PROCESS FOR THE PREPARATION OF DIVERSELY SUBSTITUTED CYANOCYCLOPROPYL - HETEROARENES OR ARENES

The present invention relates to the preparation of diversely substituted cyanocyclopropyl- heteroarenes or arenes that are useful as intermediates for the preparation of active ingredients.

Certain cyanocyclopropyl-heteroarenes or arenes are useful intermediates for the preparation of biologically active compounds as previously described, for example, in: WO16121997, W020013147 and WO22043468.

Known synthesis of such cyanocyclopropyl-heteroarenes from Halo-heteroarenes involve many reaction steps or require the use of expensive transition metals. Most often, those steps are first, replacement of the halogen or sulfone by alkyl-2-cyanoacetate in a nucleophilic aromatic substitution, followed by saponification of the ester, decarboxylation of the acid thus obtained, and finally cyclopropanation with 1 ,2-di-halo-ethane and a base. Alternatively, when the Leaving Group is a halogen activated enough for oxidative insertion by a transition metal-based catalyst such as [Pd-L _n ], direct coupling with the anion of cycanocyclopropyl may be considered. Both approaches are shown in Scheme 1 (A = C or N ; LG = Leaving Group, such as halogen or sulfone).

Scheme 1 . Typical routes to cyanocyclopropyl-heteroarenes or arenes

Such long and laborious syntheses are not optimal for preparing large amount of material due to low overall yields and large amount of waste generated, or to the use of expensive noble metal catalysts. Therefore, it would be advantageous to have available a more efficient and economical route to these useful intermediates.

The present invention therefore provides a process for the preparation of cyanocyclopropyl-arenes or heteroarenes of formula (I) wherein R is selected from R _a or Rb, wherein R _a is aryl substituted by at least one electron withdrawing group; Rb is an unsubstitued or substituted heteroaryl and Ri , R2, R3, and R4 are, independently from each other, hydrogen, alkyl, aryl, aryloxyalkyl or haloaryloxyalkyl, wherein at least one of R3 or R4 is hydrogen.

In accordance with a first aspect of the present invention, the direct replacement of a halogen atom or a sulfone group in electrophilic, activated positions of arenes (R _a ) or heteroarenes (Rb) of formula (II) and (III), using a base and a reagent of formula (IV)-a yields in a single step a compound of formula (l)-a wherein R is defined as previously and LG is a leaving group constituted of a halogen atom or a sulfone group (Scheme 2).

Scheme 2

The compound of formula (IV)-a is known, commercially available and its synthesis described by Yamagata, Kenji et al in Chemical & Pharmaceutical Bulletin, 30(12), 4396-401 ; 1982 ; or by Wamhoff, Heinrich and Thiemig, Heinz Albrecht in Chemische Berichte, 118(11), 4473-85; 1985.

Aryl and alkyl substituents can be introduced by using more elaborated reagents of formula (IV) wherein R1 , R2, R3, and R4 are as defined above (Scheme 3),

Scheme 3

The compounds of formula (IV) are prepared by the same way as compound of formula (IV)-a, but by using substituted thiiranes of formula (VI) (wherein R1 , R2, R3, and R4 are as defined above) which are made simply from corresponding epoxides and potassium thiocyanate (KSCN) (Scheme 4),

Scheme 4 as described by Naoto Aoyagi et al in Chemistry Select, 2, 4466-4468; 2017 ; followed by treatment with malonitrile and a base as NaH as described in Yamagata, Kenji et al in Chemical & Pharmaceutical Bulletin, 30(12), 4396-401 ; 1982 ; (NMP as solvent instead of DMSO for safety reasons) or by LiOH.FW (in THF or MeTHF as solvent) or alternatively, by NaH in DME as solvent as described in Wamhoff, Heinrich and Thiemig, Heinz Albrecht in Chemische Berichte, 118(1 1), 4473-85; 1985. In scheme 4, Ri , R2, RS, and R4 are as defined above.

Thus, according to the present invention there is provided a process for the preparation of a compound of formula (I) wherein

R is selected from R _a or Rb, wherein R _a is an aryl group substituted by at least one electron withdrawing substituent; Rb is an unsubstitued or substituted heteroaryl group and R1 , R2, R3, and R4 are, independently from each other, hydrogen, alkyl, aryl, aryloxyalkyl or haloaryloxyalkyl, wherein at least one of Ra or R4 is hydrogen; which process comprises: reacting a compound of formula (II) or (III)

±G wherein R _a and Rb are as defined in formula (I); and LG is a halogen or a sulfone group, with a compound of formula (IV), wherein R-i, R2, R3, and R4 are as defined in formula (I); in the presence of a suitable base, in an appropriate solvent (or diluent); to produce a compound of formula (I) wherein R, R1, R2, R3, and R4 are as defined under formula I above.

In one embodiment, the present invention relates to a process for the preparation of a compound of formula (I) as described above, with the exception of a process for the preparation of 5-(1- cyanocyclopropyl)-pyridine-2-carboxylic acids, esters, amides and nitriles of formula l-b or agrochemically acceptable salts thereof

(l-b) wherein Rib is -CO2R4b, -CO(NR5bReb), carboxylate or cyano; R2b is hydrogen, halogen or -SRsb; Rsb is Ci-C4alkyl or C3-Cecycloalkyl-Ci-C4alkyl; R4b is hydrogen, -Si(CH3)3 or Ci-Cealkyl; and Reb and Reb are, independently from each other, hydrogen or Ci-C4alkyl.

A second aspect of the present invention provides certain compounds of formula I represented by the compounds of formula (l)-a

(l)-a wherein R is as defined in formula (I) above.

In another embodiment, the present invention relates to certain compounds of formula I represented by the compounds of formula (l)-a as described above, with the exception of a compound of formula (l)-a which is a 5-(1-cyanocyclopropyl)-pyridine-2-carboxylic acid, ester, amide or nitrile of formula l-b or an agrochemically acceptable salt thereof

(l-b) wherein Rib is -CO2R4b, -CO(NR5bReb), carboxylate or cyano; R2b is hydrogen, halogen or -SRsb; Rsb is Ci-C4alkyl or C3-C6cycloalkyl-Ci-C4alkyl; R4b is hydrogen, -Si(CH3)3 or Ci-Cealkyl; and Rsb and Reb are, independently from each other, hydrogen or Ci-C4alkyl. The process of the present invention is demonstrated to be of great usefulness as it allows the synthesis of key building blocks for the preparation of active ingredients in higher yields and with more favorable conditions with respect to previously described routes.

Additional aspects of the process according to the invention for making compounds of formula (I) are further detailed and explained by reference to scheme 5, wherein R, LG, Ri to R4 are defined as above. Some intermediates compounds are made and further transformed in the process of making compounds of formula (I), which can then be detailed as passing through the following intermediates in a single pot operation (Scheme 5).

Scheme 5

The intermediate salts can sometimes be protonated, isolated and characterized under the forms of INT I, INT II, or INT III before their complete transformations into compounds of formula (I). In this regard, the compounds INT I, INT II, or INT III can also be resubmitted to basic conditions in a separate, subsequent step to provide compounds of formula (I). In the process according to the invention for making compounds of formula (I), examples of suitable bases are alkali metal hexamethyldisilazides, alkaline earth metal hexamethyldisilazides, alkali metal hydroxides, alkali metal alkoxides or alkaline earth metal alkoxides. Examples which may be mentioned are sodium hydroxide, potassium hydroxide, sodium methanolate, sodium tertiobutanolate, and potassium tertiobutanolate; preferably an alkali metal hydroxide, more preferably sodium hydroxide.

In the process according to the invention of making compounds of formula (I), appropriate solvents (or diluents) are polar solvents, such as dimethylformamide, dimethylsulfoxide, N-methyl-pyrrolidine, dimethylacetamide, sulfolane, N,N'-dimethylpropyleneurea (DMPU); more preferably polar organic solvents chosen from dimethylformamide, dimethylsulfoxide, N-methyl-pyrrolidine. In one embodiment, in the process according to the invention of making compounds of formula (I), the reaction is advantageously carried out in a temperature range from approximately 0°C to approximately +100°C, preferably from approximately +20°C to approximately +80°C.

Another preferred embodiment of the process for the preparation of compounds of formula I as shown and explained in scheme 5 is further detailed by reference to scheme 6 which shows specific embodiments of the formulae I, III, INT 1 , INT II and INT III as represented by compounds of formulae (l)-a, (IV)-a, INT la, INT Ila and INT Illa, respectively.

Scheme 6

In one embodiment, the anions of INT I are intermediates which often do accumulate to a reasonable extent during the course of the reaction, so that if the reaction is interrupted before completion, INT I can be isolated and purified, as can be seen in the preparatory examples. In particular, if the first steps to anions of INT I are run at lower temperature (room temperature or even -10°C to -20°C), a good yield of INT I can be achieved, if it is wished to interrupt the reaction at this stage.

In another embodiment, anions of INT II and INT III do not accumulate to significant levels in the reaction mixture. In some cases, they can be observed as anions by in situ monitoring or (as their protonated forms) by LCMS of reactions samples, but their amounts are too low to be able to interrupt the reaction, isolate and characterize pure samples of INT II or INT III.

In another aspect, the present invention also relates to compounds of the formula INT I

INT I wherein R, Ri , R2, R3, and R4 are defined as under formula I above.

In one embodiment, the present invention also relates to compounds of the formula INT I as described above, with the exception of a compound of formula INT lb

INT lb wherein Rib is -CO2R4b, -CO(NR5bReb), carboxylate or cyano; R2b is hydrogen, halogen or -SR3b; Rsb is Ci-C4alkyl or C3-C6cycloalkyl-Ci-C4alkyl; R4b is hydrogen, -Si(CH3)3 or Ci-Cealkyl; and Rsb and Reb are, independently from each other, hydrogen or Ci-C4alkyl.

Certain preferred embodiments according to the invention are provided as set out below.

Embodiment 1 provides a process for preparing compounds of formula I as defined above.

Preferably embodiment 1 relates to a process for the preparation of a compound of formula (I) as described above, with the exception of a process for the preparation of 5-(1-cyanocyclopropyl)- pyridine-2-carboxylic acids, esters, amides and nitriles of formula l-b or agrochemically acceptable salts thereof as described above.

Embodiment 2 provides a process for the preparation of a compound of formula (I) which process comprises: reacting a compound of formula (II) or (III) with a compound of formula (IV), to produce a compound of formula (I) as defined above.

Preferably embodiment 2 relates to a process for the preparation of a compound of formula (I) as described above, with the exception of a process for the preparation of 5-(1-cyanocyclopropyl)- pyridine-2-carboxylic acids, esters, amides and nitriles of formula l-b or agrochemically acceptable salts thereof as described above.

Embodiment 3 provides a process for the preparation of a compound of formula l-a which process comprises: reacting a compound of formula (II) or (III) with a compound of formula (IV)-a, to produce a compound of formula l-a as provided in scheme 2 as defined above.

Preferably embodiment 3 relates to a process for the preparation of a compound of formula (l-a) as described above, with the exception of a process for the preparation of 5-(1-cyanocyclopropyl)- pyridine-2-carboxylic acids, esters, amides and nitriles of formula l-b or agrochemically acceptable salts thereof as described above.

Embodiment 4 provides a process for the preparation of a compound of formula (I) which process comprises: reacting a compound of formula (II) or (III) with a compound of formula (IV), to produce a compound of formula (I) as provided in scheme 3 as defined above.

Preferably embodiment 4 relates to a process for the preparation of a compound of formula (I) as described above, with the exception of a process for the preparation of 5-(1 -cyanocyclopropyl)- pyridine-2-carboxylic acids, esters, amides and nitriles of formula l-b or agrochemically acceptable salts thereof as described above.

Embodiment 5 provides a process for the preparation of a compound of formula (I) which process comprises: reacting a compound of formula (II) or (III) with a compound of formula (IV), to produce a compound of formula (I) as provided in scheme 5 as defined above.

Preferably embodiment 5 relates to a process for the preparation of a compound of formula (I) as described above, with the exception of a process for the preparation of 5-(1-cyanocyclopropyl)- pyridine-2-carboxylic acids, esters, amides and nitriles of formula l-b or agrochemically acceptable salts thereof as described above.

Embodiment 6 provides a process for the preparation of a compound of formula l-a which process comprises: reacting a compound of formula (II) or (III) with a compound of formula (IV)-a, to produce a compound of formula l-a as provided in scheme 6 as defined above.

Preferably embodiment 6 relates to a process for the preparation of a compound of formula (l-a) as described above, with the exception of a process for the preparation of 5-(1-cyanocyclopropyl)- pyridine-2-carboxylic acids, esters, amides and nitriles of formula l-b or agrochemically acceptable salts thereof as described above.

Embodiment 7 provides a compound of formula l-a as defined above.

Preferably embodiment 7 relates to a compound of formula (l-a) as described above, with the exception of compounds that are 5-(1-cyanocyclopropyl)-pyridine-2-carboxylic acids, esters, amides and nitriles of formula l-b or agrochemically acceptable salts thereof as described above.

Embodiment 8 provides a compound of formula INT I as defined above.

Preferably embodiment 8 relates to a compound of formula INT I as described above, with the exception of a compound of formula INT lb as described above.

With respect to embodiments 1 - 8, preferred values of R, Ri, R2, R3, and R4 are, in any combination thereof, as set out below:

Preferably R is selected from R _a or Rb, wherein R _a is aryl substituted by at least one electron withdrawing group; Rb is an unsubstitued or substituted heteroaryl.

Preferably R _a is a carbocyclic aromatic ring system (such as phenyl or naphthyl) that is mono- or polysubstituted (preferably mono- or di-substitued) by substituents selected from the group consisting of halogen (such as chloro, bromo), cyano, alkyl, haloalkyl, nitro, phenyl, halophenyl, esters, ketones, amides; and wherein at least one such substituent is an electron withdrawing substituent selected from CF3, NO2, CN, esters, ketones, and amides. In one embodiment, Ra is phenyl which is mono- or disubstituted by an electron withdrawing substituent selected from CF3, NO2, CN, esters, ketones, and amides.

Preferably Rb is is a five- to ten-membered heteroaromatic ring system that is unsubstitued or is mono- or polysubstituted by substituents selected from the group consisting of halogen, cyano, Ci-Cealkyl, Ci-Cshaloalkyl, nitro, phenyl and halophenyl; and wherein said ring system can contain 1 or more ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur.

In one embodiment, Rb is pyrimidyl, benzothiazolyl, thiazolyl, pyridyl, pyridazinyl, isoxazolyl, pyrazolyl, quinoxalinyl, or pyrazinyl that is unsubstitued or is mono- or di-substitued by substituents selected from the group consisting of halogen, cyano, Ci-C alkyl, Ci-C haloalkyl, nitro, phenyl and halophenyl

Preferably Ri, R2, R3, and R4 are, independently from each other, hydrogen, alkyl, aryl, aryloxyalkyl or haloaryloxyalkyl, wherein at least one of Rs or R4 is hydrogen.

Also preferred is when R1, R2, R3, and R4 are, independently from each other, hydrogen, Ci-C alkyl, phenyl, phenyloxymethyl or halophenyloxymethyl, wherein at least one of Rs or R4 is hydrogen.

More preferably R1, R2, R3, and R4 are each hydrogen.

Alkyl groups preferably have a chain length of from 1 to 7 carbon atoms and refers to a saturated straight-chain or branched hydrocarbon radical attached via any of the 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, 1 -ethyl-2-methylpropyl, or heptyl.

Haloalkyl groups preferably have a chain length of from 1 to 7 carbon atoms. Haloalkyl is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1 , 1 -difluoro-2,2,2-trichloroethyl, 2, 2,3,3- tetrafluoroethyl and 2,2,2-trichloroethyl; preferably trichloromethyl, difluorochloromethyl, difluoromethyl, trifluoromethyl and dichlorofluoromethyl

Halogen is generally fluorine, chlorine, bromine or iodine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl or halophenyl.

The preparatory examples which follow are intended to illustrate the invention and show preferred compounds of formulae I, and INT I that can be used and/or prepared according to the process described above.

Preparatory examples:

“Mp or m.p.” means melting point in °C. Purity of starting materials, crudes and products was determined with quantitative ¹ H NMR using 1 ,3,5-trimethoxy benzene as an internal standard.

