Iminoamide-type compounds as ligands for copper-catalyzed coupling reactions of (hetero)ARYL halides

Abstract

The present invention relates to novel iminoamide-type compounds of the general formula (I) and use thereof as ligands in copper-catalyzed coupling reactions of (hetero)aryl halides forming C-C, C-N, C-S, C-O, C-P-bonds and other bonds, in particular the use of the compounds of formula (I) as ligand in copper-catalyzed coupling reactions of aryl halides forming C-O-bonds.

Description

[0001] IMINOAMIDE-TYPE COMPOUNDS AS LIGANDS FOR COPPER-CATALYZED COUPLING REACTIONS OF (HETERO)ARYL HALIDES

[0002] The present invention relates to novel iminoamide-type compounds of the general formula (I) and use thereof as ligands in copper-catalyzed coupling reactions of (hetero)aryl halides forming C-C, C-N, C-S, C-O, C-P-bonds and other bonds, in particular the use of the compounds of formula (I) as ligand in copper- catalyzed coupling reactions of aryl halides forming C-O-bonds.

[0003] Copper-catalyzed hydroxylation reactions of (hetero)aryl halides to form phenols are known in the literature and can be achieved by reacting (hetero)aryl halides (X = I, Br, Cl) with overstochiometric amount of alkali hydroxide (LiOH, NaOH, KOH, CsOH) in the presence of a copper salt and various different ligand classes (Ma D. et al. Org. Proc. Res. Dev. 2022, 26, 1690-1750). Known ligands for this type of transformation can be categorized into first-generation bidentate ligands (Ma et al., Org. Process Res. Dev. 2022, 26, 1690- 1750) such as N.O-bidcntatc ligands (e.g. 8 -hydroxy quinoline (Ma et al., Synlett 2010 (6), 976-978), Li-Proline (Zhou et al., RSC Adv. Comm. 2013, 3, 22837-22840), DMEDA (Leadbeater et al., Cat. Comm. Vol 12(1) 2010, 64-66)), O,O-bidentate ligands (e.g. TMHD or 2, 2,6,6- tetramethyl-3,5-heptanedione (Taillefer et al., Angew. Chem. 2009, 121, 8881-8884), D-glucose (Sekar et al., Chem Comm. 2011, 47, 6692-6694), sucrose (Takita et al., Org. Biomol. Chem. 2020, 18, 7827- 7831), glycolic acid (Chae, J. Org. Chem. 2013, 78, 5804-5809), 8 -hydroxy quinolin-N-oxide (Jiang et al, Org. Lett. 2011, 13, 16, 4340-4343)), W-bidcntatc ligands (e.g. phenanthroline (You et al., Angew. Chem. Int. Ed. 2009, 48, 8729-8732), pyridine-2-aldoxime (Fu et al., Chem. Eur. J. 2010, 16, 2366-2370), 5-bromo-2-(lH-imidazol-2-yl)pyridine (Ma et al., Tet. Lett. 52 (2011) 5593-5595)). The second- generation of bidentate ligands such as oxalic diamides and related amides (e.g. N,N'-bis(4-hydroxyl-2,6- dimethylphenyl)oxalamide (Ma et al., J. Am. Chem. Soc. 2016. 138, 13493-13496), N,N’-bis(thiophene- 2-ylmethyl)oxalamide (Nett et al., ChemCatChem 2019, 11, 5748-5753)) also represent ligand systems for the copper-catalyzed hydroxylation to form phenols. WO2017 / 012379 discloses oxalic acid monoamides and WO2017 / 177979 amides as ligands for copper-catalyzed coupling reactions.

[0004] CN112142567 describes the preparation of 3-chloro-2-fluorophenol starting from l,3-dichloro-2-fluoro- 4-nitrobenzene through a multistep procedure. The preparation of 3-chloro-2-fluorophenol through Sandmeyer hydroxylation under harsh conditions is described in Finger et al., J. Am. Chem. Soc. 1959, 81, 1, 94-101.

[0005] Overall, the prior art syntheses of 3-chloro-2-fluorophenol are not suitable for production on large scale. The number of steps, harsh conditions and low product yield make the processes inefficient for large scale production. Previously identified ligands for this specific substrate led to unsatisfactory reaction outcomes under desirable reaction conditions. Literature known copper-coupling reaction conditions, require high copper salt and ligand loadings, extremely high temperatures for aryl-bromides and aryl-chlorides (130- 180°C) and predominantly rely on using dimethyl sulfoxide as (co-)solvent to ensure high solubility of the substrate and ensure efficient coupling of challenging substrates. Due to cost, sustainability and safety concerns these conditions are not suitable for large scale production scale.

[0006] The present invention provides novel iminoamide ligands of formula (I) enabling copper-catalyzed coupling reactions of (hetero)aryl halides forming C-C, C-N, C-O, C-S and C-P-bonds and other bonds, in a technically feasible, more economical process which is suitable for industrial scale. In particular, the present invention relates to the use of the novel iminoamide compounds of formula (I) as ligand in copper- catalyzed coupling reactions of aryl halides providing an efficient method for the preparing of halogenated phenols, more specifically 3-chloro-2-fluorophenol.

[0007] Surprisingly, it has been found that copper-catalyzed coupling reactions of (hetero)aryl halides forming C-C-, C-N-, C-S-, C-O- and C-P-bonds are easily accessible applying iminoamide-type ligands of formula (I).

[0008] The object of the present invention is to provide a catalytic system that is useful for copper-catalyzed coupling reaction of (hetero)aryl halides forming C-C-, C-N-, C-S-, C-O- and C-P-bonds applying compounds of formula (I) as ligands.

[0009] In one embodiment the present invention relates to the use of a compound of formula (I), s

[0010] N

[0011] D

[0012] R3D, wherein

[0013] R1is hydrogen, Ci-Ce-alkyl, phenyl or 5- to 10-membered heteroaryl, wherein Ci-Ce-alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein said phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce- alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, and wherein phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl,

[0014] R2is hydrogen, benzyl, phenylethyl, phenyl, naphthyl, or 5- to 14-membered heteroaryl, wherein benzyl, phenylethyl, phenyl, naphthyl and 5- to 14- membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci- Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, phenyl and phenoxy,

[0015] R3is hydrogen, Ci-Ce-alkyl, phenyl or 5- to 10-membered heteroaryl, wherein Ci-Ce-alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein said phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce- alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, and wherein phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce- alkylsulfonyl, characterized in that it is used as a ligand for copper-catalyzed coupling reaction of a (hetero)aryl halide, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl chloride, (hetero)aryl bromide, (hetero)aryl iodide, and the combinations thereof.

[0016] Preferably, the present invention relates to the use of a compound of formula (I), wherein

[0017] R1is hydrogen, Ci-Cr-alkyl or phenyl, wherein Ci -Ch-alky I is optionally substituted with 1 substituent phenyl, wherein said phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-Cr-alkyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl and ethylsulfinyl, and wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl and ethylsulfinyl,

[0018] R2is benzyl, phenylethyl, phenyl, naphthyl, pyrrolyl, imidazolyl, indolyl, benzimidazolyl or carbazolyl, wherein benzyl, phenylethyl, phenyl, naphthyl, pyrrolyl, imidazolyl, indolyl, benzimidazolyl and carbazolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-Cr-alkyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl, ethylsulfinyl, phenyl and phenoxy,

[0019] R3is hydrogen or Ci -Cr-alkyl, characterized in that it is used as a ligand for copper-catalyzed coupling reaction of a (hetero)aryl halide, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, Cu(OAc)2, CuSOr, CuSOr x 5 H2O, CU2O, CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2, and combinations thereof and wherein the (hetero)aryl halide is selected from the group consisting of aryl bromide or aryl iodide, and the combinations thereof.

[0020] More preferably, the present invention relates to to the use of a compound of formula (I), wherein

[0021] R1is hydrogen, Ci-Cr-alkyl, phenyl or benzyl, wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy,

[0022] R2is phenyl, naphthyl, pyrrolyl or indolyl, wherein phenyl, naphthyl, pyrrolyl and indolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, phenyl and phenoxy,

[0023] R3is hydrogen, characterized in that it is used as a ligand for copper-catalyzed coupling reaction of a (hetero)aryl halide, wherein the copper source is selected from the group consisting of Cui and CuCl and wherein the (hetero)aryl halide is an aryl bromide.

[0024] Likewise more preferably, the present invention relates to to the use of a compound of formula (I), wherein

[0025] R1is hydrogen, Ci-Cr-alkyl, phenyl or benzyl, wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy,

[0026] R2is phenyl, naphthyl, pyrrolyl or indolyl, wherein phenyl, naphthyl, pyrrolyl and indolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, phenyl and phenoxy,

[0027] R3is hydrogen, characterized in that it is used as a ligand for copper-catalyzed coupling reaction of a (hetero)aryl halide, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl chloride, (hetero)aryl bromide, (hetero)aryl iodide, and the combinations thereof.

[0028] Even more preferably, the present invention relates to the use of a compound of formula (I), wherein the compound of formula (I) is selected from the group consisting of characterized in that it is used as a ligand for copper-catalyzed coupling reaction of a (hetero)aryl halide, wherein the copper source is selected from the group consisting of Cui and CuCl.

[0029] Most preferably, the present invention relates to the use of a compound of formula (I), wherein the compound of formula (I) is selected from the group consisting of

[0030] characterized in that it is used as a ligand for copper-catalyzed coupling reaction of a (hetero)aryl halide, wherein the (hetero)aryl halide is an aryl bromide and wherein the copper source is selected from the group consisting of Cui and CuCl.

[0031] In a further embodiment the present invention relates to a coupling reaction method of a (hetero)aryl halide, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl chlorides, (hetero)aryl bromides, (hetero)aryl iodides and combinations thereof, comprising the step of carrying out a coupling reaction using a copper source and a compound of formula (I) (I), wherein R1is hydrogen, Ci-Ce-alkyl, phenyl or 5- to 10-membered heteroaryl, wherein Ci-Ce-alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein said phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce- alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, and wherein phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl,

[0032] R2is hydrogen, benzyl, phenylethyl, phenyl, naphthyl, or 5- to 14-membered heteroaryl, wherein benzyl, phenylethyl, phenyl, naphthyl and 5- to 14- membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci- Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, phenyl and phenoxy,

[0033] R3is hydrogen, Ci-Ce-alkyl, phenyl or 5- to 10-membered heteroaryl, wherein Ci-Ce-alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein said phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, hydroxy, Ci- Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce- alkylsulfonyl, and wherein phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce- alkylsulfonyl, as a ligand. In a preferred embodiment the present invention relates to a method for the formation of C-C-, C-N-, C- S-, C-O- and C-P-bonds via copper-catalyzed reaction of (hetero)aryl halides, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl chlorides, (hetero)aryl bromides, (hetero)aryl iodides and combinations thereof, using a catalyst system comprising a copper source and a compound of formula (I), wherein

[0034] R1is hydrogen, Ci-Cr-alkyl or phenyl, wherein Ci-Cr-alkyl is optionally substituted with 1 substituent phenyl, wherein said phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-Cr-alkyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl and ethylsulfinyl, and wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl and ethylsulfinyl,

[0035] R2is benzyl, phenylethyl, phenyl, naphthyl, pyrrolyl, imidazolyl, indolyl, benzimidazolyl or carbazolyl, wherein benzyl, phenylethyl, phenyl, naphthyl, pyrrolyl, imidazolyl, indolyl, benzimidazolyl and carbazolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-Cr-alkyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl, ethylsulfinyl, phenyl and phenoxy,

[0036] R3is hydrogen or Ci -Ch-alky I, as a ligand, a suitable base and a suitable solvent.

[0037] In a more preferred embodiment the present invention relates a method for the formation of C-O-bonds via copper-catalyzed reaction of (hetero)aryl halides, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl bromides and (hetero)aryl iodides, using a catalyst system comprising a copper source, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, CU(OAC)2, CUSC>4, CUSC>4 x 5 H2O, CirO, CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2, and combinations thereof, a compound of formula (I), wherein

[0038] R1is hydrogen, Ci-Cr-alkyl, phenyl or benzyl, wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy,

[0039] R2is phenyl, naphthyl, pyrrolyl or indolyl, wherein phenyl, naphthyl, pyrrolyl and indolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, phenyl and phenoxy,

[0040] R3is hydrogen, as a ligand, a hydroxylating agent, optionally a suitable base and a suitable solvent. In a likewise more preferred embodiment the present invention relates to a method for the formation of C-O-bonds via copper-catalyzed reaction of (hetero)aryl halides, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl bromides and (hetero)aryl iodides, using a catalyst system comprising a copper source, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, Cu(MeCN)4BF4, Cu(OAc)2, CuSCL, CuSOr x 5 H2O, CU2O, Cu(OEt)2, copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) (Cu(TMHD)2), CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2 and combinations thereof, a compound of formula (I), wherein the compound of formula (I) is selected from the group consisting of as a ligand, a hydroxylating agent, optionally a suitable base and a suitable solvent.

[0041] In an even more preferred embodiment the present invention relates to a method for the formation of C-O- bonds via copper-catalyzed reaction of (hetero)aryl halides, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl bromides and (hetero)aryl iodides, using a catalyst system comprising a copper source, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, Cu(MeCN)4BF4, Cu(0Ac)2, G1SO4, C11SO4 x 5 H2O, CU2O, Cu(OEt)2, copper bis(2, 2,6,6- tetramethyl-3,5-heptanedionate) (Cu(TMHD)2), CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2 and combinations thereof, a compound of formula (I), wherein the compound of formula (I) is selected from the group consisting of

[0042]

[0043] In a still even more preferred embodiment the present invention relates to a method for the formation of C-O-bonds via copper-catalyzed reaction of (hetero)aryl halides, wherein the compound of formula (I) is selected from the group consisting of

[0044]

[0045] In a further embodiment the present invention relates to a process for the preparation of a compound of the general the formula (II) wherein n is 1, 2, 3, 4 or 5,

[0046] R4is halogen, characterized in that a compound of formula (III)

[0047] (ill), wherein R4is as defined above and X is chloro, bromo or iodo, is reacted in a suitable solvent in the presence of a copper source, a compound of formula (I) wherein

[0048] R1is hydrogen, Ci-Ce-alkyl, phenyl or 5- to 10-membered heteroaryl, wherein Ci-Ce-alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein said phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, hydroxy, Ci- Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce- alkylsulfonyl, and wherein phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl,

[0049] R2is benzyl, phenylethyl, phenyl, naphthyl, or 5- to 10 membered heteroaryl, wherein benzyl, phenylethyl, phenyl, naphthyl and 5- to 10 membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci- Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, phenyl and phenoxy,

[0050] R3is hydrogen, Ci-Ce-alkyl, phenyl or 5- to 10-membered heteroaryl, wherein Ci-Ce-alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein said phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, hydroxy, Ci- Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce- alkylsulfonyl, and wherein phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce- alkylsulfonyl, as a ligand and optionally a suitable base with a hydroxylating agent.

[0051] In preferred embodiment the present invention relates to a process for the preparation of a compound of the general the formula (II)

[0052] (II), wherein n is 1, 2 or 3,

[0053] R4is halogen, characterized in that a compound of formula (III)

[0054] (HI), wherein R4is as defined above and

[0055] X is chloro, bromo or iodo, is reacted in a suitable solvent in the presence of a copper source, wherein the copper source is selected from the group consisting of of Cui, CuBr, CuCl, CuTc, Cu(MeCN)4BF4, Cu(OAc)2, CuSO4, CuSO4 x 5 H2O, CU2O, Cu(OEt)2, copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) (Cu(TMHD)2), CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2 and combinations thereof, a compound of formula (I), wherein

[0056] R1is hydrogen, Ci-Cr-alkyl or phenyl, wherein Ci-C4-alkyl is optionally substituted with 1 substituent phenyl, wherein said phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-Cr-alkyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl and ethylsulfinyl, and wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl and ethylsulfinyl,

[0057] R2is benzyl, phenylethyl, phenyl, naphthyl, pyrrolyl, imidazolyl, indolyl or benzimidazolyl, wherein benzyl, phenylethyl, phenyl, naphthyl, pyrrolyl, imidazolyl, indolyl and benzimidazolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-Cr-alkyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl, ethylsulfinyl, phenyl and phenoxy,

[0058] R3is hydrogen or Ci -Ch-alky I, as a ligand and optionally a suitable base with a hydroxylating agent, wherein the hydroxylating agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide .

[0059] In a more preferred embodiment the present invention relates to a process for the preparation of a compound of the general the formula (II) , ,

[0060] R4is halogen, characterized in that a compound of formula (III)

[0061] (III), wherein R4is as defined above and

[0062] X is chloro, bromo or iodo, is reacted in a suitable solvent in the presence of a copper source, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, Cu(0Ac)2, CuSOr, CuSOr x 5 H2O, CU2O, CuBr2, C11CI2, CuO, CuSCN, CuCN, Cu(acac)2, and combinations thereof, a compound of formula (I), wherein the compound of formua (I) is selected from the group consisting of as a ligand and optionally a suitable base with a hydroxylating agent, wherein the hydroxylating agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide.

[0063] Even more preferably the present invention relates to a process for the preparation of a compound of the general the formula (II- A) characterized in that a compound of formula (III- A)

[0064] (III-A), wherein

[0065] X is chloro, bromo or iodo, is reacted in a suitable solvent in the presence of a copper source, wherein the copper source is selected from the group consisting of CuCl and Cui, a compound of formula (I), wherein

[0066] R1is hydrogen, Ci-Cr-alkyl, phenyl or benzyl, wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy,

[0067] R2is phenyl, naphthyl, pyrrolyl or indolyl, wherein phenyl, naphthyl, pyrrolyl and indolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, phenyl and phenoxy,

[0068] R3is hydrogen, as a ligand with a hydroxylating agent, wherein the hydroxylating agent is sodium hydroxide.

[0069] Most preferably the present invention relates to a process for the preparation of a compound of the general the formula (II- A)

[0070] (II-A), characterized in that a compound of formula (III-A)

[0071] (III-A), wherein

[0072] X is chloro, bromo or iodo, is reacted in a suitable solvent in the presence of a copper source, wherein the copper source is selcted from the group consisting of CuCl and Cui, a compound of formula (I), wherein the compound of formula (I) is selected from the group consisting of as a ligand with a hydroxylating agent, wherein the hydroxylating agent is sodium hydroxide.

[0073] More preferably, the compound of formula (I) is selected from the group consisting of

[0074] Even more preferably, the compound of formula (I) is selected from the group consisting of

[0075] Most preferably, the compound of formula (I) is selected from the group consisting of

[0076] Even more preferably, the (hetero)aryl halide is an aryl halide of formula (III).

[0077] Still even more preferably, the (hetero)aryl halide is an aryl halide of formula (III- A). Most preferably, the (hetero)aryl halide is an aryl halide of formula (III- A), wherein X is bromo.

[0078] In a further embodiment the present invention relates to the preparation of 3-chloro-2-fluoro-iodobenzene, l,3-dichloro-2-fluorobenzene and l-bromo-3-chloro-2-fluorobenzene via Sandmeyer iodination, bromination and chlorination, in scalable synthetic processes in which the formation of hazardous intermediates is minimized.

[0079] General definition

[0080] Unless otherwise stated, the following definitions apply for the substituents and residues used throughout this specification and claims:

[0081] The term “Ci-Ce-alkyl” as used herein refers to a saturated, branched or straight hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of Ci-Ce-alkyl include but are not limited to methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1 -methylpropyl (sec -butyl), 2-methylpropyl (isobutyl), 1,1 -dimethylethyl (tert-butyl), pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethyl- propyl, 1 -ethylpropyl, 1,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 1,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethyl- butyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-tri- methylpropyl, 1 -ethyl- 1 -methylpropyl and l-ethyl-2-methylpropyl. Particularly, said hydrocarbon chain has 1, 2, 3 or 4 carbon atoms (“Ci-Cr-alkyl”), e.g. methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, isobutyl or tert-butyl.

[0082] The term “Ci-Ce-haloalkyl” as used herein refers to a Ci-Ce-alkyl group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different. Examples of Ci-Ce-haloalkoxy include but are not limited to chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoro- ethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and l,l,l-trifluoroprop-2-yl. Preferred are fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 2-fluoroethyl, 2,2-difluoro-ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and l,l,l-trifluoroprop-2-yl.

[0083] The term “Ci-Ce-alkoxy” as used herein refers to a group of formula (Ci-Ce-alkyl)-O-, in which the term "Ci-Ce-alkyl" is as defined herein. Examples of Ci-Ce-alkoxy include but are not limited to methoxy, ethoxy, n-propoxy, 1 -methylethoxy, n-butoxy, 1 -methylpropoxy, 2-methylpropoxy, 1,1 -dimethylethoxy, n-pentoxy, 1 -methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1 -ethylpropoxy, 1,1 -dimethylpropoxy, 1 ,2-dimethylpropoxy, n-hexyloxy, 1 -methylpentoxy, 2-methylpentoxy, 3-methyl- pentoxy, 4-methylpentoxy, 1,1 -dimethylbutoxy, 1 ,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethyl- butoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1 -ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1 -ethyl- 1 -methylpropoxy and l-ethyl-2-methylpropoxy. This definition also applies to alkoxy as part of a composite substituent, for example alkoxyalkyl, alkoxyalkoxy, unless defined elsewhere.

[0084] The term “Ci-Ce-haloalkoxy” as used herein refers to a Ci-Ce-alkoxy group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different. Examples of Ci-Ce-haloalkoxy include but are not limited to chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoro- methoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1 -chloroethoxy, 1 -bromoethoxy, 1 -fluoro- ethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2- difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1- trifluoroprop-2-oxy.

[0085] The terms “C i-Cx-cycloal ky I” as used herein refers to a saturated, monocyclic hydrocarbon ring containing 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of Ci-Cs-cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Particularly, said cycloalkyl has 3 to 6 carbon atoms.

[0086] The term “5- to 14-membered heteroaryl” as used herein refers to an aromatic ring system comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. If the ring system contains more than one oxygen atom, they are not directly adjacent. Aromatic heterocycles include 5- or 6-membered monocyclic heteroaryls and 7- to 14-membered bi- or tricyclic heteroaryls. The 5- to 14-membered heteroaryl can be connected to the parent molecular moiety through any carbon atom or nitrogen atom contained within the heterocycle.

[0087] The term “5- or 6-membered heteroaryl” as used herein refers to a 5- or 6-membered aromatic monocyclic ring system containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Examples of 5-membered monocyclic heteroaryl include but are not limited to furyl (furanyl), thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isothiazolyl, thiazolyl, thiadiazolyl and thiatriazolyl. Examples of 6-membered monocyclic heteroaryl include but are not limited to pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl.

[0088] The term “7- to 14-membered heteroaryl” as used herein refers to a 7-, 8-, 9-, 10-, 11-, 12- or 14- membered aromatic bicyclic ring system containing 1 , 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Bicyclic heteroaryls may consist of a monocyclic heteroaryl as defined herein fused to an aryl (e.g. phenyl) or to a monocyclic heteroaryl. Examples of bicyclic heteroaryls include but are not limited to 9-membered ring such as indolyl, indolizinyl, isoindolyl, benzimadozolyl, imidazopyridinyl, indazolyl, benzotriazolyl, purinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl and benzisoxazolyl or 10-membered ring such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pteridinal and benzodioxinyl. In 9- or 10-membered bicyclic heteroaryls comprising two fused 5- or 6-membered monocyclic heteroaryls, nitrogen atom may be at the bridgehead (e.g. imidazo[l,2-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]oxazolyl, furo[2,3-d]isoxazolyl) or carbazolyl.

[0089] Formula (I) provides a general definition of the ligand used the process according to the invention. Preferred radical definitions for formula (I) shown above and below are given below. These definitions apply to the end products of formula (I) and likewise to all starting materials and intermediates bearing the respective radical(s).

[0090] The compounds of formula (I) wherein R1, R2and R3are defined as above, can exist in two isomeric forms, (E)-isomer and (Z)-isomer

[0091] E-lsomer Z- Isom er , as well as mixtures of (E)- and (Z)-isomer in all proportions. The present invention relates to both isomeric forms (E)-Isomer and (Z)-Isomer as well as mixtures of (E)- and (Z)-isomer in all proportions.

[0092] The above specified definitions of n, R1, R2, R3, R4and X (broad definition as well as preferred, more preferred, even more preferred and most preferred definitions) can be combined in various manners. These combinations of definitions thus provide sub-classes of compounds according to the invention, such as for instance the ones disclosed below.

[0093] Preference is given to those compounds of formula (I) in which each of the definitions (substituents and variables) have the abovementioned preferred meanings. Particular preference is given to those compounds of formula (I) in which each of the definitions (substituents and variables) have the abovementioned more, even more and / or most preferred meanings.

[0094] As outlined above, compounds of formula (I) are valuable intermediates in the synthesis of compounds useful in the field of crop protection, in particular the heterocyclic-substituted pyridazine derivatives disclosed in WO 2020 / 127780 Al.

[0095] A further object of the present invention are compounds of formula (I) wherein

[0096] R1is hydrogen, Ci-Ce-alkyl, phenyl or 5- to 10-membered heteroaryl, wherein Ci-Ce-alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein said phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce- alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, and wherein phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl,

[0097] R2is hydrogen, benzyl, phenylethyl, phenyl, naphthyl, or 5- to 10 membered heteroaryl, wherein benzyl, phenylethyl, phenyl, naphthyl and 5- to 10 membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci- Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, phenyl and phenoxy,

[0098] R3is hydrogen, Ci-Ce-alkyl, phenyl or 5- to 10-membered heteroaryl, wherein Ci-Ce-alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein said phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce- alkyl, Ci-Ce-haloalkyl, hydroxy, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce-alkylsulfonyl, and wherein phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylsulfanyl, Ci-Ce-alkylsulfinyl and Ci-Ce- alkylsulfonyl.

[0099] Preferably, the present invention relates to compounds of formula (I), wherein

[0100] R1is hydrogen, Ci-Cr-alkyl or phenyl, wherein Ci-Cr-alkyl is optionally substituted with 1 substituent phenyl, wherein said phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-Cr-alkyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl and ethylsulfinyl, and wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl and ethylsulfinyl,

[0101] R2is benzyl, phenylethyl, phenyl, naphthyl, pyrrolyl, imidazolyl, indolyl or benzimidazolyl, wherein benzyl, phenylethyl, phenyl, naphthyl, pyrrolyl, imidazolyl, indolyl and benzimidazolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-Cr-alkyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl, ethylsulfinyl, phenyl and phenoxy,

[0102] R3is hydrogen or Ci -Ch-alky I.

[0103] More preferably, the present invention relates to compounds of formula (I), wherein R1is hydrogen, Ci-Cr-alkyl, phenyl or benzyl, wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, R2is phenyl, naphthyl, pyrrolyl or indolyl, wherein phenyl, naphthyl, pyrrolyl and indolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, phenyl and phenoxy,

[0104] R3is hydrogen. Even more preferably, the present invention relates to compounds of formula (I), wherein the compound of formula (I) is selected from the group consisting of

[0105]

[0106] Most preferably, the present invention relates to compounds of formula (I), wherein the compound of formula (I) is selected from the group consisting of

[0107] The compounds of formula (I) may also be applied in combination with other ligands suitable for copper- catalyzed coupling reactions. Those other ligands are known to a person skilled in the art from literature such as Ma D. et al. Org. Proc. Res. Dev. 2022, 26, 1690-1750; Ma et al., Org. Process Res. Dev. 2022, 26, 1690- 1750; Ma et al., Synlett 2010 (6), 976-978; Zhou et al., RSC Adv. Comm. 2013, 3, 22837- 22840; Leadbeater et al., Cat. Comm. Vol 12(1) 2010, 64-66; Taillefer et al., Angew. Chem. 2009, 121, 8881-8884; Sekar et al., Chem Comm. 2011, 47, 6692-6694; Takita et al., Org. Biomol. Chem. 2020, 18, 7827-7831; Chae, J. Org. Chem. 2013, 78, 5804-5809; Jiang et al, Org. Lett. 2011, 13, 16, 4340-4343; You et al., Angew. Chem. Int. Ed. 2009, 48, 8729-8732; Fu et al., Chem. Eur. J. 2010, 16, 2366-2370; Ma et al., Tet. Lett. 52 (2011) 5593-5595; Ma et al., J. Am. Chem. Soc. 2016. 138, 13493-13496; Nett et al., ChemCatChem 2019, 11, 5748-5753; WO2017 / 012379 and WO2017 / 177979.

[0108] In a further embodiment the present invention relates to a catalyst system for aryl coupling reaction forming C-0 bonds, comprising a copper source, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, Cu(OAc)2, CuSCL, CuSCh x 5 H2O, CU2O, CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2, Cu(MeCN)4BF4, Cu(OEt)2, copper bis(2,2,6,6-tetramethyl-3,5- heptanedionate) (Cu(TMHD)2) and combinations thereof, a ligand of formula (I) as defined above, a hydroxylating agent, wherein the hydroxylating agent is selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide, or a combination of water and alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal phosphates such as potassium phosphate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate and a solvent wherein the solvent is selected from the group consisting of 1,4-dioxane, 1 ,2-dimethoxy ethane (DME), tetrahydrofuran (THF), alcohols such as methanol, ethanol, tert-butanol, 1 -butanol, l-methoxy-2-propanol, cyclohexanol and isopropanol, other solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidon (NMP), acetonitrile and water and / or combinations thereof. In a further embodiment, the present invention relates to a process for the preparation of compounds of formula (I), (I), wherein R1and R2are defined as above, characterized in that a compound of formula (IV) wherein R1is defined as above and

[0109] T1is hydroxy, halogen or (Ci-C4)alkoxy, is reacted in the presence of a suitable base, optionally in the presence of a suitable coupling reagent, with an amine of formula (V)

[0110] 2

[0111] R— N H2

[0112] (V), wherein R2is defined as above, to yield a compound of formula (VI)

[0113] (VI), wherein R1and R2are defined as above, which is then reacted with a compound of formula (VII) H2N-" ^R3

[0114] (VII), wherein R3is defined as above.

[0115] Compounds of formula (IV), wherein T1is a hydroxyl group can be reacted with an amine of formula (V) in the presence of a condensing reagent by means of methods described in the literature (e.g. Tetrahedron 2005, 61, 10827-10852). Examples of suitable condensing reagents include, but are not limited to, halogenating reagents (e.g. phosgene, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide, oxalyl chloride or thionyl chloride), dehydrating reagents (e.g. ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, isobutyl chloroformate or methanesulfonyl chloride), carbodiimides (e.g. N,N' -dicyclohexylcarbodiimide (DCC)) or other customary condensing (or peptide coupling) reagents (e.g. phosphorous pentoxide, polyphosphoric acid, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N'-carbonyldiimidazole, 2-ethoxy-N-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ), triphenylphosphine / tetrachloro-methane, 4-(4,6-dimethoxy[1.3.5]-triazin-2-yl)-4-methylmorpholinium chloride hydrate, bromo-tripyrrolidinophosphoniumhexafluorophosphate or propanephosphonic anhydride (T3P).

[0116] Compounds of formula (IV), wherein T1is a halogen atom can be reacted with an amine of formula (V) in the presence of an acid scavenger by means of well-known methods. Suitable acid scavengers include any inorganic and organic bases, as described herein, which are customary for such reactions. Preference is given to alkali metal carbonates, alkaline earth metal acetates, tertiary amines or aromatic bases.

[0117] Compounds of formula (IV), wherein T1is a Ci-Ce-alkoxy group can be reacted with an excess of amine of formula (V), optionally in the presence of a Lewis acid such as trimethylaluminum.

[0118] The reaction of compounds of formula (VI) with compounds of formula (VII) is performed according to methods described in the literature (e.g. Molecules, 9 (6), 405-426; 2004; WO2017203474).

[0119] Alternatively, compounds of formula (I), wherein R1and R2are defined as above, may be prepared by reaction of a compound of formula (VIII)

[0120] (VIII), wherein R1and R2are defined as above, with a compound of formula (VII),

[0121] H2N^ R3

[0122] (VII), wherein R3is defined as above, in the presence of an oxidizing agent.

[0123] Suitable oxidizing agents are oxygen, ozone, hydrogen peroxide, nitric acid, potassium clorate. Process description

[0124] The process of the present invention is illustrated in Scheme 1 below.

[0125] Scheme 1

[0126] Cu source

[0127] Ligand of formula (I) hydroxylating agent solvent

[0128] In the present invention, an aryl halide of formula (III), wherein n is 1, 2, 3, 4 or 5,

[0129] R4is halogen,

[0130] X is chloro, bromo or iodo, is reacted with a hydroxylating agent using a copper source in combination with a compound of formula (I) as a ligand and optionally a base in a suitable solvent to form a halogenated phenol of formula (II), wherein n and R4are defined as before.

