Process for manufacturing 6-perfluorophenyl benzoxazinones

Abstract

The present application relates to processes and intermediates used in the manufacture of polyfluorophenyl benzoxazinones, as protoporphyrinogen oxidase (PPO) inhibitor herbicides. The benzoxazinone herbicide having a phenyl ring at the benzoxazinone 6-position and the phenyl ring is further substituted with 5 fluorine atoms.

Description

26327-20015.40 ^ PROCESS FOR MANUFACTURING 6-PERFLUOROPHENYL BENZOXAZINONES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 502,350, filed May 15, 2023, and U.S. Provisional Patent Application No.63 / 502,346, filed May 15, 2023, each of which is incorporated herein by reference in its entirety. FIELD

[0002] The present invention relates to processes and intermediates used in the manufacture of 6-pentafluorophenyl benzoxazinones. BACKGROUND

[0003] Herbicides that inhibit protoporphyrinogen oxidase (hereinafter referred to as Protox or PPO; EC:1.3.3.4), a key enzyme in the biosynthesis of protoporphyrin IX, have been used for selective weed control since the 1960s. PPO catalyzes the last common step in chlorophyll and heme biosynthesis, which is the oxidation of protoporphyrinogen IX to protoporphyrin IX [Matringe M. et al., Protoporphyrinogen oxidase as a molecular target for diphenyl ether herbicides, Biochemistry Journal (1989) 260: 231-235]. Application of PPO- inhibiting herbicides results in the accumulation of protoporphyrinogen IX in the chloroplast and mitochondria, which is believed to leak into the cytosol where it is oxidized by a peroxidase. When exposed to light, protoporphyrin IX causes formation of singlet oxygen in the cytosol and the formation of other reactive oxygen species, which can cause lipid peroxidation and membrane disruption leading to rapid cell death [Lee H.J. et al., Cellular localization of protoporphyrinogen-oxidizing activities of etiolated barley leaves, Plant Physiology (1993) 102: 881].

[0004] PPO-inhibiting herbicides having a benzoxazinone core have been described in the literature. See Hao, et al., Protoporphyrinogen oxidase inhibitor: an ideal target for herbicide discovery, Chimia (2011), Vol.65(12), pgs.961-969. Methods of their manufacture have also been reported. See U.S. Pat. No.9,359,312. A common element found in commercially-available PPO benzoxazinone herbicides is a heterocyclic ring at the benzoxazinone 6-position. To date, no registered benzoxazinone herbicide has a phenyl ring 1s^f-592218826327-20015.40 ^ at this position. The present invention describes methods of preparing such compounds, where the phenyl ring is further substituted with 5 fluorine atoms. BRIEF SUMMARY

[0005] Provided herein are methods of preparing fluorinated phenyl PPO inhibitors that have high herbicidal activity, even at low application rates.

[0006] Accordingly, provided is a method of preparing benzoxazinones having formula (I):where R is alkyl, alkenyl, alkynyl, cyclopropyl, CH2-cycloalkyl, phenyl or alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; R1ais OR1b, CH2OC(O)alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2alkyl, or NHOR1b; and each R1bis, independently, H, cycloalkyl, CH2phenyl, or alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b. DETAILED DESCRIPTION

[0007] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains,” “containing,” “characterized by,” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, or method that includes or comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method. 2s^f-592218826327-20015.40 ^

[0008] Further, unless expressly stated to the contrary, “or” refers to an inclusive ‘or’ and not to an exclusive ‘or.’ For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0009] Also, the indefinite articles “a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

[0010] In the above recitations, the term “alkyl,” used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, or hexyl isomers. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl, and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2- propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl, and the different butynyl, pentynyl, and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5- hexadiynyl.

[0011] “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy, and hexyloxy isomers.

[0012] “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0013] The term “halogen” or “halo” either alone or in compound words such as “haloalkyl,” or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine, or iodine.

[0014] The total number of carbon atoms in a substituent group is indicated by the “C1- Cj” or “Ci-j” prefix, where i and j are numbers from 1 to 10. For example, C1-4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl; C2alkoxyalkyl designates CH3OCH2-; C3alkoxyalkyl designates, for example, CH3CH(OCH3)-, CH3OCH2CH2-, or CH3CH2OCH2-; and C4alkoxyalkyl designates the various isomers of an alkyl group substituted with an 3s^f-592218826327-20015.40 ^ alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2- and CH3CH2OCH2CH2-.

[0015] When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, the substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g., (R1)m, where m is 0, 1, 2 or 3. Further, when the subscript indicates a range, e.g. (R)i-j, then the number of substituents may be selected from the integers between ‘i’ and ‘j’ inclusive. When a group contains a substituent, which can be hydrogen (H), for example, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to the group being unsubstituted. When a variable group is shown to be optionally attached to a position, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be “not substituted” or “unsubstituted,” then hydrogen atoms are attached to take up any free valency.

[0016] The term “optionally substituted” in connection with the heterocyclic rings refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated. The term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term “(un)substituted.” Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.

[0017] The term “active ester” refers to activated carboxylic acid esters that can be reacted with an amino group to form an amide. Examples of active esters include intermediate products that are the result of reacting a carboxylic acid with carbodiimides, uronium salts, and phosphonium salts. Methods for preparing active esters are described by Hollanders, et al., A New Wave of Amide Bond Formations for Peptide Synthesis, Synthesis (2019), Vol.51(11), pages 2261-2277 and by Albericio & El-Faham, Choosing the Right Coupling Reagent for Peptides: A Twenty-Five-Year Journey, Organic Process Research & Development (2018), Vol.22(7), pages 760-772, the entire content of each of which is incorporated herein. 4s^f-592218826327-20015.40 ^ Preparation of Compounds of the Invention

[0018] A wide variety of synthetic methods are known in the art to enable preparation of aromatic and nonaromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve-volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.

[0019] One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus, a wide variety of salts of compounds of the invention are useful for control of undesired vegetation (i.e. are agriculturally suitable). The salts of compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic, or valeric acids. When a compound of the invention contains an acidic moiety such as a carboxylic acid or phenol, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine, or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium, or barium. Scheme A1

[0020] In some embodiments, compounds of formula (I) can be prepared as shown in Scheme A1. 5s^f-592218826327-20015.40 ^Scheme A1 As shown in step 1 of Scheme A1, compounds of formula (c) can be prepared by acylating an aniline of formula (a), where X is Br or I, with a compound formula (b) in the presence of a non-nucleophilic base. L1of the compound of formula (b) can be F or Cl, or L1C(O) can be an alkyl ester or an active ester. Suitable bases include trialkylamines, such as ethyl diisopropylamine, or other non-nucleophilic bases such as inorganic hydrides (e.g., sodium hydride), non-nucleophilic alkoxides (e.g., sodium or potassium tert-butoxide), or inorganic bases (e.g., sodium carbonate, potassium carbonate, sodium phosphate, or potassium phosphate). Compounds of formula (c) can be isolated as the phenol or as phenolate salt (d) or, as shown in step 2, cyclized directly in the presence of a non-nucleophilic base similar to those that may be used in Step 1 to form compounds of formula (e). As shown in step 3, compounds of formula (e) can be reacted with 2 to 2.5 equivalents of an alkyl lithium reagent at a low temperature of between -30ºC and -78ºC to form a di-lithio intermediate, which, as shown in step 4, is reacted directly with hexafluorobenzene at a low temperature of between -30ºC and -78ºC, followed by warming to 25ºC to form a compound of formula (f). As shown in step 5, the compound of formula (f) can be N-alkylated with compounds of formula R-L2, where L2is a leaving group such as iodo, bromo, chloro, or sulfonate, or L2is an intermediate resulting from reaction with a diazodicarboxylate in a Mitsinobu reaction. R can be C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1aor CH2C(O)R1aand each optionally substituted with up to 3 F or Cl atoms, wherein 6s^f-592218826327-20015.40 ^ each C1-6alkyl is also optionally substituted with íOR1b; wherein R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b.

[0021] Accordingly, in one aspect provided is a method of preparing a compound of formula (I) as described herein, or a salt thereof:including reacting a compound of formula (a), or a salt thereof, with a base and a compound of formula (b) to produce a compound of formula (c), or a salt thereof,L1C(O) is an alkyl ester or an active ester, to produce an amide of formula (c) or salt thereof; treating a compound of formula (c), with a base to produce an intermediate of formula (d) and, subsequently, a compound of formula (e),; 7s^f-592218826327-20015.40 ^ reacting a compound of formula (e) with from 2 to 2.5 equivalents of an alkyl lithium reagent, followed by treating the di-lithio intermediate with hexafluorobenzene to produce a compound of formula (f),; and alkylating a compound of formula (f) with alkylating agent L2-R, where L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with an azodicarboxylate in a Mitsinobu reaction, to produce a compound of formula (I),, where R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms, wherein R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b.

[0022] It should be understood that the compound of formula (a) may be obtained from any commercially available sources, or produced according to any methods or techniques known in the art. For example, in some variations, the compound of formula (a) may be obtained according to the following scheme: 8s^f-592218826327-20015.40 ^, wherein Rpis a suitable protecting group and X is as defined for formula (a) above. As depicted in the scheme above, the initial compound undergoes substitution (step 1), deprotection (step 2), then followed by reduction (step 3) to obtain the compound of formula (a). However, one of ordinary skill in the art would appreciate that the compound of formula (a) may be produced by varying the order of substitution, deprotection and reduction using suitable starting materials and reaction conditions.

