the present invention includes processes for preparing a compound of formula ( i ): r is — cho , — ch ( oh ) 2 or — ch ( oh )( or 4 ); p 1 is h or a hydroxyl protecting group ; p 3 is h or a carboxy protecting group ; r 3 is h , halogen , hydroxy , optionally substituted lower alkyl , optionally substituted cycloalkyl , optionally substituted lower alkenyl , optionally substituted lower alkoxy , optionally substituted lower alkenyloxy , optionally substituted aryl , optionally substituted aryloxy , optionally substituted heterocyclic group , optionally substituted heterocycleoxy and optionally substituted amino ; r 4 is lower alkyl ; r x is h , halo or r 2 — x — nr 1 — c ( o )—; r 2 is optionally substituted aryl ; x is a single bond , a heteroatom group selected from o , s , so , so 2 , and nh or lower alkylene or lower alkenylene wherein each may be intervened by the heteroatom ; and r 1 is h or lower alkyl ; wherein r 5 and r 6 are independently lower alkyl or r 5 and r 6 can be alkyl and joined to form a 5 -, 6 -, or 7 - membered ring , the term “ lower alkyl ”, alone or in combination with any other term , refers to a straight - chain or branched - chain saturated aliphatic hydrocarbon radical containing 1 to 6 carbon atoms . examples of alkyl radicals include , but are not limited to , methyl , ethyl , n - propyl , isopropyl , n - butyl , isobutyl , sec - butyl , tert - butyl , pentyl , isoamyl , n - hexyl and the like . the term “ lower cycloalkyl ” refers to a saturated or partially saturated carbocyclic ring composed of 3 - 6 carbons in any chemically stable configuration . examples of suitable carbocyclic groups include cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , and cyclohexenyl . the term “ lower alkenyl ,” alone or in combination with any other term , refers to a straight - chain or branched - chain alkyl group with one or two carbon - carbon double bonds . examples of alkenyl radicals include , but are not limited to , ethenyl , propenyl , isopropenyl , butenyl , isobutenyl , pentenyl , hexenyl , hexadienyl and the like . the term “ lower alkylene ” refers to a straight or branched chain divalent hydrocarbon radical , preferably having from one to six carbon atoms , unless otherwise defined . examples of “ alkylene ” as used herein include , but are not limited to , methylene , ethylene , propylene , butylene , isobutylene and the like . the term “ lower alkenylene ” refers to a straight or branched chain divalent hydrocarbon radical , one or two carbon - carbon double bonds . the term “ lower alkoxy ” refers to an alkyl ether radical , wherein the term “ alkyl ” is defined above . examples of suitable alkyl ether radicals include , but are not limited to , methoxy , ethoxy , n - propoxy , isopropoxy , n - butoxy , isobutoxy , sec - butoxy , tert - butoxy and the like . the term “ halogen ” refers fluorine ( f ), chlorine ( cl ), bromine ( br ), or iodine ( i ). the term “ aryl ” alone or in combination with any other term , refers to a carbocyclic aromatic moiety ( such as phenyl or naphthyl ) containing 6 carbon atoms , and more preferably from 6 - 10 carbon atoms . examples of aryl radicals include , but are not limited to , phenyl , naphthyl , indenyl , azulenyl , fluorenyl , anthracenyl , phenanthrenyl , tetrahydronaphthyl , indanyl , phenanthridinyl and the like . unless otherwise indicated , the term “ aryl ” also includes each possible positional isomer of an aromatic hydrocarbon radical , such as in 1 - naphthyl , 2 - naphthyl , 5 - tetrahydronaphthyl , 6 - tetrahydronaphthyl , 1 - phenanthridinyl , 2 - phenanthridinyl , 3 - phenanthridinyl , 4 - phenanthridinyl , 7 - phenanthridinyl , 8 - phenanthridinyl , 9 - phenanthridinyl and 10 - phenanthridinyl . examples of aryl radicals include , but are not limited to , phenyl , naphthyl , indenyl , azulenyl , fluorenyl , anthracenyl , phenanthrenyl , tetrahydronaphthyl , indanyl , phenanthridinyl and the like . the term “ aralkyl ” refers to an alkyl group substituted by an aryl . examples of aralkyl groups include , but are not limited to , benzyl and phenethyl . the term “ heterocyclic group ,” and “ heterocycle ” as used herein , refer to a 3 - to 7 - membered monocyclic heterocyclic ring or 8 - to 11 - membered bicyclic heterocyclic ring system any ring of which is either saturated , partially saturated or unsaturated , and which may be optionally benzofused if monocyclic . each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of n , o and s , and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized , and the nitrogen atom may optionally be quaternized , and including any bicyclic group in which any of the above - defined heterocyclic rings is fused to a benzene ring . the heterocyclic ring may be attached at any carbon or heteroatom , provided that the attachment results in the creation of a stable structure . preferred heterocycles include 5 - 7 membered