Continuous deoxyfluorination of ketones using in SITU formed dast

Abstract

The present invention relates to a method for continuous deoxyfluorination of ketones with the fluorination reagent diethylaminosulfur trifluoride (DAST) which is prepared continuously in situ from SF4.

Description

Our Ref. : LZA32043PCT 1 TITLE OF THE INVENTION CONTINUOUS DEOXYFLUORINATION OF KETONES USING IN SITU FORMED DAST FIELD OF THE INVENTION The present invention relates to a method for continuous deoxyfluorination of ketones with the fluorination reagent diethylaminosulfur trifluoride (DAST) which is prepared continuously in situ from SF4. BACKGROUND OF THE INVENTION Fluorinated organic compounds are used as pharmaceutically active substances and as agrochemicals. Umemoto et al, Journal of Fluorine Chemistry (2012), 140, 17-27, discloses the conversion of cyclohexanone in the presence of HF-pyridine with the fluorinating agent phenylsulfur trifluoride, which was in situ generated from phenyl sulfur chlorotetrafluoride and pyridine, with a yield of 94% of 1,1-difluorocyclohexane (run 6 in table 2). Phenylsulfur trifluoride requires additional steps for its preparation likewise the preparation of HF-pyridine. The handling of pyridine is not desired. Umemoto et al. in J. AM. CHEM. SOC.2010, 132, 18199–18205, discloses conversion of ethyl-4-oxocyclohexanecarboxylate with 1.5 eq Fluolead™ (4-tert- butyl-2,6-dimethylphenylsulfur trifluoride) with a yield of 81% and a of 99 / 1 ratio of geminal difluoro (called herein RCF2) / vinylfluoro (called herein RCF) (run 3 table 2). The conversion was done in the presence of 0.4 eq HF-pyridine. Fluolead™ was prepared from 1-tert-butyl-3,5-dimethylbenzene by reaction with an equivalent amount of S2Cl2in acetic acid at room temperature in the presence of a catalytic amount of ZnCl2 for 4 h to produce bis(4-tert-butyl-2,6- dimethylphenyl) disulfide (2k), which then was converted by oxidation with Cl2 / KF to Fluolead™ (1k).Our Ref. : LZA32043PCT 2 The disclosed reactions have various disadvantages: The fluorinating agent such as phenylsulfur trifluoride or Fluolead™ needs to be prepared in more than one separate steps; some procedures use pyridine of HF-pyridine which requires separate preparation and generates additional waste which needs to be treated, the handling of pyridine is in general not welcome due to its smell and potential hazardousness. Other disclosures show rather high content of the undesired vinyl fluoride byproduct (RCF). For example Haycock at al. in Organic Process Research & Development 2008, 12, 1094–1103, discloses (point 2.2. and Scheme 5) the conversion of ethyl-4-oxocyclohexanecarboxylate with DAST with crude 96% yield containing 20% of vinyl fluoride byproduct (RCF), which is rather high. So the prior art discloses methods which require further substances, which require separate preparation and produce undesired waste, or fluorinating agents are used which need to be prepared separately, or methods are disclosed which have rather high content of the undesired vinyl fluoride byproduct (RCF) or the yield of the desired product is rather low. The separation of the undesired vinyl fluoride byproduct (RCF) from the desired compound with two geminal fluorine atoms (RCF2) requires additional process steps: Price et al., in Tetrahedron Letters 2005, 46, 5005–5007, discloses on page 5005 right column that the conversion of compound 1, the ethyl 4-cyclohexanone carboxylate, was converted with DAST in dichloromethane to an inseparable 1:1 mixture the the desired difluoro compound 2 (RCF2) and the vinylfluoride 3 (RCF). Price continues saying that the formation of vinylfluoride co-products from treatment of ketones with DAST is known in the literature and appears difficult to control. Optimization studies undertaken to influence the ratio of products including temperature, reagent stoichiometry and solvents were unsuccessful. The obtained 1:1 mixture had to be subjected to further process steps, i.e. a dihydroxylation followed by column chromatography in order to separate the undesired RCF from the desired RCF2.Our Ref. : LZA32043PCT 3 WO2014184561A1 discloses on page 36 in Scheme 1 a deoxyfluorination with DAST providing a mixture of RCF2 and RCF; further on on page 37 lines 12 to 18 the deoxyfluorination of ethyl 4-oxocyclohexanecarboxylate with DAST in dichloromethane, providing a mixture of desired RCF2 and undesired RCF; the inseparable and undesired vinyl fluoride impurity (RCF) requires for its separation from the desired RCF2 an oxidization and further steps. There is a need for a method that does not require the separate preparation of a fluorinating agent, which does not require the presence of further substances, which has rather high yield of the desired product (RCF2) and rather low yield of the undesired vinyl fluoride byproduct (RCF). The inventors of present invention found a method for continuous deoxyfluorination of ketones as substrates which provides good results such as conversion, yield, selectivity and low amount of undesired vinyl fluoride byproduct (RCF), wherein two reactions, the preparation of the fluorinating agent DAST and the fluorination reaction of a ketone with said DAST, are continuously done consecutively and coupled to each other without interrupting the flow of the reaction mixture: at first, that is upstream relative to the fluorination rection, DAST is continuously prepared and then second, that is downstream from the DAST preparation , the fluorination takes place. In addition the method provides for shorter residence times. The risk associated with the handling of DAST is minimized. SUMMARY OF THE INVENTION Subject of the invention is a method for deoxyfluorination of a ketone in a solvent, by exchange of the oxo residue of the ketone against two geminal fluorine atoms providing the respective difluoro compound, in a continuous flow reaction set up comprising two reactions, ^ a first reaction for the preparation of diethylaminosulfur trifluoride (DAST), andOur Ref. : LZA32043PCT 4 ^ a second reaction for the deoxyfluorination of the ketone by said DAST as fluorinating agent; wherein the solvent in said continuous flow reaction set up is selected from the group of dichloromethane, dichloroethane and mixtures thereof and both the first reaction and the second reaction take place in said solvent; the first reaction is done by combining SF4 continuously with a secondary amine, herein abbreviated with BASE, providing DAST; the second reaction is done by combining said DAST from the first reaction continuously with the ketone; the combining of SF4with BASE providing said DAST is done at a first position of said continuous flow reaction set up, which is separated from and located upstream to a second position of said continuous flow reaction set up where the combining of said DAST with the ketone takes place; with the direction of the flow of the reagents SF4 and BASE going to the first position, where the SF4 and the BASE are continuously combined with each other, providing at this first position a first reaction mixture containing said DAST and continuously flowing further on in downstream direction from the first position to the second position, where the ketone is continuously combined with said first reaction mixture providing a second reaction mixture containing the product, the difluoride, and continuously flowing further on in downstream direction from the second position; with the first and second position being in fluid connection with each other so that the flow of the first reaction mixture passes uninterrupted and continuously to and through the second position. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the (A1) Flow Configuration for “Commercial DAST in flow, 2 feeds”, wherein commercial DAST is the fluorinating reagent, which is not generated continuously. Figure 2 shows the (A2) Flow Configuration for “DAST in situ, 3 feeds”, which shows an embodiment of the continuous flow reaction set up according to the invention, with the first position where SF4and Et2NH areOur Ref. : LZA32043PCT 5 mixed to provide a first reaction mixture containing DAST which flows downstream to the second position, where said first reaction mixture is mixed with the ketone for the deoxyfluorination to take place. Figure 3 shows the (A3) Flow Configuration for “DAST in situ, 2 feeds” which is an embodiment wherein SF4, EtNH2and the ketone are mixed in one position for the deoxyfluorination to take place. LIST OF CITATIONS ^ Umemoto et al, Journal of Fluorine Chemistry (2012), 140, 17-27 ^ Umemoto et al., J. AM. CHEM. SOC.2010, 132, 18199–18205 ^ Haycock at al., Organic Process Research & Development 2008, 12, 1094– 1103 ^ US 6,686,509 B2 ^ CN110372572A ^ CN115850156A ^ WO2004050619A1 ^ Beaulieu et al., Org. Lett., 2009, Vol.11, No.21, 2009, 5050-5053 ^ L'Heureux et al., Journal of Organic Chemistry 2010, 75(10), 3401-3411 ^ WO2020198368A1 ^ WO2022040487A1 ^ Wityak et al. in J. Med. Chem.2015, 58, 2967−2987 ^ WO2015025962A1 ^ Price et al., Tetrahedron Letters 2005, 46, 5005–5007 ^ WO2014184561A1 DETAILED DESCRIPTION OF THE INVENTION The invention relates to a deoxyfluorination of a ketone as substrate with DAST as fluorinating reagent. The reaction is a deoxyfluorination reaction. Both two terms deoxofluorination and deoxyfluorination are used in the prior art to describe an exchange of an oxygen atom against one or two fluorine atoms, as the case may be. In this specification these two terms are used synonymously. The desired product provided by the deoxyfluorination of the invention is a compound with two geminal fluorine atoms (RCF2). These two geminal fluorine atoms areOur Ref. : LZA32043PCT 6 both bonded to the C atom of the keto residue of the ketone that if being deoxyfluorinated. So the oxygen atom of the keto residue of the substrate is exchanged against two geminal fluorine atoms. It is known in the art, that deoxyfluorination reactions of ketone as substrate might also provide the unwanted vinyl fluoro byproduct (RCF) as depicted in Scheme 0.In one embodiment, the reaction is done under anhydrous conditions; preferably the residual amount of water in the reaction mixture at the beginning of the reaction is 1'000 ppm or less, more preferably 750 ppm or less, even more preferably 500 ppm or less, especially 250 ppm or less, more especially 100 ppm or less, even more especially 75 ppm or less, in particular 50 ppm or less, more in particular 25 ppm or less, even more in particular, 10 ppm or less. Onto a certain excess of residual water, that may be present, an excess of SF4can be used to react this residual water to HF which no longer interacts with the reaction. Preferably, BASE is selected from the group consisting of R1(R2)NH and pyrrolidine; wherein R1 and R2 are identical or different and independently from each other C1-4 alkyl or benzyl;Our Ref. : LZA32043PCT 7 more preferably, BASE is selected from the group consisting of dibutylamine, dipropylamine, diethylamine (Et2NH), dimethylamine, N-methylbutylamine, and pyrrolidine; even more preferably, BASE is selected from the group consisting of diethylamine (Et2NH), N-methylbutylamine, and pyrrolidine; especially, BASE is diethylamine (Et2NH). Preferably, the solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane and mixtures thereof; more preferably, the solvent is dichloromethane or 1,2-dichloroethane. Preferably, the amount of solvent is chosen such that the concentration of the substrate in the solvent is from 0.001 to 5 M, more preferably from 0.01 to 3 M, even more preferably from 0.01 to 2 M. Preferably, the first reaction and the second reaction are done without any addition of HF to any of the two reactions. Preferably, the first reaction and the second reaction are done without the presence of a salt of HF with pyridine. Preferably, the first reaction and the second reaction are done without the presence of TEA-3HF. Preferably, the first reaction and the second reaction are done without the presence of a salt of HF with TEA. Preferably, the first reaction and the second reaction are done without any addition of a salt of HF with an organic base. Preferably, the first reaction and the second reaction are done without any addition of a salt of HF with a base. Preferably, the first reaction and the second reaction are done without the presence of an organic base except for BASE. Preferably, the first reaction and the second reaction are done without the presence of a base except for BASE. Preferably, the second reaction is done with DAST being the only fluorinating agent.Our Ref. : LZA32043PCT 8 Preferably, the deoxyfluorination reaction is done with DAST being the only fluorinating agent. Preferably, the first reaction and the second reaction are done without the presence of anyone fluorinating agent of the group phenylsulfur trifluoride, 4- tert-butyl-2,6-dimethylphenylsulfur trifluoride (also called Fluolead™), bis(2- methoxyethyl)aminosulfur trifluoride (also called deoxo-fluor), diethylaminodifluorosulfinium tetrafuoroborate (also called XtalFluor E™), and morpholinodifluorosulfinium tetrafluoroborate (also called XtalFluor-M™). Preferably, the amount of SF4is from 2 to 10 equiv, more preferably from 2 to 5 equiv, even more preferably from 2 to 4 equiv, the equiv being molar equiv based on the molar amount of substrate. Preferably, the amount of BASE is from 2 to 10 equiv, more preferably from 2 to 5 equiv, even more preferably from 2 to 4 equiv, the equiv being molar equiv based on the molar amount of substrate. If the substrate has more than one keto residue per molecule that are intended to be deoxyfluorinated, then said equiv are molar equiv based on the molar amount of keto residues of the substrate. If the substrate has more than one keto residue per molecule that are intended to be deoxyfluorinated and the substrate has any further residues such as OH, C(O)H or COOH, which can react with SF4or with DAST, then said equiv are molar equiv based on the total molar amount of keto residues and said any further residues, which can react with SF4 or with DAST, of the substrate. Preferably, the molar amount of SF4and the molar amount of BASE are identical. The first reaction is done at a reaction temperature which is herein called REACTEMP1; preferably REACTEMP1 is a predefined and chosen reaction temperature. Lower limits of REACTEMP1 can be -25 °C, -10 °C, 0 °C, 10 °C or 20 °C. Upper limits of REACTEMP1 can be 200 °C or 175 °C. In one embodiment of the invention, REACTEMP1 can be from -25 to 200 °C, preferably from -10 to 200 °C, more preferably from 0 to 200 °C, even moreOur Ref. : LZA32043PCT 9 preferably from 10 to 200 °C, especially from 10 to 175 °C, more especially from 15 to 175 °C, even more especially from 20 to 175 °C. The second reaction is done at a reaction temperature which is herein called REACTEMP2; preferably REACTEMP2 is a predefined and chosen reaction temperature. REACTEMP1 and REACTEMP2 can be different or identical. Lower limits of REACTEMP2 can be -25 °C, -10 °C, 0 °C, 10 °C, 20 °C or 30 °C. Upper limits of REACTEMP2 can be 200 °C or 175 °C. In one embodiment of the invention REACTEMP2 can be from -25 to 200 °C, preferably from -10 to 200 °C, more preferably from 0 to 200 °C, even more preferably from 10 to 200 °C, especially from 10 to 175 °C, more especially from 15 to 175 °C, even more especially from 20 to 175 °C, in particular from 30 to 175 °C. The continuous combining of SF4with BASE is preferably a continuous mixing. The continuous combining of DAST from the first reaction with the substrate is preferably a continuous mixing. Preferably, neat SF4 is continuously combined with BASE. Preferably, BASE is first mixed with the solvent, and this mixture of BASE with the solvent is combined continuously with SF4; more preferably, the mixture of BASE with the solvent is a solution of the BASE in the solvent. Preferably, the substrate is first mixed with the solvent, and this mixture of the substrate with the solvent is combined continuously with the reaction mixture from the first reaction; more preferably, the mixture of the substrate with the solvent is a solution of the substrate in the solvent. In the continuous flow reaction set up the BASE and the SF4 are mixed continuously in a first mixing device (MIXDEV1).Our Ref. : LZA32043PCT 10 The continuous mixing in MIXDEV1 is done by continuously feeding two feeds, a first feed (FEED1) and a second feed (FEED2) FEED1 containing the BASE and FEED2 containing SF4, into and through MIXDEV1. The reaction mixture exiting MIXDEV1 is called herein the first reaction mixture. Preferably, FEED1 contains a mixture of BASE in the solvent, more preferably a solution of BASE in the solvent. In the continuous flow reaction set up the first reaction mixture and the substrate are mixed continuously in a second mixing device (MIXDEV2). MIXDEV2 is located in downstream direction relative to MIXDEV1. The continuous mixing in MIXDEV2 is done by continuously feeding two feeds, the first reaction mixture and a third feed (FEED3), FEED3 containing the substrate, into and through MIXDEV2. The reaction mixture exiting MIXDEV2 is called herein the second reaction mixture. Preferably, FEED3 contains a mixture of the substrate in the solvent, more preferably a solution of the substrate in the solvent. FEED1 can be the BASE neat or can be a solution of BASE in the solvent, preferably FEED1 is a solution of BASE in the solvent. FEED2 contains the SF4, preferably FEED2 is the SF4 neat. FEED3 is a solution of the substrate in the