[0023] In one embodiment, the compound of formula (a), or a salt thereof, is formed from the compoundby reduction of the -NO2 group to form the -NH2 group in the compound of formula (a). In another embodiment, the compound of formula (a), or a salt thereof, is formed from the compoundwherein Rpis a suitable protecting group, and this compound undergoes deprotection and reduction, in either order. In another embodiment, the compound of formula (a), or a salt therof, is formed from the compound, wherein Rpis a suitable protecting group, and this compound undergoes substitution, deprotection, and reduction in any suitable order under suitable conditions.

[0024] In another embodiment, X is introduced without employing a protecting group (i.e., Rpis H and the deprotection step is not required).

[0025] In one embodiment, Compound (e) is 6-bromo-2,2,7-trifluoro-2H- benzo[b][1,4]oxazin-3(4H)-one. In another embodiment, Compound (e) is 2,2,7-trifluoro-6- iodo-2H-benzo[b][1,4]oxazin-3(4H)-one.

[0026] In another embodiment, compound (e) is reacted with 2.0 to 2.5 equivalents of an alkyl lithium reagent, such a n-butyl lithium or secondary butyl lithium, at –30ºC to –78ºC in a non-protic solvent such as pentane, hexane, heptane, methyl tert-butyl ether, THF, 2- methyl-THF, or mixtures thereof. 9s^f-592218826327-20015.40 ^

[0027] In one embodiment, R is, where R1bis H, alkyl, or cyclopropyl. In a further embodiment, R1bis H.

[0028] In another embodiment, R is CH(CH3)C(O)OC1-4alkyl.

[0029] In another embodiment, R is CH(CH3)C(O)OH.

[0030] In another aspect, provided is a compound selected from:salts thereof.

[0031] In one embodiment, provided is a compound selected from:

[0032] In another embodiment, provided is a compound selected from:salts thereof

[0033] In a further embodiment, provided is a compound selected from:Scheme B1

[0034] In other embodiments, compounds of formula (I) can be prepared as shown in Scheme B1. 10s^f-592218826327-20015.40 ^Scheme B1 As shown in step 1 of Scheme B1, compounds of formula (c) can be prepared by acylating an aniline of formula (a), where X is Br or I, with a compound formula (b) in the presence of a non-nucleophilic base. L1of the compound of formula (b) can be F or Cl, or L1C(O) can be an alkyl ester or an active ester. Suitable bases include trialkylamines, such as ethyl diisopropylamine, or other non-nucleophilic bases such as inorganic hydrides (e.g., sodium hydride), non-nucleophilic alkoxides (e.g., sodium or potassium tert-butoxide), or inorganic bases (e.g., sodium carbonate, potassium carbonate, sodium phosphate, or potassium phosphate). Compounds of formula (c) can be isolated as the phenol or as phenolate salt (d) or, as shown in step 2, cyclized directly in the presence of a non-nucleophilic base similar to those that may be used in Step 1 to form compounds of formula (e). As shown in step 3, compounds of formula (e) can be reacted with pentafluorobenzene in the presence of CuI and 1,10-phenanthroline to form a compound of formula (f). Other Cu(I) salts, such as CuBr and CuCl, can also be used. As shown in step 4, the compound of formula (f) can be N-alkylated with compounds of formula R- L2, where L2is a leaving group such as iodo, bromo, chloro, or sulfonate, or L2is an intermediate resulting from reaction with a diazodicarboxylate in a Mitsinobu reaction. R can be C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1aor CH2C(O)R1aand each optionally substituted with up to 3 F or Cl atoms, wherein each C1-6alkyl is also optionally substituted with íOR1b; wherein R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), 11s^f-592218826327-20015.40 ^ NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b.

[0035] Accordingly, in one aspect provided is a method of preparing a compound of formula (I) as described herein, or a salt thereof:including reacting a compound of formula (a), or a salt thereof, with a base and a compound of formula (b) to produce a compound of formula (c), or a salt thereof,L1C(O) is an alkyl ester or an active ester, to produce an amide of formula (c) or salt thereof; treating a compound of formula (c), with a base to produce an intermediate of formula (d) and, subsequently, a compound of formula (e),reacting a compound of formula (e) with pentafluorobenzene in the presence of CuI and a copper ligand to produce a compound of formula (f), 12s^f-592218826327-20015.40 ^and alkylating a compound of formula (f) with alkylating agent L2-R, where L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with an azodicarboxylate in a Mitsinobu reaction, to produce a compound of formula (I),, where R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms, wherein R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b.

[0036] In some embodiments, a compound of formula (e) is reacted with pentafluorobenzene in the presence of a Cu(I) salt and a copper ligand to produce a compound of formula (f). In some such embodiments, the Cu(I) salt is CuCl, CuBr, or CuI. In some such embodiments, the Cu(I) salt is CuCl. In some such embodiments, the Cu(I) salt is CuBr. In some such embodiments, the Cu(I) salt is CuI.

[0037] It should be understood that the compound of formula (a) may be obtained from any commercially available sources, or produced according to any methods or techniques known in the art. For example, in some variations, the compound of formula (a) may be obtained according to the following scheme: 13s^f-592218826327-20015.40 ^, wherein Rpis a suitable protecting group and X is as defined for formula (a) above. As depicted in the scheme above, the initial compound undergoes substitution (step 1), deprotection (step 2), then followed by reduction (step 3) to obtain the compound of formula (a). However, one of ordinary skill in the art would appreciate that the compound of formula (a) may be produced by varying the order of substitution, deprotection and reduction using suitable starting materials and reaction conditions.

[0038] In one embodiment, the compound of formula (a), or a salt thereof, is formed from the compoundby reduction of the -NO2group to form the -NH2group in the compound of formula (a). In another embodiment, the compound of formula (a), or a salt thereof, is formed from the compoundwherein Rpis a suitable protecting group, and this compound undergoes deprotection and reduction, in either order. In yet another embodiment, the compound of formula (a), or a salt therof, is formed from the compound, wherein Rpis a suitable protecting group, and this compound undergoes substitution, deprotection, and reduction in any suitable order under suitable conditions.

[0039] In another embodiment, X is introduced without employing a protecting group (i.e., Rpis H and the deprotection step is not required).

[0040] In one embodiment, Compound (e) is 6-bromo-2,2,7-trifluoro-2H- benzo[b][1,4]oxazin-3(4H)-one. In another embodiment, Compound (e) is 2,2,7-trifluoro-6- iodo-2H-benzo[b][1,4]oxazin-3(4H)-one.

[0041] In one embodiment, the reaction of pentafluorobenzene with a compound of formula (e) is performed at 100°C to 140°C in DMF in the presence of K3PO4and a bidentate ligand for Cu(I). In a further embodiment, the ligand is 1,10-phenanthroline. In another further embodiment, the bidentate ligand is selected from 1,2-dimethylethylenediamine 14s^f-592218826327-20015.40 ^ (DMEDA), , trans-1,2-cyclohexanediamine (CyDA), trans-N,N’-dimethyl-1,2- cyclohexanediamine (DMCyDA), 2,2-bipyridine (BPY) or an oxalic diamide such as BTMPO, BPMPO, BPPO, BMPO, BHMPO, BBPO, BFMO, BTMO, DPEO, DBO, BNMO, PMPBO, PPBO, NFO, MNFO, MNBO, or MNPMO.

[0042] In one embodiment, R is, where R1bis H, alkyl, or cyclopropyl. In a further embodiment, R1bis H.

[0043] In another embodiment, R is CH(CH3)C(O)OC1-4alkyl.

[0044] In another embodiment, R is CH(CH3)C(O)OH.

[0045] In another aspect, provided is a compound selected from:salts thereof.

[0046] In one embodiment, provided is a compound selected from:

[0047] In another embodiment, provided is a compound selected from:

[0048] In a further embodiment, provided is a compound selected from:15s^f-592218826327-20015.40 ^ ENUMERATED EMBODIMENTS