monocyclic heterocycles and 8 - 10 membered bicyclic heterocycles . when the heterocyclic ring has substituents , it is understood that the substituents may be attached to any atom in the ring , whether a heteroatom or a carbon atom , provided that a stable chemical structure results . “ heteroaromatics ” or “ heteroaryl ” are included within the heterocycles as defined above and generally refers to a heterocycle in which the ring system is an aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms , preferably five to ten carbon atoms , in which one or more ring carbons , preferably one to four , are each replaced by a heteroatom such as n , o , s and p . preferred heteroaryl groups include 5 - 6 membered monocyclic heteroaryls and 8 - 10 membered bicyclic heteroaryls . also included within the scope of the term “ heterocycle , “ heterocyclic ” or “ heterocyclyl ” is a group in which a non - aromatic heteroatom - containing ring is fused to one or more aromatic rings , such as in an indolinyl , chromanyl , phenanthridinyl or tetrahydro - quinolinyl , where the radical or point of attachment is on the non - aromatic heteroatom - containing ring . unless otherwise indicated , the term “ heterocycle , “ heterocyclic ” or “ heterocyclyl ” also included each possible positional isomer of a heterocyclic radical , such as in 1 - indolinyl , 2 - indolinyl , 3 - indolinyl . examples of heterocycles include imidazolyl , imidazolinoyl , imidazolidinyl , quinolyl , isoquinolyl , indolyl , indazolyl , indazolinolyl , perhydropyridazyl , pyridazyl , pyridyl , pyrrolyl , pyrrolinyl , pyrrolidinyl , pyrazolyl , pyrazinyl , quinoxolyl , piperidinyl , pyranyl , pyrazolinyl , piperazinyl , pyrimidinyl , pyridazinyl , morpholinyl , thiamorpholinyl , furyl , thienyl , triazolyl , thiazolyl , carbolinyl , tetrazolyl , thiazolidinyl , benzofuranoyl , thiamorpholinyl sulfone , oxazolyl , oxadiazolyl , benzoxazolyl , oxopiperidinyl , oxopyrrolidinyl , oxoazepinyl , azepinyl , isoxozolyl , isothiazolyl , furazanyl , tetrahydropyranyl , tetrahydrofuranyl , thiazolyl , thiadiazoyl , dioxolyl , dioxinyl , oxathiolyl , benzodioxolyl , dithiolyl , thiophenyl , tetrahydrothiophenyl , sulfolanyl , dioxanyl , dioxolanyl , tetahydrofurodihydrofuranyl , tetrahydropyranodihydrofuranyl , dihydropyranyl , tetrahydrofurofuranyl and tetrahydropyranofuranyl . protecting groups may be selected from groups known to those skilled in the art , including protecting groups disclosed in greene , theodora w . ; wuts , peter g . m . protective groups in organic synthesis . 2nd ed . ( 1991 ), 473 pp . or kocienski , philip j . protecting groups . 3rd ed . 2005 , ( 2005 ), 679 pp . the present invention features a process as described above wherein in said compound of formula ( i ), r 3 is h . the present invention features a process as described above wherein in said compound of formula ( i ), r is — cho . the present invention features a process as described above wherein in said compound of formula ( i ), r is — ch ( oh ) 2 . the present invention features a process as described above wherein in said compound of formula ( i ), r is — ch ( oh )( or 4 ). the present invention features a process as described above wherein in said compound of formula ( i ), r 3 is h , halogen , hydroxy , optionally substituted lower alkyl , optionally substituted cycloalkyl , optionally substituted lower alkenyl , optionally substituted lower alkoxy . the present invention features a process as described above wherein in said compound of formula ( i ) is of the formula ( vii ): the present invention features a process as described above wherein in said compound of formula ( i ) is of the formula ( ia ): the present invention features a process as described above wherein in said compound of formula ( i ) is of the formula ( viii ): the present invention features a process as described above wherein in said compound of formula ( i ) is of the formula ( ix ): the present invention features a process as described above wherein in said compound of formula ( ii ) is of the formula ( iia ): the present invention includes processes for preparing a compound of formula ( i ): r is — ch ( oh )( or 4 ); p 1 is a hydroxyl protecting group ; p 3 is h ; r 3 is h ; r 4 is lower alkyl ; r x is r 2 — x — nr 1 — c ( o )—; r 2 is optionally substituted aryl ; x is lower alkylene ; and r 1 is h ; specific compounds used in the processes of the present invention include those of the following formulae ( iia ), ( via ), ( vib ) and ( ia ) utilized in examples which follow : the product ( ia ) of a synthetic sequence of the present invention can be condensed with an amine , eg of the formula h 2 nch 2 ch 2 ch 2 oh , brominated if r x is h , carbonylated and amidated and finally , debenzylated to yield a compound of wo 2006 / 116764 designated ( i - 7 ) at page 240 wherein ( r ) m is 4 - f and r a is h . alternatively , such a