solvent. Preferably, FEED1 consists of a solution of BASE in the solvent; FEED2 consists of SF4; FEED3 consists of a solution of the substrate in the solvent. The concentration of the substrate in FEED3 is primarily limited by the solubility of the substrate in the solvent and the chosen temperature of FEED3. Preferably, the concentration of the substrate in FEED3 is from 0.01 to 10 M, more preferably from 0.01 to 5 M, even more preferably from 0.01 to 3 M. The continuous mixing in MIXDEV1 and MIXDEV2, that is the pumping or dosing of FEED1, FEED2 and FEED3 into and through MIXDEV1 andOur Ref. : LZA32043PCT 11 MIXDEV2, is preferably done using a back pressure regulation device BPR. The BPR is located downstream from MIXDEV2. The BPR provides for having a predetermined pressure in MIXDEV1 and MIXDEV2 and for maintaining this predetermined pressure in MIXDEV1 and MIXDEV2 at a constant level. The first reaction and the second reaction can be done at different pressures. This can for example be realized by inserting respective pressure regulating devices between MIXDEV1 and MIXDEV2. The first reaction is preferably done at a pressure which is above the vapor pressure, at REACTEMP1, of the reaction mixture of the first reaction containing all components of the reaction mixture of the first reaction except for the SF4, and / or above the vapor pressure of SF4 at REACTEMP1. The second reaction is preferably done at a pressure which is above the vapor pressure, at REACTEMP2, of the reaction mixture of the second reaction containing all components of the reaction mixture of the second reaction except for any SF4which may be present in the reaction mixture of the second reaction, and / or above the vapor pressure of SF4 at REACTEMP2. In more preferred embodiment, the first reaction and the second reaction are done under the same pressure, herein called REACPRESS. REACTEMP1 and REACTEMP2 may be identical or different; if REACTEMP1 and REACTEMP2 are different, then one of the two is the higher one, called herein REACTEMPHIGHER; if REACTEMP1 and REACTEMP2 are identical then REACTEMPHIGHER is REACTEMP1; preferably REACPRESS is above the vapor pressure, at REACTEMPHIGHER, of the reaction mixture of the first reaction and the second reaction containing all components of the respective reaction mixtures of the first reaction and second reaction except for any SF4, and / or REACPRESS is above the vapor pressure of SF4 at REACTEMPHIGHER. In a preferred embodiment for the method of deoxyfluorination of this invention in the continuous flow reaction set up, especially on industrial scale, the first reaction and the second reaction are done under the same pressure,Our Ref. : LZA32043PCT 12 REACPRESS, and REACPRESS is above the vapor pressure of SF4 at REACTEMPHIGHER, that is above the vapor pressure which SF4has at the reaction temperature of the first reaction and of the second reaction; so SF4 is used in liquid state. More preferably, any reaction pressure is above the vapor pressure of any reaction mixture at any chosen reaction temperature. Typical ranges for any reaction pressure can be from 0 to 200 barg, more preferably from 0 to 150 barg, even more preferably from 0 to 100 barg. In the absolute unit bar any reaction pressure can be from atmospheric pressure to 200 bar, more preferably from atmospheric pressure to 150 bar, even more preferably from atmospheric pressure to 100 bar. In one embodiment the first reaction and the second reaction are done under the same pressure, REACPRESS, that is the pressure in MIXDEV1 and MIXDEV2 is the same, i.e. REACPRESS, and REACPRESS can be chosen and set by the BPR. Suitable back pressure regulation devices BPR are known to the skilled person and are available on the market, such as from companies like Swagelok Company, Solon, Ohio, US, or Zaiput Flow Technologies, Scottsdale, Arizona, US. Preferably, the BPR features a small dead volume, precise pressure control and / or a large enough channel width to ensure a smooth flow without clogging. For conveying anyone of FEED1, FEED2, FEED3 and / or any reaction mixture respective pumps can be used. The dosing and feeding of FEED2, that is of the SF4gas, can also be driven by its own respective vapor pressure, for example if the pressure in MIXDEV1 is below the vapor pressure of SF4 at the chosen reaction temperature in MIXDEV1. Depending on the components, on the pressure and on the temperature, each of FEED1, FEED2, FEED3, and any reaction mixture can either be gaseous or liquid. For determining any gaseous flow rate V̇g and / or any liquid flow rate V̇l respective flow meters or mass flow controllers can be used. Pressure andOur Ref. : LZA32043PCT 13 temperature can be measured by respective measuring devices. All such devices are know to the skilled person. Mass flow controllers MFC can be used to determine and control and maintain any flow rate, be it gaseous or liquid of any of the components of the reaction mixture. For example a MFC can be used upstream before the MIXDEV, to determine and control and maintain the gaseous flow rate V̇gof SF4. For cleaning and especially for drying of any devices which come into contact with any of the components of the reaction mixture N2can be used. The mixing devices MIXDEV1 and MIXDEV2 can be identical or different types of mixing devices and can be any suitable device with means for combining two fluid feeds or for combining a fluid feed with a gaseous feed to provide a reaction mixture. Any of the two mixing devices can further comprise means for mixing the reaction mixture. Any of the two mixing devices MIXDEV1 and MIXDEV2 can be for example a T-piece, a microreactor, a mixing device, such as a static mixing device, or any combination thereof. In case any of the two mixing devices is a T-piece, which has two entrance channels, the two feeds entering the mixing device are fed each into one of the two separate entrance channels, the two separate entrance channels combine in the T-piece into the one exit channel of the T-piece, through which the mixed feeds, that is the reaction mixture, exits. Mixing devices such as dynamic mixing devices or static mixing devices, e.g. static mixers, are well established and widespread in all fields of chemical process technology. It is characteristical for static mixing devices, in contrast to dynamic mixing devices, that only the media to be mixed are in motion. The feeds, liquid or gaseous, are mixed by their motion only, while the geometrically defined mixing elements in the static mixing devices remain fixed and in their positions. Companies such as Fluitec, Seuzachstrasse, 8413 Neftenbach, Switzerland, or Sulzer Ltd, Neuwiesenstrasse 15, 8401 Winterthur, Switzerland, are well known suppliers among others of such static mixing devices.Our Ref. : LZA32043PCT 14 Preferably, the static mixing device has the form of a tube or a plate containing means that present obstacles for the flow of the reaction mixture and thereby effecting the mixing of the feeds. The actual combining of the two feeds may be done within a mixing device, or first the two feeds are combined by a T-piece and downstream after the T-piece the reaction mixture passes through a mixing device, in this embodiment the respective MIXDEV1 and / or MIXDEV2 comprises both the T-piece and the mixing device. Micro reactors, also called micro structured reactors, are devices in which chemical reactions take place in a confinement with typical lateral dimensions below 1 mm; the most typical form of such confinement are micro channels. A micro reactor is a continuous flow reactor. Microreactors have been successfully applied in lab, pilot and production scale. E.g. the Fraunhofer Institute for Chemical Technology ICT, Joseph-von-Fraunhofer Strasse 7, 76327 Pfinztal, Germany, or Ehrfeld Mikrotechnik GmbH, Mikroforum Ring 1, 55234 Wendelsheim, Germany, develop and offer such micro reactors. Preferably, the micro reactor contains micro channels which are arranged in such a way as to effect the mixing of the feeds. One embodiment of a microreactor is called a split and recombine mixer. Usually a microreactor comprises both the means for combining the two feeds and the means for mixing the obtained reaction mixture. The first reaction starts when FEED1 and FEED2 are mixed in MIXDEV1; MIXDEV1 provides the first reaction mixture. The time which the first reaction mixture needs for passing through MIXDEV1 is a mixing time tMix1. The reaction time of the first reaction is equal to or larger than tMix1. If MIXDEV1 is a simply T piece then tMix1is rather short. The first reaction mixture exiting from MIXDEV1 can be passed through a first residence device (RESDEV1) before entering MIXDEV2. RESDEV1 provides for additional reaction time of the first reaction. RESDEV1 is located downstream from MIXDEV1.Our Ref. : LZA32043PCT 15 In one embodiment, the first reaction mixture is passed through a RESDEV1 after having passed through MIXDEV1 and before entering MIXDEV2; RESDEV1 provides for additional reaction time of the first reaction. In the case that both MIXDEV1 and RESDEV1 are used and a back pressure regulation device is used between MIXDEV1 and MIXDEV2, then this back pressure regulation device is preferably located downstream of RESDEV1. In a preferred embodiment, no back pressure regulation device is used between MIXDEV1 and MIXDEV2 The time which the first reaction mixture needs for passing through RESDEV1 is a residence time tRes1. tRes1is part or the first reaction time. If not RESDEV1 is present, tRes1is zero. RESDEV1 has a channel through which the first reaction mixture passes through, the length and the inner diameter of this channel are chosen in such a way that a desired tRes1 is provided for. RESDEV1 may for example be a tube, the tube may have the shape of a coil, herein also called the first reactor coil. Additional tRes1means additional first reaction time, in which the first reaction can take place. In the case that RESDEV1 is used then the first reaction time is equal to or larger than the sum of tMix1and tRes1. Dimensional limitation of the inner diameter of MIXDEV1 and of RESDEV1 may be required primarily in connection with the use of SF4in gaseous state; this may for example be the case in small scale reactions, that is for example in lab scale reactions. In order to have an optimum of mixing in lab scale the inner diameter of MIXDEV1 and / or RESDEV1, that is the inner diameter of any channel in MIXDEV1 and / or RESDEV1, through which the first reaction mixture passes, should be rather small, such as 2 mm or less, preferably 1 mm or less. In a particular embodiment, the inner diameter of MIXDEV1 and / or RESDEV1, that is the inner diameter of any channel in MIXDEV1 and / or RESDEV1, through which the first reaction mixture passes, is 2 mm or less, preferably 1 mm or less. The handling of SF4 in liquid state is easier to be realized on industrial scale than in the lab. When both the feed of SF4and the feed of the substrate are inOur Ref. : LZA32043PCT 16 liquid state then the mixing pertains to a liquid-liquid mixing, thereby a mixing can be effected more easily by respective and well-known mixing elements in MIXDEV1 than a gaseous-liquid mixing (as may be required e.g. on lab scape due to limitations of pressure resistance of any devices on lab scale). The second reaction starts when the first reaction mixture, provided by MIXDEV1, and FEED3 are mixed in MIXDEV1; MIXDEV1 provides the second reaction mixture. The time which the second reaction mixture needs for passing through MIXDEV2 is a mixing time tMix2. The reaction time of the second reaction is equal to or larger than tMix2. If MIXDEV2 is a simply T piece then tMix2is rather short. The second reaction mixture exiting from MIXDEV2 can be passed through a second residence device (RESDEV2); preferably the second reaction mixture exiting from MIXDEV2 passes through a RESDEV2 before passing through any other device, so MIXDEV2 and RESDEV2 are directly connected with each other. RESDEV2 provides for additional reaction time of the second reaction. RESDEV2 is located downstream from MIXDEV2. Preferably, RESDEV2 is in downstream direction the next device after MIXDEV2. In a particular embodiment, the second reaction mixture is passed through a RESDEV2 after having passed through MIXDEV2 and before entering any other device. In the case that both MIXDEV2 and RESDEV2 are used and a BPR is used after MIXDEV2, then this BPR is preferably located downstream of RESDEV2. The time which the second reaction mixture needs for passing through RESDEV2 is a residence time tRes2. tRes2is part or the second reaction time. If not RESDEV2 is present, tRes2 is zero. RESDEV2 has a channel through which the second reaction mixture passes through, the length and the inner diameter of this channel are chosen in such a way that a desired tRes2 is provided for. RESDEV2 may for example be a tube, the tube may have the shape of a coil, herein also called the first reactor coil. Additional tRes2 means additional second reaction time, in which the second reaction can take place.Our Ref. : LZA32043PCT 17 In the case that RESDEV2 is used then the second reaction time is equal to or larger than the sum of tMix2and tRes2. In one embodiment, the inner diameter of MIXDEV2 and / or RESDEV2, that is the inner diameter of any channel in MIXDEV2 and / or RESDEV2, through which the second reaction mixture passes, is 2 mm or less, preferably 1 mm or less. The product is isolated from the second reaction mixture existing MIXDEV2, or, if present, exiting RESDEV2; methods and means for isolation are known to the skilled person. Preferably the product is isolated from the second reaction mixture after a BPR located downstream of MIXDEV2. In particular embodiment, the second reaction mixture is separated in a separation device (SEPDEV) into a gaseous stream and a liquid stream, or into a more hydrophobic and a more hydrophilic stream, as the case may be. This can be done by any means known to the skilled person for separating gas from liquid or hydrophobic components from hydrophilic components; preferably SEPDEV is a membrane separator. In one embodiment SEPDEV separates any residual SF4 from the reaction mixture. The time which the second reaction mixture needs for passing through a SEPDEV is a separation time tSep. tSep is part of the reaction time of the second reaction. If not SEPDEV is present, tSepis zero. A SEPDEV is located downstream after MIXDEV2. When a RESDEV2 is used, then a SEPDEV is located downstream after RESDEV2. A SEPDEV can be located upstream before a BPR or downstream after a BPR. Preferably a SEPDEV is located downstream after a BPR, Depending on the nature of the product, such as its boiling point or its solubility in the solvent in the reaction mixture, the product may be in the gaseous stream or in the liquid stream or in both of these two streams, likewise the product may be in the hydrophilic stream or in the hydrophobic stream or in both streams.Our Ref. : LZA32043PCT 18 Means for isolation of the product from the respective stream are known to the skilled person. In a particular embodiment, the second reaction mixture is passed through a separation device SEPDEV which is located downstream of MIXDEV2, the RESDEV2 (if present) and the BPR (if present). In one embodiment, the second reaction mixture passes through SEPDEV which is a membrane separator comprising a hydrophobic membrane to separate the second reaction mixture into a hydrophilic stream, which will be retained by the membrane, and a hydrophobic stream, which can pass through the membrane. In one embodiment, the separation device SEPDEV is a membrane separator comprising a hydrophobic membrane. In this embodiment the hydrophobic stream contains primarily the solvent and any dissolved compounds such as residual substrate and the product. In order to capture unreacted SF4and / or any by-products such as HF or SOF2, anyone of the gaseous and liquid stream or both streams, or anyone of the hydrophilic and hydrophobic stream or in both streams respectively, can be quenched by suitable bases, preferably aqueous bases, for example with aqueous NaOH or NaHCO3. With reference to the devices the first reaction time can be defined as the time during which the first reaction mixture passes from the point of mixing of the SF4 with FEED1 in MIXDEV1 on through a RESDEV1, if a RESDEV1 is used, and on into MIXDEV2, until the first reaction mixture is mixed with the FEED3. The second reaction may or may not be end in a SEPDEV, where some components in the reaction mixture of the second reaction are separated from the second reaction mixture. Preferably, after the second reaction the reaction mixture of the second reaction and therewith the reaction therein is quenched. This quenching can be done by any suitable means. Suitable means are for examples mixing the reaction mixture with a suitable base, preferably aqueousOur Ref. : LZA32043PCT 19 base, such as aqueous NaOH or NaCO3. This quenching is preferably done after any RESDEV2, after any BPR and after any SEPDEV. With reference to the devices the second reaction time, during which the second reaction can occur, can be defined as at least the time during which the second reaction mixture passes from the point of mixing of the first reaction mixture with FEED3 in MIXDEV2 on through a RESDEV2, if a RESDEV2 is used, and on into a SEPDEV, if a SEPDEV is used, and on into to a quenching, if a quenching is done. Preferably, a quenching is done and terminates the second reaction, so the