[0131] Preferably, the copper source is selected from the group consisting of Cui, CuBr, CuCl, copper thiophene- 2-carboxylate (CuTc), Cu(OAc)z, CuSOr. CuSOr x 5 H2O, CU2O, CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2, Cu(MeCN)4BF4, Cu(OEt)2, copper bis(2, 2,6, 6-tetramethyl-3,5-heptanedionate) (Cu(TMHD)2) and combinations thereof; more preferably the copper source is Cui, CuBr, CuCl, Cu(OAc)2, CuSCE, CuSOrx 5 H2O, CU2O, CuBr2, Cu(OEt)2 or CuO and combinations thereof, even more preferably the copper source is Cu(OEt)2, CuCl, Cui or CuBr2 and still even more preferably the copper source is CuCl, Cui or CuBr2.

[0132] Preferably, a catalytic amount of copper source is used. More preferably, the ratio of the compound of formula (III) to copper source is in the range from 10:1 to 1000:1. Even more preferably, the ratio of the compound of formula (III) to copper source is from 20:1 to 100:1.

[0133] Optionally, the reaction according to the invention is carried out in the presence of an additive, wherein the additive is selected from the group consisting of sodium ascorbate, silanes (e.g. methyldiethoxy silane, poly (methylhydrosiloxane)), triethylenediaminine bis(trimethylaluminum) or diethyl 1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.

[0134] The ratio of additive to compound of formula (III) is in the range of 0.1 : 1 to 1:1.

[0135] The ratio of compound of formula (I) to copper source is in the range from 10:1 to 1:5, preferably in the range of 5:1 to 1:2, more preferably, in the range of 3:1 to 1:1.

[0136] Suitable hydroxylating agents are alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide. Alternatively, a combination of water and alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal phosphates such as potassium phosphate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, may be applied as hydroxylating agent in the reaction according to the invention.

[0137] Optionally, the reaction is carried out in the presence of a suitable base. Suitable bases for the reaction according to the invention are alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal phosphates such as potassium phosphate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide or alkali metal acetates such as sodium acetate, and combinations thereof. More preferably, sodium hydroxide is used in the reaction according to the invention. In a preferred embodiment, an excess of base, optionally in combination with water, is used in the reaction according to the invention to act both as hydroxylating agent and as base. More preferably, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide are used to act both as hydroxylating agent and as base. Most preferably, sodium hydroxide is used as base and hydroxylating agent.

[0138] Suitable solvents for the reaction according to the present invention are, for example ethers such as 1,4- dioxane, 1 ,2-dimethoxy ethane (DME), tetrahydrofuran (THF), alcohols such as methanol, ethanol, tertbutanol, 1 -butanol, l-methoxy-2-propanol, cyclohexanol and isopropanol, other solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N- methylpyrrolidon (NMP), acetonitrile and water and / or combinations thereof. More preferably 1- methoxy-2-propanol, iso-propanol and / or water are used in the reaction according to the invention. Most preferably l-methoxy-2-propanol or iso-propanol in combination with water is used.

[0139] Preferable is (III) diluted with an appropriate amount of solvent so that the final concentration is in the range of 0.1 M to 3.0 M, preferably in the range of 0.1 M to 2.0M, more preferably in the range of 0.1 M to 1.0 M. Even more preferably is a final dilution of 0.24 M to 0.75 M.

[0140] The reaction according to the invention can be performed at reaction temperatures in the range of +20°C to +180°C, preferably in the range of +70°C to +110 °C.

[0141] The reaction time typically lies in the range from 1 to 24 hours.

[0142] Most preferably, the reaction according to the present invention is carried out with CuCl as copper source in combination with a compound of formula (I) as a ligand, wherein the ratio of ligand to copper source is in the range from 3:1 to 1:1, and sodium hydroxide as base and as hydroxylating agent.

[0143] The invention is illustrated by but not limited to the following examples:

[0144] EXAMPLES

[0145] A-l. Abbreviations A-2. General Considerations

[0146] The LC / MS measurement was performed on a Water Acquity HPLC using a gradient of acetonitrile and water (+0.6% trifluoroacetic acid) combined with an SQD2 and a PDA detector. All UPLC / MS measurements were conducted with Acquity UPLC Lclass instruments from Waters using a EC HPLC column (NUCLEODUR Cl 8 Gravity, 1.8 pm) and a water / acetonitrile gradient (0.1% formic acid) as eluent. Compounds were detected by an UV detector and a QDA detetor from Waters.

[0147] A-3. Examples

[0148] A-3.1 Preparation of substrates

[0149] Example 1-A: Preparation of 3-chloro-2-fluoro-iodobenzene

[0150] In a IL double jacketed vessel equipped with a mechanical stirrer under nitrogen at 22°C were placed sulfuric acid (50%, 720 g, 5.48 eq.), which was then warmed to 75 - 80°C. 3-Chloro-2-fluoroaniline (97%, 100 g, 1.00 eq., 0.666 mol) was added within 20 min. The initially formed suspension was stirred until formation of a clear solution. The solution was cooled to 0 - 2°C within 1 h. At about 65 °C the anilinehydrosulfate started to crystallize. Finally, a thick, but stirrable suspension had formed. Jacket temperature was set to -4 °C. Aqueous sodium nitrite solution (40%, 129.4 g, 0.75 mol, 1.11 eq.) was added over 1 h. The inner temperature remained under 2°C during addition.After dosing was finished, the clear yellow solution was stirred for 15 min at 0 °C. In a 2L double jacketed vessel equipped with a mechanical stirrer under nitrogen at 22 °C were placed aqueous sodium iodide solution (50%, 224 g, 0.75 mol, 1.11 eq.), 100 g water and 160 ml acetonitrile and the resulting solution cooled to 0 - 1 °C with a jacket temperature of -1°C. Within 1 h the diazonium salt solution in the IL vessel was dosed into the mixture in the 2L vessel. The temperature rose up to 9 °C. The mixture turned brown and the evolution of gas (N2) is observed. After completed addition, stirring was continued for 15 min at 5 °C. 200 ml water and 200 ml dichloromethane were added, the mixture was stirred for 20 min while adding a total of 9.5 g sodium metabisulfite in several portions. Then the phases were separated. The lower organic phase was removed and the upper aqueous phase was extracted again with 140 ml dichloromethane. To achieve a complete phase separation 100 ml water was added. The lower organic phase was removed and combined with the organic phase of the first extraction. The aqueous phase (1435 g, 1staq. phase) was discarded. The combined organic phases were washed with 100 ml water and additional 2 g sodium metabisulfite and then washed with 100 ml water. Finally, 700 g organic phase and 213 g aqueous phase (2ndaq. phase) were obtained. The solvent of the organic phase was distilled off at 45 °C and a pressure down to 5 mbar to afford 159 g of crude product as a red-orange oil.

[0151] Purity: 92% (qNMR)

[0152] Yield: 83%

[0153] >H NMR (400 MHz, DMSO-d6) 5 7.85, 7.84, 7.83, 7.83, 7.83, 7.83, 7.81, 7.81, 7.63, 7.62, 7.61, 7.61, 7.61, 7.60, 7.59, 7.59, 7.06, 7.06, 7.04, 7.04, 7.02, 7.02.

[0154] 19F NMR (376 MHz, DMSO-d6) 5 -96.22, -96.23, -96.25.

[0155] Example 2- A: Preparation of l-bromo-3-chloro-2-fluorobenzene

[0156] A 100 mL reactor vessel was equipped with a mechanical stirrer and reflux condenser and purged with nitrogen for 30 min. A flue gas scrubber was attached to the condenser. The vessel was charged with 24 g water and 22.5 g concentrated sulfuric acid were added over 1 min causing the internal temperature to rise to approx. 60 °C. At 85 °C, 3-chloro-2-fluoroaniline (6.00 g, 40.0 mmol, 1.00 eq.) was added under stirring over 30 min. The solution is then cooled to -5 °C over 1 h. At approx. 65 °C the formed ammonium salt started to precipitate. At -2 °C, a solution of sodium nitrite (3.06 g, 44.4 mmol, 1.11 eq.) in 5 g water is added over 1 h resulting in a bright yellow solution.

[0157] A separate 100 mL reactor vessel was charged with copper(I)bromide (0.57 g, 4.0 mmol, 0.10 eq.) and 7.8 g acetonitrile and then under stirring at room temperature with 10 g water, hydrobromic acid (48% w / w in water, 9.7 g, 3.0 eq.), and 0.22 g copper(II) bromide (0.22 g, 1.0 mmol, 0.025 eq.). At -5°C, the cooled solution of diazonium salt is dosed into this red / brownish solution over 30 min.

[0158] After stirring for 30 min at 0 °C, 35 mL MTBE were added and the formed phases were separated. The organic phase was washed with 10 mL hydrochloric acid (20%) twice and once with brine. 7.78 g of product was obtained after drying over magnesium sulfate and solvent removal at reduced pressure as crystals that quickly formed from an initially obtained dark red oil.

[0159] Yield: 83%

[0160] Purity: 89% (qNMR) 'H NMR (400 MHz, DMSO-d6) 5 7.74, 7.73, 7.72, 7.72, 7.71, 7.70, 7.70, 7.66, 7.65, 7.64, 7.64, 7.63, 7.62, 7.62, 7.24, 7.23, 7.22, 7.21, 7.20, 7.19.

[0161] 19F NMR (376 MHz, DMSO-d6) 5 -109.31, -109.33, -109.35.

[0162] Example 3-A: Preparation of l,3-dichloro-2-fluorobenzene

[0163] A 100 mL reactor vessel was equipped with a mechanical stirrer and reflux condenser and purged with nitrogen for 30 min. A flue gas scrubber was attached to the condenser. The vessel was charged with 5.0 g water and 13.25 mL hydrochloric acid (37% w / w in water, 8.0 eq.) were added over 1 min causing the internal temperature to rise. At 85°C, 3-chloro-2-fluoroaniline (3.00 g, 20.0 mmol, 1.00 eq.) was added under stirring. The solution was then cooled to -5 °C. At approx. 50 °C the formed ammonium salt started to precipitate. At -2°C, a solution of sodium nitrite ( 1.53 g, 22.2 mmol, 1.11 eq.) in 2.5 g water was added over 1 h resulting in a yellow / orange solution.

[0164] A separate 100 mL reactor vessel was charged with copper(I)chloride (0.49 g, 5.0 mmol, 0.25 eq.), hydrochloric acid (37% w / w in water, 2.5 mL, 1.5 eq.), 10 g water and then 7.8 g acetonitrile. At -6°C, the cooled solution of diazonium salt was dosed into this green / brownish suspension over 45 min.

[0165] After stirring for 30 min at -6°C and 30 min at room temperature, 40 mL MTBE were added and the formed phases were separated. The organic phase was washed with 20 mL hydrochloric acid (10%), 20 mL water, and 15 mL brine (sat.). 2.80 g of product were obtained after drying over magnesium sulfate and solvent removal at reduced pressure as crystals that quickly formed from an initially obtained dark red oil.

[0166] Yield: 75%

[0167] Purity: 88% (qNMR)

[0168] >H NMR (400 MHz, DMSO-d6) 5 7.62, 7.60, 7.60, 7.58, 7.30, 7.29, 7.28, 7.27, 7.26, 7.25.

[0169] 19F NMR (376 MHz, DMSO-d6) 5 -117.56, -117.58, -117.60.

[0170] A-3.2 Preparation of Ligands

[0171] Example 1-B: Preparation of (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-propanamide Step 1: N-(2,6-diemthylphenyl)-2-oxo-propanamide

[0172] In a lOOmL three neck round bottom flask was introduced BOP (25.3 g, 0.057 mol, 1.20 eq), 2.6- dimethylaniline (5.90 mL, 0.048 mol, 1.00 eq), DIPEA (16.6 mL, 0.095 mol, 2.00 eq) in dichloromethane (84.0 mL). This solution was cooled to 10°C and slowly was added Pyruvic Acid (3.90 mL, 0.048 mol, 1.00 eq) (exothermic reaction). At the end of the addition the ice was removed, and the reaction mixture was stirred at 23 °C for 5h until LCMS analysis showed complete conversion.

[0173] The solution was diluted with dichloromethane and washed three times with a IM aqueous HC1 solution and then twice with a IN aqueous NaOH solution. The organic layer was then dried over MgSCh. filtered and concentrated under vacuum to afford the intermediate product (13.0 g, 0.030 mol, 62%) as a brownish oil.

[0174] This residue was purified by normal phase chromatography using about 275g silica and eluting with a 15 / 85 EtOAc:heptane mixture. Purest fractions were combined and evaporated to dryness to afford the product (2.40 g, 0.013 mol, 26%) as an off-white solid.

[0175] Step 2: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-propanamide

[0176] In a 100 mL flask was introduced the previously prepared amide (2.30 g, 0.006 mol, 1.00 eq) followed by EtOH (11.5 mL) and H2O (4.60 mL). To this solution was added hydroxylamine (50% aqueous solution, 0.553 mL, 0.009 mol, 1.50 eq) and the solution was stirred at 45°C for 18 h.

[0177] The solution was allowed to cool down to 23 °C and water was added leading to a precipitation. The suspension was stirred for Ih and then the solid was filtered off. The wet solid was triturated in a mixture of EtOH and H2O for 1 hour at 23 °C and then collected by filtration, washed with water and dried under vacuum at 45°C for 24 hours to afford the desired product (1.20 g, 0.006 mol, 97%) as a white solid (mixture of isomers, 99% qNMR assay).

[0178] >H NMR (400 MHz, DMSO) 5 11.08, 9.61, 2.18, 2.16, 2.15, 2.15, 2.13, 2.12, 2.11, 2.03, 2.02, 2.01, 2.00, 2.00, 1.97, 1.96, 1.95, 1.94.13C NMR (101 MHz, DMSO) 5 162.9, 162.5, 150.4, 150.2, 135.6, 135.3, 135.0, 134.1, 127.6, 127.6, 126.7, 126.6, 18.1, 18.0, 17.3, 9.7.

[0179] LC / MS m / z (M+H)+= 207.4

[0180] Example 2-B: preparation of (2Z / E)-N,2-bis(2,6-dimethylphenyl)-2-hydroxyimino-acetamide

[0181] Step 1: 2-(2,6-dimethylphenoxy)-2-oxo-acetic acid

[0182] In a 10 mL round bottom flask equipped with a magnetic stir bar, ethyl 2-(2,6-dimethylphenyl)-2- oxoacetate (1.0 g, 4.85 mmol, 1.00 eq) was dissolved in MeOH (10.0 mL) and NaOH (0.580 g, 14.6 mmol, 3.00 eq) was added. The reaction mixture was stirred at 45 °C for 1 h. After that time an LCMS analysis was performed showing a complete conversion. DCM and HC1 (IM) were added and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over NaiSCL. filtered and concentrated under reduced pressure giving 831 mg of a yellow solid in 96% yield. The product was used as such in subsequent step without further purification.

[0183] >H NMR (400 MHz, CDC13) 5 8.1, 7.3, 7.3, 7.3, 7.1, 7.1, 2.3.

[0184] LC / MS m / z (M-H) = 176.9

[0185] Step 1: 2-(2,6-dimethylphenyl)-2-oxo-acetic acid (alternative route)

[0186] In a round-bottom flask, NaOH (29.09 g, 0.73 mol, 3.0 eq) was added to a solution of ethyl 2-(2,6- dimethylphenyl)-2-oxoacetate (50.0 g, 0.24 mol, 1.0 eq) in 2-MeTHF (500.0 mL), MeOH (50.0 mL) and water (100.0 mL). The reaction mixture was stirred at 60°C. An aliquot was taken after Ih quenched with water, diluted with MeOH and analyzed by HPLC / MS. LCMS analysis after this time showed complete conversion. The reaction mixture was allowed to cool down to 23 °C and water (lOOmL) then 2N aqueous HC1 (363.7 mL, 0.73 mol, 3.0 eq) were added. After phase separation, aqueous layer was extracted once with 2-MeTHF (300 mL). Organic layers were combined, washed with water, dried over sodium sulfate, filtered and concentrated under vacuum. The oil obtained was solubilized in acetone and concentrated 2 times to remove residual 2-MeTHF. The oil crystallized at 20°C and was taken-up in heptane (150 mL). The obtained suspension was stirred for 40min and the solid was recovered by filtration to give 2-(2,6- dimethylphenyl)-2-oxoacetic acid (38.0 g, 0.21 mol, 88%) as a yellow solid.

