Process for the preparation of microbiocidal oxadiazole derivatives

Abstract

The present invention provides, inter alia, a process for the preparation of substituted oxadiazole derivatives of formula (I), which can be obtained through reaction of amidoximes of formula (II) in the presence of an organic guanidine base, wherein the substituents are as defined in the claims. The present invention further provides intermediate compounds utilized in said process, and methods for producing said intermediate compounds.

Description

The present invention relates to a process for the preparation of substituted oxadiazole derivatives of formula (I), which can be obtained through reaction of amidoximes of formula (II) in the presence of an organic guanidine base. Substituted oxadiazole derivatives are versatile intermediates, which can be converted to substituted 3-aryl-5-trifluoro-1,2,4-oxadiazoles, that are known to be useful for controlling phytopathogenic fungi, for example, from WO2015 / 185485, WO2017 / 055473A1, WO2017 / 211649, WO2017 / 178245, WO2018 / 177894, WO2019 / 022061, WO2021 / 100745, WO2022 / 207494, WO2022 / 239725. Methods for preparing oxadiazole compounds have been disclosed for example in WO2017 / 055473, WO2018 / 177894, WO2019 / 020501, WO2019 / 020451, WO2020 / 212513. WO2019 / 020501, and WO2019 / 020451 describe the formation of 1,2,4-oxadiazole derivatives by reacting amidoximes with trifluoroacetic halide in the presence of an organic solvent or in substance. All synthetic examples disclose the use of at least 2 equivalents of trifluoroacetic halide, which leads to the formation of at least one equivalent of free trifluoroacetic acid (TFA) as a side product, along with hydrogen halides, which requires special reaction equipment to avoid corrosion. WO2020 / 212513 describes the formation of 1,2,4-oxadiazole derivatives by reacting amidoximes with trifluoroacetates in the presence of metal alkoxylates. Metal alkoxylates are non-recyclable bases, and further restrict the solvents that can be employed for this conversion. WO2021 / 156174 describes the formation of 1,2,4-oxadiazole derivatives by reacting amidoximes with trifluoroacetates in the presence of a base. All synthetic examples disclose the use of at least 2 equivalents of trifluoroacetate, based on the amount of amidoxime, in the presence of sodium methylate as a base. Sodium methylate is a non-recyclable base, and further restricts the solvents that can be employed for this conversion. WO2021 / 156175 describes the formation of 1,2,4-oxadiazole derivatives by reacting amidoximes with trifluoroacetates in the presence of a base, such as metal alkoxylates. All synthetic examples disclose the use of 5 equivalents of trifluoroacetate, based on the amount of amidoxime, in the presence of sodium methylate as a base. Sodium methylate is a non-recyclable base, and further restricts the solvents that can be employed for this conversion. Beside the use of metal alkoxylates, which are non-recyclable bases, the use of such metal alkoxylates or sodium methylate as a base restrict the solvents that can be employed for this conversion, thereby restricting the versatility and industrial efficacy of this transformation. It is known that trifluoroacetates are less reactive than trifluoroacetic halides or trifluoroacetic anhydride (TFAA), and such in order to achieve high yields of the desired product the presence of a base and the use of excess of acylating agent is required. Such there is a need for an economically friendly industrial large-scale production process for 3-aryl-1,2,4-oxadiazole-derivatives, which overcomes the disadvantages of the prior art, and which enables the production of 1,2,4-oxadiazole derivatives with lower amount of waste-products. The current invention provides an industrial large-scale, environmentally friendly, and cost-efficient production process, which employs readily available, non-toxic, recyclable and cheap reagents. The reaction process may be performed with a low excess of acylating reagent based on the amidoxime starting material and such leads to less waste products. Furthermore, fast conversion is achieved, at moderate reaction temperatures with high yields of the required 3-aryl-1,2,4-oxadiazole-derivatives. Further for the process of the present invention the organic solvent that can be used is not restricted due to the nature of the base used. According to a first aspect of the present invention, there is provided a process for preparing compound of formula (I) — N r2 (I) wherein R1 is selected from hydroxy, thiol, cyano, halogen, hydroxymethyl, Ci-Cs-alkyl, Ci-C2-haloalkyl, cyclopropyl, -C(=O)H, -C(=O)OH, -C(=O)Hal, -C(=W)N(R3R4), -CH2-C(=W)N(R3R4), -CH2-N(R3)-C(=W)R4, wherein the staggered line denotes the connection to the phenyl-group; R2 is selected from Ci-C2-haloalkyl; R3 is selected from hydrogen, Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, or cyclopropyl; R4 is selected from Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, Cs-Ce-cycloalkyl, Ci-C2-alkoxy-Ci-C3-alkyl, or phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen; R5 is selected from hydrogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or Ci-C4-alkoxy-Ci-C2-alkoxy; and W is selected from O, or S; said process comprising the reaction of an amidoxime compound of formula (II) (II), wherein R1, R3, R4 and R5 are as defined for compounds of formula (I), with a haloacetic ester of formula (III) O r2 / ^or6 (III), wherein R2 is as defined for compounds of formula (I), and R6 is selected from Ci-Ci2-alkyl, C2-C6-alkenyl, C-i-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; in the presence of at least one base, wherein said process is characterized in that said at least one base is selected from a guanidine-base. Surprisingly, it has been now found that the process of the invention advantageously provides a mean to produce compounds of formula (I) at high isolated yields. Further it has been surprisingly found that the process of the present invention may be performed with a low excess of acylating reagent based on the amidoxime starting material and such leads to less waste products. Furthermore, fast conversion is achieved, at moderate reaction temperatures with high yields of the required 3-aryl-1,2,4-oxadiazole-derivatives. Further for the process of the present invention the organic solvent that can be used is not restricted due to the nature of the base used, and the base is non-toxic, and recyclable, and such provides an environmentally friendly, and cost-efficient industrial large-scale production process. As used herein, the term "halogen" or “halo” refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine, or bromine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl, and haloalkoxy. As used herein, thiol means a -SH group. As used herein, cyano means a -CN group. As used herein, the term “hydroxyl” or “hydroxy” means an -OH group. As used herein, the term “carboxylic acid” means a -COOH group. As used herein, the term "Ci-Cn-alkyl” refers to a saturated straight-chain or branched hydrocarbon radical attached via any of the carbon atoms having 1 to n carbon atoms, for example, any one of the radicals methyl, ethyl, n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl. As used herein, the term “C2-Cn-alkenyl” refers to a straight or branched alkenyl chain moiety having from two to n carbon atoms and one or two double bonds, for example, ethenyl, prop-1-enyl, but-2-enyl. As used herein, the term “Cs-Cn-cycloalkyl” refers to three (3) to n membered cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term "Ci-Cn-alkoxy" refers to a straight-chain or branched saturated alkyl radical having one (1) to n carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of the radicals methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methyl propoxy and 1,1-dimethylethoxy. As used herein, the term “Ci-Cn-alkoxy Ci-Cnalkoxy” refers to a radical of the formula Ra-O-Rb- wherein Ra is a Ci-Cnalkyl radical as generally defined above, and Rb is a Ci-Cnalkoxy radical as generally defined above. As used herein, the term "Ci-Cn-haloalkyl" refers to a straight-chain or branched saturated alkyl radical attached via any of the carbon atoms having 1 to n carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these radicals may be replaced by fluorine, chlorine, bromine and / or iodine, i.e., for example, any one of chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl. As used herein, the term“Ci-Cn-haloalkoxy” as used herein refers to a Ci-Cn-alkoxyl radical substituted with one or more halo atoms which may be the same or different. As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. As used herein, the term "controlling" refers to reducing the number of pests, eliminating pests and / or preventing further pest damage such that damage to a plant