reaction time of the second reaction preferably is the time from the mixing of the first reaction mixture with FEED3 in MIXDEV3 until the quenching. In one particular embodiment, when a BPR is used and a quenching after the second reaction is done, the second reaction time can be defined as the time during which the second reaction mixture passes from the point of mixing of the first reaction mixture with FEED3 in MIXDEV2 on through a RESDEV2, if a RESDEV2 is used, and on through the BPR, and further on through a SEPDEV, if SEPDEV is used and is located downstream after BPR, and further on until the quenching. Preferably, the first reaction time, that is the reaction time of the first reaction, is from 0.01 to 60 min, more preferable from 0.01 to 50 min, even more preferably from 0.01 to 40 min. The first reaction time is equal to or larger than the sum of tMix1and any tRes1. The first reaction time can for example be larger than the sum of tMix1 and any tRes1if a passage through connecting tubes or pipes between MIXDEV1 and RESDEV1 contribute to the first reaction time. In the examples the RESDEV1 is a reactor coil. tRes1 is calculated based on the liquid flow rate V̇l. The first reaction time in the set up in the examples of the (A2) Flow Configuration for “DAST in situ, 3 feeds” as shown in Figure 2, was approximately as large as tres1, preferably not more than factor 1.5 times tRes1,Our Ref. : LZA32043PCT 20 more preferably not more than factor 1.25 times tRes1, even more preferably not more than factor 1.1 times tRes1, since any connections between devices have been very short, likewise the tMix1 has been very short due to the small dimensions of MIXDEDV1, so there was no significant contribution to the first reaction time from the passage time before or after RESDEV1. Preferably, the second reaction time, that is the reaction time of the second reaction, is from 0.01 to 120 min, more preferable from 0.01 to 90 min, even more preferably from 0.01 to 60 min. The second reaction time is equal to or larger than the sum of tMix2, tRes2and any tSep. The second reaction time can for example be larger than the sum of tMix2, tRes2 and any tSep if a passage through connecting tubes or pipes between MIXDEV2 and RESDEV2 contribute to the second reaction time. In the examples the RESDEV2 is the reactor coil. tRes2 is calculated based on the liquid flow rate V̇l. The second reaction time in the set up in the examples of the (A2) Flow Configuration for “DAST in situ, 3 feeds” as shown in Figure 2, was approximately as large as tres2, preferably not more than factor 1.5 times tRes2, more preferably not more than factor 1.25 times tRes2, even more preferably not more than factor 1.1 times tRes2, since any connections between devices have been very short, also the connections after SEPDEV until the quenching have been very short, likewise the tMix2has been very short due to the small dimensions of MIXDEV2, so there was no significant contribution to the second reaction time from the passage time before or after RESDEV2. The chosen reaction temperature can be attained and maintained by respective heating or cooling of one or more of anyone of the reactants, feeds, reaction mixtures, devices through which the feeds and the reaction mixtures pass. In one embodiment, any mixing device is heated or cooled and / or a residence devices is heated or cooled to attain and maintain the chosen reaction temperature. For pressure control, for example if any of the devices has a lower limit below which the pressure must not fall, or has an upper limit of pressure which mustOur Ref. : LZA32043PCT 21 not be exceeded, line pressure regulators LPR or BPRs can be installed as required. In an embodiment, the first reaction, the second reaction and / or both are done in the presence of an additive, wherein the additive is selected from the group BF3*OEt2, EtOH or mixtures thereof. The amount of an additive can be from 0.01 to 1 eq, preferably from 0.1 to 1 eq, more preferably from 0.1 to 0.75 eq, based on the molar amount of substrate. The additive can be added to FEED1, to FEED 3 or to both. The following definitions are used: ^ Aryl is a carbocyclic aromatic ring or ring system, or a heterocyclic aromatic ring or ring system. A terminal aryl within the meaning of the invention is an aryl which is not substituted by another aryl. ^ Cycloalkyl is a carbocyclic non-aromatic ring or ring system, or a heterocyclic non-aromatic ring or ring system. A terminal cycloalkyl within the meaning of the invention, is a cycloalkyl which is not substituted by another cycloalkyl. ^ Preferably, any heterocyclic aromatic ring can have 1, 2 or 3 identical or different endocyclic heteroatoms selected from the group consisting of N, O and S, if not defined explicitly otherwise. ^ Any alkyl is unbranched or branched alkyl. More specifically, C3-n alkyl comprises unbranched or branched C3-n alkyl with n > 3. ^ Any alkenyl is unbranched or branched. More specifically, C3-n alkenyl comprises unbranched or branched C3-nalkenyl with n > 3. Any alkenyl can have one or more unsaturated bonds depending on the size and connectivity of its carbon scaffold. ^ Alkylene is a disubstituted alkyl. Alkylene comprises unbranched or branched alkylene. More specifically, C2-n alkylene comprises unbranched or branched C2-n alkylene n > 2. ^ Alkenylene is a disubstituted alkenyl. Alkenylene comprises unbranched or branched alkenylene. More specifically, C2-nalkenylene comprises unbranched or branched C2-n alkenylene with n > 2. Any alkenylene canOur Ref. : LZA32043PCT 22 have one or more unsaturated bonds depending on the size and connectivity of its carbon scaffold. ^ Propylene is n-propylene or isopropylene. ^ Cyclic ketone is a non-aromatic carbocycle or non-aromatic heterocycle with an endocyclic keto residue C=O. The endocyclic atoms of the cyclic ketone are also called ring atoms herein. ^ Non-cyclic ketone is a compound of formula (NCK) wherein R200 and R201 are not covalently bonded to each other except for the keto residue C=O in between, so R200 and R201 together with the keto residue C=O in between do not form a ring. Preferably, the ketone, that is the substrate, is a non-cyclic ketone or a cyclic ketone. In one embodiment, the substrate is an unsubstituted or substituted cyclic ketone. Any cyclic ketone being the substrate and mentioned herein, comprises 0 to n-3 endocyclic heteroatoms Y4, with n being the number of ring atoms of the cyclic ketone including the C atom of the endocyclic keto residue of the cyclic ketone, preferably up to n-4 endocyclic heteroatoms Y4 in case that n > 5; more preferably, the cyclic ketone comprises 0, 1 or 2 endocyclic heteroatoms Y4, with Y4 being O, S or N; this possibility for the cyclic ketone of having endocyclic hetreoatoms expressly applies also for example in case that said cyclic ketone is said to be selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone. So for example a cyclohexanone with an endocyclic carbon atom exchanged against NH is a piperidinone and is comprised in the definition of the cyclic ketone of this invention. Any endocyclic N of the cyclic ketone can be unsubstituted or substituted, in case of any saturated endocyclic N of the cyclic ketone any said saturated endocyclic NOur Ref. : LZA32043PCT 23 is preferably substituted, more preferably by a residue R5, R5 is a protecting group which is stable under reaction conditions, with R5 being as defined herein, also with all its embodiments. In one embodiment, the substrate is an unsubstituted or substituted cyclic ketone, which can be partially unsaturated. In one embodiment, the substrate is an unsubstituted or substituted cyclic ketone, which can be partially unsaturated, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL. Any cyclic ketone mentioned herein can be bridged by 1, 2 or 3 atoms selected from C or N; in case that the bridge contains N and the N is a saturated N, then the N is preferably substituted, more preferably by R5; R5 is a protecting group which is stable under reaction conditions, with R5 begin also as defined herein, also with all its embodiments. In one embodiment, the substrate is an unsubstituted or substituted cyclic ketone, which is saturated or monounsaturated, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL. In one embodiment, the substrate is a saturated or monounsaturated cyclic ketone, which is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL; R100 is selected from the group consisting of oxo, OH, C1-22 alkyl, C2-22 alkenyl, F, Cl, Br, I, CN, NO2, O-C1-6alkyl, O-C2-6alkenyl,Our Ref. : LZA32043PCT 24 C(O)H, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, COOH, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, O-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl; with C1-6 alkyl, C2-6 alkenyl, C1-22 alkyl, C2-22 alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments. In one embodiment, the substrate is a saturated or monounsaturated cyclic ketone, which is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic aryl residue called FUSEDARYL, wherein FUSEDARYL is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100; with R100 as defined herein, also with all its embodiments. Preferably, any cyclic ketone mentioned herein is selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone, preferred members of this group are cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone. More preferably, the ketone, that is the substrate, is a cyclic ketone and is selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone, preferred members of this group are cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone;Our Ref. : LZA32043PCT 25 wherein each cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone and cyclopentenone can be unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100; each cyclobutanone and cyclobutenone can be unsubstituted or substituted by 1, 2 or 3 identical or different substituents R100; and wherein each cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptanone, cyclohexanone, cyclohexenone, cyclopentanone and cyclopentenone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL, wherein FUSEDARYL is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100; with R100 and FUSEDARYL as defined herein, also with all their embodiments. In one embodiment, the ketone, that is the substrate, is a non-cyclic ketone and is a compound of formula (NCK),wherein R200 and R201 are identical or different and independently from each other selected from the group consisting of C1-22 alkyl, C2-22 alkenyl, cycloalkyl, and aryl; with C1-22alkyl, C2-22alkenyl, cycloalkyl, and aryl as defined herein, also with all their embodiments.Our Ref. : LZA32043PCT 26 Any cycloalkyl residue mentioned herein, independently from any other cycloalkyl residue, is 4, 5, 6, or 7 membered cycloalkyl residue, a 4 membered cycloalkyl residue contains 0 or 1 endocyclic heteroatom Y3, a 5 membered cycloalkyl residue contains 0, 1 or 2 identical or different endocyclic heteroatoms Y3, a 6 and a 7 membered cycloalkyl residue contain 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y3, any heteroatom Y3 is, independently from any other Y3, selected from the group consisting of O, S, and N, said N is unsubstituted or substituted, preferably substituted by R5, any cycloalkyl residue, independently from any other cycloalkyl residue, is unsubstituted or substituted by one or more identical or different substituents R110, with R110 as defined herein, also with all its embodiments. Any aryl mentioned herein is, independently from any other aryl, ^ a 5 or 6 membered monocyclic aryl residue, ^ a bicyclic aryl residue formed by a 5 or 6 membered ring fused with a 6 membered ring, or ^ a 5 or 6 membered non-aromatic ring, any 5 membered ring in the aryl contains 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y2, any 6 membered ring in the aryl contains 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y2, and any aryl is unsubstituted or substituted by one or more identical or different substituents R110, with R110 as defined herein, also with all its embodiments. Any R110 mentioned herein, independently from any other R110, is selected from the group consisting of oxo, OH, C1-6alkyl, C2-6alkenyl, F, Cl, Br, I, CN, NO2,Our Ref. : LZA32043PCT 27 O-C1-6 alkyl, O-C2-6 alkenyl, C(O)H, C(O)-C1-6alkyl, C(O)-C2-6alkenyl, COOH, C(O)-O-C1-6 alkyl, C(O)-O-C2-6 alkenyl, O-R5, N(H)R5, a terminal cycloalkyl, a terminal aryl, and (Y1)-aryl which is a terminal aryl; with C1-6alkyl, C2-6alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments. Any heteroatom Y2 mentioned herein is, independently from any other Y2, selected from the group consisting of O, S, and saturated or unsaturated N, said saturated N is unsubstituted or substituted, preferably substituted by R5. Any Y1 mentioned herein is, independently from any other Y1, a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, C(O), (O-CH2-CH2)1-20-O, (O-propylene)1-20-O, (O-CH2-CH2)1-20-O-C(O)-C1-6alkylene-C(O)-O, (O-propylene)1-20-O-C(O)-C1-6alkylene-C(O)-O, O-C(O)-C1-6 alkylene-C(O)-(O-CH2-CH2)1-20-O, and O-C(O)-C1-6alkylene-C(O)-(O-propylene)1-20-O. Any C1-22 alkyl mentioned herein and any C2-22 alkenyl mentioned herein is, independently from any other C1-22alkyl and C2-22alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical of different substituents selected from the group consisting of oxo, OH, F, Cl, Br, I, NO2, O-C1-6 alkyl, O-C2-6 alkenyl, C(O)H, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, COOH, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl,Our Ref. : LZA32043PCT 28 O-R5, S-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl; with C1-6alkyl, C2-6alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments. Any C1-6alkyl mentioned herein and any C2-6alkenyl mentioned herein is, independently from any other C1-6 alkyl and C2-6 alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical or different substituents selected from a group consisting of oxo, OH, F, Cl, Br, I, NO2, O-C1-4alkyl, O-C2-3alkenyl, C(O)H, C(O)-C1-4 alkyl, C(O)-C2-3 alkenyl, COOH, C(O)-O-C1-4 alkyl, C(O)-O-C2-3 alkenyl, O-R5, S-R5, and N(H)R5. Any R5 mentioned herein is a protecting group which is stable under reaction conditions, in particular any R5 mentioned herein is a protecting group for protecting OH, SH, NH or NH2, which is stable under reaction conditions; such protecting groups are known to the skilled person. Preferably, ^ if OH is to be protected then R5 is Fmoc, Boc, benzoyl, Cbz, C(O)-C1-10 alkyl, TBDMS (tert-Butyldimethylsilyl), triisopropylsilyl, PNB (p- Nitrobenzyl), ONB (o-Nitrobenzyl), Bn (Benzyl), Al (Allyl), or tBu (tert- Butyl), more preferably Fmoc, Boc, benzoyl, Cbz, C(O)-C1-6 alkyl, PNB (p- Nitrobenzyl), ONB (o-Nitrobenzyl), Bn (Benzyl), Al (Allyl), or tBu (tert- Butyl), even more preferably Fmoc, Boc, benzoyl, Cbz, C(O)-C1-3 alkyl, or Bn (Benzyl); ^ if NH2is to be protected then R5 is Fmoc, Boc, benzoyl, Cbz, C(O)-C1-10alkyl, Bn (Benzyl), or Alloc (Allyloxycarbonyl),Our Ref. : LZA32043PCT 29 more preferably Fmoc, Boc, benzoyl, Cbz, C(O)-C1-6 alkyl, Bn (Benzyl), or Alloc (Allyloxycarbonyl); ^ if SH is to be protected then R5 is Fmoc, Boc, benzoyl, Cbz, C1-2alkyl, C(O)- C1-10 alkyl, Bn (Benzyl), Meb (p-Methylbenzyl), Acm (Acetamidomethyl), or Trt, more preferably Fmoc, Boc, benzoyl, Cbz, C1-2alkyl, C(O)-C1-6alkyl, Bn (Benzyl), Meb (p-Methylbenzyl), or Acm (Acetamidomethyl). In particular, if OH is to be protected then R5 is Boc, benzoyl, Cbz, Fmoc, C(O)- C1-6 alkyl or Bn (Benzyl). Preferably, any cyclic keton and / or any cyclododecenone, cycloundecenone, cyclodecenone, cyclononenone, cyclooctenone, cycloheptenone, cyclohexenone, cyclopentenone mentioned herein contains only 1 endocyclic double bond; more preferably, any cyclic keton and / or any cyclododecenone, cycloundecenone, cyclodecenone, cyclononenone, cyclooctenone, cycloheptenone, cyclohexenone, cyclopentenone mentioned herein contains only 1 endocyclic double bond which is not conjugated with the double bond of the endocyclic keto residue which is deoxyfluorinated. In an especially preferred embodiment, any R100 mentioned herein, independently from any other R100, is selected from the group consisting of C1-22alkyl, C2-22alkenyl, F, Cl, Br, I, CN, NO2, O-C1-6 alkyl, O-C2-6 alkenyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, O-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl; with C1-6 alkyl, C2-6 alkenyl, C1-22 alkyl, C2-22 alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments.Our Ref. : LZA32043PCT 30 In an especially preferred embodiment, any R110 mentioned herein, independently from any other R110, is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, F, Cl, Br, I, CN, NO2, O-C1-6alkyl, O-C2-6alkenyl, C(O)-O-C1-6 alkyl, C(O)-O-C2-6 alkenyl, O-R5, N(H)R5, a terminal cycloalkyl, a terminal aryl, and (Y1)-aryl which is a terminal aryl; with C1-6alkyl, C2-6alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments. In an especially preferred embodiment, any Y1 mentioned herein is, independently from any other Y1, a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, (O-CH2-CH2)1-20-O, (O-propylene)1-20-O, (O-CH2-CH2)1-20-O-C(O)-C1-6 alkylene-C(O)-O, (O-propylene)1-20-O-C(O)-C1-6alkylene-C(O)-O, O-C(O)-C1-6alkylene-C(O)-(O-CH2-CH2)1-20-O, and O-C(O)-C1-6 alkylene-C(O)-(O-propylene)1-20-O. In an especially preferred embodiment, any C1-22alkyl mentioned herein and any C2-22 alkenyl mentioned herein is, independently from any other C1-22 alkyl and