[0187] 'H NMR (400 MHz, CDC13) 5 8.1, 7.3, 7.3, 7.3, 7.1, 7.1, 2.3.

[0188] LC / MS m / z (M-H) = 176.9

[0189] Step 2: (2,6-dimethylphenyl)-2-(2,6-dimethylanilino)-2-oxo-acetate

[0190] In a 100 mL round bottom flask equipped with a magnetic stir bar, 2-(2,6-dimethylphenyl)-2-oxoacetic acid (0.860 g, 4.80 mmol, 1.00 eq), TCFH (1.60 g, 5.80 mmol, 1.20 eq) and the 1 -methylimidazole (0.850 mL, 10.7 mmol, 2.20 eq) were dissolved in acetonitrile (15 mL). The reaction mixture was stirred at room temperature for 15 min. Then, 2,6-dimethylaniline (0.597 mL, 4.85 mmol, 1.00 eq) was added via a syringe. The reaction mixture was stirred at 23 °C for 20 min. A slight change of color from deep yellow to yellow / colorless was observed. After 30 min the TLC showed no more aniline. The reaction was quenched with 1 M HC1 and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over NaiSCL and filtered. After evaporation 2.02 g of yellow solid were obtained. The product was dissolved in MeOH and water was added. The precipitate was filtered leading to 1.17 g of white powder in 86% yield.

[0191] Step 3: (2Z / E)-N,2-bis(2,6-dimethylphenyl)-2-hydroxyimino-acetamide

[0192] In a 50 mL round bottom flask were charged N,2-bis(2,6-dimethylphenyl)-2-oxoacetamide (1.00 g, 3.60 mmol, 1.00 eq), hydroxylamine hydrochloride (247 mg, 3.60 mmol, 1.00 eq) and EtOH (15.0 mL). Then, at room temperature titanium (IV) isopropoxide (4.20 mL, 14.2 mmol, 4.00 eq) was added dropwise via a syringe. The reaction mixture was stirred at 80 °C for 6 hours. LCMS analysis showed a 63% conversion without formation of side products (the product formed as two isomers E / Z 5 / 95).

[0193] To avoid degradation, the reaction mixture was quenched with IM HC1 and extracted with DCM (three times). A large amount of white solid was formed in aqueous layer (titan salts). The combined organic layers were washed with a saturated NaCl solution, dried over NaiSCL. filtered and concentrated under reduced pressure. The product (E / Z mixture) was purified by chromatography on silica gel eluting with Heptane / EtOAc 90:10 to 50:50. Purest fractions were combined and evaporated to dryness to afford the desired product (418 mg, 1.41 mmol, 40%) as a white solid.

[0194] 'H NMR (400 MHz, DMSO) 5 12.1, 11.9, 9.8, 9.6, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 2.3, 2.2, 2.2, 2.1.

[0195] LC / MS m / z (M+H)+ = 297.4

[0196] Example 3-B: Preparation of (2Z / E)-N-(2,6-dimethylphenyl)-2-(4-hydroxy-2,6-dimethyl-phenyl)-2- hydroxyimino-acetamide

[0197] Step 1: 2-(4-methoxy-2,6-dimethylphenyl)-2-oxoacetic acid

[0198] In a 100 mL round bottom flask, was charged ethyl 2-(4-methoxy-2,6-dimethylphenyl)-2-oxoacetate (2.80 g, 0.012 mol, 1.00 eq.) followed by 4 M aqueous NaOH (1.42 g, 0.036 mol, 3.00 eq.) and MeOH (24 mL). The reaction mixture was stirred at 23 °C for 10 min until complete saponification. MeOH was evaporated under vacuum, then DCM and a 1 M HC1 aqueous solution were added. The product was extracted with DCM two times and the combined organic layers were washed with brine, dried over MgSO-i. filtered and evaporated under reduced pressure affording a yellow / green solid (2.30 g, 0.011 mol, 93%). The product was used without further purification in the subsequent step.

[0199] >H NMR (400 MHz, CDCh) 5 6.6, 3.8, 3.5, 2.3.

[0200] LC / MS m z (M-H)- = 207.3

[0201] Step 2: N-(2,6-dimethylphenyl)-2-(4-methoxy-2,6-dimethylphenyl)-2-oxoacetamide

[0202] In a 10 mL round bottom flask, was charged 2-(4-methoxy-2,6-dimethylphenyl)-2-oxoacetic acid (115 mg, 0.55 mmol, 1.0 eq) followed by acetonitrile (1.7 mL). TCLH (186 mg, 0.660 mmol, 1.20 eq) and 1 -Methylimidazole (100 mg, 1.20 mmol, 2.20 eq) were added at 23°C. The mixture turned yellow to orange. After 15 min at 23 °C, 2,6-dimethylaniline (0.068 mL, 0.550 mmol, 1.00 eq) was added as a solution in acetonitrile (0.5 mL). The reaction mixture was stirred for 10 min at 23°C. A 95% conversion was obtained after this time so the reaction was quenched with water. The precipitate was collected by filtration, washed with water and dried for 16 h under reduced pressure at 45 °C affording the intermediate product (140 mg, 81%) as a yellow solid.

[0203] 'H NMR (400 MHz, CDC13) 5 8.4, 7.2, 7.2, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 6.6, 3.8, 2.3, 2.3.

[0204] LC / MS m / z (M+H)+= 312.1

[0205] Step 3: N-(2,6-dimethylphenyl)-2-(4-hydroxy-2,6-dimethylphenyl)-2-oxoacetamide

[0206] In a 5 mL round bottom flask was introduced N-(2,6-dimethylphenyl)-2-(4-methoxy-2,6- dimethylphenyl)-2-oxoacetamide (31.4 mg, 0.500 mmol, 1.00 eq) followed by acetic acid (1.0 mL). Then, hydroiodic acid (0.067 mL, 1.00 mmol, 5.00 eq) was added dropwise via a syringe. The reaction mixture was stirred at 80 °C for 16 h. After that time another portion of HI (0.1 mL) was added and the reaction was stirred at 80 °C for 3 hours. The analysis of the mixture by LCMS showed a 87% conversion which did not increased with time. It was quenched with water and extracted with EtOAc. The organic layer was dried over NaiSCL. filtered and concentrated at reduced pressure.The crude (brown oil) was used as such in subsequent step without further purification.

[0207] >H NMR (400 MHz, CDCL) 5 8.5, 8.5, 7.2, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 7.1, 7.1, 6.4, 3.8, 2.3, 2.2. LC / MS m / z (M+H)+= 298.2

[0208] Step 4: (2Z / E)-N-(2,6-dimethylphenyl)-2-(4-hydroxy-2,6-dimethyl-phenyl)-2-hydroxyimino- acetamide

[0209] In a 50 mL round bottom flask was charged N-(2,6-dimethylphenyl)-2-(4-hydroxy-2,6-dimethylphenyl)- 2-oxoacetamide (1.29 g, 0.004 mol, 1.00 eq) followed by hydroxylamine hydrochloride (0.450 g, 0.007 mol, 1.50 eq) and Ethanol (20 mL). Then, titanium isopropoxide (7.70 mL, 0.026 mol, 6.00 eq) was added and the reaction mixture was stirred at 80 °C for 16 h. The product was formed as two isomers Z / E (around 70 / 30).The reaction was cooled down to 80 °C, DCM and NH4CI saturated solution were added and the product was extracted three times with DCM. The combined organic layers were dried over NaiSCL. filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (heptane / EtOAc, from 80 / 20 to 60 / 40) affording a white powder containing 5% of starting material. A recrystallization from EtOAc / heptane (around 70 / 30) was performed affording the desired product (310 mg, 23%) as a white solid.

[0210] 'H NMR (400 MHz, DMSO) 5 11.9, 11.8, 9.7, 9.5, 9.3, 9.3, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 6.5, 6.5, 2.2, 2.2, 2.2, 2.0.

[0211] LC / MS m / z (M+H)+= 313.1

[0212] Example 4-B: (2Z / E)-N-(2,6-dimethylphenyl)-2-hydroxyimino-2-(4-methoxy-2,6-dimethyl- phenyl)acetamide

[0213] In a 50 mL round bottom flask, N-(2,6-dimethylphenyl)-2-(4-methoxy-2,6-dimethylphenyl)-2- oxoacetamide (1.09 g, 3.48 mmol, 1.00 eq) and hydroxylamine hydrochloride were dissolved in EtOH (15 mL). At 23°C, titanium isopropoxide (4.10 mL, 13.9 mmol, 4.00 eq) was added dropwise and the reaction mixture was stirred for 16h at 80°C.The reaction mixture was quenched by addition of water at 23°C and acidified with a 1 M HC1 solution. Then, the product was extracted with DCM (three times). The combined organic layers were washed with brine, dried over MgSCL. filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (90 / 10, Heptane / EtOAc). Only the major isomer was isolated to afford the desired product (566 mg, 41%) as a white powder.

[0214] 'H NMR (400 MHz, >H NMR (400 MHz, DMSO) 5 12.0, 9.7, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 6.7, 3.7, 2.3, 2.2.

[0215] LC / MS m / z (M+H)+= 327.0

[0216] Example 5-B: (2E)-N-(4-hydroxy-2,6-dimethyl-phenyl)-2-hydroxyimino-propanamide

[0217] Step 1: [4-(2-chloropropanoylamino)-3,5-dimethyl-phenyl] 2-chloropropanoate

[0218] A solution of 4-hydroxy-2,6-dimethylaniline (5.00 g, 0.036 mol, 1.00 eq) and 2-chloropropionyl chloride (14.6 mL, 0.084 mol, 2.30 eq) in DCM (50.0 mL) was cooled to 0°C. DIPEA was then slowly added (7.80 mL, 0.080 mol, 2.20 eq) and the reaction mixture was warmed to 23 °C and stirred at this temperature for 30 minutes. LCMS analysis after this time showed complete conversion into disubstituted product. The reaction was quenched by addition of 50mL of water and phases were separated. The organic layer was dried over Na^SOr and evaporated under reduced pressure to a yellow residue. This residue was stirred in 50 mL of DIE at 23°C for 10 minutes and turned to a solid which was collected by filtration, washed with DIE and dried under vacuum at 45°C for 18 hours to afford the intermediate product (11.0 g, 0.035 mol, 94%) as a beige solid.

[0219] >H NMR (400 MHz, DMSO) 5 9.7, 6.9, 5.0, 5.0, 4.7, 4.7, 2.1, 1.7, 1.7, 1.7, 1.6.

[0220] LC / MS m / z (M+H)+= 318.2

[0221] Step 2: 2-chloro-N-(4-hydroxy-2,6-dimethyl-phenyl)propanamide

[0222] To a solution of previously prepared [4-(2-chloropropanoylamino)-3,5-dimethyl-phenyl] 2-chloro- propanoate (10.0 g, 0.031 mol, 1.00 eq) in methanol (100 mL) and water (50.0 mL) was added sodium hydroxide (30% aqueous solution, 3.5 mL, 0.035 mol, 1.10 eq) and the solution was stirred at 23 °C for 1 h. LCMS analysis after this time showed complete conversion. The reaction mixture was diluted with 200 mL of EtOAc and 200 mL of 2 M aqueous HC1. Phases were separated and the organic layer was evaporated to dryness. The residue was triturated in 100 mL of DIE at 23°C for 30 minutes and the solid was collected by filtration, washed with DIE and dried under vacuum at 45 °C for 18 hours to afford 2- chloro-N-(4-hydroxy-2,6-dimethyl-phenyl)propanamide (5.30 g, 0.023 mol, 74%) as a beige solid.

[0223] 'H NMR (400 MHz, DMSO) 5 9.3, 9.2, 6.5, 4.7, 4.7, 4.7, 4.6, 2.0, 1.6, 1.6.

[0224] Step 3: (2E)-N-(4-hydroxy-2,6-dimethyl-phenyl)-2-hydroxyimino-propanamide

[0225] To a solution of 2-chloro-N-(4-hydroxy-2,6-dimethyl-phenyl)propanamide (5.30 g, 0.023 mol, 1.00 eq) and hydroxylamine hydrochloride (4.85 g, 0.070 mol, 3.00 eq) in DMSO (46.0 mL) was added sodium hydroxide (2.79 g, 0.070 mol, 3.00 eq). The solution was warmed to 80°C and stirred at this temperature for 20 h. Extra hydroxylamine hydrochloride (4.85 g, 0.070 mol, 3.00 eq) and sodium hydroxide (2.79 g, 0.070 mol, 3.00 eq) were added and stirring at 80°C for pursued for 24 hours. The reaction mixture was cooled to 60°C and hydrogen peroxide (50.0 mL, 0.645 mol, 27.7 eq) was added portionwise (25 mL every 2 hours). LCMS analysis after this time showed full conversion of the intermediate into target compound. The reaction mixture was cooled to 23 °C, diluted with EtOAc (50 mL) and phases were separated. The aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, washed with water (20 mL) dried over Na^SO-i. filtered and evaporated under reduced pressure to afford an orange oil. This oil was triturated in Heptane / EtOAc 9:1 (50 mL) and a solid precipitated and was eliminated by filtration. The filtrate was evaporated to dryness and this operation was repeated one more time. The residue was then recrystallized from iPrOH (10 mL) and water (25 mL). The solid was collected by filtration, washed with water and dried under vacuum at 45 °C for 18 hours to afford the desired product (1.10 g, 0.005 mol, 21%) as a beige solid.

[0226] >H NMR (400 MHz, DMSO) 5 11.8, 9.2, 9.0, 6.5, 2.0, 1.9.

[0227] LC / MS m / z (M+H)+= 223.2

[0228] Example 6-B: (2E / Z)-2-hydroxyimino-N-(4-methoxy-2,6-dimethyl-phenyl)propanamide

[0229] Step 1: N-(4-methoxy-2,6-dimethylphenyl)-2-oxo-propanamide

[0230] A solution of pyruvic acid (2.80 mL, 0.040 mol, 1.20 eq) and DME (1.30 mL, 0.017 mol, 0.500 eq) in dichloromethane (80.1 mL) was cooled at 0 °C and oxalyl chloride (3.40 mL, 0.040 mol, 1.20 eq) was added slowly. The reaction mixture was stirred at 23°C for 3 hours. The solution was then cooled to 0°C and a solution of 4-methoxy-2,6-dimethylaniline (5.00 g, 0.033 mol, 1.00 eq) and triethylamine (6.90 mL, 0.050 mol, 1.50 eq) in 20 mL of DCM was added. The reaction mixture was stirred at 23 °C for 18 hours. LCMS analysis showed full conversion after this time. The reaction was quenched by addition of water and 2M HC1 and extracted with DCM two times. The organic layers were combined and concentrated to dryness under reduced pressure to afford the intermediate product (7.40 g, 0.033 mol, 83%) as a red oil which was used as such for the next step.

[0231] 'H NMR (400 MHz, DMSO) 5 9.8, 6.7, 3.7, 2.4, 2.1.

[0232] Step 2: (2E / Z)-2-hydroxyimino-N-(4-methoxy-2,6-dimethyl-phenyl)propanamide

[0233] To a solution of the intermediate product (7.40 g, 0.033 mol, 1.00 eq) in acetonitrile (66.1 mL) was slowly added aqueous hydroxylamine (6.10 mL, 0.100 mol, 3.00 eq) at 50°C. LCMS analysis showed full conversion after 18h. The reaction was quenched by addition of 50 mL of H2O. The aqueous phase was extracted with 50 mL of EtOAc. The organic layer was concentrated to afford an orange oil (7.20 g). This residue was recrystallized in iPrOH (8 mL) and water (16 mL). The obtained solid was washed with heptane / DCM 4:1 (25 mL) to afford the desired product (3.40 g, 0.014 mol, 43%) as a brown solid.

[0234] >H NMR (400 MHz, DMSO) 5 11.8, 9.1, 6.7, 3.7, 2.1, 1.9.