compound may be synthesized according to the invention by starting with ( i ) where r x is p - f - phenyl - ch 2 — nh — c ( o )—, r 3 is h , p 1 is benzyl ( bn ) and p 3 is a carboxy protecting group . in addition , compounds of formula ( i ) which may be produced by processes of the invention include those of the following formulae ( vii ), ( viii ) and ( ix ): in more detail , step i ) can be carried out in a protic or aprotic solvent such as etoh , thf or dmf at a temperature of about 50 - 150 ° c . for about 1 - 10 hours . in more detail , step ii ) can be carried out for the diol starting material ( vi ) with an oxidizing agent such as naio 4 , ruo 4 or pb ( oac ) 4 in a solvent such as h 2 o , meoh or ch 3 cn at ambient temperature for one or more hours . for the acetal type starting material such as ( v ), reaction may be in an acid such as hcl , cf 3 cooh or hco 2 h optionally with heating . step ii ) can also involve refunctionalization at the r x position , eg r x ═ h to r x ═ br optionally with further refunctionalization to r x ═ r 2 — x — nr 1 — c ( o )—. step ii ) can also involve refunctionalization of p 3 , eg p 3 ═ h to p 3 = me . the present invention features a process as described above , wherein said refunctionalizing step ii ) comprises demethylating the intermediate of formula ( v ) to produce the compound of formula ( i ). the present invention features a process as described above wherein said refunctionalizing step ii ) comprises reacting the intermediate of formula ( vi ) with naio 4 to produce the compound of formula ( i ). the present invention features a compound of the following formula ( v ): p 1 is h or a hydroxyl protecting group ; p 3 is h or a carboxy protecting group ; r 3 is h , halogen , hydroxy , optionally substituted lower alkyl , optionally substituted cycloalkyl , optionally substituted lower alkenyl , optionally substituted lower alkoxy , optionally substituted lower alkenyloxy , optionally substituted aryl , optionally substituted aryloxy , optionally substituted heterocyclic group , optionally substituted heterocycleoxy and optionally substituted amino ; r x is h , halo or r 2 — x — nr 1 — c ( o )—; r 2 is optionally substituted aryl ; x is a single bond , a heteroatom group selected from o , s , so , so 2 , and nh or lower alkylene or lower alkenylene wherein each may be intervened by the heteroatom ; r 1 is h or lower alkyl ; and r 5 and r 6 are independently lower alkyl or r 5 and r 6 can be alkyl and joined to form a 5 -, 6 -, or 7 - membered ring . the present invention features a compound of the formula ( v ) above wherein r 3 is h . the present invention features a compound of the following formula ( va ): p 1 is h or a hydroxyl protecting group ; p 3 is h or a carboxy protecting group ; r 3 is h , halogen , hydroxy , optionally substituted lower alkyl , optionally substituted cycloalkyl , optionally substituted lower alkenyl , optionally substituted lower alkoxy , optionally substituted lower alkenyloxy , optionally substituted aryl , optionally substituted aryloxy , optionally substituted heterocyclic group , optionally substituted heterocycleoxy and optionally substituted amino ; r x is h , halo or r 2 — x — nr 1 — c ( o )—; r 2 is optionally substituted aryl ; x is a single bond , a heteroatom group selected from o , s , so , so 2 , and nh or lower alkylene or lower alkenylene wherein each may be intervened by the heteroatom ; and the present invention features a compound of the formula ( v ) above wherein r 3 is h . the present invention features a compound of the following formula ( vi ): p 1 is h or a hydroxyl protecting group ; p 3 is h or a carboxy protecting group ; r 3 is h , halogen , hydroxy , optionally substituted lower alkyl , optionally substituted cycloalkyl , optionally substituted lower alkenyl , optionally substituted lower alkoxy , optionally substituted lower alkenyloxy , optionally substituted aryl , optionally substituted aryloxy , optionally substituted heterocyclic group , optionally substituted heterocycleoxy and optionally substituted amino ; r x is h , halo or r 2 — x — nr 1 — c ( o )—; r 2 is optionally substituted aryl ; x is a single bond , a heteroatom group selected from o , s , so , so 2 , and nh or lower alkylene or lower alkenylene wherein each may be intervened by the heteroatom ; and r 1 is h or lower alkyl . the present invention features a compound of the formula ( v ) above wherein r 3 is h . the present invention features a compound of the following formula ( i ): r is — ch ( oh )( och 3 ); p 1 is - bn ; p 3 is — ch 3 ; r 3 is — h ; and r x is br . the present invention features a compound of the following formula ( 14 ): the present invention features a compound of the following formula ( 15 ): the present invention features a compound of the following formula ( i ): r is — ch ( oh ) 2 ; p 1 is h or a hydroxyl protecting group ; p 3 is h or a