyl), a substituted or unsubstituted phenyl, a substituted or unsubstituted 5- to 6- membered heteroaryl, a substituted or unsubstituted 3- to 6-membered cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl.In preferred embodiments, Ri, R2, R3, Rs, R7, Rs>, Rio, R11, and R12 are each independently selected from H, F, Cl, Br, -OH, -CH3, -CH2CH3, -OCH3, and -OCH2CH3.In preferred embodiments, R4 is selected from H, F, Cl, Br, -OH, -CH3, -CH2CH3, - OCH3, -OCH2CH3. a substituted or unsubstituted phenyl, a substituted or unsubstituted 5- to 6-membered heteroaryl, a substituted or unsubstituted 3- to 6-membered cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl.In preferred embodiments, Ro is selected from H, F, Cl, Br, or -CH3; more preferably Re is H.In preferred embodiments, Rs is selected from H, F, Cl, Br, -OH, -CH3, -CH2CH3, - OCH3, -OCH2CH3, a substituted or unsubstituted phenyl, a substituted or unsubstituted 5- to 6-membered heteroaryl, a substituted or unsubstituted 3- to 6-membered cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl.In some cases, R4 and Rs are independently selected from H, F, Cl, Br, -OH, -CH3, - CH2CH3, -OCH3, -OCH2CH3, a substituted or unsubstituted phenyl, a substituted or unsubstituted 5- to 6-membered heteroaryl, a substituted or unsubstituted 3- to 6-membered cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, including:wherein each of the groups above is substituted with zero, one, two, three, or four substituents. In some preferred embodiments, n is 0. In additional embodiments, n is 1 .In some embodiments, Ris and Ru are independently selected from H, halogen, a -Ci-6 alkyl, a -O-Ci-6 alky l, NRARB, -CN. Preferably, R13 and Ri4 are independently selected from -H, F, Cl, Br. -CH3, -OCHS, -NH2. Preferably. R13 and R14 are both -CH3.In additional embodiments, R13 and R14 together with the carbon to which they are attached form a substituted or unsubstituted cycloalkyl. For example, n is 1, C / R13 / R14 is a substituted or unsubstituted cycloalkyl including:, wherein each of the groups above is substituted with zero, one, two, three, or four substituents.In some embodiments, R15 is absent, -OH, H, F, Cl, Br, or a substituted or unsubstituted Ci-6 alkyl (such as -CH3, -CH2CH3, isopropyl, cyclopropyl. -CH2OH, -CF3, - CHF2, or -CH2F).In some embodiments, R15 is -OH, F, Cl, -CH3, -CH2CH3, -CH2OH, -CFs, -CHF2, or - CH2F.In some embodiments, R15 is -OH.In some embodiments. R15 is -CH3.In some preferred embodiments, Z is carbon. In additional embodiments, Z is nitrogen. In some preferred embodiments, Ri6 and R17 together with Z form a substituted or unsubstituted cycloalkyl, heterocycloakyl. aryl, heteroaryl, a cycloalkenyl, or a cycloalkadienyl. In additional embodiments, R15, Ri6 and R17 together with Z form a bridged ring structure.In some embodiments, Ri6 and R17 together with Z form a ring structure, or R15, Ri6 and R17 together with Z form a bridged ring structure; and the ring structure or bridged ring structure include, but is not limited to:wherein each of the groups above is substituted with zero, one, two, three, four, or five substituents selected from -OH, a C1-3 alkyl, a -O-C1-3 alkyl, -CN, and =0.Non-limiting examples for the combination of Ris and Z / Ris / Rn include:R15 Z / R16 / R17 R15 Z / R16 / R17R15 Z / R16 / R17 R15 Z / R16 / R17R15 Z / R16 / R17 R15 Z / R16 / R17R15 Z / R16 / R17 R15 Z / R16 / R17R15 Z / R16 / R17 R15 Z / R16 / R17R15 Z / R16 / R17 R15 Z / R16 / R17R15 Z / R16 / R17 R15 Z / R16 / R17R15 Z / R16 / R17 R15 Z / R16 / R17absent absentR15 Z / R16 / R17 R15 Z / R16 / R17R15 Z / R16 / R17 R15 Z / R16 / R17 absent absentabsent absentabsent absentabsent absentR15 Z / R16 / R17 R15 Z / R16 / R17When R15, Ri6, and R17 together form a bridged ring structure, non-limiting examples of the bridged ring structure includes but are not limited to:Z / R15 / R16 / R17In additional embodiments, Ri6 and R17 are each independently selected from a substituted or unsubstituted C1-6 alkyl, such as -CH3, -CH2CH3, isopropyl, cyclopropyl, - CH2OH, -CF3, -CHF2, or -CH2F. Non-limiting examples of Z / R16 / R17 include -Z(CH3)CH3, - Z(CH2CH3)CH3, -Z(CH2CH3)CH2CH3.In some embodiments, X is -COORA; RB and R17 together form a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyd, a substituted or unsubstituted heterocycloalkyl; or R15, Ri6, and R17 together form a bridged ring structure; resulting in Formula (IV) or Formula (V):Formula (V);The variables Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11, R12, R , R14, and Ris are as defined above, including all preferred and additional embodiments.The dashed circle inside the 6-membered ring in Formula (IV) represents varying degrees of unsaturation in addition to the ring, such as 0, 1, 2, or 3. Z, Zi, Z2, and Z3 are independently selected from C, N, and O.Ris is H, D, substituted or unsubstituted alkyl, substituted or unsubstituted aryl. substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.Ri9. R20, R21, R22, R23, R24, and R25 are each independently selected from absent, H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, ORA, CN, NRBRC, NRAC(O)RA, S(O)RA, S(O)2RA, SO2NRBRC, SO3RA, COORA, C(O)RA, and C(O)NRBRC; each RA, RB, and Rc is independently as defined above. Alternatively, each pair of R19 and R20, R20 and R21 or R22, R21 or R22 and R23, R23 and R24 or R25 together with the ring to which they are attached independently form a fused ring system. Alternatively, any two or three of R15, R19, R20, R21, R22, R23, R24, and R25 together with the ring to which they are attached form a bridged ring structure.Preferably, R19 is H, F. Cl, Br, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted -O-C1-6 alkyl, -OH, -CN, or -COOH. More preferably, R19 is H, F, Cl, -OH, - CH3, or -OCHs. Most preferably, R19 is -CH3.Preferably, R20 is H, F, Cl, Br, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted -O-C1-6 alkyl, -OH, -CN, or -COOH. More preferably, R20 is H, F. Cl, -OH, - CH3, or -OCH3. Most preferably, R20 is H.Alternatively, R19 and R20 together with the ring to which they are attached form a 7- to 10-membered fused ring system.Preferably, R21 and R22 are independently selected from H, F, Cl, Br, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted -O-C1-6 alkyl, -OH, -CN, or -COOH; or R21 and R22 together form an oxy (=0); or R21 is absent and R22 is H, F, Cl, Br, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted -O-C1-6 alky l, -OH, -CN, or -COOH.Preferably, R23 and R24 are independently selected from absent, H, F, Cl, Br, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted -O-C1-6 alkyl, -OH, -CN, or -COOH. Alternatively, R23 and R24 together with the ring to which they are attached form a 7- to 10-membered fused ring system. More preferably, R23 and R24 are independently absent, H, or -CH3.Preferably. R25 is H, F. CL Br. a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted -O-C1-6 alky l, -OH, -CN, or -COOH. More preferably, R25 is H, F, Cl, -OH, - CH3, or -OCHs. Most preferably , R25 is -OCH3.In some cases, Z, Zi, Z2, and Z3 are each C.In some cases, Z. Z2. and Z3are each C, and Zi is O.In some cases, R15 is absent, Z is N, Zi is O, and Z2, and Z3 are both C.In some cases, Ris is absent, Z is N and Zi, Z2, and Z3 are each C.In some cases, Z, Zi, Z3 are each C and Z2 is N.In some cases, Z, Zi, Z2 are each C and Z3 is N. In some cases, Z and Zi are both C, and Z2 and Z3 are both N.With reference to Formula (IV), Z, Zi, Z2, and Z3 are each C, resulting in Formula (VI) as shown below:Formula (VI) represents a 6-membered ring group including cyclo-CeHn,The variables Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11, R12, R13, R14, R15, Ris, R19, R20, R21, R22, R23, R24, and R25 are as defined above, including all preferred and additional embodiments.With reference to Formula (VI), Ris is H,, R21 and R22 together form an oxy (=0), and R24 is absent, resulting in Formula (VII) as shown below:Formula (VII)The variables Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11, R12, R13, R14, Ris, R19, R20, R23, and R25 are as defined above, including all preferred and additional embodiments.In some preferred embodiments, Ri is a substituted or unsubstituted C1-3 alkyl, or -O- C1-3 alkyl, preferably a C1-3 alkyl.In some preferred embodiments, R2, R3, Rs, R7, R9, Rio, and R19 are each independently a substituted or unsubstituted C1-3 alkyl.In some preferred embodiments, R4 and Rs are each independently selected from a substituted or unsubstituted C1-3 alkyl, a substituted or unsubstituted 5- or 6-membered aryl, a substituted or unsubstituted 5- or 6-membered heteroaryl, a substituted or unsubstituted 5- or 6-membered heterocycloalkyl; wherein the heteroatoms include nitrogen or oxygen; wherein the substituents include F, Cl, Br, or C1-3 alkyl.In some preferred embodiments, Ro, R11, R12 are each independently selected from H, OH, F, Cl, and Br.In some preferred embodiments, Ris is OH, or a substituted or unsubstituted C1-3 alkyl.In some preferred embodiments, R25 is a -O-C1-3 alkyl, or a substituted or unsubstituted C1-3 alkyl.In additional embodiments, n is 1, X is -COOH, Rie and R17 together form a substituted or unsubstituted and, a substituted or unsubstituted heteroaryl, a substituted orunsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, resulting in Formula (VIII)Formula (VIII). The variables Z, Zi, Z2, Z3, Ri, R2, R3, R4, R5, Rs, R7, Rs, R9, Rio, R11, R12, R13, R14,Ris, R19, R20, R21, R22, R23, and R25 are as defined above, including all preferred and additional embodiments.Preferably, R13 and R14 are independently selected from H, F, Cl, Br, OH, C1-3 alkyl; or R13 and R14 with the carbon to which they are attached form a 3- to 6- membered aryl, heteroaryl, cycloalkyl, heterocycloalkyl. For example, R13 and R14 are both -CH3.In preferred embodiments, with reference to Formula (VII), R15 is OH, resulting in Formula (IX):Formula (IX). All the variables Ri, R2, , R4, Rs, Rs, R7, Rs, R9, Rio, R11, R12, R13, R14, R19, R20, R23, and R25 are as defined above, including all preferred and additional embodiments.In preferred embodiments, Ri is selected from:Rs is selected from:Rs is selected from;"CH3 "CH2CH3-OCH3-Br -CHF2Re is selected from: “ “H- _F ClR7 is selected from:R<» is selected from: ^^3 CH2CH3 BrRio is selected from:- -CH3 "CH2CH3 --Br — F --CI — CNR11 is selected from:OH OCH3 CH3 CHF2R12 is selected from:— H — F —Cl --Br — CH3— CH2CH3— OCH3— CN — CF3— CHF2-- <JR19 is selected from: CH3 CH2CH3R20 is selected from:- -H OH3R23 is selected from: --H --CH 3R25 is selected from:The following compounds of formulae (X), (XI), (XII), (XIII) and (XIV) are also included in the invention:The variables Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11, R12, R13. R14, Ris, R19, R20, R23, andR25, when present, are as defined above, including all preferred and additional embodiments.The following compounds of formulae (XV) and (XVI) are also included in the invention:The variables Ri, R2. R3. R4. Rs. Re, R7, Rs, R9, Rio. R11, and R12 are as defined above, including all preferred and additional embodiments.More preferred compounds are:Most preferred compounds are:Non-limiting exemplary compounds for this invention are provided in Table 1.Table 1 Exemplary compounds of the inventionNEach preferred embodiment described herein can be taken in combination with one, any or all other preferred embodiments, as though presented herein in every permutation.Compositions of the invention can comprise racemic mixtures, pure enantiomers, or an excess of one enantiomer over the other. For example, a composition can comprise an enantiomeric excess of at least 5, 10, 20, 30. 40. 50. 60, 70, 80 or 90%. In one embodiment, the enantiomeric excess is at least 95%.The compounds of the invention include all enantiomers which may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, as well as their racemic and optically pure forms, and is not limited to those described herein in any of their pharmaceutically acceptable forms, including enantiomers, salts in any stoichiometry, solvates in any stoichiometryincluding hemi-solvates, polymorphs (of amorphous and ciystalline nature), solvatomorphs, hydrates in any stoichiometry including hemi-hydrates, anhydrous and other crystalline forms and combinations thereof. Likewise, all tautomeric forms are intended to be included.Preferably, a pharmaceutical composition comprises the compound of the invention as an R enantiomer in substantially pure form; or a pharmaceutical composition comprises the compound of the invention as an S enantiomer in substantially pure form; or, a pharmaceutical composition comprises the compound of the invention as enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer. It is particularly preferred that the pharmaceutical composition contains the compound of the invention which is a substantially pure optical isomer. For the avoidance of doubt, the compound of the invention can, if desired, be used in the form of solvates including hydrates and in any stoichiometry.The compounds of the invention can be synthesized through a series of reactions including synthesis of intermediate ring moieties, selective protection of hydroxy groups, coupling reactions, and deprotection reactions. A representative synthetic scheme is shown below as Scheme (I):Scheme (I).Each R group in Scheme (I) respectively corresponds to and adopts the definition of R1-R25 as shown in any one of the Formulas (preferably, Formula (III)) at the same position, including all preferred and additional embodiments. Coupling reaction can be carried out using different conditions, such as trifluoroacetic anhydride (TFAA) at 80 "C; N.N'- diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (DMAP) at 25 °C; l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) and DMAP at 55 °C; benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOPCI), diisopropylethylamine (DIEA), and DMAP. with the reaction occurring between 0 °C and room temperature. Dimer oxidation can be carried out using Tris(2,2'- bipyridine)ruthenium(II) hexafluorophosphate with oxygen gas and 440 nm light, as exemplified below:Formulation of CompositionsThe administration of the compounds of the invention may be by any suitable means that results in the reduction of perceived pain sensation at the target region. The compounds of the invention may be contained in any appropriate amount in any suitable carrier substance and are generally present in amounts totaling 1 -99% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intrathecal, epidural, or ocular administration, or by injection, inhalation, or direct contact with the nasal or oral mucosa.Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 22nd edition, 2013, ed. L.V. Allen, Pharmaceutical Press, Philadelphia, and Encyclopedia of Pharmaceutical Technology, 4thEdition, ed. J. Swarbrick. 2013, CRC Press, New York).Each compound may be formulated in a variety of ways that are known in the art. For example, the compound of the invention and a biologically active agent as defined herein may be formulated together or separately. Desirably, the compound of the invention and a biologically active agent are formulated together for their simultaneous or near simultaneous administration. In another embodiment, two or more biologically active agents may be formulated together with a compound of the invention, or separately. Other examples include, but are not limited to, two or more compounds of the invention formulated together, wherein the compounds are formulated together with or without one or more biologically active agents.The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include but are not limited to kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions.The kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.Controlled Release FormulationsEach compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, can be formulated for controlled release (e.g., sustained or measured) administration, as described in U.S. Patent Application Publication Nos. 2003 / 0152637 and 2005 / 0025765, each incorporated herein by reference. For example, a compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, can be incorporated into a capsule or tablet that is administered to the patient.Any pharmaceutically acceptable vehicle or formulation suitable for local application and / or injection into a site to be treated (e.g., a painful surgical incision, wound, or joint), that is able to provide a sustained release of compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, may be employed to provide for prolonged elimination or alleviation of inflammation, as needed. Controlled release formulations known in the art include specially coated pellets, polymer formulations or matrices for surgical insertion or as sustained release microparticles, e g., microspheres or microcapsules, for implantation, insertion, infusion or injection, wherein the slow release of the active medicament is brought about through sustained or controlled diffusion out of the matrix and / or selective breakdown of the coating of the preparation or selective breakdown of a polymer matrix. Other formulations or vehicles for controlled, sustained or immediate delivery of an agent to a preferred localized site in a patient include, e.g., suspensions, emulsions, gels, liposomes and any other suitable art known delivery vehicle or formulation acceptable for subcutaneous or intramuscular administration.A wide variety of biocompatible materials may be utilized as a controlled release carrier to provide the controlled release of a compound of the invention, alone or in combination with one or more biologically active agents, as described herein. Any pharmaceutically acceptable biocompatible polymer known to those skilled in the art may be utilized. It is preferred that the biocompatible controlled release material degrade in vivowithin about one year, preferably within about 3 months, more preferably within about two months. More preferably, the controlled release material will degrade significantly within one to three months, with at least 50% of the material degrading into non-toxic residues, which are removed by the body, and 100% of the compound of the invention being released within a time period within about two weeks, preferably within about 2 days to about 7 days. A degradable controlled release material should preferably degrade by hydrolysis, either by surface erosion or bulk erosion, so that release is not only sustained but also provides desirable release rates. However, the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired reversible local antinociceptive effect over the desired time period. Suitable biocompatible polymers can be utilized as the controlled release material. The polymeric material may comprise biocompatible, biodegradable polymers, and in certain preferred embodiments, is preferably a copolymer of lactic and glycolic acid. Preferred controlled release materials which are useful in the formulations of the invention include the polyanhydrides, polyesters, co-polymers of lactic acid and glycolic acid (preferably wherein the weight ratio of lactic acid to glycolic acid is no more than 4: 1 i.e.. 80% or less lactic acid to 20% or more glycolic acid by weight) and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride. Examples of polyesters include polylactic acid, polyglycolic acid and polylactic acid-polygly colic acid copolymers. Other useful polymers include protein polymers such as collagen, gelatin, fibrin and fibrinogen and polysaccharides such as hyaluronic acid.The polymeric material may be prepared by any method known to those skilled in the art. For example, where the polymeric material is comprised of a copolymer of lactic and glycolic acid, this copolymer may be prepared by the procedure set forth in U.S. Pat. No. 4.293,539, incorporated herein by reference. Alternatively, copolymers of lactic and glycolic acid may be prepared by any other procedure known to those skilled in the art. Other useful polymers include polylactides, polyglycolides, polyanhydrides, poly orthoesters, polycaprolactones, polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and poly orthoesters or mixtures or blends of any of these.Pharmaceutically acceptable polyanhydrides that are useful in the present invention have a water-labile anhydride linkage. The rate of drug release can be controlled by the particular polyanhydride polymer utilized and its molecular weight. The polysaccharides maybe poly-l,4-glucans, e.g., starch glycogen, amylose, amylopectin, and mixtures thereof. The biodegradable hydrophilic or hydrophobic polymer may be a water-soluble derivative of a poly-l,4-glucan, including hydrolyzed amylopectin, derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like. The polyanhydride polymer may be branched or linear.Examples of polymers which are useful in the present invention include (in addition to homopolymers and copolymers of poly(lactic acid) and / or poly(gly colic acid)) poly[bis(p- carboxy phenoxy) propane anhydride] (PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides of oligomerized unsaturated aliphatic acids, polyanhydride polymers prepared from amino acids which are modified to include an additional carboxylic acid, aromatic polyanhydride compositions, and co-polymers of polyanhydrides with other substances, such as fatty acid terminated polyanhydrides, e.g., polyanhydrides polymerized from monomers of dimers and / or trimers of unsaturated fatty acids or unsaturated aliphatic acids. Polyanhydrides may be prepared in accordance with the methods set forth in U.S. Pat. No. 4,757,128, incorporated herein by reference. Poly orthoester polymers may be prepared, e.g., as set forth in U.S. Pat. No. 4.070,347, incorporated herein by reference. Polyphosphoesters may be prepared and used as set forth in U.S. Pat. Nos. 6,008,318, 6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907 and 5,194,581, each of which is incorporated herein by reference.Proteinaceous polymers may also be used. Proteinaceous polymers and their soluble derivatives include gelation biodegradable synthetic polypeptides, elastin, alkylated collagen, alkylated elastin, and the like. Biodegradable synthetic polypeptides include poly-(N- hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalk\ l)-L-glutamine, copolymers of N- hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids. Suggested amino acids include L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.In additional embodiments, the controlled release material, which in effect acts as a carrier for a compound of the invention, alone or in combination with one or more biologically active agents as described herein, can further include a bioadhesive polymer such as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or nontoxic lectins or the polymer itself may be bioadhesive, e.g., polyanhydride or polysaccharides such as chitosan.In embodiments where the biodegradable polymer comprises a gel, one such useful polymer is a thermally gelling polymer, e.g., polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer such as Pluronic™ F127 from BASF Wyandotte. In such cases, the local anesthetic formulation may be injected via syringe as a free-flowing liquid, which gels rapidly above 30° C. (e.g., when injected into a patient). The gel system then releases a steady dose of a compound of the invention, alone or in combination with one or more biologically active agents as described herein, at the site of administration.Dosage Forms for Oral UseFormulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants. and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, taste masking agents (such as hydroxypropyl methylcellulose, hydroxypropyl cellulose), and the like.One or more compounds of the invention and one or more biologically active agents, as defined herein, may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned. In one example, the compound of the invention is contained on the inside of the tablet, and the biologically active agent is on the outside of the tablet, such that a substantial portion of the biologically active agent is released prior to the release of the compound of the invention.Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or assoft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.Formulations for oral administration to the mouth may also be provided as a mouthwash, an oral spray, oral rinse solution, oral ointment, or oral gel.Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and / or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, poly methacryl ale. methylmethacry late, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbon.The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.Generally, when administered to a human, the oral dosage of any of the compounds of the combination of the invention will depend on the nature of the compound, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day. Dosages up to 200 mg per day may be necessary’.Administration of each drug in a combination therapy, as described herein, can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases.Parenteral FormulationsFormulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additionally contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant body fluids) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng / ml to about 10 pg / ml, for example from about 10 ng / ml to about 1 pg / ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Parenteral formulations include formulations that can be used as long acting injectables (LAI) administered by a suitable syringe for example every 7 days or every 14 days or on different schedules and are designed to release the active medicament at an appropriate rate into the body / circulation to have the desired pharmacological effect over a long duration.Topical FormulationsThe compositions of the invention, alone or in combination with one or more of the biologically active agents described herein, can also be adapted for topical use with a topical vehicle containing from between 0.0001% and 25% (w / w) or more of active ingredient(s).In a preferred combination, the active ingredients are preferably each from between 0.0001% to 10% (w / w), more preferably from between 0.0005% to 4% (w / w) active agent. The topical formulation, including but not limited to a cream, gel, or ointment, can be applied one to four times daily, or as needed. Performing the methods described herein, the topical vehicle containing the composition of the invention, or a combination therapy containing a composition of the invention is preferably applied to the site of inflammation on the patient. For example, a cream may be applied to the hands of a patient suffering from arthritic fingers.The compositions can be formulated using any dermatologically acceptable carrier. Exemplary carriers include a solid carrier, such as alumina, clay, microcrystalline cellulose, silica, or talc; and / or a liquid carrier, such as an alcohol, a glycol, or a water-alcohol / glycol blend. The therapeutic agents may also be administered in liposomal formulations that allow therapeutic agents to enter the skin. Such liposomal formulations are described in U.S. Pat. Nos. 5,169,637; 5,000.958; 5,049,388; 4,975,282; 5,194,266; 5,023,087; 5,688,525; 5,874,104; 5.409,704; 5.552.155; 5.356.633; 5,032.582; 4,994,213; 8,822,537. and PCT Publication No. WO 96 / 40061. Examples of other appropriate vehicles are described in U.S. Pat. Nos. 4,877,805, 8,822,537, and EP Publication No. 0586106A1. Suitable vehicles of the invention may also include mineral oil, petrolatum, poly decene, stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, or vegetable oil.The composition can further include a skin penetrating enhancer, such as those described in “Percutaneous Penetration enhancers”, (eds. Smith E W and Maibach H I. CRC Press 1995). Exemplary7skin penetrating enhancers include alky l (N,N-disubstituted amino alkanoate) esters, such as dodecyl 2-(N,N dimethylamino) propionate (DDAIP), which is described in patents U.S. Pat. Nos. 6,083,996 and 6.118,020, which are both incorporated herein by reference; a water-dispersible acid polymer, such as a polyacrylic acid polymer, a carbomer (e.g., Carbopol™ or Carbopol 940P™, available from B. F. Goodrich Company (Akron, Ohio)), copolymers of polyacrylic acid (e.g., Pemulen™ from B. F. Goodrich Company or Polycarbophil™ from A. H. Robbins, Richmond, Va.; a polysaccharide gum. such as agar gum, alginate, carrageenan gum, ghatti gum, karaya gum, kadaya gum, rhamsan gum, xanthan gum, and galactomannan gum (e.g., guar gum, carob gum, and locust bean gum), as well as other gums known in the art (see for instance, Industrial Gums: Polysaccharides & Their Derivatives, Whistler R. L., BeMiller J. N. (eds.), 3rd Ed. Academic Press (1992) and Davidson, R. L., Handbook of Water-Soluble Gums & Resins, McGraw- Hill, Inc., N.Y. (1980)); or combinations thereof.Other suitable polymeric skin penetrating enhancers are cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose. Additionally, known transdermal penetrating enhancers can also be added, if desired. Illustrative are dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide (DEET), 1 -dodecylazacycloheptane-2-one (Azone™, a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate and other enhancers such as dioxolanes, cyclic ketones, and their derivatives and so on.Also illustrative are a group of biodegradable absorption enhancers which are alkylN,N-2-(disubstituted amino) alkanoates as described in U.S. Pat. No. 4.980,378 and U.S. Pat. No. 5,082,866, which are both incorporated herein by reference, including: tetradecyl (N,N- dimethylamino) acetate, dodecyl (N,N-dimethylamino) acetate, decyl (N,N-dimethylamino) acetate, octyl (N,N-dimethylamino) acetate, and dodecyl (N,N-diethylamino) acetate.Particularly preferred skin penetrating enhancers include isopropyl myristate; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalanine amide of a medium chain Patty acid; dodecyl 2-(N,N-dimethylamino) propionate or salts thereof, such as its organic (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acid addition salts) and inorganic salts (e.g., acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic. methanesulfonic, cyclohexanesulfamic, picric, and lactic acid addition salts), as described in U.S. Pat. No. 6,118,020; and alkyl 2-(N,N-disubstituted amino)- alkanoates, as described in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866.The skin penetrating enhancer in this composition by weight would be in the range ofO.5% to 10% (w / w). The most preferred range would be between 1.0% and 5% (w / w). In another embodiment, the skin penetrating enhancer comprises between 0.5%-l%, l%-2%. 