C2-22alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical of different substituents selected from the group consisting of F, Cl, Br, I, NO2, O-C1-6alkyl, O-C2-6alkenyl, C(O)-O-C1-6 alkyl, C(O)-O-C2-6 alkenyl, O-R5, S-R5, N(H)R5, cycloalkyl,Our Ref. : LZA32043PCT 31 aryl, and (Y1)-aryl; with C1-6 alkyl, C2-6 alkenyl, cycloalkyl and aryl as defined herein, also with all their embodiments. In an especially preferred embodiment, any C1-6 alkyl mentioned herein and any C2-6 alkenyl mentioned herein is, independently from any other C1-6 alkyl and C2-6alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical or different substituents selected from a group consisting of F, Cl, Br, I, NO2, O-C1-4alkyl, O-C2-3alkenyl, C(O)-O-C1-4 alkyl, C(O)-O-C2-3 alkenyl, O-R5, S-R5, and N(H)R5. In an particular embodiment, the cyclic ketone, that is the substrate, is selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone, preferred members of this group are cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone; wherein each cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone, and cyclobutanone can be unsubstituted or substituted; and wherein each cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone, and cyclobutanone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL;Our Ref. : LZA32043PCT 32 even more preferably, the ketone, that is the substrate, is selected from the group of cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone, preferred members of this group are cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone, cyclopentenone and cyclobutanone; wherein each cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptenone, cyclohexanone, cyclohexenone, cyclopentanone and cyclopentenone can be unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100; each cyclobutanone and cyclobutenone can be unsubstituted or substituted by 1, 2 or 3 substituents R100; and wherein each cyclododecanone, cyclododecenone, cycloundecanone, cycloundecenone, cyclodecanone, cyclodecenone, cyclononanone, cyclononenone, cyclooctanone, cyclooctenone, cycloheptanone, cycloheptanone, cyclohexanone, cyclohexenone, cyclopentanone and cyclopentenone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL, wherein FUSEDARYL is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100; R100 is selected from the group consisting of C1-22alkyl, C2-22alkenyl, F, Cl, Br, I, CN, NO2, O-C1-6alkyl, O-C2-6alkenyl, C(O)-O-C1-6 alkyl, C(O)-O-C2-6 alkenyl, O-R5, N(H)R5, cycloalkyl,Our Ref. : LZA32043PCT 33 aryl, and (Y1)-aryl; any mentioned cycloalkyl residue is, independently from an other cycloalkyl residue, a 4, 5, 6, or 7 membered cycloalkyl residue, a 4 membered cycloalkyl residue contains 0 or 1 endocyclic heteroatom Y3, a 5 membered cycloalkyl residue contains 0, 1 or 2 identical or different endocyclic heteroatoms Y3, a 6 and a 7 membered cycloalkyl residue contain 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y3, any heteroatom Y3 is, independently from any other Y3, selected from the group consisting of O, S, and N, said N is unsubstituted or substituted, preferably substituted by R5, any cycloalkyl residue, independently from any other cycloalkyl residue, is unsubstituted or substituted by one or more identical or different substituents R110; any mentioned aryl is, independently from any other aryl, ^ a 5 or 6 membered monocyclic aryl residue, ^ a bicyclic aryl residue formed by a 5 or 6 membered ring fused with a 6 membered ring, or ^ a 5 or 6 membered non-aromatic ring, any 5 membered ring in the aryl contains 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y2, any 6 membered ring in the aryl contains 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y2, and any aryl is, independently from any other aryl, unsubstituted or substituted by one or more identical or different substituents R110, R110 is selected from the group consisting of C1-6alkyl, C2-6alkenyl, F, Cl, Br, I, CN, NO2,Our Ref. : LZA32043PCT 34 O-C1-6 alkyl, O-C2-6 alkenyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, O-R5, N(H)R5, a terminal cycloalkyl, a terminal aryl, and (Y1)-aryl which is a terminal aryl; any mentioned heteroatom Y2 is, independently from any other Y2, selected from the group consisting of O, S, and saturated or unsaturated N, said saturated N is unsubstituted or substituted, preferably substituted by R5; any mentioned Y1 is, independently from any other Y1, a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, (O-CH2-CH2)1-20-O, (O-propylene)1-20-O, (O-CH2-CH2)1-20-O-C(O)-C1-6 alkylene-C(O)-O, (O-propylene)1-20-O-C(O)-C1-6 alkylene-C(O)-O, O-C(O)-C1-6alkylene-C(O)-(O-CH2-CH2)1-20-O, and O-C(O)-C1-6 alkylene-C(O)-(O-propylene)1-20-O; any mentioned C1-22alkyl and any mentioned C2-22alkenyl is, independently from any other C1-22 alkyl and C2-22 alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical of different substituents selected from the group consisting of F, Cl, Br, I, NO2, O-C1-6alkyl, O-C2-6alkenyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, O-R5, S-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl;Our Ref. : LZA32043PCT 35 any mentioned C1-6 alkyl and any mentioned C2-6 alkenyl is, independently from any other C1-6alkyl and C2-6alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical or different substituents selected from a group consisting of F, Cl, Br, I, NO2, O-C1-4 alkyl, O-C2-3 alkenyl, C(O)-O-C1-4 alkyl, C(O)-O-C2-3 alkenyl, O-R5, S-R5, and N(H)R5; R5 is a protecting group for protecting OH, SH, NH or NH2, which is stable under reaction conditions, also as defined herein in its embodiments. Non-limiting examples for the substrate areOur Ref. : LZA32043PCT 36In one embodiment, the substrate is not.In one embodiment, the substrate is not .Our Ref. : LZA32043PCT 37 In one embodiment, the substrate is not.Our Ref. : LZA32043PCT 38 Abbreviations and definitions used throughout the specification aq. aqueous Barg bar gauge, pressure above atmospheric pressure patm, patm is approximately 1.013 bar BPR back pressure regulation device CompEx comparative example conv conversion CV column volume(s) DAST diethylaminosulfur trifluoride, Et2NSF3 DCE 1,2-Dichloroethane DCM Dicholoromethane Deoxo-fluor Bis(2-methoxyethyl)aminosulfur trifluoride DIPEA N,N-diisopropylethylamine EA ethyl acetate EtOAc ethyl acetate equiv molar equivalent Ex example FEP fluoroethylene-propylene FFKM perfluoroelastomeric compound FID flame ionization detector Fluolead™ 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride LPR line pressure regulator M molar MFC mass flow controller MIXDEV mixing device MoC Material of Construction MTBE Methyl tert-butyl ether na not available NPT National Pipe Taper PE petroleum spirit 40-60 (40 to 60 °C boiling range) PEEK polyether ether ketone PFA perfluoralkoxy alkanes – copolymer of hexyfluoropropylene and perfuoroethersOur Ref. : LZA32043PCT 39 PP polypropylene Prod product PTFE polytetrafluoroethylene PVDF polyvinylfluorid RCF2 abbreviation in this specification designating the geminal difluoro product of the deoxyfluorination reaction RCF abbreviation in this specification designating the (undesired) vinyl fluoro byproduct, which may occur in the deoxyfluorination reaction by an elimination RESDEV residence device RT room temperature SEPDEV separation device sat. saturated sel selectivity SS stainless steel TEA triethylamine TMS Tetramethylsilan tMix mixing time tResresidence time tSep separation time TLC Thin Layer Chromatography V̇g gaseous flow rate V̇l liquid flow rate XtalFluor E™ diethylaminodifluorosulfinium tetrafluoroborate XtalFluor-M™ morpholinodifluorosulfinium tetrafluoroborate if not explicitly stated otherwise in the text.Our Ref. : LZA32043PCT 40 EXAMPLES Materials All materials were obtained from commercial suppliers (TCI, Sigma Aldrich, BLD pharm, ABCR, Alfa Aesar, Acros Organics, ThermoScientific, Apollo Scientific or VWR) and used without further purification unless otherwise noted. Dichloromethane extra dry (99.9%, water < 50 ppm, AcroSeal®) was used as a solvent. Diethylamine 99% and 4-fluorotoluene were acquired from Sigma Aldrich. DAST >90% and trifluorotoluene >99% were obtained from TCI. Table 1 shows the sources of the substrates used in the Examples.Our Ref. : LZA32043PCT 4142Our Ref : LZA32043PCT 43Method: NMR analysis NMR spectra were recorded on a NMR instrument of Bruker, Germany:1H were recorded at 300 MHz,13C spectra at 75 MHz, and19F at 282 MHz respectively, with a chemical shift relative to TMS expressed in parts per million (ppm). The samples were prepared in CDCl3. The letters s, d, t and m are used to indicate singlet, doublet, triplet, and multiplet, respectively. A Magritek Benchtop NMR (Spinsolve Ultra 43 MHz) was used for19F NMR measurements of reaction mixtures. FEP NMR liners were inserted into standard NMR tubes to prevent corrosion. Any so-called19F yield was determined using trifluorotoluene as internal standard, the respective signal is at -63.7 ppm. For the fluorination experiments of cyclohexanone, 4-fluorotoluene was used as an internal standard with the respective signal at -113.5 ppm. To calculate this19F yield, the area of the NMR signal of the internal standard was compared to the area of the NMR signal of product or impurity, as the case may be, and adjusted to the used amounts. Method: Gaschromatography (GC) Analysis GC analysis was performed on a Shimadzu GC FID 230 with a flame ionization detector (FID), using an RTX-5MS Cap. column (30 m × 0.25 mm ID × 0.25 μm) and helium as carrier gas (40 cm / sec-1linear velocity). The injector temperature was set to 280 °C. After 1 min at 50 °C, the temperature was increased by 25 °C / min to 300 °C and kept constant at 300 °C for 4 min. FID was used for detection, the detector gases used for flame ionization were hydrogen and synthetic air (5.0 quality). Quantification by GC:Our Ref. : LZA32043PCT 44 In general the detection limit for any compound in this GC method was ca.1%, that means if no peak was discernible then the amount of the compound was below 1%. So for example any conversion stated herein with >99% or any yield herein stated with <1% means "below detection limit". In particular for specific compounds conversion and yield were calculated as follows: ^ Cyclohexanone and 1,1-difluorocyclohexane were calibrated against 4- fluorotoluene as internal standard (IntStd). The peak area ratio of cyclohexanone or 1,1-difluorocyclohexanone and internal standard were plotted against the concentration ratio of the respective compounds. The yield was calculated using the obtained calibration curves based on the following formulas: Cyclohexanone: areacyclohexanonearea+c ∗ IntStdIStd0.8863 Conversion = 1 −ccyclohexanone,feed1,1-Diflurocyclohexane: Yield =ccyclohexanone,feed^ 1-Fluorocyclohexene was not commercially available so a response factor of 1-fluorocyclohexene against 1,1-difluorocyclohexane was estimated by comparing the integration area of the19F NMR and the GC area. AOur Ref. : LZA32043PCT 45 response factor of 1.18 was determined and the calibration curve of 1,1- difluoroyclohexane was used to calculate the yield: 1-Fluorocyclohexene: Yield = 1.18 ∗ccyclohexanone,feed^ For all the other tested substrates an assay yield called “Conversion GC” and “yield GC” in % was used: Quantification was done using trifluorotoluene or 4-fluorotoluene as internal standard. To calculate the percentage, the area ratio between internal standard and substrate (conversion GC) or product or impurities (yield GC), as the case may be, was compared before and after the reaction. Method: Gaschromatography-Masspectrometry (GC-MS) Analysis GC-MS analysis was performed using a Shimadzu GCMS-QP2010 SE, using an RTX-5MS column (30 m × 0.25 mm × 0.25 μm) and helium as carrier gas (40 cm / sec linear velocity). The injector temperature was set to 280 °C. After 1 min at 50 °C, the oven temperature was increased by 25 °C / min to 300 °C and then kept at 300 °C for 3 min. The mass detector was a quadrupole with pre rods and electron impact ionization. The following settings were used in the detector: ion source temperature 200 °C, interface temperature 310 °C, solvent cut time 2 min 30 sec, acquisition mode scan, mass range m / z = 50 till m / z = 400. Method: Flash Column Chromatography Automated flash column chromatography was performed on a Biotage Isolera system using columns packed with KP-SIL, 60 Å (32 to 63 μm particle size) silica. Eluent was petroleum spirit 40-60 with an increasing gradient of ethyl acetate. Method: TLCOur Ref. : LZA32043PCT 46 Analytical thin-layer chromatography (TLC) was carried out using Merck silica gel 60 GF254 plates. Compounds were visualized by means of UV or by using KMnO4 or a ninhydrine solution (400 mg ninhydrine in a total volume of 200 mL n-butanol with 0.5 vol% acetic acid and 4.5 vol% water, the vol% begin based on the total volume). Eluent was the same as used for Flash Column Chromatography or it is stated. Method: Karl Fisher Analysis Any water content was determined with Karl Fisher analysis, using an automatic Metrohm Titrando 831 KF coulometric Karl Fisher titration method (EN ISO 12937:2000) in triplicate. Material of Construction (MoC) SF4 is in general not very corrosive but as SF4 gets in contact with water, even in form of moisture, HF is immediately formed. So, a similar material of construction (MoC) as when working with HF has to be used. Therefore, wetted parts must be made out of PEEK, PTFE, PFA, PP, FEP, stainless steel or FFKM. Glass-made material cannot be used. Additionally, it is highly recommended to check all the material for corrosion regularly and perform daily leak tests before starting the system. To prevent corrosion, it must be ensured that the system is flushed by N2before starting the SF4line to remove traces of moisture in the system, which could lead to HF formation. In this way a longer lifetime of the instruments can be achieved. (A1) Flow Configuration for “Commercial DAST in flow, 2 feeds” The flow configuration is shown in Figure 1 and described in detail as follows: Standard PFA tubing (0.8 mm or 1.6 mm i.d.), PTFE fittings and T-pieces were used in the flow setup. For the gaseous feed stainless steel fittings from Fitok Group, US, were used. For pumping reagent solutions, syringe pumps (Syrris Asia, UK) equipped with 1 mL and 0.5 mL syringes were used. All pumps were used with check valves (Upchurch, CV-3321, IDEX Corporation, US) to prevent backflow into the pumps, and internal pressure sensors. The pressure limit of the pumps was set to 10 barOur Ref. : LZA32043PCT 47 for safety reasons. Before using the pumping systems, they were calibrated by pumping for a specified time and checking the mass balance. All pumps were found to dose within ± 3%. A 6-port valve with a 5 mL sample loop having an inject position and a load position was used for the FEED2, the reagent feed (DAST). The solvent was either pumped by syringe pump 2 directly into a mixing device (MIXDEV), a T- piece, this happened in the load position of the sample loop, or first through the 5 mL sample loop containing DAST and then into the T-piece for mixing with the substrate feed, this happened in the inject position of the sample loop. FEED1, containing the substrate, was pumped by a syringe pump 1 through a check valve (Upchurch, CV-3321, IDEX Corporation, US), to prevent backflow, into the syringe pump 1. The two liquid feeds were mixed in the MIXDEV, the T-piece (Tee Body IDEX H&S P-712-01, PEEK, 0.020” (0.50 mm) thru hole), whose outlet was connected to a residence device (RESDEV), a reactor coil. RESDEV (0.8 mm i.d., 16 mL volume) was heated with a coil heater (Syrris Asia, UK), and connected to an adjustable back pressure regulator (BPR) (20 bar max, Zaiput Flow Technologies, US) pressurized by compressed air to 2.5 barg. The reaction mixture subsequently passed into a separating device (SEPDEV), a membrane separator (SEP-10, Zaiput Flow Technologies, US) using a hydrophobic membrane (Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 µm pore size, 47 mm circle (100 pcs), Whatman plc, UK) cut to the required size of the membrane separator, to separate the reaction mixture into a hydrophilic stream, which was retained by the membrane and was a gaseous stream and which contained any formed gases in the reaction, and a hydrophobic stream, which passed through the membrane and was a liquid stream and which contained the solvent and any dissolved compounds. The hydrophilic (gaseous) stream was diluted via a T-piece with water (300 µL / min) and then collected in a stirred first quench bottle containing aqueous NaOH (5 wt%) and a few drops of phenolphthalein as a pH indicator (collection under the surface of the aqueous NaOH). The hydrophobic (liquid) stream was forwarded to a 4-way valve (4-way valve PEEK bulkhead single "T" Flow, IDEX Corporation, US). One outlet was a shortOur Ref. : LZA32043PCT 48 tubing for sampling. Another outlet was connected via a T-piece to dilute the hydrophobic (liquid) stream with water (200 µL / min) into a stirred second quench bottle containing aqueous NaOH (5 wt%) and a few drops of phenolphthalein as a pH indicator (collection under the surface of the aqueous NaOH). The headspace of that second quench bottle was connected into the first quench bottle from the gaseous stream (again collection under the surface of the aqueous NaOH). The headspace of this first quench bottle was connected to a third quench bottle containing aqueous NaOH (10 wt%) and a few drops of phenolphthalein as a pH indicator (collection under the surface of the aqueous NaOH). The