[0001] The following enumerated embodiments are representative of some aspects of the invention. 1. A process for manufacturing a compound of formula (I),salt thereof, wherein R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1- 2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b; the process comprising: reacting a compound of formula (a), or a salt thereof, with a non-nucleophilic base and a compound of formula (b) to produce a compound of formula (c), or a salt thereof, 16s^f-592218826327-20015.40 ^, where X is Br and L1is F or Cl, or L1C(O) is an alkyl ester or an active ester, to produce an amide of formula (c), or salt thereof; treating a compound of formula (c), or a salt thereof, with an additional non- nucleophilic base to produce an intermediate of formula (d) and, subsequently, a compound of formula (e), or a salt thereof,; reacting a compound of formula (e), or a salt thereof, with from 2 to 2.5 equivalents of an alkyl lithium reagent to produce a di-lithio intermediate, followed by treating the di-lithio intermediate with hexafluorobenzene to produce a compound of formula (f), or a salt thereof,; and alkylating a compound of formula (f), or a salt thereof, with alkylating agent L2-R, where L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with triphenylphosphine and an azodicarboxylate in a Mitsinobu reaction, to produce a compound of formula (I), or a salt thereof 17s^f-592218826327-20015.40 ^. 2. The process according to embodiment 1, wherein compound (e) is 6-bromo- 2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, or a salt thereof. 3. The process according to embodiment 1, wherein R is, where R1bis H, alkyl, or cyclopropyl. 4. The process according to embodiment 3, wherein R1bis H. 5. The process according to embodiment 1, wherein R is CH(CH3)C(O)OC1- 4alkyl. 6. The process according to embodiment 1, wherein R is CH(CH3)C(O)OH. 7. The process according to any one of embodiments 1-6, wherein the non- nucleophilic base and the additional non-nucleophilic base are the same base. 8. The process according to any one of embodiments 1-6, wherein the non- nucleophilic base and the additional non-nucleophilic base are different bases. 9. A compound having the structure:salt thereof. 10. The compound according to embodiment 9, wherein the compound is an alkyl ammonium salt. 11. The compound of embodiment 9, wherein the compound is 18s^f-592218826327-20015.40 ^12. A process, comprising: combining a compound of formula (e), or a salt thereof, with 2 to 2.5 equivalents of an alkyl lithium reagent under suitable conditions to form a di-lithio intermediate, wherein the compound of formula (e), or salt thereof, is:wherein X is Br; and combining a compound of formula (e1) with the di-lithio intermediate to produce a compound of formula (f), or a salt thereof, wherein the compounds of formula (e1) and (f) are:13. The process of embodiment 12, wherein the combining the compound of formula (e1) with the di-lithio intermediate comprises adding the compound of formula (e1) to the di-lithio intermediate. 14. The process of embodiment 12, wherein the combining the compound of formula (e1) with the di-lithio intermediate comprises adding the di-lithio intermediate to the compound of formula (e1). 15. The process of any one of embodiments 12 to 14, further comprising: 19s^f-592218826327-20015.40 ^ combining a compound of formula (c), or a salt thereof, with a non- nucleophilic base to produce the compound of formula (e), or a salt thereof, wherein the compound of formula (c), or salt thereof, is:wherein X is Br. 16. The process of any one of embodiments 12 to 15, further comprising: combining a compound of formula (a), or a salt thereof, with an additional non-nucleophilic base and a compound of formula (b) to produce the compound of formula (c), or a salt thereof, wherein the compounds of formula (a) and (b) are:wherein X is Br and L1is F or Cl, or L1C(O) together forms an alkyl ester or an active ester group. 17. The process of embodiment 16, wherein the non-nucleophilic base and additional non-nucleophilic base, when simultaneously present, are the same base. 18. The process of embodiment 16, wherein the non-nucleophilic base and additional non-nucleophilic base, when simultaneously present, are different bases. 19. The process of any one of embodiments 12 to 18, further comprising: alkylating the compound of formula (f), or a salt thereof, with an alkylating agent to produce a compound of formula (I):salt thereof, and wherein the alkylating agent is L2-R, wherein: 20s^f-592218826327-20015.40 ^ L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with an azodicarboxylate in a Mitsinobu reaction; R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3- 6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; and each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b. 20. A process for manufacturing a compound of formula (I),salt thereof, wherein R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl 21s^f-592218826327-20015.40 ^ optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b; the process comprising: reacting a compound of formula (a), or a salt thereof, with a non-nucleophilic base and a compound of formula (b) to produce a compound of formula (c), or a salt thereof,, where X is Br or I and L1is F or Cl, or L1C(O) is an alkyl ester or an active ester, to produce an amide of formula (c) or salt thereof; treating a compound of formula (c), or a salt thereof, with an additional non-nucleophilic base to produce an intermediate of formula (d) and, subsequently, a compound of formula (e), or a salt thereof,; reacting a compound of formula (e), or a salt thereof, with pentafluorobenzene in the presence of a Cu(I) salt and 1,10-phenanthroline to produce a compound of formula (f), or a salt thereof, 22s^f-592218826327-20015.40 ^; and alkylating a compound of formula (f), or a salt thereof, with alkylating agent L2-R, where L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with triphenylphosphine and an azodicarboxylate in a Mitsinobu reaction, to produce a compound of formula (I), or a salt thereof,. 21. The process according to embodiment 20, wherein the Cu(I) salt is CuCl, CuBr, or CuI. 22. The process according to embodiment 20 or embodiment 21, wherein compound (e) is 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, or a salt thereof. 23. The process according to embodiment 20 or embodiment 21, wherein compound (e) is 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazin-3(4H)-one, or a salt thereof. 24. The process according to embodiment 20 or embodiment 21, wherein R is, where R1bis H, alkyl, or cyclopropyl. 25. The process according to embodiment 24, wherein R1bis H. 26. The process according to embodiment 20 or embodiment 21, wherein R is CH(CH3)C(O)OC1-4alkyl. 23s^f-592218826327-20015.40 ^ 27. The process according to embodiment 20 or embodiment 21, wherein R is CH(CH3)C(O)OH. 28. The process according to any one of embodiments 20-27, wherein the non- nucleophilic base and the additional non-nucleophilic base are the same base. 29. The process according to any one of embodiments 20-27, wherein the non- nucleophilic base and the additional non-nucleophilic base are different bases. 30. A compound having the structure:salt thereof. 31. The compound according to embodiment 30, wherein the compound is an alkyl ammonium salt. 32. The compound of embodiment 30, wherein the compound is:33. A process, comprising: combining a compound of formula (e), or a salt thereof, with pentafluorobenzene in the presence of a Cu(I) salt and 1,10-phenanthroline to produce a compound of formula (f), or a salt thereof, wherein the compound of formula (e), or salt thereof, is:wherein X is Br or I, and the compound of formula (f), or a salt thereof, is: 24s^f-592218826327-20015.40 ^. 34. The process of embodiment 33, wherein the Cu(I) salt is CuCl, CuBr, or CuI. 35. The process of embodiment 33 or embodiment 34, further comprising: combining a compound of formula (c), or a salt thereof, with a non- nucleophilic base to produce the compound of formula (e), or a salt thereof, wherein the compound of formula (c), or salt thereof, is:36. The process of any one of embodiments 33 to 35, further comprising: combining a compound of formula (a), or a salt thereof, with an additional non-nucleophilic base and a compound of formula (b) to produce the compound of formula (c), or a salt thereof, wherein the compounds of formula (a) and (b) are: wherei1 1n L is F or Cl, or L C(O) together forms an alkyl ester or an active ester group. 37. The process of embodiment 36, wherein the non-nucleophilic base and additional non-nucleophilic base, when simultaneously present, are the same base. 38. The process of embodiment 36, wherein the non-nucleophilic base and additional non-nucleophilic base, when simultaneously present, are different bases. 39. The process of any one of embodiments 33 to 38, further comprising: alkylating the compound of formula (f), or a salt thereof, with an alkylating agent to produce a compound of formula (I): 25s^f-592218826327-20015.40 ^salt thereof, and wherein the alkylating agent is L2-R, wherein: L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with triphenylphosphine and an azodicarboxylate in a Mitsinobu reaction; R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1- 2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; and each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b. EXAMPLES

[0049] The presently disclosed subject matter will be better understood by reference to the following examples, which are provided as exemplary of the invention, and not by way of limitation.

[0050] Steps in the following examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a procedure described in other Examples or Steps.1H-NMR spectra are reported in ppm downfield from tetramethylsilane; “s” means singlet, “d” means doublet, “t” means triplet, “q” means quartet, “m” means multiplet, “dd” means doublet of doublets, “dt” 26s^f-592218826327-20015.40 ^ means doublet of triplets, and “br s” means broad singlet. Mass spectra (MS) are reported as the molecular weight of the highest isotopic abundance parent ion (M+1) formed by addition of H+(molecular weight of 1) to the molecule, or (M-1) formed by the loss of H+(molecular weight of 1) from the molecule, observed by using liquid chromatography coupled to a mass spectrometer (LCMS) using either atmospheric pressure chemical ionization (AP+) where "amu" stands for unified atomic mass units or electrospray ionization (ES+). Example 1. Preparation of 2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H- benzo[b][1,4]oxazin-3(4H)-oneScheme A2

[0051] As shown in Step 1 of Scheme A2, to an oven dried 5 L, 4-neck round bottom flask connected to a nitrogen inlet, a thermocouple, and an overhead stirrer was charged concentrated sulfuric acid (600 mL) and agitation was started. To the mixture was added triflic anhydride (16.5 g, 0.058 mol, 0.1 equiv) followed by N-bromosuccinimide (NBS, 68.64 g, 0.385 mol, 0.6 equiv.) and the mixture was stirred for 1 hour at room temperature to obtain a deep red solution. To this stirring mixture was added 5-fluoro-2-nitroanisole (100 g, 0.584 mol) at room temperature and the stirring was continued for 1 hour at room temperature. Additional NBS (45.76 g, 0.32 mol, 0.5 equiv) was added and the stirring continued for an additional 2 hours at room temperature. The reaction mixture was cooled to 27s^f-592218826327-20015.40 ^ 0-5°C and ice-water (1000 mL) was added portionwise over 30 min. (exothermia). The mixture was allowed to warm to room temperature and stirred not less than 2 hours to obtain a yellow suspension. The suspension was filtered and the the cake was washed with water (3x) followed by hexane (3x). The wet cake was added into to 1 L, 3 neck round bottom flask equipped with a overhead stirrer, followed by the addition of hexane (300 mL) and the resulting slurry was stirred for not less than 2 hours at room temperature. The suspension was then filtered and the cake was washed with hexane (3x), dried under reduced pressure for 1 hour, followed drying in a vacuum oven for not less than 12 hours at 40 °C to afford 1- bromo-2-fluoro-4-methoxy-5-nitrobenzene (Compound 1) as light-yellow solid in 59% yield with 98.5% HPLC purity:1H-NMR (DMSO-d6, 400 MHz) į 8.35 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 10.8 Hz, 2 H), 3.95 (s, 3H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 161.7 (d, JC-F = 252.0 Hz), 154.1 (d, JC-F = 10.9 Hz), 136.7 (d, JC-F = 3.2 Hz), 130.1 (d, JC-F = 3.10 Hz), 104.3 (d, JC-F = 28.29 Hz), 98.4 (d, JC-F = 23.6 Hz), 58.2 ppm;19F-NMR (DMSO-d6, 376.5 MHz) į -97.01 ppm; EI-MS (M+) calculated for C7H5BrFNO3348.94, found 349.0.