or to a plant derived product is reduced. As used herein, the term "pest" refers to insects, and molluscs that are found in agriculture, horticulture, forestry, the storage of products of vegetable origin (such as fruit, grain, and timber); and those pests associated with the damage of man-made structures. The term pest encompasses all stages in the life cycle of the pest. As used herein, the term "effective amount" refers to the amount of the compound, or a salt thereof, which, upon single or multiple applications provides the desired effect. An effective amount is readily determined by the skilled person in the art, using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, a number of factors are considered including, but not limited to the type of plant or derived product to be applied; the pest to be controlled and its lifecycle; the particular compound applied; the type of application; and other relevant circumstances. As used herein, the term “room temperature” or “RT” or “rt” or “ambient temperature” refer to a temperature of about 15° C to about 35° C. For example, rt can refer to a temperature of about 20° C to about 30° C. The compounds of formula (I) can be used in the agricultural sector and related fields of use, e.g., as versatile intermediates, or as active ingredients for controlling plant pests or on non-living materials for the control of spoilage microorganisms or organisms potentially harmful to man. In one embodiment of the invention, the compounds of formula (I) are useful as versatile intermediates for the preparation of 3-aryl-1,2,4-oxadiazole-derivatives, which show a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi, particularly phytopathogenic fungi especially Phakopsora pachyrhizi, Corynespora cassiicola, or Diaporthe spp., like Diaporthe miriciae, also known as Diaporthe ueckeri or Diaporthe ueckerae. In another embodiment of the invention, the compounds of formula (I) have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi. Thus, the compounds of formula (I) are particularly suitable for use as a fungicide. In one embodiment, the compounds of formula (I) are suitable for control of diseases caused by phytopathogenic fungi especially Phakopsora pachyrhizi, causal agent of Asian soybean rust, and to a method of controlling diseases on useful plants, especially soybeans. In another embodiment, the compounds of formula (I) are suitable for control of diseases caused by phytopathogenic fungi especially phytopathogenic microorganism Corynespora cassiicola, and to a method of controlling diseases on useful plants, for example on soybean or cotton. In one embodiment of the invention, the compounds of formula (I) are suitable for controlling Phakopsora pachyrhizi in genetically modified plants. Preferably the genetically modified plants are soybean plants. More preferably said genetically modified soybean plants are Bt soybean plants, even more preferably Bt soybean plants selected from Intacta RR2 PRO®, or Conkesta Enlist E3®. In another embodiment, the compounds of formula (I) are suitable for control of the phytopathogenic microorganism Corynespora cassiicola, in genetically modified plants, for example on soybean or cotton. Preferably the genetically modified plants are soybean plants. More preferably said genetically modified soybean plants are Bt soybean plants, even more preferably Bt soybean plants selected from Intacta RR2 PRO®, or Conkesta Enlist E3®. The term “fungicide” as used herein means a compound that controls, modifies, or prevents the growth of fungi. According to this particular aspect of the invention, the use may exclude methods for the treatment of the human or animal body by surgery or therapy. In one embodiment of the invention, in the process for preparation of compounds of formula (I), compound of formula (III) Isa haloacetic ester of formula (II) O R2 / ^OR6 (III) wherein R2 is as defined for compounds of formula (I), and R6 is Ci-Ci2-alkyl, vinyl or benzyl. Preferably in a compound of formula (III) R2 is trifluoromethyl, or difluoromethyl; and R6 is Ci-C4-alkyl. Preferably in a compound of formula (III) R2 is trifluoromethyl, or difluoromethyl; and R6 is methyl, ethyl or butyl. Preferably in a compound of formula (III) R2 is trifluoromethyl, and R6 is methyl, ethyl or butyl. Preferably the compound of formula (III) is selected from methyl trifluoroacetate, ethyl trifluoroacetate, or butyl trifluoroacetate. In one embodiment of the invention, in the process for the preparation of compound of formula (I) according to the present invention, the amount of haloacetic ester of formula (III), can be from 1.0 to 3.0 eq., from 1.0 to 2.0 eq., from 1.0 to 1.5 eq., from 1.0 to 1.25 eq., from 1.0 to 1.1 eq., or from 1.0 to 1.05 eq., based on the number of moles (mol) of amidoxime compound of formula (II). The molar ratio of haloacetic ester of formula (III), to amidoxime compound of formula (II) can be from 3:1 to 1:1, or from 2.5:1 to 1:1 or from 2:1 to 1:1 or from 1.5:1 to 1:1, or from 1.25:1 to 1:1, or from 1.1:1 to 1:1, or from 1.05:1 to 1:1. In one embodiment of the invention, in the process for the preparation of compound of formula (I) according to the present invention, the process is carried out in the presence of at least one base, wherein said base is a guanidine-base. In one embodiment of the invention, in the process for the preparation of compound of formula (I) according to the present invention, the guanidine-base is not identical with a compound of formula (I), (II), (III), or an inert organic solvent as defined herein. Guanidines have been known to chemists for over 150 years now (Strecker, A. Liebigs Ann. Chern. 1861, 118, 151) and are well recognized primarily as very strong organic bases (‘superbases’) (Ishikawa, T. In Superbases for Organic Synthesis; Ishikawa, T., Ed.; John Wiley & Sons Ltd: Chichester, 2009, 93-143). Guanidine-bases are useful reagents and catalysts in organic synthesis (I, P. Selig (Ed J, Topics in Heterocycl. Chern., Springer, 2017, vol. 50). Guanidines act as very strong nucleophilic base, and given their most interesting potential, it is quite surprising that the use of guanidines for the process of the present invention acting as nucleophilic base has not been reported up to now. The guanidine-bases suitable for preparation of compounds of formula (I) according to the present invention include, but are not limited to 1,1,3,3-tetramethylguanidine (TMG), 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton's base), 1,1,2,3-tetramethylguanidine, guanidine carbonate (Diguanidinium carbonate), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (mTBD or 7-Methyl-TBD), 1,1,2,3-tetramethylguanidine, 2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole, 1,5,6,7-tetrahydroimidazo[1,2-a]pyrimidine, 1-carbamimidoyl-3-(o-tolyl)guanidine, and N-isopropylhexahydropyrimidin-2-imine, as shown in Table 1. Table 1: Guanidine bases | entry |                       Chemical name                       |                structure                | B-1 1,1,3,3-Tetramethylguanidine (TMG) NH H3C. JL / CH3 I I ch3 ch3 B-2 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton's base) f-Bu. h3c. JL .ch3 ^N^ I        H ch3 B-3 1,1,2,3-tetra methylguanidine h3c. h3c. JI ch3 I H ch3 B-4 guanidine carbonate (Diguanidinium carbonate) NH2 HzN^^NHz 0 2 B-5 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) CO H B-6 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (mTBD; 7-Methyl-TBD) GO I ch3 B-7 2,3,5,6-tetrahydro-1 H-imidazo[1,2-a]imidazole CD N"^^N H B-8 1,5,6,7-tetrahydroimidazo[1,2-a]pyrimidine a? B-9 1-carbamimidoyl-3-(o-tolyl)guanidine ch3 H    H NH NH B-10 N-isopropylhexahydropyrimidin-2-imine ch3 ^N^^N^^CHa H In one embodiment of the invention, the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of at least one base, wherein said base is a guanidine base, wherein said guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton's base), 1,1,2,3-tetramethylguanidine, guanidine carbonate (diguanidinium carbonate), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (mTBD; 7-Methyl-TBD), 2,3,5,6-tetrahydro-1 H-imidazo[1,2-a]imidazole, 1,5,6,7-tetrahydroimidazo[1,2-a]pyrimidine, 1-carbamimidoyl-3-(o-tolyl)guanidine, or N-isopropylhexahydropyrimidin-2-imine, or a combination thereof. Preferably, the process for the preparation of a compound of formula (I) according to Scheme 1, is carried out in the presence of 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, or guanidine carbonate. More preferably the process for the preparation of a compound of formula (I) is carried out in the presence of 1,1,3,3-tetramethylguanidine, 2-tert-buty 1-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In a preferred embodiment of the present invention, the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of 1,1,3,3-tetramethylguanidine. In another preferred embodiment