head space of this third quench bottle was connected to a tubing going to the back of the fume cupboard (not shown in Figure 1). The surface of the aqueous NaOH in any of the three bottles is depicted with a wavy line. The dilution of both of the gaseous stream and the liquid stream with water served the purpose to prevent NaF formation and precipitation in the tubing, which can lead to clogging. The water was dosed via respective pumps, which are not shown in Figure 1. Additionally, the quench bottles were stirred by magnetic stirrers and if necessary cooled with an ice bath (also not shown in Figure 1). (A2) Flow Configuration for “DAST in situ, 3 feeds” The flow configuration is shown in Figure 2 and described in detail as follows: Standard PFA tubing (0.8 mm or 1.6 mm i.d.), PTFE fittings and T-pieces were used in the flow setups. For the gaseous feed stainless steel fittings from Fitok Group, US, were used. For pumping reagent solutions, syringe pumps (Syrris Asia, UK) equipped with 1 mL and 0.5 mL syringes were used. All pumps were used with check valves (Upchurch, CV-3321, IDEX Corporation, US) to prevent backflow into the pumps, and internal pressure sensors. The pressure limit of the pumps was set to 4 bar to prevent pushing the liquid back to the mass flow controller MFC for the gaseous feed. Above 4 bar pressure, the pumps would turn-off automatically for safety reasons. Before using the pumping systems, they were calibrated by pumping for a specified time and checking the mass balance. All pumps were found to dose within ± 3%.Our Ref. : LZA32043PCT 49 For optimization studies and small-scale experiments, a 6-port valve with a 5 mL sample loop having an inject position and a load position was used for the substrate feed (this sample loop is not shown in Figure 2, it was inserted between the check valve after syringe pump 2 and MIXDEV2). The FEED3 (solvent) was either pumped by the syringe pump 2 directly into a second mixing device, MIXDEV2, a T-piece, this happened in the load position of the sample loop, or first through said 5 mL sample loop and then into MIXDEV2 for mixing the substrate feed with the reaction stream, this happened in the inject position of the sample loop. For the gaseous feed, the FEED2, a bottle of SF4(1 kg, 99%, 9.65 bar pressure, lot 1377769, abcr GmbH, Germany) was connected to a magnetic valve (Type 0330, PVDF, NPT ¼, FFKM, Bürkert Werke GmbH, Germany) with a manual power switch outside the fume hood. This valve was connected to a 3-way valve (stainless steel), which was connected to a bottle of N2 (6.0, air liquide) to flush the whole system. After the 3-way valve, a line pressure regulator (LPR) (KPR1FJC412A20000, Swagelok Company, US) was used to reduce the pressure to 4 bar. The flow was controlled by a mass flow controller (MFC) (LOW-ΔP- FLOW F-201DV, Bronkhorst High-Tech B.V., NL) calibrated at p1 = 10 barg, p2 = 5 barg, T = 30 °C (accuracy ± 1%) connected via RS-232 to a controller. Flow rates of the MFC are given in mLn / min, where n presents measurement under standard conditions (Tn= 0 °C, pn= 1.013 bar). After the MFC, a check valve (wetted material: SS, Kalrez®, Fitok Group, US) was used to prevent backflow of the liquid phase. After this check valve the gas flow was mixed with a solvent flow, the FEED1, from syringe pump 1 in a first mixing device, MIXDEV1, a T- piece (Tee Body IDEX H&S P-712-01, PEEK, 0.020” (0.50 mm) thru hole), whose outlet was connected to a first residence device, RESDEV1, a reactor coil 1. RESDEV1 (0.8 mm i.d., 1.6 mL volume) was placed into a heated water bath on a magnetic stirrer. After RESDEV1 the reaction mixture was mixed with a liquid feed, the FEED 3, containing the substrate from syringe pump 2 using MIXDEV2, a T-piece (Tee Body IDEX H&S P-712-01, PEEK, 0.020” (0.50 mm) thru hole), whose outlet was connected to a second residence device RESDEV2, a reactor coil 2 (0.8 mm i.d., 16 mL volume) heated by a coil heater (Syrris Asia, UK). The liquid feed from syringe pump 2 was connected as described above withOur Ref. : LZA32043PCT 50 the 6-port valve, the check valve and optionally the sample loop (not shown in Figure 2). After RESDEV2, the flow of the reaction mixture then passed through an adjustable back pressure regulator (BPR) (20 bar max, Zaiput Flow Technologies, US) pressurized by compressed air to 2.5 barg. After the BPR the reaction mixture passed into a separating device, SEPDEV, a membrane separator (SEP-10, Zaiput Flow Technologies, US) using a hydrophobic membrane (Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 µm pore size, 47 mm circle (100 pcs), Whatman plc, UK) cut to the required size of the membrane separator, to separate the reaction mixture into a hydrophilic stream, which was retained by the membrane and was a gaseous stream and which contained any residual amount of SF4, and a hydrophobic stream, which passed through the membrane and was a liquid stream and which contained the solvent and any dissolved compounds. After the membrane separator the setup of the apparatus was identical with the setup after the respective SEPDEV described in (A1) in connection with Figure 1. (A3) Flow Configuration for “DAST in situ, 2 feeds” The flow configuration is shown in Figure 3 and described in detail as follows: Standard PFA tubing (0.8 mm or 1.6 mm i.d.), PTFE fittings and T-pieces were used in the flow setups. For the gaseous feed stainless steel fittings from Fitok Group, US, were used. For pumping reagent solutions, syringe pumps (Syrris Asia, UK) equipped with 1 mL and 0.5 mL syringes were used. All pumps were used with check valves (Upchurch, CV-3321, IDEX Corporation, US) to prevent backflow into the pumps, and internal pressure sensors. The pressure limit of the pumps was set to 4 bar to prevent pushing the liquid back to the mass flow controller MFC for the gaseous feed. Above 4 bar pressure, the pumps would turn off automatically for safety reasons. Before using the pumping systems, they were calibrated by pumping for a specified time and checking the mass balance. All pumps were found to dose within ± 3%. For optimization studies and small-scale experiments, a 6-port valve with a 5 mL sample loop (for dosing the substrate) having an inject position and a load position was used for the liquid feed FEED1 (this sample loop is not shown in Figure 3, it was inserted between the check valve after theOur Ref. : LZA32043PCT 51 syringe pump and MIXDEV). The solvent was either pumped directly into a mixing device, MIXDEV, a T-piece, this happened in the load position of the sample loop, or first through the 5 mL sample loop and then into MIXDEV for mixing the liquid feed with the gaseous feed, this happened in the inject position of the sample loop. For the gaseous feed, a bottle of SF4 (1 kg, 99%, 9.65 bar pressure, lot 1377769, abcr GmbH, Germany) was connected to a magnetic valve (Type 0330, PVDF, FFKM, Bürkert Werke GmbH, Germany) with a manual power switch outside the fume hood. This valve was connected to a 3-way valve (stainless steel), which was connected to a bottle of N2(6.0, air liquide) to flush the whole system. After the 3-way valve, a line pressure regulator (LPR) (KPR1FJC412A20000, Swagelok Company, US) was used to reduce the pressure to 4 bar. The flow was controlled by a mass flow controller (MFC) (LOW-ΔP- FLOW F-201DV, Bronkhorst High-Tech B.V., NL) calibrated at p1 = 10 barg, p2 = 5 barg, T = 30 °C (accuracy ± 1%) connected via RS-232 to a controller. Flow rates of the MFC are given in mLn / min, where n presents measurement under standard conditions (Tn = 0 °C, pn = 1.013 bar). After the MFC, a check valve (wetted material: SS, Kalrez®, Fitok Group, US) was used to prevent backflow of the liquid phase. After this check valve the gaseous flow was mixed with the liquid flow from the syringe pump in the MIXDEV, the T-piece (Tee Body IDEX H&S P-712-01, PEEK, 0.020” (0.50 mm) thru hole), whose outlet was connected to a residence device, RESDEV, a reactor coil (0.8 mm i.d., 16 mL volume) heated by a coil heater (Syrris Asia, UK). After RESDEV, the flow of the reaction mixture then passed through an adjustable back pressure regulator (BPR) (20 bar max, Zaiput Flow Technologies, US) pressurized by compressed air to 2.5 barg. The reaction mixture subsequently passed into a separating device (SEPDEV), a membrane separator (SEP-10, Zaiput Flow Technologies, US) using a hydrophobic membrane (Whatman 7585-004, PTFE Membrane, WTP Range, 0.5 µm pore size, 47 mm circle (100 pcs), Whatman plc, UK) cut to the required size of the membrane separator, to separate the reaction mixture into a hydrophilic stream, which was retained by the membrane and was a gaseous stream and which contained any residual amount of SF4, and a hydrophobic stream, whichOur Ref. : LZA32043PCT 52 passed through the membrane and was a liquid stream and which contained the solvent and any dissolved compounds. After the membrane separator the setup of the apparatus was identical with the setup after the respective SEPDEV described in (A1) in connection with Figure 1. (B1) Fluorination Procedure exemplified with cyclohexanone using the setup (A1) "Commercial DAST in flow, 2 feeds" Cyclohexanone was reacted with DAST as described in this (B1) Fluorination Procedure and as shown in Scheme 1, this (B1) Fluorination Procedure was done with the (A1) Flow Configuration for “Commercial DAST in flow, 2 feeds”.The first feed solution (FEED1) containing the substrate was prepared in a volumetric flask. Cyclohexanone (0.948 g, 10 mmol) and 4-fluorotoluene (0.551 g, 5 mmol) were dissolved in DCM (20 mL), resulting in a concentration of 0.5 M of cyclohexanone and 0.25 M of 4-fluorotoluene. After mixing, the flask was sealed under argon atmosphere, and the solution was taken out using a needle and a short tube connected to the syringe pump. The second feed solution (FEED2) containing the reagent (DAST) was prepared in a volumetric flask. DAST (0.896 g, 5 mmol) was dissolved in DCM (5 mL, resulting in a concentration of 1 M of DAST. After mixing, the flask was sealed under argon atmosphere, and the solution was taken out using a syringe and a needle and then injected into the sample loop in the load position. In order to remove moisture from the system before running the reaction, the system was flushed with DCM (V̇total = 2 mL / min) delivered from both syringe pumps for 30 min (1 mL / min each). The residence device (RESDEV), the reactor coil (16 mL internal volume) was heated to and kept at 70 °C, while the flowrates were changed to V ̇1 = 0.500 mL / min and V̇2 = 0.500 mL / min. After reachingOur Ref. : LZA32043PCT 53 in the reactor coil a temperature of 70 °C, the FEED1 was started to beingpumped at a flow rate V ̇1 of 0.500 mL / min for 3 min. Then, the 6-way valve wasturned to the inject position and the DAST loaded sample loop was fed into the reactor coil (tRes16 min) at a flow rate of V̇2of 0.500 mL / min. After 20 minutes, which corresponds to 1.25 x residence times, steady state was assumed, and sampling was started. For sampling, the 4-way valve was turned, and the outlet tubing was placed into 4 mL vials containing quench solution and a stirring bar. The following order of samples was collected, each sample was collected for 30 sec if not otherwise stated: 1) NaOH 5% 2) aq. sat. solution of NaHCO33) sampling into an FEP NMR liner without a quench 4) NaOH 5%: sampling for 2 min 30 sec 5) NaOH 5% The sample 3) in the FEP NMR liner was analyzed by NMR analysis (1H and19F). From the quenched samples 1), 2), 4) and 5), the organic phase was taken (20 µL) and diluted in MeCN (980 µL) for GC analysis, the mean value of the 4 GC values (while eliminating any obvious outlier) of these 4 samples is reported under GC results herein. The same samples were analyzed by GC-MS using their molecular weights for identification. After finishing the fluorination experiment, the system was flushed with DCM (2 mL / min) for 20 min, followed by isopropanol (2 mL / min) for 20 min. Last, the membrane separator was flushed with 10 mL H2O and 10 mL toluene to reactivate the membrane. (B2) Fluorination Procedure exemplified with cyclohexanone using the setup (A2) "DAST in situ, 3 feeds" Cyclohexanone was reacted with diethylamine and SF4as described in this (B2) Fluorination Procedure and as shown in Scheme 2, this (B2) Fluorination Procedure was done with the (A2) Flow Configuration for “DAST in situ, 3 feeds".OurThe feed solution FEED1 containing the base (Et2NH) was prepared in a volumetric flask. Diethylamine (0.731 g, 10 mmol) was dissolved in DCM (20 mL, resulting in a concentration of 0.5 M of Et2NH. After mixing, the flask was sealed under argon atmosphere, and the solution was taken out using a needle and a short tube connected to the syringe pump. FEED2 was the gaseous SF4and was fed as described in (A2). The feed solution FEED3 containing the substrate was prepared in a volumetric flask. Cyclohexanone (0.237 g, 2.5 mmol) and 4-fluorotoluene (0.138 g, 1.25 mmol) were dissolved in DCM (5 mL), resulting in a concentration of 0.5 M of cyclohexanone and 0.25 M of 4-fluorotoluene. After mixing, the flask was sealed under argon atmosphere, and the solution was taken out using a syringe and a needle and then injected into the sample loop in the load position. Alternatively, a solution of cyclohexanone (0.5 M) and 4-fluorotoluene (0.25 M) in DCM is fed into the syringe pump 2. In order to remove moisture from the system before running the reaction, the system was flushed with N2 (15 mLn / min) for 20 min, and then, the syringe pump 1 and syringe pump 2 were started (1 + 1 mL / min) and the whole system was flushed for 20 min with DCM. The heating baths for RESDEV1, the reactor coil 1, (1.6 mL internal volume) and RESDEV2, the reactor coil 2, (16 mL internal volume) were heated to and kept at 70 °C. After reaching a temperature of 70 °C in the reactor coils, the 3-way valve was turned and FEED2 containing SF4gas was started. The gaseous flow rate V̇g was set to 25 mLn / min and the mixing with DCM (liquid flow rates V̇l,1of 0.666 mL / min and V̇l,2of 0.333 mL / min) continued for 4 min. Then, the gaseous flow rate V̇g was reduced to 8.2 mLn / min (1 equiv SF4 compared to base) and FEED1 was started by changing from DCM to theOur Ref. : LZA32043PCT 55 FEED1 solution. The system was left to equilibrate until all gas was dissolved after MIXDEV1 (no N2traces left, tRes11.5 min). After 3 min in steady operation, the 6-way valve was turned to the inject position and the FEED3 loaded sample loop was fed into RESDEV2, the reactor coil 2, (tRes216 min) via MIXDEV2. After 20 minutes, which corresponds to 1.25 x residence times, steady state was assumed, and sampling was started. For sampling, the 4-way valve was turned, and the outlet tubing was placed into 4 mL vials containing quench solution and a stirring bar. The following order of samples was collected, each sample was collected for 30 sec if not otherwise stated: 1) NaOH 5% 2) aq. sat. solution of NaHCO3 3) sampling into an FEP NMR liner without a quench 4) NaOH 5%: sampling for 2 min 30 sec 5) NaOH 5% The sample 3) in the FEP NMR liner was analyzed by NMR analysis (1H and19F). From the quenched samples 1), 2), 4) and 5) the organic phase was taken (20 µL) and diluted in MeCN (980 µL) for GC analysis, the mean value of the 4 GC values (while eliminating any obvious outlier) of these 4 samples is reported under GC results herein. The same samples were analyzed by GC-MS using their molecular weights for identification. After finishing the fluorination experiment, the system was flushed with N2(15 mLn / min) and DCM (1 + 1 mL / min) for 20 min. Then, the solvents were switched to isopropanol for another 15 minutes. After that, the solvent pumps were turned off and the system was flushed with N2(15 mLn / min) for 10 more min. Last, the membrane separator was flushed with 10 mL H2O and 10 mL toluene to reactivate the membrane. (B3) Fluorination Procedure exemplified with cyclohexanone using the setup (A3), "DAST in situ, 2 feeds" Cyclohexanone was reacted with diethylamine and SF4 as described in this (B3) Fluorination Procedure and as shown in Scheme 3, this (B3) Fluorination Procedure was done with the (A3) Flow Configuration for “DAST in situ, 2 feeds”.Our Ref. : LZA32043PCT 56The feed solution FEED1 containing the base (Et2NH) and substrate (cyclohexanone) was prepared in a volumetric flask. Diethylamine (0.366 g, 5 mmol), cyclohexanone (0.237 g, 2.5 mmol) and 4-fluorotoluene (0.138 g, 1.25 mmol) were dissolved in DCM (5 mL), resulting in a concentration of 1 M of Et2NH, 0.5 M of cyclohexanone and 0.25 M of 4-fluorotoluene. After mixing, the flask was sealed under argon atmosphere, and the solution was taken out using a syringe and a needle and then injected into the sample loop in the load position. Alternatively, a solution of Et2NH (1 M), cyclohexanone (0.5 M) and 4- fluorotoluene (0.25 M) in DCM is fed into the syringe pump. FEED2 was the gaseous N2 or SF4 and was fed as described in (A3). In order to remove moisture from the system before running the reaction, the system was flushed with N2(15 mLn / min) for 20 min, and then, the syringe pump was started (1.5 mL / min) and the whole system was flushed for 20 min with DCM. RESDEV, the reactor coil, (16 mL internal volume) was heated to and kept at 70 °C. After reaching a temperature of 70 °C in the reactor coil, the 3-way valve was turned and FEED2 containing SF4 gas was started. The gaseous flow rate V̇g was set to 25 mLn / min and the mixing with DCM (liquid flow