Example 1 : Preparation of 1-pyrimidin-2-ylcyclopropanecarbonitrile To a solution of 5-amino-2,3-dihydrothiophene-4-carbonitrile (100mg, 0.79mmol) and 2-chloropyrimidine (1 equiv., 0.79 mmol) in 3.2 mL DMF were added, at room temperature, 2 equivalents of sodium tertbutanolate (1 .58mmol). After one hour stirring at room temperature, when only the intermediate 2-(2- pyrimidin-2-ylsulfanylethyl)propanedinitrile was observed, the temperature was increased to 65°C during 3 hours, after which time the reaction mixture was allowed to cool down to room temperature. It was then poured onto 10mL of saturated, aqueous NH4CI solution and stirred for 10 minutes. The resulting mixture was then acidified with 10mL of aqueous 1 N HCI and extracted four times with 10mL of dichloromethane. The combined organic layers were dried over solid MgSCU, filtered and the solvent was removed under reduced pressure to deliver 231 mg of the crude desired product as an orange solid. The crude was purified using a 12g silica chromatography column with a gradient of Cyclohexane/Ethyl acetate (up to 1 :1) to give 81 mg of the pure, desired product 1 -pyrimidin-2-ylcyclopropanecarbonitrile (Isolated Yield 77%).

Alternatively, the 1-pyrimidin-2-ylcyclopropanecarbonitrile can be obtained from isolated 2-(2-pyrimidin- 2-ylsulfanylethyl)propanedinitrile (example 2) by following the protocol below.

To a solution of 2-(2-pyrimidin-2-ylsulfanylethyl)propanedinitrile (50mg, 0.245mmol) in 1 mL of DMF at room temperature were added 0.25mL of a solution of Lithium bis(trimethylsilyl)amide (LiHMDS) 1 N in THF. The reaction mixture was then heated at 65°C for 5 hours, before being allowed to cool down to room temperature. It was then poured onto 5mL of a saturated aqueous NH4CI solution, stirred for 10 minutes and extracted 3 times with 15mL of dichloromethane. The combined organic layers were dried over solid Na2SC>4, filtered and the solvent was removed under reduced pressure to deliver 27.4mg of the crude desired product as an orange solid. The crude was quantified by Q-NMR to give a strength (w/w) of 89% and therefore the reaction gave a chemical yield of 69%. m.p. = 124.2 - 125.4 °C with gradual degradation up to 126°C; ¹ H NMR (400 MHz, CDCb): 6 (ppm) = 8.64 (d, J = 4.8 Hz, 2H), 7.17 (t, J = 5.0 Hz, 1 H), 1.89 - 1 .77 (m, 4H); ¹³ C NMR (101 MHz, CDCb): 6 (ppm) = 165.4, 157.5, 121.2, 119.4, 20.9, 17.6; IR (ATR, Diamond): v (cm’ ¹ ) = 2922 (w), 2239 (m), 1564 (s), 1429 (vs), 961 (s), 784 (s), 635 (s)

Example 2: Preparation of 2-(2-pyrimidin-2-ylsulfanylethyl)propanedinitrile

To a solution of 5-amino-2,3-dihydrothiophene-4-carbonitrile (200mg, 1 .58mmol) and 2-chloropyrimidine (1 equiv., 1.58 mmol) in 2.8 mL THF were added, at room temperature, 2 equivalents (3.2mL) of a solution of Lithium bis(trimethylsilyl)amide (LiHMDS) 1 N in THF. After one hour stirring at room temperature, the mixture was poured onto 20mL of a saturated aqueous NH4CI solution and extracted 3 times with 60mL of dichloromethane. The combined organic layers were washed three times with 20mL of 1 M aq. HCI, then once with 20mL aq. sat. NaHCCh, then finally with 20mL of brine. The combined organic phases were then dried over solid Na2SC>4, filtered and the solvent was removed under reduced pressure to deliver the crude product 2-(2-pyrimidin-2-ylsulfanylethyl)propanedinitrile as a yellowish solid. The crude was purified using a 12g silica chromatography column with a gradient of Cyclohexane/Ethyl acetate (up to 1 :1) to give 190mg of the pure, desired product 2-(2-pyrimidin-2- ylsulfanylethyl)propanedinitrile (Isolated Yield 58%). m.p. = 65.9 - 67.8 °C; ¹ H NMR (400 MHz, CDCh): 6 (ppm) = 8.55 (d, J = 4.8 Hz, 2H), 7.05 (t, J = 5.0 Hz, 1 H), 4.06 (t, J = 7.3 Hz, 1 H), 3.38 (t, J = 6.6 Hz, 2H), 2.54 (q, J = 7.0Hz, 2H); ¹³ C NMR (101 MHz, CDCh): 6 (ppm) = 170.5, 157.8, 117.4, 112.5, 31.1 , 27.5, 21.6; IR (ATR, Diamond): v (cm’ ¹ ) = 3038 (vw), 2909 (vw), 2257 (vw), 1701 (w), 1564 (m), 1550 (s), 1380 (vs), 1204 (m), 1186 (m), 774 (m)

Example 3: Preparation of 1-(1 ,3-benzothiazol-2-yl)cyclopropanecarbonitrile

To a solution of 5-amino-2,3-dihydrothiophene-4-carbonitrile (100mg, 0.79mmol) and 2-chloro-1 ,3- benzothiazole (1 equiv., 0.79 mmol) in 3.2 mL DMF were added, at room temperature, 2 equivalents (1 ,58mL) of a solution of Sodium bis(trimethylsilyl)amide (NaHMDS) 1 N in THF. After four hours stirring at room temperature, the mixture was heated to 65°C for two hours, after which time it was allowed to cool down to room temperature. It was then poured onto 10mL of a saturated aqueous NH4CI solution and extracted 3 times with 30mL of dichloromethane. The combined organic layers were washed three times with 10mL of 1 M aq. HCI, then once with 10mL aq. sat. NaHCCh, then finally with 10mL of brine. The combined organic phases were then dried over solid Na2SC>4, filtered and the solvent was removed under reduced pressure to deliver 145mg of the crude product 1-(1 ,3-benzothiazol-2- yl)cyclopropanecarbonitrile as a brownish solid. The crude was quantified by Q-NMR to give a strength (w/w) of 56% and therefore the reaction gave a chemical yield of 51 %. The crude was purified using a 12g silica chromatography column with a gradient of Cyclohexane/Ethyl acetate (up to 1 :1) to deliver the pure, desired product 1-(1 ,3-benzothiazol-2-yl)cyclopropanecarbonitrile. m.p. = 139.7 - 141.5 °C; ¹ H NMR (400 MHz, CDCh): 6 (ppm) = 7.91 (d, J = 8.1 Hz, 1 H), 7.85 (dd, J = 8.1 , 0.7 Hz, 1 H), 7.47 (ddd, J = 7.7, 7.7, 1.1 Hz, 1 H), 7.43 - 7.35 (m, 1 H), 2.07 - 2.00 (m, 2H), 1.97 - 1.90 (m, 2H); ¹³ C NMR (101 MHz, CDCh): 6 (ppm) = 166.1 , 153.1 , 134.9, 126.7, 125.4, 122.9, 121 .7, 120.6, 21 .7, 14.5; IR (ATR, Diamond): v (cnr ¹ ) = 3096 (w), 3053 (w), 2247 (m), 1510 (m), 1438 (m), 1279 (s), 1094 (s), 1062 (m), 1048 (s), 762 (vs)

Example 4: Preparation of 1-(4-chlorothiazol-2-yl)cyclopropanecarbonitrile

To a solution of 5-amino-2,3-dihydrothiophene-4-carbonitrile (87mg, 94%w/w, 0.65mmol) and 2,4- dichlorothiazole (1 equiv., 0.65 mmol) in 5.2 mL DMF were added, at room temperature, 2.2 equivalents of sodium tert-butanolate (1.43mmol). After three hours stirring at room temperature, the reaction was then poured onto 10mL of saturated, aqueous NH4CI solution and stirred for 10 minutes. The resulting mixture was then acidified with 10mL of aqueous 1 N HCI and extracted three times with 20mL of ethyl acetate. The combined organic layers were washed with 10mL aq. sat. NaHCCh, then with 10mL of brine, and finally dried over solid MgSC and filtered. The solvent was removed under reduced pressure to deliver 122mg of the crude desired product as a white crystalline solid covered in orange viscous oil. The crude was purified by chromatography column to give 74 mg of the pure, desired product 1 -(4- chlorothiazol-2-yl)cyclopropanecarbonitrile (Isolated Yield 62%). m.p. = 83.4 - 85.6 °C; ¹ H NMR (400 MHz, CDCb): 6 (ppm) = 7.03 (s, 1 H), 1 .99 - 1 .85 (m, 4H); ¹³ C NMR (101 MHz, CDCI3): 6 (ppm) = 165.7, 139.3, 120.1 , 113.3, 21.5, 14.3; IR (ATR, Diamond): v (cm ^-1 ) = 3110 (m), 2243 (m), 1488 (vs), 1285 (s), 1089 (vs), 751 (vs)

Example 5: Preparation of 1-(4-bromothiazol-2-yl)cyclopropanecarbonitrile

To a solution of 5-amino-2,3-dihydrothiophene-4-carbonitrile (520mg, 4.1 mmol) and 2,4-dibromothiazole (1g, 1 equiv., 4.1 mmol) in 15 mL DMF were added 2.2 equivalents of sodium tert-butanolate (9.1 mmol). After two hours stirring at room temperature, 5mL of ice cold water were added and the mixture was acidified with 10mL of 2N HCI. The aqueous layer was extracted three times with 20mL of ethyl acetate. The combined organic layers were washed with 10mL of brine, dried over solid MgSC and filtered. The solvent was removed under reduced pressure to deliver 2.3g of the crude desired product as an orange liquid, which was quantified by Q-NMR to give a strength (w/w) of 15% in 1 -(4-bromothiazol-2- yl)cyclopropanecarbonitrile; therefore the reaction gave a chemical yield of 33%. The crude was purified by chromatography column to give 286 mg of the pure, desired product 1 -(4-bromothiazol-2- yl)cyclopropanecarbonitrile (Isolated Yield 30%).

Alternatively, the 1-(4-bromothiazol-2-yl)cyclopropanecarbonitrile can be obtained from isolated 2-[2-(4- bromothiazol-2-yl)sulfanylethyl]propanedinitrile (example 6) by following the protocol below. To a solution of 2-[2-(4-bromothiazol-2-yl)sulfanylethyl]propanedinitrile (250mg, 0.867mmol) in 5mL of THF at room temperature were added 0.87mL of a solution of Lithium bis(trimethylsilyl)amide (LiHMDS) 1 N in THF. The reaction mixture was then heated at 65°C for 2 hours, before being allowed to cool down to room temperature. It was then poured onto 5mL of a saturated aqueous NH4CI solution, stirred for 10 minutes and extracted 3 times with 20mL of EtOAc. The combined organic layers were dried over solid Na2SO4, filtered and the solvent was removed under reduced pressure to deliver 254mg of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 67% and therefore the reaction gave a chemical yield of 84%. The crude was purified by chromatography column to give 120mg of the pure, desired product 1-(4-bromothiazol-2-yl)cyclopropanecarbonitrile as a white solid (Purity measured by Q-NMR being 92% (w/w) the isolated Yield is 56%). ¹ H NMR (400 MHz, CDCb): 6 (ppm) = 7.15 (s, 1 H), 1 .99 - 1 .84 (m, 4H).

Example 6: Preparation of 2-[2-(4-bromothiazol-2-yl)sulfanylethyllpropanedinitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged 15mL of DMF, 2,4-dibromothiazole (1.0 g, 4.1 mmol) and 5-amino-2,3-dihydrothiophene-4- carbonitrile (1 .0 equiv., 4.1 mmol). The reaction mixture became a light yellow solution. It was cooled to -10°C, then the base sodium tert-butanolate (2.2 equiv., 9.1 mmol, 2M solution in THF) was added at - 10°C for 10 min. (an exotherm of 5°C was observed). The reaction was carried on at -10°C for one hour. 5ml of ice cold water were added and the mixture was acidified with 10mL of 2N HCI at -5°C. The aqueous layer was extracted thrice with 20 mL of EtOAc, then washed with 20mL of brine. The combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure. 3.28 grams of an orange oil was obtained, which was quantified by Q-NMR to give a strength (w/w) of 25% in 2-[2-(4-bromothiazol-2-yl)sulfanylethyl]propanedinitrile ; therefore the reaction gave a chemical yield of 69%. The crude was purified using a 40g silica chromatography column with a gradient of Cyclohexane/Ethyl acetate (up to 2:1) to deliver the pure, desired product 2-[2-(4-bromothiazol-2- yl)sulfanylethyl]propanedinitrile as a white solid (0.8g, Q-NMR purity 96mass%, isolated yield 65%). ¹ H NMR (400 MHz, CDCb): 6 (ppm) = 2.59 (q, J=6.85 Hz, 2 H) 3.46 (t, J=6.66 Hz, 2 H) 4.16 (t, J=7.46 Hz, 1 H) 7.16 (s, 1 H)

Example 7: Preparation of 2-(1-cyanocyclopropyl)pyridine-3-carbonitrile To a solution of 5-amino-2,3-dihydrothiophene-4-carbonitrile (94mg, 94%w/w, 0.7mmol) and 2- chloropyridine-3-carbonitrile (1 equiv., 0.7 mmol) in 4.9 mL DMF were added, at 0°C, 2.2 equivalents of a 2M sodium tert-butanolate (1 .54mmol) solution in THF. After three hours stirring at 0°C, the reaction was allowed to warm to room temperature and stirred for 4 hours more. It was then poured onto 10mL of saturated, aqueous NF CI solution and stirred for 10 minutes. The resulting mixture was then acidified with 10mL of aqueous 1 N HCI and extracted three times with 20mL of ethyl acetate. The combined organic layers were washed with 10mL aq. sat. NaHCC , then with 10mL of brine (thrice), and finally dried over solid MgSC and filtered. The solvent was removed under reduced pressure to deliver 230mg of the crude desired product as a yellow oil. The crude was purified by chromatography column to give 90 mg of the pure, desired product 2-(1-cyanocyclopropyl)pyridine-3-carbonitrile (Isolated Yield 76%).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-[(3-cyano- 2-pyridyl)sulfanyl]ethyl]propanedinitrile (example 8) following this protocol. To a solution of 2-[2-[(3- cyano-2-pyridyl)sulfanyl]ethyl]propanedinitrile (500mg, 2.19mmol) in 5mL of THF at room temperature were added 1.1 mL of the base sodium tert-butanolate (1 equiv., 2.19 mmol, 2M solution in THF). The reaction mixture was then heated at 65°C for 2 hours, before being allowed to cool down to room temperature. It was then poured onto 5mL of a saturated aqueous NH4CI solution, stirred for 10 minutes and extracted 3 times with 20mL of EtOAc. The combined organic layers were dried over solid Na2SC>4, filtered and the solvent was removed under reduced pressure to deliver 440mg of the crude desired product as an orange liquid. The crude was purified by chromatography column to give 247mg of the pure, desired product 2-(1-cyanocyclopropyl)pyridine-3-carbonitrile as a white solid (Purity measured by Q-NMR being 96% (w/w) the isolated Yield is 64%). m.p. = 74.2 - 76.6 °C; ¹ H NMR (400 MHz, CDCb): 6 (ppm) = 8.71 (dd, J = 4.9, 1 .64 Hz, 1 H), 8.04 (dd, J = 7.99, 1 .82 Hz, 1 H), 7.42 (dd, J = 7.99, 5.09 Hz, 1 H), 1.90 - 1.78 (m, 4H); ¹³ C NMR (101 MHz, CDCb): 6 (ppm) = 156.3, 152.5, 141 .8, 123.0, 120.4, 115.2, 110.6, 17.8, 15.8; IR (ATR, Diamond): v (cm’ ¹ ) = 3076 (vw), 2236 (m), 1579 (m), 1560 (m), 1435 (vs), 1092 (m). 945 (m), 810 (s), 764 (m), 579 (m), 560 (m).