2%-3%, 3%-4%, or 4%-5%, (w / w) of the composition.The compositions can be provided in any useful form. For example, the compositions of the invention may be formulated as solutions, emulsions (including microemulsions), suspensions, creams, ointments, foams, lotions, gels, powders, or other typical solid, semisolid, or liquid compositions (e g., topical sprays) used for application to the skin or other tissues where the compositions may be used. Such compositions may contain other ingredients typically used in such products, such as colorants, fragrances, thickeners (e.g., xanthan gum, a fatty acid, a fatty acid salt or ester, a fatty alcohol, a modified cellulose, a modified mineral material, Krisgel 100™, or a synthetic polymer), antimicrobials, solvents, surfactants, detergents, gelling agents, antioxidants, fillers, dyestuffs, viscosity-controlling agents, preservatives, humectants, emollients (e.g., natural or synthetic oils, hydrocarbon oils, waxes, or silicones), hydration agents, chelating agents, demulcents, solubilizing excipients, adjuvants, dispersants, skin penetrating enhancers, plasticizing agents, preservatives, stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers, moisturizers, astringents, deodorants, and optionally including anesthetics, anti-itch actives, botanical extracts, conditioning agents, darkening or lightening agents, glitter, humectants, mica, minerals, polyphenols, silicones or derivatives thereof, sunblocks, vitamins, and phytomedicinals.The compositions can also include other like ingredients to provide additional benefits and improve the feel and / or appearance of the topical formulation. Specific classes of additives commonly use in these formulations include: isopropyl myristate, sorbic acid NF powder, polyethylene glycol, phosphatidylcholine (including mixtures of phosphatidylcholine, such as phospholipon G), Krisgel 100™ distilled water, sodium hydroxide, decyl methyl sulfoxide (as a skin penetrating enhancer), menthol crystals, lavender oil, butylated hydroxy toluene, ethyl diglycol reagent, and 95% percent (190 proof) ethanol.Formulations for Ophthalmic AdministrationThe compounds of the invention can also be formulated with an ophthalmically acceptable carrier in sufficient concentration so as to deliver an effective amount of the active compound or compounds to the optic nerve site of the eye. Preferably, the ophthalmic, therapeutic solutions contain one or more of the active compounds in a concentration range of approximately 0.0001% to approximately 5% (weight by volume) and more preferably approximately 0.0005% to approximately 0. 1% (weight by volume).An ophthalmically acceptable carrier does not cause significant irritation to the eye and does not abrogate the pharmacological activity and properties of the charged sodium channel blockers.Ophthalmically acceptable carriers are generally sterile, essentially free of foreign particles, and generally have a pH in the range of 5-8. Preferably, the pH is as close to the pH of tear fluid (7.4) as possible. Ophthalmically acceptable carriers are, for example, sterile isotonic solutions such as isotonic sodium chloride or boric acid solutions. Such carriers are typically aqueous solutions contain sodium chloride or boric acid. Also useful are phosphate buffered saline (PBS) solutions.Various preservatives may be used in the ophthalmic preparation. Preferred preservatives include, but are not limited to, benzalkonium potassium, chlorobutanol, thimerosal. phenylmercuric acetate, and phenylmercuric nitrate. Likewise, various preferred vehicles may be used in such ophthalmic preparation. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose and hydroxyethyl cellulose.Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, etc., mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed. Ophthalmically acceptable antioxidants can also be include. Antioxidants include but are not limited to sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.Formulations for Nasal and Inhalation AdministrationThe pharmaceutical compositions of the invention can be formulated for nasal or intranasal administration. Formulations suitable for nasal administration, when the carrier is a solid, include a coarse powder having a particle size, for example, in the range of approximately 20 to 500 microns which is administered by rapid inhalation through the nasal passage. When the carrier is a liquid, for example, a nasal spray or as nasal drops, one or more of the formulations can be admixed in an aqueous or oily solution and inhaled or sprayed into the nasal passage.For administration by inhalation, the active ingredient can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, tri chlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount, capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of. for example, gelatin or blisters of. for example, laminated aluminum foil, for use in an inhaler or insufflator. Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier / diluent / excipient substance) such as mono-, di or ploy- saccharides (e.g. lactose or starch). Use of lactose is preferred. In one embodiment, eachcapsule or cartridge may contain between about 2 ug to about 100 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. In a preferred embodiment, each capsule or cartridge may contain between about 10 ug to about 50 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. In another embodiment, each capsule or cartridge may contain between about 20 ug to about 10 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. Alternatively, the compound of the invention may be delivered without excipients.Suitably, the packaging / medicament dispenser is of a ty pe selected from the group consisting of a reservoir dry powder inhaler (RDPI), single use inhaler (capsule or blister inhaler), a multi-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI).Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain an aqueous medium, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient(s); a propellant as solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.Compositions formulated for nasal or inhalation administration may include one or more taste-masking agents such as flavoring agents, sweeteners, and other strategies, such as sucrose, dextrose, and lactose, carboxylic acids, menthol, amino acids or amino acid derivatives such as arginine, lysine, and monosodium glutamate, and / or synthetic flavor oils and flavoring aromatics and / or natural oils, extracts from plants, leaves, flowers, fruits, etc. and combinations thereof. These may include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, bay oil, anise oil. eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. Additional sweeteners include sucrose, dextrose, aspartame, acesulfame-K, sucralose and saccharin, organic acids (by non-limiting example citric acid and aspartic acid). Such flavors may be present at from about 0.05 to about 4 percent by weight and may be present at lower or higher amounts as a factor of one or more of potency of the effect on flavor, solubility of the flavorant, effects of the flavorant on solubility or other physicochemical or pharmacokinetic properties of other formulation components, or other factors.Methods of UseThe present application also provides therapeutic methods and uses comprising administering the compounds of the invention, or pharmaceutically acceptable salts thereof, alone or in combination with other therapeutic agents or palliative agents.In some embodiments, provided is a method for the treatment of one or more inflammatory-related diseases or disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof.In some embodiments, provided is a method for the treatment of one or more inflammatory-related diseases or disorders in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent, which amounts are together effective in treating said one or more inflammatory -related diseases or disorders.In some embodiments, provided is also a method for the treatment of a disease or disorder mediated by calcineurin in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disease or disorder, in particular an inflammatory-related disease or disorder.In some embodiments, provided is also a method of inhibiting calcineurin in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit calcineurin.The treatment regimen for the compound of the invention that is effective to treat one or more inflammatory-related diseases or disorders patient may vary7according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti- inflammatory response in the subject. While an embodiment of any of the aspects of the present application may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student's t-test, the chi2-test the U-test according to Mann and Whitney, the Kruskal -Wallis test (H-test), Jonckheere-Terpstrat-testy and the Wilcon on-test.In some embodiments, this application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in a subj ect in need thereof,comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention.In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising systemically administering to the subject a therapeutically effective amount of a compound disclosed herein. In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising parenterally administering to the subject a therapeutically effective amount of a compound disclosed herein. In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a compound disclosed herein.In some embodiments, parenteral administration includes, but is not limited to, subcutaneous administration, intramuscular administration, intravenous administration, and intrathecal administration. In some embodiments, parenteral administration is subcutaneous administration. In some embodiments, parenteral administration is intramuscular administration. In some embodiments, parenteral administration is intravenous administration. In some embodiments, parenteral administration is intrathecal administration.In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising administering via inhalation to the subject a therapeutically effective amount of a compound disclosed herein.In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of a compound disclosed herein.In some embodiments, the application includes a method of treating a condition or disorder associated with abnormal Calcineurin activity' in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the invention.In some embodiments, the application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in a subj ect in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the application includes a method of treating a diseaseor disorder characterized by elevated calcineurin activity in skin cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in ocular cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention.In some embodiments, the application also provides for a method for delaying in patient the onset of an inflammatory-related disease or disorder comprising the administration of a therapeutically effective amount of the compound of the invention to a patient in need thereof.In some embodiments, the application also provides a method of protecting a kidney by reducing immunosuppression-induced nephrotoxicity in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the invention. Preferably, a kidney is a transplanted kidney.In some embodiments, the compound of the invention may be administered in combination with a standard of care agent. In some embodiments, the compound of the invention may be administered in combination with an additional therapeutic agent or treatment.In some embodiments, the compound of the invention exhibits reduced nephrotoxicity compared to the existing CNIs as described herein, such as tacrolimus. In some embodiments, the compound of the invention exhibits reduced nephrotoxicity compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease.In some embodiments, the compound of the invention exhibits improved bioavailability compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease.In some embodiments, the compound of the invention exhibits reduced variability of exposure compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease.In some embodiments, the compound of the invention exhibits reduced food effects compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease.In some embodiments, the compound of the invention exhibits reduced maximum-to- minimum concentration (Cmax / Cmin) ratio compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease.In some embodiments, the compound of the invention exhibits reduced patient nonadherence compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease.IndicationsThe compounds, compositions, methods, and kits of the invention can be used to treat diseases or disorders, preferably inflammatory-related diseases or disorders. In some embodiments, the application includes a compound for use in the treatment and / or prevention of inflammatory-related diseases or disorders. In some embodiment, the application provides use of a compound for the manufacture of a medicament for treating inflammation-related diseases or disorders. The application also provides a method of treatment of systemic disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound of the invention. The compound of the invention can be administered to the subject in need through any route of administration as described herein. In some cases, it is systemically administered. In some cases, it is orally administered. In some cases, it is administered via subcutaneous administration. In some cases, it is administered via ophthalmic drug administration (e.g., eye drops). In some cases, it is administered via pulmonary drug delivery (e.g.. inhaler). In some cases, it is administered through topical administration.In some embodiments, the inflammation-related disease or disorder includes but is not limited to periodontitis, keratoconj unciti vitis sicca, rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, graft versus host disease, systemic lupus erythematosus, cutaneous lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis. Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, such as itch. Intervertebral disk syndrome conditions, bursitis, tendonitis, tenosynovitis or fibromyalgia syndrome; and acute or chronic pain, including but not limited to neurological pain, neuropathies,polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Holton's disease, varicose ulcers, neuralgias. Musculo-skeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, veltebral pain, post-surgery pain, herniated intervertebral disc— induced sciatica, cancer- related pain, vascular pain, visceral pain, childbirth, HIV-related pain, a metabolic disease, a chemotherapy / radiation related complication; diabetes type 1: diabetes type II; a liver disease; a gastrointestinal disorder; an ophthalmological disease; allergic conjunctivitis; diabetic retinopathy; Sjogren's syndrome; uveitis; a renal disease; HV -related cachexia; cerebral malaria; ankylosing spondylitis; leprosy; anemia; fibromyalgia, kidney failure, stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure such as heart failure, aortic valve stenosis, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary7artery bypass: hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, such as for example, acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), dot formation from surgery7, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial or venous cannulae, cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary7hypertension, diminished lung compliance, leukopenia or thrombocytopenia, or atherosclerosis.In some embodiments, the application includes a method of preventing organ transplant rejection. In some embodiments, the organ transplant is kidney, liver, heart, lung, pancreas, or intestine. In some embodiments, the application includes a method of treating an infection. In some embodiments, an infection is a fungal infection.In some embodiments, the application includes a method of preventing organ transplant rejection and the organ is preferably a kidney. In some embodiments, the application includes a method of treating a disorder or condition associated with kidney transplant in a subject in need. The method comprises administering to the subject in need a therapeutically effective amount of the compound of the invention. Preferably, the methodcomprises systematically administering to the subject in need a therapeutically effective amount of the compound of the invention, e.g., via oral administration, intravenous administration, intramuscular administration, subcutaneous administration, inhalation administration, or rectal administration; preferably, oral or subcutaneous administration.In some embodiments, the application includes a method of treating or ameliorating lupus nephritis in a subject in need. In some embodiments, the application includes a method of treating a disorder or condition associated with lupus nephritis in a subject in need. In some embodiments, the application includes a method of treating or ameliorating ANCA- associated vasculitis in a subject in need. In some embodiments, the application includes a method of treating a disorder or condition associated with ANCA-associated vasculitis in a subject in need. The method comprises systematically administering to the subject in need a therapeutically effective amount of the compound of the invention, e.g., via oral administration, intravenous administration, intramuscular administration, subcutaneous administration, inhalation administration, or rectal administration; preferably , oral or subcutaneous administration.In some embodiments, the application includes the methods of treating inflammatory- related diseases or disorders, including skin or ocular disorders. In some embodiments, the application includes a compound for use in the treatment and / or prevention of inflammatory- related diseases or disorders. Thus, in one embodiment, the application provides use of a compound for the manufacture of a medicament for treating and / or inflammatory-related diseases or disorders. The application also provides a method of treatment of a skin disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the application. The application also provides a method of treatment of an ocular disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the application.In some embodiments, the infl ammatory -related disease or disorder is a skin disease or disorder. In some embodiments, a skin disease or disorder is selected from the group consisting of psoriasis, dermatitis, eczema (also known as atopic dermatitis), hives, lichen planus, lichen scleroses, vitiligo, discoid lupus, cutaneous lupus erythematosus and pityriasis alba. In some embodiments, a skin disease or disorder is psoriasis. In some embodiments, a skin disease or disorder is dermatitis. In some embodiments, a skin disease or disorder is eczema. In some embodiments eczema is seborrheic eczema. In some embodiments, dermatitis is selected from the group consisting of contact dermatitis, atopic dermatitis,nummular dermatitis, seborrheic dermatitis, and stasis dermatitis. Preferably, the compound of the invention is administered topically.In some embodiments, an inflammatory -related disease or disorder is an ocular disease or disorder. In some embodiments an ocular disease or disorder is selected from the group consisting of dry eye syndrome (DES), Sjogren's syndrome, uveitis (such as refractory anterior uveitis), conjunctivitis (pink eye), keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC). autoimmune disorders of the ocular surface, including cicatrizing conjunctivitis, blepharitis, and scleritis. In some embodiments an ocular disease or disorder is dry eye syndrome (DES). In some embodiments an ocular disease or disorder is Sjogren's syndrome. In some embodiments an ocular disease or disorder is uveitis, preferably refractory anterior uveitis. Preferably, the compound of the invention is administered via ophthalmic drug administration (e.g., eye drops).In some embodiments, the application includes a method of treating an infection. In some embodiments, an infection is a fungal infection. In some embodiments, a fungal infection is a nail fungal infection. In some embodiments, a fungal infection is a toenail fungal infection. In some embodiments, a fungal infection is a fingernail fungal infection.In some embodiments, the application includes the methods of treating inflammatory- related diseases or disorders, including pulmonary’ disorders. In some embodiments, the application includes a compound for use in the treatment and / or prevention of inflammatory- related diseases or disorders. Thus, in one embodiment, the application provides use of a compound for the manufacture of a medicament for treating and / or inflammatory- related diseases or disorders. The application also provides a method of treatment of a pulmonary disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the application.In some embodiments, infl ammalor -related disease or disorder is a pulmonary disease or disorder. In some embodiments, a pulmonary7disease or disorder is selected from the group consisting of allergic rhinitis, asthma, adult respiratory7distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection and respiratory tract inflammation.In some embodiments, the application includes a method of preventing organ transplant rejection. In some embodiments, the organ is lung. In some embodiments, the application includes a method of treating a disorder or condition associated with lung transplant in a subject in need. The method comprises administering to the subject atherapeutically effective amount of the compound of the invention. Conditions requiring lung transplant include but are not limited to chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension. In some cases, the subject is a recipient of transplanted lung. In some cases, the disorder or condition associated with lung transplant is a post-transplant complication. In some cases, the disorder or condition associated with lung transplant is a post-transplant complication including graft rejection wherein the recipient's immune system treats the transplanted lung as foreign and mounts an immune response, i.e., graft-versus-host disease (GvHD), infections, bronchiolitis obliterans syndrome (BOS), and other postoperative complications.In some embodiments, the application includes a method of treating a pulmonary disease or disorder in a subject in need. In some embodiments, the subject is diagnosed with asthma, such as steroid-unresponsive asthma. In some embodiments, the pulmonary disease or disorder includes asthma (such as steroid-unresponsive asthma), chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary7hypertension, bronchiectasis, sarcoidosis, interstitial lung disease (ILD), pneumonia, tuberculosis. In some embodiments, the pulmonary disease or disorder is asthma, such as steroid-unresponsive asthma. Preferably, the compound of the invention is administered systematically such as oral or subcutaneous administration. Preferably, the compound of the invention is administered via pulmonary drug delivery such as using an inhaler. DefinitionsAs used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, references to “the method” includes one or more methods, and / or steps of the ty pe described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.The term “comprising”, which is used interchangeably with “including”, “containing”, or “characterized by”, is inclusive or open-ended language and does not exclude additional, unrecited elements or method steps.The phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. The phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. The application contemplates embodiments of the invention compositions and methods corresponding to the scope of each of these phrases. Thus, acomposition or method comprising recited elements or steps contemplates particular embodiments in which the composition or method consists essentially of or consists of those elements or steps.By ‘‘inflammation” is meant any types of inflammation, such those caused by the immune system (immune-mediated inflammation) and any symptom of inflammation, including redness, heat, swelling, pain, and / or loss of function.The term “pain” is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g., somatic pain and visceral pain; inflammatory' pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain. Pain receptors for tissue injury are located mostly in the skin, musculoskeletal system, or internal organs.By “patient” it means any animal. In one embodiment, the patient is a human. Other animals that can be treated using the methods, compositions, and kits of the invention include but are not limited to non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).Compounds useful in the invention include, but are not limited to, those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein.The term “pharmaceutically acceptable salt” represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, buty rate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate.persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like.In the generic descriptions of compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alky l group containing from 1 to 4 carbon atoms or Ci-4 alkyl of C1-C4 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alkyl group from 1 to 4 carbon atoms includes each of Ci, C2, C3, and C4 alkyls. Other numbers of atoms and other types of atoms may be indicated in a similar manner.“D” is deuterium.As used herein, the terms "alk I” and the prefix "alk-" are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms or 3 to 7 carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.By "C1-4 alkyl” or “C1-C4 alkyl” is meant, a branched or unbranched hydrocarbon group having from 1 to 4 carbon atoms. Similarly, a “C1-6 alkyl” or “Ci-Ce” is a branched or unbranched hydrocarbon group having from 1 to 6 carbon atoms. A “C1-3 alkyl” or “C1-C3” is a branched or unbranched hy drocarbon group having from 1 to 3 carbon atoms. An alkyl, including, for example, a C 1-4 alkyl or C1-6 alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyd, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary7amino, alkylcarboxy, and carboxyl groups. Exemplary7substituents also include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbony l, ary lcarbony l, alky lthiocarbony l, phosphate, phosphonato, phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl. sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety7. C1-4 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, secbutyl, tert-butyl, and cyclobuty l. C1-6 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, n-hexyl, cyclobutyl, cyclopentyl, and cyclohexyl.An example of a substituted alkyl is a heteroalkyl. By '‘heteroalkyl” is meant a branched or unbranched alkyl, cycloalkyl, alkenyl, or alkynyl group having one or more heteroatoms in place of the carbon atoms independently selected from the group consisting of N, O. and S. By “C 1-7 heteroalky I" is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in addition to 1. 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls can include, without limitation, tertiary7amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalky7! may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalky l group may be substituted or unsubstituted. Exemplary substituents include alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, acylamino (including alkylcarbonylamino, ary lcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of C1-7 heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.An alkenyl is a branched or unbranched hydrocarbon group containing one or more double bonds. For example, byL‘C2-6 alkenyl” or “C2-C6 alkenyl” is meant, a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 6 carbon atoms. An alkenyl may7optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The alkenyl group may be substituted or unsubstituted. Exemplary7substituents include those described above for alkyl, and specifically include alkoxy, aryloxy. sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, alkydamino, disubstituted amino, quaternary amino, alkylcarboxy, and carboxyl groups. C2-6 alkenyls include, without limitation, vinyl, allyl, 2- cyclopropyl-l -ethenyl, 1-propenyl, l-butenyl, 2-butenyl, 3-butenyl. 2-methyl-l -propenyl, and 2-methyl-2-propenyl.An alkynyl is a branched or unbranched hydrocarbon group containing one or more triple bonds. For example, by “C2-6 alkynyl’" or “C2-C6 alkynyl” is meant, a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 6 carbon atoms. An alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The alkynyl group may be substituted or unsubstituted. Exemplary’ substituents those described above for alkyl, and specifically include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary' amino, alkylcarboxy, and carboxyl groups. C2-6 alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.By “heterocyclyl,” “heterocyclic,” or “heterocycloalkyl” is meant a stable monocyclic or polycyclic (including a bicyclic or a tricyclic) heterocyclic ring which is saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic), and which consists of 2 or more carbon atoms and 1, 2, 3, 4 or more heteroatoms independently selected from N, O, and S and including any bicyclic or polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. A “3- to 6- membered heterocycloalkyl” is mean to refer to a heterocyclic ring having 3 to 6 ring atoms wherein at least one ring atom is a heteroatom selected from N, O, and S. Similarly, a “3- to 10- membered heterocycloalkyl” is mean to refer to a heterocyclic ring having 3 to 10 ring atoms wherein at least one ring atom is a heteroatom selected from N, O, and S. In certain aspects, the heterocyclyl is a 3- to 15-membered ring system, a 3- to 12- membered ring system, or a 3- to 9-membered ring system. By “C2-6 heterocyclyl” is meant a stable 5- to 7 -membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. The heterocyclyl or heteroaryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy. sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, oxo, and carboxyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., animidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A nitrogen atom in the heterocycle can be quatemized. Preferably when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation, IH-indazole, 2- pyrrolidonyl, 2H,6H-l,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH- carbazole, 4H-quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl. benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH- carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1.5.2-di thiazinyl. dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl. imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl. isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1.2.3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl. oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl. phenoxazinyl, phthalazinyl, piperazinyl. piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl. pyrrolyl, quinazolinyl. quinolinyl. 4H-quinolizinyl. quinoxalinyl. quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thi enothiazolyl, thienooxazolyl, thi enoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1 ,2.4-triazolyl, 1.2.5-triazolyl, 1.3.4-triazolyl, xanthenyl, 0-lactam, y-lactam and 5- lactam. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl. and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, quinolinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl. Preferred substituents include phenyl, methyl, ethyl, propyl, butyl, chloro, bromo, fluoro, iodo and oxo.By “cycloalkenyl” it refers to an unsaturated monocyclic or polycyclic hydrocarbon group, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. It can comprise more than one double bond, such as two like a cycloalkadienyl. It includes both unsubstituted and substituted ring systems. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. Examples of monocyclic cycloalkenyls includes, e.g.. cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.By "an 1” is meant an aromatic group having a ring system comprised of carbon atoms with conjugated 71 electrons (e.g., phenyl). A “C6-Ci2 aryl” or “Ce-Cio aryl" is an aryl group that has from 6 to 12 carbon atoms or 6 to 10 carbon atoms, respectively. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. A bicyclic or tricyclic ring system can be fused (e.g., naphthyl) or not (e.g., biphenyl). The aryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, alkylcarboxy, amino, alkylamino, monosubstituted amino, disubstituted amino, and quaternary amino groups. A preferred aryl group is phenyl. By "heteroaryl" it is meant an aromatic ring group having a ring system comprised of hetero atoms (such as N. O, S) and carbon atoms with conjugated it electrons (e.g.. pyridine, pyrimidine, triazine). A “5- to 6- membered heteroaryl” refers to a heteroaryl having 5 to 6 ring atoms with conjugated it electrons wherein at least one ring atom is a heteroatom selected from N, O, and S. Similarly, a “5- to 12- membered heteroaryl" refers to a heteroaryl having 5 to 12 ring atoms with conjugated it electrons wherein at least one ring atom is a heteroatom selected from N, O, and S. The heteroaryl groups can include monocyclic, bicyclic, or tricyclic rings, with each ring typically having five or six members. Bicyclic or tricyclic ring systems within heteroaryls can be fused (e.g., quinoxaline) or not. Heteroary l groups may be substituted or unsubstituted, with possible substituents including various functional groups such as substituted or unsubstituted alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, alkylcarboxy, amino, alkylamino, monosubstituted amino, disubstituted amino, and quaternary amino groups. An example of a preferred heteroary l group is a phenyl group with heteroatoms replacing one or more carbon atoms in the ring.By “aralkyl” is meant a substituted or unsubstituted alkyl that is substituted by a substituted or unsubstituted aryl (including, for example, (e.g., benzyl, phenethyl, or 3.4- dichlorophenethyl).By “C7-14 aralkyl” is meant, an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.By “halide” or “halogen” is meant, bromine, chlorine, iodine, or fluorine. By “fluoroalkyl” is meant, an alkyl group that is substituted with a fluorine atom. By “alkylcarboxy” is meant a chemical moiety with the formula — (R) — COOH, wherein R is selected from C 1-7 alky l, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, Ce-i2 aryl, C 7-14 aralkyl, C3-10 heterocycloalkyl, or C1-7 heteroalkyl.By “alkoxy” is meant a chemical substituent of the formula — OR, wherein R is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl or R can be selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C2-6 heterocyclyl, Ce-i2 aryl, C 7-14 aralkyl. C3-10 heterocycloalkyl, or C 1-7 heteroalkyl.By “aryloxy” is meant a chemical substituent of the formula — OR, wherein R is a Ceil aryl group. By “alkylthio” is meant a chemical substituent of the formula — SR, wherein R is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, Ce- aryl, C7- 14 aralkyl, C3-10 heterocycloalkyl, or C1-7 heteroalkyl.By “arylthio” is meant, a chemical substituent of the formula — SR. wherein R is a Ce- 12 aryl group.By “charged moiety” is meant a moiety which gains a proton at physiological pH thereby becoming positively charged (e.g., ammonium, guanidinium, or amidinium) or a moiety that includes a net formal positive charge without protonation (e.g., quaternary ammonium). The charged moiety may be either permanently charged or transiently charged.By “therapeutically effective amount” or “effective amount” means an amount sufficient to produce a desired result, for example, the reduction or elimination of any symptoms in a patient (e g., a human) suffering from an inflammatory -related disease or disorder.By “patient nonadherence” as used herein refers to the failure or reluctance of patients to follow prescribed medical advice or treatment plans. In the context of organ transplantation and immunosuppressive therapy, nonadherence can manifest as patients not taking medications as prescribed, missing doses, altering doses without medical guidance, or discontinuing medications altogether. Nonadherence is a significant concern intransplantation because maintaining the proper balance of immunosuppressive medications is crucial to prevent organ rejection.The term '‘toxicity’’ refers to a condition that results in damage to the organism. By “nephrotoxicity” means a condition that results in damage to kidney. “Immunosuppression- induced nephrotoxicity ” refers to a condition resulting in damage to kidney that is induced by administration of immunosuppressive regimens, such as administration of CNIs including tacrolimus. “Reduced immunosuppression-induced nephrotoxicity” means the condition has been ameliorated or eliminated because of the replacement of an existing CNI by a compound of this invention.By “food effect” as used herein means refer to the impact of food consumption on the pharmacokinetics of a drug, influencing its absorption, distribution, metabolism, and excretion. The presence of food in the gastrointestinal tract can affect the way a drug is absorbed, altering the rate and extent of its entry into the bloodstream. In certain embodiments, the compound of the invention reduces or eliminates the food effect. As used herein, “reducing the food effect” refers to narrowing the difference in bioavailability’ for a drug administered with or close to consumption of food in comparison to the drug administered without consumption of food for a certain period of time. In certain aspects, the food effect is eliminated. Thus, upon oral administration of a compound of the invention to a subject in need thereof, there is not a significant food effect. In other words, the difference between a pharmacokinetic parameter measured after oral administration to a mammal with and without food, respectively, is less than 40%, e.g., less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10 or less than 5%. Preferably the composition or the pharmaceutical composition of the invention has at least 15% reduced food effect, preferably 20%, preferably 25%, preferably 30%, preferably 40%, reduced food effect.By “bioavailability” it indicates the extent to which a drug or another substance, especially a CNI, is utilized systematically or by a target tissue after administration. Changes in bioavailability can impact the therapeutic efficacy and safety of a drug.The compounds of the present invention, including salts of the compounds, can exist in unsolvated forms as well as solvated forms, including hydrated forms and unhydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Nonlimiting examples of hydrates include monohydrates, dihydrates, hemihydrates, etc. In certain aspects, the compound is a hemihydrate. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.The compounds of the invention may exist in multiple cry stalline or amorphous forms. In general, all physical forms are equivalent for uses contemplated by the present invention and are intended to be within the scope of the invention.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described.Examples Synthesis of the compoundsThe synthetic scheme of Compound No. 9 was presented below as an example. In the preparation of intermediates, each of the four ring moieties was synthesized and labeled from left to right as A, B, C, and D as show n below :Step 1. Synthesis of A-Ring and AB moiety of Compound No. 9:Step 2. Synthesis of C-Ring of Compound No. 9:Step 3. Synthesis of D-Ring of Compound No. 9:Step 5. Bn deprotection and dimer oxidation:The product of Step 5 was the CD moiety of Compound No. 9.Step 6. Reacting CD moiety with AB moiety and MOM deprotectionReaction conditions including reagents and temperatures for each step were shown in the synthetic schemes. Coupling reactions were carried out respectively using different conditions: trifluoroacetic anhydride (TFAA) at 80 °C; N,N'-diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (DMAP) at 25 °C; l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) and DMAP at 55 °C; benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOPCI), diisopropylethylamine (DIEA), and DMAP, with the reaction occurring between 0°C and room temperature. Deprotection for benzyl was achieved using 10% Pd / C and hydrogen gas (15 psi) at 25 °C. Deprotection for methoxymethyl (MOM) group was achieved using HC1 at 25 °C. Dimer oxidation was carried out using Tris(2,2'-bipyridine)ruthenium(II) hexafluorophosphate with oxygen gas and 440 nm light.All the compounds of the invention can be synthesized following the synthetic schemes analogous to Steps 1-6 as shown above. Additional examples for preparing the intermediate ring moieties were provided below.Synthesis of intermediate ring moieties of Compound No. 3Synthesis of intermediate ring moieties of Compound No. 4Synthesis of intermediate ring moieties of Compound No. 5Synthesis of intermediate ring moieties of Compound No. 7Synthesis of intermediate ring moieties of Compound No. 8Synthesis of intermediate ring moieties of Compound No. 10Synthesis of intermediate ring moieties of Compound No. 11Synthesis of intermediate ring moieties of Compound No. 12Synthesis of intermediate ring moieties of Compound No. 145 Synthesis of intermediate ring moieties of Compound No. 15Synthesis of intermediate ring moieties of Compound No. 16Synthesis of A-Ring of Compound No. 16:Synthesis of B-Ring of Compound No. 16:Synthesis of intermediate ring moieties of Compound No. 17Synthesis of intermediate ring moieties of Compound No. 18Synthesis of intermediate ring moieties of Compound No. 19Characterization of exemplary compounds using LCMS and NMR were provided in Table 2.Table 2. Characterization of exemplar}' compoundsSynthesis of Monomer Building BlocksSynthesis of 4-hydroxy-2,3,5,6-tetramethylbenzoic acid and its derivatized monomer building blocksStep 1: To the stirred solution of l,4-dibromo-2,3,5,6-tetramethylbenzene (30 g, 1.0 eq., 103 mmol) in dry THF (300 mL) was added 2.5 M n-BuLi in hexane (45.2 mL, 1.1 eq.. 113 mmol) under nitrogen atmosphere at -78 °C dropwise over 20 minutes. The resultant grey suspension was stirred at -78 °C for 30 minutes followed by addition of dry Ice (~30 g, w / w) in instalments over 30 minutes. Further, the reaction mixture was stirred at room temperature for 1 h. After complete consumption of starting material, reaction mixture was acidified with 1N-HC1 to adjust the pH~2-3 at 0 °C and aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude residue. The crude residue was triturated with n-pentane to get 4-bromo-2.3.5,6-tetramethylbenzoic acid (23 g, 87%) as white solid.LCMS m'z = 254.90ppm 13.07 (s, 1H), 2.34 (s, 6H), 2.20 (s, 6H).Step 2: A solution of 4-bromo-2,3,5,6-tetramethylbenzoic acid (20 g, 1.0 eq., 77.8 mmol) in dioxane (80 mL) : water (40 mL) mixture at room temperature was degassed for 30 minutes with nitrogen gas. To the above reaction mixture, potassium hydroxide (8.73 g, 2 eq., 156 mmol), Pd2(dba)s (7.12 g, 0.1 eq., 7.78 mmol) and / BuXPhos (6.61 g, 0.2 eq., 15.6 mmol) were added sequentially. Then, reaction mixture was heated at 110 °C for 16 h. After complete consumption of starting material, the reaction mixture was filtered through celite bed, and the filtrate was acidified with hydrochloric acid (1 N) to achieve pH- 2. The aqueous layer was extracted with ethyl acetate; combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude material was triturated with pentane to get 4-hydroxy-2, 3,5,6- tetramethylbenzoic acid (10 g, 66%) as brown solid. LCMS m / z = 193.05 [M-l]’; 'H NMR (400 MHz, DMSO-cL) 8 ppm 12.66 (s, 1H), 8.14 (s, 1H), 2.09 (s, 6H), 2.08 (s, 6H).Step 3: To the stirred solution of 4-hydroxy-2,3,5,6-tetramethylbenzoic acid (10 g, 1.0 eq., 51.5 mmol) in DMF (0. 1 L) was added sodium hydrogen carbonate (6.49 g, 1.5 eq., 77.2 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 75 °C for 30 minutes. Further, the Reaction mixture was cooled to room temperature followed by addition of benzyl bromide (6.12 mL, 1.0 eq., 51.5 mmol) and reaction mixture was allow ed to stir at 55 °C for 12 h. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layers were washed with water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material, which was purified by Combi-flash to get benzyl 4- hydroxy-2,3,5,6-tetramethylbenzoate (11 g, 75%) as a white solid. LCMS m / z = 285.05 [M+l]+; H NMR (400 MHz, DMSO-cL) 8 ppm 8.29 (s, 1H), 7.45 - 7.35 (m, 1H), 5.30 (s, 2H), 2.07 (s, 6H), 2.02 (s, 6H).Step 4: To a stirred solution of 4-hydroxy-2,3,5,6-tetramethylbenzoic acid (50 g, 1.0 eq., 257 mmol) in DMF (162 ml) was added sodium hydrogen carbonate (108 g, 5 eq., 1.29 mol) at room temperature under nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 15 minutes followed by dropwise addition of MOM-CI (24 mL, 1.2 eq., 309 mmol) at 0°C. Reaction mixture w as stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC, which shows complete consumption of starting material. Reaction mixture was diluted with water and extracted with ethyl acetate, combined organiclayer was washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get methoxymethyl 4-hydroxy-2,3,5,6-tetramethylbenzoate (50 g, 78%) as white solid. LCMS m / z = 237.05 [M-H]‘; ' H NMR (400 MHz, DMSO-O O' ppm 8.32 (s, 1H), 5.38 (s, 2H), 3.44 (s, 3H), 2.08 (s, 12H).Synthesis of ethyl 4,6-dihydroxy-2,3-dimethylbenzoate and its derivatized monomer building blocksStep 1: To the stirred solution of (3Z)-3-methylpent-3-en-2-one (150 g, 1.0 eq., 1.53 mol) and 1,3-diethyl propanedioate (367 g, 1.5 eq., 2.29 mol) in ethanol (1.5 L) at 0 °C under nitrogen atmosphere was added sodium ethoxide (208 g. 2 eq.. 3.06 mol) portion wise over 20 minutes and mixture was allowed to stir for 4 h at room temperature. After complete consumption of starting material, reaction mixture was quenched with 4 N HC1 to adjust pH ~7. The reaction mixture was concentrated under reduced pressure to get the crude compound. Further, crude mixture was acidified to pH ~2 with 4 N HC1 and aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine solution, dried with anhydrous sodium sulphate, filtered and concentrated on rota-vapour to get ethyl 2,2-dimethyl-4,6- di oxocy cl ohexane-1 -carboxylate (320 g crude; LCMS purity 75%) as a pale-yellow oil. LCMS m / z = 213.0 [M+H]+.Step 2: To the stirred solution of ethyl 2,3-dimethyl-4,6-dioxocyclohexane-l -carboxylate (100 g, 1.0 eq., 471 mmol) in acetonitrile (682 mL) at room temperature under nitrogen atmosphere was added CuC12 (127 g, 2 eq., 942 mmol) and MgC12 (22.4 g, 0.5 eq., 236 mmol). Then, reaction mixture was heated at 90 °C for 4 h. The progress of reaction was monitored by TLC. After completion, reaction mixture was concentrated under reduced pressure near to dryness, then diluted with IN HC1 and extracted with ethyl acetate. Organic layer was washed with brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude material was purified by column chromatography to get ethyl 4,6-dihydroxy-2,3-dimethylbenzoate (40 g, 40%) as yellow solid. LCMS m / z =210.95 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.64 (s, 1H), 9.56 (s, 1H), 6.26 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2. 10 (s, 3H), 1.94 (s, 3H). 1.26 (1. J = 7.2 Hz. 3H).Step 3: To the stirred solution of ethyl 4,6-dihydroxy-2,3-dimethylbenzoate (100 g, 1.0 eq., 476 mmol) in DCM (1.5 L) was added DIPEA (247 mL, 3.0 eq., 1.43 mol) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 20 minutes before the addition of M0MC1 (44.2 mL, 1.2 eq., 571 mmol) at the same temperature. The reaction mixture was allowed to stir for 2 h at room temperature. After complete consumption of starting material. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine solution followed by saturated sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduce pressure. The crude residue was purified by manual column chromatography to get ethyl 6-hydroxy-4- (methoxymethoxy)-2,3 -dimethylbenzoate (68 g, 56 %) as a yellow solid. LCMS m / z = 255.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.66 (s, 1H), 6.49 (s, 1H), 5.15 (s, 2H), 4.23 (q, J = 7.2 Hz. 2H), 3.35 (s. 3H), 2.11 (s, 3H), 2.01 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).Step 4: To the stirred solution of ethyl 4-(benzyloxy)-6-hydroxy-2.3-dimethylbenzoate (68 g. 1 eq., 256 mmol) in acetone (700 mL) was added K2CO3 (71 g, 2 eq., 51 1 mmol) under nitrogen atmosphere at room temperature followed by dropwise addition of Mel (63.7 mL, 4 eq.. 1.02 mol) at 0 °C. The mixture was allowed to stir at 60 °C for 16 h. After complete consumption of starting material, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get ethyl 6-methoxy-4-(methoxymethoxy)-2,3- dimethylbenzoate (60 g, 87%) as a yellow liquid. LCMS m / z = 269.0 [M+H]+.Step 5: To the stirred solution of ethyl 6-methoxy-4-(methoxymethoxy)-2,3-dimethylbenzoate (50 g, 1 eq, 186 mmol) in DMSO (250 mL) was added KOH (105 g, 10 eq. 1.86 mol) (dissolved in 250 mL H2O) at room temperature. The mixture was stirred at 100 °C for 16 h. After complete consumption of starting material. The reaction mixture was acidified with 2N-HC1 (pH~2). Precipitated solid was filtered and dried under reduced pressure to get 6-methoxy-4- (methoxymethoxy)-2,3-dimethylbenzoic acid (35 g. 77%) as a Light brown solid. LCMS m / z = 241.0 [M+H]+: 1H NMR (400 MHz, DMSO-d6) 5 ppm 12.69 (s. 1H), 6.64 (s. 1H), 5.25 (s. 2H), 3.72 (s, 3H), 3.40 (s, 3H), 2.12 (s, 3H), 2.06 (s, 3H).Step 6: To the stirred solution of 6-methoxy-4-(methoxymethoxy)-2,3-dimethylbenzoic acid (85 g, 1 eq., 354 mmol) in DMF (850 mL) was added NaHCO3 (59 g. 2.0 eq., 708 mmol) at room temperature under nitrogen atmosphere. Then, reaction mixture was heated to 50 °C for30 min. Further, the reaction mixture was cooled to room temperature followed by dropwise addition of BnBr (44 mL, 1.05 eq., 371 mmol) and mixture was stirred at 50 °C for 4 h. After complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude residue. The crude residue was purified by Manual column chromatography to get benzyl 6-methoxy- 4-(methoxymethoxy)-2,3-dimethylbenzoate (80 g, 68 %) as a light yellow solid. LCMS m / z = 331.05 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 ppm 7.47 - 7.34 (m, 5H), 6.66 (s, 1H), 5.28 (s, 2H), 5.26 (s, 2H), 3.72 (s, 3H), 3.39 (s, 3H), 2.04 (s, 6H).Step 7: A solution of benzyl 6-methoxy-4-(methoxymethoxy)-2,3-dimethylbenzoate (13 g, 1 eq.. 39.3 mmol) and 4.0M HC1 in Dioxane (26 mL, 2 vol.) was stirred at room temperature for 1 h. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with Ethyl acetate. The combined organic layers were washed with NaHCO3, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude material was purified by combi flash to get benzyl 4-hydroxy-6-methoxy-2.3-dimethylbenzoate (6 g. 53 %) as Light yellow' solid. LCMS m / z = 287.05 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 ppm 9.61 (s, 1H), 7.43 - 7.33 (m, 5H), 6.38 (s, 1H), 5.25 (s, 2H), 3.66 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H).Synthesis of methoxymethyl 3-bromo-4-hydroxy-2-(methoxymethoxy)-5,6-dimethyl benzoate, methoxymethyl 3-chloro-4-hydroxy-2-(methoxymethoxy)-5,6- dimethylbenzoate and other derivatized monomer building blocksStep 1: To the stirred solution of ethyl 4,6-dihydroxy-2.3-dimethylbenzoate (50 g, 1.0 eq., 238 mmol) in acetone (500 mL), was added K2CO- (32.9 g, 1.0 eq., 238 mmol) at room temperature under nitrogen atmosphere and then, Benzyd bromide (44.7 g, 1.1 eq., 262 mmol) w as added.Further, the reaction mixture was heated at 50 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. Then, the reaction mixture was cooled to room temperature and filtered through celite bed. Filtrate was concentrated on rotavapor to get the crude residue, which was diluted with water and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The obtained crude compound was purified by column chromatography to get ethyl 4-(benzyloxy)-6-hydroxy-2,3-dimethylbenzoate (45 g, 63%) as a white solid. LCMS m / z = 299.00 [M-H]'; 'H NMR (400 MHz, DMSO-rfb) <5 ppm 9.77 (s, 1H), 7.47 - 7.31 (m, 5H), 6.42 (s, 1H), 5.07 (s, 2H), 4.24 (q, J= 7.0 Hz, 2H), 2.13 (s, 3H), 2.04 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H).Step 2: To the stirred solution of ethyl 4-(benzyloxy)-6-hydroxy-2,3-dimethylbenzoate (40 g, l .O eq., 133 mmol) in ACN (400 mL) was added NBS (28.4 g, 1.2 eq., 160 mmol) portion-wise under nitrogen atmosphere at 0 °C. The resulting mixture was heated at 50 °C for 20 h. The progress of reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The obtained crude compound was purified by neutral alumina to get ethyl 4-(bcnzyloxy)-3-bromo-2-hydroxy-5.6- dimethylbenzoate (25 g, 50%) as yellow solid. LCMS m / z = 376.95 [M-H]'; 'H NMR (400 MHz, DMSO <76) <5 ppm 9.61 (br s, 1H), 7.59 - 7.53 (m. 2H), 7.45 - 7.35 (m, 3H). 4.83 (s, 2H), 4.30 (q, .7= 7.2 Hz, 2H), 2.14 (s, 3H), 2. 12 (s, 3H), 1.29 (t, J= 12 Hz, 3H).Step 3: To the solution of ethyl 4-(benzyloxy)-3-bromo-2-hydroxy-5,6-dimethylbenzoate (27 g, 1.0 eq., 71.2 mmol) in DMSO (150 mL) was added KOH (20 g. 5 eq., 356 mmol) (dissolved in 150 mL water) drop wise at room temperature. The reaction mixture was heated at 100 °C for 14 h. After complete consumption of starting material, the mixture w as acidified with Aq. 2N HC1 (pH~2) and precipitated solid was filtered, washed with cold water, dried overnight under vacuum to get 4-(benzyloxy)-3-bromo-2-hydroxy-5,6-dimethylbenzoic acid (20 g, 80%) as brown solid. LCMS m / z = 348.90 [M-H]'; 'H NMR (400 MHz. DMSO- 6) 8 ppm 10.64 (br s. 1H). 7.58 - 7.53 (m, 2H), 7.45 - 7.37 (m, 3H), 4.84 (s. 2H), 2.25 (s. 3H), 2.14 (s. 3H); - COOH proton not visible).Step 4: To the stirred solution of 4-(benzyloxy)-3-bromo-2-hydroxy-5.6-dimethylbenzoic acid (20 g, 1.0 eq., 56.9 mmol) in dichloromethane (200 mL) under nitrogen atmosphere w as added DIPEA (69.4 mL, 7 eq., 399 mmol) at 0 °C and reaction mixture was allowed to stir at sametemperature for 20 minutes. To the above reaction mixture, MOM-CI (13 mL, 3.0 eq., 171 mmol) was added and mixture was allowed to be stirred at room temperature for 1 h under nitrogen atmosphere. After complete consumption of starting material, the reaction mixture was diluted with ethyl acetate and washed with water. Combine organic layer were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain methoxymethyl 4-(benzyloxy)-3-bromo-2-(methoxymethoxy)-5,6-dimethylbenzoate (25 g, 99%) as brown liquid. LCMS m / z = 439.00 [M+H]+; 1H NMR (400 MHz. DMSO- 6) d ppm 7.58 - 7.54 (m, 2H), 7.45 - 7.37 (m, 3H), 5.44 (s, 2H), 5.03 (s, 2H), 4.87 (s, 2H), 3.44 (s, 6H), 2.21 (s, 3H), 2.16 (s, 3H).Step 5: To the solution of methoxymethyl 4-(benzyloxy)-3-bromo-2-(methoxymethoxy)-5,6- dimethylbenzoate (25 g, 1.0 eq., 56.9 mmol) in degassed tetrahydrofuran (250 mL) was added 10% Pd / C (w / w; 25 g,) under nitrogen atmosphere. Then, the suspension was hydrogenated in autoclave under hydrogen atmosphere at 18 psi for 16 h at room temperature. After complete consumption of starting material, the reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain crude material. The obtained crude compound was triturated with pentane, filtered and dried to get methoxymethyl 3-bromo-4-hydroxy-2-(methoxymethoxy)-5,6- dimethylbenzoate (20 g, 99%) as viscous brown solid. LCMS m / z = 346.85 [M-H]'; 'H NMR (400 MHz, DMSO-J6) 6 ppm 9.32 (br s, 1H), 5.40 (s, 2H), 4.98 (s. 2H), 3.44 (s, 3H), 3.45 (s, 3H), 2.15 (s, 3H), 2.13 (s, 3H).Step 6: To the stirred solution of ethyl 4-(benzyloxy)-6-hydroxy-2,3-dimethylbenzoate (10 g, 1.0 eq., 33.3 mmol) in acetonitrile (150 mL) at room temperature under nitrogen atmosphere was added MgC12 (41.2 g, 10 eq., 333 mmol) and copper dichloride (58.2 g, 10 eq., 333 mmol) portion wise. The resulting reaction mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was filtered on celite bed. Filtrate was evaporated on rotavapor to get the crude material, which was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduce pressure to obtained crude product. The obtained crude product was purified by silica gel flash chromatography to get ethyl 4-(benzyloxy)-3-chloro-2-hydroxy-5,6- dimethylbenzoate (7.0 g, 63%) as a white solid. LCMS m / z = 333.0 [M-H]'; 'H NMR (400 MHz, DMSO-c / 6) 8 ppm 9.69 (s, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.44 - 7.37 (m, 3H), 4.85 (s, 2H), 4.29 (q, J= 7.2 Hz, 2H), 2.10 (s, 3H), 2.09 (s, 3H), 1.28 (t, J= 7.2 Hz, 3H).Step 7-9: Following the same protocol described in steps 3-5, the monomer building blocks were synthesized accordingly.Synthesis of benzyl 6-bromo-2,4-dihydroxy-3-methylbenzoate and its derivatized monomer building blocksStep 1: To a solution of 4-bromo-2.6-dimethoxybenzaldehyde (50 g, 1 eq, 0.20 mol) in diethylene glycol (750 g, 676 mL, 35 eq, 7.07 mol) were added KOH (0.11 kg, 10 eq, 2.0 mol) and hydrazine hydrate (0.36 kg, 85% Wt, 30 eq, 6.1 mol). The mixture was stirred at 150 °C for Ih. TLC (PE / EA = 10 / 1, UV) showed starting material was consumed completely and new spots formed. The mixture was diluted with H2O (800 mL) and extracted with EA (1000 mL x 2). The combined organic layers were washed with 4N HC1 (800 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-bromo-l,3-dimethoxy-2- methylbenzene (50 g) as a yellow solid. LCMS: m / z = 233.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6) S 6.79 (s, 2 H), 3.77 (s, 6 H), 1.93 (s. 3 H).Step 2: To a solution of 5-bromo-l,3-dimethoxy -2 -methylbenzene (50 g, 1 eq, 0.22 mol) in DCM (1000 mL) were added TiCh (86 g, 50 mL, 2.1 eq, 0.45mol) and dichloro(methoxy)methane (50 g, 2 eq, 0.43 mol) at 0 °C. The mixture was stirred at 25 °C for 2 hours. TLC (PE / EA = 10 / 1, UV) showed starting material was consumed completely and new spots formed. The reaction mixture was quenched with H2O (500 mL) and extracted with DCM (500 mLx2). The combined organic layers were washed with brine (1000 mLx2), dried with anhydrous Na2SO-i. filtered and concentrated under reduced pressure to give 6-bromo-2,4-dimethoxy-3-methylbenzaldehyde (50 g) as a yellow solid. LCMS m / z = 261.1 [M+H]+.Step 3: To a solution of 6-bromo-2,4-dimethoxy-3-methylbenzaldehyde (200 g, 1 eq, 112 mmol) in ACN (1000 mL) was added NaFhPCh (16.2g) in ACN (1000 mL) and fEO (100 mL), followed by the addition of sodium chlorite (279 g, 4 eq, 3.09 mol) and hydrogen peroxide (175 g, 30% Wt, 2 eq, 1.54 mol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. TLC (PE / EA = 10 / 1, UV) showed starting material was consumed completely and new spots formed. The mixture was diluted with H2O (800 mL) and extracted with EA (1000 mL x2). The combined organic layers were washed with Na2S20s (800 mL x2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 6-bromo-2,4-dimethoxy-3- methylbenzoic acid (200g) as a yellow solid. LCMS m, z = 277.1 [M+H]+;XH NMR (400 MHz, DMSO-O 5 7.01 (s, 1 H), 3.82 (s, 3 H), 3.70 (s, 3 H), 2.02 (s, 3 H).Step 4: To a solution of 6-bromo-2,4-dimethoxy-3-methylbenzoic acid (50 g, 1 eq, 0.18 mol) in DCM (800 mL) was added tribromoborane (0. 18 kg, 70 mL. 4 eq, 0.73 mol) in DCM (200 mL) at 0 °C. The mixture was stirred at 25 °C for 16 hours. TLC (PE / EA = 3 / 1, UV) showed starting material was consumed completely and new spots formed. The reaction mixture was quenched with H2O (500 mL) at 0 °C and extracted with EA (1000 mL x 2). The combined organic layers were washed with brine (1000 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was diluted with H2O (500 mL), adjusted pH = 10 with Na2COs and extracted with EA (500 mL x 2). The aqueous was adjusted pH = 3 with 12N HC1 and extracted with EA (1000 mL x 2). The combined organic layers were washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 6-bromo-2,4-dihydroxy-3-methylbenzoic acid (60 g) as a brown solid.Step 5: To a solution of 6-bromo-2,4-dihydroxy-3-methylbenzoic acid (480 g, 1 eq, 1.94 mol) in DMF (1 L) were added NaHCCh (37.4 g) and (bromomethyl)benzene (349 g, 1.05 eq, 2.04 mol). The mixture was stirred at 50 °C for 5 hours. TLC (PE / EA = 10 / 1, UV) showed starting material was consumed completely and new spots formed. The mixture was combined withLMT-0023-115, LMT-0019-195 and LMT-0014-359. The reaction mixture was quenched with H2O (2000 mL) and extracted with EA (3000 mL * 2). The combined organic layers were washed with brine (2000 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by TLC (PE / EA = 10 / 1) to give benzyl 6-bromo-2,4-dihydroxy-3-methylbenzoate (320 g, 48.8% yield) as a yellow solid. LCMS: m / z = 339.1 [M+H]+.‘H NMR (400 MHz. DMSO- e) 5 10.26 (br s. 1 H). 10.03 (br s. 1 H). 7.47 (br d. J= 6.8 Hz. 2 H), 7.42 - 7.32 (m, 3 H), 6.68 (s, 1 H), 5.32 (s, 2 H), 1.96 (s, 3 H).Synthesis of 2,4-dihydroxy-6-methylbenzoic acid and its derivatized monomer building blocksStep 1: The phosphorus oxychloride (100 mL) was added dropwise to the DMF (500 mL) at 0 °C with rapid stirring over 0.5 h. Further, 3,5-Dihydroxytoluene (100 g, 1 eq., 0.80 mol) (dissolved in 100 mL of DMF) was added to the above mixture slowly keeping the temperature < 10 °C and the mixture was stirred for 3 h at room temperature. The reaction mixture was then quenched with Ice and 10% aq. NaOH until the solid appeared. Further, the mixture was heated at 105 °C for 1 h. Again, the reaction mixture was cooled to room temperature and acidified with 10% aq. HC1 under cooling conditions. Precipitated solid was filtered and dried to give 2,4-dihydroxy-6-methylbenzaldehyde (99 g, 80% yield) as a yellow solid. LCMS m / z = 151.00 [M-H]’; 'H NMR (400 MHz, DMSO-ds) d ppm 12.05 (br s. 1H), 10.67 (br s. 1H), 10.05 (s, 1H), 6.20 (s, 1H), 6.12 (s, 1H), 2.48 (s, 3H).Step 2: To solution of 2,4-dihydroxy-6-methylbenzaldehyde (50 g, 1.0 eq., 329 mmol) in DMSO, was added saturated solution of NaCICh (71.3 g, 2.4 eq., 789 mmol) at 0 °C followed by the dropwise addition of saturated solution of NaH2PO4.2H2O (128 g, 2.5 eq., 822 mmol). The reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture wasdiluted with water and the aqueous layer was extracted with ethyl acetate. The complete organic layer was washed with the brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2,4-dihydroxy-6-methylbenzoic acid (53 g, 95%) as yellow solid. 