rate V̇l,1 of 1 mL / min) continued for 4 min. Then, the gaseous flow rate V̇g was reduced to 12.1 mLn / min (1 equiv SF4 compared to base) and the system was left to equilibrate until all gas was dissolved after MIXDEV (no N2traces left). After 3 min in steady operation, the 6-way valve was turned to the inject position and the FEED1 loaded sample loop was fed into the reactor coil (tRes 16 min) via MIXDEV. After 20 minutes, which corresponds to 1.25 x residence times, steady state was assumed, and sampling was started. For sampling, the 4-way valve was turned, and the outlet tubing was placed into 4 mL vials containing quenchOur Ref. : LZA32043PCT 57 solution and a stirring bar. The following order of samples was collected, each sample was collected for 30 sec if not otherwise stated: 1) NaOH 5% 2) aq. sat. solution of NaHCO3 3) sampling into an FEP NMR liner without a quench 4) NaOH 5%: sampling for 2 min 30 sec 5) NaOH 5% The sample 3) in the FEP NMR liner was analyzed by offline NMR analysis (1H and19F). From the quenched samples 1), 2), 4) and 5) the organic phase was taken (20 µL) and diluted in MeCN (980 µL) for GC analysis, the mean value of the 4 GC values (while eliminating any obvious outlier) of these 4 samples is reported under GC results herein. The same samples were analyzed by GC-MS using their molecular weights for identification. After finishing the fluorination experiment, the system was flushed with N2 (15 mLn / min) and DCM (1.5 mL / min) for 20 min. Then, the solvent was switched to isopropanol for another 15 minutes. After that, the solvent pump was turned off and the system was flushed with N2 (15 mLn / min) for 10 more min. Last, the membrane separator was flushed with 10 mL H2O and 10 mL toluene to reactivate the membrane. (B4) Fluorination Procedure exemplified with cyclohexanone using the setup (A3), "DAST in situ, 2 feeds" but with Et3N instead of Et2NH Cyclohexanone was reacted with SF4 as described in this (B4) Fluorination Procedure and as shown in Scheme 4.The (B4) Fluorination Procedure is similar to the (B3) Fluorination procedure, instead of creating DAST in situ by a reaction between Et2NH and SF4, no Et2NHOur Ref. : LZA32043PCT 58 was used but Et3N, thereby SF4 itself was the fluorinating agent, no DAST is generated in situ. The (B4) Fluorination Procedure was done with the (A3) Flow Configuration with the following differences to (A3) Flow Configuration: ^ the sample loop for the liquid FEED1 (which is not shown in Figure 3) was not inserted between the check valve after the syringe pump and MIXDEV, but between the syringe pump and the check valve; ^ the residence device, RESDEV, was not a reactor coil with 16 mL volume, but with 4.6 ml volume; ^ the heating of RESDEV was not done with a coil heater (Syrris Asia, UK), but RESDEV was placed in a heated water bath on a magnetic stirrer; ^ after RESDEV the flow of the reaction mixture did not enter directly into the BPR, but between RESDEV and BPR the flow of the reaction mixture passed thorough an inline NMR analysis (ca.1 ml internal volume) (not shown in Figure 3); The feed solution FEED1 containing the substrate was prepared in a volumetric flask. Cyclohexanone (245 mg, 2.5 mmol), triethylamine (253 mg, 2.5 mmol, 1 equiv) and trifluorotoluene (183 mg, 1.25 mmol) were dissolved in ethyl acetate (5 mL, resulting in a concentration of 0.5 M of cyclohexanone and 0.25 M of trifluorotoluene). After mixing, the flask was sealed under argon atmosphere, and the solution was taken out using a syringe and a needle and then injected into the sample loop in the load position. In order to remove moisture from the system before running the reaction, the system was flushed with N2(15 mLn / min) for 20 min, and then, the EtOAc pump was started (0.50 mL / min) and the whole system was flushed for 15 min. The heating bath for the reactor coil (4.6 mL internal volume) was heated to and kept at 50 °C. After reaching in the heating bath the temperature of 50 °C, the 3-way valve was turned and SF4 feed FEED2 was started. The gaseous flow rate V̇g was set to 25 mLn / min and the mixing with EtOAc (liquid flow rate V̇lof 0.5 mL / min) continued for 4 min. Then, the gaseous flow rate V̇g was reduced to 6.1 mLn / minOur Ref. : LZA32043PCT 59 (1 equiv SF4) and the system was left to equilibrate until all gas was dissolved after the T-piece mixer (no N2traces left). The 6-way valve was then turned to the inject position and the substrate / base loaded sample loop was fed into the reactor coil (tRes 552 sec). When steady state was observed using the in-line NMR analysis, 30 sec were waited until sampling into the collection flasks was started to ensure that the reaction mixture had passed through the remaining volume of the system and had reached the sampling outlet. For sampling, the 4-way valve was turned and the outlet tubing was placed into 4 mL vials containing quench solution and a stirring bar. The following order of samples was collected, each sample was collected for 30 sec if not otherwise stated: 1) NaOH 5% 2) aq. sat. solution of NaHCO33) sampling into an FEP NMR liner without a quench 4) NaOH 5%: sampling for 2 min 30 sec 5) NaOH 5% The sample 3) in the FEP NMR liner was analyzed by offline NMR analysis (1H and19F). From the quenched samples 1), 2), 4) and 5) the organic phase was taken (10 µL) and diluted in MeCN (990 µL) for GC analysis, the mean value of the 4 GC values (while eliminating any obvious outlier) of these 4 samples is reported under GC results herein. The same samples were analyzed by GC-MS using their molecular weights for identification. After finishing the fluorination experiment, the system was flushed with N2 (15 mLn / min) and EtOAc (1 mLn / min) for 10 min. Then, the solvent pump was turned off and the system was flushed with N2(15 mLn / min) for 10 more min. Last, the membrane separator was flushed with 10 mL H2O and 10 mL toluene to reactivate the membrane. (C) Isolation procedure The following isolation procedure was used after the (B1), (B2), or (B3) Fluorination procedures: The organic phase of sample 4) was separated from the aqueous phase and washed with an aq. sat. solution of NaHCO3, water, aq. citric acid (5 w%), water, and with an aq. sat. solution of NaCl. The organic phase wasOur Ref. : LZA32043PCT 60 dried over Na2SO4 and filtered. For non-volatile products, the organic solvent was removed under reduced pressure (2 mbar at 40 °C) to afford the desired fluorinated products. A flash column chromatography was performed in case the product purity was not satisfying. Isolated compounds were characterized by NMR analysis. Isolated yields were corrected based on assay. Examples on Influence of Temperature - Substrate Cyclohexanone Cyclohexanone was reacted according to (B2) Fluorination Procedure; deviations from the protocol of the (B2) Fluorination Procedure are given in Table 1. Example 1 gives the respective values for (B2) Fluorination Procedure without deviations, that is at the temperature of 70 °C of reactor coil 1 and reactor coil 2. Table 1 reactor reactor Example coil 1 coil 2 Conversion Yield RCF2 Yield RCF Temp Temp GC [%] GC [%] GC [%] [°C] [°C] 1 70 70 94 71 < 1 2 25 70 98 72 <1 3 70 50 86 62 <1 For all reactions: SF4(2 equiv), Et2NH (2 equiv), DCM, 0.5 M (both base and substrate), 1.5 min tres1in reactor coil 1, 16 min tres2in reactor coil 2. Examples on Influence of Stoichiometry - Substrate Cyclohexanone Cyclohexanone was reacted according to (B2) Fluorination Procedure; deviations from the protocol of the (B2) Fluorination Procedure are given in Table 2. Example 1 gives the respective values for (B2) Fluorination Procedure without deviations. Table 2 Concentration ubstrate Et2NH Yield Yield Example s SF4Conversion [eq] [ RCF2 RCF + base [M] eq] GC [%] GC [%] GC [%] 1 0.5 2 2 94 71 <1 6 0.5 3 3 99 75 <1 7 0.5 4 4 >99 77 <1Our Ref. : LZA32043PCT 61For all reactions: DCM, 70 °C / 1.5 min tres1in reactor coil 1, 70 °C / 16 min tres2in reactor coil 2. Examples on Influence of Residence Time - Substrate Cyclohexanone Cyclohexanone was reacted according to (B2) Fluorination Procedure; deviations from the protocol of the (B2) Fluorination Procedure are given in Table 3. Example 1 gives the respective values for (B2) Fluorination Procedure without deviations.For all reactions: SF4(2 equiv), Et2NH (2 equiv), DCM, 70 °C in reactor coil 1 and reactor coil 2, 0.5 M (both base and substrate). (1) Exchange of reactor coil 1 as a short piece of tubing (1 / 16”, ca.10 cm). Examples on Influence of Base - Substrate Cyclohexanone Cyclohexanone was reacted according to (B2) Fluorination Procedure; deviations from the protocol of the (B2) Fluorination Procedure are given in Table 4. Example 1 gives the respective values for (B2) Fluorination Procedure without deviations.Our Ref. : LZA32043PCT 62For all reactions: SF4 (2 equiv), base (2 equiv), 0.5 M (both base and substrate), 70 °C / 1.5 min tres1 in reactor coil 1, 70 °C / 16 min tres2 in reactor coil 2. Examples on Influence of Solvent - Substrate Cyclohexanone Cyclohexanone was reacted according to (B) Fluorination Procedure; deviations from the protocol of the (B) Fluorination Procedure are given in Table 5. Example 1 gives the respective values for (B2) Fluorination Procedure without deviations.For all reactions: SF4(2 equiv), Et2NH (2 equiv), 0.5 M (base + substrate), 70 °C / 1.5 min tres1 in reactor coil 1, 70 °C / 16 min tres2 in reactor coil 2. (1) Reactor coil 1 and reactor coil 2 temperatures were increased from 70 °C to 90 °C. Examples on Influence of concentration - Substrate Cyclohexanone Cyclohexanone was reacted according to (B2) Fluorination Procedure; deviations from the protocol of the (B2) Fluorination Procedure are given in Table 6. Example 1 gives the respective values for (B2) Fluorination Procedure without deviations.Our Ref. : LZA32043PCT 63For all reactions: SF4 (2 equiv), Et2NH (2 equiv), 70 °C / 1.5 min tres1 in reactor coil 1, 70 °C / 16 min tres2in reactor coil 1. Examples on Influence of Water - Substrate Cyclohexanone Cyclohexanone was reacted according to (B2) Fluorination Procedure; deviations from the protocol of the (B2) Fluorination Procedure are given in Table 7. Example 1a is a repetition of example 1 and shows the good reproducibility of (B2) Fluorination Procedure when compared with the results of example 1. In examples 9, 31, and 33 the given amount of water was added to the base feed (FEED 1) and the water content was measured before and after water addition. The water content in the substrate was measured to be 91 ppm.For all reactions: Et2NH (2 equiv), 70 °C / 1.5 min tres1in reactor coil 1, 70 °C / 16 min tres2 in reactor coil 2. Examples on Influence of Additives - Substrate Cyclohexanone Cyclohexanone was reacted according to (B2) Fluorination Procedure; deviations from the protocol of the (B2) Fluorination Procedure are given in Table 8. The example 1 gives the respective values for (B2) Fluorination Procedure itself.Our Ref. : LZA32043PCT 64For all reactions: DCM, 0.5 M (base + substrate), 70 °C / 1.5 min tres1 in reactor coil 1, 70 °C / 16 min tres2in reactor coil 2. (1) The additive was added to the substrate feed. The two examples show that the method is not affected by the presence of these two additives. Examples - Various Substrates = Various ketones The examples shown in Table 9 were done according to (B2) Fluorination Procedure; the example 9 gives the respective values for (B) Fluorination Procedure itself, that is with cyclohexanone as substrate.Our Ref. : LZA32043PCT 65Our Ref. : LZA32043PCT 66(*) concentration of the substrate feed at 1 M instead of 0.5 M (**) concentration of the substrate feed at 1 M instead of 0.5 M, 8 equiv DAST instead of 2 equiv DAST. (***) concentration of the substrate feed at 1 M instead of 0.5 M, 4 equiv DAST instead of 2 equiv DAST. (****) Ex 42 was repeated with 5 h sampling in steady state, results for the 5th hour collection were: conversion 99%, RCF293%, RCF 6% and isolated yield 84% This shows that the method runs stable also under longer steady state conditions. (*****) C30 is an example for a bridged cyclic ketone, the bridge contains one N atom which is substituted by BOC [0] Umemoto et al, Journal of Fluorine Chemistry (2012), 140, 17-27, discloses the batch conversion of cyclohexanone in the presence of HF-pyridine with the fluorinating agent phenylsulfur trifluoride, which was in situ generatedOur Ref. : LZA32043PCT 67 from phenyl sulfur chlorotetrafluoride and pyridine, with a yield of 94% of 1,1-diF-cyclohexane (run 6 in table 2). Phenylsulfur trifluoride is prepared from phenylsulfur chlorotetrafluoride and therefore requires additional steps for its preparation, whereas DAST in the inventive method is prepared in situ from SF4and Et2NH. Also the preparation of HF-pyridine requires additional separate process steps, and the handling of pyridine in production is not desired. [1] Umemoto et al. in J. Am. Chem. Soc.2010, 132, 18199–18205, discloses conversion of ethyl-4-oxocyclohexanecarboxylate with 1.5 eq Fluolead™ with a yield of 81% and a of 99 / 1 ratio of RCF2 / RCF (run 3 table 2). The conversion was done in the presence of 0.4 eq HF-pyridine. The preparation of Fluolead™ requires additional steps: it was prepared from 1-tert-butyl-3,5-dimethylbenzene by reaction with an equivalent amount of S2Cl2 in acetic acid at room temperature in the presence of a catalytic amount of ZnCl2for 4 h to produce bis(4-tert-butyl-2,6- dimethylphenyl) disulfide (2k), which then was converted by oxidation with Cl2 / KF to Fluolead™ (1k). Also the preparation of HF-pyridine requires additional separate process steps, and the handling of pyridine in production is not desired. Haycock at al. in Organic Process Research & Development 2008, 12, 1094– 1103, discloses (2.2. and Scheme 5) the conversion of ethyl-4- oxocyclohexanecarboxylate with DAST with crude 96% yield containing 20% of vinyl fluoride. US 6,686,509 B2, discloses the fluorination of ethyl 4-cyclohexanone carboxylate with DAST providing 87% conversion and a RCF2 / RCF ratio of 2.6:1 (Example 4) and with Deoxo-fluor (tradename, bis(2- methoxyethyl)aminosulfur trifluoride, manufactured by Air Products) providing a conversion of 89% and a RCF2 / RCF ratio of 1.5:1 (Example 5). Deoxo-fluor requires additional steps for its preparation, whereas DAST in the inventive method is prepared in situ.Our Ref. : LZA32043PCT 68 Price et al., in Tetrahedron Letters 2005, 46, 5005–5007, discloses on page 5005 right column that the conversion of compound 1, the ethyl 4- cyclohexanone carboxylate. was converted with DAST in dichloromethane to an inseparable 1:1 mixture the the desired difluoro compound 2 (RCF2) and the vinylfluoride 3 (RCF). Price continues saying that the formation of vinyl fluoride co-products from treatment of ketones with DAST is known in the literature and appears difficult to control. Optimization studies undertaken to influence the ratio of products including temperature, reagent stoichiometry and solvents were unsuccessful. The obtained 1:1 mixture had to be subjected to further process steps, i.e. a dihydroxylation followed by column chromatography in order to separate the undesired RCF from the desired RCF2. WO2014184561A1 discloses on page 36 in Scheme 1 a deoxyfluorination with DAST providing a mixture of RCF2 and RCF; further on on page 37 lines 12 to 18 the deoxyfluorination of ethyl 4-oxocyclohexanecarboxylate with DAST in dichloromethane, providing a mixture of desired RCF2 and undesired RCF; the inseparable and undesired vinyl fluoride impurity (RCF) requires for its separation from the desired RCF2 an oxidization and further steps. [2] CN110372572A published in 2019 discloses in example 2 the transformation of N-benzylpiperidone using DAST in a 88% yield with a purity of 98%, so 86% yield of the pure product. CN115850156A published in 2023 discloses in example 6 the transformation of N-benzylpiperidone using DAST with a 90% yield requiring a second step wherein olefin by-products are destroyed with potassium permanganate. [3] WO2004050619A1 discloses in Description 277 the reaction of 1, 1- dimethylethyl (4-oxocyclohexyl)carbamate with DAST and reports a yield ofOur Ref. : LZA32043PCT 69 1.03 g, 93%, of a product as a beige solid which was used in the next step without further purification. The product of Example 39 was white, not beige, with RCF below the detection limit. [4] Beaulieu et al. in Org. Lett., 2009, 11, 5050-5053, discloses the conversion of 4-tert-butyl-cyclohexanone with XtalFluor E™ 85% yield isolated containing 4% of vinyl fluoride (table 2, entry 4). XtalFluor E™ requires additional process steps to be prepared, whereas in the method of the invention DAST is prepared in situ. L'Heureux et al. in Journal of Organic Chemistry 2010, 75(10), 3401-3411, discloses the conversion of 4-tert-butyl-cyclohexanone with XtalFluor E™ + 2 equiv TEA-3HF 91% yield with a 62:1 ratio; and conversion XtalFluor M™ + 2 equiv TEA-3HF 61% yield with a 17:1 ratio (table 3 entries 3 and 4). XtalFluor E™ requires additional process steps to be prepared, whereas in the method of the invention DAST is prepared in situ. In addition a further substance must be prepared and handled, the TEA- 3HF, which is also a corrosive and toxic substance. LHeureux also discloses in the footnote c under Table 3 that in case that the product was a mixture of RCF2 and RCF then this mixture was not separated, the footnote d discloses that the ratio RCF2 : RCF was calculated by1H NMR on crude product. [5] WO2020198368A1 discloses in