Example 8: Preparation of 2-[2-[(3-cyano-2-pyridyl)sulfanyl1ethyllpropanedinitrile

In a 3 necked 50 mL round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (911 mg, 1 equiv., 7.07 mmol, 98 mass%) in one portion and 2-chloropyridine-3-carbonitrile (1.00 g, 7.07 mmol, 98 mass%). The reaction mixture took a light yellowish color. It was then cooled to -10°C (Ice and brine solution), and sodium tert-butanolate (2.2 equiv., 15.6 mmol) was added in three portions (0.5g per portion) at -10°C (5-6°C Exotherm was observed). The reaction was stirred at -10°C for one hour, then water was added (10mL), followed by cold 15mL 2N aq. HCI and cold 5mL of ethyl acetate. The mixture had then reached a temperature of 5°C and a precipitation had occurred upon the addition of the ethyl acetate. The solid was filtered through sintered funnel and washed with water (10mL). The solid was then dried under reduced pressure at 50°C to deliver 1.55g of a white solid. Q-NMR gave a reading of 94mass% and the yield thus obtained is 90%. ¹ H NMR (400 MHz, D6-DMSO) 6 (ppm) = 8.71 (dd, J = 4, 1 .5 Hz, 1 H), 8.26 (dd, J = 8, 0.8 Hz, 1 H), 7.36 (dd, J = 8, 4 Hz, 1 H), 4.95 (t, J = 6 Hz, 1 H), 3.43 (t, J = 7 Hz, 2H), 2.44 (q, J = 7 Hz, 2H).

Example 9: Preparation of 2-(1-Cvanocvclopropyl)benzonitrile

To a solution of 5-amino-2,3-dihydrothiophene-4-carbonitrile (127mg, 94%w/w, 0.95mmol) and 2- fluorobenzonitrile (1 equiv., 0.95 mmol) in 7.6 mL DMF were added, at room temperature, 2.2 equivalents of a 2M sodium tert-butanolate (2.09mmol) solution in THF. After overnight stirring at room temperature, the reaction mixture was heated up to 80°C for 24 hours, before being allowed to cool down to room temperature. It was then poured onto 10mL of saturated, aqueous NH4CI solution and stirred for 10 minutes. The resulting mixture was then acidified with 10mL of aqueous 1 N HCI and extracted three times with 20mL of ethyl acetate. The combined organic layers were washed with 10mL aq. sat. NaHCCh, then with 10mL of brine (twice), and finally dried over solid MgSCU and filtered. The solvent was removed under reduced pressure to deliver 164mg of the crude desired product as an orange oil. The crude was quantified by Q-NMR to give a strength (w/w) of 65% and therefore the reaction gave a chemical yield of 66%.The crude was purified by chromatography column to give 88mg of the pure, desired product 2-(1-Cyanocyclopropyl)benzonitrile as a white solid (Isolated Yield 56%). m.p. = 106.2 - 108.1 °C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 7.73 (dd, 1 H, J=0.91 , 7.81 Hz), 7.63 (dt, 1 H J=0.91 , 7.81 Hz), 7.54 (dd, 1 H, J=0.91 , 7.81 Hz), 7.50 (dt, 1 H J=0.91 , 7.81 Hz), 1 .82-1 .93 (m, 2H), 1.45-1.55 (m, 2H); ¹³ C NMR (CDCb, 101 MHz) 6 139.1 , 133.7, 133.3, 130.9, 129.3, 120.9, 116.5, 114.8, 16.1 , 13.1 ; IR (ATR, Diamond): v (cm’ ¹ ) = 3108 (w), 3072 (w), 2233 (s), 2223 (s), 1599 (m), 1451 (m), 1422 (m), 1051 (m), 946 (m), 773 (vs), 559 (s), 493 (m)

Example 10: Preparation of 2-[2-(2-cyanophenyl)sulfanylethyllpropanedinitrile In a 3 necked 250 mL round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (58 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (917mg, 1 equiv., 7.27 mmol) in one portion and 2-chlorobenzonitrile (1.00 g, 7.27 mmol). Sodium tert-butanolate (2.2 equiv., 16 mmol) was added in three portions (~0.5g per portion) at room temperature. The reaction was stirred for one hour, then cooled down to 0°C before water was added (5mL). A solid precipitation was observed. The mixture was further acidified by dropwise addition of cold 2N aq. HCI and extra 20mL of water. The solid was filtered through sintered funnel and washed with water (10mL). The solid was then dried under reduced pressure at 50°C to deliver 1.06g of a white solid. Q-NMR gave a reading of 91 mass% and the yield thus obtained is 59%. ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 2.34 (q, J = 7 Hz, 2H); 3.26 (t, J = 7 Hz, 2H); 4.22 (t, J = 6 Hz, 1 H); 7.43 (td, J = 7.43, 1 .53 Hz, 1 H) 7.52 - 7.65 (m, 2H) 7.68 - 7.75 (m, 1 H).

Example 11 : Preparation of 1-pyridazin-3-ylcyclopropanecarbonitrile

To a solution of 5-amino-2,3-dihydrothiophene-4-carbonitrile (86mg, 94%w/w, 0.64mmol) and 3- bromopyridazine (1 equiv., 0.64 mmol) in 5.1 mL DMF were added, at room temperature, 2.2 equivalents of a 2M sodium tert-butanolate (1 .4mmol) solution in THF. After overnight stirring at room temperature, the reaction mixture was heated up to 60°C for 24 hours, before being allowed to cool down to room temperature. It was then poured onto 10mL of saturated, aqueous NH4CI solution and stirred for 10 minutes. The resulting mixture was then acidified with 10mL of aqueous 1 N HCI and extracted three times with 20mL of ethyl acetate. The combined organic layers were washed with 10mL aq. sat. NaHCCh, then with 10mL of brine (twice), and finally dried over solid MgSCM and filtered. The initial aqueous phase (NH4CI acidified by HCI) was extracted twice with 20mL of CHCH. The organic phases are combined and the solvents removed under reduced pressure to deliver 46mg of the crude desired product as an orange crystalline solid. The crude was quantified by Q-NMR to give a strength (w/w) of 50% and therefore the reaction gave a chemical yield of 42%. The crude was purified by chromatography column to give 36mg of the pure, desired product 1 -pyridazin-3-ylcyclopropanecarbonitrile as white pinkish needles (Isolated Yield 39%).

Alternatively, the title product can be made from 3-(benzenesulfonyl)pyridazine instead of 3- bromopyridazine. Indeed, to a solution of 3-(benzenesulfonyl)pyridazine (101 mg, 0.436 mmol, 95 mass%) and 5-amino-2,3-dihydrothiophene-4-carbonitrile (58mg, 94%w/w, 0.436mmol) in DMF (3.4mL) at room temperature is added a 2M solution of sodium tert-butanolate (2.2eq. ; 0.958mmol ; 480|j.L). The reaction mixture is stirred overnight before being heated up to 65°C for 7h. After cooling down the reaction mixture to room temperature, 10mL of a saturated aqueous solution of NH4CI is added. The resulting mixture is poured into a 50mL Erlenmeyer and acidified by 10mL of 1 N HCI. It is then extracted 3 times by EtOAc (20mL each time), the combined organic phases are washed with 10mL of sat. NaHCCh, washed further with 10mL of Brine, then dried over solid MgSCU and filtered. The solvents were removed under reduced pressure to deliver 174mg of the crude desired product as an dark solid. The crude was quantified by Q-NMR to give a strength (w/w) of 52% and therefore the reaction gave a chemical yield of 14%. The crude was purified by chromatography column to give 6mg of the pure, desired product 1-pyridazin-3-ylcyclopropanecarbonitrile as a white solid (isolated yield is 10%).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-(2-pyridazin- 3-ylsulfanylethyl)propanedinitrile (example 12) following this protocol. To a solution of 2-(2-pyridazin-3- ylsulfanylethyl)propanedinitrile (500mg, 2.45mmol) in 5mL of THF at room temperature were added 1.22mL of the base sodium tert-butanolate (1 equiv., 2.45 mmol, 2M solution in THF). The reaction mixture was then heated at 65°C for 2 hours, before being allowed to cool down to room temperature. It was then poured onto 5mL of a saturated aqueous NH4CI solution, stirred for 10 minutes and extracted 3 times with 20mL of EtOAc. The combined organic layers were dried over solid Na2SO4, filtered and the solvent was removed under reduced pressure to deliver 270mg of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 92% and therefore the reaction gave a chemical yield of 70%. The crude was purified by chromatography column to give 240mg of the pure, desired product 1-pyridazin-3-ylcyclopropanecarbonitrile as a white solid (Purity measured by Q-NMR being 98% (w/w) the isolated Yield is 66%). m.p. = 111 .7 - 114.5 °C with gradual degradation up to 115°C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 9.1 1 (dd, 1 H, J=1 .45, 4.72 Hz), 7.91 (dd, 1 H, J=1 .63, 8.54 Hz), 7.52 (dd, 1 H, J=8.54, 4.9 Hz), 2.1-2.2 (m, 2H), 1 .83-1 .94 (m, 2H); ¹³ C NMR (CDCb, 101 MHz) 6 (ppm) 157.5, 149.9, 126.5, 124.6, 120.9, 21 .1 , 14.5; IR (ATR, Diamond): v (cm’ ¹ ) = 3100 (w), 3051 (m), 2238 (s), 1579 (m), 1439 (vs), 1136 (s), 948 (s), 845 (s), 798 (s), 732 (s)

Example 12: Preparation of 2-(2-pyridazin-3-ylsulfanylethyl)propanedinitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (810mg, 1 equiv., 6.29 mmol, 98mass%) in one portion and 3-bromopyridazine (1.00 g, 6.29 mmol). Sodium tert- butanolate (2.2 equiv., 13.8 mmol) was added in two portions at room temperature. The reaction was stirred for one hour, then 10ml of ice-cold water were added and the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 50 mL of EtOAc, then the combined organic layers were washed with 20mL of brine and dried over solid Na2SO4. After filtration, the solvents were removed under reduced pressure to deliver 2.66g of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 36.5% and therefore the reaction gave a chemical yield of 70%. The crude was purified by chromatography column to give 912mg of the pure, desired product 2-(2-pyridazin-3-ylsulfanylethyl)propanedinitrile as a yellow liquid (Purity measured by Q-NMR being 96% (w/w) the isolated Yield is 68%). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 2.63 (q, J = 6.85 Hz, 2H), 3.57 (t, J = 6.79 Hz, 2H), 4.13 (t, J = 6.79 Hz, 1 H), 7.32 (dd, J = 8.5, 5 Hz, 1 H), 7.37 (dd, J = 1.3, 8.5 Hz, 1 H), 8.96 (dd, J = 1.4, 4.7 Hz, 1 H).

Example 13: Preparation of 1-[5-(trifluoromethyl)-2-pyridyl1cyclopropanecarbonitrile

DMF (3.4 mL) was added to 5-amino-2,3-dihydrothiophene-4-carbonitrile (76mg, 1 equiv., 0.57 mmol, 94mass%) and 2-chloro-5-(trifluoromethyl)pyridine (106mg, 0.57 mmol, 97mass%). Sodium tertbutanolate (2.2 equiv., 0.121 mg, 1.25 mmol) was added in one portion at room temperature. After 30 minutes stirring, the reaction was heated up to 65°C and stirred for two and a half hours, before being allowed to cool down to room temperature. 10ml of saturated aqueous NH4CI were added and the resulting mixture was stirred for 10 minutes. It was then transferred to a 50mL Erlenmeyer and acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, then the combined organic layers were washed with 20mL of brine. The combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.426g of the crude desired product as an orange liquid. The crude was purified by chromatography column to give 74mg of the pure, desired product 1-[5-(trifluoromethyl)-2-pyridyl]cyclopropanecarbonitrile as a white powder (isolated Yield is 62%).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-[[5- (trifluoromethyl)-2-pyridyl]sulfanyl]ethyl]propanedinitrile (example 14) following this protocol. To a solution of 2-[2-[[5-(trifluoromethyl)-2-pyridyl]sulfanyl]ethyl]propaned initrile (500mg, 1.84mmol) in 5mL of THF at room temperature were added 0.92mL of the base sodium tert-butanolate (1 equiv., 1.84 mmol, 2M solution in THF). The reaction mixture was then heated at 65°C for 3 hours, before being allowed to cool down to room temperature. It was then poured onto 5mL of a saturated aqueous NH4CI solution, stirred for 10 minutes and extracted 3 times with 20mL of EtOAc. The combined organic layers were dried over solid Na2SO4, filtered and the solvent was removed under reduced pressure to deliver 506mg of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 68% and therefore the reaction gave a chemical yield of 88%. The crude was purified by chromatography column to give 335mg of the pure, desired product 1-[5-(trifluoromethyl)-2- pyridyl]cyclopropanecarbonitrile as a white solid (Purity measured by Q-NMR being 96% (w/w) the isolated Yield is 82%). m.p. = 74.3-76.5°C; ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 8.72 (dd, 1 H, J=0.9, 3.1 Hz), 7.9-8.0 (m, 1 H), 7.8-7.9 (m, 1 H), 1.9-2.0 (m, 2H), 1.8-1 .9 (m, 2H); ¹³ C NMR (CDCh, 101 MHz) 6 158.7, 146.6, 133.8, 125.0, 121.2, 120.6, 123.4, 20.8, 15.6; ¹⁹ F NMR (CDCh, 377 MHz) 6 -62.33 (s, 3F) ; IR (ATR, Diamond): v (cm’ ¹ ) = 3062 (vw), 2240 (w), 1606 (m), 1328 (s), 1122 (vs), 1079 (s), 1016 (m)

Example 14: Preparation of 2-[2-[[5-(trifluoromethyl)-2-pyridyl1sulfanyl1ethyllpropaned initrile

In a 3 necked 50 mL round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (690mg, 1 equiv., 5.3 mmol, 98mass%) in one portion and 2-chloro-5-(trifluoromethyl)pyridine (1.00 g, 5.3 mmol, 97mass%). It was then cooled to -10°C (Ice and brine solution), and sodium tert-butanolate (2.2 equiv., 12 mmol) was added in three portions at -10°C. The reaction was stirred at -10°C for one hour, then ice- cold water was added (5mL), followed by cold 10mL 1 N aq. HCI. The aqueous layer was then extracted thrice with 20 mL of EtOAc, and the combined organic layers washed with 20mL of brine. The combined organic layers were dried over solid Na2SC>4, filtered and the solvents were removed under reduced pressure to deliver 3.3g of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 33% and therefore the reaction gave a chemical yield of 75%. The crude was purified by chromatography column to give 1 ,058g of the pure, desired product 2-[2-[[5- (trifluoromethyl)-2-pyridyl]sulfanyl]ethyl]propanedinitrile as a white solid (Purity measured by Q-NMR being 90% (w/w) the isolated Yield is 62%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 2.54 (q, J=6.85 Hz, 2 H), 3.48 (t, J=6.66 Hz, 2 H), 4.03 (t, J=7.34 Hz, 1 H), 7.32 (d, J=8.44 Hz, 1 H), 7.74 (dd, J=8.44, 2.20 Hz, 1 H), 8.71 (s, 1 H).