carboxy protecting group ; r 3 is h , halogen , hydroxy , optionally substituted lower alkyl , optionally substituted cycloalkyl , optionally substituted lower alkenyl , optionally substituted lower alkoxy , optionally substituted lower alkenyloxy , optionally substituted aryl , optionally substituted aryloxy , optionally substituted heterocyclic group , optionally substituted heterocycleoxy and optionally substituted amino ; r 1 is h or lower alkyl ; r x is h , halo or r 2 — x — nr 1 — c ( o )—; r 2 is optionally substituted aryl ; and x is a single bond , a heteroatom group selected from o , s , so , so 2 , and nh or lower alkylene or lower alkenylene wherein each may be intervened by the heteroatom . in the following examples and throughout this specification , the following abbreviations may be used : me ( methyl ), bn ( benzyl ), aq ( aqueous ), et ( ethyl ), c ( centrigrade ). the following examples are intended for illustration only and are not intended to limit the scope of the invention in any way . the starting material of example 1e is the compound of formula ( iia ) of the invention process which is also shown as compound 5 below and compound # 101 at page 113 of wo 2006 / 116764 . the product of the invention process is depicted below as compound 8 , which is of the formula ( i ) of the invention process . the final product shown below as compound 13 is a compound of formula ( i - 7 ) at page 240 of wo 2006 / 116764 wherein ( r ) m is 2 , 4 - di - f and r a is h , provided , however , that there is an alpha methyl at the position designated r 16 in formula ( xxvi ) at page 65 . thus , in the above sequence for example 1 , compound 5 is identical to compound 101 at page 113 of wo 2006 / 116764 and to formula ( iia ) of the process of the present invention ; compound 6 above is identical to formula ( via ) of the process of the present invention ; compound 7 above is identical to formula ( vib ) of the process of the present invention ; and compound 8 is identical to formula ( ia ) of the process of the present invention . step i ) of the invention process is 5 to 6 above while step ii ) is 6 to 8 . to a slurry of 2000 g of compound 1 ( 1 . 0 eq .) in 14 . 0 l of mecn were added 2848 g of benzyl bromide ( 1 . 05 eq .) and 2630 g of k 2 co 3 ( 1 . 2 eq .). the mixture was stirred at 80 ° c . for 5 h and cooled to 13 ° c . precipitate was filtered and washed with 5 . 0 l of mecn . the filtrate was concentrated and 3 . 0 l of thf was added to the residue . the thf solution was concentrated to give 3585 g of crude compound 2 as oil . without further purification , compound 2 was used in the next step . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 60 ( d , j = 5 . 7 hz , 1h ), 7 . 4 - 7 . 3 ( m , 5h ), 6 . 37 ( d , j = 5 . 7 hz , 1h ), 5 . 17 ( s , 2h ), 2 . 09 ( s , 3h ). to 904 g of the crude compound 2 was added 5 . 88 l of thf and the solution was cooled to − 60 ° c . 5 . 00 l of 1 . 0 m of lithium bis ( trimethylsilylamide ) in thf ( 1 . 25 eq .) was added dropwise for 2 h to the solution of compound 2 at − 60 ° c . then , a solution of 509 g of benzaldehyde ( 1 . 2 eq .) in 800 ml of thf was added at − 60 ° c . and the reaction mixture was aged at − 60 ° c . for 1 h . the thf solution was poured into a mixture of 1 . 21 l of conc . hcl , 8 . 14 l of ice water and 4 . 52 l of etoac at less than 2 ° c . the organic layer was washed with 2 . 71 l of brine ( twice ) and the aqueous layer was extracted with 3 . 98 l of etoac . the combined organic layers were concentrated . to the mixture , 1 . 63 l of toluene was added and concentrated ( twice ) to provide toluene slurry of compound 3 . filtration , washing with 0 . 90 l of cold toluene and drying afforded 955 g of compound 3 ( 74 % yield from compound 1 ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 62 ( d , j = 5 . 7 hz , 1h ), 7 . 5 - 7 . 2 ( m , 10h ), 6 . 38 ( d , j = 5 . 7 hz , 1h ), 5 . 16 ( d , j = 11 . 4 hz , 1h ), 5 . 09 ( d , j = 11 . 4 hz , 1h ), 4 . 95 ( dd , j = 4 . 8 , 9 . 0 hz , 1h ), 3 . 01 ( dd , j = 9 . 0 , 14 . 1 hz , 1h ), 2 . 84 ( dd , j = 4 . 8 , 14 . 1 hz , 1h ). to a solution of 882 g of compound 3 ( 1 . 0 eq .) in 8 . 82 l of thf were added 416 g of et 3 n ( 1 . 5 eq .) and 408 g of methanesulfonyl chloride ( 1 . 3 eq .) at less than 30 ° c . after confirmation of disappearance of compound 3 , 440 ml of nmp and 1167 g of dbu ( 2 . 8 eq .) were added to the reaction mixture at less than 30 ° c . and the reaction mixture was aged for 30 min . the mixture was neutralized with 1 . 76 l of 16 % sulfuric acid and the organic layer was washed with 1 . 76 l of 2 % na 2 so 3 aq . after concentration of the organic layer , 4 . 41 l of toluene was added and the mixture was concentrated ( tree times ). after addition of 4 . 67 l of hexane , the mixture was cooled with ice bath . filtration , washing with 1 . 