[0436] : The substrate tert-butyl 3- oxopyrrolidine-1-carboxylate 5 g

[0185] = 27 mmol was converted with DAST to provide Boc-3,3-difluoropyrrolidine yield 5.9 g

[0207] = 28.5 mmol. Obviously a very crude yield is given without any purification and and information of a content of any by-product. [6] WO2022040487A1 discloses as L15 -> L16 on scheme page 126 and in

[0355] : L15 (1.95 g, 8.01 mmol, 1.0 equiv) was converted in DCM with DAST providing L16 as a yellow oil. (2.0 g, yield: 94%). It is an isolated yield after a flash chromatography.Our Ref. : LZA32043PCT 70 Nothing about any elimination (vinyl) is said, no purity is given. The combined assay yield in example 43 is 98%, with an isolated yield of RCF2 84%. The flash chromatography in

[0355] of WO2022040487A1 does not separate RCF from RCF2, so the product in WO2022040487A1 still contains the RCF.

[0012] Wityak et al. in J. Med. Chem.2015, 58, 2967−2987, discloses (under "Preparation of tert-Butyl (3,3-difluorocyclobutyl)carbamate") the conversion of tert-butyl (3-oxocyclobutyl)carbamate with DAST and 70% yield after purification with flash column chromatography as an "off-white solid", no info on the vinyl fluoride level is given. The method of the invention yields the difluoro compound with a contamination of the undesired vinyl compound of below 1% without the need of a flash column chromatography.

[0032] WO2015025962A1 discloses in example 165 the conversion of 5,6,8,9- tetrahydro-7H­ benzo[7]annulen-7-one with bis (2-methoxyethyl) aminosulfur trifluoride as fluorinating reagent with purification by silica gel column chromatography without solvent gradient, which will not separate RCF2 from RCF; the yield was 84%, no information about purity are given. Bis (2-methoxyethyl) aminosulfur trifluoride requires additional steps for its preparation, whereas DAST in the inventive method is prepared in situ. Comparative Examples Table 10 shows the results of comparative examples. The example 1 #271_1# in Table 10 gives the respective values for (B2) Fluorination Procedure itself according to this invention. Comparative Example 1 - Reaction in Batch with DAST according to Scheme 6Our Ref. : LZA32043PCT 71Cyclohexanone (196 mg, 2 mmol), 4-fluorotoluene (189 mg, 1 mmol) and DCM as solvent (5 mL, resulting in a concentration of 0.4 M of cyclohexanone) were placed into a round bottom flask (10 mL). The vial was sealed, cooled to -15 °C, and flushed with argon for 10 min. DAST (540 µL, 4 mmol, 2 equivalents) was then added dropwise under vigorous stirring using a needle and a syringe, while a slight exotherm was observed. After completion, the reaction mixture was allowed to warm up to room temperature and was stirred for 4 hours. An aq. sat. solution of NaHCO3was then added slowly to quench the reaction and a sample from the organic phase was taken for GC analysis. The batch example shows considerably higher amount of the RCF compared to Example 1. Comparative Example 2a and Comparative Example 2b Comparative Example 2a shows the results of (B4) Fluorination Procedure as described above: direct fluorination of cyclohexanone with SF4 in the presence of Et3N, no presence of Et2NH and therefore no in situ generation of DAST. Fluorination with SF4 provides predominantly RCF compared to Example 1. Comparative Example 2b was done according to Comparative Example 2a with the sole difference that DCM was used instead of EtOAc. Comparative Example 3 Comparative Example 3 shows the results of (B1) Fluorination Procedure exemplified with cyclohexanone using the setup (A1) "Commercial DAST in flow, 2 feeds", with the sole difference that EtOAc was used as solvent instead of DCM. EtOAc as solvent provides considerably higher amount of the RCF compared to Example 1 with DCM as solvent.Our Ref. : LZA32043PCT 72 Comparative Example 4 Comparative Example 4 shows a repetition of Example 1 #270_1# with the sole difference that EtOAc was used as solvent instead of DCM. EtOAc as solvent provides considerably higher amount of the RCF compared to Example 1 with DCM as solvent. Comparative Example 5 Comparative Example 3 shows the results of (B1) Fluorination Procedure exemplified with cyclohexanone using the setup (A1) "Commercial DAST in flow, 2 feeds". So, using DAST itself as fluorinating agent in continuous flow, without in situ preparation thereof, increases the amount of RCF considerably compared to Example 1. Comparative Example 6 Comparative Example 3 shows the results of (B3) Fluorination Procedure exemplified with cyclohexanone using the setup (A3), "DAST in situ, 2 feeds". Simultaneous generation of DAST in situ together with the fluorination reaction itself (only one MIXDEV and only one RESDEV), lowers the conversion and the yield of RCF2 considerably compared to Example 1, where the in situ generation of DAST is done first (in MIXDEV1 and RESDEV1) and separately from the ensuing fluorination reaction (in MIXDEV2 and RESDEV2).73

Claims

Our Ref. : LZA32043PCT 74 CLAIMS 1. A method for deoxyfluorination of a ketone in a solvent, by exchange of the oxo residue of the ketone against two geminal fluorine atoms providing the respective difluoro compound, in a continuous flow reaction set up comprising two reactions, ^ a first reaction for the preparation of diethylaminosulfur trifluoride (DAST), and ^ a second reaction for the deoxyfluorination of the ketone by said DAST as fluorinating agent; wherein the solvent in said continuous flow reaction set up is selected from the group of dichloromethane, dichloroethane and mixtures thereof and both the first reaction and the second reaction take place in said solvent; the first reaction is done by combining SF4continuously with a secondary amine, herein abbreviated with BASE, providing DAST; the second reaction is done by combining said DAST from the first reaction continuously with the ketone; the combining of SF4 with BASE providing said DAST is done at a first position of said continuous flow reaction set up, which is separated from and located upstream to a second position of said continuous flow reaction set up where the combining of said DAST with the ketone takes place; with the direction of the flow of the reagents SF4and BASE going to the first position, where the SF4 and the BASE are continuously combined with each other, providing at this first position a first reaction mixture containing said DAST and continuously flowing further on in downstream direction from the first position to the second position, where the ketone is continuously combined with said first reaction mixture providing a second reaction mixture containing the product, the difluoride, and continuously flowing further on in downstream direction from the second position; with the first and second position being in fluid connection with each other so that the flow of the first reaction mixture passes uninterrupted and continuously to and through the second position.Our Ref. : LZA32043PCT 75 2. The method according to claim 1, wherein BASE is selected from the group consisting of R1(R2)NH and pyrrolidine; wherein R1 and R2 are identical or different and independently from each other C1-4alkyl or benzyl; more preferably, BASE is selected from the group consisting of dibutylamine, dipropylamine, diethylamine (Et2NH), dimethylamine, N-methylbutylamine, and pyrrolidine; even more preferably, BASE is selected from the group consisting of diethylamine (Et2NH), N-methylbutylamine, and pyrrolidine; especially, BASE is diethylamine (Et2NH).