Example 15: Preparation of 2-(1-cvanocvclopropyl)-5-(trifluoromethyl)benzonitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (3 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (79mg, 1 equiv., 0.59 mmol, 94mass%) and 2-fluoro-5-(trifluoromethyl)benzonitrile (0.111g, 1 equiv., 0.59 mmol). Sodium tert-butanolate (2.2 equiv., 1.29 mmol) was added at room temperature. The reaction was stirred for three hours, then 10ml of saturated aqueous NF CI were added and the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed with 10ml of aqueous saturated NaHCCh, and dried with 20mL of brine. The combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.242g of the crude desired product as a yellow liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 44.7% and therefore the reaction gave a chemical yield of 84%. The crude was purified by chromatography column to give 87mg of the pure, desired product 2-(1- cyanocyclopropyl)-5-(trifluoromethyl)benzonitrile as a white solid (the isolated yield is 63%).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-[2-cyano- 4-(trifluoromethyl)phenyl]sulfanylethyl]propanedinitrile (example 16) following this protocol. In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (4 mL). To this was added 2-[2-[2-cyano-4-(trifluoromethyl)phenyl]sulfanylethyl]propan edinitrile (0.5g, 1 equiv., 1.69 mmol). Sodium tert-butanolate (1 equiv., 1.69 mmol) was added at room temperature. The reaction was heated up to 65°C and stirred for three hours, then allowed to cool down to room temperature. 5ml of saturated aqueous NH4CI were added and the aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.45g of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 62% and therefore the reaction gave a chemical yield of 69%. The crude was purified by chromatography column to give 249mg of the pure, desired product 2-(1-cyanocyclopropyl)-5-(trifluoromethyl)benzonitrile as a yellow solid (Purity measured by Q-NMR being 93% (w/w) the isolated yield is 58%). m.p. = 104.0 - 105.9 °C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 7.99 (d, J=1 .45 Hz, 1 H), 7.89 (dd, J=8.36, 1 .45 Hz, 1 H), 7.70 (d, 1 H, J=8 Hz), 1.96-1.93 (m, 2H), 1.56-1.52 (m, 2H); ¹³ C NMR (CDCb, 101 MHz) 6 142.7, 131.7, 132.2, 130.6, 130.1 , 120.0, 122.5, 115.8, 115.2, 16.3, 13.2; ¹⁹ F NMR (CDCb, 377 MHz) 6 -63.23 (s, 3F); IR (ATR, Diamond): v (cnr ¹ ) = 3076 (vw), 2238 (w), 1615 (w), 1327 (s), 1162 (s), 1128 (vs), 1095 (s), 857 (m), 733 (m)

Example 16: Preparation of 2-[2-[2-cyano-4-(trifluoromethyl)phenyl1sulfanylethyllpropan edinitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (667mg, 1 equiv., 5.29 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (1g, 1 equiv., 5.29 mmol). The mixture was cooled down at -40°C, and the base Sodium tert-butanolate (2.2 equiv., 11.6 mmol) was added. The reaction was stirred for one hour, then 5ml of ice cold water were added dropwise (temperature not exceeding -30°C) followed by 10ml of 2N HCI. After being allowed to reach room temperature, the aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 4.4g of the crude desired product as a yellow liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 27% and therefore the reaction gave a chemical yield of 77%. The crude was purified by chromatography column to give 1.1g of the pure, desired product 2-[2-[2-cyano-4- (trifluoromethyl)phenyl]sulfanylethyl]propanedinitrile as an orange solid (Purity measured by Q-NMR being 80% (w/w) the isolated yield is 58%). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 7.94 (d, J = 1 .63 Hz, 1 H), 7.83 (dd, J = 8.51 , 1.63 Hz, 1 H), 7.60 (d, J = 8.38 Hz, 1 H), 4.15 (t, J = 7.07 Hz, 1 H), 3.37 (t, J = 7.07 Hz, 2H), 2.42 (q, J = 7.07 Hz, 2H). (16% of the cyclized product 2-(1-cyanocyclopropyl)-5- (trifluoromethyl)benzonitrile was also isolated from the column in another fraction).

Example 17: Preparation of 3-(1-cvanocvclopropyl)-5-(trifluoromethyl)pyridine-2-carboni trile

To 2.8mL of DMF were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (77mg, 1.2 equiv., 0.57 mmol, 94mass%) and 3-chloro-5-(trifluoromethyl)pyridine-2-carbonitrile (100 mg, 0.47 mmol, 1 equiv., 98mass%). Sodium tert-butanolate (2.2 equiv., 1.04 mmol) was added at room temperature. The reaction was stirred for three hours, then 10ml of saturated aqueous NH4CI were added and the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed with 10ml of aqueous saturated NaHCOs, and washed with 20mL of brine. The combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.178g of the crude desired product as a brownish liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 48% and therefore the reaction gave a chemical yield of 76%. The crude was purified by chromatography column to give 88mg of the pure, desired product 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)pyridine-2-carboni trile as a light yellow oil (95% purity assumed ; 74% isolated yield).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-[[2-cyano- 5-(trifluoromethyl)-3-pyridyl]sulfanyl]ethyl]propanedinitril e (example 18) following this protocol. In a 3 necked 25mL round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5 mL). To this was added 2-[2-[[2-cyano-5-(trifluoromethyl)-3-pyridyl]sulfanyl]ethyl] - propanedinitrile (0.2g, 1 equiv., 0.675 mmol). Sodium tert-butanolate (1 equiv., 0.675 mmol) was added at room temperature. The reaction was stirred at this temperature for one hour, then was diluted with 10mL of water and acidified with 5mL of aqueous HCI 2N. The aqueous layer was extracted thrice with 50 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.21 g of the crude desired product. The crude was quantified by Q-NMR to give a strength (w/w) of 49% and therefore the reaction gave a chemical yield of 64%. The crude was purified by chromatography column to give 106mg of the pure, desired product 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)pyridine-2-carboni trile as a yellow liquid (Purity measured by Q-NMR being 92% (w/w) the isolated yield is 61 %). m.p. = 101.5 - 103.6 °C; ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 8.97-8.95 (m, 1 H), 8.12-8.09 (m, 1 H), 2.09-1.95 (m, 2H), 1 .65-1 .54 (m, 2H); ¹³ C NMR (CDCh, 101 MHz) 6 (ppm) = 147.6, 138.9, 136.6, 136.0, 129.6, 119.3, 122.0, 114.2, 16.5, 11 .6; ¹⁹ F NMR (CDCh, 377 MHz) 6 -62.78 (s, 3F); IR (ATR, Diamond): v (cm’ ¹ ) = 3074 (vw), 2244 (w), 1566 (w), 1421 (m), 1346 (s), 1289 (vs), 1164 (s), 1147 (s), 1133 (s), 1085 (s), 933 (m)

Example 18: Preparation of 2-[2-[[2-cyano-5-(trifluoromethyl)-3-pyridyl]sulfanyl]ethyl] propanedinitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (623mg, 1 equiv., 4.84 mmol, 98mass%) and 3-chloro-5-(trifluoromethyl)pyridine-2-carbonitrile (1 g, 4.84 mmol). The mixture was cooled down at -40°C, and the base Sodium tert-butanolate (2.2 equiv., 10.7 mmol) was added. The reaction was stirred for half an hour, then 10ml of ice cold water were added dropwise (temperature not exceeding -30°C) followed by 10ml of 2N HCI. After being allowed to reach room temperature, the aqueous layer was extracted thrice with 50 mL of EtOAc, the combined organic layers were washed with 20mL of brine, dried over solid Na2SC>4, filtered and the solvents were removed under reduced pressure to deliver 2.9g of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 35% and therefore the reaction gave a chemical yield of 70%. The crude was purified by chromatography column to give 0.92g of the pure, desired product 2- [2-[[2-cyano-5-(trifluoromethyl)-3-pyridyl]sulfanyl]ethyl]pr opanedinitrile as an orange solid (Purity measured by Q-NMR being 93% (w/w) the isolated yield is 60%). ¹ H NMR (D6-DMSO, 400 MHz) 6 (ppm) = 9-8.93 (m, 1 H), 8.55-8.49 (m, 1 H), 4.89 (t, J = 7.1 Hz, 1 H), 3.46 (t, J = 7.1 Hz, 2H), 2.39 (q, J = 7.1 Hz, 2H).

Example 19: Preparation of 2-(1-cyanocyclopropyl)-4-(trifluoromethyl)benzonitrile

In a 20mL vial was charged DMF (4.3 mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (73mg, 1 equiv., 0.54 mmol, 94mass%) and 2-fluoro-4-(trifluoromethyl)benzonitrile (0.103g, 1 equiv., 0.54 mmol). Sodium tert-butanolate (2.2 equiv., 1.2 mmol) was added at room temperature. The reaction was stirred for six hours, then 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed with 10ml of aqueous saturated NaHCC , and washed with 20mL of brine. The combined organic layers were dried over solid Na2SC>4, filtered and the solvents were removed under reduced pressure to deliver 0.15g of the crude desired product as an orange solid. The crude was quantified by Q-NMR to give a strength (w/w) of 67% and therefore the reaction gave a chemical yield of 78%. The crude was purified by chromatography column to give 89mg of the pure, desired product 2-(1-cyanocyclopropyl)-4-(trifluoromethyl)benzonitrile as a white solid (the isolated yield is 69%). m.p. = 94.8 - 97.7 °C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 7.89 (d, 1 H, J=7.6 Hz), 7.7-7.8 (m, 2H), 1.9-2.0 (m, 2H), 1.5-1 .6 (m, 2H); ¹³ C NMR (CDCb, 101 MHz) 6 (ppm) = 140.3, 135.1 , 134.4, 127.9, 126.3, 120.1 , 122.6, 118.4, 115.2, 16.3, 13.2; ¹⁹ F NMR (1-CDCI3, 377 MHz) 6 (ppm) = -63.46 (s, 3F); IR (ATR, Diamond): v (cm’ ¹ ) = 3093 (vw), 2925 (vw), 2238 (w), 1428 (w), 1338 (s), 1295 (s), 1280 (s), 1176 (s), 1130 (vs), 1084 (s), 952 (m), 844 (m), 564 (m)

Example 20: Preparation of 2-[2-[2-cyano-5-(trifluoromethyl)phenyl]sulfanylethyl]propan edinitrile

In a 20mL vial was charged DMF (4.4 mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (75mg, 1 equiv., 0.56 mmol, 94mass%) and 2-fluoro-4-(trifluoromethyl)benzonitrile (0.105g, 1 equiv., 0.56 mmol). Sodium tert-butanolate (2.2 equiv., 1 .22 mmol) was added at room temperature. The reaction was stirred for ten minutes, then 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed with 10mL of brine. The combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.379g of the crude desired product as an orange liquid. The crude was purified by chromatography column to give 112mg of the pure, desired product 2-[2-[2-cyano-5- (trifluoromethyl)phenyl]sulfanylethyl]propanedinitrile as a white solid (the isolated yield is 68%). m.p. = 110.7 - 113.2 °C ¹ H NMR (400 MHz, CDCb) 6 (ppm) = 7.87 (1 H, d, J=7.99 Hz), 7.78 (1 H, s), 7.68 (1 H, dd, J=7.99, 0.73 Hz), 4.19 (1 H, t, J=7.27 Hz), 3.36 (2 H, t, J=6.90 Hz), 2.42 (2 H, q, J=7.14 Hz) ¹³ C NMR (1-CDCI3, 101 MHz) 6 139.9, 135.3, 134.6, 127.6, 124.8, 1 18.6, 118.5, 123.2, 115.7, 11 1.6, 30.8, 30.1 , 21.3; IR (ATR, Diamond): v (cm’ ¹ ) = 2916 (vw), 2230 (vw), 1321 (vs), 1176 (s), 1132 (s), 1083 (m), 845 (m)

Example 21 : Preparation of 1-(6-chloropyridazin-3-yl)cyclopropanecarbonitrile

In a 20mL vial was charged DMF (3.2 mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (100mg, 1 equiv., 0.79 mmol) and 3,6-dichloropyridazine (0.118g, 1 equiv., 0.79 mmol). Sodium tert-butanolate (2 equiv., 1 .58 mmol) was added at room temperature. The reaction was heated to 65°C and stirred for six hours, before being allowed to cool down to room temperature. 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 30 mL of DCM, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.244g of the crude desired product. The crude was quantified by Q-NMR to give a strength (w/w) of 22% and therefore the reaction gave a chemical yield of 37%. The crude was purified by chromatography column to give 33mg of the pure, desired product 1-(6-chloropyridazin-3- yl)cyclopropanecarbonitrile (the isolated yield is 23%). (15mg (9% yield) of [6-(1- cyanocyclopropyl)pyridazin-3-yl] thiocyanate were also isolated in another fraction).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-(6- chloropyridazin-3-yl)sulfanylethyl]propanedinitrile (example 22) following this protocol.

In a 3 necked Round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5 mL). To this was added 2-[2-(6-chloropyridazin-3-yl)sulfanylethyl]propanedinitrile (0.5g, 1 equiv., 2.09 mmol). Sodium tert-butanolate (1 equiv., 2.09 mmol) was added at room temperature. The reaction was heated up to 65°C and stirred for three hours, then allowed to cool down to room temperature. 5ml of water were added then acidified with 10mL of 2N HCI the aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SC>4, filtered and the solvents were removed under reduced pressure to deliver 0.36g of the crude desired product as an orange liquid. The crude was purified by chromatography column to give 202mg of the pure, desired product 1-(6-chloropyridazin-3-yl)cyclopropanecarbonitrile as a white solid (Purity measured by Q-NMR being 97% (w/w) the isolated yield is 50%). m.p. = 134.2 - 136.6 °C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 7.88 (d, 1 H, J=8.9 Hz), 7.54 (d, 1 H, J=9.17 Hz), 2.18-2.08 (m, 2H), 1.99-1.88 (m, 2H); ¹³ C NMR (CDCb, 101 MHz) 6 (ppm) = 156.8, 155.7, 128.3, 127.0, 120.5, 21.4, 14.1 ; IR (ATR, Diamond): v (cm’ ¹ ) = 3046 (m), 2244 (m), 1422 (vs), 1163 (m), 1133 (s), 871 (m)

Example 22: Preparation of 2-[2-(6-chloropyridazin-3-yl)sulfanylethyllpropanedinitrile In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (860mg, 1 equiv., 6.7 mmol, 98mass%) and 3,6-dichloropyridazine (1 g, 6.7 mmol). The mixture was cooled down at -40°C, and the base Sodium tert-butanolate (2.2 equiv., 15 mmol) was added. The reaction was stirred for 15 minutes, then 10ml of ice cold water were added. A solid precipitated out, the reaction was further acidified by 2ml of 2N HCI. The solid precipitate was filtered off on Buchner funnel under vacuum. The white solid obtained was dried under reduced pressure at 50°C. 0.596g of the pure, desired product 2- [2-(6-chloropyridazin-3-yl)sulfanylethyl]propanedinitrile (Purity measured by Q-NMR being 98% (w/w) the isolated yield is 36%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 7.38-7.31 (m, 2H), 4.07 (t, J = 6.9 Hz, 1 H), 3.55 (t, J = 6.55 Hz, 2H), 2.63 (q, J = 6.92 Hz, 2H).

Example 23: Preparation of 1-[2-(trifluoromethyl)-4-pyridyl1cyclopropanecarbonitrile

In a 20mL vial was charged DMF (3.2 mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (72mg, 1 equiv., 0.534 mmol, 94mass%) and 4-chloro-2-(trifluoromethyl)pyridine (0.1g, 1 equiv., 0.534 mmol, 97mass%). Sodium tert-butanolate (2.4 equiv., 1.28 mmol) was added at room temperature. The reaction was stirred one hour at this temperature, and then was heated to 65°C and stirred for three hours, before being allowed to cool down to room temperature. 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 25 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.383g of the crude desired product as an orange oil. The crude was quantified by Q-NMR to give a strength (w/w) of 23% and therefore the reaction gave a chemical yield of 78%. The crude was purified by chromatography column to give 75mg of the pure, desired product 1 -[2-(trifluoromethyl)-4- pyridyl]cyclopropanecarbonitrile (97mass%, isolated yield is 65%).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-[[2- (trifluoromethyl)-4-pyridyl]sulfanyl]ethyl]propanedinitrile (example 24) following this protocol.

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5 mL). To this was added 2-[2-[[2-(trifluoromethyl)-4-pyridyl]sulfanyl]ethyl]propaned initrile (0.5g, 1 equiv., 1.84 mmol). Sodium tert-butanolate (1 equiv., 1.84 mmol) was added at room temperature. The reaction was heated up to 65°C and stirred for three hours, then allowed to cool down to room temperature. The reaction mixture was then poured onto 5ml of aqueous saturated NH4CI, stirred for 10 minutes and the aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.45g of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 55% and therefore the reaction gave a chemical yield of 63%. The crude was purified by chromatography column to give 0.2g of the pure, desired product 1 -[2- (trifluoromethyl)-4-pyridyl]cyclopropanecarbonitrile as a white solid (Purity measured by Q-NMR being 96% (w/w) the isolated yield is 52%). m.p. = 58.8 - 61 .2 °C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 8.71 (d, 1 H, J=5.1 Hz), 7.49 (d, 1 H, J=1.5 Hz), 7.42 (dd, 1 H, J=1.8, 5.1 Hz), 2.02-1.95 (m, 2H), 1 .63-1 .58 (m, 2H); ¹³ C NMR (CDCb, 101 MHz) 6 (ppm) = 150.5, 149.2, 147.9, 122.4, 120.1 , 121.3, 116.1 , 20.5, 13.8; ¹⁹ F NMR (CDCb, 377 MHz) 6 (ppm) = -68.12 (s, 3F); IR (ATR, Diamond): v (cm’ ¹ ) = 3026 (vw), 2926 (vw), 2242 (w), 1610 (m), 1429 (m), 1340 (m), 1310 (m), 1183 (s), 1128 (vs), 1090 (s), 956 (m), 892 (m), 700 (s)

Example 24: Preparation of 2-[2-[[2-(trifluoromethyl)-4-pyridyl1sulfanyl1ethyllpropaned initrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (709mg, 1 equiv., 5.51 mmol, 98mass%) and 4-chloro-2-(trifluoromethyl)pyridine (1g, 1 equiv., 5.51 mmol). The mixture was cooled at -10°C, and Sodium tert-butanolate (2.2 equiv., 12.1 mmol) was added at this temperature. The reaction was stirred for thirty minutes, then 5ml of ice cold water were added, followed by ice cold 10ml of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed with 20mL of brine. The combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 3.5g of the crude desired product as an orange liquid. The crude was quantified by Q-NMR to give a strength (w/w) of 38% and therefore the reaction gave a chemical yield of 88%. The crude was purified by chromatography column to give 1.02g of the pure, desired product 2-[2-[[2-(trifluoromethyl)-4- pyridyl]sulfanyl]ethyl]propanedinitrile as a white solid (Purity measured by Q-NMR being 91 % (w/w) the isolated yield is 62%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 2.46 (q, J=7.09 Hz, 2 H), 3.35 (t, J=7.07 Hz, 2 H), 4.06 (t, J=6.94 Hz, 1 H), 7.32 (d, J=5.25 Hz, 1 H), 7.52 (s, 1 H), 8.60 (d, J=5.25 Hz, 1 H).