[0052] In a similar fashion, reaction of 5-fluoro-2-nitroanisole with N-iodosuccinimide (NIS) produced 1-fluoro-2-iodo-5-methoxy-4-nitrobenzene (Compound 2):1H-NMR (DMSO-d6, 400 MHz) į 8.38 (d, J = 6.63 Hz, 1H), 7.43 (d, J = 10.1 Hz, 1H), 3.94 (s, 3H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 164.6 (d, JC-F = 249.3 Hz), 154.8 (d, JC-F = 11.0 Hz), 137.2 (d, JC-F = 2.47 Hz), 135.4 (d, JC-F = 5.5 Hz), 103.4 (d, JC-F = 30.5 Hz), 70.7 (d, JC-F = 29.63 Hz), 58.03 ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í84.35 ppm; EI-MS (M+) calculated for C7H5FINO3296.93, found 297.1.

[0053] As shown in step 2 of Scheme A2, to a 3 L, 3 neck round bottom flask equipped with an overhead stirrer and a thermocouple was added 1-bromo-2-fluoro-4-methoxy-5- nitrobenzene (90.0 g, 89.6 wt%) and CH2Cl2 (5 V) and the mixture was cooled to 0°C. A solution of 1 M BCl3in CH2Cl2(2 equiv) was added slowly via an addition funnel. The mixture was allowed to warm to room temperate and stirred for 18 hours. After this time, the mixture was re-cooled to 0 °C and additional BCl3(1 equiv) was added, and the stirring was continued for an additional 24 h at room temperature, at which time complete conversion of starting material was indicated by HPLC analysis. The mixture was cooled to 0°C, treated with satd. NaHCO3 (5 V), diluted with water and extracted with CH2Cl2 (3 x 3-4 V). The organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 4-bromo-5-fluoro-2-nitrophenol (Compound 3, 85.3 g, 89 wt% by NMR, 98% yield) as light-yellow solid:1H-NMR (DMSO-d6, 400 MHz) į 11.78 (s, 1H), 8.26 (d, J = 7.4 Hz), 7.08 (d, J = 10.11 Hz) ppm;13C-NMR (DMSO-d6, 101 MHz) į 161.6 (d, JC-F = 28s^f-592218826327-20015.40 ^ 252.9 Hz), 154.0 (d, JC-F = 12.32 Hz), 135.0 (d, JC-F = 2.57 Hz), 130.4 (d, JC-F = 3.42 Hz), 107.2 (d, JC-F = 26.00 Hz), 97.3 (d, JC-F = 23.64 Hz) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í97.92 ppm; EI-MS (M+) calculated for C6H3BrFNO3234.93 , found 235.1.

[0054] In a similar fashion, reaction of 1-fluoro-2-iodo-5-methoxy-4-nitrobenzene (Compound 2) with BCl3 afforded 5-fluoro-4-iodo-2-nitrophenol (Compound 4):1H-NMR (DMSO-d6, 400 MHz) į 11.71 (br d, J = 8 Hz, 1H), 8.32 (d, J = 4 Hz, 1H), 6.98 (d, J = 12 Hz, 1H) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í85.37 ppm.

[0055] As shown in step 3 of Scheme A2, to a 2 L jacketed reactor equipped with a chiller, a overhead stirrer and a thermocouple was charged 4-bromo-5-fluoro-2-nitrophenol (99 g, 0.407 mol) followed by the addition of EtOH (7.5 V) and Water (7.5 V). The mixture was stirred, cooled to 10-12°C (internal), and to the resulted yellow suspension was added Na2S2O4(212 g, 85% purity, 1.06 mmol) portionwise, maintaining the temperature below 30 °C. The resulting suspension was gradually heated to 80°C and stirred at this temperature for 2 hours, at which time the suspension turned to a clear orange solution. The mixture was gradually cooled to room temperature and kept stirring overnight, after which EtOH was distilled off using a rotary evaporator at 40°C. The resulting yellow suspension was filtered and the cake was washed with water and then hexane. After drying the resulting solid in a vacuum oven for 12-14 h at 40 °C, 2-amino-4-bromo-5-fluorophenol (43.4 g, 87 wt%, 97% purity) was obtained as yellow solid:1H-NMR (DMSO-d6, 400 MHz) į 9.77 (s, 1H), 6.77 (d, J = 7.39 Hz), 6.61 (s, J = 10.06 Hz), 4.64 (br s, 1H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 150.1 (d, JC-F = 232.0 Hz), 144.7 (d, JC-F = 9.24 Hz), 135.5 (d, JC-F = 1.93 Hz), 116.2, 103.3 (d, JC-F = 25.18 Hz), 95.7 (d, JC-F = 21.42 Hz) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í123.75 ppm; EI-MS (M+) calculated for C6H5BrFNO 204.95, found 205.0.

[0056] In a similar fashion, reaction of 5-fluoro-4-iodo-2-nitrophenol (Compound 4) with Na2S2O4afforded 2-amino-5-fluoro-4-iodophenol (Compound 6): EI-MS (M+) calculated for C6H5FINO 252.94 found 253.1.

[0057] As shown in step 4 of Scheme A2, to a stirring solution of 2-amino-4-bromo-5- fluorophenol (19.0 g) and ethyl bromodifluoroacetate (3.0 equiv) in MeOH (10 V) was added diisopropylethylamine (DIEA, 6 equiv) to obtain a reddish orange solution. The mixture was stirred at room temperature for 2 hours and the volatiles removed by rotary evaporation at 30°C to obtain a yellow suspension. The solid was filtered off and the cake washed with hexane (3 V x 4) until the filtrate runs clear. The resulting solid was dried under suction for 2 hours followed air drying over 14 h to afford 4-bromo-2-(2-bromo-2,2-difluoroacetamido)-5- 29s^f-592218826327-20015.40 ^ fluorophenolate, N-ethyl-N-isopropylpropan-2-aminium salt (Compound 7, 44 g, 97% yield): EI-MS (M+) calculated for C8H4BrF3NO2(free base) 360.86, found 360.9.

[0058] In a similar fashion, reaction of 2-amino-5-fluoro-4-iodophenol with ethyl bromodifluoroacetate provided 2-(2-bromo-2,2-difluoroacetamido)-5-fluoro-4-iodophenolate, N-ethyl-N-isopropylpropan-2-aminium salt: (Compound 8).

[0059] As shown in step 5 of Scheme A2, to a stirred solution of 4-bromo-2-(2-bromo- 2,2-difluoroacetamido)-5-fluorophenolate, N-ethyl-N-isopropylpropan-2-aminium salt (Compound 7, 38.0 g) in DMF (10 V) was added K2CO3(2.5 equiv) and the mixture was stirred at 50°C for 14 hours. The mixture was acidified with 2M HCl (aq) until the pH = 4-5, diluted with water, and extracted with EtOAc (2 V x 3). The combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting dark brown wet solid was treated with water, stirred, and filtered. The resulting dark solid was slurried in CH2Cl2 (3 V), filtered, and the cake washed with CH2Cl2 followed by hexanes (1 V) to obtain the product as a pink color solid (14.7 g, 1st crop). A second crop (4.6 g, 2nd crop) was obtained from the CH2Cl2 mother liquor following the same procedure to yield 6- bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 9, 19.3 g, 74.8%):1H- NMR (DMSO-d6, 400 MHz) į 12.08 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 6.7 Hz, 1H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 154.6 (d, JC-F = 242.1 Hz) 153.2 (d, JC-F = 37.62 Hz) 138.1 (dt, JC-F = 11.58 and 2.19 Hz), 123.2 (d, JC-F = 3.11 Hz), 120.2, 113.2 (d JC-F = 262.64 Hz), 107.1 (d, JC-F = 28.62 Hz), 104.0 (d, JC-F = 22.86 Hz) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í75.55, í111.73 ppm; EI-MS (M+) calculated for C8H3BrF3NO2280.93, found 281.0.

[0060] In a similar fashion, to a 250 mL round bottom flask were added 2-(2-bromo-2,2- difluoroacetamido)-5-fluoro-4-iodophenolate, N-ethyl-N-isopropylpropan-2-aminium salt: (Compound 8, 9.8 g, 23.67 mmol) and DMF (45 mL, 5V) followed by the addition of K2CO3(5.0 g, 48 mmol, 2 equiv.). The mixture was stirred at 50°C for 12 hours, cooled to room temperature, and the pH adjusted to 7. The resulted aqueous phase was extracted with EtOAc (2 x 10 V), and the combined organics were washed with brine (10 V), dried (Na2SO4), concentrated by reduced pressure, and purified by flash chromatography (100% hexanes to 10% EtOAc / Hexane) to afford 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 10, 3.63 g, 62% yield from Compound 6) as orange solid:1H-NMR (DMSO-d6, 400 MHz) 12.02 (br s, 1H), 7.46-7.44 (m, 2H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 157.7 (d, JC-F = 239.18 Hz), 153.2 (t, JC-F = 37.53 Hz), 138.9 (d, JC-F = 11.68 Hz), 125.6 (d, JC-F = 3.06 Hz), 123.5 (d, JC-F = 3.14 Hz), 113.2 (t, JC-F = 262.56 Hz), 106.0 (d, JC-F = 30.81 30s^f-592218826327-20015.40 ^ Hz), 77.3 (d, JC-F = 28.4 Hz) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í75.61, í98.86 ppm; EI-MS (M+) calculated for C8H3F3INO2328.92, found 329.1.