of the present invention, the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). In another preferred embodiment of the present invention, the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of 2-tert-butyl-1,1,3,3-tetramethylguanidine. In another preferred embodiment of the present invention, the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment of the invention, in the process for the preparation of compound of formula (I) according to the present invention, the amount of said guanidine-base can be from 0.05 to 3.0 eq., from 0.1 to 2.5 eq., from 0.1 to 2.0 eq., from 0.1 to 1.5 eq., from 0.1 to 1.25 eq., based on the number of moles (mol) of amidoxime compound of formula (II). The molar ratio of said guanidine-base to amidoxime of formula (II) can be from 3:1 to 0.1:1, or from 1.25 :1 to 0.2:1, preferably from 1.25:1 to 0.2:1, or from 1.25:1 to 0.25:1, or from 0.02:1 to 0.2:1. In one embodiment of the invention, the process for the preparation of compound of formula (I) can be carried out in the presence of an additional base, wherein said additional base is selected from an inorganic base or an organic base, and wherein said additional base is not a guanidine base. Examples of suitable second bases include inorganic bases and organic bases. A person skilled in the art is well aware that the selection of the appropriate additional base for the process of the present invention should be based on factors such as desired reaction conditions, compatibility with other reactants, and regulatory considerations. Example of suitable inorganic bases are for example, but not limited to alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal formats; alkali metal and alkaline earth metal acetates; alkali metal and alkaline earth metal carbonates; alkali metal and alkaline earth metal citrates; alkali metal and alkaline earth metal sulfates and any combination thereof. Preferably the inorganic base is selected from alkali metal carbonates or alkali metal acetates, or any combination thereof. Particular preferred are sodium carbonate, potassium carbonate, or sodium acetate. As used herein, the term “alkali metal” refers to the elements in group 1 of the Periodic Table, preferably to lithium (Li), sodium (Na), or potassium (K). Examples of suitable organic bases are for example, but no limited to tertiary amines, substituted or nonsubstituted pyridine, bicyclic amines, alkali metal Ci-Csalkoxylates, and mixtures thereof. Preferably the organic base is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5- ethyl-2-methyl-pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or mixtures thereof. Preferably said organic base is selected from triethylamine. In one embodiment of the invention, the process for the preparation of compound of formula (I) can be carried out in the presence of an acid. Example of suitable acids are for example, but not limited to organic acids or inorganic acids. Examples of suitable organic acids are for example, but no limited to acetic acid, citric acid, formic acid, benzoic acid, lactic acid, trifluoracetic acid, propionic acid, and any combination thereof. A person skilled in the art is well aware that the selection of the appropriate acid for the process of the present invention should be based on factors such as desired reaction conditions, compatibility with other reactants, and regulatory considerations. Examples of suitable inorganic acids are for example, but no limited to sulfuric acid, hydrochloric acid, phosphoric acid, and any combination thereof. A person skilled in the art is well aware that the selection of the appropriate acid for the process of the present invention should be based on factors such as desired reaction conditions, compatibility with other reactants, and regulatory considerations. Preferably the acid is selected from acetic acid, citric acid or trifluoroacetic acid. In one embodiment of the invention, the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) in the presence of at least one base, wherein said base is a guanidine-base, can be carried out in the presence of an inert organic solvent, or mixtures of such solvents. The term "inert organic solvent" as used herein, refers to an organic solvent, which does not enter into any appreciable reaction with either the reactants or the products under the reaction conditions of the process of this invention. The organic solvent that can be used for the process of the present invention is one that will be suitable of dissolving compounds of formula (II) and miscible with the base being used. A person of skill in the art will recognize that there are a number of organic solvents which meet these specifications. Examples of suitable organic solvents are, but not limited to polar protic solvent, polar aprotic solvent, or a nonpolar solvent. Examples of polar protic solvents include, but are not limited to, methanol, ethanol, / -propanol, n-butanol, terf-butanol, or 2-pentanol. Examples of polar aprotic solvents include, but are not limited to, acetone, acetonitrile, dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethyl carbonate, / V, / V-dimethylformamide (DMF), methyl isobutyl ketone (MIBK), ethyl acetate, butyl acetate, propyl acetate, ethyl valerate, ethyl propionate, pyridine, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), or tetramethylene sulfone (sulfolane). Examples of nonpolar solvents are, but not limited to, hydrocarbon solvents, like alkanes and aromatic solvents, for example pentane, hexane, methylcyclohexane, toluene and xylene; ether solvents, for example 1,4-dioxane, diethyl ether, or chloroform. In one embodiment of the present invention, the organic solvent may be selected from 2-butanol, n-butanol, ethanol, i-butanol, 2-pentanol, dimethyl carbonate, toluene, benzonitrile, methyl isobutyl ketone, acetonitrile, 2-methyltetrahydrofuran, dioxolane, N-methylpyrrolidone, sulfolane, ethyl acetate, butyl acetate, propyl acetate, ethyl valerate, ethyl propionate, pentyl acetate, methylcyclohexane, diethoxymethane, or mixtures thereof. The process of the present invention can be carried out under atmospheric pressure or under elevated or reduced pressure. Typically, the atmospheric and elevated pressure is employed. In a preferred embodiment the process of the present invention can be carried out at pressure ranges typically from 0.8 atmospheres (atm) to 80 atm, preferably form 1.0 atm to 20 atm, in particular from 1.0 to 7 atm. The temperature used in the process of the present invention can vary widely and is preferably from -30 to 150°C, more preferably from -10 to 120°C, or even more preferably from 0 to 100°C, 20 to 80°C, or 25 to 75°C. Typical reaction times are in the range of from 1 to 20 hours, preferably from 1 to 15 hours, or more preferably from 1 to 10 hours, or from 1 to 5 hours. The following list provides definitions, including preferred definitions, for substituents R1, R2, R3, R4, R5, and W with reference to the compounds of formula (I) of the present invention. For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below or elsewhere in this document. In one embodiment of the invention, R1 is selected from hydroxy, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, Ci-C2-haloalkyl, cyclopropyl, -C(=O)H, -C(=O)OH, -C(=O)Hal, -C(=W)N(R3R4), -CH2-C(=W)N(R3R4), -CH2-N(R3)-C(=W)R4, 5 wherein the staggered line denotes the connection to the phenyl-group. Preferably R1 is selected from hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, -C(=O)N(R3R4), -CH2-C(=O)N(R3R4), -CH2-N(R3)-C(=O)R4, wherein the staggered line denotes the connection to the phenyl-group. 