77 l of hexane and drying provided 780 g of compound 4 ( 94 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 69 ( d , j = 5 . 7 hz , 1h ), 7 . 50 - 7 . 25 ( m , 10h ), 7 . 22 ( d , j = 16 . 2 hz , 1h ), 7 . 03 ( d , j = 16 . 2 hz , 1h ), 6 . 41 ( d , j = 5 . 7 hz , 1h ), 5 . 27 ( s , 2h ). to a mixture of 822 g of compound 4 ( 1 . 0 eq .) and 11 . 2 g of rucl 3 . nh 2 o ( 0 . 02 eq .) in 2 . 47 l of mecn , 2 . 47 l of etoac and 2 . 47 l of h 2 o was added 2310 g of naio 4 ( 4 . 0 eq .) at less than 25 ° c . after aging for 1 h , 733 g of naclo 2 ( 3 . 0 eq .) was added to the mixture at less than 25 ° c . after aging for 1 h , precipitate was filtered and washed with 8 . 22 l of etoac . to the filtrate , 1 . 64 l of 50 % na 2 s 2 o 3 aq , 822 ml of h 2 o and 630 ml of coc . hcl were added . the aqueous layer was extracted with 4 . 11 l of etoac and the organic layers were combined and concentrated . to the residue , 4 l of toluene was added and the mixture was concentrated and cooled with ice bath . filtration , washing with 1 l of toluene and drying provided 372 g of compound 5 ( 56 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 78 ( d , j = 5 . 7 hz , 1h ), 7 . 54 - 7 . 46 ( m , 2h ), 7 . 40 - 7 . 26 ( m , 3h ), 6 . 48 ( d , j = 5 . 7 hz , 1h ), 5 . 6 ( brs , 1h ), 5 . 31 ( s , 2h ). a mixture of 509 g of compound 5 ( 1 . 0 eq .) and 407 g of 3 - amino - propane - 1 , 2 - diol ( 2 . 5 eq .) in 1 . 53 l of etoh was stirred at 65 ° c . for 1 h and at 80 ° c . for 6 h . after addition of 18 . 8 g of 3 - amino - propane - 1 , 2 - diol ( 0 . 1 eq .) in 200 ml of etoh , the mixture was stirred at 80 ° c . for 1 h . after addition of 18 . 8 g of 3 - amino - propane - 1 , 2 - diol ( 0 . 1 eq .) in 200 ml of etoh , the mixture was stirred at 80 ° c . for 30 min . after cooling and addition of 509 ml of h 2 o , the mixture was concentrated . to the residue , 2 . 54 l of h 2 o and 2 . 54 l of acoet were added . after separation , the aqueous layer was washed with 1 . 02 l of etoac . to the aqueous layer , 2 . 03 l of 12 % sulfuric acid was added at less than 12 ° c . to give crystal of compound 6 . filtration , washing with 1 . 53 l of cold h 2 o and drying provided 576 g of compound 6 ( 83 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 7 . 67 ( d , j = 7 . 5 hz , 1h ), 7 . 5 - 7 . 2 ( m , 5h ), 6 . 40 ( d , j = 7 . 5 hz , 1h ), 5 . 07 ( s , 2h ), 4 . 2 - 4 . 0 ( m , 1h ), 3 . 9 - 3 . 6 ( m , 2h ), 3 . 38 ( dd , j = 4 . 2 , 10 . 8 hz , 1h ), 3 . 27 ( dd , j = 6 . 0 , 10 . 8 hz , 1h ). to a slurry of 576 g of compound 6 ( 1 . 0 eq . : 5 . 8 % of h 2 o was contained ) in 2 . 88 l of nmp were added 431 g of nahco 3 ( 3 . 0 eq .) and 160 ml of methyl iodide ( 1 . 5 eq .) and the mixture was stirred at room temperature for 4 h . after cooling to 5 ° c ., 1 . 71 l of 2n hcl and 1 . 15 l of 20 % naclaq were added to the mixture at less than 10 ° c . to give crystal of compound 7 . filtration , washing with 1 . 73 l of h 2 o and drying provided 507 g of compound 7 ( 89 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 7 . 59 ( d , j = 7 . 5 hz , 1h ), 7 . 40 - 7 . 28 ( m , 5h ), 6 . 28 ( d , j = 7 . 5 hz , 1h ), 5 . 21 ( d , j = 5 . 4 hz , 1h ), 5 . 12 ( d , j = 10 . 8 hz , 1h ), 5 . 07 ( d , j = 10 . 8 hz , 1h ), 4 . 83 ( t , j = 5 . 7 hz , 1h ), 3 . 97 ( dd , j = 2 . 4 , 14 . 1 hz , 1h ), 3 . 79 ( s , 3h ), 3 . 70 ( dd , j = 9 . 0 , 14 . 4 hz , 1h ), 3 . 65 - 3 . 50 ( m , 1h ), 3 . 40 - 3 . 28 ( m , 1h ), 3 . 26 - 3 . 14 ( m , 1h ). to a mixture of 507 g of compound 7 ( 1 . 0 eq .) in 5 . 07 l of mecn , 5 . 07 l of h 2 o and 9 . 13 g of acoh ( 0 . 1 eq .) was added 390 g of naio 4 ( 1 . 2 eq .) and the mixture was stirred at room temperature for 2 h . after addition of 1 . 52 l of 10 % na 2 s 2 o 3 aq ., the mixture was concentrated and cooled to 10 ° c . filtration , washing with h 2 o and drying provided 386 g of compound 8 ( 80 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 7 . 62 ( d , j = 7 . 5 hz , 1h ), 7 . 42 - 7 . 30 ( m , 5h ), 6 . 33 ( d , j = 6 . 0 hz , 2h ), 6 . 29 ( d , j = 7 . 5 hz , 1h ), 5 . 08 ( s , 2h ), 4 . 95 - 4 . 85 ( m , 1h ), 3 . 80 ( s , 3h ), 3 . 74 ( d , j = 5 . 1 hz , 2h ). after dissolution of a mixture of 378 g of compound 8 ( 1 . 0 eq .) in 3 . 78 l of meoh by heating , the solution was concentrated . to the residue , 1 . 51 l of toluene was added and the mixture was concentrated . to the residue , 1 . 89 l of toluene , 378 ml of acoh and 137 g of ( r )- 3 - amino - butan - 1 - ol ( 1 . 3 eq .) were added and the mixture was heated to 90 ° c ., stirred at 90 ° c . for 2 . 5 h and concentrated . to the residue , 1 . 89 l of toluene was added and the mixture was concentrated . the residue was extracted with 3 . 78 l and 1 . 89 l of chcl 3 and washed with 2 × 1 . 89 l of h 2 o . the organic layers were combined and concentrated . to the residue , 1 . 89 l of etoac was added and the mixture was concentrated . after addition of 1 . 