[0061] As shown in steps 6 and 7 of Scheme A2, 6-bromo-2,2,7-trifluoro-2H- benzo[b][1,4]oxazin-3(4H)-one (Compound 9, 0.5 g, 1.77 mmol) was charged into a 50 mL Schlenk flask and anhydrous THF (3.5 mL), MTBE (3.5 mL) and heptane (3.5 mL) was added under a nitrogen atmosphere. The mixture was cooled to í78°C and 1.6 M n-BuLi (2.33 mL, 3.72 mmol, 2.1 equiv) in hexane was added dropwise over 5 minutes. The mixture was stirred for 20 min at í78 °C and a THF (5.0 mL) solution of hexafluorobenzene (0.61 mL, 5.32 mmol, 3 equiv.) was added dropwise (5 min) to the reaction mixture at í78 °C. The reaction temperature was allowed to warm up to í40 °C over 4 hours and the reaction quenched with an aqeuous NH4Cl solution and allowed to warm to 21°C. The reaction mixture was diluted and extracted with EtOAc (3 x 10 mL), dried over Na2SO4, filtered, the volatiles removed under reduced pressure, and the crude product purified by flash column chromatography (10% EtOAc / Hexane) to provide 2,2,7-trifluoro-6-(perfluorophenyl)-2H- benzo[b][1,4]oxazin-3(4H)-one (Compound 11, 0.36 g, 55% yield) as a white solid:1H-NMR (DMSO-d6, 400 MHz) į 12.21 (s, 1H), 7.69 (d, J = 9.9 Hz, 1H), 7.23 (d, J = 6.6 Hz, 1H);13C- NMR (101 MHz, DMSO-d6) į 155.5 (d, JC-F = 246.2 Hz), 153.3 (t, JC-F = 37.3 Hz), 144.3 (dm, JC-F = 246.7 Hz), 141.3 (dm, JC-F = 257.4 Hz), 140.03 (d, JC-F = 12.7 Hz), 137.8 (dm, JC-F = 246.1 Hz), 122.6 (dm, JC-F = 2.9 Hz), 119.3 (s), 113.2 (t, JC-F = 262.5 Hz), 110.4 (d, JC-F = 17.9 Hz), 108.7 (td, JC-F = 18.6, 3.7 Hz), 106.5 (d, JC-F = 28.3 Hz) ppm;19F-NMR (376 MHz, DMSO) į í75.13, í116.76 (t, J = 10.0 Hz), í141.13 (dt, J = 24.5, 8.0 Hz), í153.51 (t, J = 22.3 Hz), í155.41 to í172.00 (m) ppm; LCMS: m / z [M-1]- calculated for C14H3F8NO2368.00, found 367.7.

[0062] As shown in step 8 of Scheme A2, to a solution of 2,2,7-trifluoro-6- (perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 11, 200 mg, 0.54 mmol) in DMF (2 mL) were added K2CO3 (74 mg, 0.54 mmol) and 3-bromoprop-1-yne (70 mg, 0.54 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0-30% ethyl acetate in petroleum ether) to afford 2,2,7-trifluoro-6- (perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 12, 120 mg, 54% yield) as an off-white solid: GCMS calculated for (C17H5F8NO2) 407.0, found 407.0;1H-NMR (400 MHz, DMSO-d6) į 7.81 – 7.67 (m, 2 H), 4.88 (s, 2H), 3.45 (s, 1H);19F- NMR (400 MHz, DMSO-d6) į í74.85, í115.56, í140.50, í153.03, í162.01. 31s^f-592218826327-20015.40 ^

[0063] The following compounds were produced by procedures analogous to that of Step 8 of Scheme A2 by reacting Compound 11 with the appropriate alkyl halide or alkyl triflate: 2,2,7-trifluoro-4-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C15H5F8NO2) 383.0, found 383.0;1H-NMR (400 MHz, DMSO-d6) į 7.87 – 7.62 (m, 2H), 3.43 (s, 3H);19F-NMR (376 MHz, DMSO-d6) į í74.05, í116.55, í140.32, í153.34, í162.15; 4-benzyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C21H9F8NO2) 459.1, found 459.0; 1H-NMR (400 MHz, methanol-d4) į 7.42 – 7.37 (m, 4H), 7.35 – 7.31 (m, 3H), 5.33 (s, 2H); 19F-NMR (376 MHz, methanol-d4) į í78.80, í116.83, í142.52, í155.24 í164.83;

[0064] 4-allyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid. GCMS calculated for (C17H7F8NO2) 409.0, found 409.0; 1H-NMR (400 MHz, DMSO-d6) į 7.79 – 7.74 (m, 1H), 7.62 (d, J = 6.4 Hz, 1H), 5.88 (m, 1H), 5.27 – 5.14 (m, 2H), 4.68 – 4.62 (m, 2H);19F-NMR (376 MHz, DMSO-d6) į í74.67, í116.18, í140.50, í153.27, í162.03;

[0065] 4-ethyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C16H7F8NO2) 397.0, found 397.0;1H-NMR (400 MHz, DMSO-d6) į 7.80 (d, J = 6.4 Hz, 1H), 7.78 – 7.72 (m, 1H), 4.05 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H);19F-NMR (376 MHz, DMSO-d6) į í74.60, í116.48, í140.36, í153.44, í162.15;

[0066] 2,2,7-trifluoro-6-(perfluorophenyl)-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C17H9F8NO2) 411.1, found 411.0;1H-NMR (400 MHz, DMSO-d6) į 7.82 – 7.72 (m, 2H), 3.98 (t, J = 7.2 Hz, 2H), 1.65 – 1.59 (m, 2H), 0.91 (t, J = 6.8 Hz, 3H);19F-NMR (400 MHz, DMSO-d6) į í74.70, í116.40, í140.10, í153.46, í162.12;

[0067] 4-(3-cyclopropylprop-2-yn-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H- benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C20H9F8NO2) 447.1, found 447.1;1H-NMR (400 MHz, DMSO-d6) į 7.76 (d, J = 9.6 Hz, 1H), 7.71 (d, J = 6.4 Hz, 1H), 4.80 (s, 2H), 1.32 – 1.24 (m, 1H), 0.80 – 0.69 (m, 2H), 0.58 – 0.50 (m, 2H);19F-NMR (376 MHz, DMSO-d6) į í74.72, í115.70, í140.77, í153.12, í162.06;

[0068] 4-(but-2-yn-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin- 3(4H)-one as a white solid: GCMS calculated for (C18H7F8NO2) 421.0, found 421.1;1H- NMR (400 MHz, DMSO-d6) į 7.78 – 7.73 (m, 2H), 4.83 – 4.78 (m, 2H), 1.78 (s, 3H);19F- NMR (376 MHz, DMSO-d6) į í74.68, í115.65, í140.58, í153.09, í161.96; 32s^f-592218826327-20015.40 ^

[0069] 2,2,7-trifluoro-4-(2-methylallyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin- 3(4H)-one as a white solid: GCMS calculated for (C18H9F8NO2) 423.0, found 423.0;1H- NMR (400 MHz, DMSO-d6) į 7.77 (d, J = 9.6 Hz, 1H), 7.53 (d, J = 6.4 Hz, 1H), 4.92 – 4.88 (m, 1H), 4.72 – 4.66 (m, 1H), 4.56 (s, 2H), 1.75 (d, J = 1.2 Hz, 3H);19F-NMR (376 MHz, DMSO-d6) į í75.05, í116.00, í140.57, í153.23, í162.01;

[0070] 2,2,7-trifluoro-6-(perfluorophenyl)-4-(2,2,2-trifluoroethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C16H4F11NO2) 451.0, found 451.0;1H-NMR (400 MHz, DMSO-d6) į 7.97 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 5.08 – 4.97 (m, 2H);19F-NMR (400 MHz, DMSO-d6) į í67.95, í75.15, í115.30, í140.49, í152.81, í161.86;

[0071] 2,2,7-trifluoro-4-(2-fluorobenzyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin- 3(4H)-one as a white solid: MS (ESI) calculated for (C21H8F9NO2) [M+1]+478.2, found 477.9;1H-NMR (400 MHz, DMSO-d6) į 7.78 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.43 – 7.33 (m, 1H), 7.33 – 7.21 (m, 2H), 7.18 – 7.16 (m, 1H), 5.32 (s, 2H);19F-NMR (400 MHz, DMSO-d6) į í74.91, í115.69, í117.44, í140.68, í153.15, í162.02;

[0072] 2,2,7-trifluoro-4-isopropyl-6-(perfluorophenyl)-2H-benzo[b][1,4] oxazin-3(4H)- one as a light yellow solid: GCMS calculated for (C17H9F8NO2) 411.0, found 411.0;1H-NMR (400 MHz, DMSO-d6) į 7.72 – 7.62 (m, 2H), 5.41 – 5.30 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H);19F-NMR (400 MHz, DMSO-d6) į í67.27, í112.83, í140.84, í153.73, í162.21. 33s^f-592218826327-20015.40 ^ Example 2. Preparation of 2,2,7-trifluoro-6-(perfluorophenyl)-4-(prop-2-yn-1-yl)-2H- benzo[b][1,4]oxazin-3(4H)-oneScheme B2