[0235] LC / MS m / z (M+H)+= 237.3

[0236] Example 7-B: (2E / Z)-2-hydroxyimino-N-(2,4,6-trimethoxyphenyl)propanamide

[0237] Step 1: N-(2,4,6-trimethoxyphenyl)-2-oxo-propanamide

[0238] To a solution of pyruvic acid (2.30 mL, 0.033 mol, 1.20 eq) and DMF (1.1 mL, 0.014 mol, 0.500 eq) in DCM (66.1 mL) was slowly added oxalyl chloride (2.80 mL, 0.033 mol, 1.20 eq) at 0 °C. The reaction mixture was stirred at 23°C for 3 hours. The solution was cooled to 0°C and a solution of 2,4,6- methoxyaniline (5.00 g, 0.027 mol, 1.00 eq) and triethylamine (5.70 mL, 0.041 mol, 1.50 eq) in 20 mL of DCM was added and the reaction mixture was stirred at 23 °C for 18 hours. The reaction was quenched by addition of water and 2M HC1 and extracted with DCM two times. The organic layers were combined and concentrated to afford the intermediate product (5.90 g) as a red oil which was used as such for next step.

[0239] >H NMR (400 MHz, DMSO) 5 6.3, 3.8, 3.7, 2.4.

[0240] LC / MS m / z (M+H)+= 254.4

[0241] Step 2: (2E / Z)-2-hydroxyimino-N-(2,4,6-trimethoxyphenyl)propanamide

[0242] To a solution of the intermediate of step 1 (5.90 g, 0.023 mol, 1.00 eq) in MeCN (46.1 mL) was slowly added aqueous hydroxylamine (4.30 mL, 0.070 mol, 3.00 eq) and the reaction mixture was warmed to 50°C. LCMS analysis after 1.5 h showed poor conversion. Extra aqueous hydroxylamine (4.30 mL, 0.070 mol, 3.00 eq) was added to the solution and stirring at 50°C was pursued for 18 h. LCMS analysis after this time showed full conversion. The reaction mixture was quenched by addition of 50 mL of H2O. Aqueous phase was extracted with 50 mL of EtOAc but led to the precipitation of a solid which was collected by filtration which matched with the target compound. The organic layer was evaporated to dryness to afford an orange oil and the residue was passed over a short silica pad eluting with EtOAc to afford an orange solid which was further triturated with iPrOH (10 mL) and DIE (25 mL). The solid was collected by filtration. It was mixed with the previously obtained batch in 2 mL of iPrOH and 18 mL of H2O. The solid was collected by filtration and dried under vacuum to afford the desired product (2.00 g, 0.007 mol, 32%) as a purple solid.

[0243] >H NMR (400 MHz, DMSO) 5 11.8, 8.4, 6.3, 3.8, 3.7, 1.9.

[0244] LC / MS m / z (M+H)+= 269.4

[0245] Example 8-B : (2E / Z)-2-hydroxyimino-N-(2-phenylphenyl)propanamide

[0246] Step 1 : 2-oxo-N-(2-phenylphenyl)propanamide

[0247] 6,7

[0248] To a solution of pyruvic acid (2.50 mL, 0.035 mol, 1.20 eq) and DME (1.10 mL, 0.015 mol, 0.500 eq) in DCM (71.6 mL) was slowly added oxalyl chloride (3.00 mL, 0.035 mol, 1.20 eq) at 0 °C. The reaction mixture was stirred at 23 °C for 3 hours. The reaction mixture was cooled to 0°C and a solution of 2- aminobiphenyl (5.000 g, 0.030 mol, 1.000 eq) and triethylamine (6.2 mL, 0.044 mol, 1.500 eq) in 20 mL of DCM was slowly added and the reaction mixture was stirred at 23 °C for 18 h. LCMS analysis showed full conversion after 18h. The reaction was quenched by addition of water and 2M HC1 and extracted with DCM two times. The organic layers were combined and concentrated to afford the intermediate product (6.70 g, 80%) as a red oil which was used as such for the next step.

[0249] >H NMR (400 MHz, DMSO) 59.5, 8.0, 8.0, 8.0, 7.9, 7.9, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3,

[0250] 2.3.

[0251] Step 2: (2E / Z)-2-hydroxyimino-N-(2-phenylphenyl)propanamide

[0252] To a solution of the intermediate (6.70 g, 0.028 mol, 1.00 eq) in MeCN (55.4 mL) was slowly added aqueous hydroxylamine (5.10 mL, 0.084 mol, 3.00 eq) at 50°C. The reaction mixture was stirred at this temperature for 18 hours. LCMS analysis after 18h showed full conversion. The reaction mixture was quenched by addition of 50 mL of H2O. Aqueous phase was extracted with 50 mL of EtOAc. The organic layer was concentrated to obtain an orange oil. This residue was triturated in 20 mL of iPrOH / fLO 1 : 1 and the solid washed with heptane / DCM 9:1. This residue was recrystallized using iPrOH 4 mL and water 8 mL. The solid was washed with heptane / DCM 4:1 (25 mL) to afford the desired product (2.80 g, 0.011 mol, 39%) as a colorless solid.

[0253] >H NMR (400 MHz, DMSO) 5 11.9, 9.0, 8.1, 8.1, 8.1, 8.1, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.2, 7.2, 7.2, 7.2, 1.9. LC / MS m / z (M+H)+= 255.3

[0254] Example 9-B : (2E / Z)-2-hydroxyimino-N-(2-phenoxyphenyl)propanamide

[0255] Step 1 : 2-oxo-2-(2-phenoxyanilino)propanamide

[0256] To a solution of pyruvic acid (2.30 mL, 0.033 mol, 1.20 eq) and DMF (1.00 mL, 0.013 mol, 0.500 eq) in DCM (65.4 mL) was slowly added oxalyl chloride (2.80 mL, 0.032 mol, 1.20 eq) at 0 °C. The reaction mixture was stirred at 23 °C for 3 h and then cooled to 0°C. A solution of 2-phenoxyaniline (5.00 g, 0.027 mol, 1.00 eq) and triethylamine (5.60 mL, 0.040 mol, 1.50 eq) in 20 mL of DCM was slowly added to the mixture which was warmed to 23 °C and stirred for 18 h. LCMS analysis showed incomplete conversion after this time. Nevertheless, the reaction was quenched by addition of water and 2M HC1 and was extracted with DCM two times. The organic layers were combined and concentrated to afford the intermediate product (6.90 g, 82%) as a red oil which was used as such for next step.

[0257] 'H NMR (400 MHz, DMSO) 59.6, 8.1, 8.1, 8.1, 8.1, 8.1, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 7.1, 7.0, 7.0, 7.0, 7.0, 6.9, 6.9, 6.9, 6.9, 6.9, 6.9, 6.9, 5.8, 2.4.

[0258] Step 2: (2E / Z)-2-hydroxyimino-N-(2-phenoxyphenyl)propanamide

[0259] To a solution of the intermediate (6.90 g, 0.027 mol, 1.00 eq) in MeCN (53.5 mL) was slowly added aqueous hydroxylamine (5.00 mL, 0.081 mol, 3.00 eq) at 50°C and the solution was stirred for 18 h at this temperature. LCMS analysis after this time showed full conversion. The reaction mixture was quenched by addition of 50 mL of H2O. Aqueous phase was extracted with 50 mL of EtOAc. The organic layer was concentrated to afford an orange oil. This residue was triturated in 20 mL of iPrOH / H2O 1 : 1 and washed with heptane / DCM 9:1. This residue was recrystallized using iPrOH (4 mL) and water (8 mL). The solid was washed with heptane / DCM 4:1 (25 mL) to afford the desired product (3.00 g, 0.011 mol, 41%) as a colorless solid.

[0260] >H NMR (400 MHz, DMSO) 5 12.2, 9.3, 8.3, 8.3, 8.3, 8.3, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 6.9, 6.9, 6.9, 6.9, 6.9, 6.9, 2.0.

[0261] LC / MS m / z (M+H)+= 271.4

[0262] Example 10-B : (2E / Z)-N-benzyl-2-hydroxyimino-propanamide

[0263] Step 1 : N-benzyl-2-oxo-propanamide

[0264] In a 600 mL reactor with mechanical stirring under N2 was charged pyruvic acid (3.90 mL, 0.056 mol, 1.20 eq) followed by DCM (113 mL) and DMF (1.80 mL, 0.023 mol, 0.500 eq). The solution was cooled at 0 °C and oxalyl chloride (4.80 mL, 0.056 mol, 1.20 eq) was slowly added keeping the internal temperature below 10°C. At the end of the addition, the reaction mixture was warmed to 23°C over 30 minutes and stirred at this temperature for 3 h.

[0265] After this time the solution was cooled to 0°C and a solution of benzylamine (5.10 mL, 0.047 mol, 1.00 eq) and triethylamine (9.70 mL, 0.070 mol, 1.50 eq) in 10 mL of DCM was added to the mixture keeping the internal temperature below 10°C. At the end of the addition, the reaction mixture was warmed to 23 °C over 30 minutes and stirred at this temperature for 18 hours. The reaction mixture was diluted with DCM (200 mL) and 2M aqueous HC1 (200 mL). Phases were separated and the organic layer was washed times a 1 M aqueous HC1 solution (50 mL) and then with water (2x 50 mL), dried over MgSCL. filtered and concentrated under vacuum to afford the intermediate product (6.30 g, 0.036mol, 76%) as a brownish oil. This product was used in the next step without any further purification.

[0266] Step 2: (2E / Z)-N-benzyl-2-hydroxyimino-propanamide

[0267] In a 250 mL round bottom flask under nitrogen was charged the crude oil from the previous step (6.30 g, 0.036 mol, 1.00 eq) followed by acetonitrile (70.0 mL). The solution was warmed to 50°C (full dissolution) and then 50% aqueous hydroxylamine solution (6.50 mL, 0.107 mol, 3.00 eq) was added. The solution was stirred at 50°C for Ih. After this time the solution was cooled to 23°C and diluted with water (50 mL) and EtOAc (100 mL). Phases were separated and the organic layer was washed with water (50 mL), dried over MgSCL. filtered and concentrated under vacuum to afford a brown oil which was purified by chromatography over Si CL eluting with heptane :EtOAc 7 / 3. Purest fractions were combined and evaporated to dryness under reduced pressure to afford the desired product (2.00 g, 0.010 mol, 29%) as a white solid.

[0268] >H NMR (400 MHz, DMSO) 5 11.7, 8.4, 8.4, 8.4, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.2, 7.2, 7.2, 7.2, 7.2, 4.3, 4.3, 3.3, 1.9.

[0269] LC / MS m / z (M+H)+= 193.3

[0270] Example 11-B : (2E / Z)-2-hydroxyimino-N-(2-methyl-l-naphthyl)propanamide

[0271] Step 1 : N-(2-methylnaphthalen-l-yl)-2-oxopropanamide In a 250 mL reactor with mechanical stirring under N2 was charged pyruvic acid(2.70 mL, 0.038 mol, 1.20 eq) followed by DCM (77.1 mL) and DMF ( 1.2'0 mL, 0.016 mol, 0.500 eq). The solution was cooled at 0 °C and oxalyl chloride (3.30 mL, 0.038 mol, 1.20 eq) was slowly added keeping the internal temperature below 10°C. At the end of the addition, the reaction mixture was warmed to 23°C over 30 minutes and stirred at this temperature for 3 hours. After this time the solution was cooled to 0°C and a solution of 2- methylnaphthalen-1 -amine (5.00 g, 0.032 mol, 1.00 eq) and triethylamine (6.60 mL, 0.048 mol, 1.50 eq) in 20 mL of DCM was added to the mixture keeping the internal temperature below 10°C. At the end of the addition, the reaction mixture was warmed to 23 °C over 30 minutes and stirred at this temperature for 18 hours.

[0272] The reaction mixture was diluted with DCM (200 mL) and 2M aqueous HC1 (200 mL). Phases were separated and the organic layer was washed times a IM aqueous HC1 solution (50 mL) and then with water (2x 50 mL), dried over MgSO4, filtered and concentrated under vacuum to afford the desired product (6.10 g, 0.027mol, 84%) as a brownish oil which was used as such for the next step.

[0273] >H NMR (400 MHz, DMSO) 5 10.4, 7.9, 7.9, 7.9, 7.9, 7.9, 7.9, 7.8, 7.8, 7.8, 7.8, 7.8, 7.8, 7.8, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 2.5, 2.3.

[0274] LC / MS m / z (M+H)+= 228.3

[0275] Alternative route

[0276] In a IL three-neck round-bottom flask, under nitrogen, a solution of pyruvic acid (39.8 mL, 0.57 mol, 1.8 eq) and DMF (4.9 mL, 63.6 mmol, 0.2 eq) in DCM (330.0 mL) was cooled to 8-10°C before the dropwise addition of oxalyl chloride (46.4 mL, 0.54 mol, 1.7 eq) over 20 min. The solution was stirred at 10°C for 30 min then at 15-20°C for Ih (no more gas release observed). The reaction mixture was then cooled down to 0°C for the addition dropwise over 1.5 h of a solution of 2-methyl-l -naphthylamine (50.0 g, 0.32 mol, 1.0 eq) and triethylamine (66.3 mL, 0.48 mol, 1.5 eq) in DCM (250.0 mL). The reaction mixture was stirred at 0-5 °C for 30 min, an aliquot was taken-up, diluted in MeCN / water and analyzed by LCMS showing complete conversion. Water (500 mL) was added at 5°C. After phase separation, the organic layer was washed with 500 mL of an aqueous saturated solution of NaHCCL and then with water, dried over magnesium sulfate, filtered, and concentrated to dryness to give N-(2-methylnaphthalen-l-yl)-2- oxopropanamide (66.0 g, 0.29 mol, 91%) as a beige solid with a LC purity of 87%. The product was used in the next step without any further purification.

[0277] >H NMR (400 MHz, DMSO) 5 10.4, 7.9, 7.9, 7.9, 7.9, 7.9, 7.9, 7.8, 7.8, 7.8, 7.8, 7.8, 7.8, 7.8, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 2.5, 2.3.

[0278] LC / MS m / z (M+H)+= 228.3

[0279] Step 2: (2E / Z)-2-hydroxyimino-N-(2-methyl-l-naphthyl)propanamide

[0280] In a 250 mL round bottom flask under Nitrogen was charged the crude oil from the previous step (6.10 g, 0.027 mol, 1.00 eq) followed by acetonitrile (53.1 mL). The solution was warmed to 50°C (full dissolution) and then 50% aqueous hydroxylamine solution (4.90 mL, 0.081 mol, 3.00 eq) was added. The solution was stirred at 50°C for 18 h. After this time the solution was cooled to 23 °C and diluted with water (50 mL) and EtOAc (100 mL). Phases were separated and the organic layer was washed with water (50 mL), dried over MgSO4, filtered and concentrated under vacuum to afford an orange oil. This oil was solubilized in 10 mL of DCM and heptane (25 mL) was added at 23 °C until a solid appears. The solid was collected by filtration, recrystallized from z'PrOH (7 mL) and water (20 mL) collected by filtration, washed with water and dried a at 45°C under vacuum to afford the desired product (2.00 g, 0.008 mol, 31%) as a white solid.

[0281] >H NMR (400 MHz, DMSO) 5 11.9, 9.7, 7.9, 7.9, 7.9, 7.9, 7.9, 7.8, 7.8, 7.8, 7.8, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 3.3, 2.3, 2.0.

[0282] LC / MS m / z (M+H)+= 243.2

[0283] Alternative route

[0284] A solution of hydroxylamine 50% in water (35.1 mL, 0.57 mol, 2.0 eq) was added to a mixture of N-(2- methylnaphthalen-l-yl)-2-oxopropanamide (65.0 g, 0.286 mol, 1.0 eq) in MeCN (650.0 mL). The reaction mixture was stirred at 50°C for 17 h. Reaction mixture was filtered to remove slight insoluble material and the filtrate was partially concentrated under vacuum. EtOAc and water were added. After phase separation, organic layer was washed with 500mL of an aqueous saturated solution of NH4CI then with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product (85 g) as an orange solid was solubilized in IPA (460 mL) at 80°C, then Water (680 mL) was added dropwise. The solution was slowly cooled down to 23 °C over 4h leading to crystallization. The suspension was filtered and the obtained solid was washed with water and dried under vacuum (45 °C) over the weekend to give 2-(hydroxyimino)-N-(2-methylnaphthalen-l-yl)propanamide (49.7 g, 0.205 mol, 72%) as a pale purple solid. Three different batches of 2-(hydroxyimino)-N-(2-methylnaphthalen-l-yl)propanamide (115.5 g, 0.48 mol) were dissolved in IPA (600mL) at reflux then water (980 mL) was slowly added. The solution was slowly cooled down to 23 °C leading to crystallization. The suspension was stirred at 23 °C for 2h then filtered. The obtained solid was dried under vacuum (45°C) for 48 h to give 2-(hydroxyimino)-N-(2- methylnaphthalen-l-yl)propenamide (111.4 g, 0.46 mol, 97%) as a slightly purple solid. >H NMR (400 MHz, DMSO) 5 11.9, 9.7, 7.9, 7.9, 7.9, 7.9, 7.9, 7.8, 7.8, 7.8, 7.8, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 3.3, 2.3, 2.0.