Example 25: Preparation of 1-(3-phenylisoxazol-5-yl)cyclopropanecarbonitrile

In a 20mL vial was charged DMF (4.4 mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (75mg, 1 equiv., 0.557 mmol, 94mass%) and 5-chloro-3-phenyl-isoxazole (0.1g, 1 equiv., 0.557 mmol). Sodium tert-butanolate in THF (2M) (2.2 equiv., 1.28 mmol) was added at room temperature. The reaction was stirred overnight at this temperature, and then was heated to 65°C and stirred for 24 hours, before being allowed to cool down to room temperature. 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.132g of the crude desired product as an orange oil. The crude was quantified by Q-NMR to give a strength (w/w) of 21 % and therefore the reaction gave a chemical yield of 24%. The crude was purified by chromatography column to give 23mg of the pure, desired product 1-(3-phenylisoxazol-5-yl)cyclopropanecarbonitrile (Isolated yield is 20%). m.p. = 102.2 - 105.4 °C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 7.82-7.78 (m, 2H), 7.50-7.46 (m, 3H), 6.72 (s, 1 H), 1 .86-1.84 (m, 4H); ¹³ C NMR (CDCb, 101 MHz) 6 (ppm) = 166.6, 162.9, 130.3, 128.9, 128.2, 126.7, 119.4, 100.3, 18.2, 8.8; IR (ATR, Diamond): v (cnr ¹ ) = 3128 (vw), 3026 (vw), 2245 (w), 1603 (m), 1581 (m), 1407 (s), 998 (m), 765 (vs), 692 (s)

Example 26: Preparation of 1-(5-methylpyrazin-2-yl)cyclopropanecarbonitrile

In a 20mL vial was charged DMF (4.6 mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (103mg, 1 equiv., 0.766 mmol, 94mass%) and 2-chloro-5-methyl-pyrazine (0.098g, 1 equiv., 0.766 mmol). Sodium tert-butanolate in THF (2M) (2.2 equiv., 1.69 mmol) was added at room temperature. The reaction was stirred overnight at this temperature, and then was heated to 65°C and stirred for 24 hours, before being allowed to cool down to room temperature. 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.105g of the crude desired product as a brown oil. The crude was purified by chromatography column to give 5mg of the pure, desired product 1-(5-methylpyrazin-2-yl)cyclopropanecarbonitrile (Isolated yield is 4%). m.p. = 57.7 - 59.2 °C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 8.85 (d, 1 H, J=1.5 Hz), 8.29 (d, 1 H, J=1.1 Hz), 2.56 (s, 3H), 1.82-1.78 (m, 4H); ¹³ C NMR (CDCb, 101 MHz) 6 (ppm) = 152.3, 147.3, 143.7, 141.1 , 121 .0, 21 .1 , 19.7, 13.0; IR (ATR, Diamond): v (cm’ ¹ ) = 3012 (w), 2240 (m), 1488 (vs), 1337 (s), 1033 (vs)

Example 27: Preparation of 5-(1-cvanocvclopropyl)-1-phenyl-pyrazole-4-carbonitrile

In a 20mL vial was charged DMF (3.8 mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (64mg, 1 equiv., 0.476 mmol, 94mass%) and 5-chloro-1-phenyl-pyrazole-4-carbonitrile (0.102g, 1 equiv., 0.476 mmol). Sodium tert-butanolate in THF (2M) (2.2 equiv., 1.05 mmol) was added at room temperature. The reaction was stirred overnight at this temperature, and then was heated to 65°C and stirred for 24 hours, before being allowed to cool down to room temperature. 10ml of saturated aqueous NF CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SC>4, filtered and the solvents were removed under reduced pressure to deliver 0.088g of the crude desired product. The crude was quantified by Q-NMR to give a strength (w/w) of 5% and therefore the reaction gave a chemical yield of 4%. m.p. = 128.2 - 129.3 °C; ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 7.94 (s, 1 H), 7.65-7.55 (m, 5H), 1 .7-1 .8 (m, 2H), 1 .3-1 .4 (m, 2H); ¹³ C NMR (CDCh, 101 MHz) 6 (ppm) = 142.4, 141 .9, 137.7, 130.0, 129.8, 125.3, 119.5, 112.0, 96.1 , 17.3, 5.1 ; IR (ATR, Diamond): v (cnr ¹ ) = 3112 (vw), 2236 (s), 1501 (vs), 1405 (m), 767 (s), 695 (m), 662 (m)

Example 28: Preparation of 1-[6-(trifluoromethyl)-2-pyridyl1cyclopropanecarbonitrile

In a 20mL vial was charged DMF (4.9 mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (82mg, 1 equiv., 0.612 mmol, 94mass%) and 2-fluoro-6-(trifluoromethyl)pyridine (0.102g, 1 equiv., 0.612 mmol). A solution of Lithium bis(trimethylsilyl)amide (LiHMDS) 1 N in THF (2.2 equiv., 1.35 mmol) was added at room temperature. The reaction was stirred overnight at this temperature, and then was heated to 65°C and stirred for 24 hours, before being allowed to cool down to room temperature. 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.146g of the crude desired product 1 -[6-(trifluoromethyl)-2- pyridyl]cyclopropanecarbonitrile. The crude was quantified by Q-NMR to give a strength (w/w) of 32% and therefore the reaction gave a chemical yield of 36%. Alternatively, the compound could be made from 2-chloro-6-(trifluoromethyl)pyridine following this protocol: In a 20mL vial was charged DMF (5.6 mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (75mg, 1 equiv., 0.562 mmol, 94mass%) and 2-chloro-6-(trifluoromethyl)pyridine (0.102g, 1 equiv., 0.561 mmol). Sodium tertbutanolate in THF (2M) (2.2 equiv., 1 .24 mmol) was added at room temperature. The reaction was stirred one hour at this temperature, and then was heated to 65°C and stirred for 24 hours, before being allowed to cool down to room temperature. 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were dried over solid Na2SO4, filtered and the solvents were removed under reduced pressure to deliver 0.270g of the crude desired product 1 -[6- (trifluoromethyl)-2-pyridyl]cyclopropanecarbonitrile. The crude was quantified by Q-NMR to give a strength (w/w) of 16% and therefore the reaction gave a chemical yield of 35%. The crude was purified by chromatography column to give 25mg of the pure, desired product 1 -[6-(trifluoromethyl)-2- pyridyl]cyclopropanecarbonitrile as a white solid (the isolated yield is 20%).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-[[6- (trifluoromethyl)-2-pyridyl]sulfanyl]ethyl]propanedinitrile (example 29) following this protocol.

In a 20mL vial was charged DMF (1.16 mL). To this was added 2-[2-[[6-(trifluoromethyl)-2- pyridyl]sulfanyl]ethyl]propanedinitrile (52mg, 1 equiv., 0.194 mmol). A solution of Lithium bis(trimethylsilyl)amide (LiHMDS) 1 N in THF (1.1 equiv., 0.213 mmol) was added at room temperature. The reaction was heated to 60°C and stirred for 3 days, before being allowed to cool down to room temperature. 5ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 5mL of 1 N HCI. The aqueous layer was extracted thrice with 10 mL of EtOAc, the combined organic layers were washed with 5mL of aqueous saturated NaHCOs and twice with 10mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.034g of the crude desired product 1 -[6-(trifluoromethyl)-2- pyridyl]cyclopropanecarbonitrile. The crude was quantified by Q-NMR to give a strength (w/w) of 49% and therefore the reaction gave a chemical yield of 40%. The crude was purified by chromatography column to give 13mg of the pure, desired product 1 -[6-(trifluoromethyl)-2- pyridyl]cyclopropanecarbonitrile as white needles (the isolated yield is 27%). m.p. = 75.4 - 77.3 °C; ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 7.96 (dd, 1 H, J=0.92, 7.52 Hz), 7.9 (t, J=7.52Hz, 1 H), 7.57 (dd, 1 H, J=0.92, 7.52 Hz), 1 .98-1 .87 (m, 2H), 1 .86-1 .76 (m, 2H); ¹³ C NMR (CDCb, 101 MHz) 6 (ppm) = 155.7, 148.2, 138.1 , 123.7, 121.3, 118.5, 121.1 , 20.7, 15.2; ¹⁹ F NMR (CDCb, 377 MHz) 6 (ppm) = -68.44 (s, 3F); IR (ATR, Diamond): v (cm’ ¹ ) = 3084 (vw), 3022 (vw), 2241 (w), 1596 (m), 1461 (m), 1346 (s), 1304 (s), 1277 (m), 1194 (s), 1148 (vs), 1087 (s), 807 (s), 704 (s) Example 29: Preparation of 2-[2-[[6-(trifluoromethyl)-2-pyridyl1sulfanyl1ethyllpropaned initrile

In a 100mL RBF was charged DMF (30mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (808mg, 1 equiv., 6.016 mmol, 94mass%) and 2-fluoro-6-(trifluoromethyl)pyridine (1g, 1 equiv., 6.016 mmol, 99mass%). Sodium tert-butanolate in THF (2M) (2.2 equiv., 13.24 mmol) was added at room temperature. The reaction was stirred one hour at this temperature. 30ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 30mL of 1 N HCI. The aqueous layer was extracted thrice with 50 mL of EtOAc, the combined organic layers were washed with 30mL of aqueous saturated NaHCCh and twice with 30mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1 .845g of the crude desired product as an orange oil. The crude was purified by chromatography column to give 1.41 g of the pure, desired product 2-[2-[[6-(trifluoromethyl)-2-pyridyl]sulfanyl]ethyl]propaned initrile as an colorless oil which solidified overnight (Isolated yield is 86%). m.p. = 61.7 - 64.9 °C; ¹ H NMR (CDCH, 400 MHz) 6 (ppm) = 7.72 (1 H, t, J=7.81 Hz), 7.45 (1 H, d, J=7.27 Hz), 7.40 (1 H, d, J=7.99 Hz), 4.09 (1 H, t, J=7.45 Hz), 3.46 (2 H, t, J=6.54 Hz), 2.57 (2 H, q, J=6.66 Hz); ¹³ C NMR (CDCI3, 101 MHz) 6 (ppm) = 158.3, 148.2, 137.5, 125.3, 121 .2, 116.6, 112.2, 30.7, 26.6, 21.4; IR (ATR, Diamond): v (cnr ¹ ) = 2914 (vw), 2259 (vw), 1445 (m), 1337 (vs), 1189 (s), 1136 (vs), 1109 (vs), 804 (m), 716 (m)

Example 30: Preparation of 1-[6-chloro-3-(4-chlorophenyl)pyridazin-4-yl]cyclopropanecar bonitrile

In a 20mL vial was charged DMF (3mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (49mg, 1 equiv., 0.368 mmol, 94mass%) and 4,6-dichloro-3-(4-chlorophenyl)pyridazine (100mg, 1 equiv., 0.368 mmol, 95mass%). A solution of Sodium bis(trimethylsilyl)amide (NaHMDS) 1 N in THF (2.1 equiv., 0.77 mmol) was added at room temperature. The reaction was stirred for 3 hours. 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed with 10mL of aqueous saturated NaHCOs and twice with 15mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.131g of the crude desired product 1-[6-chloro-3-(4-chlorophenyl)pyridazin-4- yl]cyclopropanecarbonitrile as an orange liquid. The crude was purified by chromatography column to give 75mg of the pure, desired product 1-[6-chloro-3-(4-chlorophenyl)pyridazin-4- yl]cyclopropanecarbonitrile as an orange liquid (the isolated yield is 70%). m.p. = 152.8 - 155.5 °C with gradual degradation up to 156 °C; ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 7.74-7.7 (m, 2H), 7.63 (s, 1 H), 7.61-7.57 (m, 2H), 1.76-1.65 (m, 2H), 1.26-1.15 (m, 2H); ¹³ C NMR (CDCh, 101 MHz) 6 (ppm) = 160.5, 155.9, 136.6, 136.2, 133.3, 130.7, 129.8, 129.2, 120.5, 17.6, 12.4; IR (ATR, Diamond): v (cm’ ¹ ) = 3060 (vw), 2924 (w), 2239 (w), 1393 (vs), 1344 (s), 1093 (vs), 836 (s), 734 (vs)

Example 31 : Preparation of 1-(4-nitrophenyl)cyclopropanecarbonitrile

In a 20mL vial was charged DMF (3.2mL). To this were added 5-amino-2,3-dihydrothiophene-4- carbonitrile (100mg, 1 equiv., 0.792 mmol) and 1-fluoro-4-nitro-benzene (112mg, 1 equiv., 0.792 mmol). Sodium tert-butanolate (2 equiv., 1 .58 mmol) was added at room temperature. The reaction was stirred for 3 hours at this temperature, then heated at 65°C for three extra hours. The reaction was then allowed to cool down to room temperature, then 10ml of saturated aqueous NH4CI were added. After transfer to an Erlenmeyer the mixture was acidified with 10mL of 1 N HCI. The aqueous layer was extracted thrice with 20 mL of DCM, the combined organic layers were dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.294g of the crude desired product 1 -(4- nitrophenyl)cyclopropanecarbonitrile. The crude was quantified by Q-NMR to give a strength (w/w) of 16% and therefore the reaction gave a chemical yield of 32%. The crude was purified by chromatography column to give 44mg of the pure, desired product 1-(4-nitrophenyl)cyclopropanecarbonitrile (the isolated yield is 30%).

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-(4- nitrophenyl)sulfanylethyl]propanedinitrile (example 32) following this protocol.

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5 mL). To this was added 2-[2-(4-nitrophenyl)sulfanylethyl]propanedinitrile (0.5 g, 2mmol). The base Sodium tert-butanolate (1 equiv., 2 mmol) was added. The reaction was stirred one hour at this temperature, then 10ml of ice cold water were added. The reaction was further acidified by 2ml of 2N HCI - a solid precipitated out. The reaction was further diluted with 10mL of water. The solid precipitate was filtered off on Buchner funnel under vacuum and the solid was washed with 15mL of water before being collected. The white solid obtained was dried under reduced pressure at 50°C. 0.354g of the pure, desired product 1-(4-nitrophenyl)cyclopropanecarbonitrile was obtained (Purity measured by Q-NMR being 94% (w/w) the isolated yield is 90%). m.p. = 145.9 - 147.1 °C gradual decomposition up to 147 °C; ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 8.22 (d, J=8.93Hz, 2H), 7.43 (d, J=8.8Hz, 2H), 1 .94-1 .86 (m, 2H), 1.57-1.49 (m, 2H); ¹³ C NMR (CDCh, 101 MHz) 6 (ppm) = 147.2, 143.5, 126.0, 124.2, 121.1 , 19.9, 14.1 ; IR (ATR, Diamond): v (cm’ ¹ ) = 3108 (w), 3086 (w), 2237 (w), 1599 (m), 1515 (vs), 1346 (vs), 862 (m), 748 (m)

Example 32: Preparation of 2-[2-(4-nitrophenyl)sulfanylethyllpropanedinitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (940mg, 1.04 equiv., 7.4 mmol) and 1-fluoro-4-nitro-benzene (1g, l equiv., 7.087 mmol). The mixture was cooled down at -40°C, Sodium tert-butanolate (2.03equiv., 14.4 mmol) was added at this temperature. The reaction was stirred for 1 hour at this temperature, then 5ml of ice cold water were added and the mixture was acidified with 10mL of ice cold 1 N HCI. The aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed with 20mL of brine and dried over solid Na2SC>4 and filtered. The solvents were removed under reduced pressure to deliver 2.5g of the crude desired product 2-[2- (4-nitrophenyl)sulfanylethyl]propanedinitrile as a yellow liquid which slowly solidified. Addition of 10mL of water and stirring led to a suspension which was filtered on a Buchner funnel and the solid was collected after having being washed with 15mL of water. The solid was then dried under vacuum at 50°C ; 1 ,25g of a yellowish solid was then obtained and quantified by Q-NMR to give a strength (w/w) of 72% and therefore the reaction gave a chemical yield of 51 %. ¹ H NMR (D6-DMSO, 400 MHz) 6 (ppm) = 8.16 (2H, d, J=8.9Hz, 2H), 7.57 (2H, d, J=8.8Hz), 4.95 (1 H, t, J=7Hz), 3.29 (2H, t, J=6.5Hz), 2.4 (2 H, q, J=6.7Hz).