[0073] As shown in Step 1 of Scheme B2, to an oven dried 5 L, 4-neck round bottom flask connected to a nitrogen inlet, a thermocouple, and an overhead stirrer was charged concentrated sulfuric acid (600 mL) and agitation was started. To the mixture was added triflic anhydride (16.5 g, 0.058 mol, 0.1 equiv) followed by N-bromosuccinimide (NBS, 68.64 g, 0.385 mol, 0.6 equiv.) and the mixture was stirred for 1 hour at room temperature to obtain a deep red solution. To this stirring mixture was added 5-fluoro-2-nitroanisole (100 g, 0.584 mol) at room temperature and the stirring was continued for 1 hour at room temperature. Additional NBS (45.76 g, 0.32 mol, 0.5 equiv) was added and the stirring continued for an additional 2 hours at room temperature. The reaction mixture was cooled to 0-5°C and ice-water (1000 mL) was added portionwise over 30 min. (exothermia). The mixture was allowed to warm to room temperature and stirred not less than 2 hours to obtain a yellow suspension. The suspension was filtered and the the cake was washed with water (3x) followed by hexane (3x). The wet cake was added into to 1 L, 3 neck round bottom flask equipped with a overhead stirrer, followed by the addition of hexane (300 mL) and the resulting slurry was stirred for not less than 2 hours at room temperature. The suspension was then filtered and the cake was washed with hexane (3x), dried under reduced pressure for 1 34s^f-592218826327-20015.40 ^ hour, followed drying in a vacuum oven for not less than 12 hours at 40 °C to afford 1- bromo-2-fluoro-4-methoxy-5-nitrobenzene (Compound 1) as light-yellow solid in 59% yield with 98.5% HPLC purity:1H-NMR (DMSO-d6, 400 MHz) į 8.35 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 10.8 Hz, 2 H), 3.95 (s, 3H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 161.7 (d, JC-F = 252.0 Hz), 154.1 (d, JC-F = 10.9 Hz), 136.7 (d, JC-F = 3.2 Hz), 130.1 (d, JC-F = 3.10 Hz), 104.3 (d, JC-F = 28.29 Hz), 98.4 (d, JC-F = 23.6 Hz), 58.2 ppm;19F-NMR (DMSO-d6, 376.5 MHz) į -97.01 ppm; EI-MS (M+) calculated for C7H5BrFNO3348.94, found 349.0.

[0074] In a similar fashion, reaction of 5-fluoro-2-nitroanisole with N-iodosuccinimide (NIS) produced 1-fluoro-2-iodo-5-methoxy-4-nitrobenzene (Compound 2):1H-NMR (DMSO-d6, 400 MHz) į 8.38 (d, J = 6.63 Hz, 1H), 7.43 (d, J = 10.1 Hz, 1H), 3.94 (s, 3H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 164.6 (d, JC-F = 249.3 Hz), 154.8 (d, JC-F = 11.0 Hz), 137.2 (d, JC-F = 2.47 Hz), 135.4 (d, JC-F = 5.5 Hz), 103.4 (d, JC-F = 30.5 Hz), 70.7 (d, JC-F = 29.63 Hz), 58.03 ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í84.35 ppm; EI-MS (M+) calculated for C7H5FINO3296.93, found 297.1.

[0075] As shown in step 2 of Scheme B2, to a 3 L, 3 neck round bottom flask equipped with an overhead stirrer and a thermocouple was added 1-bromo-2-fluoro-4-methoxy-5- nitrobenzene (90.0 g, 89.6 wt%) and CH2Cl2(5 V) and the mixture was cooled to 0°C. A solution of 1 M BCl3 in CH2Cl2 (2 equiv) was added slowly via an addition funnel. The mixture was allowed to warm to room temperate and stirred for 18 hours. After this time, the mixture was re-cooled to 0 °C and additional BCl3 (1 equiv) was added, and the stirring was continued for an additional 24 h at room temperature, at which time complete conversion of starting material was indicated by HPLC analysis. The mixture was cooled to 0°C, treated with satd. NaHCO3(5 V), diluted with water and extracted with CH2Cl2(3 x 3-4 V). The organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 4-bromo-5-fluoro-2-nitrophenol (Compound 3, 85.3 g, 89 wt% by NMR, 98% yield) as light-yellow solid:1H-NMR (DMSO-d6, 400 MHz) į 11.78 (s, 1H), 8.26 (d, J = 7.4 Hz), 7.08 (d, J = 10.11 Hz) ppm;13C-NMR (DMSO-d6, 101 MHz) į 161.6 (d, JC-F = 252.9 Hz), 154.0 (d, JC-F = 12.32 Hz), 135.0 (d, JC-F = 2.57 Hz), 130.4 (d, JC-F = 3.42 Hz), 107.2 (d, JC-F = 26.00 Hz), 97.3 (d, JC-F = 23.64 Hz) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í97.92 ppm; EI-MS (M+) calculated for C6H3BrFNO3234.93 , found 235.1.

[0076] In a similar fashion, reaction of 1-fluoro-2-iodo-5-methoxy-4-nitrobenzene (Compound 2) with BCl3 afforded 5-fluoro-4-iodo-2-nitrophenol (Compound 4):1H-NMR (DMSO-d6, 400 MHz) į 11.71 (br d, J = 8 Hz, 1H), 8.32 (d, J = 4 Hz, 1H), 6.98 (d, J = 12 Hz, 1H) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í85.37 ppm. 35s^f-592218826327-20015.40 ^

[0077] As shown in step 3 of Scheme B2, to a 2 L jacketed reactor equipped with a chiller, a overhead stirrer and a thermocouple was charged 4-bromo-5-fluoro-2-nitrophenol (99 g, 0.407 mol) followed by the addition of EtOH (7.5 V) and Water (7.5 V). The mixture was stirred, cooled to 10-12°C (internal), and to the resulted yellow suspension was added Na2S2O4 (212 g, 85% purity, 1.06 mmol) portionwise, maintaining the temperature below 30 °C. The resulting suspension was gradually heated to 80°C and stirred at this temperature for 2 hours, at which time the suspension turned to a clear orange solution. The mixture was gradually cooled to room temperature and kept stirring overnight, after which EtOH was distilled off using a rotary evaporator at 40°C. The resulting yellow suspension was filtered and the cake was washed with water and then hexane. After drying the resulting solid in a vacuum oven for 12-14 h at 40 °C, 2-amino-4-bromo-5-fluorophenol (43.4 g, 87 wt%, 97% purity) was obtained as yellow solid:1H-NMR (DMSO-d6, 400 MHz) į 9.77 (s, 1H), 6.77 (d, J = 7.39 Hz), 6.61 (s, J = 10.06 Hz), 4.64 (br s, 1H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 150.1 (d, JC-F = 232.0 Hz), 144.7 (d, JC-F = 9.24 Hz), 135.5 (d, JC-F = 1.93 Hz), 116.2, 103.3 (d, JC-F = 25.18 Hz), 95.7 (d, JC-F = 21.42 Hz) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í123.75 ppm; EI-MS (M+) calculated for C6H5BrFNO 204.95, found 205.0.

[0078] In a similar fashion, reaction of 5-fluoro-4-iodo-2-nitrophenol (Compound 4) with Na2S2O4 afforded 2-amino-5-fluoro-4-iodophenol (Compound 6): EI-MS (M+) calculated for C6H5FINO 252.94 found 253.1.

[0079] As shown in step 4 of Scheme B2, to a stirring solution of 2-amino-4-bromo-5- fluorophenol (19.0 g) and ethyl bromodifluoroacetate (3.0 equiv) in MeOH (10 V) was added diisopropylethylamine (DIEA, 6 equiv) to obtain a reddish orange solution. The mixture was stirred at room temperature for 2 hours and the volatiles removed by rotary evaporation at 30°C to obtain a yellow suspension. The solid was filtered off and the cake washed with hexane (3 V x 4) until the filtrate runs clear. The resulting solid was dried under suction for 2 hours followed air drying over 14 h to afford 4-bromo-2-(2-bromo-2,2-difluoroacetamido)-5- fluorophenolate, N-ethyl-N-isopropylpropan-2-aminium salt (Compound 7, 44 g, 97% yield): EI-MS (M+) calculated for C8H4BrF3NO2 (free base) 360.86, found 360.9.

[0080] In a similar fashion, reaction of 2-amino-5-fluoro-4-iodophenol with ethyl bromodifluoroacetate provided 2-(2-bromo-2,2-difluoroacetamido)-5-fluoro-4-iodophenolate, N-ethyl-N-isopropylpropan-2-aminium salt: (Compound 8).

[0081] As shown in step 5 of Scheme B2, to a stirred solution of 4-bromo-2-(2-bromo- 2,2-difluoroacetamido)-5-fluorophenolate, N-ethyl-N-isopropylpropan-2-aminium salt (Compound 7, 38.0 g) in DMF (10 V) was added K2CO3 (2.5 equiv) and the mixture was 36s^f-592218826327-20015.40 ^ stirred at 50°C for 14 hours. The mixture was acidified with 2M HCl (aq) until the pH = 4-5, diluted with water, and extracted with EtOAc (2 V x 3). The combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting dark brown wet solid was treated with water, stirred, and filtered. The resulting dark solid was slurried in CH2Cl2 (3 V), filtered, and the cake washed with CH2Cl2 followed by hexanes (1 V) to obtain the product as a pink color solid (14.7 g, 1st crop). A second crop (4.6 g, 2nd crop) was obtained from the CH2Cl2 mother liquor following the same procedure to yield 6- bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 9, 19.3 g, 74.8%):1H- NMR (DMSO-d6, 400 MHz) į 12.08 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 6.7 Hz, 1H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 154.6 (d, JC-F = 242.1 Hz) 153.2 (d, JC-F = 37.62 Hz) 138.1 (dt, JC-F = 11.58 and 2.19 Hz), 123.2 (d, JC-F = 3.11 Hz), 120.2, 113.2 (d JC-F = 262.64 Hz), 107.1 (d, JC-F = 28.62 Hz), 104.0 (d, JC-F = 22.86 Hz) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í75.55, í111.73 ppm; EI-MS (M+) calculated for C8H3BrF3NO2 280.93, found 281.0.