89 l of etoac , filtration , washing with 1 . 13 l of etoac and drying provided 335 g of compound 9 ( 83 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 70 - 7 . 58 ( m , 2h ), 7 . 40 - 7 . 24 ( m , 3h ), 7 . 14 ( d , j = 7 . 5 hz , 2h ), 6 . 47 ( d , j = 7 . 5 hz , 1h ), 5 . 35 ( d , j = 10 . 2 hz , 1h ), 5 . 28 ( d , j = 10 . 2 hz , 1h ), 5 . 12 ( dd , j = 3 . 9 , 6 . 3 hz , 1h ), 5 . 05 - 4 . 90 ( m , 1h ), 4 . 07 ( dd , j = 3 . 9 , 13 . 5 hz , 1h ), 4 . 00 - 3 . 86 ( m , 3h ), 2 . 23 - 2 . 06 ( m , 1h ), 1 . 48 ( ddd , j = 2 . 4 , 4 . 5 , 13 . 8 hz , 1h ), 1 . 30 ( d , j = 6 . 9 hz , 3h ). to a slurry of 332 g of compound 9 ( 1 . 0 eq .) in 1 . 66 l of nmp was added 191 g of nbs ( 1 . 1 eq .) and the mixture was stirred at room temperature for 2 h . after addition of 1 . 26 l of h 2 o , the mixture was stirred for 30 min . after addition of 5 . 38 l of h 2 o and aging of the mixture at 10 ° c . for 30 min and at 5 ° c . for 1 h , filtration , washing with 1 . 33 l of cold h 2 o and drying provided 362 g of compound 10 ( 89 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 69 - 7 . 63 ( m , 2h ), 7 . 59 ( s , 1h ), 7 . 38 - 7 . 24 ( m , 3h ), 5 . 33 ( d , j = 10 . 2 hz , 1h ), 5 . 25 ( d , j = 9 . 9 hz , 1h ), 5 . 12 ( dd , j = 3 . 9 , 5 . 7 hz , 1h ), 5 . 05 - 4 . 90 ( m , 1h ), 4 . 11 ( dd , j = 3 . 9 , 13 . 2 hz , 1h ), 4 . 02 - 3 . 88 ( m , 3h ), 2 . 21 - 2 . 06 ( m , 1h ), 1 . 49 ( ddd , j = 2 . 4 , 4 . 5 , 14 . 1 hz , 1h ), 1 . 31 ( d , j = 6 . 9 hz , 3h ). under carbon mono - oxide atmosphere , a mixture of 33 . 5 g of compound 10 ( 1 . 0 eq . ), 34 . 8 ml of i - pr 2 net ( 2 . 5 eq . ), 14 . 3 ml of 2 , 4 - difluorobenzylamine ( 1 . 5 eq .) and 4 . 62 g of pd ( pph 3 ) 4 ( 0 . 05 eq .) in 335 ml of dmso was stirred at 90 ° c . for 5 . 5 h . after cooling , precipitate was filtered and washed with 50 ml of 2 - propanol . after addition of 502 ml of h 2 o and 670 ml of acoet to the filtrate , the organic layer was washed with 335 ml of 0 . 5n hclaq . and 335 ml of h 2 o and the aqueous layer was extracted with 335 ml of acoet . the organic layers were combined and concentrated . to the residue , 150 ml of 2 - propanol was added and the mixture was concentrated . after addition of 150 ml of 2 - propanol , concentration , cooling to 20 ° c . and filtration , crude crystal of compound 11 was obtained . after dissolution of the crude crystal in 380 ml of acetone by heating , precipitate was filtered and the filtrate was concentrated . after addition of 200 ml of etoh , concentration , addition of 150 ml of etoh , concentration , cooling and filtration , crude crystal of compound 11 was obtained . after dissolution of the crude crystal in 450 ml of acetone by heating , the solution was concentrated . to the residue , 150 ml of 2 - propanol was added and the mixture was concentrated ( twice ). after cooling of the residue , filtration , washing with 2 - propanol and drying provided 34 . 3 g of compound 11 ( 84 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 10 . 40 ( t , j = 6 . 0 hz , 1h ), 8 . 35 ( s , 1h ), 7 . 66 - 7 . 58 ( m , 2h ), 7 . 42 - 7 . 24 ( m , 5h ), 6 . 78 - 6 . 74 ( m , 2h ), 5 . 30 ( d , j = 9 . 9 hz , 1h ), 5 . 26 ( d , j = 10 . 2 hz , 1h ), 5 . 15 ( dd , j = 3 . 9 , 5 . 7 hz , 1h ), 5 . 05 - 4 . 90 ( m , 1h ), 4 . 64 ( d , j = 5 . 4 hz , 2h ), 4 . 22 ( dd , j = 3 . 9 , 13 . 5 , 1h ), 4 . 09 ( dd , j = 6 . 0 , 13 . 2 hz , 1h ), 4 . 02 - 3 . 88 ( m , 2h ), 2 . 24 - 1 . 86 ( m , 1h ), 1 . 50 ( ddd , j = 2 . 4 , 4 . 5 , 14 . 1 hz , 1h ), 1 . 33 ( d , j = 7 . 2 hz , 3h ). under hydrogen atmosphere , a mixture of 28 . 0 g of compound 11 ( 1 . 0 eq .) and 5 . 6 g of 10 % pd — c in 252 ml of thf and 28 ml of meoh was stirred for 1 h . after precipitate ( pd — c ) was filtered and washed with 45 ml of thf , 5 . 6 g of 10 % pd — c was added and the mixture was stirred for 1 . 5 h under hydrogen atmosphere . after pd — c was filtered and washed with 150 ml of chcl 3 / meoh ( 9 / 1 ), the filtrate was concentrated . after dissolution of the residue in 1 . 38 l of etoh by heating , the solution was gradually cooled to room temperature . after filtration , the filtrate was concentrated and cooled . filtration , washing with etoh and drying provided 21 . 2 g of compound 12 ( 92 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 12 . 51 ( s , 1h ), 10 . 36 ( t , j = 5 . 7 hz , 1h ), 8 . 50 ( s , 1h ), 7 . 39 ( td , j = 8 . 7 , 6 . 3 hz , 1h ), 7 . 24 ( ddd , j = 2 . 6 , 9 . 5 , 10 . 8 hz , 1h ), 7 . 12 - 7 . 00 ( m , 1h ), 5 . 44 ( dd , j = 3 . 9 , 5 . 7 hz , 1h ), 4 . 90 - 4 . 70 ( m , 1h ), 4 . 65 - 4 . 50 ( m , 1h ), 4 . 54 ( d , j = 5 . 1 hz , 2h ), 4 . 35 ( dd , j = 6 . 0 , 13 . 8 hz , 1h ), 4 . 10 - 3 . 98 ( m , 1h ), 3 . 96 - 3 . 86 ( m , 1h ), 2 . 10 - 1 . 94 ( m , 1h ), 1 . 60 - 1 . 48 ( m , 1h ), 1 . 33 ( d , j = 6 . 9 hz , 3h ). after dissolution of 18 . 0 g of compound 12 ( 1 . 0 eq .) in 54 ml of etoh by heating , followed by filtration , 21 . 