'H NMR (400 MHz, DMSO-t / e) <5 ppm 12.68 - 12.04 (br m, 2H), 10.12 (br s, 1H), 6.17 (s, 1H), 6.12 (d, J= 1.6 Hz, 1H), 2.39 (s, 3H).Step 3: To a solution of 2,4-dihy droxy-6-methylbenzoic acid (53 g, 1 eq., 315 mmol) in acetone (500 mL) was added K.2CO3 (21.8 g. 0.5 eq. 158 mmol) followed by dropwise addition of Mel (447 g, 10 eq, 3.15 mol) at 0 °C over 10 min. The mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and solid residue was washed with acetone (200 mL); filtrate was concentrated under reduced pressure to afford methyl 2,4-dihydroxy-6- methylbenzoate (39 g, 67%) as a white solid. LCMS m / z = 181.00 [M-H],Step 4: To the solution of methyl 2,4-dihydroxy-6-methylbenzoate (39 g, 1 eq, 214 mol) and K2CO3 (35.5 g, 1.2 eq, 257 mol) in acetone (1000 mL) was added BnBr (47.6 g, 1.3 eq., 278 mol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 55 °C for 16 h. The reaction mixture was filtered, and filtrate was concentrated under reduced pressure to get the crude compound. Crude compound was diluted with ethyl acetate and washed with water. Combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude material. The crude product was purified by manual column chromatography to give methyl 4- (benzyloxy)-2-hydroxy-6-methylbenzoate (42 g, 72 %) as a white solid. LCMS m z = 271.05 [M-H]’; 'H NMR (400 MHz, DMSO-rty) b ppm 10.60 (s, 1H), 7.43 - 7.31 (m, 5H), 6.42 (d, .7= 2.0 Hz, 1H), 6.38 (d, J= 2.4 Hz, 1H), 5.09 (s, 2H), 3.80 (s, 3H), 2.29 (s, 3H).Step 5: To a solution of methyl 4-(benzyloxy)-2-hydroxy-6-methylbenzoate (42 g, 1.0 eq., 154 mmol) in acetone (750 mL) was added K.2CO3 (43.4 g, 1.5 eq, 314 mmol) followed by dropwise addition of Mel (297 g, 10.0 eq, 15.4 mol) at 0 °C over 10 min. The mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered and solid residue was washed with acetone (200 mL); filtrate was concentrated under reduce pressure to afford methyl 4-(benzyloxy)-2- methoxy-6-methyl benzoate (39 g. 52%, LCMS Purity -80%) as a yellow liquid; LCMS m / z = 287.00 [M+H]+Step 6: To a solution of methyl 4-(benzyloxy)-2-methoxy-6-methyl benzoate (39 g, 1.0 eq., 130 mol) in DMSO (195 mL) was added KOH (72.9 g, 10 eq., 1.30 mol) (dissolved 195 mL H2O) and the mixture was stirred at 90 °C for 16 h. After complete consumption of starting material, the mixture was carefully acidified with 2 N HC1 under cooling conditions. Theprecipitated solid was filtered and dried to give 4-(benzyloxy)-2-methoxy-6-methylbenzoic acid (34 g, 96%) as off white solid. LCMS m / z = 271.05 [M-H]'; 'H NMR (400 MHz, DMSO- d6) 8 ppm 12.46 (br s, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.35 - 7.32 (m, 1H), 6.53 (s, 1H), 6.50 (s, 1H), 5.11 (s, 2H), 3.73 (s, 3H), 2.17 (s, 3H).Step 7: To the stirred solution of methyl methyl 4-(benzyloxy)-2-methoxy-6-methylbenzoate (6 g, 1.0 eq., 21 mmol) in degassed tetrahydrofuran (60 mL) was added 10% Pd / C (w / w, 6 g, 50% wet) under nitrogen atmosphere at room temperature. Then, the reaction mixture was hydrogenated under hydrogen balloon pressure at room temperature for 16 h. After complete consumption of starting material, the reaction mixture was filtered through celite bed and filtrate was evaporated on Rota vapor to get crude residue. The crude residue was triturated with pentane to get methyl 4-hydroxy-2-methoxy-6-methylbenzoate (4 g, 97%) as yellow liquid. LCMS m z = 194.90 [M-H]’;'H NMR (400 MHz, DMSO- s) S ppm 9.75 (s, 1H), 6.29 (d, J= 2.0 Hz, 1H), 6.23 (d, J= 1.6 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.11 (s, 3H).Step 8: To the stirred solution of methyl methyl 4-hydroxy-2-methoxy-6-methylbenzoate (4 g, 1.0 eq.. 20.4 mmol) in di chloromethane (50 mL) was added DIPEA (13.2 g, 5 eq., 102 mmol) at room temperature under nitrogen atmosphere and mixture was stirred for 10 minutes before the addition of chloromethoxymethane (1.86 mL, 1.2 eq., 24.5 mmol) at 0° C. Then, the reaction mixture was allowed to stir at room temperature for 2 h. After complete consumption of starting material, the reaction mixture w as diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to get methyl 2-methoxy-4-(methoxymethoxy)-6- methylbenzoate (4 g, 82%) as white solid. LCMS dz = 240.80 [M+H]+;Step 9: To the stirred solution of methyl 2-methoxy-4-(methoxymethoxy)-6-methylbenzoate (4.0 g, 1.0 eq., 16.6 mmol) in dimethyl sulfoxide (40 mL), water (40 mL) mixture was added potassium hydroxide (4.67 g, 5 eq., 83.2 mmol) at room temperature and reaction was allowed to stir at 100 °C for 16 h. After completion, the reaction mixture was cooled to 0 °C and acidified (pH -4-5) with saturated solution of citric acid; Further, aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get methyl 2-methoxy-4-(methoxymethoxy)-6- methylbenzoate (3.5 g, 93%) as white solid. LCMS m / z = 226.75 [M+H]+; 'H NMR (400 MHz, DMSO-cL) 8 ppm 12.69 (br s, 1H), 6.54 (d, J= 2.0 Hz, 1H), 6.49 (d, J= 1.6 Hz, 1H), 5.21 (s, 2H), 3.74 (s, 3H), 3.38 (s, 3H), 2.20 (s, 3H).Synthesis of 2,4-dihydroxy-3,6-dimethylbenzoic acid and its derivatized monomer building blocksStep 1: To the stirred solution of methyl 2,4-dihydroxy-3,6-dimethylbenzoate (50 g, 1 eq, 0.253 mol) in acetone (0.8 L) was added dipotassium carbonate (42.3 g, 1.2 eq., 306 mmol) and the reaction mixture was heated at 55 °C for 30 min. Further, the reaction mixture was cooled to room temperature and (bromomethyl)benzene (39.3 mL, 1.3 eq.. 331 mmol) was added dropwise. Then, the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with ice cold water and precipitated solid was fdtered, dried overnight to get methyl 4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoate (50 g, 66%) as a white solid. LCMS m / z = 287. 15 [M+H]+; 'H NMR (400 MHz, DMSO- 6) 5 ppm 11.23 (s, 1H), 7.47 (d, J= 7.2 Hz, 2H), 7.41 (d, J= 7.2 Hz, 2H). 7.35 - 7.32 (m, 1H). 6.60 (s. 1H), 5.18 (s, 2H), 3.87 (s, 3H), 2.43 (s, 3H), 2.02 (s, 3H).Step 2: To the stirred solution of methyl 4-(benzy loxy)-2-hydroxy-3,6-dimethylbenzoate (10 g, 1.0 eq., 34.9 mmol) in tetrahydrofuran (50 mL) : water (50 mL) mixture was added LiOH.H2O (7.33 g, 5 eq., 175 mmol) at room temperature. Then, reaction mixture was heated at80 °C for 16 h. After complete consumption of starting material, the reaction mixture was acidified with 2 N HC1 and the precipitated solid was filtered through sintered funnel, dried under vacuum to obtained 4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoic acid (6.5 g, 65%) as a brown solid. LCMS m / z = 273.2 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 ppm 13.68 (br s, 1H), 12.49 (br s, 1H), 7.46 (d, J= 7.2 Hz, 2H), 7.42 - 7.39 (m, 2H), 7.35 - 7.33 (m, 1H), 6.57 (s, 3H), 5.18 (s, 2H), 2.49 (s, 3H), 2.01 (s, 3H).Step 3: To the solution of methyl 2,4-dihydroxy-3,6-dimethylbenzoate (200 g, 1.0 eq.. 1.02 mol) in Dioxane (1 L) was added KOH (400 g. 7.0 eq., 7.14 mol) at room temperature. The mixture was stirred at 85 °C for 5 hr. Further, the reaction mixture was carefully acidified with 2 N HC1 up to pH~2 under cold condition. Precipitated solid was filtered and dried overnight under vacuum to give 2,4-dihydroxy-3,6-dimethylbenzoic acid (150 g, 80 %) as brown solid.LCMS m / z = 181.15 [M-H]';NMR (400 MHz, DMSO-r / 6) 3 ppm 13.43 (br s, 1H), 12.62 (br s, 1H), 10.04 (s, 1H). 6.25 (s, 1H), 2.39 (s. 3H), 1.92 (s, 3H).Step 4: To the solution of 2,4-dihydroxy-3,6-dimethylbenzoic acid (100 g, 1 eq., 0.55 mol) in DMF (1 L) was added sodium hydrogen carbonate (46 g, 1 eq., 0.55 mol) at 25 °C and the mixture was stirred at 75 °C for 30 min. Then, Reaction mixture was cooled to room temperature followed by dropwise addition of benzyl bromide (94 g, 65 mL. 1.00 eq.. 0.55 mol) and the reaction mixture was stirred at 75 °C for 3 h. The reaction mixture was diluted with H2O and precipitated solid was filtered through sintered funnel; Solid compound was dissolved in ethyl acetate and washed with water; organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give benzyl 2,4-dihydroxy-3.6-dimethyl benzoate (100 g, 67 % yield) as a yellow solid. LCMS m / z = 271.10 [M-H]’; 'H NMR (400 MHz, DMSO-c 6) 3 ppm 11.60 (s, 1H), 10.11 (br s, 1H), 7.47 (d, J= 7.2 Hz, 2H), 7.42 - 7.33 (m, 3H), 6.27 (s, 1H), 5.36 (s, 2H), 2.34 (s, 3H), 1.94 (s, 3H).Step 5: To the solution of benzy l 2,4-dihydroxy-3,6-dimethylbenzoate (65 g, 1 eq., 239 mmol) in DMF (650 mL), was added DIPEA (124 mL, 3.0 eq., 716 mmol) under nitrogen atmosphere at0 °C and the reaction mixture was stirred at 0 °C for 20 min, followed by dropwise addition of TBDPS-C1 (60.6 mL, 1 eq., 239 mmol). Then, the reaction mixture was allowed to be stirred at room temperature for 4 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bi carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude compound. The crude material was purified by silica-gel column chromatography to get benzyl 4-((tert-butyldiphenylsilyl)oxy)-2 -hydroxy-3, 6-dimethylbenzoate (75 g, 58%) as a white solid. LCMS m / z = 509.30 [M-H]’; *HNMR (400 MHz, DMSO-J6) 3 ppm 11.22 (s, 1H), 7.66 - 7.64 (m, 4H), 7.49 - 7.31 (m, 11H), 5.77 (s, 1H), 5.31 (s, 2H), 2.17 (s, 3H), 1.96 (s, 3H), 1.05 (s, 9H).Step 6: To the stirred solution ofbenzyl 4-((tert-butyldiphenylsilyl)oxy)-2-hydroxy-3,6- dimethyl benzoate (60 g, 1.0 eq., 117 mol) in degassed THF (600 mL) was added 10 % Pd / C (60 g, w / w, 50% wet) under nitrogen atmosphere at room temperature. The suspension was hydrogenated in autoclave at 15 psi for 6 h. Further, catalyst was carefully filtered and filtrate was concentrated under reduced pressure to get the crude compound; crude residue was triturated with n-pentane to give 4-((tert-butyldiphenylsilyl)oxy)-2-hydroxy-3,6- dimethylbenzoic acid (40 g, 81%) as a white solid. LCMS m / z = 419.25 [M-H]-; 'H NMR (400MHz, DMSO d6) 3 ppm 7.66 - 7.64 (m, 4H), 7.52 - 7.43 (m, 6H), 5.75 (s, 1H), 2.16 (s. 3H), 2.04 (s. 3H), 1.05 (s, 9H); -COOH and -OH protons not visible.Synthesis of 4-(benzyloxy)-3-bromo-6-hydroxy-2,5-dimethylbenzoic acid and its derivatized monomer building blocksStep 1: To the solution of methyl 4-(benzyloxy)-2-hvdroxy-3.6-dimethyl benzoate (50 g. 1 ,0 eq.. 175 mmol) in dichloromethane (500 mL). was added NBS (37,3 g. 1,2 eq.. 210 mmol) under nitrogen atmosphere at 0 °C. Further, the reaction mixture was allowed to be stirred at room temperature for 3 h. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with saturated solution of Na2S20s, dried over anhydrous sodium sulphate, filtered and concentrated under reduce pressure to get methyl 4-(benzyloxy)-3-bromo-6-hydroxy-2.5- dimethylbenzoate (50 g. 78%) as yellow solid. LCMS m / z = 364.90 [M+H]+; 'H NMR (400 MHz, DMSO-r / 6) 3 ppm 9.54 (s, 1H), 7.54 (d, J = 6.8 Hz, 2H), 7.45 - 7.38 (m, 3H), 4.85 (s, 2H), 3.83 (s, 3H), 2.29 (s, 3H), 2.13 (s, 3H).Step 2: To the stirred solution of methyl 4-(benzyloxy)-3-bromo-6-hydroxy-2.5- dimethylbenzoate (50 g, 1.0 eq., 137 mmol) in mixture of 1,4-dioxane (250 mL) and water (250 mL) was added potassium hydroxide (76.8 g, 10 eq.. 1.37 mol) at room temperature.The reaction mixture was heated at 85 °C for 6 h. The reaction mixture cooled to room temperature and concentrated under reduced pressure to obtain crude material. The obtained crude product was acidified with Aq. 2 N HC1 (pH~2) and precipitated solid was filtered, dried overnight under vacuum to get 4-(benzyloxy)-3-bromo-6-hydroxy-2,5-dimethylbenzoic acid (45 g, 94%) as brown solid. LCMS m / z = 349.00 [M-H]'.Step 3: To the solution of 4-(benzyloxy)-3-bromo-6-hydroxy-2,5-dimethylbenzoic acid (5 g, 1.0 eq., 14.2 mmol) in DCM (50 mL) was added DIPEA (14.86 mL, 6 eq., 85.4 mmol) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at same temperature for 20 min. Then, MOMC1 (3.39 mL, 3 eq.. 42.7 mmol) was added and the mixture was stirred at room temperature for 3 h. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers w ere w ashed with saturated brine, dried over anhydrous sodium sulphate, filtered and concentrated under reducedpressure to get a crude material. The crude product was purified by Combi-flash using neutral alumina to get methoxymethyl 4-(benzyloxy)-3-bromo-6-(methoxy methoxy)-2,5- dimethylbenzoate (5.1 g, 73%) as light yellow solid. LCMS m'z = 439.05 [M+H]+;!H NMR (400 MHz, DMSO-tL) 8 ppm 7.55 (d, J= 6.8 Hz, 2H), 7.46 - 131 (m, 3H), 5.44 (s, 2H), 4.96 (s, 2H), 4.90 (s, 2H), 3.47 (s, 3H), 3.45 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H).Step 4: To the stirred solution of methoxymethyl 4-(benzyloxy)-3-bromo-6- (methoxymethoxy)-2,5-dimethylbenzoate (4 g, 1.0 eq., 9.11 mmol) in degassed THF (40 mL) was added 10% Pd / C (4.0 g, w / w, 50% wet) under nitrogen atmosphere at room temperature. Then, reaction mixture was stirred for 4 h at 15 psi under hydrogen atmosphere at room temperature. After complete consumption of starting material, the reaction mixture was filtered through a celite bed. and the filtrate was evaporated under reduced pressure to get the crude material. Crude material was triturated with n-pentane to get methoxymethyl 3-bromo-4- hydroxy-6-(methoxymethoxy)-2,5-dimethylbenzoate (2.7 g, 85%) as a white solid. LCMS m / z = 349.05 [M+H]+; 'H NMR (400 MHz, DMSO-tL) 8 ppm 9.49 (br s, 1H), 5.39 (s, 2H), 4.90 (s, 2H), 3.45 (s, 3H), 3.42 (s, 3H), 2.26 (s, 3H). 2.14 (s, 3H).Synthesis of 4-hydroxy-2,3,6-trimethylbenzoic acid and its derivatized monomer building blocksStep 1: To the stirred solution of 4-methoxy-2,3,6-trimethylbenzaldehyde (10 g, 1.0 eq., 56.1 mmol) in DMSO (30 mL) was added saturated solution of NaClO2 (12.2 g, 2.4 eq., 135 mmol) at 0 °C over the period of 20 minutes. The saturated solution of NaH2PO4.2H2O (16.8 g, 2.5 eq., 140 mmol) was then added slowly over the period of 20 minutes to the above mixture and the reaction mixture was allowed to stir at room temperature for 6 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was diluted with water and carefully acidified to pH ~2 by 1 N aq. HC1. Precipitated solid was filtered via sintered funnel and washed with water, dried overnight to get 4-methoxy-2,3,6- trimethylbenzoic acid (6 g, 55%) as white solid. LCMS m / z = 193.05 [M-H]';1H NMR (400 MHz, DMSO-O 5 ppm 12.73 (br s, 1H), 6.69 (s, 1H), 3.73 (s, 3H), 2.23 (s, 3H), 2.15 (s. 3H), 2.04 (s, 3H).Step 2: To the stirred solution of 4-methoxy-2,3,6-trimethylbenzoic acid (11.0 g, 1.0 eq., 56.6 mmol) in DCM (150 mL) was added BBr3 (1.0 M in DCM) (170 mL, 3.0 eq., 169.8 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was further stirred at 25 °C for 2 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material. The mixture was quenched with ice, and aqueous layer was extracted with 15% MeOH:DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, fdtered and concentrated under reduced pressure to get the crude compound. The crude product was triturated with pentane and ether to get 4-hydroxy-2,3,6- trimethylbenzoic acid (7 g, 69%) as yellow solid. LCMS m / z = 179.00 [M-H]';JH NMR (400 MHz, DMSO-O <5 ppm 12.68 (br s, 1H), 9.36 (s, 1H), 6.50 (s, 1H), 2.14 (s, 3H), 2.12 (s. 3H), 2.01 (s, 3H).Step 3: To the stirred solution of 4-hydroxy-2,3,6-trimethylbenzoic acid (38.5 g, 1.0 eq., 214 mmol) in DMF (0.4 L) was added sodium bicarbonate (21.5 g, 1.2 eq., 256 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 30 min at 75 °C then cool to room temperature followed by dropwise addition of benzyl bromide (37.3 g, 1.02 eq.. 218 mmol). Then, the reaction mixture was stirred for 4 h at 55 °C. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude was purified by column chromatography to get benzyl 4-hydroxy-2,3,6- trimethylbenzoate (32 g, 55%) as white solid. LCMS m / z = 269.05 [M-H]‘; ’H NMR (400 MHz, DMSO-<A) <5 ppm 9.50 (s, 1H), 7.44 - 7.33 (m, 5H), 6.51 (s, 1H), 5.28 (s, 2H), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H).Synthesis of 4-(benzyloxy)-2,3,6-trimethylbenzoic acid and 2,3,4,5,6-pentafluorophenyl4-(benzyloxy)-2,3,6-trimethylbenzoateStep 1: To the stirred solution of 4-methoxy-2,3,6-trimethylbenzaldehyde (60.0 g, 1.0 eq., 337 mmol) in DCM (500 mL) was added BBn (1.0 M in DCM) (1.1 L, 3.0 eq.. 1.01 mol) under nitrogen atmosphere dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. After complete consumption of starting material, the mixture was quenched with ice-cold water, and extracted with 15% MeOH:DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude material was triturated with n-pentane and di-ethyl ether to afford pure 4-hydroxy-2,3,6-trimethylbenzaldehyde (50 g, 86 %) as yellow solid. LCMS z = 165.15 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 ppm 10.37 (s, 1H), 10.18 (s, 1H), 6.58 (s, 1H), 2.45 (s, 6H), 2.06 (s, 3H).Step 2: To the stirred solution of 4-hydroxy-2,3,6-trimethylbenzaldehyde (43 g. 1 eq., 236 mmol) in Acetone (387 mL) was added K2CO3 (49 g, 1.5 eq., 354 mmol) followed by dropwise addition of Benzyl bromide (38.6 mL, 1.2 eq., 283 mmol) at room temperature under nitrogen atmosphere. Further, reaction mixture was stirred at 55 °C for 16 h. Progress the reaction was monitored by TLC. After complete consumption of starting material, reaction mixture was filtered through celite bed and washed with acetone; Filtrate was evaporated on rotavapor to get the crude residue. The crude residue was diluted with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude material was purified by Manual column chromatography to get 4-(benzyloxy)-2,3,6- trimethylbenzaldehyde (50 g, 83 %) as a brown solid. LCMS m z = 255.05 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 8 ppm 10.43 (s, 1H), 7.47 (d, J= 7.6 Hz, 2H), 7.43 (t, J= 7.6 Hz, 2H), 7.34 (t, J= 7.2 Hz, 1H), 6.89 (s, 1H), 5.20 (s, 2H), 2.52 (s, 3H), 2.46 (s, 3H), 2.13 (s, 3H).Step 3: To the stirred solution of 4-(benzyloxy)-2.3.6-trimethylbenzaldehyde (78 g, 1.0 eq., 307 mmol) in dimethyl sulfoxide (0.7 L), saturated solution of sodium chlorite (277 g, 10 eq., 3.07 mol) was added dropwise at 0 °C over the period of 20 minutes followed by the dropwise addition of saturated solution of sodium dihydrogen phosphate (368 g, 10 eq., 3.07 mol) over the period of 20 minutes. The reaction mixture was allowed to stir at room temperature for 2 h. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was diluted with w ater and carefully acidified to pH ~2 by 1 N aq. HC1. The reaction mixture w as diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude materialwas purified by manual column chromatography to get 4-(benzyloxy)-2,3,6-trimethylbenzoic acid (55 g, 66%) as a white solid. LCMS m,'z = 268.95 [M-H]’;1H NMR (400 MHz, DMSO- d6) 5 ppm 12.87 (s, 1H), 7.49 - 7.46 (m, 2H), 7.42 (t, J= 7.6 Hz, 2H), 7.32 (t, J= 7.2 Hz, 1H), 6.80 (s, 1H), 5.10 (s, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H).Step 4: To the stirred solution of 4-(benzyloxy)-2,3,6-trimethylbenzoic acid (20 g, 1.0 eq., 74 mmol) in DCM (75 mL) was added EDC.HC1 (21.3 g, 1.5 eq., I l l mmol) and DMAP (1.81 g, 0.2 eq.. 14.8 mmol) at 0 °C under nitrogen atmosphere. Then, the stock solution of 2,3,4,5,6- pentafluorophenol (15 g, 1.1 eq., 81.4 mmol) (dissolved in 10 mL DCM) was added dropwise and the reaction mixture was stirred for 1 h at room temperature. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was directly evaporated under reduced pressure to get the crude residue. The crude material was triturated with MeOH to get 2,3,4,5,6-pentafluorophenyl 4-(benzyloxy)-2,3,6- trimethylbenzoate (18 g, 52%) as a white solid. 'H NMR (400 MHz, DMSO-rie) 8 ppm 7.46 (d, J= 7.2 Hz, 2H), 7.40 (t, J= 7.2 Hz. 2H), 7.33 (t, J= 7.2 Hz, 1H), 6.98 (s, 1H), 5.17 (s, 2H), 2.35 (s. 3H), 2.29 (s, 3H), 2.14 (s, 3H).Synthesis of 3-ethyl-4-hydroxy-2,5,6-trimethylbenzoic acid and its derivatized monomer building blocksstep-4Step 1: To the stirred solution of benzyl 4-hydroxy-2,3,6-trimethylbenzoate (27 g, 1.0 eq., 99.9 mmol) in acetic acid (190 mL) was added HBr (46% in H2O) (540 ml, 20 V) under nitrogen atmosphere at room temperature; then DMSO (190 mL) was added, and resulting reaction mixture was stirred for 16 h at room temperature. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layers were washed with brine and saturated sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude material. The crudematerial was purified by using combi flash to get benzyl 3-bromo-4-hydroxy-2,5,6- trimethylbenzoate (25 g. 72%) as brown solid. LCMS m / z = 346.90 [M-H]'; 'H NMR (400 MHz, DMSO-rfc) d ppm 9.12 (br s, 1H), 7.47 - 7.35 (m, 5H), 5.33 (s, 2H), 2.19 (s, 3H), 2.13 (s, 3H), 2.04 (s, 3H).Step 2: To the stirred solution of benzyl 3-bromo-4-hydroxy-2,5,6-trimethylbenzoate (10 g, 28.6 mmol) & ethylboranediol (31.7 g, 15 eq., 430 mmol) in toluene (250 mL) were added K2CO3 (15.2 g, 5 eq., 143 mmol) & SPhos (4.7 g, 0.4 eq., 11.5 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was degassed with nitrogen gas for 20 minutes, before the addition of Pd2(dba)3 (7.87 g, 0.3 eq., 8.59 mmol). After the addition, resultant reaction mixture was degassed with nitrogen gas for 20 min and stirred at 80 °C for 16 h. After complete consumption of starting material, the reaction mixture was cooled to room temperature, filtered through a Celite bed and washed with ethyl acetate. Filtrate was evaporated reduced pressure to get the crude residue. The residue was dissolved in ethyl acetate and washed with water. Organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude material was purified by combi-flash column chromatography to get benzyl 3-ethyl-4-hydroxy-2.5,6- trimethylbenzoate (8 g, 93%) as yellow solid. LCMS m / z = 297.00 [M-H]';1H NMR (400 MHz, DMSO-tL) 8 ppm 8.24 (s, 1H), 7.54 - 7.36 (m, 5H), 5.29 (s, 2H), 2.59 (q, J= 7.2 Hz, 2H), 2.05 (s, 6H), 1.96 (s, 3H), 0.98 (t, J= 7.2 Hz, 3H).Step 3: To the solution of benzyl 3-ethyl-4-hydroxy-2,5,6-trimethylbenzoate (5 g, 1.0 eq., 16.8 mmol) in degassed tetrahydrofuran (50 mL) was added 10% Pd / C (5 g, w / w, 50% wet) under Nitrogen atmosphere at room temperature. The suspension was hydrogenated in autoclave at 35 psi for 16 h. Progress of the reaction was monitored by TLC. After completion, catalyst was carefully filtered, and filtrate was concentrated under reduced pressure to get the crude material, which was triturated with pentane and filtered to get 3-ethyl-4-hydroxy-2,5,6- trimethylbenzoic acid (3 g, 86%) as a white solid. LCMS m / z = 207.0 [M-H]'; 'l4 NMR (400 MHz, DMSO-d6) 5 ppm 12.74 (br s, 1H), 8.13 (br s, 1H), 2.59 (q, J = 7.6 Hz, 2H), 2.12 (s, 3H), 2.08 (s, 6H), 1.00 (t, J= 7.2 Hz, 3H).Step 4: To the stirred solution of 3-ethyl-4-hydroxy-2,5,6-trimethylbenzoic acid (3 g. 14.4 mmol) in DMF (30 mL) was added sodium hydrogencarbonate (3.03 g, 2.5 eq., 36 mmol) at room temperature under nitrogen atmosphere and the mixture was heated at 50 °C for 1 h. Further, the reaction mixture was cooled to room temperature followed by addition of M0MC1 (1.64 mL, 1.5 eq., 21.6 mmol) and reaction mixture was allowed to stir for 2 h at roomtemperature. After the complete consumption of the starting material, the reaction mixture was poured into cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the crude material. Crude material was purified by combi to get methoxymethyl 3-ethyl-4-hydroxy-2,5,6- trimethylbenzoate (2.5 g, 69%) as white solid. LCMS m z = 251.0 [M-H]';1HNMR (400 MHz, DMSO-d6) 5 ppm 8.36 (s, 1H), 5.38 (s, 2H), 3.47 (s, 3H), 2.61 (q, J = 7.2 Hz, 2H), 2.15 (s, 3H), 2.07 (s, 6H), 1.00 (t, J= 7.6 Hz, 3H).Synthesis of methoxymethyl 3-bromo-4-hydroxy-2-methoxy-5,6-dimethylbenzoateTo the stirred solution of methoxymethyl 4-hydroxy-6-methoxy-2,3-dimethylbenzoate (2 g, 1.0 eq.. 8.32 mmol) in acetonitrile (17.7 mL), was added NBS (1.78 g. 1.2 eq.. 9.99 mmol) portionwise under nitrogen atmosphere at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material; the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude material. The crude compound was purified by flash chromatography to get methoxymethyl 3-bromo-4- hydroxy-2-methoxy-5,6-dimethylbenzoate (1.6 g, 60%, LCMS purity' -56%) as yellow liquid. LCMS m'z = 316.90 [M-H]'Scheme for Synthesis of methoxymethyl 2-bromo-4-hydroxy-3,5,6-trimethylbenzoateStep 1: A solution of 2,3,6-trimethylphenol (70 g, 514 mmol) in AcOH (210 mL) was stirred for 10 minutes at 0 °C followed by dropwise addition of Br2 (32.2 mL, 1.0 eq., 624 mmol) (dissolve in 20 ml acetic acid) at 0 °C under nitrogen atmosphere. The reaction mixture wasstirred for 2 h at room temperature. The progress of the reaction was monitored by LCMS. After complete consumption of the starting material reaction mixture was quenched with ice cold water and aoff white solid precipitated. The precipitate was filtered and washed with chilled water, dried under vacuum for 2 h to get 4-bromo-2,3,6-trimethylphenol (70 g, 63%) as an off white solid. LCMS m,z = 214.85 [M-H]’;'H NMR (400 MHz, DMSO-cfc) <5 ppm 8.35 (s, 1H), 7.14 (s, 1H), 2.25 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H).Step 2: To a solution of 4-bromo-2.3,6-trimethylphenol (70 g, 1.0 eq., 325 mmol) and K.2CO3 (20.2 g, 1.5 eq., 146 mmol) in DMF (700 mL) was added methyl iodide (203 mL, 10 eq., 3.25 mol) slowly and resulting mixture was stirred at 55°C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The combined organic layers were washed with ice cold water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude residue. The crude residue obtained was purified by silica gel column chromatography to afford l-bromo-4-methoxy-2,3,5-trimethylbenzene (50 g, 67%) as colourless viscous liquid. 'H NMR (400 MHz, DMSO-flL) 5 ppm 7.29 (s, 1H). 3.61 (s. 3H), 2.25 (s, 3H), 2.20 (s, 3H). 2.18 (s, 3H). Step 3: A solution of l-bromo-4-methoxy-2,3,5-trimethylbenzene (40 g, 1.0 eq., 175 mmol) in tetrahydrofuran (352 mL) was cooled to -78 °C. To the above reaction mixture n- BuLi (164 mL, 1.5 eq., 1.6 M in Hexane, 262 mmol) was added drop wise over 10 minutes under nitrogen atmosphere. The resultant grey suspension was stirred at -78 °C for 30 minutes. Then, Dry Ice (46.1 g, 6.0 eq., 1.05 mol) was added in instalments over 10 min. The reaction mixture was further allowed to attain room temperature over the period of 2 h. The progress of the reaction was monitored by TLC. Then, IN HC1 was added to the reaction mixture at 0 °C to achieve pH- 2 and aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude material. The above crude material was purified by combi-flash to afford 4-methoxy-2,3,5-trimethylbenzoic acid (18 g, 53%) as white solid. LCMS m ,'z = 192.95 [M-H]-; ' H NMR (400 MHz, DMSO-cL) 3 ppm 12.60 (s, 1H), 7.45 (s, 1H), 3.64 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H).Step 4: To a solution of 4-methoxy-2.3.5-trimethylbenzoic acid (18 g. 1.0 eq.. 92.7 mmol) in anhydrous dichloromethane (200 mL) and cat. DMF (2 mL) was added oxalyl dichloride (48 mL, 6 eq., 556 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to attain room temperature and stirred for 15 minutes. Further, methanol (180 mL) was added, and reaction mixture was allowed to stir for 1 h. Progress of the reaction was monitoredby TLC. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get crude material. The obtained crude residue was purified by manual silica gel column chromatography to get methyl 4-methoxy-2,3,5- trimethylbenzoate (20 g, Quant.) as colorless liquid. LCMS m ,'z = 208.80 [M+H]+,XH NMR (400 MHz, DMSO- Q 5 ppm 7.44 (s, 1H), 3.81 (s, 3H), 3.64 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H).Step 5: To the solution of methyl 4-methoxy-2,3,5-trimethylbenzoate (20 g, 1.0 eq., 96 mmol) in ACN (200 mL) was added Bromine (25 mL, 5 eq., 456 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was further stirred for 16 h at room temperature. Progress of the reaction was monitored by TLC which shows complete consumption of starting material. The above reaction mixture was quenched with cold aq. NaHCCL solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude material. Crude was purified by combi-flash to afford methyl 2-bromo-4-methoxy-3,5.6-trimethyl benzoate (15 g, 54%) as off- white solid. 'H NMR (400 MHz, DMSO-tL) 8 ppm 3.88 (s, 3H), 3.64 (s, 3H), 2.38 (s. 3H), 2.17 (s, 3H), 2.16 (s, 3H).Step 6: To the solution of methyl 2-bromo-4-methoxy-3,5,6-trimethylbenzoate (15 g, 1.0 eq., 52.2 mmol) in dichloromethane (105 mL) was added BBn (157 g, 12 eq., 1.0 M in DCM, 627 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 24 h. Progress of the reaction was monitored by TLC. The above reaction mixture was quenched with ice water and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduce pressure to get the crude material, which was triturated with DCM (20 mL) to get 2-bromo-4-hydroxy-3,5,6- trimethylbenzoic acid (6.5 g. 48%) as white solid. 'HNMR (400 MHz, DMSO-rfe) 3 ppm 13. 12 (br s, 1H), 8.79 (s, 1H), 2.26 (s, 3H), 2.14 (s, 3H), 2.08 (s, 3H).Step 7: A solution of 2-bromo-4-hydroxy-3,5,6-trimethylbenzoic acid (6.5 g, 1.0 eq., 25.1 mmol) and NaHCOs (8.43 g, 4 eq., 0.1 mol) in DMSO (50 mL) was stirred at 75 °C for 30 minutes. Then. MOM-CI (2.42 g, 1.2 eq., 30.1 mmol) was added dropwise at 0 °C and the reaction mixture was stirred for 4 h at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate and ice-cold water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain crude material, which was further purified usingsilica-gel column chromatography to get methoxymethyl 2-bromo-4-hydroxy-3,5,6- trimethylbenzoate (5.5 g, 75%) as white solid. LCMS m / z = 302.80 [M-H]'; 'H NMR (400 MHz, DMSO-ufe) <5 ppm 8.95 (s, 1H), 5.40 (s, 2H), 3.46 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H).Scheme for synthesis of methoxymethyl 4-hydroxy-2,3,5-trimethylbenzoateStep 1: To the stirred solution of 4-methoxy-2,3,5-trimethylbenzoic acid (6.8 g, 1 eq., 35 mmol) in dichloromethane (180 mL), was added BBr3 (IM in DCM) (17.5 g, 2 eq., 70 mmol) dropwise at 0 °C and then the reaction mixture was stirred at room temperature for 2 h. After complete consumption of starting material, the reaction mixture was quenched with ice cold water and extracted with 10% Methanol in DCM. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to get crude compound. The obtained crude material was triturated with n-pentane to afford 4-hydroxy-2,3,5-trimethylbenzoic acid (5.2 g, 82%) as pale brown solid. 'H NMR (400 MHz. DMSO-tL) 5 ppm 12.23 (br s, 1H), 8.72 (s, 1H), 7.42 (s, 1H), 2.40 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H).Step 2: To the stirred solution of 4-hydroxy-2,3,5-trimethylbenzoic acid (5.2 g, 1 eq., 28.9 mmol). in N,N-dimethylformamide (52 mL) was added sodium hydrogen carbonate (4.85 g, 2 eq.. 57.7 mmol) at room temperature and then the reaction mixture was heated at 80 °C for 1 h. After 1 h, the reaction was cool-down to room temperature and was added MOMCI (3.5 g. 1.5 eq., 43.3 mmol) at room temperature and the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitor by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into ice-cold water and was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated on rotavapor to obtain the crude compound. Crude compound was purified by combi-flash chromatography to obtain methoxymethyl 4-hydroxy-2,3,5-trimethylbenzoate (4 g, 62%) as yellow liquid. LCMS m'z = 223.05 [M-H]'; 'l l NMR (400 MHz, DMSO-Je) 5 ppm 8.93 (br s. 1H), 7.48 (s, 1H), 5.35 (s, 2H), 3.44 (s, 3H). 2.40 (s, 3H), 2.18 (s. 3H), 2.14 (s, 3H).Scheme for synthesis of methoxymethyl 2-chloro-4-hydroxy-3,5,6-trimethylbenzoateStep 1: To the stirred solution of methyl 2-bromo-4-methoxy-3,5,6-trimethylbenzoate (3 g, 1 eq.. 10.4 mmol) in dimethylformamide (30 mL) was added copper dichloride (28.1 g, 20 eq., 209 mmol) at room temperature; then the reaction mixture was stirred at 140 °C for 30 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with EtOAc. Combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude material. The obtained crude compound was purified by Combi-flash to get methyl 2-chloro-4-methoxy-3,5,6-trimethylbenzoate (2.2 g, 86%) as off-white solid. 'H NMR (400 MHz, DMSO-d6): 8 3.86 (s, 3H), 3.65 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H).Step 2: To a solution of methyl 2-chloro-4-methoxy-3.5,6-trimethylbenzoate (2 g, 1 eq. 8.24 mmol) in dichloromethane (20 mL), was added BBr3 (1.0 M in DCM) (24.8 g. 12 eq.. 98.9 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was further stirred at 25 °C for 24 h. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice cold H2O and extracted with DCM. The combined organic layers were washed with Saturated brine solution, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the crude material. The obtained crude compound was purified by Combi-flash to get 2-chloro-4- hydroxy-3,5,6-trimethylbenzoic acid (1.5 g, 85%) as brown solid. LCMS m'z = 212.90 [M-H]’ . 'H NMR (400 MHz, DMSO-d6): 6 13.15 (br s, 1H). 8.93 (s, 1H). 2.21 (s, 3H), 2.16 (s. 3H), 2.09 (s, 3H).Step 3: To a solution of 2-chloro-4-hydroxy-3,5,6-trimethylbenzoic acid (1.5 g, 1 eq., 6.99 mmol) in dimethylformamide (15 mL) at 0 °C was added NaHCO3 (2.94 g, 5 eq., 34.9 mmol) at 0 °C under nitrogen atmosphere. Then, MOM-CI (1.17 g, 2 eq., 14 mmol) was added and the reaction mixture was stirred for 6 h at room temperature. The reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice cold H2O and extracted with DCM. The combined organic layers were washed with saturated brine solution, dried over Na2SO4. filtered and concentrated under reduced pressure to give the crude material. The obtained crude compound was purified bv Combi-flash to getmethoxymethyl 2-chloro-4-hydroxy-3,5,6-trimethylbenzoate (1 g, 55%) as Off-white solid.LCMS m 'z = 256.80 [M-H]’.Scheme for synthesis of methoxymethyl 2-(difluoromethyl)-4-hydroxy-3,5,6-trimethyl benzoateStep 1: To the stirred solution of methyl 2-bromo-4-methoxy-3,5,6-trimethylbenzoate (8 g, 1 eq., 27.9 mmol) in dichloromethane (80 rnL) was added tribromoborane (IM in DCM) (8.38 g, 1.2 eq., 33.4 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was further stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. The mixture was quenched with ice cold water and extracted with 10% Methanol: DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford methyl 2-bromo-4-hydroxy-3,5,6- trimethylbenzoate (7 g, 92 %) as light brown solid. LCMS m / z = 273.00 [M-H]’; 'HNMR (400 MHz, DMSO-rfe) 8 ppm 8.92 (s. 1H), 3.82 (s, 3H), 2.26 (s, 3H), 2.09 (s, 6H).Step 2: To the stirred solution of methyl 2-bromo-4-methoxy-3,5,6-trimethylbenzoate (7 g, 1 eq., 25.6 mmol) in acetone (70 mL) was added dipotassium carbonate (10.6 g, 3 eq., 76.9 mmol) at 0 °C under nitrogen atmosphere. Then, (bromomethyl)benzene (3.65 mL, 1.2 eq., 30.8 mmol) was added at 0°C and reaction mixture was stirred at 55 °C for 6 h. Progress of the reaction was monitored by TLC and LCMS. Further, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude material. The crude compound was purified by combi flash to get methyl 4-(benzyloxy)- 2-bromo-3.5.6-trimethylbenzoate (6.5 g. 70 %) as white solid. 