[0285] LC / MS m / z (M+H)+= 243.2

[0286] Example 12-B : (2E / Z)-2-hydroxyimino-N-(3-phenylpropyl)propanamide

[0287] Step 1: 2-oxo-2-(3-phenylpropylamino)acetic acid

[0288] In a 250 mL reactor with mechanical stirring under N2 was charged pyruvic acid (3.10 mL, 0.044 mol, 1.20 eq) followed DCM (89.6 mL) and DMF (1.40 mL, 0.018 mol, 0.500 eq). The solution was cooled at 0 °C and oxalyl chloride (3.80 mL, 0.044 mol, 1.20 eq) was slowly added keeping the internal temperature below 10°C. At the end of the addition, the reaction mixture was warmed to 23°C over 30 minutes and stirred at this temperature for 3 h. After this time the solution was cooled to 0°C and a solution of 3- phenylpropylamine (5.00 g, 0.037 mol, 1.00 eq) and triethylamine (12.9 mL, 0.092 mol, 2.50 eq) in 10 mL of DCM was added to the mixture keeping the internal temperature below 10°C. At the end of the addition, the reaction mixture was warmed to 23 °C over 30 minutes and stirred at this temperature for 18 h. The reaction mixture was diluted with DCM (200 mL) and 2M aqueous HC1 (200 mL). Phases were separated and the organic layer was washed times a IM aqueous HC1 solution (50 mL) and then with water (2x 50 mL), dried over MgSCL. filtered and concentrated under vacuum to afford the intermediate product (6.30 g, 0.041mol, 70%) as a brownish oil. This product was used in the next step without any further purification.

[0289] Step 2: (2E / Z)-2-hydroxyimino-N-(3-phenylpropyl)propanamide

[0290] In a 250 mL round bottom flask under nitrogen was charged the crude oil from the previous step (8.50 g, 0.041 mol, 1.00 eq) followed by acetonitrile (81.9 mL). The solution was warmed to 50°C (full dissolution) and then 50% aqueous hydroxylamine solution (7.60 mL, 0.124 mol, 3.00 eq) was added. The solution was stirred at 50°C for 18h. After this time the solution was cooled to 23 °C and diluted with water (50 mL) and EtOAc (100 mL). Phases were separated and the organic layer was washed with water (50 mL), dried over MgSCL. filtered and concentrated under vacuum to afford an orange oil. This oil was purified by chromatography over SiCL eluting with heptane:EtOAc 7 / 3. Purest fractions were combined and evaporated to dryness under reduced pressure to afford the desired product (2.10 g, 0.010 mol, 23%) as a white solid.

[0291] 'H NMR (400 MHz, DMSO) 5 11.6, 7.9, 7.9, 7.9, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 3.2, 3.2, 3.2, 3.2, 3.2, 3.2, 3.1, 2.6, 2.6, 2.5, 2.5, 2.5, 2.5, 2.5, 2.5, 2.5, 2.5, 2.5, 2.5, 2.5, 2.5, 1.9, 1.8, 1.8, 1.8, 1.8, 1.7, 1.7, 1.7, 1.7, 1.7, 1.7, 1.7.

[0292] LC / MS m / z (M+H)+= 221.3

[0293] Example 13-B: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-3-methyl-butanamide

[0294] Step 1: N-(2,6-dimethylphenyl)-2-oxo-3-methyl-butanamide

[0295] In a 50 mL round bottom glass flask was charged 3-methyl-2-oxobutanoic acid (1.66 g, 14.0 mmol, 1.00 eq) in DCM (15.8 mL) and DMF (0.020 mL). At 23 °C under a nitrogen flux, oxalyl chloride (1.30 mL, 15.4 mmol, 1.10 eq) was added slowly. The reaction mixture was stirred at 23 °C for 1 hour and then cooled to 0°C. A solution of 2,6-dimethylaniline (1.70 mL, 14.02 mmol, 1.00 eq) and DIPEA (3.2 mL, 18.213 mmol, 1.300 eq) diluted in DCM (6.0 mL) was added dropwise and the reaction mixture was stirred at 23 °C for 1 hour. LCMS analysis after this time showed full conversion. The reaction mixture was hydrolyzed with water. The organic phase was washed with water, then with IM aqueous NaHCCh solution and finally with water. The resulting organic layer was concentrated under reduced pressure to afford the crude intermediate product as a clear oily residue. This crude product was purified by chromatography over silica gel, using heptane / EtOAc 9:1 as eluent to afford the intermediate product (1.40 g, 6.38 mmol, 46%) as a colorless liquid.

[0296] >H NMR (400 MHz, DMSO) 5 10.0, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 3.5, 3.5, 3.4, 3.4, 3.4, 2.1, 1.1, 1.1.

[0297] LC / MS m / z (M+H)+= 220.2

[0298] Step 2: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-3-methyl-butanamide In a 100 mL round bottom single neck glass flask was charged the previously prepared intermediate (1.40 g, 6.38 mmol, 1.00 eq) followed by MeCN (14.0 mL). At 23°C, aqueous hydroxylamine (2.00 mL, 31.9 mmol, 5.00 eq) was added and the reaction mixture was stirred at 50°C. After 5h, extra aqueous hydroxylamine (2.00 mL, 31.9 mmol, 5.00 eq) was added. The reaction mixture was stirred at 60°C for 1 hour, and then at 23 °C for 18 hours. Extra aqueous hydroxylamine (0.978 mL, 15.9 mmol, 2.50 eq) was added and the reaction mixture was stirred for 6 hours. The reaction was quenched by addition of water until crystallization occurred. Then, the mixture was stirred 30 minutes at 23 °C and the solid collected by filtration. The solid was washed with water and dried under vacuum at 45 °C for 18 hours to afford the desired product (1.09 g, 4.65 mmol, 73%) as a white crystalline powder (mixture of isomers, 99% qNMR assay).

[0299] >H NMR (400 MHz, DMSO) 5 11.5, 11.0, 9.6, 9.4, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 3.4, 3.4, 3.3, 3.3, 2.8, 2.8, 2.7, 2.7, 2.7, 2.2, 2.1, 1.2, 1.2, 1.2, 1.2.

[0300] LC / MS m / z (M+H)+= 220.2

[0301] Example 14-B: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-2-(4-methoxyphenyl)acetamide

[0302] Step 1 : N-(2,6-dimethylphenyl)-2-oxo-2-(4-methoxyphenyl)acetamide

[0303] To a solution of (4-methoxyphenyl)glyoxylic acid (986 mg, 5.20 mmol, 1.00 eq) in DCM (9.40 mL) and DMF (0.100 mL) was added slowly at 23°C oxalyl chloride (0.669 mL, 7.80 mmol, 1.50 eq). The reaction mixture was stirred at 23 °C for 1 hour and then cooled to 0°C. A solution of 2,6-dimethylaniline (0.640 mL, 5.20 mmol, 1.00 eq) and DIPEA (1.40 mL, 7.80 mmol, 1.50 eq) in DCM (4.7 mL) was added slowly to the reaction mixture and the solution was warmed to 23°C and stirred at this temperature for 30 minutes. LCMS analysis showed full conversion after this time. The reaction mixture was hydrolyzed with water and phases were separated. The organic layer was washed two times with water, then with a 1 M aqueous NaHCCL solution, and finally with water. Evaporation under reduced pressure afforded the intermediate product (1440 mg, 5.08 mmol, 98%) as an off-white powder.

[0304] >H NMR (400 MHz, CDCh) 5 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 7.1, 7.0, 7.0, 7.0, 7.0, 7.0, 7.0, 3.9, 2.3.

[0305] LC / MS m / z (M+H)+= 284.0

[0306] Step 2: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-2-(4-methoxyphenyl)acetamide

[0307] In a 100 mL round bottom glass flask, to a solution of the previously prepared intermediate (1.44 g, 5.08 mmol, 1.00 eq) in acetonitrile (16.2 mL) was added aqueous hydroxylamine (3.10 mL, 50.8 mmol, 10.0 eq) at 23 °C and reaction mixture was heated to reflux for 2 h. Extra aqueous hydroxylamine (1.60 mL, 25.4 mmol, 5.00 eq) was added and the reaction mixture stirred at 80°C for 2 hours. Extra aqueous hydroxylamine (1.60 mL, 25.4 mmol, 5.00 eq) was added and the reaction mixture was further stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a beige powder which was solubilized in EtOH (15.0 mL). To this solution was added hydroxylamine hydrochloride (0.177 g, 2.54 mmol, 0.500 eq) and titanium isopropoxide (0.756 mL, 2.54 mmol, 0.500 eq). The reaction mixture was heated at 45 °C for 18 h. The reaction mixture was cooled down near 20°C and hydrolyzed with 1 M aqueous HC1 and water to achieve crystallization. The suspension was stirred for 30 minutes at 23 °C and the solid collected by filtration and washed with water. The solid was dried in an oven at 45 °C overnight to afford the crude product (1.22 g, 4.09 mmol, 80%) as a beige powder. The crude product was stirred in a mixture of heptane / EtOAc 7:3, filtered and washed with heptane before drying in an oven at 45°C overnight to afford the desired product (1.12 g, 4.09 mmol, 81%) as an off-white powder (mixture of isomers, 96% qNMR assay).

[0308] >H NMR (400 MHz, DMSO) 5 11.9, 11.5, 9.9, 9.7, 7.7, 7.7, 7.6, 7.6, 7.6, 7.6, 7.6, 7.6, 7.6, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 7.0, 7.0, 7.0, 7.0, 3.8, 3.3, 2.3, 2.2.

[0309] LC / MS m / z (M+Na)+= 321.2

[0310] Example 15-B: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-2-[4-(trifluoromethyl)phenyl]acet- amide

[0311] Step 1 : N-(2,6-dimethylphenyl)-2-oxo-2-[4-(trifluoromethyl)phenyl]acetamide

[0312] To a solution of [4-(trifluoromethyl)phenyl]glyoxylic acid (950 mg, 4.14 mmol, 1.00 eq) in dichloromethane (9.0 mL) and DMF (0.100 mL) was added dropwise oxalyl chloride (0.532 mL, 6.21 mmol, 1.50 eq) at 23 °C. The reaction mixture was stirred for 5h at this temperature. Extra oxalyl chloride (0.355 mL, 4.14 mmol, 1.00 eq) was added and stirring at 23°C was pursued for 2 hours. The reaction mixture was cooled to 0°C and a solution of 2,6-dimethylaniline (0.510 mL, 4.14 mmol, 1.00 eq) and DIPEA (1.20 mL, 7.03 mmol, 1.70 eq) in dichloromethane (4.5 mL) was slowly added. LCMS analysis showed full conversion after 2h. The reaction mixture was hydrolyzed with water, phases were separated, the organic layer was washed two times with water, then with 1 M aqueous NaHCCh solution and finally with water. The resulting organic layer was concentrated under reduced pressure to afford the intermediate product (1100 mg, 3.42 mmol, 83%) as a green powder.

[0313] >H NMR (400 MHz, CDCh) 5 8.6, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.5, 8.4, 7.8, 7.8, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 2.3.

[0314] LC / MS m / z (M+H)+= 322.0

[0315] Step 2: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-2-[4-(trifluoromethyl)phenyl]acetamide

[0316] To a solution of the previously prepared intermediate (1.11 g, 3.46 mmol, 1.00 eq) in acetonitrile (10.4 mL) at 23 °C was added aqueous hydroxylamine (2.10 mL, 34.5 mmol, 10.0 eq). The reaction mixture was heated at 80°C and stirred at this temperature for 2 hours. LCMS analysis after this time showed limited conversion. Extra aqueous hydroxylamine (1.10 mL, 17.3 mmol, 5.00 eq) was added and stirring at 80°C was pursued. LCMS analysis showed 47% of expected product after 1.5h. Extra aqueous hydroxylamine (1.10 mL, 17.3 mmol, 5.00 eq) was added and stirring at 80°C was pursued. After another 1.5h, LCMS analysis showed no improvement. The reaction mixture was concentrated under reduced pressure to afford a beige powder, which was solubilized in EtOH (15.0 mL). To this solution was added hydroxylamine hydrochloride (0.072 g, 1.04 mmol, 0.300 eq) and titanium isopropoxide (0.308 mL, 1.04 mmol, 0.300 eq). This heterogeneous mixture was heated at 60°C for 18 h (clear solution). LCMS analysis after this time showed full conversion. The reaction mixture was cooled down near 20°C and hydrolyzed with water and HC1 IM inducing crystallization. The mixture was stirred for 30 minutes near 5-10°C, filtered, washed with water and dried under vacuum at 45°C for 18 hours to afford the crude product (0.814 g, 2.42 mmol, 70%) as a beige powder. This powder was stirred in a mixture of heptane / EtOAc 70:30 at 23°C, filtered, washed with heptane and dried under vacuum at 45°C for 18 hours to afford the desired product (565 mg, 2.42 mmol, 70%) as a beige powder (mixture of isomers, 95% qNMR assay).

[0317] >H NMR (400 MHz, DMSO) 5 12.4, 12.1, 10.1, 9.8, 7.9, 7.9, 7.9, 7.9, 7.9, 7.9, 7.8, 7.8, 7.8, 7.7, 7.1, 7.1, 7.1, 7.1, 3.3, 2.3, 2.2.13C NMR (101 MHz, DMSO) 5 162.1, 161.4, 151.8, 149.6, 136.3, 135.5, 135.3, 134.6, 134.1, 133.8, 130.2, 130.0, 129.6, 129.3, 129.0, 128.1, 127.8, 127.7, 126.9, 126.8, 126.4, 125.9, 125.8, 125.8, 125.8, 125.4, 124.8, 124.7, 122.7, 18.5, 18.1.

[0318] Example 16-B: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-3-phenyl-propanamide

[0319] Step 1: 2-hydroxyimino-3-phenyl-propanoic acid

[0320] To a solution of phenylpyruvic acid (1.08 g, 6.58 mmol, 1.00 eq) in 4N aqueous NaOH (5.00 mL, 20.0 mmol, 3.04 eq) was added hydroxylamine hydrochloride (0.630 g, 9.07 mmol, 1.38 eq) at 23 °C and the solution was stirred at this temperature for 2.5h. LCMS analysis after this time showed full conversion.The reaction mixture was quenched with 2N aqueous HC1, inducing a precipitation. The precipitate was collected by filtration and dried under vacuum at 45 °C overnight to afford the intermediate product (1.07 g, 79%) as a white solid. This product was used in the next step without any further purification.

[0321] Step 2: (2E / Z)-N-(2,6-dimethylphenyl)-2-hydroxyimino-3-phenyl-propanamide

[0322] In a 8mL vial was introduced the previously prepared intermediate combined with another batch (obtained using similar procedures, 1.59 g in total, 0.009 mol, 1.00 eq) followed with DCM (40.0 mL), 2,6- dimethylaniline (1.20 mL, 0.010 mol, 1.08 eq) and NMI (1.10 mL, 0.014 mol, 1.55 eq). To this solution was added 2-chloro-l,3-dimethylimidazolinium chloride (1.80 g, 0.011 mol, 1.20 eq) and the solution was stirred at 23 °C for 2 h. LCMS analysis after this time showed incomplete conversion. NMI (0.550 mL, 0.007 mol, 0.778 eq) and DMC (0.950 g, 0.006 mol, 0.633 eq) were added to the reaction mixture and stirring at 23°C was pursued for Ih. LCMS analysis after this time showed 78% conversion. NMI (0.550 mL, 0.007 mol, 0.778 eq) was added to the reaction mixture and stirring at 23°C was pursued for Ih. LCMS analysis showed full conversion after this time. The reaction mixture was quenched with water, phases were separated, and the organic layer was washed with saturated aqueous NH4CI, then saturated aqueous NaHCCL solution and finally with brine. The organic layer was dried over NaiSCh. filtered and evaporated under reduced pressure to afford the crude product as a yellow oil. This residue was purified by flash chromatography (40g SiCL). eluting with heptane / EtOAc 1 / 0 to 7 / 3 to afford the purified product as a yellow solid. This solid was triturated with 4 mL of DIE for 15 minutes, collected by filtration and dried under vacuum at 45 °C overnight to afford the desired product (350 mg, 1.20 mmol, 12%) as an off- white solid (82% qNMR assay).