10 In one embodiment of the invention, R1 is selected from hydroxy, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, Ci-C2-haloalkyl, or-CH2-N(R3)-C(=O)R4. Preferably R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, or -C(=O)N(R3R4). In one embodiment of the invention, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, Ci-Cs-alkyl, Ci-C2-haloalkyl, or -C(=O)N(R3R4). Preferably, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, 15 trichloromethyl, or-C(=O)N(R3R4). In one embodiment of the invention, R1 is selected from CH2-N(R3)-C(=O)R4. In one embodiment of the invention, R1 is selected from -C(=O)N(R3R4). In one embodiment of the invention, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, Ci-Cs-alkyl, Ci-C2-haloalkyl, -CH2-C(=O)N(R3R4), wherein the staggered line denotes the connection to the phenyl-group. Preferably, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -CH2-C(=O)N(R3R4), wherein the staggered line denotes the connection to the phenyl-group. In one embodiment of the invention, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, Ci-Cs-alkyl, C1-C2-haloalkyl, or -CH2-C(=O)N(R3R4). Preferably, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, or -CH2-C(=O)N(R3R4). In one embodiment of the invention, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, Ci-Cs-alkyl, C1-C2-haloalkyl, -C(=O)H, or wherein the staggered line denotes the connection to the phenyl-group. Preferably, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, or O wherein the staggered line denotes the connection to the phenyl-group. In one embodiment of the invention, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, Ci-Cs-alkyl, C1-C2-haloalkyl, -C(=O)H, wherein the staggered line denotes the connection to the phenyl-group. Preferably, R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, O wherein the staggered line denotes the connection to the phenyl-group. In one embodiment R1 is O wherein the staggered line denotes the connection to the phenyl-group. In one embodiment R1 is wherein the staggered line denotes the connection to the phenyl-group. In one embodiment R1 is wherein the staggered line denotes the connection to the phenyl-group. In one embodiment of the invention, R1 is -C(=O)N(R3R4), wherein R3 is methyl, or 2-fluorophenyl; and R4 is hydrogen. In one embodiment R1 is -C(=O)NH(2-fluorophenyl). In another embodiment, R1 is -C(=O)NH(methyl). In one embodiment of the invention, R1 is -CH2-N(R3)-C(=O)R4, wherein R3 is hydrogen, or methoxy; and R4 is cyclopropyl, or 1-methoxyethyl. Preferably R1 is -CH2-N(R3)-C(=O)R4, wherein R3 is methoxy; and R4 is cyclopropyl, or 1-methoxyethyl. In one embodiment of the invention, R2 is selected from Ci-C2-haloalkyl. Preferably R2 is CF3, or CF2CI. In one embodiment of the invention, R2 is CF3. In another embodiment of the invention, R2 is CF2CI. In one embodiment of the invention, R3 is selected from hydrogen, Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, or cyclopropyl. Preferably R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, or cyclopropyl. In one embodiment of the invention, R4 is selected from Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C6-cycloalkyl, Ci-C2-alkoxy-Ci-C3-alkyl, or phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen. Preferably R4 is methyl, ethyl, methoxy, ethoxy, cyclopropyl, 1-methoxyethyl, or 2-fluoro-phenyl. In one embodiment of the invention, R5 is selected from hydrogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or C1-C4-alkoxy-Ci-C2-alkoxy. Preferably R5 is hydrogen, Ci-Cs-alkoxy, or Ci-Cs-haloalkoxy. More preferably R5 is hydrogen, methoxy, ethoxy, or methoxy-ethoxy. In one embodiment of the invention, W is selected from O, or S. In one embodiment of the invention, W is O. In another embodiment of the invention, W is S. In one embodiment of the invention, R6 is selected from Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl. Preferably R6 is Ci-Ci2-alkyl, vinyl or benzyl. More preferably, R6 is methyl, ethyl, / -propyl, n-butyl, tert-butyl, vinyl or benzyl. Even more preferably, R6 is methyl, ethyl, n-butyl, or terf-butyl. The present invention, accordingly, makes available a compound of formula (I) having R1, R2, R3, R4, R5 and W, as defined above in all combinations / each permutation. Embodiments according to the invention are provided as set out below. Process for the preparation of compounds of formula (I) The process for the preparation of compound of formula (I), from amidoxime compound of formula (II) by reaction with a haloacetic ester of formula (III) in the presence of at least one base, wherein said process is characterized in that said at least one base is selected from a guanidine-base is shown to Scheme 1. Scheme 1: Process for the preparation of compounds of formula (I) from compounds of formula (II) O In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I) wherein R1 is selected from hydroxy, thiol, cyano, halogen, hydroxymethyl, Ci-Cs-alkyl, Ci-C2-haloalkyl, cyclopropyl, -C(=O)H, -C(=O)OH, -C(=O)Hal, -C(=W)N(R3R4), -CH2-C(=W)N(R3R4), -CH2-N(R3)-C(=W)R4, wherein the staggered line denotes the connection to the phenyl-group; R2 is selected from Ci-C2-haloalkyl; R3 is selected from hydrogen, Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, or cyclopropyl; R4 is selected from Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, Cs-Ce-cycloalkyl, Ci-C2-alkoxy-Ci-C3-alkyl, or phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen; R5 is selected from hydrogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or Ci-C4-alkoxy-Ci-C2-alkoxy; and W is selected from O, or S; said process comprising the reaction of an amidoxime compound of formula (II) wherein R1, R3, R4 and R5 are as defined for compounds of formula (I), with a haloacetic ester of formula (III) O wherein R2 is as defined for compounds of formula (I), and R6 is selected from Ci-Ci2-alkyl, C2-C6-alkenyl, C-i-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 7,7,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, -C(=O)N(R3R4), -CH2- C(=O)N(R3R4), -CH2-N(R3)-C(=O)R4, wherein the staggered line denotes the connection to the phenyl-group; R2 is CF3, or CF2CI; R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, or cyclopropyl; R4 is methyl, ethyl, methoxy, ethoxy, cyclopropyl, 1-methoxyethyl, or 2-fluoro-phenyl; R5 is hydrogen, methoxy, ethoxy, or methoxy-ethoxy; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 7,7,3,3-tetramethylguanidine, 2-terf-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning R1 is CH2-N(R3)-C(=O)R4; R2 is CF3; R3 is hydrogen, or Ci-C2-alkoxy; R4 is C3-C6-cycloalkyl, or Ci-C2-alkoxy-Ci-C3-alkyl; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 7,7,3,3-tetramethylguanidine, 2-terf-butyl-1,1,3,3- tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, or-CH2-N(R3)-C(=O)R4; R2 is CF3; R3 is hydrogen, or methoxy; R4 is cyclopropyl, or 1-methoxyethyl; and R6 is methyl, ethyl, / -propyl, n-butyl, tert-butyl, vinyl or benzyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 7,7,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, or -C(=O)N(R3R4); R2 is CF3; R3 is methyl, or 2-fluorophenyl; R4 is hydrogen; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 7,7,3,3-tetramethylguanidine, 2-te / 7-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -CH2-C(=O)N(R3R4), wherein the staggered line denotes the connection to the phenyl-group; R2 is CF3, or CF2CI; R3 is hydrogen, cyclopropyl, or Ci-C2-alkoxy; R4 is Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, Cs-Ce-cycloalkyl, or Ci-C2-alkoxy-Ci-C3-alkyl; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 7,7,3,3-tetramethylguanidine, 2-terf-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, or wherein the staggered line denotes the connection to the phenyl-group; R2 is CF3, or CF2CI; R5 is hydrogen, methoxy, ethoxy, or methoxy-ethoxy; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 7,7,3,3-tetramethylguanidine, 2-terf-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment, the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning R1 is hydroxy, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, O wherein the staggered line denotes the connection to the phenyl-group; R2 is CF3; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 7,7,3,3-tetramethylguanidine, 2-terf-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. In one embodiment of the invention, the compound of formula (I) is selected from N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide according to structure (l-A) (i-A); N,2-dimethoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]propanamide according to structure (l-B) (l-B); N-(2,2,2-trifluoroethyl)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]oxazole-4-carboxamide according to structure (l-C) ethyl 1 -[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy]methyl]pyrazole-4-carboxylate according to 5 structure (l-D) 4-(2-methoxyethoxy)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]pyridazin-3-one according to structure (l-E) 10 ethyl 1-[[4-[5-[chloro(difluoro)methyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl]pyrazole-4-carboxylate according to structure (l-F) 5,5-dimethyl-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]isoxazolidin-3-one according to structure (l-G) N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide according to structure (l-H) F N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzenecarbothioamide according to structure (l-J) 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole according to structure (l-K) In one preferred embodiment of the invention, compound of formula (I) is N-methoxy-N-[[4-[5-(trifluoromethyl)- 1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide according to structure (l-A). In another preferred embodiment of the invention, compound of formula (I) is N,2-dimethoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]propanamide according to structure (l-B). In another preferred embodiment of the invention, compound of formula (I) is N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide according to structure (l-H). In another preferred