Example 33: Preparation of 1-(6-chloroquinoxalin-2-yl)cyclopropanecarbonitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (634mg, 1 equiv., 5.02 mmol) and 2,6-dichloroquinoxaline (1g, 1 equiv., 5.02 mmol). Sodium tert-butanolate (2.2 equiv., 11.1 mmol) was added at room temperature. The reaction was stirred for 3 hours then 10ml of water were added. The reaction was further acidified by 5ml of 2N HCI while a solid was precipitating out. The solid precipitate was filtered off on Buchner funnel under vacuum ; the brownish solid obtained was dried under reduced pressure at 50°C. 1 ,71g of the crude, desired product 1 -(6-chloroquinoxalin-2- yl)cyclopropanecarbonitrile was obtained (Purity measured by Q-NMR being 47% (w/w) the chemical yield is 70%). The crude was purified by chromatography column to give 0.79g of the pure, desired product 1-(6-chloroquinoxalin-2-yl)cyclopropanecarbonitrileas a white solid (Purity measured by Q-NMR being 98% (w/w) the isolated yield is 67%)

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-(6- chloroquinoxalin-2-yl)sulfanylethyl]propanedinitrile (example 34) following this protocol.

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5mL). To this was added 2-[2-(6-chloroquinoxalin-2-yl)sulfanylethyl]propanedinitrile (500mg, 1 equiv., 1.73 mmol). Sodium tert-butanolate (1 equiv., 1.73 mmol) was added at room temperature. The reaction was stirred for 1 hour then 10ml of ice cold water were added. The reaction was further acidified by 2ml of 2N HCI while a solid had precipitated out. The mixture was further diluted by 10mL of water, the solid precipitate was filtered off on Buchner funnel under vacuum and rinsed with 15mL of water; the white solid obtained was dried under reduced pressure at 50°C. 0.364g of the pure, desired product 1-(6-chloroquinoxalin-2-yl)cyclopropanecarbonitrile was obtained (Purity measured by Q-NMR being 93% (w/w) the isolated yield is 85%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 1.89 - 1.96 (m, 2H), 1.99 - 2.06 (m, 2H), 7.71 (dd, J=9.05, 2.32 Hz, 1 H), 7.89 (d, J=9.05 Hz, 1 H), 8.12 (d, J=2.32 Hz, 1 H), 9.27 (s, 1 H).

Example 34: Preparation of 2-[2-(6-chloroquinoxalin-2-yl)sulfanylethyllpropanedinitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (634mg, 1 equiv., 5.02 mmol) and 2,6-dichloroquinoxaline (1g, 1 equiv., 5.02 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 11.1 mmol) was added at this temperature. The reaction was stirred one hour at this temperature. 5mL of ice-cold water were added, followed by 10mL of ice cold 2N HCI; the aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1 ,35g of the crude desired product 2-[2-(6- chloroquinoxalin-2-yl)sulfanylethyl]propanedinitrile as an orange oil. (Purity measured by Q-NMR being 85% (w/w) the chemical yield is 79%). The crude was purified by chromatography column to give 0.99g of the pure, desired product 2-[2-(6-chloroquinoxalin-2-yl)sulfanylethyl]propanedinitrile as a white solid (Purity measured by Q-NMR being 97% (w/w) the isolated yield is 66%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 2.59 (q, J=6.92 Hz, 2H), 3.60 (t, J=6.88 Hz, 2H), 4.03 (t, J=7.00 Hz, 1 H), 7.69 (d, J=8.51 Hz, 1 H), 7.97 (d, J=8.88 Hz, 1 H), 8.04 (d, J=2.38 Hz, 1 H), 8.63 (s, 1 H). Example 35: Preparation of 1-(3-chloropyrazin-2-yDcyclopropanecarbonitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (847mg, 1 equiv., 6.71 mmol) and 2,3-dichloropyrazine (1g, 1 equiv., 6.71 mmol). Sodium tert-butanolate (2.2 equiv., 14.8 mmol) was added at room temperature, then the reaction was heated up to 65°C, stirred for nine hours at this temperature, and overnight at room temperature. 10mL of water were added, followed by 10mL of 1 N HCI; the aqueous layer was extracted thrice with 50 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 2.77g of the crude desired product 1 -(3-chloropyrazin-2- yl)cyclopropanecarbonitrile as an orange liquid. (Purity measured by Q-NMR being 33% (w/w) the chemical yield is 77%). The crude was purified by chromatography column to give 0.75g of relatively pure, desired product 1-(3-chloropyrazin-2-yl)cyclopropanecarbonitrile as a yellow liquid (Purity measured by Q-NMR being 84% (w/w) the isolated yield is 52%). Higher purity can be achieved by proceeding to an extra column chromatography.

Alternatively, the title product can be made from cyclisation of the isolated intermediate 2-[2-(3- chloropyrazin-2-yl)sulfanylethyl]propanedinitrile (example 36) following this protocol.

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5mL). To this was added 2-[2-(3-chloropyrazin-2-yl)sulfanylethyl]propanedinitrile (500mg, 1 equiv., 2.09 mmol). Sodium tert-butanolate (1 equiv., 2.09 mmol) was added at room temperature, then the reaction was heated up to 65°C and stirred for four hours at this temperature, before being allowed to cool down to room temperature. 5mL of water were added, followed by 10mL of 1 N HCI ; the aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.52g of the crude desired product 1 -(3-chloropyrazin-2- yl)cyclopropanecarbonitrile as an orange liquid. (Purity measured by Q-NMR being 45% (w/w) the chemical yield is 62%). The crude was purified by chromatography column to give 0.22g of pure, desired product 1-(3-chloropyrazin-2-yl)cyclopropanecarbonitrile as a colorless liquid (Purity measured by Q- NMR being 94% (w/w) the isolated yield is 55%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 1 .68 - 1 .73 (m, 2H), 1 .80 - 1 .85 (m, 2H), 8.38 (d, J=2.38 Hz, 1 H), 8.44 (d, J=2.38 Hz, 1 H).

Example 36: Preparation of 2-[2-(3-chloropyrazin-2-yl)sulfanylethyllpropanedinitrile In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (10mL). To this were added 5-amino-2,3-dihydrothiophene-4-carbonitrile (860mg, 1 equiv., 6.7 mmol) and 2,3-dichloropyrazine (1g, 1 equiv., 6.7 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 15 mmol) was added at this temperature. The reaction was stirred two hours at -40°C, then 5mL of ice-cold water were added, followed by 10mL of ice-cold 1 N HCI; the solid precipitate was then filtered off on Buchner funnel under vacuum and rinsed with 15mL of water; the yellow solid obtained was dried under reduced pressure at 50°C. 1. 4g of the pure, desired product 2-[2-(3-chloropyrazin-2-yl)sulfanylethyl]propanedinitrile. Purity measured by Q- NMR being 95% (w/w) the isolated yield is 83%. ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 2.50 (q, J=7.13 Hz, 2H), 3.44 (t, J=6.88 Hz, 2H), 4.00 (t, J=7.25 Hz, 1 H), 8.13 (d, J=2.63 Hz, 1 H), 8.36 (d, J=2.63 Hz, 1 H).

Example 37: Preparation of diversely substituted 5-amino-2,3-dihydrothiophene-4-carbonitriles

The following nine diversely substituted 5-amino-2,3-dihydrothiophene-4-carbonitriles: 5-amino-2-[(4-chlorophenoxy)methyl]-2,3-dihydrothiophene-4-c arbonitrile; 5-amino-2-(phenoxymethyl)- 2,3-dihydrothiophene-4-carbonitrile; 5-amino-2-hexyl-2,3-dihydrothiophene-4-carbonitrile; 5-amino-2- phenyl-2,3-dihydrothiophene-4-carbonitrile as a mixture with 5-amino-3-phenyl-2,3-dihydrothiophene- 4-carbonitrile; 5-amino-2,2-diethyl-3H-thiophene-4-carbonitrile; 5-amino-3-ethyl-2-heptyl-2,3- dihydrothiophene-4-carbonitrile; and 5-amino-3-ethyl-2-phenyl-2,3-dihydrothiophene-4-carbonitrile in a mixture with 5-amino-2-ethyl-3-phenyl-2,3-dihydrothiophene-4-carbonitrile : were made simply from corresponding epoxides and potassium thiocyanate (KSCN) (Scheme 4),

Scheme 4 as described byNaoto Aoyagi et al in ChemistrySelect, 2, 4466-4468; 2017 ; followed by treatment with malonitrile and a base as NaH as described in Yamagata, Kenji et al in Chemical & Pharmaceutical Bulletin, 30(12), 4396-401 ; 1982 ; (NMP as solvent instead of DMSO for safety reasons) or by IJOH.H2O (in THF or MeTHF as solvent) or alternatively, by NaH in DME as solvent as described in Wamhoff, Heinrich and Thiemig, Heinz Albrecht in Chemische Berichte, 118(11), 4473-85; 1985. In scheme 4, R1 - R4 are as defined above. They were used as starting materials in the preparation of examples 38 to 51.

Example 38: Preparation of 2-[2-[(4-chlorophenoxy)methyl1-1-cyano-cyclopropyllpyridine- 3-carbonitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-2-[(4-chlorophenoxy)methyl]-2,3-dihydrothiophene-4- carbonitrile (481 mg, 1 equiv., 1.80 mmol) and 2-chloropyridine-3-carbonitrile (0.25g, 1 equiv., 1.80 mmol). Sodium tert-butanolate (2.2 equiv., 3.97 mmol) was added at room temperature, then the reaction was stirred for four hours at this temperature. 5mL of ice cold water were added, followed by 10mL of 1 N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed twice with 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 4.4g of the crude desired product 2-[2-[(4- chlorophenoxy)methyl]-1-cyano-cyclopropyl]pyridine-3-carboni trile as an orange liquid. (Purity measured by Q-NMR being 6% (w/w) for the major diastereoisomer and 2% for the minor diastereoisomer, the total chemical yield is 58% (45% for the major and 13% for the minor diastereoisomer). The crude was purified by chromatography column to give 0.19g of pure, desired product 2-[2-[(4-chlorophenoxy)methyl]-1-cyano-cyclopropyl]pyridine- 3-carbonitrile (Major Isomer) and 54mg of the minor diastereoisomer of the title compound as white solids (Purity measured by Q-NMR being 97% (w/w) for both fractions, the total isolated yield is 43% (33% Major and 10% minor isomer). Alternatively, the title product can be made from cyclisation of an isolated intermediate 2-[3-(4- chlorophenoxy)-2-[(3-cyano-2-pyridyl)sulfanyl]propyl]propane dinitrile (example 39) following this protocol. In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5mL). To this was added 2-[3-(4-chlorophenoxy)-2-[(3-cyano-2- pyridyl)sulfanyl]propyl]propanedinitrile (250mg, 1 equiv., 0.68 mmol). Sodium tert-butanolate (1 equiv., 0.68 mmol) was added at room temperature, then the reaction was stirred for three hours at this temperature. The reaction mixture was poured onto 5mL of aqueous saturated NH4CI, stirred for 10 minutes and the aqueous layer was extracted thrice with 20 mL of EtOAc. The combined organic layers were dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.2g of the crude desired product 2-[2-[(4-chlorophenoxy)methyl]-1-cyano-cyclopropyl]pyridine- 3- carbonitrile as an orange liquid. (Purity measured by Q-NMR being 45% (w/w) for the major diastereoisomer and 18% for the minor diastereoisomer, the total chemical yield is 60%. The crude was purified by chromatography column to give 72mg of pure, desired product 2-[2-[(4- chlorophenoxy)methyl]-1-cyano-cyclopropyl]pyridine-3-carboni trile (Major Isomer) and in another fraction 32mg of the minor diastereoisomer of the title compound as yellow solids (the total isolated yield is 47% (34% Major and 13% minor isomer). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = for the Major Fraction 1.87 (dd, J=7.44, 5.69 Hz, 1 H), 2.21 (dd, J=9.01 , 5.63 Hz, 1 H), 2.39 - 2.47 (m, 1 H), 4.29 - 4.4 (m, 2 H), 6.93 (d, J=8 Hz, 2 H), 7.26 (d, J=8 Hz, 2 H), 7.43 (dd, J=7.75, 4.88 Hz, 1 H), 8.06 (dd, J=7.82, 1.81 Hz, 1 H), 8.73 (dd, J=4.88, 1 .75 Hz, 1 H). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = for the minor Fraction 1 .99 (dd, J=9.35, 5.94 Hz, 1 H), 2.46 (dd, J=7.60, 5.97 Hz, 1 H), 2.57 - 2.73 (m, 1 H), 3.29 (dd, J=10.68, 8.33 Hz, 1 H), 4.11 (dd, J=10.69, 4.41 Hz, 1 H), 6.53 - 6.59 (m, 2 H), 7.09 - 7.13 (m, 2 H), 7.34 (dd, J=7.85, 4.91 Hz, 1 H), 7.95 (dd, J=7.85, 1.75 Hz, 1 H), 8.67 (dd, J=4.91 , 1.75 Hz, 1 H). 2D-NMR’s (including NOESY) did show that the major isomer is the racemic mixture of 2-[(1 S,2R)-2-[(4- chlorophenoxy)methyl]-1-cyano-cyclopropyl]pyridine-3-carboni trile and its enantiomer ; whereas the minor isomer is the racemic mixture of 2-[(1 R,2R)-2-[(4-chlorophenoxy)methyl]-1-cyano- cyclopropyl]pyridine-3-carbonitrile and its enantiomer.

Example 39: Preparation of 2-[3-(4-chlorophenoxy)-2-[(3-cyano-2-pyridyl)sulfanyl]propyl lpropanedinitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-2-[(4-chlorophenoxy)methyl]-2,3-dihydrothiophene-4- carbonitrile (481 mg, 1 equiv., 1.80 mmol) and 2-chloropyridine-3-carbonitrile (0.25g, 1 equiv., 1.80 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 3.97 mmol) was added at this temperature. The reaction was stirred one hour at this temperature. 5mL of ice-cold water were added, followed by 10mL of ice cold 1 N HCI; the aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1.59g of the crude desired product 2-[3-(4-chlorophenoxy)-2-[(3-cyano-2-pyridyl)sulfanyl]propyl ]propanedinitrile as an orange liquid. (Purity measured by Q-NMR being 47% (w/w) the chemical yield is 75%). The crude was purified by chromatography column to give 0.38g of pure, desired product 2-[3-(4-chlorophenoxy)- 2-[(3-cyano-2-pyridyl)sulfanyl]propyl]propanedinitrile as a white solid (Purity measured by Q-NMR being 94% (w/w) the isolated yield is 53%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 2.52 (ddd, J=14.49, 9.96, 5.62 Hz, 1 H), 2.79 (ddd, J=14.49, 9.84, 4.77 Hz, 1 H), 4.1 1 - 4.18 (m, 2 H), 4.29 (dd, J=9.72, 3.73 Hz, 1 H), 4.59 - 4.67 (m, 1 H), 6.78 - 6.83 (m, 2 H), 7.14 - 7.22 (m, 3 H), 7.83 (dd, J=7.76, 1.77 Hz, 1 H), 8.58 (dd, J=4.89, 1.71 Hz, 1 H).