[0323] 'H NMR (400 MHz, DMSO) 5 12.0, 9.4, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.3, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 7.0, 3.9, 2.1.

[0324] Example 17-B: (2E / Z)-2-hydroxyimino-N-(2-methylindol-l-yl)propanamide

[0325] Step 1: 2-methylindol-l-amine

[0326] In a 4 L double jacketed glass reactor, 2-methylindole (45.0 g, 0.34 mol, 1.0 eq) was dissolved in DMF (450 mL) and this solution was cooled to 5°C. Under mechanical stirring and nitrogen stream, Sodium tert-pentoxide (188.9 g, 1.71 mol, 5.0 eq) and hydroxylamine-O-sulfonic acid (77.6 g, 0.69 mol, 2.0 eq) were added in 10 equal parts over 2h and the internal temperature was allowed to return to 5 °C before the next fractions of both reagents were added. While maintaining the temperature below 20°C, cold water (2.7 L) was slowly added: a solid began to precipitate. The suspension was stirred at 20°C for 2 h then filtered and the obtained solid was washed thoroughly with water to neutral pH and colorless liquors then dried under vacuum (40°C) overnight to give 27 g of a brown solid. This crude product was combined with previous batches (53 g) and was purified by flash chromatography eluting with DCM / Heptane 50 / 50 then DCM / EtOAc 95 / 5. The purest fractions were combined and evaporated to dryness to give 2-methyl- IH-indol-l -amine (32 g, 0.22 mol, 32%) as a pale yellow crystalline solid.

[0327] 'H NMR (400 MHz, DMSO) 57.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.1, 7.1, 7.0, 7.0, 7.0, 7.0, 7.0, 7.0, 6.9, 6.9, 6.9, 6.9, 6.9, 6.9, 6.1, 6.1, 6.1, 5.6, 2.4, 2.4.

[0328] LC / MS m / z (M+H)+= 146.9

[0329] Step 2: (2E)-N-(2-methylindol-l-yl)-2-(2-methylindol-l-yl)imino-propanamide To a solution of pyruvic acid (1.90 mL, 0.027 mol, 0.500 eq) in DCM (40 mL) was slowly added oxalyl chloride (2.30 mL, 0.027 mol, 0.500 eq) and the reaction mixture was stirred at 23°C for 2 hours. This solution was then added to a solution of 2-methyl-l -aminoindole (8.00 g, 0.055 mol, 1.00 eq) and triethylamine (11.4 mL, 0.082 mol, 1.50 eq) in dichloromethane (60 mL) at 0 °C. The solution was warmed to 23 °C and stirred at this temperature for 18 hours. LCMS analysis after this time showed complete conversion. The reaction mixture was quenched with 150 mL of water. Phases were separated and the organic layer was washed with 150 mL of 2 M aqueous NaOH, then 50 ml of 2M aqueous NaOH. The organic layer was evaporated to dryness to afford the intermediate product (3.30 g, 0.010 mol, 18%) as a red oil. This product was used in the next step without any further purification.

[0330] Step 3: (2E / Z)-2-hydroxyimino-N-(2-methylindol-l-yl)propanamide

[0331] To a solution of the previously prepared intermediate (3.30 g, 0.010 mol, 1.00 eq) in acetonitrile (30 mL) at 50°C was slowly added aqueous hydroxylamine (5.00 mL, 0.082 mol, 8.52 eq). The solution was stirred at this temperature for 1 h. LCMS analysis after this time showed incomplete conversion. Extra aqueous hydroxylamine (2.50 mL, 0.041 mol, 4.26 eq) was added and the reaction mixture was stirred at 23°C for 48h. LCMS analysis after this time showed complete conversion. The reaction mixture was quenched with 100 mL of IN HC1. Phases were separated and the aqueous phase was extracted with 100 mL of MeTHF. The organic layer was washed with 50mL of water and then concentrated to obtain an orange oil . This oil was solubilized in 20 mL of acetonitrile and 75 mL of DIE. A precipitate appeared and was eliminated by filtration. The filtrate was evaporated under reduced pressure and the residue was purified by chromatography on silica gel eluting with heptane / EtOAc 8 / 3 to afford the desired product (0.450 g, 0.002 mol, 20%) as a yellow powder (89%, qNMR assay).

[0332] 'H NMR (400 MHz, DMSO) 5 12.1, 11.1, 7.5, 7.5, 7.5, 7.4, 7.4, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 7.0, 7.0, 7.0, 7.0, 7.0, 7.0, 7.0, 7.0, 6.3, 6.3, 6.3, 2.2, 2.2, 2.0.

[0333] 13C NMR (101 MHz, DMSO) 5 163.8, 149.3, 137.0, 136.0, 125.6, 120.8, 119.7, 119.4, 108.4, 98.0, 11.2, 9.8.

[0334] Example 18-B: (2E / Z)-N-(2,5-dimethylpyrrol-l-yl)-2-hydroxyimino-propanamide

[0335] Step 1: (2E / Z)-2-hydroxyimino- propanoic acid

[0336] To a solution of aqueous hydroxylamine (4.00 mL, 0.065 mol, 4.54 eq) was added pyruvic acid (1.00 mL, 0.014 mol, 1.00 eq). A precipitate formed rapidly, and water (4.0 mL) was added to improve stirring. The reaction mixture was stirred at 23 °C for 4 h, then the reaction mixture was quenched with 6 N HC1. The solution was then extracted with 3x 20 mL of EtOAc. The combined organic layers were dried over NaiSO-i. filtered and evaporated under vacuum to afford the intermediate product (1.34 g, 0.013 mol, 90%) as a white solid. This product was used in the next step without any further purification.

[0337] Step 2: Benzyl N-(2,5-dimethylpyrrol-l-yl)carbamate

[0338] In a 10 L double jacketed reactor, benzyl hydrazinecarboxylate (800.0 g, 4.81 mol, 1.0 eq) was dissolved in EtOH (7.2 L) and AcOH (800.0 mL, 13.97 mol, 2.9 eq). Then 2,5-hexanedione (690.1 mL, 5.88 mol, 1.2 eq) was added dropwise at 23 °C (exotherm to 32°C). The reaction mixture was stirred at 35-40°C. An aliquot was taken after 18 h, diluted with MeOH, and analyzed by HPLC / MS. LCMS analysis after this time showed complete conversion. EtOH was removed under reduced pressure to a total volume of 4 L, then at 30°C water (4 L) was added. The reaction mixture was stirred at 70°C until complete solubilization and the obtained solution was allowed to cool down to 23°C leading to crystallization; the suspension was stirred at 23 °C for 18h. The solid was collected by filtration, washed three times with 1.5 L of water and dried under vacuum (45°C) for 48 h to yield benzyl (2,5-dimethyl-lH-pyrrol-l-yl)carbamate (1129.0 g, 4.62 mol, 96%) as a pale pink solid.

[0339] 'H NMR (400 MHz, DMSO) 5 10.3, 7.4, 7.4, 7.4, 7.4, 7.4, 7.3, 7.3, 7.2, 5.6, 5.2, 5.1, 2.0.

[0340] LC / MS m / z (M+H)+= 245.0

[0341] Step 3: 2,5-Dimethylpyrrol-l-amine In a pressure reactor was charged benzyl (2,5-dimethyl-lH-pyrrol-l-yl)carbamate (50.0 g, 204.6 mmol, 1.0 eq) in THF (400.0 mL) then Pd / C 5% (20 g, 50% wet) was added under nitrogen stream. The reaction mixture was stirred at 23°C under 2.5 bars of hydrogen. The reaction mixture was then stirred at 23°C under 4 bars of hydrogen for further 20h. The reaction mixture was filtered over celite cake. The cake was washed with THF (2 x lOOmL) and the filtrate was evaporated to dryness. The sticky solid obtained was taken-up in Heptane (100 mL) and the suspension was stirred at 23 °C for Ih. The solid was collected by filtration and dried under vacuum (35 °C) for 18 h to give 16 g of pure product. The filtrate was evaporated to dryness and after trituration in heptane (20 mL), another batch of product (2.8 g) was obtained. The two solids were combined to give 2,5-dimethylpyrrol-l -amine (18.8 g, 170.7 mmol, 83%) as a white solid.

[0342] >H NMR (400 MHz, DMSO) 5 5.5, 5.2, 2.1.

[0343] LC / MS m / z (M+H)+= 110.9

[0344] Step 4: (2E / Z)-N-(2,5-dimethylpyrrol-l-yl)-2-hydroxyimino-propanamide

[0345] To a solution of the previously prepared intermediate (1.00 g, 0.010 mol, 1.00 eq) and 2,5-dimethylpyrrol- 1-amine (1.28 g, 0.012 mol, 1.20 eq) and NMI (1.50 mL, 0.019 mol, 2.00 eq) in DMF (45.0 mL) was added DMC (2.46 g, 0.015 mol, 1.50 eq) and the solution was stirred at 23 °C for 2 hours. LCMS analysis after this time showed incomplete conversion. Extra NMI (0.750 mL, 0.009 mol, 0.970 eq) and DMC (1.00 g, 0.006 mol, 0.610 eq) were added and the reaction mixture was stirred at 23°C for 18 h. The reaction mixture was diluted with 200 mL of water and extracted with 200 mL of EtOAc. The organic layer was washed with a 2N aqueous HC1 solution, dried over NaiSOr. filtered and concentrated to afford crude product (1.40 g) as brown oil. This crude residue was purified by flash chromatography over silica gel (24 g) eluting with DCM / MeOH 1 :0 to 95:5. Purest fractions were combined and evaporated to dryness to afford the desired product (0.115 g, 0.001 mol, 6%) as white solid. This solid was combined with another batch obtained according to a similar process to afford desired product (0.157 g,) as a beige solid.

[0346] >H NMR (400 MHz, DMSO) 5 12.1, 10.8, 5.6, 2.0, 1.9.

[0347] LC / MS m / z (M+H)+= 196.0

[0348] Example 19-B: (2E / Z)-N-(2,5-dimethylpyrrol-l-yl)-2-hydroxyimino-2-phenyl-acetamide

[0349] Step 1: (2E / Z)-2-hydroxyimino-2-phenyl-acetic acid

[0350] To a solution of phenylglyoxylic acid (1.41 g, 0.009 mol, 1.00 eq) in 4N NaOH (5.00 mL, 0.020 mol, 2.13 eq) was added hydroxylamine hydrochloride (0.783 g, 0.011 mol, 1.20 eq) at 23 °C. The reaction mixture was stirred at 23°C until LCMS analysis showed complete conversion. After Ih, the reaction mixture was quenched with 6 N aqueous HC1. The mixture was extracted with EtOAc (3x 20 mL), dried over NaiSOr. filtered and dried under vacuum to afford the crude intermediate product (1.44 g, 0.009 mol, 93%) as a white solid.

[0351] >H NMR (400 MHz, DMSO) 5 13.0, 12.3, 7.41, 7.40, 7.39, 7.38.

[0352] LC / MS m / z (M+H)+= 165.9

[0353] Step 2: (2E / Z)-N-(2,5-dimethylpyrrol-l-yl)-2-hydroxyimino-2-phenyl-acetamide

[0354] To a solution previously prepared intermediate (1.44 g, 0.009 mol, 1.00 eq) and 2,5-dimethylpyrrol-l- amine (1.10 g, 0.010 mol, 1.15 eq) in DMF (40.0 mL), was added N-methylimidazole (1.40 mL, 0.017 mol, 2.00 eq) followed by 2-chloro-4,5-dihydro-l,3-dimethyl-lH-imidazolium chloride (2.21 g, 0.013 mol, 1.50 eq) and the solution was stirred at 23 °C for 2 h. LCMS analysis after this time showed incomplete conversion. Extra N-methylimidazole (0.700 mL, 0.009 mol, 1.01 eq) and 2-chloro-4,5- dihydro-l,3-dimethyl-l / 7-imidazolium chloride (1.00 g, 0.006 mol, 0.678 eq) were added to the reaction mixture, which was stirred at 23 °C for 18 h. The reaction mixture was diluted with 200 mL of water and extracted with 200 mL of EtOAc. The organic layer was washed with a 2N aqueous HC1 solution, dried over NaiSO-i. filtered and concentrated to afford crude product as a brown oil. The crude oil was purified by flash chromatography over SiOz eluting with DCM / MeOH 1 :0 to 95:5. Purest fractions were combined and evaporated under reduced pressure to afford the desired product (0.190 g, 0.001 mol, 9%) as white solid (90% qNMR assay).

[0355] >H NMR (400 MHz, DMSO) 5 12.3, 11.1, 7.6, 7.6, 7.6, 7.6, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 7.4, 5.7, 2.1.

[0356] LC / MS m / z (M+H)+= 257.9 Example 20-B: (2E / Z)-2-(2,6-dimethylphenyl)-N-(2,5-dimethylpyrrol-l-yl)-2-hydroxyimino-acet- amide

[0357] Step 1: 2-(2,6-dimethylphenyl)-N-(2,5-dimethylpyrrol-l-yl)-2-oxo-acetamide

[0358] In a three-neck round-bottom flask, 2-(2,6-dimethylphenyl)-2-oxoacetic acid (2.00 g, 11.2 mmol, 1.00 eq) and 2,5-dimethyl-lH-pyrrol-l-amine (1.11 g, 10.1 mmol, 0.90 eq, prepared in analogy to Hartwig et al., Angew. Chem. Int. Ed. 2021, 60, 8203-8211) were solubilized in toluene (25.3 mL). At 23°C, triethylamine (3.90 mL, 28.0 mmol, 2.50 eq) then a 50% solution of T3P in DMF (17.2 mL, 28.0 mmol, 2.50 eq) were added and the reaction mixture was stirred at 105°C for Ih leading to complete conversion. At 23 °C, water (25 mL) was added. After phase separation, organic layer was washed once with a saturated aqueous solution of NaHCCh. then water and evaporated to dryness. The crude product obtained was stirred in a mixture DIE / heptane 9 / 1 and the product was isolated by filtration to afford the desired product (1.74 g, 6.4 mmol, 57%) as an off-white solid.

[0359] 'H NMR (400 MHz, DMSO) 5 11.9, 7.3, 7.3, 7.3, 7.3, 7.2, 7.1, 5.7, 2.2, 2.0.

[0360] LC / MS m / z (M+H)+= 270.7

[0361] Alternative route

[0362] A solution of 50% T3P in EtOAc (201.5 mL, 329.06 mmol, 2.5 eq) was added dropwise over 15 min to a solution at 45°C of 2-(2,6-dimethylphenyl)-2-oxoacetic acid (25.8 g, 144.79 mmol, 1.1 eq), 2,5- dimethylpyrrol-1 -amine (14.5 g, 131.63 mmol, 1.0 eq) and triethylamine (45.8 mL, 329.07 mmol, 2.5 eq) in toluene (350.0 mL). The reaction mixture was stirred at 45°C. While cooling with an ice bath, saturated aqueous solution of NaHCCh (300 mL) was added dropwise then EtOAc (300 mL). After phase separation, organic layer was washed twice with saturated aqueous solution of NaHCCh (until pH of aqueous layer was pH=8), then with brine, dried over sodium sulfate, filtered, and evaporated to dryness. The crude was taken-up in heptane. The obtained suspension was stirred for 20 min at 23 °C then the solid was collected by filtration and dried under vacuum (40°C) for 18 h to give N-(2,5-dimethylpyrrol-l-yl)-2-(2,6- dimethylphenyl)-2-oxoacetamide (34.1 g, 126.14 mmol, 96%) as a yellow solid.

[0363] >H NMR (400 MHz, DMSO) 5 11.9, 7.3, 7.3, 7.3, 7.3, 7.2, 7.1, 5.7, 2.2, 2.0.

[0364] LC / MS m / z (M+H)+= 270.7 Step 2: (2E / Z)-2-(2,6-dimethylphenyl)-N-(2,5-dimethylpyrrol-l-yl)-2-hydroxyimino-acetamide

[0365] Hydroxylamine hydrochloride (0.490 g, 7.10 mmol, 1.10 eq) then titanium(IV) isopropoxide (7.70 mL, 25.8 mol, 4.00 eq) were added to a solution of 2-(2,6-dimethylphenyl)-N-(2,5-dimethylpyrrol-l-yl)-2- oxo-acetamide (1.74 g, 6.4 mmol, 1.00 eq) in EtOH (31 mL). The reaction mixture was stirred at 80°C for 18 h. Hydroxylamine hydrochloride (89.0 mg, 1.28 mmol, 0.20 eq) was added and reaction mixture was stirred at 80°C for further 18 h leading to 86% of conversion. Reaction mixture was concentrated under vacuum then 2-MeTHF and 2N aqueous HC1 were added. After phase separation, organic layer was concentrated under vacuum to give crude product as an orange oil. The crude product was dissolved iPrOH and activated charcoal was added. The suspension was stirred at 50°C for 15min then filtered. The filtrate was concentrated under vacuum and purified by flash chromatography eluting with toluene / EtOAc 90 / 10. The purest fractions were combined and evaporated to dryness to afford the desired product (170 mg, 0.600 mmol, 9%) as a beige solid (mixture of isomers, 88% qNMR assay).