embodiment of the invention, compound of formula (I) is N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzenecarbothioamide according to structure (l-J). In another preferred embodiment of the invention, the compound of formula (I) is ethyl 1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy]methyl]pyrazole-4-carboxylate according to structure (l-D). In another preferred embodiment of the invention, the compound of formula (I) is 4-(2-methoxyethoxy)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]pyridazin-3-one according to structure (l-E). In another preferred embodiment of the invention, the compound of formula (I) is ethyl 1-[[4-[5-[chloro(difluoro)methyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl]pyrazole-4-carboxylate according to structure (l-F). In another preferred embodiment of the invention, the compound of formula (I) is 5,5-dimethyl-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]isoxazolidin-3-one according to structure (l-G). In another preferred embodiment of the invention, the compound of formula (I) is 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole according to structure (l-K). In one embodiment of the invention, a compound of formula (I), wherein R1 is methyl, is converted to a valuable chemical product or other intermediate. Accordingly, in one embodiment, compounds of formula (I) wherein R1 is methyl, can be further chlorinated to obtain a compound of formula (l-a), and wherein R2 is as defined as for compounds of formula (I) The methyl-group (R1) of compounds of formula (I) can be converted to a trichloromethyl-group as disclosed in WO2019 / 020451A1 and references cited therein. In another embodiment of the invention, a compound of formula (l-a) can be further converted to a compound of formula (l-b), wherein R1 is -C(=O)CI, and wherein R2 is as defined as for compounds of formula (I). This has been disclosed in WO2019 / 020451A1 and the references cited therein. The present invention also relates to intermediates of any of formulae (V) and (VI) which are formed in the process of the invention from the step of reacting a compound of formula (II) with a compound of formula (III) in the presence of a guanidine base (Scheme 1). The intermediates so obtained may be characterized by any suitable analytical techniques such as NMR and IR spectroscopy. The compound of formula (III) reacts with a guanidine-base to the corresponding acetamide of formula (V), and then the acyl-moiety is transferred to the compound of formula (II) under formation of intermediate of formula (VI). The guanidine-base may act as acyltransfer reagent. The intermediate of formula (V) leads after cyclisation to the compound of formula (I). Scheme 1 shows the mechanism and the intermediates with 1,1,3,3 tetramethylguanidine as base. A person skilled in the art is well aware that the same mechanism applies to the use of other guanidine bases. Scheme 1 A person skilled in the art is well aware that these intermediates of formula (V) and (VI) (as shown in Scheme 1) wherein R1, R2, and R6 are as defined for compounds of formula (I), (II) and (III) according to the present invention, are within the scope of the invention. Further a person skilled in the art is well aware that the above mechanism applies to any guanidine-base that can be used for the process of the present invention. According to another aspect of the invention, there is provided an intermediate compound of formula (V-a) Iio R (V-a) wherein R2 is as defined for compounds of formula (I), (II), and (III) according to the present invention, and wherein R7, R8, R9, R10 are independently selected from hydrogen, or Ci-C4-alkyl. In one embodiment of the invention, in the intermediate compound of formula (V-a) R7, R8, R9, R10 are independently selected from hydrogen, or methyl and R2 is Ci-C2-haloalkyl. Preferably, in the intermediate compound of formula (V-a) R7, R8, R9, R10 are independently selected from hydrogen, or methyl and R2 is trifluoromethyl, or difluoromethyl. The disclosure in the present application makes available each and every combination of embodiments disclosed herein. EXAMPLES The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. ABBREVIATIONS BuOAc        n-butyl acetate CDCI3         deuterated chloroform DBU           1,8-diazabicyclo[5.4.0]undec-7-ene eq.            equivalent h / hrs           hour / hours K2CO3        potassium carbonate NaOEt        sodium ethanolate NaOtBu       sodium tert-butoxide rt             room temperature Rt              retention time TBD           1,5,7 triazabicyclo[4.4.0]dec-5-ene (or triazabicyclodecene) TEA          triethylamine TLC           thin layer chromatography TMG          1,1,3,3-tetramethylguanidine PREPARATORY EXAMPLES The compounds of formula (I) according to the invention may be prepared using the synthetic techniques described both above and below. Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. Free radicals represent methyl groups. 1H NMR and 19F NMR measurements were recorded on a Bruker 400MHz spectrometer (or as indicated), chemical shifts are given in ppm relevant to a TMS (1H) and CFCI3 (19F) standard. Spectra measured in deuterated solvents as indicated. Example P1: Preparation of N-methoxv-N-IT4-r5-(trifluoromethvl)-1,2,4-oxadiazol-3-vllphenvl1methyl1-cyclopropanecarboxamide with ethyl trifluoroacetate (Compound P-1, Table P) A screening vial is at room temperature charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy-cyclopropanecarboxamide (amidoxime) (94%, 280 mg, 1 mmol) and butyl acetate (2 mL) to obtain a suspension. To this suspension ethyl trifluoroacetate (99%, 287 mg, 2 mmol) and TMG (99%, 144 mg, 1.25 mmol) are added and the resulting reaction mixture is stirred at 75°C for 5 hrs (homogenous after 10 min). After end of the reaction (monitored by NMR) the crude reaction mixture is quenched by addition of acetic acid (99.5%, 162 mg, 2.7 eq.) and the chemical yield is determined by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. The desired product N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide is formed in 82% chemical yield. 1H NMR (400 MHz, CDCI3) 6 ppm: 8.09 (d, 2H), 7.53 (d, 2H), 4.87 (s, 2H), 3.73 (s, 3H), 2.19 (m, 1H), 1.05 (m, 2H), 0.86 (m, 2H). 19F NMR (400 MHz, CDCI3) 6 ppm: -65.33 (s) Example P2: Preparation of N-methoxv-N-IT4-r5-(trifluoromethvl)-1,2,4-oxadiazol-3-vllphenvl1-methyl1-cyclopropanecarboxamide with methyl trifluoroacetate (Compound P-1, Table P) A screening vial is at room temperature charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy-cyclopropanecarboxamide (amidoxime) (94%, 280 mg, 1 mmol) and butyl acetate (2 mL) to obtain a suspension. To this suspension methyl trifluoroacetate (99%, 259 mg, 2 mmol) and TMG (99%, 144 mg, 1.25 mmol) are added and the resulting reaction mixture is stirred at 75°C for 5 hrs (homogenous after 10 min). After end of reaction (monitored by NMR) the crude reaction mixture is quenched by addition of acetic acid (99.5%, 162 mg, 2.7 eq.) and the chemical yield is determined by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. The desired product N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide is formed in 83% chemical yield. Example P3: Preparation of N-methoxv-N-IT4-r5-(trifluoromethvl)-1,2,4-oxadiazol-3-vllphenvl1methyl1-cyclopropanecarboxamide with ethyl trifluoroacetate (Compound P-1, Table P) A screening vial (20 mL) is charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy-cyclopropanecarboxamide (98%, 4 mmol, 1.07 g), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 50°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 50°C. Afterwards water (1 g) is added, the layer are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 94% (product in aqueous and organic layer) is 94%. Isolated yield (product in organic layer): 93% 1H NMR (400 MHz, d6-DMSO) 6 ppm: 8.04 (d, 2H), 7.50 (d, 2H), 4.90 (s, 2H), 3.75 (s, 3H), 2.23-2.16 (m, 1H), 0.88-081 (m, 4H). 