5 ml of 2n naohaq . ( 1 . 0 eq .) was added to the solution at 80 ° c . the solution was gradually cooled to room temperature . filtration , washing with 80 ml of etoh and drying provided 18 . 8 g of compound 13 ( 99 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 10 . 70 ( t , j = 6 . 0 hz , 1h ), 7 . 89 ( s , 1h ), 7 . 40 - 7 . 30 ( m , 1h ), 7 . 25 - 7 . 16 ( m , 1h ), 7 . 06 - 6 . 98 ( m , 1h ), 5 . 22 - 5 . 12 ( m , 1h ), 4 . 87 - 4 . 74 ( m , 1h ), 4 . 51 ( d , j = 5 . 4 hz , 2h ), 4 . 35 - 4 . 25 ( m , 1h ), 4 . 16 ( dd , j = 1 . 8 , 14 . 1 hz , 1h ), 4 . 05 - 3 . 90 ( m , 1h ), 3 . 86 - 3 . 74 ( m , 1h ), 2 . 00 - 1 . 72 ( m , 1h ), 1 . 44 - 1 . 32 ( m , 1h ), 1 . 24 ( d , j = 6 . 9 hz , 3h ). example 1m shows a process for preparation of the crystalline compound 13b which is monohydrate form of compound 13 . after dissolution of 30 . 0 g of compound 13 ( 1 . 0 eq .) in 600 ml of thf - water solution ( 8 : 2 ) by 30 ° c ., 36 . 0 ml of 2n naohaq ( 1 . 0 eq .) was added to the solution . the mixture was stirred at room temperature for 2 hours . the precipitation was filtered , washing with 150 ml of thf - water solution ( 8 : 2 ), 150 ml of thf . drying at 85 ° c . and humidity conditioning provided 30 . 4 g of compound 13b ( monohydrate form of compound 13 , 93 % yield ) as a crystal . to a slurry of 2000 g of compound 1 ( 1 . 0 eq .) in 14 . 0 l of mecn were added 2848 g of benzyl bromide ( 1 . 05 eq .) and 2630 g of k 2 co 3 ( 1 . 2 eq .). the mixture was stirred at 80 ° c . for 5 h and cooled to 13 ° c . precipitate was filtered and washed with 5 . 0 l of mecn . the filtrate was concentrated and 3 . 0 l of thf was added to the residue . the thf solution was concentrated to give 3585 g of crude compound 2 as oil . without further purification , compound 2 was used in the next step . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 60 ( d , j = 5 . 7 hz , 1h ), 7 . 4 - 7 . 3 ( m , 5h ), 6 . 37 ( d , j = 5 . 7 hz , 1h ), 5 . 17 ( s , 2h ), 2 . 09 ( s , 3h ). to 904 g of the crude compound 2 was added 5 . 88 l of thf and the solution was cooled to − 60 ° c . 5 . 00 l of 1 . 0 m of lithium bis ( trimethylsilylamide ) in thf ( 1 . 25 eq .) was added dropwise for 2 h to the solution of compound 2 at − 60 ° c . then , a solution of 509 g of benzaldehyde ( 1 . 2 eq .) in 800 ml of thf was added at − 60 ° c . and the reaction mixture was aged at − 60 ° c . for 1 h . the thf solution was poured into a mixture of 1 . 21 l of conc . hcl , 8 . 14 l of ice water and 4 . 52 l of etoac at less than 2 ° c . the organic layer was washed with 2 . 71 l of brine ( twice ) and the aqueous layer was extracted with 3 . 98 l of etoac . the combined organic layers were concentrated . to the mixture , 1 . 63 l of toluene was added and concentrated ( twice ) to provide toluene slurry of compound 3 . filtration , washing with 0 . 90 l of cold toluene and drying afforded 955 g of compound 3 ( 74 % yield from compound 1 ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 62 ( d , j = 5 . 7 hz , 1h ), 7 . 5 - 7 . 2 ( m , 10h ), 6 . 38 ( d , j = 5 . 7 hz , 1h ), 5 . 16 ( d , j = 11 . 4 hz , 1h ), 5 . 09 ( d , j = 11 . 4 hz , 1h ), 4 . 95 ( dd , j = 4 . 8 , 9 . 0 hz , 1h ), 3 . 01 ( dd , j = 9 . 0 , 14 . 1 hz , 1h ), 2 . 84 ( dd , j = 4 . 8 , 14 . 1 hz , 1h ). to a solution of 882 g of compound 3 ( 1 . 0 eq .) in 8 . 82 l of thf were added 416 g of et 3 n ( 1 . 5 eq .) and 408 g of methanesulfonyl chloride ( 1 . 3 eq .) at less than 30 ° c . after confirmation of disappearance of compound 3 , 440 ml of nmp and 1167 g of dbu ( 2 . 8 eq .) were added to the reaction mixture at less than 30 ° c . and the reaction mixture was aged for 30 min . the mixture was neutralized with 1 . 76 l of 16 % sulfuric acid and the organic layer was washed with 1 . 76 l of 2 % na 2 so 3 aq . after concentration of the organic layer , 4 . 41 l of toluene was added and the mixture was concentrated ( tree times ). after addition of 4 . 67 l of hexane , the mixture was cooled with ice bath . filtration , washing with 1 . 77 l of hexane and drying provided 780 g of compound 4 ( 94 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 69 ( d , j = 5 . 7 hz , 1h ), 7 . 50 - 7 . 25 ( m , 10h ), 7 . 22 ( d , j = 16 . 2 hz , 1h ), 7 . 03 ( d , j = 16 . 2 hz , 1h ), 6 . 41 ( d , j = 5 . 7 hz , 1h ), 5 . 27 ( s , 2h ). to a mixture of 10 . 0 g of compound 4 and 13 . 6 mg of rucl 3 . nh 2 o in 95 ml of mecn and 10 ml of water , mixture of 155 ml of water , 7 . 2 g of hydrosulfuric acid , and 15 . 5 g of naio 4 was added for 2 . 5 h at 20 ° c . after aging for 1 h , organic and aqueous layers were separated and aqueous layer was extracted by 30 ml of ethyl acetate . aqueous layer was extracted again by 30 ml of ethyl acetate and organic layers were combined . 6 ml of 5 % nahso3 solution was added to the combined organic layer and the layers were separated . the organic layer was adjusted to ph 6 . 