Example 40: Preparation of 2-[1-cyano-2-(phenoxymethyl)cyclopropyllpyridine-3-carbonitr ile In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-2-(phenoxymethyl)-2,3-dihydrothiophene-4- carbonitrile (420mg, 1 equiv., 1.80 mmol) and 2-chloropyridine-3-carbonitrile (0.25g, 1 equiv., 1.80 mmol). Sodium tert-butanolate (2.2 equiv., 4 mmol) was added at room temperature, then the reaction was stirred for four hours at this temperature. 5mL of ice cold water were added, followed by 10mL of 1 N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed with 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.64g of the crude desired product 2-[1-cyano-2- (phenoxymethyl)cyclopropyl]pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 36% (w/w) for the major diastereoisomer and 11 % for the minor diastereoisomer, the total chemical yield is 60% (46% for the major and 14% for the minor diastereoisomer). The crude was purified by chromatography column to give 0.23g of pure, desired product 2-[1-cyano-2- (phenoxymethyl)cyclopropyl]pyridine-3-carbonitrile (Major Isomer) and in another fraction 70mg of the minor diastereoisomer of the title compound as white solids (Purity measured by Q-NMR being >95% (w/w) for both fractions, the total isolated yield is 54% (44% Major and 10% minor isomer).

Alternatively, the title product can be made from cyclisation of an isolated intermediate 2-[2-[(3-cyano- 2-pyridyl)sulfanyl]-3-phenoxy-propyl]propanedinitrile (example 41) following this protocol.

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (4mL). To this was added 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-3-phenoxy- propyl]propanedinitrile (250mg, 1 equiv., 0.75 mmol). Sodium tert-butanolate (1 equiv., 0.75 mmol) was added at room temperature, then the reaction was heated up to 65°C and stirred at this temperature for three hours. The reaction mixture was allowed to cool down to room temperature and poured onto 5mL of aqueous saturated NH4CI, stirred for 10 minutes and the aqueous layer was extracted thrice with 20 mL of EtOAc. The combined organic layers were dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.21g of the crude desired product 2-[1-cyano-2- (phenoxymethyl)cyclopropyl]pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 29% (w/w) for the major diastereoismer and 10% for the minor diastereoisomer, the total chemical yield is 54% (39% for the major and 15% for the minor diastereoisomer). The crude was purified by chromatography column to give 60mg of pure, desired product 2-[1-cyano-2- (phenoxymethyl)cyclopropyl]pyridine-3-carbonitrile (Major Isomer) and in another fraction 20mg of the minor diastereoisomer of the title compound as pale yellow solids (the total isolated yield is 42% (30% in the Major isomer and 12% for the minor isomer). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = for the Major Fraction 1.89 (dd, J=7.32, 5.82 Hz, 1 H), 2.21 (dd, J=9.01 , 5.63 Hz, 1 H), 2.39 - 2.53 (m, 1 H), 4.25 - 4.34 (m, 1 H), 4.45 (dd, J=10.44, 6.82 Hz, 1 H), 6.97 - 7.06 (m, 3 H), 7.21 - 7.39 (m, 2 H), 7.42 (dd, J=7.85, 4.88 Hz, 1 H) 8.04 (dd, J=7.85, 1 .75 Hz, 1 H) 8.73 (dd, J=4.88, 1.75 Hz, 1 H). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = for the minor Fraction 2.10 (dd, J=9.36, 5.89 Hz, 1 H), 2.55 - 2.60 (m, 1 H), 2.68 - 2.86 (m, 1 H), 3.49 (dd, J=10.71 , 8.05 Hz, 1 H), 4.23 (dd, J=10.74, 4.42 Hz, 1 H), 6.71 - 6.76 (m, 2 H), 6.89 - 7.09 (m, 1 H), 7.24 - 7.29 (m, 2 H), 7.43 (ddd, J=7.84, 4.90, 0.89 Hz, 1 H), 8.05 (d, J=7.80 Hz, 1 H), 8.78 (d, J=4.96 Hz, 1 H). Example 41 : Preparation of 2-[2-[(3-cyano-2-pyridyl)sulfanyl1-3-phenoxy-propyllpropaned initrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-2-(phenoxymethyl)-2,3-dihydrothiophene-4- carbonitrile (419mg, 1 equiv., 1.80 mmol) and 2-chloropyridine-3-carbonitrile (0.25g, 1 equiv., 1.80 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 3.97 mmol) was added at this temperature. The reaction was stirred 1 .5 hour at this temperature. 5mL of ice- cold water were added, followed by 10mL of ice cold 1 N HCI; the aqueous layer was extracted thrice with 20 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1.9g of the crude desired product 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-3-phenoxy-propyl]propaned initrile as an orange liquid. (Purity measured by Q-NMR being 23% (w/w) the chemical yield is 72%). The crude was purified by chromatography column to give 0.47g of pure, desired product 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-3- phenoxy-propyl]propanedinitrile as a pale yellow solid (Purity measured by Q-NMR being 72% (w/w) the isolated yield is 56%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 2.61 (ddd, J=14.70, 9.44, 5.75 Hz, 1 H), 2.85 - 2.93 (m, 1 H), 4.19 - 4.28 (m, 2 H), 4.33 - 4.48 (m, 1 H), 4.63 - 4.80 (m, 1 H), 6.95 (d, J=8.38 Hz, 2 H), 7.02 (t, J=7.19 Hz, 1 H), 7.22 (dd, J=7.69, 4.94 Hz, 1 H), 7.30 - 7.37 (m, 2 H), 7.90 (dd, J=7.75, 1.38 Hz, 1 H), 8.63 - 8.68 (m, 1 H).

Example 42: Preparation of 2-(1-cyano-2-hexyl-cyclopropyl)pyridine-3-carbonitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-2-hexyl-2,3-dihydrothiophene-4-carbonitrile (759mg, 1 equiv., 3.61 mmol) and 2-chloropyridine-3-carbonitrile (0.5g, 1 equiv., 3.61 mmol). Sodium tert- butanolate (2.2 equiv., 7.94 mmol) was added at room temperature, then the reaction was stirred for two hours at this temperature. 10mL of ice cold water were added, followed by 5mL of 2N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed with 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1 ,68g of the crude desired product 2-(1-cyano-2-hexyl- cyclopropyl)pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 30% (w/w) for the major diastereoisomer and 10% for the minor diastereoisomer, the total chemical yield is 74% (55.5% for the major and 18.5% for the minor diastereoisomer). The crude was purified by chromatography column to give 0.265g of pure (91 % w/w as measured by QNMR), desired product 2- (1-cyano-2-hexyl-cyclopropyl)pyridine-3-carbonitrile (Major Isomer) and in another fraction 52mg of a mixture of major and minor diastereoisomers of the title compound in a 2:1 ratio. The purity measured for the minor fraction is, by Q-NMR, around 60% (w/w) for the total of both isomers, the overall isolated yield from both fractions combined is 66% (54% Major and 12% minor isomer).

Alternatively, the title product can be made from cyclisation of an isolated intermediate 2-[2-[(3-cyano- 2-pyridyl)sulfanyl]octyl]propaned initrile (example 43) following this protocol. In a 3 necked 25mL Round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5mL). To this was added 2-[2-[(3-cyano-2-pyridyl)sulfanyl]octyl]propanedinitrile (500mg, 1 equiv., 1 .60 mmol). Sodium tert-butanolate (1 equiv., 1 .60 mmol) was added at room temperature, then the reaction was stirred at this temperature for two hours. The reaction mixture was poured onto 2mL of 2N HCI, stirred for 10 minutes and the aqueous layer was extracted thrice with 20 mL of EtOAc. The combined organic layers were dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.37g of the crude desired product 2-(1-cyano-2-hexyl- cyclopropyl)pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 55% (w/w) for the major diastereoismer and 28% for the minor diastereoisomer, the total chemical yield is 76% (50% for the major and 26% for the minor diastereoisomer). The crude was purified by chromatography column to give three fractions. First fraction (20mg) is the minor isomer only (5% Chemical yield for this fraction), the second fraction (155mg) is a mixture of the two isomers (Purity measured by Q-NMR is 59% (w/w) for the major diastereoismer and 33% for the minor diastereoisomer, the chemical yield in this fraction is 34% (22% for the major and 12% for the minor diastereoisomer), and the third fraction (69mg) is the major isomer only (17% Chemical yield for this fraction). The total, combined fractions, isolated yield is thus 56% overall. ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = for the major isomer 0.88 - 0.91 (m, 3 H), 1 .24 - 1 .44 (m, 6 H), 1 .53 - 1 .72 (m, 5 H), 1 .84 - 2.00 (m, 2 H), 2.11 (dd, J=8.66, 5.14 Hz, 1 H), 7.38 (dd, J=7.88, 4.88 Hz, 1 H), 8.02 (dd, J=7.78, 1.76 Hz, 1 H), 8.70 (dd, J=4.77, 1.76 Hz, 1 H). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = for the minor isomer 0.48 - 0.54 (m, 1 H), 0.83 (t, J=7.03 Hz, 3 H), 1.10 - 1.28 (m, 6 H), 1.31 - 1.46 (m, 3 H), 1.86 (dd, J=9.03, 5.52 Hz, 1 H), 2.05 (dd, J=7.78, 5.52 Hz, 1 H), 2.12 - 2.16 (m, 1 H), 7.43 (dd, J=7.91 , 4.89 Hz, 1 H), 8.04 (dd, J=7.78, 1.76 Hz, 1 H), 8.75 (dd, J=4.77, 1.76 Hz, 1 H). 2D-NMR’s (including NOESY) did show that the major isomer is the racemic mixture of 2-[(1 R,2S)-1 -cyano-2-hexyl- cyclopropyl]pyridine-3-carbonitrile and its enantiomer ; whereas the minor isomer is the racemic mixture of 2-[(1 R,2R)-1-cyano-2-hexyl-cyclopropyl]pyridine-3-carbonitrile and its enantiomer.

Example 43: Preparation of 2-[2-[(3-cyano-2-pyridyl)sulfanyl1octyllpropanedinitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-2-hexyl-2,3-dihydrothiophene-4-carbonitrile (759mg,

1 equiv., 3.61 mmol) and 2-chloropyridine-3-carbonitrile (0.5g, 1 equiv., 3.61 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 3.97 mmol) was added at this temperature. The reaction was stirred 4.5 hours at this temperature. 5mL of ice-cold water were added, followed by 10mL of ice cold 2N HCI; the aqueous layer was extracted thrice with 50 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1.6g of the crude desired product 2-[2-[(3-cyano-2-pyridyl)sulfanyl]octyl]propanedinitrile as an orange liquid. (Purity measured by Q-NMR being 50% (w/w) the chemical yield is 70%). The crude was purified by chromatography column to give 0.75g of pure, desired product 2-[2-[(3-cyano-2-pyridyl)sulfanyl]octyl]propanedinitrile as a pale yellow liquid (Purity measured by Q-NMR being 97% (w/w) the isolated yield is 65%). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 0.82 - 0.94 (m, 3 H), 1 .24 - 1 .37 (m, 6 H), 1 .43 - 1 .60 (m, 2 H), 1 .83 (q, J=7.30 Hz,

2 H), 2.42 (ddd, J=14.51 , 9.69, 5.19 Hz, 1 H), 2.57 (ddd, J=14.26, 10.01 , 4.13 Hz, 1 H), 4.10 (dd, J=10.01 , 5.13 Hz, 1 H), 4.21 - 4.29 (m, 1 H), 7.18 (dd, J=7.75, 4.88 Hz, 1 H), 7.87 (dd, J=7.75, 1.75 Hz, 1 H), 8.62 (dd, J=4.88, 1.75 Hz, 1 H).

Example 44: Preparation of 2-(1-cyano-2-phenyl-cyclopropyDpyridine-3-carbonitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added a mixture of 5-amino-2-phenyl-2,3-dihydrothiophene-4- carbonitrile and 5-amino-3-phenyl-2,3-dihydrothiophene-4-carbonitrile in almost a 1 :1 ratio (730mg, 1 equiv., 3.61 mmol) and 2-chloropyridine-3-carbonitrile (0.5g, 1 equiv., 3.61 mmol). Sodium tert- butanolate (2.2 equiv., 7.94 mmol) was added at room temperature, then the reaction was stirred for two hours at this temperature. 10mL of ice cold water were added, followed by 10mL of 2N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed with 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 2.3g of the crude desired product 2-(1-cyano-2-phenyl- cyclopropyl)pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 16% (w/w) for the major diastereoisomer and 2.1% for the minor diastereoisomer, the total chemical yield is 46% (40% for the major and 6% for the minor diastereoisomer). The crude was purified by chromatography column to give 0.3g of pure (94% w/w as measured by QNMR), desired product 2-(1-cyano-2-phenyl- cyclopropyl)pyridine-3-carbonitrile (Major Isomer ; isolated yield 30%) and in another fraction a mixture of major and minor diastereoisomers of the title compound. Alternatively, the title product can be made from cyclisation of isolated intermediates mixture consisting of 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-2- phenyl-ethyl]propanedinitrile and 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-1-phenyl-ethyl]propanedin itrile (example 45) following this protocol. In a 3 necked 25mL Round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5mL). To this were added a mixture consisting of 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-2-phenyl-ethyl]propanedin itrile and 2-[2-[(3-cyano-2- pyridyl)sulfanyl]-1-phenyl-ethyl]propanedinitrile (500mg, 1 equiv., 1.64 mmol). Sodium tert-butanolate (1 equiv., 1 .64 mmol) was added at room temperature, then the reaction was stirred at this temperature overnight. The reaction mixture was poured onto 2mL of 2N HCI, stirred for 10 minutes and the aqueous layer was extracted thrice with 20 mL of EtOAc. The combined organic layers were dried over solid Na2SC>4 and filtered. The solvents were removed under reduced pressure to deliver 0.35g of the crude desired product 2-(1-cyano-2-phenyl-cyclopropyl)pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 56% (w/w) for the major diastereoismer and 21 % for the minor diastereoisomer, the total chemical yield is 67% (49% for the major and 18% for the minor diastereoisomer). The crude was purified by chromatography column to separate the two isomers (43% Isolated yield for the major isomer and 8% isolated yield for the minor isomer). The total, combined fractions, isolated yield is thus 51% overall. ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = for the major isomer 2.31 (dd, J=8.00, 5.88 Hz, 1 H), 2.48 (dd, J=9.11 , 5.81 Hz, 1 H), 3.19 (t, J=8.63 Hz, 1 H), 7.33 - 7.54 (m, 6 H), 8.07 (dd, J=7.82, 1 .69 Hz, 1 H), 8.78 (dd, J=4.89, 1 .83 Hz, 1 H) ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = for the minor isomer 2.20 (dd, J=9.4, 6.4 Hz, 1 H), 2.94 (dd, J=8.3, 6.5 Hz, 1 H), 3.47 (t, J=8.9 Hz, 1 H), 6.95 - 7.03 (m, 2 H), 7.05 - 7.11 (m, 3 H), 7.21 (dd, J=7.9, 4,9 Hz, 1 H), 7.74 (dd, J=7.9, 1 .8 Hz, 1 H), 8.63 (dd, J=5.0, 1 .8 Hz, 1 H). 2D-NMR’s (including NOESY) did show that the major isomer is the racemic mixture of 2-[(1 S,2S)-1-cyano-2-phenyl-cyclopropyl]pyridine-3-carbonitrile and its enantiomer ; whereas the minor isomer is the racemic mixture of 2-[(1 R,2S)-1-cyano-2-phenyl- cyclopropyl]pyridine-3-carbonitrile and its enantiomer.