3. The method according to claim 1 or 2, wherein the solvent is selected from the group consisting of dichloromethane, 1,2- dichloroethane and mixtures thereof; more preferably, the solvent is dichloromethane or 1,2-dichloroethane.

4. The method according to one or more of claims 1 to 3, wherein the amount of SF4 is from 2 to 10 equiv, more preferably from 2 to 5 equiv, even more preferably from 2 to 4 equiv, the equiv being molar equiv based on the molar amount of substrate; and / or the amount of BASE is from 2 to 10 equiv, more preferably from 2 to 5 equiv, even more preferably from 2 to 4 equiv, the equiv being molar equiv based on the molar amount of substrate; and / or the molar amount of SF4 and the molar amount of BASE are identical.

5. The method according to one or more of claims 1 to 4, wherein BASE is first mixed with the solvent, and this mixture of BASE with the solvent is combined continuously with SF4; preferably, the mixture of BASE with the solvent is a solution of the BASE in the solvent; and / or the substrate is first mixed with the solvent, and this mixture of the substrate with the solvent is combined continuously with the reaction mixture from theOur Ref. : LZA32043PCT 76 first reaction; preferably, the mixture of the substrate with the solvent is a solution of the substrate in the solvent.

6. The method according to one or more of claims 1 to 5, wherein the first reaction is done at a pressure which is above the vapor pressure, at the reaction temperature of the first reaction, called REACTEMP1, of the reaction mixture of the first reaction containing all components of the reaction mixture of the first reaction except for the SF4, and / or above the vapor pressure of SF4 at REACTEMP1; and / or the second reaction is done at a pressure which is above the vapor pressure, at the reaction temperature of the second reaction, called REACTEMP2, of the reaction mixture of the second reaction containing all components of the reaction mixture of the second reaction except for any SF4 which may be present in the reaction mixture of the second reaction, and / or above the vapor pressure of SF4at REACTEMP2; preferably, the first reaction and the second reaction are done under the same pressure, called REACPRESS, and REACPRESS is above the vapor pressure which SF4has at the reaction temperature of the first reaction and of the second reaction.

7. The method according to one or more of claims 1 to 6, wherein in the continuous flow reaction set up the BASE and the SF4 are mixed continuously in a first mixing device (MIXDEV1), the reaction mixture exiting MIXDEV1 is called herein the first reaction mixture; the first reaction mixture and the substrate are mixed continuously in a second mixing device (MIXDEV2); MIXDEV2 is located in downstream direction relative to MIXDEV1, the reaction mixture exiting MIXDEV2 is called herein the second reaction mixture; preferably, Any of the two mixing devices MIXDEV1 and MIXDEV2 is a T-piece, a microreactor, a mixing device, such as a static mixing device, or any combination thereof.Our Ref. : LZA32043PCT 77 8. The method according to claim 7, wherein the first reaction mixture exiting from MIXDEV1 is passed through a first residence device (RESDEV1) after having passed through MIXDEV1 and before entering MIXDEV2; RESDEV1 provides for additional reaction time of the first reaction, preferably, the inner diameter of MIXDEV1 and / or RESDEV1, that is the inner diameter of any channel in MIXDEV1 and / or RESDEV1, through which the first reaction mixture passes, is 2 mm or less, more preferably 1 mm or less; and / or the second reaction mixture exiting from MIXDEV2 is passed through a second residence device (RESDEV2); preferably the second reaction mixture exiting from MIXDEV2 passes through a RESDEV2 before passing through any other device, RESDEV2 provides for additional reaction time of the second reaction, preferably, the inner diameter of MIXDEV2 and / or RESDEV2, that is the inner diameter of any channel in MIXDEV2 and / or RESDEV2, through which the second reaction mixture passes, is 2 mm or less, more preferably 1 mm or less.

9. The method according to one or more of claims 1 to 8, wherein the first reaction time, that is the reaction time of the first reaction, is from 0.01 to 60 min, preferable from 0.01 to 50 min, more preferably from 0.01 to 40 min; and / or the second reaction time, that is the reaction time of the second reaction, is from 0.01 to 120 min, preferable from 0.01 to 90 min, more preferably from 0.01 to 60 min.

10. The method according to one or more of claims 1 to 9, wherein the ketone, that is the substrate, is a non-cyclic ketone or a cyclic ketone.

11. The method according to one or more of claims 1 to 10, whereinOur Ref. : LZA32043PCT 78 the substrate is an unsubstituted or substituted cyclic ketone; the cyclic ketone comprises 0 to n-3 endocyclic heteroatoms Y4, with n being the number of ring atoms of the cyclic ketone including the C atom of the endocyclic keto residue of the cyclic ketone, preferably up to n-4 endocyclic heteroatoms Y4 in case that n > 5; more preferably, the cyclic ketone comprises 0, 1 or 2 endocyclic heteroatoms Y4, with Y4 being O, S or N; any endocyclic N of the cyclic ketone can be unsubstituted or substituted, in case of any saturated endocyclic N of the cyclic ketone any said saturated endocyclic N is preferably substituted, more preferably by a residue R5, R5 is a protecting group which is stable under reaction conditions; and / or the substrate is an unsubstituted or substituted cyclic ketone, which can be partially unsaturated; and / or the substrate is an unsubstituted or substituted cyclic ketone, which can be partially unsaturated, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL; and / or any cyclic ketone can be bridged by 1, 2 or 3 atoms selected from C or N; in case that the bridge contains N and the N is a saturated N, then the N is preferably substituted, more preferably by R5, R5 is a protecting group which is stable under reaction conditions; and / or the substrate is an unsubstituted or substituted cyclic ketone, which is saturated or monounsaturated, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL; and / or the substrate is a saturated or monounsaturated cyclic ketone, which is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein theOur Ref. : LZA32043PCT 79 cyclic ketone can be fused to a 5 or 6 membered monocyclic, unsubstituted or substituted aryl residue called FUSEDARYL; R100 is selected from the group consisting of oxo, OH, C1-22 alkyl, C2-22 alkenyl, F, Cl, Br, I, CN, NO2, O-C1-6 alkyl, O-C2-6 alkenyl, C(O)H, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, COOH, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, O-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl; and / or the substrate is a saturated or monounsaturated cyclic ketone, which is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100, wherein the cyclic ketone comprises 4 to 12 ring atoms, wherein the cyclic ketone can be fused to a 5 or 6 membered monocyclic aryl residue called FUSEDARYL, wherein FUSEDARYL is unsubstituted or substituted by 1, 2, 3 or 4 identical or different substituents R100.

12. The method according to one or more of claims 1 to 10, wherein In one embodiment, the ketone, that is the substrate, is a non-cyclic ketone and is a compound of formula (NCK), whereinOur Ref. : LZA32043PCT 80 R200 and R201 are identical or different and independently from each other selected from the group consisting of C1-22alkyl, C2-22alkenyl, cycloalkyl, and aryl.

13. The method according to one or more of claims 11 to 12, wherein any cycloalkyl residue, independently from any other cycloalkyl residue, is 4, 5, 6, or 7 membered cycloalkyl residue, a 4 membered cycloalkyl residue contains 0 or 1 endocyclic heteroatom Y3, a 5 membered cycloalkyl residue contains 0, 1 or 2 identical or different endocyclic heteroatoms Y3, a 6 and a 7 membered cycloalkyl residue contain 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y3, any heteroatom Y3 is, independently from any other Y3, selected from the group consisting of O, S, and N, said N is unsubstituted or substituted, preferably substituted by R5, any cycloalkyl residue, independently from any other cycloalkyl residue, is unsubstituted or substituted by one or more identical or different substituents R110; and / or any aryl is, independently from any other aryl, ^ a 5 or 6 membered monocyclic aryl residue, ^ a bicyclic aryl residue formed by a 5 or 6 membered ring fused with a 6 membered ring, or ^ a 5 or 6 membered non-aromatic ring, any 5 membered ring in the aryl contains 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y2, any 6 membered ring in the aryl contains 0, 1, 2 or 3 identical or different endocyclic heteroatoms Y2, and any aryl is unsubstituted or substituted by one or more identical or different substituents R110; and / or any R110, independently from any other R110, is selected from the group consisting ofOur Ref. : LZA32043PCT 81 oxo, OH, C1-6 alkyl, C2-6 alkenyl, F, Cl, Br, I, CN, NO2, O-C1-6 alkyl, O-C2-6 alkenyl, C(O)H, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, COOH, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, O-R5, N(H)R5, a terminal cycloalkyl, a terminal aryl, and (Y1)-aryl which is a terminal aryl; and / or any heteroatom Y2 is, independently from any other Y2, selected from the group consisting of O, S, and saturated or unsaturated N, said saturated N is unsubstituted or substituted, preferably substituted by R5; and / or any Y1 mentioned herein is, independently from any other Y1, a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, C(O), (O-CH2-CH2)1-20-O, (O-propylene)1-20-O, (O-CH2-CH2)1-20-O-C(O)-C1-6 alkylene-C(O)-O, (O-propylene)1-20-O-C(O)-C1-6alkylene-C(O)-O, O-C(O)-C1-6alkylene-C(O)-(O-CH2-CH2)1-20-O, and O-C(O)-C1-6 alkylene-C(O)-(O-propylene)1-20-O; and / or any C1-22alkyl mentioned herein and any C2-22alkenyl mentioned herein is, independently from any other C1-22 alkyl and C2-22 alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical of different substituents selected from the group consisting of oxo, OH, F, Cl, Br, I, NO2, O-C1-6alkyl, O-C2-6alkenyl, C(O)H, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, COOH, C(O)-O-C1-6 alkyl, C(O)-O-C2-6 alkenyl, O-R5, S-R5, N(H)R5,Our Ref. : LZA32043PCT 82 cycloalkyl, aryl, and (Y1)-aryl; and / or any C1-6alkyl mentioned herein and any C2-6alkenyl mentioned herein is, independently from any other C1-6 alkyl and C2-6 alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical or different substituents selected from a group consisting of oxo, OH, F, Cl, Br, I, NO2, O-C1-4alkyl, O-C2-3alkenyl, C(O)H, C(O)-C1-4alkyl, C(O)-C2-3alkenyl, COOH, C(O)-O-C1-4 alkyl, C(O)-O-C2-3 alkenyl, O-R5, S-R5, and N(H)R5; and / or any R5 mentioned herein is a protecting group for protecting OH, SH, NH or NH2, which is stable under reaction conditions, preferably, ^ if OH is to be protected then R5 is Fmoc, Boc, benzoyl, Cbz, C(O)-C1-10 alkyl, TBDMS (tert-Butyldimethylsilyl), triisopropylsilyl, PNB (p- Nitrobenzyl), ONB (o-Nitrobenzyl), Bn (Benzyl), Al (Allyl), or tBu (tert- Butyl), more preferably Fmoc, Boc, benzoyl, Cbz, C(O)-C1-6alkyl, PNB (p- Nitrobenzyl), ONB (o-Nitrobenzyl), Bn (Benzyl), Al (Allyl), or tBu (tert-Butyl), even more preferably Fmoc, Boc, benzoyl, Cbz, C(O)-C1-3alkyl, or Bn (Benzyl), ^ if NH2 is to be protected then R5 is Fmoc, Boc, benzoyl, Cbz, C(O)-C1-10 alkyl, Bn (Benzyl), or Alloc (Allyloxycarbonyl), more preferably Fmoc, Boc, benzoyl, Cbz, C(O)-C1-6alkyl, Bn (Benzyl), or Alloc (Allyloxycarbonyl), ^ if SH is to be protected then R5 is Fmoc, Boc, benzoyl, Cbz, C1-2 alkyl, C(O)-C1-10alkyl, Bn (Benzyl), Meb (p-Methylbenzyl), Acm (Acetamidomethyl), or Trt,Our Ref. : LZA32043PCT 83 more preferably Fmoc, Boc, benzoyl, Cbz, C1-2 alkyl, C(O)-C1-6 alkyl, Bn (Benzyl), Meb (p-Methylbenzyl), or Acm (Acetamidomethyl), in particular, if OH is to be protected then R5 is Boc, benzoyl, Cbz, Fmoc, C(O)-C1-6 alkyl or Bn (Benzyl); and / or any cyclic keton and / or any cyclododecenone, cycloundecenone, cyclodecenone, cyclononenone, cyclooctenone, cycloheptenone, cyclohexenone, cyclopentenone mentioned herein contains only 1 endocyclic double bond, preferably, any cyclic keton and / or any cyclododecenone, cycloundecenone, cyclodecenone, cyclononenone, cyclooctenone, cycloheptenone, cyclohexenone, cyclopentenone mentioned herein contains only 1 endocyclic double bond which is not conjugated with the double bond of the endocyclic keto residue which is deoxyfluorinated.

14. The method according to one or more of claims 11 to 13, wherein any R100, independently from any other R100, is selected from the group consisting of C1-22 alkyl, C2-22 alkenyl, F, Cl, Br, I, CN, NO2, O-C1-6 alkyl, O-C2-6 alkenyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, O-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl.

15. The method according to one or more of claims 11 to 14, wherein any R110, independently from any other R110, is selected from the group consisting of C1-6alkyl, C2-6alkenyl, F, Cl, Br, I, CN, NO2, O-C1-6 alkyl, O-C2-6 alkenyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl,Our Ref. : LZA32043PCT 84 O-R5, N(H)R5, a terminal cycloalkyl, a terminal aryl, and (Y1)-aryl which is a terminal aryl.

16. The method according to one or more of claims 11 to 15, wherein any Y1 is, independently from any other Y1, a connecting group selected from the group consisting of O, C1-6 alkylene, C2-6 alkenylene, (O-CH2-CH2)1-20-O, (O-propylene)1-20-O, (O-CH2-CH2)1-20-O-C(O)-C1-6 alkylene-C(O)-O, (O-propylene)1-20-O-C(O)-C1-6alkylene-C(O)-O, O-C(O)-C1-6 alkylene-C(O)-(O-CH2-CH2)1-20-O, and O-C(O)-C1-6 alkylene-C(O)-(O-propylene)1-20-O.

17. The method according to one or more of claims 11 to 16, wherein any C1-22 alkyl mentioned herein and any C2-22 alkenyl is, independently from any other C1-22alkyl and C2-22alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical of different substituents selected from the group consisting of F, Cl, Br, I, NO2, O-C1-6 alkyl, O-C2-6 alkenyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, O-R5, S-R5, N(H)R5, cycloalkyl, aryl, and (Y1)-aryl.

18. The method according to one or more of claims 11 to 17, wherein any C1-6 alkyl and any C2-6 alkenyl is, independently from any other C1-6 alkyl and C2-6 alkenyl respectively, unsubstituted or substituted by 1, 2, 3, 4, 5, or 6 identical or different substituents selected from a group consisting ofOur Ref. : LZA32043PCT 85 F, Cl, Br, I, NO2, O-C1-4alkyl, O-C2-3alkenyl, C(O)-O-C1-4 alkyl, C(O)-O-C2-3 alkenyl, O-R5, S-R5, and N(H)R5.

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