19F NMR (376 MHz, d6-DMSO) 6 ppm: -64.9 (s). Example P4: Preparation of N,2-dimethoxv-N-IT4-r5-(trifluoromethvl)-1,2,4-oxadiazol-3-vllphenvl1-methyl1-propanamide (Compound P-2, Table P) A screening vial (20 mL) is charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N,2-dimethoxy-propanamide (97%, 4 mmol, 1.16 g), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 50°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 50°C. Afterwards water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield is 93% (product in aqueous and organic layer) . Isolated yield (product in organic layer): 87% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.05 (d, 2H), 7.51 (d, 2H), 4.99 (d, 1H), 4.83 (d, 1H), 4.28 (q, 1H), 3.73 (s, 3H), 3.22 (s, 3H), 1,22 (d, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -64.85 (s). Example P5: Preparation of 3-(p-tolvl)-5-(trifluoromethyl)-1,2,4-oxadiazole (Compound P-3, Table P) A screening vial (20 mL) is charged with N'-hydroxy-4-methyl-benzamidine (97%, 4 mmol, 796.7 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g). Then, the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Afterwards water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 93% (product in aqueous and organic layer). Isolated yield (product in organic layer): 92% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 7.94 (d, 2H), 7.41 (d, 2H), 2.40 (s, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.14 (s). Example P6: Preparation of 5-rchloro(difluoro)methvl1-3-(p-tolyl)-1,2,4-oxadiazole (Compound P-4, Table P) N—o A screening vial (20 mL) is charged with N'-hydroxy-4-methyl-benzamidine (97%, 4 mmol, 796.7 mg), BuOAc (2 mL) and ethyl chlorodifluoroacetate (97%, 8.4 mmol, 1.37 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hours at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 92% (product in aqueous and organic layer). Isolated yield (product in organic layer): 90% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 7.94 (d, 2H), 7.42 (d, 2H), 2.40 (s, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -54.45 (s). Example P7: Preparation of 3-phenyl-5-(trifluoromethyl)-1,2,4-oxadiazole (Compound P-5, Table P) A screening vial (20 mL) is charged with N'-hydroxybenzamidine (98%, 4 mmol, 555.7 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min. at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 92% (product in aqueous and organic layer). Isolated yield (product in organic layer): 91%. 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.05 (d, 2H), 7.66-7.58 (m, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.26 (s). Example P8: Preparation of methyl 4-r5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl1benzoate (Compound P-6, Table El F A screening vial (20 mL) is charged with methyl 4-[N'-hydroxycarbamimidoyl]benzoate (97%, 4 mmol, 800.8 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 89% (product in aqueous and organic layer). Isolated yield (product in organic layer): 88% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.19-8.14 (m, 4H), 3.90 (s, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.17 (s). Example P9: Preparation of 4-r5-(trifluoromethvl)-1,2,4-oxadiazol-3-yl1benzonitrile (Compound P-7, Table P) A screening vial (20 mL) is charged with 4-cyano-N-hydroxybenzimidamide, (97%, 4 mmol, 664.6 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 minutes at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layer are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 95% (product in aqueous and organic layer). Isolated yield (product in organic layer): 94% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.22 (d, 2H), 8.07 (d, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.10 (s). Example P10: Preparation of 3-(4-bromophenvl)-5-(trifluoromethyl)-1,2,4-oxadiazole (compound P-8, Table P) A screening vial (20 mL) is charged with 4-bromo-N'-hydroxy-benzamidine (98%, 4 mmol, 878.0 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 minutes at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 94% (product in aqueous and organic layer). Isolated yield (product in organic layer): 90% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 7.99 (d, 2H), 7.82 (d, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.07 (s). Example P11: Preparation of 3-(4-chlorophenvl)-5-(trifluoromethyl)-1,2,4-oxadiazole (compound P-9, Table P) A screening vial (20 mL) is charged with 4-chloro-N'-hydroxy-benzamidine (97%, 4 mmol, 703.5 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 minutes at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layer are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 93% (product in aqueous and organic layer). Isolated yield (product in organic layer): 92% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.07 (d, 2H), 7.69 (d, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -64.92 (s). Example P12: Preparation of r4-r5-(trifluoromethyl)-1,2,4-oxadiazol-3-vllphenyl1methanol (compound P-11, Table P) A screening vial (20 mL) is charged with N-hydroxy-4-(hydroxymethyl)benzimidamide (97%, 4 mmol, 685.4 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hr at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 93% (product in aqueous and organic layer). Isolated yield (product in organic layer): 91% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.02 (d, 2H), 7.56 (d, 2H), 4.61 (s, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -64.95. Example P13: Preparation of N-methvl-4-r5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl1benzamide (Compound P12, Table P) A screening vial (20 mL) is charged with 4-(N-hydroxycarbamimidoyl)-N-methyl-benzamide (95%, 4 mmol, 813.5 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layers are separated at 50°C and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 94% (product in aqueous and organic layer). Isolated yield (product in organic layer): 90% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.65 (br q, 1H), 8.15 (d, 2H), 8.06 (d, 2H), 2.83 (d, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.10 (s). Example P14: Preparation of N-IT4-r5-(difluoromethvl)-1,2,4-oxadiazol-3-vllphenvl1methyl1-N-methoxv-cyclopropanecarboxamide (Compound P-13, Table P) A screening vial (20 mL) is charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy-cyclopropanecarboxamide (98%, 4 mmol, 1.07 g), BuOAc (3 mL) and ethyl trifluoroacetate (98%, 8.4 mmol, 1.06 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hours at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 92% (product in aqueous and organic layer). Isolated yield (product in organic layer): 91% 1H NMR (400 MHz, d6-DMS0) 6 ppm: 8.03 (d, 2H), 7.54 (t, 1H), 7.49 (d, 2H), 4.89 (s, 3H), 3.75 (s, 3H), 2.232.16 (m, 1H), 0.85-0.82 (m, 4H). 19F NMR (376 MHz, d6-DMS0) 6 ppm: -121.90 (d). Example P15: Preparation of N-rr4-r5-(chloro(difluoro)methvl1-1,2,4-oxadiazol-3-vl1phenvl1methyl1-N-methoxv-cyclopropanecarboxamide (Compound P-14, Table P) , / 0H nh2 H3C. _n. A screening vial (20 mL) is charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy-cyclopropanecarboxamide (98%, 4 mmol, 1.07 g), BuOAc (2 mL) and ethyl chlorodifluoroacetate (97%, 8.4 mmol, 1.37 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hours at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 88% (product in aqueous and organic layer). Isolated yield (product in organic layer): 87% 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.03 (d, 2H), 7.50 (d, 2H), 4.90 (s, 2H), 3.75 (s, 3H), 2.23-2.16 (m, 1H), 0.85-0.82 (m, 4H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -54.49 (s). Example P16: Preparation of N-(2-fluorophenvl)-4-r5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl1benzamide (compound P-15, Table P) A screening vial (20 mL) is charged with N-(2-fluorophenyl)-4-[(Z)-N-hydroxycarbamimidoyl]benzamide (95%, 4 mmol, 1150.6 mg), BuOAc (4 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. The reaction mixture is cooled to rt, and the final product is filtered and analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 97% (product in aqueous and organic layer). Isolated yield 90% (product in organic layer). 1H NMR (400 MHz, d6-DMSO) 5 ppm: 10.38 (brs, 1H), 8.24-8.19 (m, 4H), 7.63 (dt, 1H), 7.34-7.22 (m, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -64.72 (s), -120.97 (dd). Example P17: Preparation of 3-r4-(trifluoromethoxv)phenvl1-5-(trifluoromethyl)-1,2,4-oxadiazole (compound P10, Table P) A screening vial (20 mL) is charged with N-hydroxy-4-(trifluoromethoxy)benzimidamide (98%, 4 mmol, 898.6 mg), BuOAc (2 mL) and ethyl trifluoroaceatete (99%, 8.4 mmol, 1.21 g). The resulting suspension is stirred for 2 min at 60 °C followed by addition of 1TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 60 °C. Water (1 g) is added and the layer are separated and both layers are analyzed by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Chemical yield 91% (product in aqueous and organic layer). Isolated yield 89% (product in organic layer). 