[0082] In a similar fashion, to a 250 mL round bottom flask were added 2-(2-bromo-2,2- difluoroacetamido)-5-fluoro-4-iodophenolate, N-ethyl-N-isopropylpropan-2-aminium salt: (Compound 8, 9.8 g, 23.67 mmol) and DMF (45 mL, 5V) followed by the addition of K2CO3(5.0 g, 48 mmol, 2 equiv.). The mixture was stirred at 50°C for 12 hours, cooled to room temperature, and the pH adjusted to 7. The resulted aqueous phase was extracted with EtOAc (2 x 10 V), and the combined organics were washed with brine (10 V), dried (Na2SO4), concentrated by reduced pressure, and purified by flash chromatography (100% hexanes to 10% EtOAc / Hexane) to afford 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 10, 3.63 g, 62% yield from Compound 6) as orange solid:1H-NMR (DMSO-d6, 400 MHz) 12.02 (br s, 1H), 7.46-7.44 (m, 2H) ppm;13C-NMR (DMSO-d6, 101 MHz) į 157.7 (d, JC-F = 239.18 Hz), 153.2 (t, JC-F = 37.53 Hz), 138.9 (d, JC-F = 11.68 Hz), 125.6 (d, JC-F = 3.06 Hz), 123.5 (d, JC-F = 3.14 Hz), 113.2 (t, JC-F = 262.56 Hz), 106.0 (d, JC-F = 30.81 Hz), 77.3 (d, JC-F = 28.4 Hz) ppm;19F-NMR (DMSO-d6, 376.5 MHz) į í75.61, í98.86 ppm; EI-MS (M+) calculated for C8H3F3INO2328.92, found 329.1.

[0083] As shown in step 6 of Scheme B2, 6-bromo-2,2,7-trifluoro-2H- benzo[b][1,4]oxazin-3(4H)-one (Compound 10, 1.47 g, 4.47 mmol) and 1,10-phenanthroline (202 mg, 1.12 mmol, 0.25 equiv) were charged into 75 mL Schlenk tube. In a glove box under an atmosphere of nitrogen, K3PO4 (3.8 g, 17.9 mmol, 4 equiv), CuI (170 mg, 0.9 mmol, 0.2 equiv) and DMF (15 mL, 10V) were added followed by pentafluorobenzene (1.5 mL13.4 mmol, 3 equiv). The tube was sealed inside the glove box and pre-stirred at room temperature 37s^f-592218826327-20015.40 ^ for 15 min before stirring at 110 °C for 20 h. After this time, the reaction mixture was diluted with EtOAc (10V) and washed with satd. brine (2 x 10V), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (15% EtOAc / hexane) to provide 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 11, 1.33 g, 74% yield) as a white solid:1H-NMR (DMSO-d6, 400 MHz) į 12.21 (s, 1H), 7.69 (d, J = 9.9 Hz, 1H), 7.23 (d, J = 6.6 Hz, 1H);13C-NMR (101 MHz, DMSO-d6) į 155.5 (d, JC-F = 246.2 Hz), 153.3 (t, JC-F = 37.3 Hz), 144.3 (dm, JC-F = 246.7 Hz), 141.3 (dm, JC-F = 257.4 Hz), 140.03 (d, JC-F = 12.7 Hz), 137.8 (dm, JC-F = 246.1 Hz), 122.6 (dm, JC-F = 2.9 Hz), 119.3 (s), 113.2 (t, JC-F = 262.5 Hz), 110.4 (d, JC-F = 17.9 Hz), 108.7 (td, JC-F = 18.6, 3.7 Hz), 106.5 (d, JC-F = 28.3 Hz) ppm;19F-NMR (376 MHz, DMSO) į í75.13, í116.76 (t, J = 10.0 Hz), í141.13 (dt, J = 24.5, 8.0 Hz), í153.51 (t, J = 22.3 Hz), í155.41 to í172.00 (m) ppm; LCMS: m / z [M-1]- calculated for C14H3F8NO2368.00, found 367.7.

[0084] 2,2,7-Trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one could also be produced from 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 9) in a similar fashion.

[0085] As shown in step 7 of Scheme B2, to a solution of 2,2,7-trifluoro-6- (perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 11, 200 mg, 0.54 mmol) in DMF (2 mL) were added K2CO3(74 mg, 0.54 mmol) and 3-bromoprop-1-yne (70 mg, 0.54 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0-30% ethyl acetate in petroleum ether) to afford 2,2,7-trifluoro-6- (perfluorophenyl)-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 12, 120 mg, 54% yield) as an off-white solid: GCMS calculated for (C17H5F8NO2) 407.0, found 407.0;1H-NMR (400 MHz, DMSO-d6) į 7.81 – 7.67 (m, 2 H), 4.88 (s, 2H), 3.45 (s, 1H);19F- NMR (400 MHz, DMSO-d6) į í74.85, í115.56, í140.50, í153.03, í162.01.

[0086] The following compounds were produced by procedures analogous to that of Step 7 of Scheme B2 by reacting Compound 11 with the appropriate alkyl halide or alkyl triflate: 2,2,7-trifluoro-4-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C15H5F8NO2) 383.0, found 383.0;1H-NMR (400 MHz, DMSO-d6) į 7.87 – 7.62 (m, 2H), 3.43 (s, 3H);19F-NMR (376 MHz, DMSO-d6) į í74.05, í116.55, í140.32, í153.34, í162.15; 38s^f-592218826327-20015.40 ^ 4-benzyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C21H9F8NO2) 459.1, found 459.0; 1H-NMR (400 MHz, methanol-d4) į 7.42 – 7.37 (m, 4H), 7.35 – 7.31 (m, 3H), 5.33 (s, 2H); 19F-NMR (376 MHz, methanol-d4) į í78.80, í116.83, í142.52, í155.24 í164.83;

[0087] 4-allyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid. GCMS calculated for (C17H7F8NO2) 409.0, found 409.0; 1H-NMR (400 MHz, DMSO-d6) į 7.79 – 7.74 (m, 1H), 7.62 (d, J = 6.4 Hz, 1H), 5.88 (m, 1H), 5.27 – 5.14 (m, 2H), 4.68 – 4.62 (m, 2H);19F-NMR (376 MHz, DMSO-d6) į í74.67, í116.18, í140.50, í153.27, í162.03;

[0088] 4-ethyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C16H7F8NO2) 397.0, found 397.0;1H-NMR (400 MHz, DMSO-d6) į 7.80 (d, J = 6.4 Hz, 1H), 7.78 – 7.72 (m, 1H), 4.05 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H);19F-NMR (376 MHz, DMSO-d6) į í74.60, í116.48, í140.36, í153.44, í162.15;

[0089] 2,2,7-trifluoro-6-(perfluorophenyl)-4-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C17H9F8NO2) 411.1, found 411.0;1H-NMR (400 MHz, DMSO-d6) į 7.82 – 7.72 (m, 2H), 3.98 (t, J = 7.2 Hz, 2H), 1.65 – 1.59 (m, 2H), 0.91 (t, J = 6.8 Hz, 3H);19F-NMR (400 MHz, DMSO-d6) į í74.70, í116.40, í140.10, í153.46, í162.12;

[0090] 4-(3-cyclopropylprop-2-yn-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H- benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C20H9F8NO2) 447.1, found 447.1;1H-NMR (400 MHz, DMSO-d6) į 7.76 (d, J = 9.6 Hz, 1H), 7.71 (d, J = 6.4 Hz, 1H), 4.80 (s, 2H), 1.32 – 1.24 (m, 1H), 0.80 – 0.69 (m, 2H), 0.58 – 0.50 (m, 2H);19F-NMR (376 MHz, DMSO-d6) į í74.72, í115.70, í140.77, í153.12, í162.06;

[0091] 4-(but-2-yn-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin- 3(4H)-one as a white solid: GCMS calculated for (C18H7F8NO2) 421.0, found 421.1;1H- NMR (400 MHz, DMSO-d6) į 7.78 – 7.73 (m, 2H), 4.83 – 4.78 (m, 2H), 1.78 (s, 3H);19F- NMR (376 MHz, DMSO-d6) į í74.68, í115.65, í140.58, í153.09, í161.96;

[0092] 2,2,7-trifluoro-4-(2-methylallyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin- 3(4H)-one as a white solid: GCMS calculated for (C18H9F8NO2) 423.0, found 423.0;1H- NMR (400 MHz, DMSO-d6) į 7.77 (d, J = 9.6 Hz, 1H), 7.53 (d, J = 6.4 Hz, 1H), 4.92 – 4.88 (m, 1H), 4.72 – 4.66 (m, 1H), 4.56 (s, 2H), 1.75 (d, J = 1.2 Hz, 3H);19F-NMR (376 MHz, DMSO-d6) į í75.05, í116.00, í140.57, í153.23, í162.01;

[0093] 2,2,7-trifluoro-6-(perfluorophenyl)-4-(2,2,2-trifluoroethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one as a white solid: GCMS calculated for (C16H4F11NO2) 451.0, 39s^f-592218826327-20015.40 ^ found 451.0;1H-NMR (400 MHz, DMSO-d6) į 7.97 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 5.08 – 4.97 (m, 2H);19F-NMR (400 MHz, DMSO-d6) į í67.95, í75.15, í115.30, í140.49, í152.81, í161.86;