Example 45: Preparation of 2-[2-[(3-cyano-2-pyridyl)sulfanyl1-2-phenyl-ethyllpropanedin itrile and 2-[2- [(3-cyano-2-pyridyl)sulfanyl1-1-phenyl-ethyllpropanedinitril e In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added a mixture of 5-amino-2-phenyl-2,3-dihydrothiophene-4- carbonitrile and 5-amino-3-phenyl-2,3-dihydrothiophene-4-carbonitrile in almost a 1 :1 ratio (730mg, 1 equiv., 3.61 mmol) and 2-chloropyridine-3-carbonitrile (0.5g, 1 equiv., 3.61 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 3.97 mmol) was added at this temperature. The reaction was stirred 2 hours at this temperature. 5mL of ice-cold water were added, followed by 10mL of ice cold 1 N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 2.3g of the crude desired products 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-2-phenyl-ethyl]propanedin itrile and 2-[2-[(3-cyano-2- pyridyl)sulfanyl]-1-phenyl-ethyl]propanedinitrile as an orange liquid. (Purity measured by Q-NMR being 31 % (w/w) the chemical yield is 74%). The crude was purified by chromatography column to give a mixture (~1 :1) of 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-2-phenyl-ethyl]propanedin itrile and 2-[2-[(3-cyano-2- pyridyl)sulfanyl]-1-phenyl-ethyl]propanedinitrile with a total isolated yield of 68% and as a pale yellow liquid. ¹ H NMR (CDCb, 400 MHz) 6 (ppm) of the mixture = 2.67 - 2.76 (m, 1 H), 2.94 - 3.01 (m, 1 H), 3.60 - 3.72 (m, 2 H), 3.79 (dd, J=14.26, 6.50 Hz, 1 H), 3.93 (dd, J=14.20, 8.32 Hz, 1 H), 4.41 (d, J=5.13 Hz, 1 H), 5.33 (dd, J=9.63, 6.00 Hz, 1 H), 7.19 (ddd, J=7.69, 4.94, 1.75 Hz, 2 H), 7.36 - 7.48 (m, 8 H), 7.86 (ddd, J=7.72, 4.03, 1.75 Hz, 2 H), 8.03 (dd, J=7.75, 2.00 Hz, 1 H), 8.64 (ddd, J=9.26, 4.88, 1 .88 Hz, 2 H), 8.70 (dd, J=4.94, 1.81 Hz, 1 H).

Example 46: Preparation of 2-(1-cvano-2,2-diethyl-cvclopropyl)pyridine-3-carbonitrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-2,2-diethyl-3H-thiophene-4-carbonitrile (0.395g, 1 equiv., 2.17 mmol) and 2-chloropyridine-3-carbonitrile (0.3g, 1 equiv., 2.17 mmol). Sodium tert- butanolate (2.2 equiv., 4.76 mmol) was added at room temperature, then the reaction was stirred for two and a half hours at this temperature. 5mL of ice cold water were added, followed by 5mL of 2N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed with 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1 ,19g of the crude desired product 2-(1-cyano-2,2-diethyl- cyclopropyl)pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 27% (w/w), the chemical yield is 62%). The crude was purified by chromatography column to give 0.29g of pure (97% w/w as measured by QNMR), desired product 2-(1 -cyano-2,2-diethyl-cyclopropyl)pyridine-3- carbonitrile. Alternatively, the title product can be made from cyclisation of isolated intermediate 2-[2- [(3-cyano-2-pyridyl)sulfanyl]-2-ethyl-butyl]propanedinitrile (example 47) following this protocol. In a 3 necked 25mL Round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (4mL). To this was added 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-2-ethyl-butyl]propanedini trile (180mg, 1 equiv., 0.63 mmol). Sodium tert-butanolate (1 equiv., 0.63 mmol) was added at room temperature, then the reaction was stirred at this temperature overnight. The reaction mixture was poured onto 2mL of 2N HCI, stirred for 10 minutes and the aqueous layer was extracted thrice with 20 mL of EtOAc. The combined organic layers were dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.13g of the crude desired product 2-(1-cyano-2,2- diethyl-cyclopropyl)pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 53% (w/w), the chemical yield is 48%). The crude was purified by chromatography column to deliver 60mg of pure 2-(1-cyano-2,2-diethyl-cyclopropyl)pyridine-3-carbonitrile in an isolated yield of 40%. ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 0.52 - 0.59 (m, 1 H), 0.86 (t, J=7.38 Hz, 3 H), 1 .25 (t, J=7.38 Hz, 3 H), 1.37 - 1.49 (m, 1 H), 1.54 (dd, J=5.44, 1 .19 Hz, 1 H), 1.74 (dq, J=14.81 , 7.36 Hz, 1 H), 2.05 (dq, J=14.87, 7.51 Hz, 1 H), 2.23 (d, J=5.38 Hz, 1 H), 7.40 (dd, J=7.82, 4.94 Hz, 1 H), 8.03 (dd, J=7.82, 1 .81 Hz, 1 H), 8.75 (dd, J=4.88., 1 ..75 Hz, 1 H).

Example 47: Preparation of 2-[2-[(3-cvano-2-pyridyl)sulfanyl1-2-ethyl-butyllpropanedini trile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-2,2-diethyl-3H-thiophene-4-carbonitrile (395mg, 1 equiv., 2.17 mmol) and 2-chloropyridine-3-carbonitrile (0.3g, 1 equiv., 2.17 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 4.76 mmol) was added at this temperature. The reaction was stirred 4 hours at this temperature. 5mL of ice-cold water were added, followed by 5mL of ice cold 2N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1 .815g of the crude desired product 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-2-ethyl-butyl]propanedini trile as an orange liquid. (Purity measured by Q-NMR being 17% (w/w) the chemical yield is 50%). The crude was purified by chromatography column to give 0.28g of pure, desired product 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-2- ethyl-butyl]propaned initrile as a white solid (Purity measured by Q-NMR being 87% (w/w) the isolated yield is 40%). ¹ H NMR (CDCh, 400 MHz) 6 (ppm) = 1.01 (t, J=7.40 Hz, 6 H), 1 .76 (dq, J=14.56, 7.29 Hz, 2 H), 1 .84 - 1 .96 (m, 2 H), 2.81 (d, J=6.24 Hz, 2 H), 4.62 (t, J=6.30 Hz, 1 H), 7.22 - 7.30 (m, 1 H), 7.91 (dd, J=7.82, 1.83 Hz, 1 H), 8.65 (dd, J=4.89, 1.83 Hz, 1 H).

Example 48: Preparation of 2-(l-cvano-2-ethyl-3-heptyl-cvclopropyl)pyridine-3-carbonitr ile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-3-ethyl-2-heptyl-2,3-dihydrothiophene-4-carbonitrile (0.547g, 1 equiv., 2.17 mmol) and 2-chloropyridine-3-carbonitrile (0.3g, 1 equiv., 2.17 mmol). Sodium tert-butanolate (2.2 equiv., 4.76 mmol) was added at room temperature, then the reaction was stirred for five hours at this temperature. 5mL of ice cold water were added, followed by 5mL of 2N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed with 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 1 . 9g of the crude desired product 2-(1-cyano-2-ethyl-3-heptyl- cyclopropyl)pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 19% (w/w), the chemical yield is 55%). The crude was purified by chromatography column to give 0.35g of pure (92% w/w as measured by QNMR), desired product 2-(1-cyano-2-ethyl-3-heptyl-cyclopropyl)pyridine- 3-carbonitrile as a white solid. Alternatively, the title product can be made from cyclisation of isolated intermediate 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-1-ethyl-nonyl]propanedini trile (example 49) following this protocol. In a 3 necked 25mL Round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (4mL). To this was added 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-1-ethyl- nonyl]propanedinitrile (250mg, 1 equiv., 0.71 mmol). Sodium tert-butanolate (1 equiv., 0.71 mmol) was added at room temperature, then the reaction was stirred at this temperature 2 hours. The reaction mixture was poured onto 2mL of 2N HCI, stirred for 10 minutes and the aqueous layer was extracted thrice with 20 mL of EtOAc. The combined organic layers were dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.154g of the crude desired product 2- (1-cyano-2-ethyl-3-heptyl-cyclopropyl)pyridine-3-carbonitril e as an orange liquid. (Purity measured by Q-NMR being 87% (w/w), the chemical yield is 64%). The crude was purified by chromatography column to deliver pure 2-(1-cyano-2-ethyl-3-heptyl-cyclopropyl)pyridine-3-carbonitr ile in an isolated yield of 50%. ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 0.83 - 0.94 (m, 4 H), 1 .19 (t, J=7.40 Hz, 3 H), 1 .25 - 1.87 (m, 13 H), 1.96 - 2.17 (m, 2 H), 7.36 (dd, J=7.78, 4.77 Hz, 1 H), 8.00 (dd, J=7.78, 1.76 Hz, 1 H), 8.70 (dd, J=5.02, 1.76 Hz, 1 H).

Example 49: Preparation of 2-[2-[(3-cyano-2-pyridyl)sulfanyl1-1-ethyl-nonyllpropanedini trile In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added 5-amino-3-ethyl-2-heptyl-2,3-dihydrothiophene-4-carbonitrile (550mg, 1 equiv., 2.17 mmol) and 2-chloropyridine-3-carbonitrile (0.3g, 1 equiv., 2.17 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 4.76 mmol) was added at this temperature. The reaction was stirred 2 hours at this temperature. 5mL of ice-cold water were added, followed by 5mL of ice cold 2N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.903g of the crude desired product 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-1-ethyl-nonyl]propanedini trile as an orange liquid. (Purity measured by Q-NMR being 46% (w/w) the chemical yield is 54%). The crude was purified by chromatography column to give 0.38g of pure, desired product 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-1- ethyl-nonyl]propanedinitrile as a white solid (Purity measured by Q-NMR being 93% (w/w) the isolated yield is 46%). ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 0.80 - 0.96 (m, 4 H), 1 .10 - 2.05 (m, 16 H), 2.38 - 2.50 (m, 1 H), 4.19 - 4.41 (m, 2 H), 7.16 (ddd, J=7.70, 4.89, 0.73 Hz, 1 H), 7.86 (dd, J=7.70, 1.71 Hz, 1 H), 8.61 (dt, J=4.89, 1.47 Hz, 1 H).

Example 50: Preparation of 2-(1-cvano-2-ethyl-3-phenyl-cvclopropyl)pyridine-3-carbonitr ile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added a mixture of 5-amino-3-ethyl-2-phenyl-2,3-dihydrothiophene- 4-carbonitrile and 5-amino-2-ethyl-3-phenyl-2,3-dihydrothiophene-4-carbonitrile in a 1 :2 ratio

(500mg, 1 equiv., 2.17 mmol) and 2-chloropyridine-3-carbonitrile (0.3g, 1 equiv., 2.17 mmol). Sodium tert-butanolate (2.2 equiv., 4.77 mmol) was added at room temperature, then the reaction was stirred overnight at this temperature. 5mL of ice cold water were added, followed by 5mL of 2N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed with 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.72g of the crude desired product 2-(1-cyano-2-ethyl-3-phenyl- cyclopropyl)pyridine-3-carbonitrile as an orange liquid. (Purity measured by Q-NMR being 56.4% (w/w), the chemical yield is 67%). The crude was purified by chromatography column to give 0.354g of pure (90% w/w as measured by QNMR), desired product 2-(1-cyano-2-ethyl-3-phenyl- cyclopropyl)pyridine-3-carbonitrile as a white solid (in a 8:1 mixture of diastereoisomers) in an isolated yield of 54% ; the major isomer NMR being ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 1 .25 (t, J=7.4 Hz, 3 H), 1.59 (ddd, J=14.6, 8.6, 7.4 Hz, 1 H), 1 .88 (ddd, J=14.5, 7.3, 5.8 Hz, 1 H), 2.43 (td, J=9.1 , 5.6 Hz, 1 H), 3.37 (d, J=9.5 Hz, 1 H), 7.31 - 7.37 (m, 2 H), 7.39 - 7.48 (m, 3 H), 7.56 (d, J=7.6 Hz, 2 H), 8.07 (dd, J=7.9, 1.8 Hz, 1 H), 8.76 (dd, J=4.9, 1.8 Hz, 1 H). Some clear, isolated diagnostic peaks for the minor diastereoisomer are ¹ H NMR (CDCb, 400 MHz) 6 (ppm) = 8.82 (dd, J=5.02, 1 .76 Hz, 1 H) and 3.57 (d, J=8.03 Hz, 1 H). Alternatively, the title product can be made from cyclisation of isolated intermediates mixture consisting of 2-[1-[(3-cyano-2-pyridyl)sulfanyl-phenyl-methyl]propyl]propa nedinitrile and 2-[2- [(3-cyano-2-pyridyl)sulfanyl]-1-phenyl-butyl]propanedinitril e (example 51) following this protocol. In a 3 necked 25mL Round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged THF (5mL). To this was added a mixture consisting of 2-[1-[(3-cyano-2-pyridyl)sulfanyl- phenyl-methyl]propyl]propanedinitrile and 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-1-phenyl- butyl]propanedinitrile in a 1 :2 ratio (200mg, 1 equiv., 0.602 mmol). Sodium tert-butanolate (1 equiv., 0.602 mmol) was added at room temperature, then the reaction was stirred at this temperature during four hours. The reaction mixture was poured onto 2mL of 2N HCI, stirred for 10 minutes and the aqueous layer was extracted thrice with 20 mL of EtOAc. The combined organic layers were dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 0.16g of the crude desired product 2-(1-cyano-2-ethyl-3-phenyl-cyclopropyl)pyridine-3-carbonitr ile as an orange liquid. (Purity measured by Q-NMR being 33% (w/w), the chemical yield is 32%). The crude was purified by chromatography column to give 0.08g of pure desired product 2-(1-cyano-2-ethyl-3-phenyl- cyclopropyl)pyridine-3-carbonitrile (in a 9:1 mixture of diastereoisomers) giving an isolated yield of 27%

Example 51 : Preparation of 2-[1-[(3-cvano-2-pyridyl)sulfanyl-phenyl-methyllpropyllpropa nedinitrile and 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-1-phenyl-butyl]propanedin itrile

In a 3 necked round bottom flask equipped with magnetic bar, thermometer and nitrogen inlet was charged DMF (5mL). To this were added a mixture of 5-amino-3-ethyl-2-phenyl-2,3-dihydrothiophene- 4-carbonitrile and 5-amino-2-ethyl-3-phenyl-2,3-dihydrothiophene-4-carbonitrile in a 1 :2 ratio (500mg, 1 equiv., 2.17 mmol) and 2-chloropyridine-3-carbonitrile (0.3g, 1 equiv., 2.17 mmol). The reaction mixture was cooled down to -40°C and Sodium tert-butanolate (2.2 equiv., 3.97 mmol) was added at this temperature. The reaction was stirred 2 hours at this temperature. 5mL of ice-cold water were added, followed by 10mL of ice cold 1 N HCI; the aqueous layer was extracted thrice with 30 mL of EtOAc, the combined organic layers were washed 20mL of brine, before being dried over solid Na2SO4 and filtered. The solvents were removed under reduced pressure to deliver 2.3g of the crude desired products 2-[1-[(3-cyano-2-pyridyl)sulfanyl-phenyl-methyl]propyl]propa nedinitrile and 2-[2-[(3- cyano-2-pyridyl)sulfanyl]-1-phenyl-butyl]propanedinitrile as an orange liquid. The crude was purified by chromatography column to give a 1 :2 mixture of 2-[1-[(3-cyano-2-pyridyl)sulfanyl-phenyl- methyl]propyl]propanedinitrile and 2-[2-[(3-cyano-2-pyridyl)sulfanyl]-1-phenyl-butyl]propanedin itrile with a total isolated yield of 30% and as a pale yellow liquid. ¹ H NMR (CDCh, 400 MHz) 6 (ppm) of the mixture = 0.95 - 1 .02 (m, 3 H), 1 .06 (q, J=7.34 Hz, 2 H), 1 .63 - 1 .88 (m, 3 H), 2.64 - 2.73 (m, 0.5 H), 3.52 (dd, J=11.57, 4.06 Hz, 1 H), 3.79 (dd, J=10.38, 4.25 Hz, 0.5 H), 4.48 (d, J=3.50 Hz, 0.5 H), 4.53 (d, J=10.38 Hz, 0.3 H), 4.75 (ddd, J=11.63, 8.57, 3.19 Hz, 1 H), 4.80 (d, J=4.13 Hz, 1 H), 4.82 - 4.90 (m, 0.35 H), 5.39 (d, J=9.88 Hz, 0.5 H), 7.13 - 7.29 (m, 3 H), 7.32 - 7.56 (m, 10 H), 7.83 - 7.92 (m, 1.5 H), 8.66 (dt, J=4.88, 1.31 Hz, 0.7 H), 8.68 - 8.72 (m, 1 H).