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.19 (d, 2H), 7.60 (d, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -56.96 (s), -64.99 (s). General Procedure of Base-screening A screening vial is at rt charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy-cyclopropanecarboxamide (4 mmol, amidoxime) and butyl acetate (0.5 mL / mmol amidoxime) to obtain a suspension. To this suspension ethyl trifluoroacetate (2.1 eq. based on amidoxime) and TMG (1.1 eq. based on amidoxime) are added, and the resulting reaction mixture is stirred at 60°C for 4 hrs (homogenous after 10 min). After end of the reaction (monitored by NMR) the crude reaction mixture is quenched by addition of acetic acid (2.7 eq. based on base) and the chemical yield is determined by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Table B1 summarizes the results obtained for the different bases used. Amidoxime Oxadiazole Table B1: Results of base-screening Example Base Chemical Yield Oxadiazole [%] Chemical Yield Amidoxime [%] Mass Balance B.01 None 1% 99% 100% B.02 TMG 94% 5% 99% B.03 DBU 86% 4% 90% B.04 TBD 86% 10% 96% B.05 3,5-Lutidine 8% 91% 99% B.06 TEA 11% 89% 100% B.07 K2CO3 34% 62% 96% B.08 NaOtBu 60% 18% 78% B.09 NaOEt 87% 1% 88% The above results show that high yields of the required oxadiazole derivatives were achieved by using TMG as a base at moderate reaction temperatures. Such TMG outperformed other strong bases in terms of chemical yield and mass balance. Under the applied reaction conditions using NaOEt (sodium ethanolate) resulted in decomposition of starting material. General Procedure of Solvent Screening A screening vial is at room temperature charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-5 methoxy-cyclopropanecarboxamide (4 mmol, amidoxime) and solvent to obtain a suspension. To this suspension ethyl trifluoroacetate (2 to 2.2 eq. based on amidoxime) and 1,1,3,3-tetramethylguanidine (1.1 to 1.25 eq. based on amidoxime) are added and the resulting reaction mixture is stirred at 30 to 75°C (see examples) for 4 to 5 hrs (homogenous after 10 min). After end of the reaction (monitored by NMR) the crude reaction mixture is quenched by addition of acetic acid (2.7 eq. based on base) and the chemical yield is 10 determined by quantitative NMR analysis using 1,3,5-trimethoxybenzene as internal standard. Table B2, B3 and B4 summarize the results obtained for the different solvents used. Example Solvent-Screening 1: Amidoxime TMG ( 1.1 eq.) solvent (0.75 ml / mmol amidoxime) Table B2: Solvent Screening with 2.1 eq. ethyl trifluoroacetate, 1.1 eq. TMG, 0.75 mL solvent / mmol 15 amidoxime Example solvent Temperature [°C] Chemical Yield Oxadiazole [%] Chemical Yield Amidoxime [%] B.10 toluene 30 85% 15% B.11 toluene 50 90% 8% B.12 diethyl carbonate 30 83% 15% B.13 diethyl carbonate 50 88% 8% B.14 butyl acetate 30 82% 16% B.15 butyl acetate 50 92% 8% B.16 n-butanol 30 69% 23% B.17 n-butanol 50 92% 8% B.18 6.3 eq. ethyl trifluoroacetate 30 89% 11% B.19 6.3 eq. ethyl trifluoroacetate 50 95% 4% B.20 ethyl acetate 50 91% 8% B.21 fluorobenzene 50 92% 7% B.22 2,2,2-T rifluorethanol 50 76% 23% Table B3: Solvent Screening with 2.2 eq. ethyl trifluoroacetate, 1.25 eq. TMG, 2 mL solvent / mmol amidoxime Example solvent Temperature [°C] Chemical Yield Oxadiazole [%] Chemical Yield Amidoxime [%] B.23 ethanol 75 78% b 78% b B.24 acetonitrile 75 85% b 85% b B.25 methyl isobutyl ketone (MIBK) 75 85% b 85% b B.26 dimethyl carbonate (DMC) 75 87% b 87% b B.27 toluene 75 86% b 86% b B.28 methylcyclohexane (MCH) 75 87%c 87%c B.29 benzonitrile (PhCN) 75 87% b 87% b B.30 diethoxymethane 75 86% b 86% b B.31 N,N-dimethylformamid (DMF) 75 76%c 76%c B.32 butyronitrile 75 84%c 84%c B.33 trifluorotoluene 75 89% b 89% b B.34 anisole 75 87% b 87% b B.35 1,3-dichloro benzene 75 87% b 87% b B.36 n-Propyl acetate 75 86%c 86%c B.37 ethyl valerate 75 82%c 82%c B.38 ethyl propionate 75 86%c 86%c B.39 pentyl acetate 75 85%c 85%c B.40 i-propyl acetate 75 83%c 83%c B.41 butyl acetate 75 82%c 82%c b]: determined by quantitative HPLC analysis, [c]: determined by quantitative NMR analysis of reaction mixture using 1,2,3-trimethoxybenzene as internal standard Table B4: Solvent Screening with 45 mmol amidoxime 2.1 eq. ethyl trifluoroacetate, 1.1 eq. TMG, 0.5 mL 5 solvent / mol amidoxime, 60°C Example solvent Reaction time Chemical Yield Oxadiazole [%] Chemical Yield Amidoxime [%] B.42 butyl acetate 5 hr 93% 3% B.43 tetrahydrofuran 5 hr 93% 7% B.44 ethyl acetate 5 hr 89% 8% B.45 fluorobenzene 21 hr 96% 3% B.46 dimethyl carbonate (DMC) 21 hr 89% 4% B.47 propyl acetate 21 hr 97% 3% B.48 / so-propyl acetate 21 hr 97% 3% The above results show that in the process of the present invention the organic solvent that can be used is not restricted due to the nature of the base used. The above results show that high yields of the required oxadiazole derivatives were achieved by using TMG as a base at moderate reaction temperatures in various solvents. Although the invention has been described with reference to preferred embodiments and examples thereof, 5 the scope of the present invention is not limited only to those described embodiments. As will be apparent to persons skilled in the art, modifications and adaptations to the above-described invention can be made without departing from the spirit and scope of the invention, which is defined and circumscribed by the appended claims. All publications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were specifically and individually indicated to be so incorporated 10 by reference Examples of synthesized compounds of formula (I) according to the present invention are shown in Table P. Table P: Synthesized compounds and Spectral and Physical Chemical Data Entry lUPAC-Name Structure NMR-data P-1 N-methoxy-N-[[4-[5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl]phenyl]methyl] cyclopropanecarboxamide ru       N—0 a r j x 0 1H NMR (400 MHz, CDCI3) 6 ppm: 8.09 (d, 2H), 7.53 (d, 2H), 4.87 (s, 2H), 3.73 (s, 3H), 2.19 (m, 1H), 1.05 (m, 2H), 0.86 (m, 2H). 19F NMR (400 MHz, CDCI3) 6 ppm: -65.33 (s) P-2 N,2-dimethoxy-N-[[4-[5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl]phenyl]methyl] propanamide h3c o     CH       N—q 0 1H NMR (400 MHz, CDCI3) 6 ppm: 8.09 (d, 2H), 7.48 (d, 2H), 4.98 (m, 1H), 4.80 (m, 1H), 4.27 (m, 1H), 3.71 (s, 3H), 3.34 (s, 3H), 1.37 (d, 3H). 19F NMR (400 MHz, CDCI3) 6 ppm: -65.35 (s). P-3 3-(p-tolyl)-5-(trifluoromethyl)-l ,2,4-oxadiazole \ / / "-o h3c—a  ')—( / 1 \= / \^<F r f F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 7.94 (d, 2H), 7.41 (d, 2H), 2.40 (s, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.14 (s). P-4 5-[chloro(difluoro)methyl]-3-(p-tolyl)-1,2,4-oxadiazole N—O h3c^\^      Cl F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 7.94 (d, 2H), 7.42 (d, 2H), 2.40 (s, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -54.45 (s). P-5 3-phenyl-5-(trifluoromethyl)-l ,2,4-oxadiazole N—0 J X / i F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.05 (d, 2H), 7.66-7.58 (m, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.26 (s). P-6 methyl 4-[5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl]benzoate 1 7 o oz \ o to I 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.19-8.14 (m, 4H), 3.90 (s, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.17 (s). P-7 4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile N—0 J II F 1H NMR (400 MHz, d6-DMSO) 6 ppm: 8.22 (d, 2H), 8.07 (d, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.10 (s). P-8 3-(4-bromophenyl)-5-(trifluoromethyl)-l ,2,4-oxadiazole N—O J JI              \~F F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 7.99 (d, 2H), 7.82 (d, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.07 (s). P-9 3-(4-chlorophenyl)-5-(trifluoromethyl)-l ,2,4-oxadiazole N—O J 1               \~F a'^\^      F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.07 (d, 2H), 7.69 (d, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -64.92 (s). P-10 3-[4-(trifluoromethoxy)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole f-4-^=^nA<f F                      F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.19 (d, 2H), 7.60 (d, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -56.96 (s), -64.99 (s). P-11 [4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methanol N—O J \_ / Jl              \~F F HO 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.02 (d, 2H), 7.56 (d, 2H), 4.61 (s, 2H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -64.95. P-12 N-methyl-4-[5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl]benzamide F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.65 (br q, 1H), 8.15 (d, 2H), 8.06 (d, 2H), 2.83 (d, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -65.10 (s). P-13 N-[[4-[5-(difluoromethyl)- 1,2,4-oxadiazol-3-yl]phenyl]methyl]-N-methoxycyclopropanecarboxamide 1 ch3 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.03 (d, 2H), 7.54 (t, 1H), 7.49 (d, 2H), 4.89 (s, 3H), 3.75 (s, 3H), 2.23-2.16 (m, 1H), 0.85-0.82 (m, 4H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -121.90 (d). P-14 N-[[4-[5- [chloro(difluoro)methyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl]-N-methoxycyclopropanecarboxamide A              N-O. F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 8.03 (d, 2H), 7.50 (d, 2H), 4.90 (s, 2H), 3.75 (s, 3H), 2.23-2.16 (m, 1H), 0.850.82 (m, 4H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -54.49 (s). P-15 N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-l ,2,4-oxadiazol-3-yl]benzamide F 1H NMR (400 MHz, d6-DMSO) 5 ppm: 10.38 (br s, 1H), 8.24-8.19 (m, 4H), 7.63 (dt, 1H), 7.34-7.22 (m, 3H). 19F NMR (376 MHz, d6-DMSO) 5 ppm: -64.72 (s), -120.97 (dd).