[0094] 2,2,7-trifluoro-4-(2-fluorobenzyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazin- 3(4H)-one as a white solid: MS (ESI) calculated for (C21H8F9NO2) [M+1]+478.2, found 477.9;1H-NMR (400 MHz, DMSO-d6) į 7.78 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.43 – 7.33 (m, 1H), 7.33 – 7.21 (m, 2H), 7.18 – 7.16 (m, 1H), 5.32 (s, 2H);19F-NMR (400 MHz, DMSO-d6) į í74.91, í115.69, í117.44, í140.68, í153.15, í162.02;

[0095] 2,2,7-trifluoro-4-isopropyl-6-(perfluorophenyl)-2H-benzo[b][1,4] oxazin-3(4H)- one as a light yellow solid: GCMS calculated for (C17H9F8NO2) 411.0, found 411.0;1H-NMR (400 MHz, DMSO-d6) į 7.72 – 7.62 (m, 2H), 5.41 – 5.30 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H);19F-NMR (400 MHz, DMSO-d6) į í67.27, í112.83, í140.84, í153.73, í162.21. 40s^f-5922188

Claims

26327-20015.40 ^ CLAIMS What is claimed is:

1. A process for manufacturing a compound of formula (I),salt thereof, wherein: R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b; the process comprising: reacting a compound of formula (a), or a salt thereof, with a non-nucleophilic base and a compound of formula (b) to produce a compound of formula (c), or a salt thereof,, 41s^f-592218826327-20015.40 ^ where X is Br and L1is F or Cl, or L1C(O) is an alkyl ester or an active ester, to produce an amide of formula (c), or salt thereof; treating a compound of formula (c), or a salt thereof, with an additional non- nucleophilic base to produce an intermediate of formula (d) and, subsequently, a compound of formula (e), or a salt thereof,reacting a compound of formula (e), or a salt thereof, with from 2 to 2.5 equivalents of an alkyl lithium reagent to produce a di-lithio intermediate, followed by treating the di- lithio intermediate with hexafluorobenzene to produce a compound of formula (f), or a salt thereof,; and alkylating a compound of formula (f), or a salt thereof, with alkylating agent L2-R, where L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with triphenylphosphine and an azodicarboxylate in a Mitsinobu reaction, to produce a compound of formula (I), or a salt thereof. 42s^f-592218826327-20015.40 ^ 2. The process according to claim 1, wherein compound (e) is 6-bromo-2,2,7-trifluoro- 2H-benzo[b][1,4]oxazin-3(4H)-one, or a salt thereof.

3. The process according to claim 1, wherein R is, where R1bis H, alkyl, or cyclopropyl.

4. The process according to claim 3, wherein R1bis H.

5. The process according to claim 1, wherein R is CH(CH3)C(O)OC1-4alkyl.

6. The process according to claim 1, wherein R is CH(CH3)C(O)OH.

7. The process according to any one of claims 1-6, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base.

8. The process according to any one of claims 1-6, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases.

9. A compound having the structure:salt thereof.

10. The compound according to claim 9, wherein the compound is an alkyl ammonium salt.

11. The compound of claim 9, wherein the compound is43s^f-592218826327-20015.40 ^ 12. A process, comprising: combining a compound of formula (e), or a salt thereof, with 2 to 2.5 equivalents of an alkyl lithium reagent under suitable conditions to form a di-lithio intermediate, wherein the compound of formula (e), or salt thereof, is:wherein X is Br; and combining a compound of formula (e1) with the di-lithio intermediate to produce a compound of formula (f), or a salt thereof, wherein the compounds of formula (e1) and (f) are:

13. The process of claim 12, wherein the combining the compound of formula (e1) with the di-lithio intermediate comprises adding the compound of formula (e1) to the di-lithio intermediate.

14. The process of claim 12, wherein the combining the compound of formula (e1) with the di-lithio intermediate comprises adding the di-lithio intermediate to the compound of formula (e1).

15. The process of any one of claims 12 to 14, further comprising: combining a compound of formula (c), or a salt thereof, with a non-nucleophilic base to produce the compound of formula (e), or a salt thereof, wherein the compound of formula (c), or salt thereof, is:wherein X is Br. 44s^f-592218826327-20015.40 ^ 16. The process of any one of claims 12 to 15, further comprising: combining a compound of formula (a), or a salt thereof, with an additional non- nucleophilic base and a compound of formula (b) to produce the compound of formula (c), or a salt thereof, wherein the compounds of formula (a) and (b) are: wher1 1ein X is Br and L is F or Cl, or L C(O) together forms an alkyl ester or an active ester group.

17. The process of claim 16, wherein the non-nucleophilic base and additional non- nucleophilic base, when simultaneously present, are the same base.

18. The process of claim 16, wherein the non-nucleophilic base and additional non- nucleophilic base, when simultaneously present, are different bases.

19. The process of any one of claims 12 to 18, further comprising: alkylating the compound of formula (f), or a salt thereof, with an alkylating agent to produce a compound of formula (I):salt thereof, and wherein the alkylating agent is L2-R, wherein: L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with an azodicarboxylate in a Mitsinobu reaction; R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; and 45s^f-592218826327-20015.40 ^ each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b.

20. A process for manufacturing a compound of formula (I),salt thereof, wherein: R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b; the process comprising: reacting a compound of formula (a), or a salt thereof, with a non-nucleophilic base and a compound of formula (b) to produce a compound of formula (c), or a salt thereof, 46s^f-592218826327-20015.40 ^, where X is Br or I and L1is F or Cl, or L1C(O) is an alkyl ester or an active ester, to produce an amide of formula (c) or salt thereof; treating a compound of formula (c), or a salt thereof, with an additional non- nucleophilic base to produce an intermediate of formula (d) and, subsequently, a compound of formula (e), or a salt thereof,; reacting a compound of formula (e), or a salt thereof, with pentafluorobenzene in the presence of a Cu(I) salt and 1,10-phenanthroline to produce a compound of formula (f), or a salt thereof,and alkylating a compound of formula (f), or a salt thereof, with alkylating agent L2-R, where L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with triphenylphosphine and an azodicarboxylate in a Mitsinobu reaction, to produce a compound of formula (I), or a salt thereof, 47s^f-592218826327-20015.40 ^.

21. The process according to claim 20, wherein the Cu(I) salt is CuCl, CuBr, or CuI.

22. The process according to claim 20 or claim 21, wherein compound (e) is 6-bromo- 2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, or a salt thereof.

23. The process according to claim 20 or claim 21, wherein compound (e) is 2,2,7- trifluoro-6-iodo-2H-benzo[b][1,4]oxazin-3(4H)-one, or a salt thereof.

24. The process according to claim 20 or claim 21, wherein R is , where R1bis H, alkyl, or cyclopropyl.

25. The process according to claim 24, wherein R1bis H.

26. The process according to claim 20 or claim 21, wherein R is CH(CH3)C(O)OC1-4alkyl.

27. The process according to claim 20 or claim 21, wherein R is CH(CH3)C(O)OH.

28. The process according to any one of claims 20-27, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base.

29. The process according to any one of claims 20-27, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases.

30. A compound having the structure: salt thereof. to claim 30, wherein the compound is an alkyl ammonium48s^f-592218826327-20015.40 ^ 32. The compound of claim 30, wherein the compound is:

33. A process, comprising: combining a compound of formula (e), or a salt thereof, with pentafluorobenzene in the presence of a Cu(I) salt and 1,10-phenanthroline to produce a compound of formula (f), or a salt thereof, wherein the compound of formula (e), or salt thereof, is: X is Br or I, and formula (f), or a salt thereof, is:.

34. The process of claim 33, wherein the Cu(I) salt is CuCl, CuBr, or CuI.

35. The process of claim 33 or claim 34, further comprising: combining a compound of formula (c), or a salt thereof, with a non-nucleophilic base to produce the compound of formula (e), or a salt thereof, wherein the compound of formula (c), or salt thereof, is:49s^f-592218826327-20015.40 ^ 36. The process of any one of claims 33 to 35, further comprising: combining a compound of formula (a), or a salt thereof, with an additional non- nucleophilic base and a compound of formula (b) to produce the compound of formula (c), or a salt thereof, wherein the compounds of formula (a) and (b) are: (b), wherein L1is1F or Cl, or L C(O) together forms an alkyl ester or an active ester group.

37. The process of claim 36, wherein the non-nucleophilic base and additional non- nucleophilic base, when simultaneously present, are the same base.

38. The process of claim 36, wherein the non-nucleophilic base and additional non- nucleophilic base, when simultaneously present, are different bases.

39. The process of any one of claims 33 to 38, further comprising: alkylating the compound of formula (f), or a salt thereof, with an alkylating agent to produce a compound of formula (I):wherein the alkylating agent is L2-R, wherein: L2is iodo, bromo, chloro, a sulfonate, or a reactive intermediate resulting from reacting an alcohol with triphenylphosphine and an azodicarboxylate in a Mitsinobu reaction; R is C1-6alkyl, C3-4alkenyl, C3-4alkynyl, cyclopropyl, CH2C3-6cycloalkyl, phenyl or C1-2alkyl-phenyl, each optionally substituted with C(O)R1a, CH2C(O)R1a, R1b, and up to 3 F or Cl atoms; 50s^f-592218826327-20015.40 ^ R1ais OR1b, CH2OC(O)C1-4alkyl, C(O)OR1b, N(R1b)(R1c), ON(R1b)(R1c), NHN(R1b)(R1c), NHS(O)2N(R1b)2, NHS(O)2C1-4alkyl, or NHOR1b; and each R1bis, independently, H, C3-6cycloalkyl, CH2phenyl, or C1-4alkyl optionally substituted with up to 3 F or Cl atoms; and R1cis H or C1-4alkyl optionally substituted with C(O)OR1bor R1band R1ctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from íC(O)OR1band íC(O)R1b. 51s^f-5922188

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