'H NMR (400 MHz, DMSO-rfc) 8 ppm 7.51 - 7.39 (m, 5H), 4.77 (s, 2H), 3.87 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H), 2.14 (s, 3H).Step 3: To the stirred solution of methyl 4-(benzyloxy)-2-bromo-3,5,6-trimethylbenzoate (6.5 g, 1 eq., 17.9 mmol) in dimethylformamide (65 mL) was added lithium chloride (379 mg, 0.5 eq.. 8.95 mmol) under nitrogen atmosphere at room temperature. Then, mixture was degassed with nitrogen gas for 20 minutes before the addition of Bis(triphenylphosphine)palladium (II)dichloride (1.26 g, 0.1 eq., 1.79 mmol) and Tributyl(vinyl)tin (17 g, 3 eq., 53.7 mmol). Further, the resulting mixture was refluxed at 90 °C for 16 h. After complete consumption of starting material, the reaction mixture was cooled to room temperature, filtered through a celite bed. Filtrate was concentrated under reduced pressure to get the crude material. The crude residue was purified by combi-flash to afford methyl 4-(benzyloxy)-2,3,5-trimethyl-6-vinylbenzoate (3.2 g, 58%) as brown liquid. LCMS m / z = 310.85 [M+H]+; 'H NMR (400 MHz, DMSO-tL) 8 ppm 7.52 - 7.36 (m, 5H), 6.79 - 6.72 (m, 1H). 5.42 - 5.39 (m, 1H). 5.25 - 5.20 (m, 1H), 4.73 (s, 2H), 3.78 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H).Step 4: To the stirred solution of methyl 4-(benzyloxy)-2,3,5-trimethyl-6-vinylbenzoate (3.2 g, 1 eq., 10.3 mmol) in tetrahydrofuran (30 mL) and water (30 mL) at 0 °C under nitrogen atmosphere was added osmium tetroxide (3.93 g, 1.5 eq.. 15.5 mmol) dropwise at 0°C. Then, reaction mixture was stirred for 1 h at room temperature before the addition of NaIC (6.62 g, 3 eq., 30.9 mmol). Further, reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate. Collected the organic phase and concentrated under reduced pressure to get the crude material. The crude was purified by combi-flash to afford methyl 4-(benzyloxy)-2-formyl-3,5,6-trimethylbenzoate as light brown solid. LCMS m / z = 312.80 [M+H]+; 'H NMR (400 MHz, DMSO-tL) 8 ppm 10.28 (s, 1H), 7.54 - 7.38 (m, 5H), 4.79 (s, 2H), 3.82 (s, 3H), 2.56 (s, 3H), 2.28 (s, 3H), 2.13 (s, 3H).Step 5: To the stirred solution of methyl 4-(benzyloxy)-2-formyl-3.5.6-trimethylbenzoate (1.8 g, 1 eq., 5.76 mmol) in dichloromethane (20 mL) at 0 °C under nitrogen atmosphere was added N,N-diethyl(trifluorothio)amine (1.39 g, 1.5 eq., 8.64 mmol). Then, the reaction mixture was stirred at room temperature for 16 h. After the complete consumption of the starting material, the reaction mixture was quenched with water at 0 °C and extracted with ethyl acetate. Then, the combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude residue. Crude compound was purified by combi-flash to afford methyl 4-(benzyloxy)-2-(difluoromethyl)-3,5,6-trimethylbenzoate (1 g, 52 %) as colourless liquid. ’H NMR (400 MHz, DMSO-tfc) 8 ppm 7.53 - 7.50 (m. 2H), 7.46 - 7.37 (m, 3H), 7.03 (t, J= 56.0 Hz, 1H), 4.77 (s, 2H), 3.86 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 2.13 (s. 3H).Step 6: To the solution of methyl 4-(benzyloxy)-2-(difluoromethyl)-3,5,6-trimethylbenzoate (1 g, 1 eq., 2.99 mmol) in water (10 mL) and dimethyl sulfoxide (10 mL) as a solvent (1 : 1) was added lithium hydroxide (358 mg. 5 eq., 15 mmol) at room temperature. Reaction was furtherstirred at 100 °C for 16 h. After completion consumption of starting material, reaction mixture was quenched with 1 N HC1 at 0 °C. The precipitated solid was filtered and dried to afford 4- (benzyloxy)-2-(difluoromethyl)-3,5,6-trimethylbenzoic acid (0.8 g, 83%) as a white solid. LCMS m / z = 319.09 [M-H]'; 'H NMR (400 MHz, DMSO- e) 8 ppm 13.49 (br s, 1H), 7.50 (d, J= 6.8 Hz, 2H), 7.46 - 7.37 (m, 3H), 6.97 (t, J= 56.0 Hz, 1H), 4.76 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H). 2.19 (s, 3H).Step 7: To the stirred solution of methoxymethyl 4-(benzyloxy)-2-(difluoromethyl)-3,5,6- trimethylbenzoate (0.8 g, 1 eq., 2.5 mmol) in dimethylformamide (10 mL) was added sodium hydrogencarbonate (1.05 g, 5 eq., 12.5 mmol) at room temperature under nitrogen atmosphere and chloromethoxymethane (241 mg, 1.2 eq., 3 mmol) at 0 °C. Further, the reaction mixture was heated at 55 °C for 3 h. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude compound. The obtained crude material was purified by Combi-flash to get methoxymethyl 4-(benzyloxy)-2-(difluoromethyl)-3,5,6-trimethylbenzoate (0.8 g, 88 %) as white solid. LCMS m / z = 381.90 [M+NH4]+; 'H NMR (400 MHz, DMSO-t / c) 8 ppm 7.53 - 7.51 (m, 2H), 7.47 - 7.37 (m, 3H), 7.07 (t, J= 53.2 Hz, 1H), 5.44 (s, 2H), 4.77 (s, 2H), 3.46 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H), 2.18 (s, 3H).Step 8: To the stirred solution of methoxymethyl 4-(benzyloxy)-2-(difluoromethyl)-3,5,6- trimethylbenzoate (0.8 g, 1 eq., 2.2 mmol) in tetrahydrofuran (20 mL) & acetic acid (0.5 mL,) was added 10% platinum dioxide (0.8 g, w / w) to the reaction mixture at room temperature under nitrogen atmosphere. Then, the reaction mixture stirred at 20 psi hydrogen pressure at room temperature for 16 h. Progress of reaction mixture was monitor by LCMS. Catalyst was filtered on celite bed and filtrate was concentrated on rotavapor to get crude material. The above crude material was purified by combi-flash to get methoxymethyl 2-(difluoromethyl)-4- hydroxy-3,5,6-trimethylbenzoate (650 mg, 78%) as white solid. LCMS m / z = 272.90 [M-H]'; 'H NMR (400 MHz, DMSO-tT) 8 ppm 8.88 (br s, 1H), 6.98 (t, J= 53.4 Hz, 1H), 5.40 (s, 2H), 3.44 (s, 3H), 2.26 (s, 3H), 2. 15 (s, 3H), 2. 14 (s, 3H).Following the same DAST fluorination protocol, the below monomers were synthesized:Scheme for synthesis of methoxymethyl 3-bromo-5-ethyl-4-hydroxy-2-(methoxymethoxy )-6-methylbenzoateStep 1: To the stirred solution of methyl 3,5-dihydroxy-2-toluate (11 g, 1 eq., 60.4 mmol) in N,N-dimethylformamide (0.1 L) was added dipotassium carbonate (83.4 g, 10 eq., 604 mmol) and (methoxysulfonyloxy)methane (19 mL, 3 eq., 181 mmol) at room temperature. Then, reaction mixture was heated at 70 °C for 16 h. After complete consumption of starting material, reaction mixture was diluted with ethyl acetate and washed with ice cold water. Organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude compound was purified by Combi-flash chromatography over silica gel to get methyl 2,4-dimethoxy-6-methylbenzoate (9 g, 71%) as colourless semi solid. LCMS m / z = 210.75 [M+H]+; ’H NMR (400 MHz. DMSO-cfc) d ppm 6.47 (d. J= 2.16 Hz. 1H), 6.43 - 6.42 (m. 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H). 2.17 (s, 3H).Step 2: A 500 mL RBF charged with methyl 2,4-dimethoxy-6-methylbenzoate (9 g, 1 eq., 40.7 mmol) in dichloromethane (50 mL) and reaction mixture was stirred vigorously at 0 °C. Then, titanium tetrachloride (15.4 g, 2 eq., 81.3 mmol) was added drop wise. After 10 min, di chloromethoxy methane (11.7 g, 2.5 eq., 102 mmol) was added and mixture was further stirred at room temperature for 16 h until all the starting material was consumed. The reactionmixture was quenched with water and the resulting mixture was extracted with DCM. Combined organic layers were washed with brine, dried over anhydrous sodium sulphate and evaporated on rotavapor to get the crude material. The crude compound was purified by silica gel column to get methyl 3-formyl-4,6-dimethoxy-2-methylbenzoate (8 g, 83 %) as off white solid. ’H NMR (400 MHz, DMSO-cL) 3 ppm 10.38 (s, 1H), 6.74 (s, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.79 (s, 3H), 2.34 (s, 3H).Step 3: To the stirred solution of methyltriphenylphosphonium bromide (18.0 g. 1.5 eq., 50.3 mmol) in tetrahydrofuran (50 mL) was added 'BuOK (7.54 g, 2 eq., 67.2 mmol) portions under nitrogen atmosphere and the mixture was stirred at room temperature for 1 h. Then, methyl 3- formyl-4,6-dimethoxy-2-methylbenzoate (8 g, 1 eq., 33.6 mmol) (dissolved in 20 mL THF) was added to the above mixture drop wise. Further, the reaction mixture was stirred for 1 h at 60 °C. After completion of the reaction, mixture was quenched with water and extracted with EtOAc. Combined organic layers were washed with saturated NaHCCh solution, brine solution, dried over anhydrous Na2SO4 and concentrated on rotavapor to get the crude compound. Crude compound was purified by silica gel column chromatography to obtain methoxy methyl 3-ethyl- 4-hydroxy-2.6-xylenecarboxylate e (6 g, 76%) of white solid. LCMS m / z = 236.80 |M+HJ+; 'H NMR (400 MHz, DMSO- s) 3 ppm 6.66 - 6.58 (m, 2H), 5.53 - 5.41 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 2.15 (s, 3H).Step 4: To the stirred solution of methoxymethyl 3-ethyl-4-hydroxy-2,6-xylenecarboxylate (6 g, 1 eq., 25.4 mmol) in degassed EtOAc (30 mL) was added 10% Palladium on carbon (w / w, 6.0 g) under nitrogen atmosphere at room temperature. Reaction mixture was stirred under hydrogen balloon pressure at room temperature for 1 h. After complete consumption of starting material, the reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to get methyl 3-ethyl-4,6-dimethoxy-2- methyl benzoate (5.5 g, 91%) as white solid mass. 'H NMR (400 MHz, DMSO-de) 3 ppm 6.56 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 2.56 - 2.52 (m, 2H), 2.10 (s, 3H), 0.98 (t, J = 7.4 Hz, 3H).Step 5: To the solution of methyl 3-ethyl-4,6-dihydroxy-2-methylbenzoate (5.5 g, 1 eq., 23.1 mmol) in dichloromethane (50 mL) was added BBr3 (IM in DCM) (138.6 mL. 6 eq., 138.6 mmol) dropwise at 0 °C and reaction mixture was stirred at room temperature for 16 h. After complete consumption of starting material, reaction mixture was quenched with ice cold w ater and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude compound as brownsolid. The crude material was purified by Combi-flash chromatography to get methyl 3-ethyl- 4,6-dihydroxy-2-methylbenzoate (3.5 g, LCMS purity~63%) as brown solid. LCMS m / z = 210.75 [M+H]+.Step 6: To a stirred solution of methyl 3-ethyl-4,6-dihydroxy-2-methylbenzoate (3.5 g, 1 eq., 11.7 mmol) in acetic acid (24.5 mL) was added HBr (70 mL) at room temperature under nitrogen atmosphere, DMSO (24.5 mL) was added, and reaction mixture was stirred for 16 h at room temperature. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give crude compound. The crude material was purified using combi-flash column chromatography to obtain methyl 3-bromo-5-ethyl-2,4-dihydroxy-6-methylbenzoate (3 g, 60%) as yellow solid. LCMS: m / z = 288.80 [M+H]+ 1H NMR (400 MHz, DMSO- s) 5 ppm 9.93 (s, 1H), 9.17 (s, 1H), 3.81 (s, 3H), 2.64 -2.58 (m, 2H), 2.18 (s, 3H), 0.98 (t, J= 7.4 Hz, 3H)Step 7: To the stirred solution of methyl 3-bromo-5-ethyl-2,4-dihydroxy-6-methylbenzoate (3 g, 1 eq., 8.51 mmol) in acetone (50 mL) was added dipotassium carbonate (1.29 g, 1. 1 eq., 9.36 mmol) at room temperature and reaction mixture was heated at 50 °C for 2 h. After 2 h, the reaction mixture was cooled at room temperature and (bromomethyl)benzene (1.31 g, 0.9 eq., 8.5 mmol) was added. The mixture was stirred at 50 °C temperature for 6 h. After complete consumption of starting material, the reaction mixture was diluted with ethyl acetate and washed with ice cold water. Organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude compound. The crude material was purified by Combi-flash chromatography to get methyl 4-(benzyloxy)-3-bromo-5-ethyl-2- hydroxy-6-methylbenzoate (4.5 g. LCMS purity’ ~ 39 %) as white solid, which was dissolved in DMSO (18 mL) and water (18 mL). Potassium hydroxide (0.6 g, 5 eq., 12.1 mmol) was added at room temperature. The reaction mixture was heated at 100 °C for 6 h. After completion, the reaction mixture was quenched with 1 N HC1 at 0 °C and aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with cold water and dried over anhydrous sodium sulfate, filtered off and evaporated filtrate to afford the crude material as brown liquid. The material was dissolved in dichloromethane (50 mL). N,N- ethyldiisopropylamine (4.74 g, 10 eq., 36.7 mmol) at room temperature under nitrogen atmosphere. Then, chloromethoxy methane (1.77 g, 6 eq., 22.0 mmol) was added drop- ise and reaction mixture was stirred for 4 h at room temperature. After complete consumption ofstarting material, the reaction mixture was diluted with water and extracted with DCM. Combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get crude material, which was purified by normal phase column chromatography to get methoxymethyl 4-(benzyloxy)-3-bromo-5-ethyl-2-(methoxymethoxy)- 6-methylbenzoate (0.9 g, 54 %) as white solid. LCMS m,z = 452.95 [M+H]+; 'H NMR (400 MHz, DMSO- e) 5 ppm 7.56 - 7.54 (m, 2H), 7.47 - 7.39 (m, 3H), 5.44 (s, 2H), 5.05 (s. 2H), 4.95 (s. 2H). 3.47 (s. 3H), 3.46 (s. 3H), 2.71 - 2.67 (m. 2H). 2.22 (s. 3H), 1.07 (t. J = 7.6 Hz 3H).Step 8: To the solution of methoxymethyl 4-(benzyloxy)-3-bromo-5-ethyl-2- (methoxymethoxy)-6-methylbenzoate (0.9 g, 1 eq., 1.99 mmol) in degassed tetrahydrofuran (20 mL) was added 10% Palladium on carbon (0.9 g, w / w) at room temperature under nitrogen atmosphere. The reaction mixture was then hydrogenated under hydrogen balloon pressure at room temperature for 2 h. After complete consumption of starting material, reaction mixture was filtered through celite bed and washed with ethyl acetate; combined filtrates were evaporated on rotavapor to get methoxymethyl 3-bromo-5-ethyl-4-hydroxy-2- (methoxymethoxy)-6-methylbenzoate (0.7 g. 97%) as a colorless semi solid. LCMS m / z = 362.80 | M-H | 'H NMR (400 MHz, DMSO-r / e) 8 ppm 9.31 (s, 1H), 5.40 (s, 2H), 4.98 (s, 2H), 3.46 (s, 3H), 3.45 (s, 3H), 2.65 (q, J= 7.5 Hz, 2H), 2.17 (s, 3H), 1.03 (t, J= 7.4 Hz 3H).Synthesis of ethyl 3-allyl-4-(benzyloxy)-2-hydroxy-6-methylbenzoateStep 1: To the stirred solution of methyl (E)-but-2-enoate (150 g, 1.0 eq., 1.5 mol) and ethyl 3- oxobutanoate (292 g, 1.5 eq. 2.25 mol) in ethanol (3 L) was added sodium ethoxide (204 g. 2 eq. 3 mol) portion wise under nitrogen atmosphere at 0 °C. The resulting reaction mixture was heated at 85 °C for 16 h. progress of reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was cooled to room temperature and adjusted to pH ~7 using 4 M HC1 solution. Then, the reaction mixture was concentrated on rotavapor to obtain crude residue. The obtained crude material was acidifiedwith 4 M HC1 (up to pH -2) then extracted with Ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain ethyl 2-hydroxy-6-methyl-4-oxo-2- cyclohexene-1 -carboxylate (150 g, LCMS purity -60%) as yellow liquid. LCMS mJz = 198.75 [M+H]+.Step 2: To the stirred solution of ethyl 2-hydroxy-6-methyl-4-oxo-2-cyclohexene-l- carboxylate (150 g, 1.0 eq. 454 mmol) in acetic acid (2 L), was added dibromide (18.7 mL. 0.8 eq., 363 mmol) under nitrogen atmosphere at 0 °C. Further, the reaction mixture was stirred at room temperature for 16 h. Progress of reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice- cold water and extracted with ethyl acetate. The combined organic layers dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get ethyl 3-bromo-2,4- dihydroxy-6-methylbenzoate (50 g, LCMS Purity -78%) as brown solid. LCMS m / z = 272.85 [M-H]’.Step 3: To the stirred solution of ethyl 3-bromo-2,4-dihydroxy-6-methylbenzoate (50 g, 1.0 eq., 142 mmol) in acetone (1.5 L), was added disodium carbonate (22.5 g, 1.5 eq. 213 mmol) and (bromomethyl)benzene (29.1 g, 1.2 eq., 170 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 16 h. Progress of reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was filtered and washed with acetone; The filtrate was concentrated under reduced pressure to obtained crude material. The crude residue was dissolved in ethyl acetate and washed with water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material. The crude compound was purified by flash chromatography to get ethyl 4- (benzyloxy)-3-bromo-2-hydroxy-6-methylbenzoate (30 g, 58%) as a brown solid. LCMS m'z = 364.75 [M-H]’; 'H NMR (400 MHz, DMSO-tL) 6 ppm 11.44 (s, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 6.74 (s, 1H), 5.25 (s, 2H), 4.34 (q, J = 6.8 Hz, 2H), 2.41 (s, 3H), 1.32 (t, J= 12 Hz, 3H).Step 4: To the stirred solution of ethyl 4-(benzyloxy)-3-bromo-2-hydroxy-6-methylbenzoate (10 g, 1.0 eq., 27.4 mmol) in dichloromethane (100 mL) was added DIPEA (17.7 g, 5.0 eq., 137 mmol), followed by MOM-CI (2.35 mL, 1.0 eq., 27.4 mmol) dropwise under nitrogen atmosphere at 0 °C. Further, the reaction mixture was allowed to stir at room temperature for 2 h. Progress of reaction was monitored by TLC and LCMS. After complete consumption ofstarting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtained crude material. The crude compound was purified by flash chromatography to get ethyl 4-(benzyloxy)-3-bromo-2-(methoxymethoxy)-6- methylbenzoate (9.0 g, 80 %) as yellow solid. LCMS m!z = 409.08 [M-H]'.Step 5: To the stirred solution of ethyl 4-(benzyloxy)-3-bromo-2-(methoxymethoxy)-6- methylbenzoate (8.66 g, 1.0 eq., 21.2 mmol) in 1,4-dioxane (90 mL), were added [(t- Bu)3P]BF4 (1.23 g, 4.23 mmol) and DIPEA (8.21 g, 3.0 eq., 63.5 mmol) under nitrogen atmosphere at room temperature. Further, the reaction mixture was purged with nitrogen gas for 10 min. Then, Pd2(dba)3 (1.94 g, 0.1 eq.. 2.12 mmol) and allyltris(butyl)stannane (21 g, 3.0 eq.. 63.5 mmol) were added and the resulting reaction mixture was heated at 90 °C for 16 h. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude compound was purified by Combi-flash to get ethyl 3-allyl-4-(benzyloxy)- 2-(methoxymethoxy)-6-methylbenzoate (6.0 g, 77 %) as colorless liquid. LCMS m / z = 370.90 [M+H]+; 'H NMR (400 MHz, DMSO- e) 5 ppm 7.46 - 7.32 (m, 5H), 6.84 (s, 1H), 5.95 - 5.86 (m, 1H), 5.15 (s, 2H) , 4.96 - 4.89 (m, 5H), 4.27 (q, J= 7.1 Hz, 2H), 3.40 (s, 3H), 3.36 (d, J = 5.8 Hz, 2H), 2.23 (s, 3H), 1.29 (t, 7.1 Hz, 3H).Step 6: To the solution of ethyl 3-allyl-4-(benzyloxy)-2-(methoxymethoxy)-6-methylbenzoate (6.0 g, 1.0 eq., 1 .2 mmol) in DCM (30 mL) was added 4 M HO in Dioxane (30 mL) under nitrogen atmosphere at 0 °C dropwise. Further, the reaction mixture was allowed to stir at room temperature for 0.5 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to obtain the crude material. The obtained crude material was triturated with n-pentane to get ethyl 3-allyl-4-(benzyloxy)-2-hydroxy-6-methylbenzoate (5.8 g, 81%, LCMS Purirt -74%) as yellow solid. LCMS mz' = 324.95 [M-H]'.Scheme for the synthesis of 4-(benzyloxy)-6-methyl-2,3-dihydrobenzofuran-7-carboxylic acidStep 1: To the solution of ethyl 3-allyl-4-(benzyloxy)-2-hydroxy-6-methylbenzoate (2.5 g, 1 eq.. 7.66 mmol) and 4-methyl-4-morpholinium-4-olate (1.35 g, 1.5 eq., 11.5 mmol) in acetone (20 mL):water (20 mL) mixture was added osmium tetraoxide (3 mL, 4 % water solution) dropwise at 0 °C. Then, the reaction mixture was stirred at room temperature for 1. After 1 h, was added NaIO4 (1.97 g, 1.2 eq., 9.19 mmol) and the reaction mixture was stirred at room temperature for 2 h. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude material was purified by Combi-flash to get ethyl 4- (benzyloxy)-2-hydroxy-6-methyl-3-(2-oxoethyl)benzoate (1.6 g, LCMS purity ~ 47%) as white solid. LCMS m / z 328.75 [M+H]+.Step 2: To the stirred solution of ethyl 5-(benzyloxy)-4-(formylmethyl)-3-hydroxy-2-toluate (1.6 g, 1 eq., 4.87 mmol) in ethanol (10 mL) was added sodium borohydride (0.221 g, 1.2 eq., 5.85 mmol) at 0 °C. Then the reaction mixture was stirred at 0 °C for 5 min. After the complete consumption of the starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. Then, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material. Crude compound was purified by normal phase chromatography to get ethyl 4-(benzyloxy)-2- hydroxy-3-(2-hydroxyethyl)-6-methylbenzoate (1.3 g, 81 %) as white Solid. LCMS m / z = 328.95 [M-H]’: *H NMR (400 MHz. DMSO-Je) 5 ppm 7.46 - 7.32 (m, 5H), 6.53 (s, 1H), 5.17 (s, 2H), 4.97 - 4.91 (m, 1H), 4.57 (t, .7 = 8.8 Hz, 2H), 4.20 (q, .7= 7.1 Hz, 2H), 3.06 (t, .7= 8.7 Hz, 2H), 2.31 (s, 3H), 1.26 - 1.21 (m, 3H); one -OH proton is not visible.Step 3: To the stirred solution of 4-(benzyloxy)-2-hydroxy-3-(2-hydroxyethyl)-6- methylbenzoate (1.3 g, 1 eq., 3.93 mmol) in tetrahydrofuran (10 mL) was added triphenylphosphine (2.58 g, 2.5 eq., 9.84 mmol) at room temperature followed by dropwise addition of DIAD (1.19 g,1.5 g, 5.9 mmol) at 0 °C under nitrogen atmosphere. Then, the reaction mixture was stirred at room temperature for 16 h. After the complete consumption of the starting material, reaction mixture was diluted with water and extracted with DCM. Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound. Crude compound was purified by column chromatography to get ethyl 4-(benzyloxy)-6-methyl-2,3-dihydrobenzofuran-7-carboxylate (0.9 g, 73 %) as colorless liquid. ’H NMR (400 MHz, DMSO-rfe) d ppm 7.46 - 7.32 (m. 5H),6.54 (s, 1H), 5.17 (s, 2H), 4.57 (t, J= 8.7 Hz, 2H), 4.20 (q, J= 7.1 Hz, 2H), 3.07 (t, J= 8.7 Hz, 2H), 2.32 (s, 3H), 1.27 - 1.22 (m, 3H).Step 4: To the solution of ethyl 4-(benzyloxy)-6-methyl-2.3-dihydrobenzofuran-7-carboxylate (0.9 g, 1 eq., 2.88 mmol) in water (10 mL) and DMSO (10 mL) as a solvent (1 : 1) was added potassium hydroxide (1.29 g, 23 mmol) at room temperature. Reaction was further heated at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to 0 °C and 1 N HC1 was added slowly to maintain pH ~ 4. Precipitated compound was filtered through sintered funnel to get 4-(benzyloxy)-6-methyl-2,3- dihydrobenzofuran-7-carboxylic acid (0.7 g, 85%) as a white solid. LCMS m / z = 284.80 [M+H]+; 'H NMR (400 MHz, DMSO- e) 5 ppm 12.45 (br, 1H), 7.46 - 7.32 (m, 5H), 6.51 (s, 1H), 5.17 (s, 2H), 4.56 (t, J= 8.7 Hz, 2H). 3.07 (t, J= 8.7 Hz, 2H). 2.33 (s, 3H).Synthesis of 4-(benzyloxy)-2-ethoxy-6-methylbenzoic acid and 4-(benzyloxy)-2- isopropoxy-6-methylbenzoic acidFollowing the same protocol described in example 28, below two D monomers were prepared with the relevant alkyl bromideScheme for the synthesis of 4-(benzyloxy)-2-methoxy-3,6-dimethylbenzoic acidStep 1: To a stirred solution of methyl methyl 2,4-dihydroxy-3,6-dimethylbenzoate (10 g. 1.0 eq., 51 mmol) in acetone (100 mL), was added dipotassium carbonate (9.16 g, 1.3 eq., 66.3 mmol) under nitrogen atmosphere at 0°C, followed by dropwise addition of (bromomethyl)benzene (10.5 g, 1.2 eq., 61.2 mmol)..and mixture was stirred at 55 °C for 16 h. The progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material; the reaction mixture was diluted with ethyl acetate and washed with cold water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get crude material. The crude compound was purified by flash chromatography to get methyl 4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoate (11 g, 75%) as a brown solid. LCMS m / z = 285.05 [M-H]';!H NMR (400 MHz, DMSO-t / fl <5 ppm 11.25 (s, 1H), 7.46 - 7.23 (m, 5H), 6.60 (s, 1H), 5.17 (s, 2H), 3.86 (s, 3H), 2.43 (s, 3H), 2.01 (s, 3H).Step 2: To the stirred solution of methyl 4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoate (11 g, 1.0 eq., 38.4 mmol) in acetone (110 mL), was added dipotassium carbonate (15.9 g, 3.0 eq.. 1 15 mmol) under nitrogen atmosphere at room temperature. Then, iodomethane (16.4 g, 3.0 eq., 115 mmol) was added and mixture was stirred at 70 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude compound was purified by flash chromatography to get methyl 4-(benzyloxy)-2-methoxy-3,6-dimethylbenzoate (10 g, 87%) as white solid. LCMS m / z = 299.00 [M-H]'; 'H NMR (400 MHz, DMSO-Jq) 3 ppm 7.46 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 6.8 Hz, 2H), 7.35 - 7.32 (m, 1H), 6.78 (s, 1H), 5.13 (s, 2H), 3.80 (s, 3H), 3.65 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H)Step 3: To the stirred solution of methyl 4-(benzyloxy)-2-methoxy-3,6-dimethylbenzoate (10 g, 1.0 eq., 33.3 mmol ) in water (100 mL):dimethyl sulfoxide (100 mL) mixture was added, potassium hydroxide (18.7 g, 10.0 eq.. 333 mmol) . under nitrogen atmosphere at room temperature. The resulting reaction mixture was heated at 90 °C for 16 h. Progress of reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was cooled down to room temperature and acidified with IN HC1 solution to obtain precipitates. The precipitated solid was filtered and dried to get 4-(benzyloxy)-2- methoxy-3,6-dimethylbenzoic acid (4.5 g, 47%) as a white solid. LCMS m z = 285.00 [M-H]' ;XH NMR (400 MHz, DMSO-cL) 3 ppm 12.85 (br s, 1H), 7.46 (d, J= 12 Hz, 2H), 7.40 (t, J = 12 Hz, 2H), 7.35 - 7.26 (m, 1H), 6.78 (s, 1H), 5.12 (s, 2H), 3.67 (s, 3H), 2.22 (s, 3H), 2.07 (s, 3H).Scheme for the synthesis of 4-(benzyloxy)-2,6-dimethoxybenzoic acidStep 1: To the stirred solution of 2,4,6-trihydroxybenzoic acid (30 g, 1.0 eq., 176 mmol) and dipotassium carbonate (24.4 g. 1.0 eq.. 176 mmol) in dimethylformamide (120 mL) was added dimethyl sulphate (24.5 g, 1.1 eq., 194 mmol) dropwise under nitrogen atmosphere at room temperature. Further, the reaction mixture was stirred at room temperature for 6 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get methyl 2,4,6- trihydroxy benzoate (26.9 g, 83%) as ayellow solid. LCMS m / z = 183.00 [M-H]'; ’HNMR (400 MHz, DMSO-c / 6) d ppm 10.40 (s, 2H), 10.18 (s, 1H), 5.83 (s, 2H), 3.83 (s, 3H).Step 2: To the stirred solution of methyl 2.4,6-trihydroxybenzoate (20 g, 1.0 eq., 109 mmol) in acetone (120 mL) was added dipotassium carbonate (30 g, 2.0 eq., 217 mmol) under nitrogen atmosphere at room temperature. Then, benzyl bromide (14.2 ml, 1.1 eq., 119 mmol) was added and the reaction mixture was heated at 50 °C for 6h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through sintered funnel and filtrate was concentrated under reduced pressure to obtain crude compound. The obtained crude compound was purified by combi-flash chromatography to get methyl 4- (benzyloxy)-2,6-dihydroxybenzoate (10 g, 29%) as a white solid. The material was dissolved in DMF (25 mL), sodium hydride (1.53 g, 3 eq., 38.3 mmol) was added portion-wise under nitrogen atmosphere at 0 °C. Then, iodomethane (18.1 g, 10 eq., 128 mmol) was added and the reaction mixture was heated at 100 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. Combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to get methyl 4-(benzyloxy)-2,6-dimethoxy benzoate (2 g, 52%) as white solid. LCMS m / z = 303.32 [M+H]+. Step 3: To the stirred solution of methyl 4-(benzyloxy)-2,6-dimethoxy benzoate (2 g, 1.0 eq., 6.62 mmol) in mixture of dimethyl sulfoxide (20 mL) and water (20 mL) was added potassium hydroxide (3.71 g, 10 eq., 66.2 mmol) under nitrogen atmosphere at room temperature. Then, the reaction mixture was heated at 100 °C for 2 h. After complete consumption of starting material, the reaction mixture was acidified with 2 N HC1 (pH~2). The precipitated solid was filtered, washed with cold water and dried overnight under vacuum to get 4-(benzyloxy)-2.6- dimethoxybenzoic acid (1.5 g, 78%) as off-white solid. LCMS m / z = 286.95 [M-H] ;’H NMR(400 MHz, DMSO- 6) 6 ppm 12.46 (br s, 1H), 7.48 - 7.32 (m, 5H), 6.34 (s, 2H), 5.15 (s. 2H), 3.73 (s, 6H).Scheme for the synthesis of 4-(benzyloxy)-2-methyl-6-(methylthio)benzoic acidStep 1: To the stirred solution of 4-hydroxy-6-methyl-2-pyranone (25 g. 1 eq., 198 mmol) in acetone (0.5 L) was added K2CO3 (82.2 g, 3 eq., 595 mmol) under nitrogen atmosphere at room temperature. Then dimethyl sulfide (28.2 mL, 1.5 eq., 297 mmol) was added and the reaction mixture was stirred for 3 h at 80 °C. After complete consumption of starting material, reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the 4-methoxy-6-methyl-2-pyranone (22 g, 79%) as a brown semisolid. LCMS m / z = 140.80 [M+H]+; 'H NMR (400 MHz, DMSO-cfc) <5 ppm 6.07 - 6.06 (m, 1H), 5.53 - 5.52 (m, 1H), 3.79 (s, 3H), 2.17 (s, 3H).Step 2: The solution of 4-methoxy-6-methyl-2-pyranone (22 g, 1 eq., 157 mmol) in dimethyl 2-butynedioate (44 mL) was heated at 200 °C for 3 h in a Parr-apparatus. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get a crude material. The crude compound was purified by flash chromatography to get dimethyl 5-methoxy-3-methylphthalate (22 g, 59%) as a light-yellow solid. LCMS m / z = 238.85 [M+H] ; 'H NMR (400 MHz, DMSO-Je) 8 ppm 7.18 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 2.6 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.28 (s, 3H).Step 3: To the solution of dimethyl 5-methoxy-2,3-toluenedicarboxylate (22 g, 92.3 mmol) in DME (110 mL) w as added 10% aq. NaOH (0. 