Claims

1. A process for the preparation of a compound of formula (I):whereinR1 is selected from hydroxy, thiol, cyano, halogen, hydroxymethyl, Ci-Cs-alkyl, Ci-C2-haloalkyl, cyclopropyl, -C(=O)H, -C(=O)OH, -C(=O)Hal, -C(=W)N(R3R4), -CH2-C(=W)N(R3R4), -CH2-N(R3)-C(=W)R4,CH3Owherein the staggered line denotes the connection to the phenyl-group;R2 is selected from Ci-C2-haloalkyl;R3 is selected from hydrogen, Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, or cyclopropyl;R4 is selected from Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, Cs-Ce-cycloalkyl, Ci-C2-alkoxy-Ci-C3-alkyl, or phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen;R5 is selected from hydrogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or Ci-C4-alkoxy-Ci-C2-alkoxy; andW is selected from O, or S;said process comprising the reaction of an amidoxime compound of formula (II)wherein R1, R3, R4 and R5 are as defined for the compounds of formula (I), with a haloacetic ester of formula (III)Or2^^or6 (III)wherein R2 is as defined for the compounds of formula (I), and R6 is selected from Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl;in the presence of at least one base, wherein said process is characterized in that said at least one base is selected from a guanidine-base.

2. The process according to claim 1, wherein said guanidine-base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton's base), 1,1,2,3-tetramethylguanidine, guanidine carbonate, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 2,3,5,6-tetrahydro-1 H-imidazo[1,2-a]imidazole, 1,5,6,7-tetrahydroimidazo[1,2-a]pyrimidine, 1-carbamimidoyl-3-(o-tolyl)guanidine, or N-isopropylhexahydropyrimidin-2-imine.

3. The process according to claim 1 or 2, wherein said guanidine-base is selected from 1,1,3,3-tetramethylguanidine, 2-terf-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, or 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

4. The process according to claim 3, wherein said guanidine-base is 1,1,3,3-tetramethylguanidine.

5. The process according to any of claims 1 to 4, wherein the amount of said guanidine-base is from 0.1to 2.5 eq. based on the number of moles (mol) of amidoxime compound of formula (II).

6. The process according to any of claims 1 to 5, wherein the amount of said guanidine-base is from 0.1 to 1.5 eq. based on the number of moles (mol) of amidoxime compound of formula (II).

7. The process according to any of claims 1 to 6, wherein the amount of said guanidine-base is from 0.1 to 1.25 eq. based on the number of moles (mol) of amidoxime compound of formula (II).

8. The process according to any of claims 1 to 7, wherein R1 is CH2-N(R3)-C(=O)R4, R2 is CF3; R3 is hydrogen, or Ci-C2-alkoxy; R4 is Cs-Ce-cycloalkyl, or Ci-C2-alkoxy-Ci-C3-alkyl; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl.

9. The process according to claim 8, wherein R1 is CH2-N(R3)-C(=O)R4, R2 is CF3; R3 is methoxy; R4 is cyclopropyl, or 1-methoxyethyl; and R6 is methyl, ethyl, / -propyl, n-butyl, tert-butyl, vinyl, or benzyl.

10. The process according to any of claim 1 to 7, wherein R1 is -C(=O)N(R3R4); R2 is CF3; R3 is methyl, or 2-fluorophenyl; R4 is hydrogen; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl.

11. The process according to any of claim 1 to 7, wherein R1 iswherein the staggered line denotes the connection to the phenyl-group; R2 is CF3; and R6 is C1-C12-alkyl, C2-C6-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl.

12. The process according to any of claim 1 to 7, wherein R1 iswherein the staggered line denotes the connection to the phenyl-group; R2 is CF3, or CF2CI; R5 is hydrogen, methoxy, ethoxy, or methoxy-ethoxy; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl.

13. The process according to any of claims 1 to 7, wherein R1 iswherein the staggered line denotes the connection to the phenyl-group; R2 is CF3, or CF2CI; and R6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl.5   14. An intermediate compound of formula (V-a)R (V-a)wherein R2 is Ci-C2-haloalkyl, and wherein R7, R8, R9, R10 are independently selected from hydrogen, or Ci-C4-alkyl.10    15. The intermediate compound of formula (V-a) according to claim 14, wherein R7, R8, R9, R10 areindependently selected from hydrogen, or methyl; and R2 is trifluoromethyl, or difluoromethyl.