[0366] Alternative route

[0367] DIPEA (30.9 mL, 0.18 mol, 1.5 eq) was added to a suspension of N-(2,5-dimethylpyrrol-l-yl)-2-(2,6- dimethylphenyl)-2-oxoacetamide (32.0 g, 0.12 mol, 1.0 eq) and hydroxylamine sulfate (29.1 g, 0.18 mol, 1.5 eq) in EtOH (640.0 mL). The reaction mixture was stirred at 20°C for 15 min before the addition of titanium(IV) isopropoxide (88.1 mL, 0.30 mol, 2.5 eq); slight exotherm was observed, temperature increased from 20°C to 27°C. The reaction mixture was then stirred at reflux. EtOH was partially removed under vacuum (-80%) then EtOAc (750 mL) and aqueous HC1 2N (500 mL) were added: heterogeneous then homogeneous biphasic solution upon stirring was obtained. After phase separation, organic layer was washed once with aqueous HC1 0.5N (400 ml), with water (400 ml), then with brine (400 mL), dried over NaiSO-i. filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography over SiCL (300 g) eluting with DCM / MeOH 100:0 to 95 / 5. Purest fractions were combined and evaporated under reduced pressure to afford a beige solid. This solid was taken-up in DIE (150 mL). The suspension was stirred for 20 min and the solid was collected by filtration and dried under vacuum (35°C) for 20 h to afford N-(2,5-dimethylpyrrol-l-yl)-2-(2,6-dimethylphenyl)-2- (hydroxyimino)acetamide (26.0 g, 91.0 mmol, 77%) as a beige solid (mixture of isomers 82:18).

[0368] 'H NMR (400 MHz, DMSO) 5 12.2, 11.1, 7.2, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 5.7, 2.1, 2.0.

[0369] LC / MS m / z (M+H)+= 285.9 Example 21-B: (2E / Z)-2-hydroxyimino-N-(2-methylindol-l-yl)-2-phenyl-acetamide

[0370] Step 1: N-(2-methylindol-l-yl)-2-oxo-2-phenyl-acetamide

[0371] In a 250 mL round-bottom glass flask, oxalyl chloride (7.90 mL, 0.092 mol, 1.60 eq) was added dropwise to a solution at 5°C of phenylglyoxylic acid (8.60 g, 0.057 mol, 1.00 eq) and few drops of DMF in DCM (100 mL); a slight gas release was observed. The reaction mixture was stirred at 20°C for 30 min then concentrated to dryness to afford a yellow liquid. At the same time, in a 250 mL round-bottom glass flask, 2-methyl-lH-indol-l -amine (8.34 g, 0.057 mol, 1.00 eq) and DIPEA (29.9 mL, 0.170 mol, 3.00 eq) were solubilized in DCM (100 mL). To this clear solution cooled at 10°C was added dropwise the previously prepared acyl chloride solution in DCM (50 mL). At the end of the addition, the ice bath was removed, and the solution was stirred at 23 °C for 20min then water was added. After phase separation, organic layer was washed with water, dried over sodium sulfate, filtered and concentrated to dryness to afford the crude product as a purple oil. The purification of the crude product was performed on silica gel chromatography eluting with DCM / heptane 60 / 40. The purest fractions were combined and concentrated to dryness to afford the crude intermediate (0.650g, 2.34 mmol, 4%). This product was used in the next step without any further purification.

[0372] Step 2: (2E / Z)-2-hydroxyimino-N-(2-methylindol-l-yl)-2-phenyl-acetamide

[0373] In a 25 mL round-bottom glass flask, hydroxylamine hydrochloride (195 mg, 2.80 mmol, 1.20 eq) was added to a mixture of the previously obtained intermediate (650 mg, 2.34 mmol, 1.00 eq) and sodium acetate (249 mg, 3.04 mmol, 1.30 eq) in EtOH (10.0 mL). The yellow suspension obtained was stirred at 80°C for 2 h then at 20°C overnight. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The remaining oily residue was solubilized in EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to give crude product as an orange oil. The product was purified by crystallization in a mixture EtOAc / heptane. The obtained solid was dried under vacuum (40°C) for 18 h to afford the desired product (480 mg, 1.64 mmol, 70%) as a beige solid (mixture of isomers, 98% qNMR assay). 'H NMR (400 MHz, DMSO) 5 12.4, 12.2, 11.7, 11.4, 7.7, 7.7, 7.7, 7.7, 7.7, 7.7, 7.6, 7.6, 7.6, 7.6, 7.6, 7.6, 7.6, 7.6, 7.6, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 7.3, 7.3, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 7.0, 6.3, 6.3, 6.3, 2.4, 2.3.

[0374] LC / MS m / z (M+H)+= 293.9

[0375] Example 22-B: (2E / Z)-2-(2,6-dimethylphenyl)-2-hydroxyimino-N-(2-methylindol-l-yl)acetamide

[0376] Step 1: 2-(2,6-dimethylphenyl)-N-(2-methyl-lH-indol-l-yl)-2-oxoacetamide

[0377] In a 500 mL round bottom flask, 2-(2,6-dimethylphenyl)-2-oxoacetic acid (3.70 g, 0.021 mol, 1.00 eq) and 2-methyl-lH-indol-l -amine (2.73 g, 0.019 mol, 0.90 eq) were solubilized in toluene (47 mL). To this solution was added triethylamine (7.20 mL, 0.052 mol, 2.50 eq) then a 50% solution of T3P in DMF (31.8 mL, 0.052 mol, 2.50 eq). The reaction mixture was stirred at 105°C for 30 min leading to complete conversion. At 23°C, water (100 mL) and a saturated aqueous solution of NaHCCh were added. After phase separation, organic layer was evaporated to dryness. The crude product obtained as a yellow solid was taken-up in a mixture of DIE (6 mL) and heptane (50 mL) and the suspension was stirred at 23 °C for 1 h then filtered to afford crude intermediate (5.40 g, 0.018 mol, 85%) as a yellow solid.

[0378] Step 2: (2E / Z)-2-(2,6-dimethylphenyl)-2-hydroxyimino-N-(2-methylindol-l-yl)acetamide

[0379] Hydroxylamine hydrochloride (1.35 g, 0.019 mol, 1.10 eq) then titanium(IV) isopropoxide (21.0 mL, 0.071 mol, 4.00 eq) were added to a solution of 2-(2,6-dimethylphenyl)-N-(2-methyl-lH-indol-l-yl)-2- oxoacetamide (5.40 g, 0.018 mol, 1.00 eq) in EtOH (85.3 mL). The reaction mixture was stirred at 80°C for 18 h. The reaction mixture was concentrated under vacuum then 2-MeTHF (100 mL) and IM aqueous HC1 (100 mL) were added. After phase separation, organic layer was washed once with water, then evaporated to dryness. The crude product containing one major impurity was recrystallized in a mixture iPrOH / water but upon heating the solution turned black (degradations observed in LC). Activated charcoal was added and the suspension was filtered to recover 2.6 g of crude product which was recrystallized in a mixture iso-propanol (22 mL) and DIE (44 mL) to give 2-(2,6-dimethylphenyl)-2-(hydroxyimino)-N-(2- methyl-lH-indol-l-yl) acetamide (0.780 g, 0.002 mol, 14%) as pure product. Previous batches obtained according to a similar process (0.300 g) were combined to give a total of 1.10 g of product. The mixed solids were stirred in DIE for 10 min then dried under vacuum at 45 °C for 18 hours to afford desired product (1.10 g) as a beige solid (93% qNMR assay).

[0380] >H NMR (400 MHz, DMSO) 5 12.3, 11.4, 7.5, 7.5, 7.5, 7.5, 7.4, 7.4, 7.2, 7.2, 7.2, 7.2, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.1, 7.0, 7.0, 7.0, 7.0, 7.0, 7.0, 7.0, 6.3, 2.3, 2.3, 2.2, 2.2.

[0381] LC / MS m / z (M+H)+= 321.9

[0382] A-3.3 Hydroxylation Reactions

[0383] A-3.3.1 Evaluation of different Ligands for the Copper-catalyzed hydroxylation

[0384] X = I, Br, Cl General Procedure for Copper-catalyzed Hydroxylation of l-bromo-3-chloro-2-fluoro-benzene

[0385] A 10 mL vial equipped with a magnetic stirrer was charged with l-bromo-3-chloro-2-fluoro-benzene (200 mg), copper(I) chloride (9 mg, 10 mol%), ligand (20 mol%), NaOH (115 mg, 3 equiv), l-methoxy-2- propanol / HiO (1:1, 1 mL) and capped with a septum cap. After stirring the mixture for 24 hours at 100 °C, 2 mL of a stock solution of internal standard, benzoic acid, in DMSO was added. Based on a three- point calibration of the isolated, pure product against the internal standard, the yield of each reaction was quantified by UPLC-MS measurement and analysis.

[0386] Table 1. Evaluation of different Ligands for the Copper-catalyzed Hydroxylation Reaction

[0387] * Quantified Yield [%] by HPLC calibration against internal standard benzoic acid

[0388] A-3.3.2 Scale-up of Copper-catalyzed hydroxylation Reaction

[0389] Table 2. Scale-up of Copper-catalyzed Hydroxylation Reaction of Aryl-Br

[0390] * Quantified Yield [%] by HPLC calibration against external standard.

[0391] General Procedure for initial scale-up experiments with l-bromo-3-chloro-2-fluoro-benzene A 50 mL flask equipped with a magnetic stirrer and a reflux condenser was charged with CuCI (0.010 g, 0.10 mmol, 0.010 eq.) and ligand (0.030 mmol, 0.030 eq.). After purging with argon for 30 min, a solution of l-bromo-3-chloro-2-fluorobenzene (2.1 g, 10 mmol, 1.0 eq.) in 9.0 mL PGME was added at room temperature. After addition of aqueous sodium hydroxide (12% w / w, 10 g, 3.0 eq.), the reaction mixture was heated to 110 °C (block temperature). After 24 h the reaction was cooled to room temperature and analyzed by quantitative HPLC.

[0392] General Procedure for initial scale-up experiments with l,3-dichloro-2-fluoro-benzene

[0393] A 50 mL flask equipped with a magnetic stirrer and a reflux condenser was charged with CuCI (0.049g, 0.50 mmol, 0.050 eq.) and ligand (1.00 mmol, 0.100 eq.). After purging with argon for 30 min, a solution of l,3-dichloro-2-fluoro-benzene (1.65 g, 10.0 mmol, 1.00 eq.) in 9.0 mL PGME was added at room temperature. After addition of aqueous sodium hydroxide (12% w / w, 10 g, 3.0 eq.), the reaction mixture is heated to 110 °C (block temperature). After 24 h the reaction was cooled to room temperature and analyzed by quantitative HPLC.

Claims

CLAIMS:

1. Use of a compound of formula (I),whereinR1is hydrogen, Ci-Cr-alkyl, phenyl or benzyl, wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy,R2is phenyl, naphthyl, pyrrolyl or indolyl, wherein phenyl, naphthyl, pyrrolyl and indolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, phenyl and phenoxy,R3is hydrogen, characterized in that it is used as a ligand for copper-catalyzed coupling reaction of a (hetero)aryl halide, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl chloride, (hetero)aryl bromide, (hetero)aryl iodide, and the combinations thereof.

2. The use according to claim 1 , wherein the compound of formula (I) is selected from the group consisting of3. The use according to claim 1 or 2, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, copper thiophene-2-carboxylate (CuTc), Cu(0Ac)2, CuSOr, CuSOr x 5 H2O, CU2O, CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2, Cu(MeCN)4BF4, Cu(OEt)2, copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) (Cu(TMHD)2) and combinations thereof.

4. The use according to any one of claims 1 to 3, wherein the compound of formula (I) is selected from the group consisting ofwherein the (hetero)aryl halide is an aryl bromide and wherein the copper source is selected from the group consisting of Cui and CuCl.

5. A method of a coupling reaction of a (hetero)aryl halide for the formation of C-O-bonds via copper-catalyzed reaction of (hetero)aryl halides, wherein the (hetero)aryl halide is selected from the group consisting of (hetero)aryl bromides and (hetero)aryl iodides, using a catalyst system comprising a copper source, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, Cu(MeCN)4BF4, Cu(OAc)z, CuSC>4, CuSC>4 x 5 H2O, CU2O, Cu(OEt)2, copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) (Cu(TMHD)2), CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2 and combinations thereof, a compound of formula (I), wherein the compound of formula (I) is selected from the group consisting ofas a ligand, a hydroxylating agent, optionally a suitable base and a suitable solvent.

6. The method according to claim 5, wherein the compound of formula (I) is selected from the group consisting ofThe method according to claims 5 or 6, wherein the copper is selected from the group consisting of the copper source is CuCl, Cui or CuBri.

7. Method according to any one of claims 5 to 7, wherein the hydroxylating agent is selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide, or a combination of water and alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal phosphates such as potassium phosphate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate.

8. Method according to any one of claims 5 to 8, wherein the ratio of compound of formula (I) to copper source is in the range from 10:1 to 1:5, preferably in the range of 5:1 to 1:2, more preferably, in the range of 3:1 to 1:1.

9. Process for the preparation of a compound of the general the formula (II)(II), wherein n is 1, 2 or 3, R4is halogen, characterized in that a compound of formula (III)(HI), wherein R4is as defined above andX is chloro, bromo or iodo, is reacted in a suitable solvent in the presence of a copper source, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, Cu(OAc)2, CuSOr, CuSOr x 5 H2O, CU2O, CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2, and combinations thereof, a compound of formula (I), wherein the compound of formua (I) is selected from the group consisting ofas a ligand and optionally a suitable base with a hydroxylating agent, wherein the hydroxylating agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide.

0. Process according to claim 10 for the preparation of a compound of the general the formula (II-characterized in that a compound of formula (III- A)(III-A), whereinX is chloro, bromo or iodo, is reacted in a suitable solvent in the presence of a copper source, wherein the copper source is selected from the group consisting of CuCl and Cui, a compound of formula (I), whereinas a ligand with a hydroxylating agent, wherein the hydroxylating agent is sodium hydroxide.

11. Compound of formula (I)wherein the compound of formula (I) is selected from the group consisting of12. Compound of formula (I) according to claim 12, wherein the compound of formula (I) is selected from the group consisting of13.wherein R1and R2are defined as in any one of claims 10 to 12, characterized in that a compound of formula (IV)(IV), wherein R1is defined as before andT1is hydroxy, halogen or (Ci-C4)alkoxy, is reacted in the presence of a suitable base, optionally in the presence of a suitable coupling reagent, with an amine of formula (V)2R — N H2(V), wherein R2is defined as before, to yield a compound of formula (VI)(VI), wherein R1and R2are defined as before, which is then reacted with a compound of formula (VII)wherein R3is defined as before.

14. A catalyst system for aryl coupling reaction forming C-0 bonds, comprising a copper source, wherein the copper source is selected from the group consisting of Cui, CuBr, CuCl, CuTc, CU(0AC)2, CUSC>4, CUSC>4 x 5 H2O, CU2O, CuBr2, CuCh, CuO, CuSCN, CuCN, Cu(acac)2, Cu(MeCN)4BF4, Cu(OEt)2, copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) (Cu(TMHD)2) and combinations thereof, a ligand of formula (I) as defined according to claim 12 or 13, a hydroxylating agent, wherein the hydroxylating agent is selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide, or a combination of water and alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metal phosphates such as potassium phosphate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate and a solvent wherein the solvent is selected from the group consisting of 1,4-dioxane, 1,2- dimethoxyethane (DME), tetrahydrofuran (THF), alcohols such as methanol, ethanol, tertbutanol, 1 -butanol, l-methoxy-2-propanol, cyclohexanol and isopropanol, other solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidon (NMP), acetonitrile and water and / or combinations thereof.

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