1 L) at room temperature. The mixture w as stirred at room temperature for 4 h. After complete consumption of starting material, the reaction mixture was acidified with 2N HC1 and aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get 5-methoxy -2 -methoxy carbonyl-3-toluic acid (20 g,97%) as off-white solid. The material was dissolved in tetrahydrofuran (0.4 L), TEA (18.7 mL, 1.5 eq., 134 mmol) and DPPA (21.1 mL, 1.1 eq., 98.1 mmol) was added dropwise under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 3 h. Further, water (170 mL) was added, and the resulting reaction mixture was stirred for 16 h at 80 °C. After complete consumption of starting material, the reaction mixture was dissolved in ethyl acetate and washed with water. Organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude compound was purified by flash chromatography to get methyl 3-amino-5-methoxy-2-toluate (9 g, 52%) as off white solid. LCMS m,z = 195.80 [M+H]+; 'H NMR (400 MHz, DMSO- 6) < ppm 6.22 (br s, 2H), 6.15 (d. J = 2.4 Hz, 1H), 6.02 - 6.00 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.31 (s, 3H).Step 4: To the stirred solution of methyl 3-amino-5-methoxy-2-toluate (3 g, 1.0 eq., 15.4 mmol) in water (30 mL) at -5 °C was added Cone. HC1 (3.0 mL). Then, NaNCh (5.3 g, 5 eq., 76.8 mmol) (dissolved in 10 mL water) was added dropwise at same temperature. Further, the reaction mixture was stirred for 10 min and Potassium ethyl xanthate (4.93 g, 2 eq., 30.7 mmol) (dissolved in 20 mL water) was added dropwise. Then, the reaction mixture was stirred for 3 h at 80 °C. After complete consumption of starting material, the reaction mixture was extracted with di-ethyl ether. Combined organic layers were, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtained methyl 2- ((ethoxycarbonothioyl)thio)-4-methoxy-6-methylbenzoate (3 g. LCMS purity~48%) as a brick red semisolid. LCMS m / z = 298.90 [M-H]‘.Step 5: To the stirred solution of methyl 3-[ethyloxy(thiocarbonyl)thio]-5-methoxy-2-toluate (3 g, 1.0 eq., 4.79 mmol) in EtOH (30 mL), was added KOH (1.08 g, 4 eq.. 19.2 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with di-ethyl ether. Combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material. The crude compound was purified by Combi-flash to get methyl 2-mercapto-4-methoxy-6- methylbenzoate (0.6 g, LCMS purity~29%) as a yellow semisolid. LCMS m / z = 210.90 [M- HJ-.Step 6: To the suspension of NaH (339 mg, 3 eq., 8.48 mmol) in DMF (15 mL) was added methyl 3-mercapto-5-methoxy-2-toluate (0.6 g, 1.0 eq., 2.83 mmol) (dissolved in 5 mL DMF) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 20 min at roomtemperature. Then, Mel (880 pL, 5 eq., 14.1 mmol) was added and the reaction mixture was stirred at 70 °C for 16 h. After complete consumption of starting material, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. Organic layer was washed with ice-cold water, dried over anhydrous sodium sulphate, fdtered and concentrated under reduced pressure to obtained crude material. The crude was purified by Combi-flash to get methyl 4- methoxy-2-methyl-6-(methylthio)benzoate (0.6 g, 17% overall yield) as a light-yellow semisolid. The material was dissolved in DCM (5 mL). BBrs (1 M in DCM) (2.7 mL, 1.2 eq.. 2.7 mmol) was added under nitrogen atmosphere at 0 °C. Then, the reaction mixture was stirred at 45 °C for 16 h. After complete consumption of starting material, the reaction mixture was cooled to room temperature, quenched with ice cold water. The aqueous layer was washed with ethyl acetate and lyophilized to get 4-hydroxy-2-methyl-6-(methylthio)benzoic acid (550 mg, 73%) as an off-white solid, which was then dissolved in DMF (10 mL). NaHCO? (2.33 g, 10 eq., 27.7 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture was stirred for 1 h at 55 °C. The reaction mixture was cooled to room temperature and M0MC1 (268 mg, 1.2 eq., 3.33 mmol) was added. The reaction mixture was stirred for 2 h at room temperature. After complete consumption of starting material, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Combined organic layers were washed with ice cold water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtained crude material. The crude was purified by Combi-flash to get methoxymethyl 4-hydroxy-2-methyl-6-(methylthio)benzoate (350 mg, 84%) as a lightyellow semisolid. LCMS m / z = 242.70 [M+H]+; 'H NMR (400 MHz, DMSO- e) <5 ppm 9.94 (s, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.48 (d, J= 2.0 Hz, 1H), 5.38 (s, 2H), 3.47 (s, 3H), 2.39 (s, 3H), 2.22 (s, 3H).Step 7: To the stirred solution of methoxymethyl 4-hydroxy-2-methyl-6-(methylthio)benzoate (350 mg, 1.0 eq., 1.44 mmol) in acetone (8 mL) was added dipotassium carbonate (599 mg, 3 eq., 4.33 mmol) under nitrogen atmosphere at room temperature followed by dropw ise addition of BnBr (296 mg, 1.2 eq., 1.73 mmol) at room temperature. The reaction mixture was stirred for 2 h at 55 °C. After complete consumption of starting material, the reaction mixture was filtered through sintered and washed with acetone. Filtrate was concentrated under reduced pressure to get crude material. The crude was purified by Combi-flash to get methoxymethyl 4-(benzyloxy)-2-methyl-6-(methylthio)benzoate (0.3 g, 73%) as an off-white solid. The material was dissolved in DCM (5 mL), 4M-HC1 in Dioxane (2.5 mL) was added under nitrogen atmosphere at 0 °C and the reaction mixture was stirred for 1 h at room temperature.After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to obtain crude material. The crude compound was triturated with n-pentane to get 4-(benzyloxy)-2-methyl-6-(methylthio)benzoic acid (280 mg, 97%) as an off-white solid. LCMS m / z = 288.75 [M+H]’; 'H NMR (400 MHz, DMSO-ty) b ppm 13.02 (s, 1H), 7.47 - 7.45 (m, 2H), 7.43 - 7.39 (m, 2H), 7.36 - 7.34 (m, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.74 (d, J = 1.9 Hz. 1H), 5.16 (s, 2H), 2.40 (s, 3H), 2.26 (s, 3H).Scheme for the synthesis of 4-(benzyloxy)-2-(dimethyIamino)-6-methylbenzoic acidStep 1: To the stirred solution of methyl 3-amino-5-methoxy-2-toluate (7 g, 1.0 eq., 35.9 mmol) in DMF (70 mL), was added sodium hydride (2.58 g, 3 eq., 108 mmol) under nitrogen atmosphere at 0 °C and reaction mixture was stirred for 15 minutes. After 15 minutes, Mel (11.2 mL, 5 eq., 179 mmol) was added and then the reaction mixture was stirred for 3 h at room temperature. After complete consumption of starting material, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get a crude compound. The obtained crude material was purified by flash column chromatography to afford methyl 3-(dimethylamino)-5-methoxy-2-toluate (4.4 g, 55%) as colourless liquid. LCMS m / z = 223.80 [M+H]+; 'H NMR (400 MHz, DMSO-ty) 5 ppm 6.38 (d, J= 1.6 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.67 (s, 6H), 2.15 (s, 3H).Step 2: To the stirred solution of methyl 3-(dimethylamino)-5-methoxy-2-toluate (4.4 g, 1 eq., 19.7 mmol) in DCM (176 mL) was added BBr3 (1.0 M in DCM) (59.2 g, 12 eq., 236 mmol) dropwise at 0 °C and then the reaction mixture was stirred at room temperature for 50 h. After completion consumption of starting material, the reaction mixture was quenched with ice cold water and extracted with 10% Methanol in DCM. Combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to get crude compound. The obtained crude material was triturated with n-pentane and diethyl ether to afford 3-(dimethylamino)-5- hydroxy-2-toluic acid (4.4 g, LCMS purity ~49 %) as yellow solid. The material was dissolved in DMF (20 mL), sodium hydrogencarbonate (8.61 g, 5 eq., 102 mmol) was added and the reaction mixture was heated at 70 °C for Ih; Further, the reaction mixture was cooled to room temperature and MOMC1 (1.98 g, 1.2 eq., 24.6 mmol) was added. Then, the reaction mixturewas stirred for 3 h at room temperature. After complete consumption of starting material, the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude compound, which was was purified by Combi-flash to get methoxymethyl 3-(dimethylamino)-5-hydroxy-2-toluate (2.6 g, 53%) as white solid. LCMS m / z = 239.80 [M+H]+; 'H NMR (400 MHz, DMSO- e) 5 ppm 9.56 (s, 1H), 6.28 (d, J= 2.1 Hz, 1H), 6.23 (d, J= 1.8 Hz. 1H), 5.34 (s, 2H), 3.44 (s, 3H), 2.64 (s, 6H). 2.13 (s, 3H).Step 3: To the stirred solution of methoxymethyl 3-(dimethylamino)-5-hydroxy-2-toluate (1.5 g, 1.0 eq., 6.27 mmol) in acetone (30 rnL), was added dipotassium carbonate (4.33 g, 5 eq., 31.3 mmol) under nitrogen atmosphere at room temperature. The resulting reaction mixture was heated at 50 °C for 30 minutes. After 30 minutes, reaction mixture was cooled to 0 °C and (bromomethyl)benzene (2.14 g, 2 eq., 12.5 mmol) was added. Then, the reaction mixture was heated at 50 °C for 16 h. After complete consumption of starting material, the reaction mixture was cooled to room temperature, filtered through a sintered funnel and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give the crude material. The crude residue was dissolved in ethyl acetate and washed with water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to crude material. The crude compound was purified by flash chromatography to get methoxymethyl 5-(benzyloxy)-3-(dimethylamino)-2-toluate (2 g, 97%) as white solid. The material was dissolved in 3M HC1 in CPME (20 mL), was stirred at room temperature for 10 minutes. The progress of the reaction was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was directly concentrated under reduced pressure to get crude compound. The obtained crude material was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get 5-(benzyloxy)-3-(dimethylamino)-2-toluic acid (1.5 g, 86%) as white solid. LCMS m / z = 285.85 [M+H]+.Scheme for the synthesis of 2-(benzyl(methyl)amino)-4-(benzyloxy)-6-methylbenzoic acidStep 1: To the stirred solution of methyl 3-amino-5-methoxy-2-toluate (10 g, 1.0 eq., 51.2 mmol) in EtOH (100 mL) was added ZnCk (14 g, 2 eq., 102 mmol) and benzaldehyde (7.84 mL, 1.5 eq., 76.8 mmol) under nitrogen atmosphere at 0 °C. Further, the reaction mixture was stirred at room temperature for 1 h. Then, NaCNBHi (9.66 g, 3 eq., 154 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layers were washed with brine solution and water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtained crude material. The obtained crude material was purified by Combi-flash to get methyl 2- (benzylamino)-4-methoxy-6-methylbenzoate (10 g, 68%) as yellow liquid. LCMS m / z = 285.85 [M+H]+; 'H NMR (400 MHz, DMSO-cL) d ppm 7.54 (t, J= 5.7 Hz, 1H), 7.35 - 7.34 (m. 4H), 7.27 - 7.24 (m. 1H), 6.07 (d, J = 2.4 Hz, 1H). 5.98 (d, J = 2.4 Hz, 1H), 4.39 (d, J = 5.7 Hz, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 2.34 (s, 3H).Step 2: To the suspension of 60% NaH (2.8 g, 2 eq., 70.1 mmol) in DMF (100 mL) was added methyl 2-(benzylamino)-4-methoxy-6-methylbenzoate (10 g, 1.0 eq., 35 mmol) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 40 min at the same temperature. Then, Mel (10.9 mL, 5 eq., 175 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to obtained crude material. The obtained crude material was purified by Combi-flash chromatography to get methyl 2-(benzyl(methyl)amino)-4-methoxy-6-methylbenzoate (10 g, 95%) as yellow liquid. LCMS m / z = 299.85 [M+H]+; 'H NMR (400 MHz, DMSO-cL) 6 ppm 7.35 - 7.22 (m. 5H), 6.51 (d, J = 2.2 Hz, 1H), 6.48 (d, J = 1.8 Hz, 1H), 4.11 (s, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 2.57 (s, 3H), 2.17 (s, 3H).Step 3: To the stirred solution of methyl 2-(benzyl(methyl)amino)-4-methoxy-6- methylbenzoate (2.0 g, 1.0 eq., 6.68 mmol) in DCM (80 mL) was added IM BBrs in DCM (2.51 g, 1.5 eq., 10 mmol) under nitrogen atmosphere at 0 °C. Further, the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice water and extracted with DCM. Combined organic layers were washed with water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material. The obtained crude was purified by Combi-flash chromatography to get methyl 2-(benzyl(methyl)amino)-4-hydroxy-6-methylbenzoate (0.8 g, 36%) as off-white solid. LCMS m / z = 285.85 [M+H]+.Step 4: To the stirred solution of methyl 2-(benzyl(methyl)amino)-4-hydroxy-6- methylbenzoate (0.8 g, 1.0 eq., 2.8 mmol) in acetone (10 mL) was added K2CO3 (1.16 g, 3.0 eq., 8.41 mmol) under nitrogen atmosphere at room temperature. Then, BnBr (0.4 mL, 1.2 eq., 3.36 mmol) was added dropwise and the reaction mixture was heated at 55 °C for 3 h. After complete consumption of starting material, the reaction mixture was cooled to room temperature and filtered through sintered. The filtrate was concentrated under reduced pressure to obtain crude material. The obtained crude was purified by Combi-flash chromatography to get methyl 2-(benz l(methyl)amino)-4-(bcnz loxy)-6-melhylbcnzoate (0.7 g, 60%) as a colourless liquid. LCMS m / z = 376.00 [M+H]+; ’H NMR (400 MHz. DMSO-t / e) d ppm 7.41- 7.21 (m, 10H). 6.60 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 1.9 Hz. 1H), 5.07 (s. 2H), 4.10 (s. 2H), 3.75 (s, 3H), 2.58 (s, 3H), 2.16 (s, 3H).Step 5: To the stirred solution of methyl 2-(benzyl(methyl)amino)-4-(benzyloxy)-6- methylbenzoate (0.7 g, 1.0 eq., 1.68 mmol) in DMSO (9 mL) :H2O (1 mL) mixture was added KOH (471 mg. 5 eq.. 8.39 mmol) under nitrogen atmosphere at room temperature. Further, the reaction mixture was heated at 110 °C for 24 h. After complete consumption of starting material, the reaction mixture was quenched with water, the aqueous layer was acidified with IN HC1, and extracted with ethyl acetate. Combined organic layers were washed with ice water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get 2-(benzyl(methyl)amino)-4-(benzyloxy)-6-methylbenzoic acid (0.5 g, 74%) as a colorless semi-solid. LCMS m / z = 361.95 [M+H]+; 'H NMR (400 MHz, DMSO-t / e) 6 ppm 14.12 (br s, 1H), 7.46 - 7.19 (m, 10H), 6.79 (s, 1H), 6.67 (s, 1H), 5.12 (s, 2H), 4.13 (s, 2H), 2.58 (s, 3H), 2.31 (s. 3H).Synthesis of 1, 2, 4, 6- tetramethylcyclohexa-2,5-diene-l -carboxylic acidAmmonia gas was condensed into a two neck 500 ml RBF fitted with guard tube at -78 °C. Then, the solution of 1-mesitylenecarboxylic acid (4 g, 24.4 mmol) in tetrahydrofuran (12 mL) was added dropwise to the above condensed ammonia. Further, Li metal granules (purchased from Aldrich) (775 mg, 4 eq., 97.4 mmol) was added portion wise (Observation: After addition, blue coloration of reaction mixture was observed) to the above mixture and then, the reaction was stirred at -78 °C for 30 minutes. Then, Mel (9.1 mL, 6 eq., 146 mmol) was added dropwise at same temperature until the blue color disappeared and yellow color appeared. The mixture was stirred one more hour at -78 °C. Reaction mixture was warmed to room temperature slowly that leads to the evaporation of ammonia. Obtained residue was diluted with water and extracted with Diethyl ether; Further, aqueous layer was acidified with 1 N HC1 (pH -2-3) and extracted with diethyl ether. Combined organic layers were dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain crude material. Purification was done by Reverse-phase chromatography using gradient (Cl 8 column, 0.1M Ammonium Acetate in acetonitrile) to obtained l,2,4,6-tetramethyl-2,5-cyclohexadiene-l-carboxylic acid (1.8 g, 41%) as an off white solid. LCMS m / z = 179.20 [M-H]’; 1H NMR (400 MHz, DMSO-c / 6) S ppm 12.31 (s, 1H). 5.44 - 5.40 (m, 2H). 2.70 - 2.68 (br m, 1H), 1.61 (s, 6H), 1.21 (d, J = 6.8 Hz Hz, 3H), 1.00 - 0.97 (m, 3H).Scheme for the synthesis of 2,6-diethyl-l-methylcyclohexa-2,5-diene-l-carboxylic acidStep 1: To the stirred solution of 2-bromo-1.3-diethylbenzene (5 g. 1 eq., 23.5 mmol) in dry tetrahydrofuran (50 mL) at -78 °C under nitrogen atmosphere was added n-BuLi (4.51 g, 3 eq., 70.4 mmol) dropwise and the reaction mixture was stirred at -78 °C for 1 h. After 1 h, dryice (5 g) was added, and the reaction mixture was stirred at -78 °C for 1 h. After complete consumption of starting material, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure to get crude material. The obtained Crude material was triturated with pentane to afford to 2, 6-di ethylbenzoic acid (4.0 g, 96%) as light yellow solid. LCMS m / z = 177.10 [M-H]’; 'H NMR (400 MHz, DMSO-rfc) 5 ppm 13.10 (br s, 1H), 7.27 (t, J= 7.6 Hz, 1H), 7.11 - 7.09 (m, 2H), 2.60 - 2.54 (m, 4H), 1.16 - 1.11 (m, 6H).Step 2: Ammonia gas was condensed into a two neck 250 mL RBF fitted with guard tube at - 78 °C. Then, the solution of 2,6-diethylbenzoic acid (3 g, 3 eq., 16.8 mmol) in tetrahydrofuran (2 mL) was added dropwise to the above condensed ammonia solution. Further, Li-Metal (156 mg, 4 eq., 22.4 mmol) was added portion wise to the above mixture and the reaction was stirred at -78 °C for 30 minutes. After 30 minutes, iodomethane (4.78 g, 6 eq., 33.7 mmol) was added dropwise and the reaction mixture was stirred at -78°C for 2 h. After completion of the reaction, the reaction mixture was warmed to room temperature slowly that leads to the evaporation of ammonia. Obtained residue was diluted with water and extracted with Diethyl ether; Further, aqueous layer was acidified with 1 N HC1 and extracted with ethyl acetate. Combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 2, 6-diethyl-l-methyl-2,5-cyclohexadiene-l-carboxylic acid (750 mg, 69%) as yellow solid. 'H NMR (400 MHz, DMSO-r / e) d ppm 12.30 (br s, 1H), 5.56 - 5.50 (m, 2H), 2.68 (s, 2H), 2.03 - 1.91 (m, 2H), 1.84- 1.74 (m, 2H), 1.20 (s, 3H), 1.02 - 0.99 (m, 6H).Scheme for the synthesis of methoxymethyl l-(difluoromethyl)-2,6-dimethylcyclohexa-2,5-diene-l-carboxylate and methoxymethyl 4-(difluoromethyl)-2,6-dimethylcyclohexa-2,5-diene-l-carboxylateStep 1: Ammonia gas was condensed into a two neck 1 L RBF fitted with guard tube at -78 °C. Then, the solution of 2,6-dimethylbenzoic acid (25 g, 1.0 eq., 166 mmol) in tetrahydrofuran (25 mL) was added dropwise to the above condensed ammonia RBF. Further, Li metal granules (purchased from Aldrich) (5.29 g, 4.0 eq., 666 mmol) was added portion wise (Observation: After addition, blue coloration of reaction mixture was observed) to the above mixture and the reaction was stirred at -78 °C for 30 minutes. Further, tert-butyl alcohol (20 mL) was added dropwise at same temperature until the blue color disappeared and yellow color observed. The reaction mixture was stirred one more hour at -78 °C. After 1 h, the reaction mixture waswarmed to room temperature slowly that leads to the evaporation of ammonia. Obtained residue was diluted with water and extracted with Diethyl ether; Further, aqueous layer was acidified with IN HC1 (pH ~2-3) and extracted with diethyl ether. Combined organic layers were dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain crude compound. The obtained crude compound was triturated with hexane and dried to get 2,6- dimethylcyclohexa-2,5-diene-l -carboxylic acid (20 g, 78%) as brown solid. LCMS m / z = 153.30 [M+H]+; 'H NMR (400 MHz, DMSO-Js) d ppm 12.38 (br s, 1H), 5.56 (s, 2H), 3.33 - 3.29 (br m, 1H), 2.62 (s, 2H), 1.66 (s, 6H).Step 2: To the stirred solution of 2, 6-dimethylcy cl ohexa-2,5-diene-l -carboxylic acid (20 g, 1.0 eq.. 131 mmol) in dimethylformamide (400 mL), was added NaHCCh (33.1 g, 3.0 eq., 394 mmol) and the reaction mixture was heated at 60 °C for 30 min. After 30 min, the reaction mixture was cooled to 0 °C and MOM-CI (1 1.6 g, 1.1 eq., 145 mmol) was added dropwise under nitrogen atmosphere at 0 °C. Further, the reaction mixture was heated at 80 °C for 5 h. The reaction progress was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was diluted with ice-cold water and extracted with diethyl ether. Combine organic layers were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to obtained crude compound. The obtained crude compound was purified by combi-flash chromatography to get methoxymethyl 2,6-dimethylcyclohexa- 2,5 -diene- 1 -carboxylate (20 g, 77%) as colorless liquid. LCMS m / z = 197.20 [M+H]+; *HNMR (400 MHz. DMSO-O d ppm 5.61 (br s, 2H), 5. 19 (s, 2H), 3.49 - 3.46 (br m, 1H). 3.34 (s, 3H), 2.71 - 2.56 (br s, 2H), 1 .66 (s, 6H).Step 3: In a flame-dried Schlenk tube, methoxymethyl 2,6-dimethylcyclohexa-2,5-diene-l- carboxylate (2.00 g, 1 Eq, 10.2 mmol) was dissolved in THF (20 mL) and Hexamethyldisilazane sodium salt solution (2.24 g, 6.11 mL, 2 M, 1.2 Eq, 12.2 mmol) was added dropwise over 10 min at -78 C. After 30 min at the same temperature (bromodifluoromethyl)trimethylsilane (3.10 g, 2.72 mL, 1.5 Eq, 15.3 mmol) was added at the same temperature. After 30 min, the mixture w as allowed to warm up to room temperature. The solution was quenched with sat. NHrCl (10 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were ashed with brine (25 mL), dried over MgSO-i. filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain an inseparable mixture of methoxymethyl l-(difluoromethyl)-2,6- dimethylcyclohexa-2,5-diene-l -carboxylate and methoxy methyl 4-(difluoromethyl)-2,6- dimethylcyclohexa-2,5-diene-l -carboxylate (~1:4 ratio, 45%, 1.13 g) as a colourless oil. 'HNMR (400 MHz, CDCh) 5 6.21 (t, J= 55.3 Hz). 5.92 (s), 5.72 (ddd, J= 57.5, 56.5, 6.6 Hz, 4H), 5.53 - 5.45 (m), 5.37 (d, J= 1.6 Hz). 5.32 (s), 3.53 (s). 3.48 (s), 2.74 (ft. J= 3.8, 1.9 Hz), 2.51 - 2.27 (m), 1.99 (s), 1.82 (s), 1.78 (p, J= 1.4 Hz);19F NMR (376 MHz, CDCh) 5 -1 15.84 - -122.79 (m), -126.04 (d, J= 55.3 Hz).Scheme for the synthesis of benzyl 4-hydroxy-2-methoxy-6-methylbenzoateStep 1: To the stirred solution of 2,4-dihydroxy-6-methylbenzoic acid (15 g, 1 eq., 89.2 mmol) in DMF (60 mL) was added NaHCCh (11.2 g, 1.5 eq., 1.34 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 70 °C for 45 min. Further, the reaction mixture was cooled at room temperature and Benzyl bromide (16.8 g. 1. 1 eq., 98. 1 mmol) was added dropwise. The reaction mixture was stirred at 60 °C for 2 h. Progress of reaction was monitored by LCMS. Reaction mixture diluted with ice cold water and aqueous layer was extracted with EtOAc; The combined organic layers were washed with ice cold brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude residue. The crude residue was purified by column chromatography to give benzyl 2,4- dihydroxy-6-methylbenzoate (9.5 g, 42%) as white solid. The material was dissolved in DCM (200 mL), were added DIPEA (14.3 g, 3.0 eq., 110 mmol) and MOM-CI (3.6 g, 1.1 eq., 40.5 mmol) at 0°C. Further, the reaction was allowed to stir at room temperature for 3 h. Progress of the reaction was monitored by TLC. After completion, the reaction was diluted with water and extracted with DCM. Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to benzy l 2-hydroxy-4- (methoxymethoxy)-6-methylbenzoate (6 g, 54%) as white solid. 'H NMR (400 MHz, DMSO- d6) d ppm 10.47 (s, 1H), 7.46 (d, J = 7.2 Hz. 2H), 7.41 - 7.33 (m, 3H). 6.42 (d, J = 2.0 Hz, 1H), 6.39 (s, 1H) 5.38 (s, 2H), 5.17 (s, 2H), 3.36 (s, 3H), 2.22 (s, 3H).Step 2: To the stirred solution of benzyl 2-hydroxy-4-(methoxymethoxy)-6-methylbenzoate (6 g, 1 eq., 19.8 mmol) in acetone (100 mL) was added dipotassium carbonate (13.7 g, 5 eq., 99.2 mmol) and iodomethane (8.45 g, 3.0 eq., 59.5 mmol) at 0 °C. Then, mixture was stirred at 70°C for 6 h. After complete consumption of starting material, the reaction mixture was concentrated on rotavapor to get the crude material. Further, crude compound was diluted with water andextracted with ethyl acetate; Combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the benzyl 2- methoxy-4-(methoxymethoxy)-6-methylbenzoate (6 g, 96%) as brown semi-solid compound. The material was dissolved in dichloromethane (20 mL) 4N HC1 in Dioxane (30 mL) was added at 0°C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 3 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was diluted with ice cold water and extracted with DCM; combined organic layers were washed with brine solution, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give benzyl 4-hydroxy-2-methoxy-6- methylbenzoate (1.7 g, 33%) as a white solid. LCMS m / z = 273.05 [M+H]+; 'H NMR (400 MHz, DMSO-tL) 8 ppm 9.78 (s. 1H), 7.43 - 7.33 (m. 5H), 6.28 (s. 1H), 6.21 (s, 1H), 5.24 (s, 2H), 3.69 (s, 3H), 2.07(s, 3H).Scheme for the synthesis of benzyl 5-hydroxy-3,4,6-trimethylpicolinateStep 1: To the stirred solution of (5-hydroxy-6-methylpyridine-3,4-diyl)dimethanol (100 g, 591 mmol) in Thionyl chloride (0.3 L) at room temperature was added cat. N,N- dimethylformamide (4.58 mL, 0.1 eq., 59.1 mmol) and the reaction mixture was heated at 80 °C for 3 h. The precipitated compound was filtered through sintered funnel and obtained solid compound was stirred in diethyl ether for 30 minutes, filtered and dried to afford 4,5- bis(chloromethyl)-2-methylpyridin-3-ol hydrochloride salt (110 g, 77 %) as yellow solid;1H NMR (400 MHz, DMSO-d6) 6 ppm 8.43 (s, 1H), 5.00 (s, 2H), 4.97(s, 2H), 2.65 (s, 3H).Step 2: To the stirred solution of 4.5-bis(chloromethyl)-2-methylpyridin-3-ol (110 g, 1 eq., 534 mmol) in acetic acid (440 mL) was added Zinc dust (105 g, 3 eq., 1.6 mol) portion wise at room temperature and then the reaction mixture was stirred at 80 °C for 2 h. The reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was concentrated underreduced pressure to get the crude material. Further, crude compound was diluted with water and aqueous layer was quenched with sat. NaHCO3 solution, extracted with ethyl acetate. Combined organic layers were dried over anhydrous sodium sulfate, filtered & concentrated under reduced pressure to get crude compound. The above crude material was purified with Combi-flash chromatography to afford 2,4,5-trimethylpyridin-3-ol (60 g, 81%) as off-white solid. LCMS m / z = 138.30 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 ppm 8.50 (br s. 1H), 7.72 (s. 1H), 2.31 (s. 3H), 2.13 (s, 3H), 2.09 (s, 3H).Step 3: To a stirred solution of 2,4,5-trimethyl-3-pyridinol (25 g, 1 eq., 182 mmol) in tetrahydrofuran (120 mL) was added l,3-Dibromo-5,5-Dimethylhydantoin (52.1 g, 1 eq., 182 mmol) portion wise at room temperature and then the reaction mixture was stirred at room temperature for 30 min. After completion, reaction mixture was concentrated under reduced pressure and poured into ice-cold water; the solid obtained was filtered and washed with n- pentane to afford 6-bromo-2,4,5-trimethyl-3-pyridinol (28 g, 71%) as light brown solid. The material was dissolved in DCM (280 mL), N-ethylbis(isopropyl)amine (90.5 mL, 4 eq., 518 mmol) and chloromethoxymethane (14.8 mL, 1.5 eq., 194 mmol) were added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. After complete consumption of starting material, reaction mixture was poured into cold water anf extracted with DCM. The combined organic layers w ere dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude material. The crude compound was purified by column chromatography to 2-bromo-5-(methoxymethoxy)-3,4,6-trimethylpyridine (22 g, 62%) light yellow oil. LCMS m / z = 261.85 [M+H]+; ‘H NMR (400 MHz, DMSO-d6) 5 ppm 4.95 (s, 2H), 3.51 (s, 3H), 2.35 (s, 3 H), 2.25 (s, 3H), 2.22 (s, 3H),Step 4: To the stirred solution of 2-bromo-5-methoxymethoxy-3,4,6-trimethylpyridine (10 g, 1 eq.. 38.4 mmol) in 1.4-dioxane (0.2 L) and water (60 mL) in a seal tube at room temperature was added disodium carbonate (12.2 g, 3 eq., 1 15 mmol) under nitrogen atmosphere. The reaction mixture was purged for 30 min before the addition of Mo(CO)6 (6.09 g, 0.6 eq., 23.1 mmol) and Hermann’s catalyst (3.64 g, 0.1 eq., 3.84 mmol) at room temperature. Further, the reaction mixture was heated at 100 °C for 16 h. Progress of reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was filtered over celite bed to remove catalyst and washed celite bed by methanol. Then the filtrate was concentrated under vacuum to afford brown residue. To this was added w ater and ether washes were given to aqueous layer to remove non-polar impurities. The compound in aqueous layerwas then concentrated under vacuum to afford 5-(methoxymethoxy)-3,4,6-trimethylpicolinic acid (10 g, 90%) as brown solid. LCMS m / z = 225.35 [M+H]+.Step 5: To the stirred solution of 5-methoxymethoxy-3,4,6-trimethyl-2-pyridinecarboxylic acid (10 g, 1 eq., 44.4 mmol) in acetone (0.1 L) at room temperature was added dipotassium carbonate (9.2 g, 1.5 eq., 66.6 mmol) 0 °C under nitrogen atmosphere. Then, (bromomethyl)benzene (9.87 g, 1.3 eq., 57.7 mmol) was added and the reaction mixture was stirred at 55 °C for 8 h. After complete consumption of starting material, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude material was purified by Combi-flash to get benzyl 5-methoxymethoxy-3,4,6-trimethyl-2-pyridinecarboxylate (6.5 g, 46%) as white solid. The material was dissolved in DCM (30 mL), 4 M HC1 in Dioxane (30 mL, 25 eq., 515 mmol) was added dropwise at 0°C and then the reaction mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC & LCMS. The reaction mixture was concentrated directly under reduced pressure to afford benzyl 5-hydroxy-3.4,6-trimethylpicolinate (4.5 g, 80%) as white solid. LCMS m / z = 271.95 |M+H]+.XH NMR (400 MHz, DMSO-d6) 5 ppm 10.14 (br s, 1H), 7.49 - 7.36 (m, 5H), 5.38 (s, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H).Scheme for the synthesis of methoxymethyl 4-hydroxy-2,6-dimethoxy-3,5- dimethylbenzoateStep 1: To the stirred solution of methyl 2,4,6-trihydroxybenzoate (20 g, 109 mmol) in acetone (200 mL). was added K2CO3 (18 g, 1.2 eq., 130 mmol) followed by dropwise addition of Benzyl bromide (14.2 mL, 1.1 eq., 119 mmol) and mixture was stirred at 55 °C for4h. Progress of reaction was monitored by LCMS. Reaction mixture was filtered, and solid residue was washed with acetone (200 mL). Filtrate was concentrated under reduced pressure to get the crude material. The crude residue was purified by column chromatography (EA: Heptane; 5%) to give methyl 4-(benzyloxy )-2,6-dihydroxybenzoate (12 g, 40%) as white solid. LCMS m / z =275. 15 [M+H]+;NMR (400 MHz, DMSO-rL) 8 ppm 10.47 (s, 2H), 7.42-7.32 (m, 5H), 6.05 (s, 2H), 5.07 (s, 2H). 3.83 (s. 3H).Step 2: To the stirred solution of methyl 4-(benzyloxy)-2,6-dihydroxybenzoate (12 g, 43.8 mmol) in acetonitrile (114 mL), was added NBS (23.4 g, 3 eq., 131 mmol) at 0 °C and then the reaction mixture was stirred for 16 h at room temperature. The progress of reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (30 mL x 2). Combined organic extracts were dried over anhydrous sodium sulphate, fdtered and concentrated under reduced pressure to give methyl 4-(benzyloxy)-3,5-dibromo-2,6-dihydroxybenzoate (15 g, 79%) as white solid. LCMS m / z = 428.8 [M-H]'; ’H NMR (400 MHz. DMSO- e) 8 ppm 10.73 (s, 2H), 7.58 (d, J = 6.84 Hz. 2H), 7.46-7.36 (m. 3H), 4.99 (s, 2H), 3.93 (s, 3H).Step 3: To the stirred solution of methyl 4-(benzyloxy)-3,5-dibromo-2,6-dihydroxybenzoate (15 g, 34.7 mmol) in DMF (125 mL), were added K2CO3 (9.6 g, 2 eq., 69.4 mmol) and DMS (7.07 mL, 2.1 eq., 72.9 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The reaction progress was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was quenched with water (300 ml) and the aqueous phase was extracted with ethyl acetate (200 ml x 2). Combined organic phases were washed with cold water and brine (100 ml x 3). Further, the organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material. The crude was purified by combi-flash using elution gradient (2-5% ethyl acetate in hexane) to get methyl 4-(benzyloxy)-3,5-dibromo-2,6- dimethoxybenzoate (10 g, LCMS Purity ~ 58%) colorless liquid. LCMS m / z = 458.9 [M+H]+. Step 4: To the stirred solution of methyl 4-(benzyloxy)-3,5-dibromo-2,6-dimethoxybenzoate (5 g, 1 eq., 10.9 mmol) in toluene (45 mL) and water (5 mL) under argon purging were added K.2CO3 (4.51 g, 3 eq., 32.6 mmol), cataCXium-A-Pd-G3 (791 mg, 0.1 eq., 1.09 mmol) and methylboronic acid (3.25 g, 5 eq., 54.3 mmol). The argon purging continued for 10 minutes and then the reaction mixture was heated at 120 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (100 ml x 2). Collected the organic phase and concentrated under reduced pressure to get crude material. Crude material was purified by normal phase column chromatography using elution gradient (5-8% EtOAc: Heptane) to get methyl 4-(benzyloxy)-2,6-dimethoxy-3,5-dimethylbenzoate (2.6 g, LCMS purity- 55%) as brown liquid. LCMS m / z = 331.0 [M+H]+.Step 5: To the stirred solution of methyl 4-(benzyloxy)-2,6-dimethoxy-3,5-dimethylbenzoate (2.6 g, 7.87 mmol) in dimethyl sulfoxide (15.6 mL) and water (1 .6 mL) at room temperature, potassium hydroxide (3.09 g, 7 eq., 55.1 mmol) was added. The reaction mixture was heated at 100 °C for 1 h. Progress of the reaction mixture was monitored by TLC. After completion, water (100 mL) was added to the reaction mixture and adjusted the PH -2-3 using 1 N HC1 solution at 0 °C and aqueous layer was extracted with ethyl acetate (100 mL x 3). Combined organic layers were washed with cold water (200 mL) and dried over anhydrous sodium sulfate, filtered off and evaporated filtrate to afford 4-(benzyloxy)-2,6-dimethoxy-3,5-dimethylbenzoic acid (2 g, LCMS purity -70%) as brown liquid. The material was dissolved in DCM (320 mL), DIPEA (4.0 eq) and MOM-CI (605 pL, 1.2 eq., 7.59 mmol) were added at 0 °C and the reaction was allowed to stir at room temperature for 3 h. Progress of the reaction was monitored by TLC (30% EtOAc:Heptane). After completion, the reaction was diluted with water (100 mL) and extracted with DCM (100 mL x 2). Combined organic layers were with brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford methoxymethyl 4-(benzyloxy)-2,6-dimethoxy-3,5-dimethylbenzoate (2 g, 87%) as brown liquid. The material was dissolved in degassed tetrahydrofuran (50 mL), mixed with Pd / C (10%. w / w) (2 g) at room temperature under nitrogen atmosphere. The reaction mixture was hydrogenated at 15 psi at room temperature for 4 h. Progress of the reaction mixture was monitored by TLC (30% EA:Heptane). After complete consumption of starting material, reaction mixture was filtered over celite bed and washed with ethyl acetate (10 mL) followed by 10% MeOH:DCM (lOmL); combined filtrates were evaporated on rotavapor to afford methoxymethyl 4-hydroxy-2,6- dimethoxy-3,5-dimethylbenzoate (1.3 g, 86%) as colorless stick}7mass. LCMS m z = 269.0 [M-H]-; ’l l NMR (400 MHz. DMSO- o) d ppm 8.88 (br s, 1H), 5.37 (s, 2H), 3.64 (s, 6H), 3.44 (s, 3H). 2.04 (s, 6H).Scheme for the synthesis of methoxymethyl 4-hydroxy-2,3,5-trimethyl-6-(trifluoromethyl)benzoateStep 1: To a 2-dram vial equipped with a stir bar was added pyridine N-oxide (913 mg, 9.60 mmol, 4.0 equiv), Ru(bpy)3C12 6H2O (18.0 mg, 1.0 mol%) and methyl 4-methoxy-2,3,5- trimethylbenzoate (500 mg, 2.40 mmol). The combined materials were then dissolved in MeCN(12.0 ml) and stirred to form a homogeneous solution. Trifluoroacetic anhvdride (2.71 mL,19.2 mmol. 8 equiv) was then added to the resulting solution. The vial was equipped with a screw-on cap with septum, and a 25-gauge needle was placed through the septum for the duration of the reaction. One 4.4 W LED light strip (positioned 2.5 cm away) were turned on and the reaction was allowed to run for 15 h before the light source was removed. Workup was performed by diluting the reaction with CH2C12 and washing with 1 N HC1, followed by saturated NaHCO3 and then brine. The organic layer was dried over sodium sulfate before filtering and concentrating at 40 °C under reduced pressure to afford crude methyl 4-methoxy- 2,3,5-trimethyl-6-(trifluoromethyl)benzoate (610 mg, 92%),JH NMR (400 MHz, CDC13) 5 3.89 (s, 3H), 3.67 (s, 3H), 2.37 (q, J = 2.3 Hz, 3H), 2.24 (s, 3H), 2.16 (s, 3H).Step 2: Methyl 4-methoxy-2,3,5-trimethyl-6-(trifluoromethyl)benzoate (500 mg, 1 Eq. 1.81 mmol) was dissolved in DCM (18.1 mL). The resulting solution was cooled to OoC. BBr3 (2.27 g, 9.05 mL, 1 molar solution, 5 Eq, 9.05 mmol) was added dropwise, and the resulting solution was stirred 48h at RT. The mixture was quenched with ice, then concentrated aq. HC1 was added, and the resulting mixture was stirred for 30 min at RT. Brine was added to the mixture and extracted 4 times with DCM. The resulting crude was washed with a small amount of chloroform to yield the desired product 4-hydroxy-2,3,5-trimethyl-6-(trifluoromethyl)benzoic acid (185 mg, 41%). The material was mixed with sodium bicarbonate (305 mg, 5 Eq, 3.63 mmol) in DMF, and this suspension was heated at 50°C for 2h. The mixture was then cooled down to RT and bromo(methoxy)methane (109 mg, 72.5 pL, 1.2 Eq, 870 pmol) was added and the mixture was stirred ON at RT. The mixture was quenched with water, extracted with diethyl ether twice. The organic layer was then wash brine, dried over sodium sulfate, filtered, evaporated and the resulting crude was then purified by column chromatography to provide the desired product methoxymethyl 4-hydroxy-2,3,5-trimethyl-6-(trifluoromethyl)benzoate (125 mg, 59%) as a colorless oil. 1H NMR (400 MHz, CDC13) 5 5.43 (s, 2H), 3.54 (s, 3H), 2.34 (d, J = 1.9 Hz, 3H), 2.24 (s, 3H), 2.23 (s, 3H).Scheme for the synthesis of methoxymethyl 4-hydroxy-2,6-dimethoxy-3,5- dimethylbenzoateStep 1: To the stirred solution of benzyl 4-(benzyloxy)-3-bromo-2,5,6-trimethylbenzoate (4.0 g, 1.0 eq., 9.1 mmol) and phenol (1.71 g, 2.0 eq., 18.2 mmol) in toluene (80 mL) was added Tripotassium phosphate (3.87 g, 2.0 eq., 18.2 mmol) under nitrogen atmosphere at room temperature. The above reaction mixture was degassed with nitrogen gas for 20 minutes before the addition of palladium acetate (0.204 g, 0.1 eq., 0.910 mmol) and 'BuXphos (773 mg, 0.2 eq.. 1.82 mmol). The resulting reaction mixture was heated at 140 °C for 16 h. Progress of reaction was monitored by TLC & LCMS. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, filtered through a celite bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give the crude material. The crude residue was dissolved in ethyl acetate and washed with water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude benzyl 4-(benzyloxy)-2,3,6-trimethyl-5- phenoxybenzoate (3.2 g, LCMS purity -16%) as yellow liquid. LCMS m / z = 451.05 [M-H]'. Step 2: To the stirred solution of benzyl 4-(benzyloxy)-2,3,6-trimethyl-5-phenoxybenzoate (2.5 g, 1.0 eq., 5.52 mmol) in tetrahydrofuran (100 mL) was added 10% Palladium on carbon (w / w, 2.5 g) under nitrogen atmosphere at room temperature. Reaction mixture was hydrogenated at 15 psi pressure at room temperature for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material; reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain crude material, which was purified by Prep-HPLC to get 4-hydroxy- 2,3,6-trimethyl-5-phenoxybenzoic acid (0.25 g, 16%) as off-white solid. The material was dissolved in DMF (3 mL) and mixed with NaHCCh (0.386 g, 5.0 eq., 4.59 mmol). The mixture was stirred at 55 °C for 30 minutes. Then, MOM-CI (0.22 g, 3.0 eq., 2.75 mmol) was added dropwise at 0 °C and the reaction mixture was stirred for 3 h at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and ice-cold water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain crude material, which was purified using silica-gel column chromatography to get methoxymethyl 4-hydroxy-2,3,6-trimethyl-5- phenoxybenzoate (0.25 g, 86%) as brown solid. LCMS m / z = 314.95 [M-H]'; 'H NMR (400 MHz, DMSO-cfc) <5 ppm 9.13 (br s, 1H), 7.29 (t, J= 8.1 Hz, 2H), 6.99 (t, J= 7.3 Hz, 1H), 6.76 (d, J= 8.0 Hz, 2H), 5.39 (s, 2H), 3.45 (s, 3H), 2.16 (s. 3H), 2.12 (s, 3H), 1.92 (s, 3H).Scheme for the synthesis of methoxymethyl 4-hydroxy-2,3-dimethyl-l-naphthoateStep 1: To the suspension of sodium hydride (4.02 g. 2 eq., 0.1 mol) in diethyl mal onate (0.1 L) was added l-(o-bromophenyl)-! -ethanone (10 g, 1.0 eq., 50.2 mmol) under nitrogen atmosphere at 0 °C. Then, copper bromide (721 mg, 0.1 eq., 5.02 mmol) was added and the reaction mixture was stirred at 80 °C for 2 h. After complete consumption of starting material, the reaction mixture was quenched with ice-cold water and extracted with DCM. The aqueous layer was acidified with 1N-HC1 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get ethyl 2,4-dihydroxy-l-naphthoate (10 g, 63 %) as a brown liquid. LCMS m z = 230.85 [M-H]'; 'H NMR (400 MHz. DMSO-Je) d ppm 11.86 (s, 1H), 11.20 (s, 1H), 8.45 (d, .7 = 8,8 Hz. 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.57 - 7.53 (m, 1H). 7.35 - 7.31 (m, 1H). 6.54 (s. 1H), 4.44 (q. J = 7.2 Hz. 2H), 1.39 (t, J= 7.1 Hz, 3H).Step 2: To the stirred solution of ethyl 2,4-dihydroxy-l-naphthoate (10 g, 1.0 eq., 31.4 mmol) in acetone (50 mL) was added K2CO3 (8.69 g, 2 eq.. 62.9 mmol) under nitrogen atmosphere at room temperature followed by dropwise addition of BnBr (4.11 mL, 1.1 eq.. 34.6 mmol) at room temperature. The reaction mixture was stirred at 55 °C for 4 h. After complete consumption of starting material, the reaction mixture was filtered through sintered and washed with acetone. The filtrate was concentrated under reduced pressure to get crude material. Crude material was triturated with n-Pentane to get ethyl 4-(benzyloxy)-2-hydroxy-l -naphthoate (5 g, 44%) as an off-white solid. The material was dissolved in DCM (36 mL), DIPEA (9.75 mL, 5 eq., 55.8 mmol) and Triflic anhydride (1.88 mL, 1.1 eq., 11.2 mmol) were added under nitrogen atmosphere at 0 °C. Then, reaction mixture was stirred for 1 h at room temperature. After complete consumption of starting material, the reaction mixture was quenched with ice water and extracted with DCM. Combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get ethyl 4-(benzyloxy)-2-(trifluoromesyloxy)- 1 -naphthoate (5 g, LCMS purity -66%) as a brown semisolid. LCMS m / z = 454.95 [M+H]+.Step 3: To the stirred solution of ethyl 4-(benzyloxy)-2-(trifluoromesyloxy)-l -naphthoate (5 g, 1.0 eq., 7.37 mmol) and methylboronic acid (2.65 g, 6 eq., 44.2 mmol) in toluene (33.5 mL) was added K2CO3 (3.06 g, 3 eq., 22.1 mmol) under nitrogen atmosphere at room temperature. Then, reaction mixture was degassed with nitrogen gas for 10 min before the addition of Pd(dppf)C12.DCM (602 mg. 0.1 eq.. 0.737 mmol) at room temperature. The reaction mixture was stirred for 16 h at 100 °C. After complete consumption of starting material, the reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was washed with water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get a crude material. The crude was purified by Combi-flash to get ethyl 4-(benzyloxy)-2- methyl-1 -naphthoate (2.4 g, 99%) as an off-white solid. LCMS m / z = 320.85 [M+H]+; 'H NMR (400 MHz, DMSO-O ri ppm 8.21 (d, J= 8.0 Hz, 1H), 7.77 (d, J= 8.4 Hz, 1H), 7.60 - 7.57 (m, 3H), 7.52 - 7.43 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 5.35 (s, 2H), 4.43 (q, J = 7.2 Hz. 2H), 2.45 (s, 3H), 1.36 (t, J = 7.00 Hz, 3H).Step 4: To the stirred solution of ethyl 4-(benzyloxy)-2-methyl-l -naphthoate (2.4 g, 1.0 eq.. 7.34 mmol) in DCM (50 mL) was added NBS (1.31 g, 1.0 eq., 7.34 mmol) portion-wise under nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. After complete consumption of starting material, the reaction mixture was quenched with ice water and extracted with DCM. Combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get a crude material. The crude was purified by Combi-flash to get ethyl 4-(benzyloxy)-3-bromo-2-methyl-l -naphthoate (1.5 g, 50%) as an off-white solid. LCMS m / z = 398.75 [M+H]+. 'l l NMR (400 MHz, DMSO-rio) 8 ppm 8.12 - 8.09 (m, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.69 - 7.60 (m, 4H), 7.50 - 7.42 (m, 3H), 5.10 (s. 2H), 4.50 (q, J= 7.12 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); one -CH3 proton merged with solvent peak. Step 5: To the stirred solution of ethyl 4-(benzyloxy)-3-bromo-2-methyl-l-naphthoate (1.5 g, 3.68 mmol) and methylboronic acid (2.2 g, 10 eq., 36.8 mmol) in toluene (15 mL) : water (3 mL) mixture was added Na2COs (1. 17 g, 3 eq., 11 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was degassed with nitrogen gas for 15 min at room temperature and PdC12(PPh3)2 (258 mg, 0.1 eq., 0.368 mmol) was added. Further, the reaction mixture w as stirred at 100 °C for 16 h. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. Organic layer was dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure to get a crude material. The crude compound was purified by Combi-flash to get ethyl 4-(benzyloxy)-2,3-dimethyl-l- naphthoate (0.8 g, 61%) as a colourless semisolid. LCMS m z = 334.85 [M+H]+. 'H NMR (400 MHz, DMSO-tL) 8 ppm 8.08 - 8.06 (m, 1H), 7.69 - 7.66 (m, 1H), 7.60 (d, J= 6.8 Hz, 2H), 7.56 - 7.52 (m, 2H), 7.48 (t, J= 7.2 Hz, 2H), 7.44 - 7.42 (m, 1H), 4.96 (s, 2H), 4.47 (q, J= 7.2 Hz, 2H), 2.37 (s, 3H), 2.35 (s, 3H), 1.37 (t, J= 7.2 Hz, 3H).Step 6: To the stirred solution of ethyl 4-(benzyloxy)-2.3-dimethyl-l-naphthoate (0.8 g, 1.0 eq., 2.25 mmol) in DMSO (5 mL) and water (5 mL) mixture was added KOH (631 mg, 5 eq., 11.2 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After complete consumption of starting material, the reaction mixture was cooled to room temperature and acidified with 1N-HC1. The solid precipitates were filtered and washed with n-Pentane to get 4-(benzyloxy)-2,3-dimethyl-l-naphthoic acid (0.6 g, 86%) as an off-white solid. The material was dissolved in DCM (5 mL), DIPEA (1.69 mL, 5 eq., 9.69 mmol) and M0MC1 (0.162 mL, 1.1 eq., 2.13 mmol) were added under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, reaction mixture was quenched with ice water and extracted with DCM. Organic layer as dried over sodium sulphate, filtered and concentrated under reduced pressure to get a crude material. Crude material was triturated with n-Pentane to get methoxymethyl 4-(benzyloxy)-2,3- dimethyl-1 -naphthoate (650 mg, 83%) as brown semisolid, which was then dissolved in degassed THF (20 mL) and mixed with 10% Pd / C (0.65 g, w / w, 50% wet) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under hydrogen atmosphere at balloon pressure. Progress of reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to get the crude material. The obtained crude material was purified by Combi-flash to get methoxymethyl 4-hydroxy-2,3-dimethyl-l -naphthoate (350 mg, 67%) as a white solid. LCMS m 'z = 258.90 [M-H]'. 'H NMR (400 MHz, DMSO-i / e) 8 ppm 9.41 (s. 1H), 8.24 - 8.22 (m. 1H), 7.66 - 7.64 (m, 1H), 7.50 - 7.45 (m, 2H). 5.53 (s. 2H), 3.50 (s. 3H), 2.35 (s, 3H), 2.31 (s, 3H).Scheme for the synthesis of 4-(benzyloxy)-2-hydroxy-3,5,6-trimethylbenzoic acidStep 1: 4-(benzyloxy)-3-bromo-6-hydroxy-2,5-dimethylbenzoic acid (1.32 g, 1 Eq, 3.6143 mmol), methylboronic acid (108 mg, 5 Eq. 1.807 mmol), XPhos Pd G3 (305.93 mg, 0.1 Eq. 361.43 pmol) and cesium carbonate (3.5328 g, 3 Eq, 10.843 mmol) were added to amicrowave vial under N2. Toluene (18 mL) and Water (0.36 mL) were added, and the reaction was heated to 120 °C in a microwave reactor for 4h. The mixture was diluted in EtOAc and washed with water, and the organic layer was dried over Na2SO4 and concentrated. Purification over silica gel (0-50% EtOAc in hexanes) afforded methyl 4-(benzyloxy)-2-hydroxy-3,5,6- trimethylbenzoate (858 mg, 2.86 mmol, 79% yield) as a white solid. LCMS m / z = 301.3 [M+H]+.Step 2: Methyl 4-(benzyloxy)-2-hydroxy-3.5,6-trimethylbenzoate (850 mg, 1 Eq, 2.86 mmol) was dissolved in MeOH:Water (6 mL, 1: 1 v / v). Potassium hydroxide (801 mg, 5 Eq, 14.3 mmol) was added, and the reaction was heated to 50 °C and stirred overnight. The mixture was diluted in EtOAc and washed with IM HC1, and the organic layer was dried over Na2SO4 and concentrated to afford 4-(benzyloxy)-2-hydroxy-3,5,6-trimethylbenzoic acid (457 mg, 1.597 mmol, 56% yield) as a white solid. LCMS m / z = 285.4 [M-H]‘.Scheme for the synthesis of 2-hydroxy-4-(methoxymethoxy)-3-methylbenzoic acidStep 1: To the stirred solution of 2,4-dihydroxy-3-methylbenzaldehyde (10 g, 1.0 eq.. 65.7 mmol) in dimethyl sulfoxide (50 mL) under nitrogen atmosphere at room temperature was added saturated solution of sodium chlorite (59.4 g, 8 eq., 526 mmol) drop wise through addition funnel at 0 °C. After 10 min. saturated solution of sodium dihydrate dihydrogen phosphate (82 g, 8 eq.. 526 mmol) was added drop wise to the above mixture and the reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was quenched with and basify with 10% KOH solution. Further, the aqueous layer was washedwith ethyl acetate and acidified with 1 N HCL solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The crude compound was titrated with n-pentane to get 2,4-dihydroxy-3- methylbenzoic acid (10 g, 72%) as white solid. LCMS m'z = 167.10 [M-H]’;JH NMR (400 MHz, DMSO- 6) <5 ppm 13.28 (br s, 1H), 11.73 (br s, 1H), 10.22 (s, 1H), 7.50 (d, J= 8.0 Hz, 1H), 6.42 (d. J= 8.0 Hz. 1H), 1.98 (s, 3H).Step 2: To the stirred solution of 2,4-dihydroxy-3-methylbenzoic acid (10 g, 1.0 eq., 59.5 mmol) in acetone (80 mL) was added potassium carbonate (24.6 g, 3 eq., 178 mmol) under nitrogen atmosphere at room temperature. Then, the reaction mixture was stirred for 15 min at room temperature. After 15 min, methyl iodide (84.4 g. 10 eq., 595 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After complete consumption of starting material; the reaction mixture was filtered through sintered funnel and the filtrate was concentrated under reduced pressure to get crude residue. The crude residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude compound was triturated with DCM and n-pentane to get methyl 2,4-dihydroxy-3-methylbenzoate (7.0 g, 52%) as an off-white solid. The material was dissolved in DCM (120 mL), DIPEA (10.1 mL, 1.5 eq., 57.6 mmol) was added under nitrogen atmosphere at room temperature and the reaction mixture was stirred for 15 min. After 15 min, chloro(methoxy)methane (4.38 mL, 1 .5 eq., 57.6 mmol) was added drop wise at same temperature and the resulting mixture was stirred at room temperature for 1 h. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to get crude material. The obtained crude material was purified by flash column chromatography to get methyl 2-hydroxy-4-(methoxymethoxy)-3-methylbenzoate (5.2 g, 49%) as white solid, which was dissolved in dimethyl sulfoxide (25 mL), and potassium hydroxide (3.1 g, 2.5 eq., 55.3 mmol) (dissolved in 25 mL water) was added dropwise at room temperature. The resulting mixture was heated at 80 °C for 16 h. After complete consumption of the starting material, the reaction mixture was acidified with 1 N HC1 solution and the precipitated solid compound was filtered, dried under vacuum to get 2-hydroxy-4- (methoxymethoxy)-3-methylbenzoic acid (4.5 g, 91%) as white solid. LCMS m / z = 211.0 [M- H]-; 'HNMR (400 MHz, DMSO-c / 6) <5 ppm 13.88 (br s. 1H), 11.78 (br s, 1H), 7.64 (d, J = 8.0 Hz. 1H), 6.68 (d. J= 8.0 Hz. 1H), 5.28 (s, 2H), 3.39 (s, 3H), 2.06 (s, 3H).Scheme for the synthesis of 3-cyclopropyl-2,4-bis(methoxymethoxy)-6-methylbenzoic acidStep 1: To the stirred solution of ethyl 3-bromo-2,4-dihydroxy-6-methylbenzoate (3.5 g, 1 eq., 12.7 mmol) in dichloromethane (20 mL) was added DIPEA (13.3 mL, 6 eq.. 76.3 mmol) and MOMCI (2.9 mL, 3 eq., 38.2 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 1 h. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with ice cold water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude material was purified by Combi-flash to give ethyl 3-bromo-2,4-bis(methoxymethoxy)-6- methylbenzoate (4 g, 87%) as yellow liquid. LCMS m / z = 363.00 [M+H]+;1HNMR(400 MHz, CDC13) 5 ppm 6.81 (s, 1H), 5.25 (s. 2H), 5.11 (s. 2H), 4.38 (q. J = 7.2 Hz, 2H), 3.58 (s. 3H), 3.50 (s, 3H), 2.30 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).Step 2: To the stirred solution of ethyl 3-bromo-2,4-bis(methoxymethoxy)-6-methylbenzoate (4 g, 1 eq., 11 mmol) in 1,4-dioxane (50 mL) was added Cesium carbonate (8.97 g, 2.5 eq., 27.5 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen gas for 20 minutes before the addition of PdC12(dppf) (0.806 g, 0. 1 eq., 1.1 mmol) and cyclopropylboranediol (3.78 g, 4 eq., 44.1 mmol). Then, resultant reaction mixture was refluxed at 100 °C for 2 h. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain brown color crude compound. The obtained crude was purified by Combi-flash to get ethyl ethyl 3- cyclopropyl-2,4-bis(methoxymethoxy)-6-methylbenzoate (2.7 g, LCMS punty -79%) as colorless liquid. LCMS m / z = 325.15 [M+H]+.Step 3: To the stirred solution of ethyl 3-cyclopropyl-2.4-bis(methoxymethoxy)-6- methylbenzoate (2.7 g, 1 eq., 8.32 mmol) in dimethyl sulfoxide (27 mL) and water (27 mL) mixture was added KOH (4.67 g, 10 eq., 83.2 mmol) was added and reaction was allowed to stir at 100 °C for 12 h. Progress of the reaction was monitored by TLC & LCMS. Aftercomplete consumption of starting material, the reaction mixture was cooled at room temperature and acidified with IN HC1. The Aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude was purified by Combi-flash to get 3-cyclopropyl-2,4-bis(methoxymethoxy)-6-methylbenzoic acid (1.7 g, 69%) as brown solid. LCMS m / z = 295.05 [M-H]'; 'H NMR (400 MHz, DMSO-d6) 5 ppm 12.87 (br s. 1H), 6.69 (s, 1H), 5.22 (s, 2H), 5.05 (s, 2H), 3.44 (s, 3H), 3.40 (s, 3H). 2.21 (s, 3H), 1.74 -1.67 (m, 1H), 0.93 - 0.85 (m, 2H), 0.71 - 0.70 (m, 2H).The above protocol was also used to prepare the below B monomer:Step 1: To a solution of ethyl 4,6-dihydroxy-2,3-dimethylbenzoate (4.00 g, 1 Eq, 19.0 mmol) in Acetone (30 mL) was added Mel (4.05 g. 1.78 mL, 1.5 Eq, 28.5 mmol) and stirred at room temperature for 2d, then the mixture was filtered, and the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with sat. Aq. NH4C1 and brine. After evaporation of the solvent, the residue was purified by FC (EtOAc 0% to 30 % in CyH) to afford ethyl 6-hydroxy-4-methoxy-2,3-dimethylbenzoate (2.03 g, 19.0 mmol, 48 %). 'H NMR (400 MHz. CDCh) 5 11.39 (s, 1H), 6.35 (s, 1H). 4.41 (q, J = 7.1 Hz, 2H). 3.82 (s. 3H), 2.46 (s, 3H), 2.09 (s, 3H), 1.41 (t, J = 7.1 Hz, 4H).Step 2: To a solution of ethyl 6-hydroxy-4-methoxy-2,3-dimethylbenzoate (2.20 g, 1 Eq, 9.81 mmol) in DMF (30 mL) was added K2CO3 (2.71 g, 2 Eq, 19.6 mmol) followed by 2-Bromo- 1,1 -dimethoxy -ethane (2.49 g, 1.74 mL, 1.5 Eq, 14.7 mmol) and stirred at 140 °C for 17 h. The mixture was allowed to cool and sat. aq. NH4C1 and 10 % aq. citric acid were added. Themixture was extracted with ether (3 x 30 mL). The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by FC on SiO2 10 to 50 % EtOAc in CyH to obtain the title compound (3.06 g, 7.46 mmol, 76 %). 'H NMR (400 MHz, CDCh) 5 6.35 (s, 1H), 4.65 (t, J = 5.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.01 (d, J = 5.2 Hz, 2H), 3.80 (s, 3H), 3.44 (s, 6H), 2.19 (s, 3H), 2.06 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).Step 3: ethyl 6-(2.2-dimethoxyethoxy)-4-methoxy-2.3-dimethylbenzoate (9.44 g. 1 Eq. 30.2 mmol) and Amberlystl5ion-exchange resin (1.90 g, .2 Eq, 6.04 mmol) was stirred in PhMe (100 mL) at 800C for 12h The resin was removed by filtration, and the crude product was purified by FC on SiO2 0 to 30 % EtOAc in CyH to obtain the product as an in consequential mixture of the methyl and ethyl ester carboxylate (256 mg), which was then dissolved in DCM (5 mL) and cooled to -78 °C. BBr3 (1.29 g, 5.16 mL, 1 molar in DCM, 5.16 mmol) was added dropwise and the mixture was allowed to gradually warm to room temperature over the course of 16 h. The reaction was quenched by the addition of water, adjusted to pH 1 using aq. Sat. KHSO4 with and extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with brine and dried over MgSO4. The resting colorless solid (213 mg) was used without further purification.Step 4: To 4-hydroxy-5,6-dimethylbenzofuran-7-carboxylic acid (50 mg, 1 Eq, 0.24 mmol) and Na2COs (26 mg, 1 Eq, 0.24 mmol) in DMF was added (bromomethyl)benzene (41 mg, 1 Eq. 0.24 mmol) and stirred for 16 h. The reaction was quenched by the addition of aq. sat. NH4C1. The aqueous layer was extracted tree times with EtOAc (3x 10 ml). The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by FC on SIO2 0 to 20 % EtOAc in CyH: EtOAc afforded the pure product (32 mg, 45%).XH NMR (400 MHz, CDCh) 5 7.54 - 7.50 (m. 2H), 7.49 (d, J = 2.2 Hz, 1H), 7.42 - 7.30 (m, 3H), 6.75 (d, J = 2.3 Hz, 1H), 5.70 (s, 1H), 5.46 (s, 2H), 2.46 (s, 3H), 2.20 (s, 3H).Scheme for the synthesis of methoxymethyl 3-bromo-4-hydroxy-6-methoxy-2,5-Step 1: To a stirred solution of 4-(benzyloxy)-3-bromo-6-hydroxy-2,5-dimethylbenzoic acid (2000 mg, 1 Eq, 5.695 mmol) in ACN (57 mL) under air was added potassium carbonate (944.4 mg, 1.2 Eq, 6.834 mmol), then MOM-CI (550.2 mg, 519.0 pL, 1.2 Eq, 6.834 mmol) dropwise. The reaction was stirred at rt for 2 h, then diluted with EtOAc, washed with NH4C1 and purified on Biotag (0-50% Ethyl acetate:Hexanes, 50 g column) to give methoxymethyl 4-(benzyloxy)- 3-bromo-6-hydroxy-2,5-dimethylbenzoate (1.22 g, 3.09 mmol, 54.2 %) as a white solid. LCMS m / z = 394.8 [M+H]+Step 2: Methoxymethyl 4-(benzyloxy)-3-bromo-6-hydroxy-2,5-dimethylbenzoate (1.20 g, 1 Eq, 3.04 mmol), 4-Nitrobenzenesulfonic acid methyl ester (1.32 g, 2 Eq, 6.07 mmol), and potassium carbonate (629 mg, 1.5 Eq, 4.55 mmol) were added to a vial under air. ACN (60.7 mL) was added, and the mixture was stirred at rt for 16 h. LCMS showed complete conversion. The mixture was diluted in DCM and washed with NH4C1. The organic layer was dried over MgSO4 and concentrated. Purification over silica gel (hexane:EtOAc 0-45%) afforded methoxymethyl 4-(benzyloxy)-3-bromo-6-methoxy-2,5-dimethylbenzoate (1.1 g, 2.7 mmol, 89 %) as a colorless oil.LCMS m / z = 410.8 | M+H|Step 3: To a stirred solution of methoxymethyl 4-(benzyloxy)-3-bromo-6-methoxy-2,5- dimethylbenzoate (880 mg, 1 Eq, 2.15 mmol) in THF (40 mL) was added Pd / C (229 mg, 10% WL 0.1 Eq, 215 pmol). The reaction flask was evacuated then backfilled with N2 three times, then with H2 three times. The reaction was stirred at rt for 16 h. showing partial conversion. The reaction mixture was again evacuated then backfilled with N2 three times, then with H2 three times and stirred at rt for a further 24 h. LCMS showed complete conversion. The reaction mixture was filtered through celite then concentrated under reduced pressure to give the crude methoxymethyl 3-bromo-4-hydroxy-6-methoxy-2,5-dimethylbenzoate (686 mg, 2.15 mmol, 100 %) as a yellow oil. LCMS m / z = 318.8 [M-H]’Scheme for the synthesis of methoxymethyl 4-hydroxy-2,3,5,6-tetramethylbenzoateStep 1: To a stirred solution of methoxymethyl 4-hydroxy-2,3,5,6-tetramethylbenzoate (2.00 g, 1.0 eq., 8.39 mmol) and imidazole (1.14 g, 2.0 eq., 16.8 mmol) in DMF (20 mL) was addedtert-butyldimethylchlorosilane (1.52 g, 1.2 eq., 10.0 mmol) at room temperature. The reaction mixture was stirred for 15 hours, treated with H2O (20 mL) and extracted with Et20 (3x20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO-i. filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain methoxymethyl 4-((tert-butyldimethylsilyl)oxy)-2, 3,5,6- tetramethylbenzoate (58%, 1.72 g) as a colorless oil. The material (522 mg, 1.0 Eq, 1.48 mmol) was added into a flame-dried Schlenk flask, mixed with 20 mL of THF and cooled to - 78 °C. Tetramethylethylenediamine (206 mg, 268 pL, 1.2 Eq, 1.78 mmol) was added followed by dropwise addition of sec-butyllithium (114 mg, 1.37 mL, 1.3 molar, 1.2 Eq, 1.78 mmol). The mixture turned to a deep red colour. After 40 min at the same temperature. N- Fluorobis(phenylsulfonyl)amine (933 mg, 2.0 Eq. 2.96 mmol) was added in one portion. After 30 min, following discoloration, the mixture was warmed to rt to yield a yellow solution. After 30 min the mixture was partitioned between 10%aq citric acid (20 mL) and EtOAc (20 mL). The organic layer was over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain methoxymethyl 4-((tert- butyldimethylsilyl)oxy)-2-(fluoromethyl)-3.5.6-trimethylbenzoate (23%, 128 mg) as a colorless solid. 'H NMR (400 MHz, CDCh) 5 5.47 (s, 2H), 5.39 (d, J = 47.9 Hz, 2H), 3.57 (s, 3H), 2.25 (d, J = 2.1 Hz, 3H), 2.22 (s, 3H), 2.15 (d, J = 2.8 Hz, 3H), 1.06 (s, 9H), 0.15 (s, 6H); 19F NMR (376 MHz, CDC13) 5 -204.57 (t, J = 47.9 Hz).Step 2: In an oven-dried flask, methoxymethyl 4-((tert-butyldimethylsilyl)oxy)-2- (fluoromethyl)-3,5,6-trimethylbenzoate (120 mg, 1 .0 Eq, 324 pmol) was dissolved in THF (1 .2 mL), then tetrabutylammonium fluoride (169 mg, 648 pL, 1.0 molar, 2.0 eq, 648 pmol) was added as a solution in THF and stirred for 15 hours. The mixture was partitioned between EtOAc (2 mL) and saturated NHrClaq (2 mL). The organic layer was washed with brine (4 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was purified by flash column chromatography to obtain methoxymethyl 4-hydroxy-2, 3,5,6- tetramethylbenzoate (24%, 20.0 mg) as a colorless solid. 'H NMR (400 MHz, CDCh) 5 5.46 (s, 2H), 5.40 (d, J= 48.4 Hz, 2H), 4.89 (s. 1H), 3.56 (s, 3H), 2.29 (d, J= 2.1 Hz, 3H), 2.25 (s, 3H), 2.20 (d. J= 2.7 Hz. 3H);19F NMR (376 MHz, CDCh) 5 -203.47 (t, J= 48.0 Hz).The below monomer was prepared using the same fluorination protocol described above:Scheme for the synthesis of methoxymethyl 4-hydroxy-2,3,6-trimethyl-5-(2,2,2- trifluoroethyl)benzoateStep 1: To the stirred solution of benzyl 3-bromo-4-hydroxy-2,5,6-trimethylbenzoate (8 g, 22.9 mmol) in acetone (80 mL) was added dipotassium carbonate (9.5 g. 3 eq., 68.7 mmol) at room temperature under nitrogen atmosphere. Then, benzyl bromide (3.27 mL, 1.2 eq., 27.5 mmol) was added and the reaction mixture was heated at 55 °C for 5 h. Progress of reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was cooled at room temperature, filtered through a celite bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to obtain crude residue. The obtained crude material was purified by Combi-flash to get benzyl 4-(benzyloxy)-3-bromo- 2,5,6-trimethylbenzoate (9.0 g, 90%) as white solid. The material was dissolved in dimethylformamide (45 mL), lithium chloride (0.434 g. 0.5 eq., 10.2 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture was degassed with nitrogen gas for 20 minutes before the addition of PdCh(PPh3)2 (1.44 g, 0.1 eq., 2.05 mmol) and allyltris(butyl)stannane (19.1 mL, 3 eq., 61.5 mmol). Further, resultant reaction mixture was heated at 90 °C for 16 h. Progress of reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain brown color crude compound. The obtained crude material was purified by Combi-flash to get benzyl 3-allyl-4-(benzyloxy )-2,5,6-trimethylbenzoate (5.2 g, 63%) as white solid. LCMS m'z = 401.35 [M+H]+; 'H NMR (400 MHz, DMSO-rfc) 8 ppm 7.48 - 7.34 (m. 10H), 5.92 - 5.84 (m, 1H), 5.34 (s, 2H), 4.98 (d, J = 10.0 Hz, 1H), 4.84 (d, J = 17.0 Hz, 1H), 4.71 (s, 2H), 3.42 - 3.41 (m, 2H), 2.16 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H).Step 2: To the stirred solution of benzyl 3-allyl-4-(benzyloxy)-2,5,6-trimethylbenzoate (5.2 g, 13 mmol) in tetrahydrofuran (50 mL) and water (50 mL) at 0 °C was added 4% OsO4 in water (5.2 g, w / w) dropwise. The reaction mixture was stirred for 1 h at room temperature. After 1 h, NaIO4 (8.33 g, 3 eq., 38.9 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Progress of reaction was monitored by TLC & LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain black color crude compound. The obtained crude was purified by Combi-flash to get benzyd 4-(benzyloxy)-2,3,6-trimethyl-5-(2-oxoethyl)benzoate (3.8 g, 73%) as white solid. The material was dissolved in acetone (40 mL), Jones reagent (8 mL) was added, and reaction mixture was stirred for 3 h at room temperature. Progress of reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude material was purified by Combi-flash to get 2-(2-(benzyloxy)-5-((benzyloxy)carbonyl)-3,4,6-trimethylphenyl)acetic acid (3 g, 76%) white solid. LCMS m / z = 417.05 [M-H]‘; 'H NMR (400 MHz, DMSO-d< 8 ppm 12.40 (br, s, 1H), 7.48 - 7.36 (m, 10H), 5.35 (s, 2H), 4.69 (s, 2H), 3.66 (s, 2H), 2.16 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H).Step 3: To the stirred solution of (bpy)Cu(CFs)3 (3.06 g, 2 eq., 7.17 mmol) in acetonitrile (12 mL) was added Dimethylzinc (2.0 M toluene) (1.03 g, 3 eq., 10.8 mmol) at room temperature under nitrogen atmosphere. After 30 minutes, silver nitrate (183 mg, 0.3 eq., 1.08 mmol), dipotassium peroxy disulfate (3.88 g, 4 eq., 14.3 mmol) and 2-(2-(benzyloxy)-5- ((benzyloxy)carbonyl)-3,4,6-trimethylphenyl)acetic acid (1.5 g, 1 eq., 3.58 mmol) were added sequentially at room temperature. Then, mixture was stirred at 40 °C for 16 h. The progress of reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. Organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crudecompound. The obtained crude was purified by Combi-flash to get benzy l 4-(benzyloxy)-2,3,6- trimethyl-5-(2,2,2-trifluoroethyl)benzoate (750 mg. 50%) as white semi solid. LCMS m / z = 460.20 [M+NH4]+; 'H NMR (400 MHz, DMSO-tfc) d ppm 7.46 - 7.37 (m, 10H), 5.36 (s, 2H), 4.76 (s, 2H), 3.62 (q, J= 10.8 Hz, 2H), 2.20 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H).Step 4: To the stirred solution of benzyl 4-(benzyloxy)-2,3,6-trimethyl-5 -(2,2,2- trifluoroethyl)benzoate (750 mg. 1 eq., 1.7 mmol) in tetrahydrofuran (20 mL) yvas added 10% Pd / C (750 mg, w / w) at room temperature under nitrogen atmosphere. The reaction mixture was hydrogenated under 15 psi pressure for 16 h. The progress of reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture yvas carefully filtered through a celite bed and washed with ethyl acetate; Filtrates were concentrated under reduced pressure to get the crude material. Crude residue yvas triturated with n-Pentane to get 4-hydroxy-2,3,6-trimethyl-5-(2,2,2-trifluoroethyl)benzoic acid (250 mg, 56%) as yvhite semi solid. The material yvas dissolved in DMF (10 mL), sodium hydrogencarbonate (0.4 g, 5 eq., 4.77 mmol) was added and the reaction mixture yvas heated at 50 °C for 30 min. After 1 h, reaction mixture was cooled to room temperature and chloromethoxy methane (123 pL, 1.5 eq., 1.43 mmol) yvas added dropyvise. Further, the mixture was stirred for 1 h at room temperature. Progress of the reaction yvas monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with ethyl acetate. Organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. The obtained crude material was purified by Combi-flash to get methoxymethyl 4-hydroxy-2,3,6- trimethyl-5-(2,2,2-trifluoroethyl)benzoate (0.2 g, 68%) as yvhite solid. LCMS m / z = 305.00 [M-H]-.Scheme for Synthesis of methoxymethyl 4-hydroxy-2-methoxy-3,5,6-trimethylbenzoate.Step 1Step 1: To the stirred solution of methoxymethyl 4-(benzyloxy)-5-bromo-2-methoxy-3,6- xylenecarboxylate (2 g, 1.0 eq., 4.89 mmol) and methylboranediol (4.39 g, 15 eq., 73.3 mmol) in toluene (40 mL) was added Na2COs (2.59 g, 5 eq., 24.4 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was degassed with nitrogen gas for 20 min beforethe addition of Pd2(dba)s (1.34 g, 0.3 eq., 1.47 mmol) and SPhos (802 mg, 0.4 eq., 1.95 mmol) at room temperature. Further, reaction mixture was stirred at 80 °C for 16 h. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, fdtered through a celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to get the crude compound. The residue was dissolved in ethyl acetate and washed with water. Organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material. Crude material was purified by Combi-flash to get methoxymethyl 4-(benzyloxy)-2-methoxy-3,5,6-trimethylbenzoate (0.7 g, 42%) as yellow solid. LCMS m / z = 345.10 [M+H]+;JH NMR (400 MHz, DMSO-cL) <5 ppm 7.52 - 7.35 (m, 5H), 5.43 (s, 2H), 4.77 (s, 2H), 3.68 (s, 3H), 3.47 (s, 3H), 2.16 (s, 6H), 2.13 (s, 3H).Step 2: To the stirred solution of methoxymethyl 4-(benzyloxy)-2-methoxy-3,5,6- trimethylbenzoate (0.5 g, 1 eq., 1.45 mmol) in degassed THF (20 mL) was added 10% Pd / C (250 mg, w / 2, 50% in wet) under nitrogen atmosphere at room temperature. Then, reaction mixture was stirred for 16 h at 15 psi under hydrogen atmosphere pressure at room temperature. After complete consumption of starting material, the reaction mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to get the crude material. Crude material was purified by Combi-flash to get methoxymethyl 4-hydroxy-2-methoxy-3,5,6-trimethylbenzoate (0.2 g, 56%) as a colorless liquid. LCMS m / z = 253.00 [M-H]'; 'H NMR (400 MHz, DMSO-tL) 3 ppm 8.62 (s, 1H). 5.38 (s, 2H), 3.63 (s, 3H), 3.45 (s, 3H), 2.09 (s, 3H), 2.07 (s, 6H).Scheme for the synthesis of 4-(benzyloxy)-6-methylbenzofuran-7-carboxylic acidStep 1: To a solution of ethyl 4-(benzyloxy)-2-hydroxy-6-methylbenzoate (1000 mg, 1 Eq. 3.49 mmol) in DMF (4 mL) was added K2CO3 (965 mg, 2 Eq, 6.96 mmol) followed by 2- bromo-1,1 -dimethoxy-ethane (590 mg, 412 pL, 1 Eq, 3.49 mmol). The mixture was heated 110 °C and stirred for 15 h. Additional 2 -bromo- 1,1 -dimethoxy-ethane (590 mg. 412 pL, 1 Eq, 3.49mmol) and a catalytic amount KI was added. Stirring continued for 4 h then the mixture was allowed to cool to room temperature. A 10 % aq. solution of citric acid was added, and the aqueous phase was extracted with ether (3 x 50 mL). The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by FC on SiO2 (0-40 % EtOAc in CyH) to afford the pure product (1.15 g, 3.49 mmol, 87 %). 'H NMR (400 MHz, CDCh) 5 7.47 - 7.29 (m, 6H). 6.43 (d, J = 2.2 Hz, 1H), 6.39 (d. J = 2.2 Hz. 1H), 5.04 (s. 2H), 4.65 (t, J = 5.2 Hz. 1H), 4.35 (q. J = 7.1 Hz. 2H). 3.97 (d, J = 5.2 Hz, 2H), 3.42 (s, 6H), 2.29 (s, 4H), 1.37 (t, J = 7.1 Hz, 3H).Step 2: To a solution of ethyl 4-(benzyloxy)-2-(2,2-dimethoxyethoxy)-6-methylbenzoate (600 mg, 1 Eq, 1.60 mmol) in toluene (10 mL) was added Amberlyst

[0015] ion-exchange resin (60 mg, 0.12 Eq, 0.19 mmol) and stirred at 90 °C for 16 h. The catalyst was removed by filtration rinsing with DCM. The solvent was removed under reduced pressure and the residue was purified by FC on SiO2 (0 to 30 % EtOAc in CyH) to afford the desired product (113 mg, 1.60 mmol, 23%). The material was dissolved in a mixture of H2O (0.5 mL), THF (0.5 mL), and MeOH (0.5 mL). LiOH (92.6 mg, 10 Eq, 3.87 mmol) was added and the mixture was heated to 80 °C for 14 h. The reaction was allowed to cool to room temperature, quenched by the addition of aq. sat. KHSO4 and extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine, the solvent was removed under reduced pressure, and dried over MgSO4. The resulting solid was used without further purification (80 mg, 280 pmol, 73%). 'H NMR (400 MHz, CDCh) 6 7.62 (d, J = 2.2 Hz, 1H). 7.51 - 7.46 (m. 2H), 7.44 - 7.39 (m, 2H), 7.40 - 7.32 (m, 1H), 6.90 (d, J = 2.2 Hz, 1H), 6.65 (s, 1H), 5.24 (s, 2H), 2.73 (s, 3H).The below fluorinated monomers were synthesized following the same fluorination protocol described in intermediates 38, 59-62.Synthesis of dimer intermediatesScheme of synthesis of (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4- oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoic acid (Intermediate 8)Step 1: Synthesis of methoxymethyl 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-bromo-2-(methoxymethoxy)-5,6-dimethylbenzoateTo a solution of 4-(benzyloxy)-2-methoxy-6-methylbenzoic acid (36.00 g, 1 eq, 132.2 mmol) and DMF (96.63 mg, 0.102 mL, 0.01 eq, 1.322 mmol) in DCM (800 mL) was added Oxalyl chloride (67.12 g, 46.45 mL, 4 eq, 528.8 mmol) at 0 °C, The mixture was stirred at 0 °C for 30 min. one main peak with MeO- version of reagent 1 in LCMS. The reaction was concentrated in vacuum to give 4-(benzyloxy)-2-methoxy-6-methylbenzoyl chloride (38 g, 0.13 mol, 99 %) as a light yellow solid. To a solution of methoxymethyl 3-bromo-4-hydroxy- 2-(methoxymethoxy)-5,6-dimethylbenzoate (38.00 g, 1 eq, 108.8 mmol) in DCM (800 mL) was added TEA (88.10 g, 121 mL, 8 eq, 870.6 mmol) and 4-(benzyloxy)-2-methoxy-6- methylbenzoyl chloride (34.80 g, 1.1 eq, 119.7 mmol) at 0 oC. The mixture was stirred at 0 °C for 2 hr. LCMS showed one peak with desired MS was detected. The mixture was quenched with H2O (100 mL), and extracted with DCM (250 mL * 3). The combined organic layers waswashed with NaHC03 aq (100 mL) and brine (100 mL) dried over Na2SO4. filtered and concentrated under reduce pressure. The crude product was triturated with MeOH (100 mL) and filtered to give methoxymethyl 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3- bromo-2-(methoxymethoxy)-5,6-dimethylbenzoate (40 g, 61 yield) as a white solid. LCMS m / z = 603.1 [M+H]+Step 2: Synthesis of tert-butyl4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy) -3- bromo-2-hydroxy-5,6-dimethylbenzoateTo a solution of methoxymethyl 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3- bromo-2-(methoxymethoxy)-5,6-dimethylbenzoate (40 g, 1 eq. 66 mmol) in dioxane (150 mL) was added 4M HCl / dioxane (150 mL).The mixture was stirred at 25 °C for 1 hr. LCMS showed one peak with desired MS was detected. The mixture was filtered and concentrated under reduce pressure to give 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-bromo- 2-hydroxy-5.6-dimethylbenzoic acid (34 g, 66 mmol, 100 % yield) as a white solid. The portion of the material (6 g, 11.6 mmol, 1.0 eq.) was dissolved in dichloromethane (300 mL) at 0°C under nitrogen atmosphere was added oxalyl chloride (7.99 mL, 93.1 mmol, 8.0 eq.) and the reaction mixture was stirred at room temperature for 2 hours. Then, tert-butyl alcohol (22.1 mL, 232 mmol, 20 eq.) was added dropwise at room temperature and the resulting reaction mixture was stirred at room temperature for another 1 hours. Progress of the reaction was monitored by TLC (EtOAc: Hexane = 30:70) that shows formation of new non polar spot and consumption of starting material. The reaction mixture was quenched with cold water (150 mL) and pH of the aqueous layer was adjusted to basic by using saturated NaHCO3 solution. Further, aqueous layer was extracted with ethyl acetate (200 ml x 2). Combined organic layers were dried over anhy. Sodium sulfate, filtered and concentrated on Rota vapor to obtain the crude residue as off white solid, which was purified by combi-flash using ~12 to 15% ethyl acetate: hexane as eluent to obtained tert-butyl 4-((4-(benzyloxy) -2-methoxy -6- methylbenzoyl)oxy)-3-bromo-2-hydroxy-5,6-dimethylbenzoate (4.0 g, 60% yield) as off-white solid compound. LCMS m / z = 568.95 |M-H]’Step 3: Synthesis of tert-butyl 3-bromo-4-((4-hydroxy-2-methoxy-6-methylbenzoyl)oxy)-2-(methoxymethoxy)-5,6-dimethylbenzoateTo the stirred solution of tert-butyl l-[4-(benzyloxy)-2-methoxy-6- toluoxy]-2-bromo-3- hydroxy-5,6-4-xylenecarboxylate (4 g, 7 mmol. 1.0 eq.) in DCM (200 mL) at 0°C under nitrogen atmosphere was added DIPEA (7.31 mL. 42 mmol, 6.0 eq.) and reaction mixture was allowed to stir at 0°C for 20 min. Then. M0MC1 (1.59 mL, 21 mmol, 3.0 eq.) was added dropwise and reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC (EtOAc: Hexane = 30:70) that shows formation of new polar spot and consumption of starting material, which was carefully quenched with H2O (150 mL), and extracted with DCM (200 mL X 2). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated on Rota vapor to obtain tert-butyl 4-((4-(benzyloxy)-2- methoxy-6-methylbenzoyl)oxy)-3-bromo-2-(methoxymethoxy)-5,6-dimethylbenzoate (4.0 g, 93%) as white solid. The material was dissolved in THF (140 mL) under nitrogen atmosphere and then, 10 % Pd / C, 50% wet (4.0 g, w / w) was added. Further, reaction mixture was hydrogenated at balloon pressure for 16 hours under room temperature. Progress of the reaction was monitored with TLC (EtOAc: Hexane = 30:70) that shows formation of new polar spot and consumption of starting material. Upon completion of the reaction, the catalyst was filtered carefully through celite bed & washed thoroughly with THF (200 mL). Combined filtrates were concentrated on Rota vapor under reduced pressure to obtain the crude residue as off white solid, which was purified by combi-flash using ~75 to 80% ethyl acetate: hexane as eluent to obtained tert-butyl 3-bromo-4-((4-hydroxy-2-methoxy-6-methylbenzoyl)oxy)-2- (methoxymethoxy)-5,6-dimethylbenzoate (2.2 g, 64% yield) as off-white solid. LCMS m / z = 523.2 [M-H]’Step 4: Synthesis of tert-butyl 3-bromo-4-((l-(tert-butylperoxy)-2-methoxy-6-methyl-4- oxocyclohexa-2,5-diene-l-carbonyl)oxy)-2-(methoxymethoxy)-5,6-dimethylbenzoateIn a 100ml flask was placed tert-butyl 3-bromo-4-((4-hydroxy-2-methoxy-6- methylbenzoyl)oxy)-2-(methoxymethoxy)-5,6-dimethylbenzoate (3.0 g, 1 Eq, 5.7 mmol) and Dirhodium(II) tetrakis(caprolactam), complex with acetonitrile (1:2) (75 mg, 0.02 Eq, O.l lmmol) in Toluene (12.0 mL). Cool to 0°C in an ice bath. Add tert-butyl hydroperoxide (7.4 g, 7.9 mL, 70% Wt, 10 Eq, 57 mmol) in water viaa syringe pump (lOml / h). Internal temperature was around 1.8°C. Upon completion of t-butx l hydroperoxide addition, LCMS showed a peak with desired mass and no starting material. Dilute the reaction with 25ml ethyl acetate. Wash with 30ml saturated sodium thiosulfate solution twice. Extract the aqueous phase with 25ml ethyl acetate twice. Combine the organic extracts and wash with 50ml brine. Dry the organic phase over sodium sulfate and concentrate in vacuo. Purified by normal phase chromatography (Biotge, 200g Sfar column, 6% to 50% ethyl acetate in hexane) to give the desired tert-butyl 3-bromo-4-((l -(tert-butylperoxy)-2-methoxy-6-methyl-4-oxocyclohexa-2.5- diene-l-carbonyl)oxy)-2-(methoxymethoxy)-5,6-dimethylbenzoate as white solid. LCMS m / z = 613.2 [M+H]+.Step 5: Synthesis of (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4- oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoic acidIn a 40ml vial was placed rac-tert-butyl (R)-3-bromo-4-((l-(tert-butylperoxy)-2-methoxy-6- methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-2-(methoxymethoxy)-5,6- dimethylbenzoate (698.6 mg, 1 Eq, 1.139 mmol) and Ferrous chloride anhydrous (577.3 mg.4 Eq, 4.555 mmol). Purge vial with nitrogen. Add THF (12 mL). Stir at room temperature overnight. LCMS showed mostly rac-tert-butyl (R)-3-bromo-4-((l-hydroxy-2-methoxy-6- methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-2-(methoxymethoxy)-5,6- dimethylbenzoate. Filter the reaction through a pad of celite. Concentrate the filtrate in vacuo. LCMS after concentration show a mixture of rac-tert-butyl (R)-3-bromo-4-((l-hydroxy-2- methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-2-(methoxymethoxy)-5,6- dimethylbenzoate and rac tert-butyl (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6- methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5.6-dimethylbenzoate (404.3 mg, 812.9 pmol, 71.39 %). The material was mixed in a 20ml vial with Amberlystl5 ion-exchangeresin(1.269 g, 5 Eq, 4.037 mmol). Add CPME (3.2 mL). Stir at room temperature overnight. A white suspension was observed. LCMS showed no starting material remaining. Dissolved the suspension with THF and filter off the Amberlyst. Concentrate the filtrate in vacuo. Crude material was purified by flash chromatography followed by SFC chiral seperation to give the desired (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5- diene-l-carbonyl)oxy)-5,6-dimethylbenzoic acid. LCMS m / z = 439.0 [M-H]’Scheme of synthesis of benzyl 4-((3-ethyl-2,4-dihydroxy-6-methylbenzoyl)oxy)-2,3,5,6- tetramethylbenzoate (Intermediate 30)Step 1: Synthesis of ethyl 2,4-bis(methoxymethoxy)-6-methyl-3-vinylbenzoateTo the stirred solution of ethyl 3-bromo-2,4-bis(methoxymethoxy)-6-methylbenzoate (5.0 g, 1 eq., 13.8 mmol) and vinylboronic acid (8.48 g, 4 eq., 55.1 mmol) in dioxane (100 mL) was added cesium carbonate (11.2 g, 2.5 eq., 34.4 mmol) under nitrogen atmosphere at room temperature. Then, reaction mixture was degassed with nitrogen gas for 20 minutes before the addition of PdCh(dppf) (1.01 g, 0.1 eq., 1.38 mmol) and resulting mixture was refluxed at 90 °C for 16 h. Progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was cooled to room temperature, filtered through a celite bed and washed with ethyl acetate. Filtrate was concentrated under reduced pressure to get the crude material. The crude residue was dissolved in ethyl acetate and washed with water. Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to get ethyl 2,4-bis(methoxymethoxy)-6-methyl-3-vinylbenzoate (3.5 g, 82%) as yellow liquid. LCMS m / z = 311.15 [M+H]+; 'H NMR (400 MHz, DMSO-rfc)5 ppm 6.84 (s, 1H), 6.78 - 6.70 (m, 1H). 5.99 (dd. J = 18.0 & 2.4 Hz, 1H), 5.48 (dd, J= 12.0, 2.4 Hz. 1H), 5.29 (s, 2H), 4.88 (s, 2H), 4.28 (q, J = 6.8 Hz. 2H), 3.40 (s. 3H), 3.39 (s. 3H), 2.21 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H).Step 2: Synthesis of ethyl 3-ethyl-2,4-bis(methoxymethoxy)-6-methylbenzoateTo the stirred solution ethyl 2,4-bis(methoxymethoxy)-6-methyl-3-vinylbenzoate (3.5 g, 1.0 eq.. 11.3 mmol) in degassed acetic acid (38 ml) was added added platinum dioxide (w / w, 3.5 g,) under nitrogen atmosphere at room temperature. Then, reaction mixture was hydrogenated under balloon pressure at room temperature for 16 h. The progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material; reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to get the crude material. The crude residue was dissolved in ethyl acetate and washed with sat. NaHCCh solution. Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get ethyl 3-ethyl-2,4-bis(methoxymethoxy)-6-methylbenzoate (3.0 g. 85%) as yellow liquid. LCMS m ,'z = 313.15 [M+H]+; 'H NMR (400 MHz. DMSO- e) 5 ppm 6.77 (s. 1H), 5.24 (s. 2H), 4.90 (s. 2H), 4.26 (q, J= 6.8 Hz, 2H), 3.43 (s, 3H), 3.38 (s, 3H), 2.59 (q, J= 7.2 Hz, 2H), 2.19 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.6 Hz, 3H).Step 3: Synthesis of 3-ethyl-2,4-bis(methoxymethoxy)-6-methylbenzoic acidTo the stirred solution of ethyl 3-ethyl-2,4-bis(methoxymethoxy)-6-methylbenzoate (3.0 g, 1.0 eq., 9.6 mmol) in water (22 mL) and DMSO (22 mL) mixture was added potassium hydroxide (2.69 g, 5 eq., 48 mmol) at room temperature and reaction mixture was heated for 12 h at 100 °C. Progress of the reaction w as monitored by TLC. After completion of reaction, mixture was cooled to 0 °C and quenched with IN HC1 solution. The precipitated solid was filtered and dned to get 3-ethyl-2.4-bis(methoxymethoxy)-6-methylbenzoic acid (2.2 g, 81%) as white solid. LCMS m / z = 283.05 [M-H]‘; 'H NMR (400 MHz, DMSO-rfc) 5 ppm 13.06 (br s, 1H),6.75 (s, 1H), 5.23 (s, 2H), 4.92 (s, 2H), 3.46 (s, 3H), 3.38 (s, 3H), 2.60 (q, J= 7.2 Hz, 2H), 2.21 (s, 3H), 1. 10 (t, J = 7.6 Hz, 3H).Step 4: Synthesis of benzyl 4-((3-ethyl-2,4-bis(methoxymethoxy)-6-methylbenzoyl)oxy)- 2,3,5,6-tetramethylbenzoateTo the stirred solution of benzyl 4-hydroxy-2,3,5,6-tetramethylbenzoate (1.1 g, 3.87 mmol), and 3-ethyl-2,4-bis(methoxymethoxy)-6-methylbenzoic acid (1.1 g, 1 eq., 3.87 mmol) in pyridine (10 mL), was added EDC. HC1 (1.11 g. 1.5 eq., 5.80 mmol) at room temperature followed by the addition of DMAP (0.236 g, 0.5 eq.. 1.93 mmol) at room temperature. Then, the reaction mixture was stirred at 75 °C for 10 h. Reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ice cold water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, washed with brine and then concentrated under reduced pressure to get the crude material (0.8 g). Further, The crude compound was dissolved in dichloromethane (10 mL) and 4M HC1 in Dioxane (10 mL) was added at room temperature. Then, the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS. TLC. After completion of the reaction, the reaction mixture was concentrated directly under reduced pressure to get crude material. Crude material was triturated multiple times with n-pentane and ether to afford pure benzy l l-(3-ethyl-2,4- dihydroxy-6-toluoxy)-2,3,5,6-tetramethyl-4-benzoate (0.5 g, 74.41 %) as white solid. LCMS m / z = 461.00 [M-H]'; 'H NMR (400 MHz. DMSO-dd) d ppm 11.53 (s, 1H), 10.40 (s, 1H), 7.47 - 7.36 (m, 5H). 6.40 (s, 1H). 5.37 (s, 2H). 2.55 (s, 3H). 2.09 (s. 6H), 2.03 (s. 6H), 1.04 (t, J = 6.4 Hz, 3H); -CH2 protons merged with solvent.Scheme for synthesis of 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-methoxy-2,5,6-trimethylbenzoic acid (Intermediate 31)Step-1: Synthesis of methoxymethyl 4-(benzyloxy)-3-bromo-2,5,6-trimethylbenzoateTo the stirred solution of methoxymethyl 3-bromo-4-hydroxy-2,5,6-trimethylbenzoate (20 g, 1.0 eq., 66 mmol) in acetone (2.0 L) was added dipotassium carbonate (27.4 g, 3.0 eq., 198 mmol) and (bromomethyl)benzene (15.7 mL, 2.0 eq., 132 mmol) under nitrogen atmosphere at room temperature. The resulting reaction mixture was heated at 55 °C for 2 h. Progress of reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was dissolved in ethyl acetate and washed with water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude material. The crude compound was purified by column chromatography to get methoxymethyl 4-(benzyloxy)-3-bromo-2,5,6-trimethylbenzoate (19 g, 73%) as white solid. 'H NMR (400 MHz, DMSO-tL) 8 ppm 7.54 (d, J = 7.2 Hz, 2H), 7.46 -7.36 (m, 3H), 5.45 (s, 2H), 4.84 (s, 2H), 3.47 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 2.15 (s, 3H).Step 2: Synthesis of methoxymethyl 4-(benzyloxy)-3-hydroxy-2,5,6-trimethylbenzoateTo the stirred solution of methoxymethyl 4-(benzyloxy)-3-bromo-2,5,6-trimethylbenzoate (14.5 g, 1.0 eq.. 36.9 mmol) in 1,4-dioxane (282 mL) and water (14.5 mL) was added potassium hydroxide (8.27 g. 4.0 eq., 147 mmol) under nitrogen atmosphere at room temperature. The above reaction mixture was degassed with nitrogen gas for 20 minutes before the addition of 'BuXPhos (3.13 g, 0.2 eq., 7.37 mmol) and Pd2(dba)s (3.38 g, 0.1 eq., 3.69 mmol). The resultingreaction mixture was heated at 115 °C for 1 h. Progress of reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was cooled at room temperature, filtered through a celite bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give the crude material. The crude residue was dissolved in ethyl acetate and washed with water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude material. The crude compound was purified by flash chromatography to get methoxymethyl 4- (benzyloxy)-3-hydroxy-2,5,6-trimethylbenzoate (7.2 g, 59%) as a brown liquid. LCMS m 'z = 329.05 [M-H]-; 'H NMR (400 MHz, DMSO-cL) <5 ppm 8.73 (s, 1H), 7.52 (d, J= 7.2 Hz, 2H), 7.43 - 7.33 (m, 3H), 5.41 (s, 2H), 4.82 (s, 2H), 3.46 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H).Step 3: Synthesis of methoxymethyl 4-hydroxy-3-methoxy-2,5,6-trimethylbenzoateTo the stirred solution of methoxymethyl 4-(benzyloxy)-3-hydroxy-2,5,6-trimethylbenzoate (7.2 g, 1.0 eq., 21.8 mmol) in tetrahydrofuran (72 mL), was added sodium hydride (1.31 g. 2.5 eq., 54.5 mmol) under nitrogen atmosphere at 0°C. The reaction mixture was stirred for 20 min. before the addition of iodomethane (13.9 g, 4.5 eq., 98. 1 mmol) dropwise at same temperature and the mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to obtain crude compound, which was dissolved in tetrahydrofuran (90 mL). 10% Palladium on carbon (w / w, 5.7 g) was added under nitrogen atmosphere at room temperature. Reaction mixture was hydrogenated under balloon pressure at room temperature for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material; reaction mixture was filtered through celite bed and washed with ehtyl acetate. The filtrate was concentrated under reduced pressure to get methoxymethyl 4-hydroxy-3-methoxy-2,5,6-trimethylbenzoate (3.7 g, 87%) as yellow liquid. LCMS m z‘ = 253.00 [M-H]'; 'H NMR (400 MHz, DMSO-Je) 8 ppm 8.94 (s, 1H). 5.38 (s, 2H), 3.60 (s, 3H), 3.44 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H).Step 4: Synthesis of methoxymethyl 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)- 3-methoxy-2, 5, 6- trimethylbenzoateTo the stirred solution of methoxymethyl 4-hydroxy-3-methoxy-2,5,6-trimethylbenzoate (2.5 g, 1.0 eq., 9.83 mmol) and 4-(benzyloxy)-2-methoxy-6-methylbenzoic acid (2.68 g, 1.0 eq., 9.83 mmol) in pyridine (25 mL) were added EDC.HC1 (2.83 g, 1.5 eq., 14.7 mmol) under nitrogen atmosphere at room temperature. Then, DMAP (601 mg, 0.5 eq., 4.92 mmol) was added and the resulting reaction mixture was heated at 65 °C for 16 h. The progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was evaporated under vacuum to obtain crude material. The crude material was diluted in ethyl acetate and washed with cold water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material. The crude compound was purified by flash chromatography to get methoxymethyl 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-methoxy-2,5,6- trimethylbenzoate (2.2 g, 44%) as white solid. LCMS m!z = 509.20 [M+H]+; 'H NMR (400 MHz, DMSO-tfe) d ppm 7.48 (d. J= 7.2 Hz, 2H), 7.42 (t, J= 7.6 Hz. 2H), 7.36 (t, J= 7.2 Hz, 1H), 6.67 (s. 1H), 6.64 (s. 1H), 5.46 (s. 2H), 5.18 (s. 2H), 3.85 (s. 3H), 3.62 (s. 3H), 3.48 (s. 3H), 2.37 (s, 3H), 2.17 (s, 9H).Step 5: Synthesis of 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-methoxy-2,5,6- trimethylbenzoic acidTo the stirred solution of methoxymethyl 4-((4-(benzyloxy)-2-methoxy-6- methylbenzoyl)oxy)-3-methoxy-2.5.6-trimethylbenzoate (1.8 g, 1.0 eq., 3.54 mmol) in dichloromethane (20 mL) was added 4N HC1 in dioxane (20 mL) under nitrogen atmosphere at 0°C, the resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting material, the reaction mixture was directly evaporated under reduced pressure to get the crude material.The reaction mixture was diluted in DCM and washed with water. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtained crude material and was purified by flash chromatography to get 4-((4- (benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-methoxy-2,5,6-trimethylbenzoic acid (1.6 g, 66%) as white solid. LCMS m,z = 463.05 [M-H]’; NMR (400 MHz, DMSO-cfc) <5 ppm 13.37 (br s, 1H), 7.48 (d, J = 7.2 Hz. 2H), 7.42 (t, J = 1.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 6.66 (s, 1H), 6.63 (s, 1H), 5.17 (s, 2H), 3.84 (s, 3H). 3.64 (s, 3H). 2.37 (s. 3H), 2.16 (s, 9H).Scheme for synthesis of 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-chloro- 2,5,6-trimethylbenzoic add (mtermedmte 32)Step 1: Synthesis of methoxymethyl 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)- 3-chloro-2, 5, 6- trimethylbenzoateTo the stirred solution of methoxymethyl 3-chloro-4-hydroxy-2,5,6-trimethylbenzoate (30 g, 1.0 eq., 116 mmol) and 4-(benzyloxy)-2-methoxy-6-methylbenzoic acid (37.9 g, 1.2 eq., 139 mmol) in dichloromethane (500 mb) was added DCC (35.9 g, 1.5 eq., 174 mmol) at room temperature under nitrogen atmosphere. Then, DMAP (7.08 g, 0.5 eq., 58 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was diluted with water and extracted with DCM; Combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude material. The obtained crude compound was trituration with methanol to get methoxymethyl4- ((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-chloro-2,5,6-trim- ethylbenzoate (45 g, 76%) as white solid. LCMS m / z = 513.05 [M+H]+; 'H NMR (400 MHz, DMSO-de) d ppm 7.48 (d, J = 7.2 Hz, 2H), 7.42 (t, J= 7.2 Hz, 2H), 131 - 134 (m, 1H), 6.68 (s, 1H), 6.64 (s, 1H), 5.49 (s, 2H), 5.19 (s, 2H), 3.85 (s, 3H), 3.49 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H), 2.21 (s. 3H).Step 2: Synthesis of 4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)-3-chloro-2,5,6- trimethylbenzoic acidintermediate 32To the stirred solution of methoxymethyl4-((4-(benzyloxy)-2-methoxy-6-methylbenzoyl)oxy)- 3-chloro-2.5.6-trimethylbenzoate (20 g. 1.0 eq.. 39 mmol) in dichloromethane (200 mL) was added 3N HC1 CPME (100 mL) under nitrogen atmosphere at 0°C. Then, the reaction mixture was stirred at room temperature for 2 h. Progress of reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to obtain crude residue. The obtained crude material was dissolved in ethyl acetate and washed with water. Combined organic layer were dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to obtained crude material. The obtained crude compound was triturated with pentane to get 4-((4-(benzyloxy)-2-me thoxy-6- methylbenzoyl)oxy)-3-chloro-2,5,6-trimethylbenzoic acid (15 g, 82%) as white solid. LCMS m / z = 466.95 [M-H]’: 'H NMR (400 MHz, DMSO- e) 8 ppm 13.54 (s, 1H), 7.49 (d, J = 7.2 Hz, 2H),...

Claims

 1. A compound represented by Formula (I): Formula (I),or a pharmaceutically acceptable salt, a stereoisomer and a mixture of stereoisomers, or a prodrug thereof;wherein X is selected from -COORA, -CONRBRC, -NHCONRBRC, -C(O)NHORA, -C(O)SRA, -S(O)3RA, -S(O)2NRBRC, -S(O)2NHC(O)RA, -NHC(O)NHS(O)2RA, and -COCH2RA;R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORA, CN, NRBRC, NRBC(O)RA, S(O)RA, S(O)2RA, SO2NRBRC, SO3RA, COORA; C(O)RA, and C(O)NRBRC; or each pair of R1 and R2, R3 and R4, R5 and R6, R7 and R8, R9 and R10, and R11 and R12 independently, together with the phenyl to which they are attached to, form a substituted or unsubstituted fused bicyclic ring system comprising zero, one, two, or more heteroatoms selected from -N-, -S-, and -O-; or R13 and R14 together form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;R15 is selected from absent, H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORA, CN, NRBRC, NRBC(O)RA, S(O)RA, S(O)2RA, SO2NRBRC, SO3RA, COORA; C(O)RA, and C(O)NRBRC;each RA, RB, and RC is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or RB and RCcan be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5, 6, 7, or 8 membered ring; R16 and R17 are each independently selected from substituted or unsubstituted alkyl; or R16 and R17 together form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl; alternatively, R15, R16 and R17 form a substituted or unsubstituted 5- to 10-membered bridged ring system that has zero, one, two, or more heteroatoms;Z is carbon or nitrogen; andn is 0 or 1. 2. The compound of claim 1, wherein X is -COOH, -COOCH3, -CONH2, -C(O)NHOH, -NHC(O)NH2, -S(O)3H, -S(O)2NH2, -S(O)2NHC(O)CH3, -NHC(O)NHS(O)2CH3, and -COCH3; preferably X is -COOH. 3. The compound of claim 1 or 2, wherein R1, R2, R3, R4, R5, R7, R8, R9, R10, R11, and R12 are each independently selected from H, F, Cl, Br, -OH, a substituted or unsubstituted C1-6 alkyl (such as -CH3, -CH2CH3, isopropyl, cyclopropyl, -CF3, -CHF2,or -CH2F), -CN, -O-C1-6 alkyl (such as -OCH3, -OCH2CH3, -O-isopropyl, or -O-cyclopropyl), a substituted or unsubstituted phenyl, a substituted or unsubstituted 5- to 6-membered heteroaryl, a substituted or unsubstituted 3- to 6-membered cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. 4. The compound of any one of the preceding claims, wherein R1, R2, R3, R5, R7, R9, R10, R11, and R12 are each independently selected from H, F, Cl, Br, -OH, -CH3, -CH2CH3, -OCH3, and -OCH2CH3. 5. The compound of any one of the preceding claims, wherein R4 and R8 are selected from H, F, Cl, Br, -OH, -CH3, -CH2CH3, -OCH3, -OCH2CH3, a phenyl, a 5- to 6-membered heteroaryl, a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycloalkyl. 6. The compound of any one of the preceding claims, wherein R6 is selected from H, F, Cl, Br, or -CH3; preferably R6 is H. 7. The compound of any one of the preceding claims, wherein n is 0. 8. The compound of any one of the preceding claims, wherein n is 1; R13 and R14 are independently selected from H, F, Cl, Br, -CH3, -OCH3, -NH2. 9. The compound of any one of claims 1-7, wherein R13 and R14 together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycloalkyl. 10. The compound of any one of the preceding claims, wherein R15 is absent, -OH, H, F, Cl, Br, or a substituted or unsubstituted C1-6 alkyl. 11. The compound of any one of the preceding claims, wherein R15 is absent, H, -OH, F, Cl, -CH3, -CH2CH3, -CH2OH, -CF3, -CHF2,or -CH2F. 12. The compound of any one of the preceding claims, wherein R16 and R17 together with Z form a substituted or unsubstantiated 6-membered cycloalkadienyl. 13. The compound of any one of claims 1-11, wherein R16 and R17 together with Z form a ring structure; or R15, R16 and R17 together with Z form a bridged ring structure; and Z / R15 / R16 / R17 is selected from: wherein each of the groups above is substituted with zero, one, two, three, four, or five substituents selected from -OH, a C1-3 alkyl, a -O-C1-3 alkyl, -CN, and =O. 14. The compound of any one of the claims 1-11, wherein R16 and R17 are each independently selected from a substituted or unsubstituted C1-6 alkyl. 15. A compound of claim 1, wherein the compound is represented by Formula (III):Formula (III);  wherein X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R15 are as defined in claim 1; andR19, R20, R23, and R25 are each independently selected from H, D, halogen, -OH, a substituted or unsubstituted C1-6 alkyl, -O-C1-6 alkyl, CN; or R19 and R20 together with the ring to which they are attached to form a fused bicyclic ring system; or R23 and R25 together with the ring to which they are attached to form a fused bicyclic ring system; or any two of R19, R20, R23, and R25 together with the ring to which they are attached to form a bridged ring system. 16. The compound of claim 1, wherein the compound is any one of those compounds in Table 1. 17. The compound of claim 1, wherein the compound is not a naturally occurring product. 18. The compound of claim 1, wherein the compound has the following structure:. 19. The compound of claim 1, wherein the compound has the following structure:. 20. The compound of claim 1, wherein the compound has the following structure: 21. A pharmaceutical composition comprising the compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 22. The composition of claim 21, wherein said composition is formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration. 23. A method for treating an inflammatory-related disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the compound of any one of claims 1-20. 24. The method of claim 23, wherein the inflammatory-related disease or disorder is a systemic inflammatory-related disease or disorder. 25. The method of claim 22, wherein the inflammatory-related disease or disorder is a pulmonary condition. 26. The method of claim 25, wherein the compound is administered to the subject via inhalation. 27. The method of claim 23, wherein the inflammatory-related disease or disorder is selected from the group consisting of allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection, and respiratory tract inflammation. 28. The method of claim 23, wherein the inflammatory-related disease or disorder is a skin condition. 29. The method of claim 23, wherein the inflammatory-related disease or disorder is selected from the group consisting of psoriasis, dermatitis, eczema, and hives. 30. The method of claim 23, wherein the inflammatory-related disease or disorder is psoriasis. 31. The method of claim 30, wherein psoriasis is selected from the group consisting of plaque psoriasis, flexural psoriasis (inverse psoriasis), guttate psoriasis, pustular psoriasis, nail psoriasis, psoriatic arthritis, and erythrodermic psoriasis. 32. The method of claim 23, wherein the inflammatory-related disease or disorder is dermatitis. 33. The method of claim 32, wherein the dermatitis is selected from the group consisting of contact dermatitis, atopic dermatitis, nummular dermatitis, seborrheic dermatitis, and stasis dermatitis. 34. The method of claim 23, wherein the inflammatory-related disease or disorder is an ocular disorder or disease. 35. The method of claim 34, wherein the ocular disorder or disease is selected from the group consisting of dry eye syndrome (DES), Sjogren's syndrome, uveitis, conjunctivitis (pink eye), keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), autoimmune disorders of the ocular surface, including cicatrizing conjunctivitis, blepharitis, and scleritis. 36. A method of inhibiting calcineurin, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20. 37. A method of preventing organ transplant rejection in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20. 38. A method of treating fungal infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20. 39. A method of protecting a kidney by reducing immunosuppression-induced nephrotoxicity in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20. 40. A method of treating a condition or disorder associated with abnormal Calcineurin activity in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20. 41. A method of treating inflammatory bowel disease or acute severe ulcerative colitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20. 42. The method of claim 23, wherein the inflammatory-related disease or disorder is selected from the group consisting of focal segmental glomerulosclerosis, lupus nephritis, IgA nephropathy or myasthenia gravis. 

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