0 by adding 4 . 0 g of 2m naoh solution and the aqueous layer was separated . after 60 ml of 5 % nahco 3 solution and 257 mg of tempo was added , 25 . 9 g of naclo solution was added to the reaction mixture at 25 ° c . for 1 h and stirred for 30 min to check the reaction was finished . after the layers were separated , 42 . 5 ml of 5 % na2so3 solution and 30 ml of acoet were added and separated . the aqueous layer was extracted by 30 ml of acoet and separated . 12 % h 2 so 4 was added to the reaction mixture at 20 ° c . for 1 h and the mixture was cooled to 5 ° c . after the mixture was stirred for 30 min , the mixture was filtered , washed with 30 ml of water twice and dryed to provide 5 . 7 g of compound 5 ( 70 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 78 ( d , j = 5 . 7 hz , 1h ), 7 . 54 - 7 . 46 ( m , 2h ), 7 . 40 - 7 . 26 ( m , 3h ), 6 . 48 ( d , j = 5 . 7 hz , 1h ), 5 . 6 ( brs , 1h ), 5 . 31 ( s , 2h ). a mixture of 509 g of compound 5 ( 1 . 0 eq .) and 407 g of 3 - amino - propane - 1 , 2 - diol ( 2 . 5 eq .) in 1 . 53 l of etoh was stirred at 65 ° c . for 1 h and at 80 ° c . for 6 h . after addition of 18 . 8 g of 3 - amino - propane - 1 , 2 - diol ( 0 . 1 eq .) in 200 ml of etoh , the mixture was stirred at 80 ° c . for 1 h . after addition of 18 . 8 g of 3 - amino - propane - 1 , 2 - diol ( 0 . 1 eq .) in 200 ml of etoh , the mixture was stirred at 80 ° c . for 30 min . after cooling and addition of 509 ml of h 2 o , the mixture was concentrated . to the residue , 2 . 54 l of h 2 o and 2 . 54 l of acoet were added . after separation , the aqueous layer was washed with 1 . 02 l of etoac . to the aqueous layer , 2 . 03 l of 12 % sulfuric acid was added at less than 12 ° c . to give crystal of compound 6 . filtration , washing with 1 . 53 l of cold h 2 o and drying provided 576 g of compound 6 ( 83 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 7 . 67 ( d , j = 7 . 5 hz , 1h ), 7 . 5 - 7 . 2 ( m , 5h ), 6 . 40 ( d , j = 7 . 5 hz , 1h ), 5 . 07 ( s , 2h ), 4 . 2 - 4 . 0 ( m , 1h ), 3 . 9 - 3 . 6 ( m , 2h ), 3 . 38 ( dd , j = 4 . 2 , 10 . 8 hz , 1h ), 3 . 27 ( dd , j = 6 . 0 , 10 . 8 hz , 1h ). to a slurry of 576 g of compound 6 ( 1 . 0 eq . : 5 . 8 % of h 2 o was contained ) in 2 . 88 l of nmp were added 431 g of nahco 3 ( 3 . 0 eq .) and 160 ml of methyl iodide ( 1 . 5 eq .) and the mixture was stirred at room temperature for 4 h . after cooling to 5 ° c ., 1 . 71 l of 2n hcl and 1 . 15 l of 20 % naclaq were added to the mixture at less than 10 ° c . to give crystal of compound 7 . filtration , washing with 1 . 73 l of h 2 o and drying provided 507 g of compound 7 ( 89 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 7 . 59 ( d , j = 7 . 5 hz , 1h ), 7 . 40 - 7 . 28 ( m , 5h ), 6 . 28 ( d , j = 7 . 5 hz , 1h ), 5 . 21 ( d , j = 5 . 4 hz , 1h ), 5 . 12 ( d , j = 10 . 8 hz , 1h ), 5 . 07 ( d , j = 10 . 8 hz , 1h ), 4 . 83 ( t , j = 5 . 7 hz , 1h ), 3 . 97 ( dd , j = 2 . 4 , 14 . 1 hz , 1h ), 3 . 79 ( s , 3h ), 3 . 70 ( dd , j = 9 . 0 , 14 . 4 hz , 1h ), 3 . 65 - 3 . 50 ( m , 1h ), 3 . 40 - 3 . 28 ( m , 1h ), 3 . 26 - 3 . 14 ( m , 1h ). to a mixture of 15 . 0 g of compound 7 ( 1 . 0 eq .) in 70 . 9 g of mecn , a mixture of 60 ml of h 2 o , 2 . 6 g of h 2 so 4 and 11 . 5 g of naio 4 was added in the range between 17 ° c . to 14 ° c . after the reaction mixture was stirred for 1 hour , precipitate was filtered . the filterate was added to the solution of 11 . 8 g of ascorbic acid sodium salt , 64 g of water and 60 mg of h 2 so 4 . after the mixture was concentrated , cooling to 5 ° c ., filtration , washing with h 2 o and drying provided 12 . 9 g of compound 8 ( 90 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 7 . 62 ( d , j = 7 . 5 hz , 1h ), 7 . 42 - 7 . 30 ( m , 5h ), 6 . 33 ( d , j = 6 . 0 hz , 2h ), 6 . 29 ( d , j = 7 . 5 hz , 1h ), 5 . 08 ( s , 2h ), 4 . 95 - 4 . 85 ( m , 1h ), 3 . 80 ( s , 3h ), 3 . 74 ( d , j = 5 . 1 hz , 2h ). a mixture of 10 . 0 g of compound 8 and 33 . 3 g of diglyme were added the solution of 3 . 3 g of ( r )- 3 - amino - butan - 1 - ol in 4 . 7 g of diglyme and 1 . 0 g of acetic acid at 60 ° c . after the reaction mixture was stirred at 95 ° c . for 9 hours , the reaction mixture was cooled to − 5 ° c . and filtered . the wet crystal was washed and dryed to give 8 . 3 g of compound 9 ( 78 %). xrd data : 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 70 - 7 . 58 ( m , 2h ), 7 . 40 - 7 . 24 ( m , 3h ), 7 . 14 ( d , j = 7 . 5 hz , 2h ), 6 . 47 ( d , j = 7 . 5 hz , 1h ), 5 . 35 ( d , j = 10 . 2 hz , 1h ), 5 . 28 ( d , j = 10 . 2 hz , 1h ), 5 . 12 ( dd , j = 3 . 9 , 6 . 3 hz , 1h ), 5 . 05 - 4 . 90 ( m , 1h ), 4 . 07 ( dd , j = 3 . 9 , 13 . 5 hz , 1h ), 4 . 00 - 3 . 86 ( m , 3h ), 2 . 23 - 2 . 06 ( m , 1h ), 1 . 48 ( ddd , j = 2 . 4 , 4 . 5 , 13 . 8 hz , 1h ), 1 . 30 ( d , j = 6 . 9 hz , 3h ). to slurry of 5 . 7 g of nbs in 26 . 5 g of dichloromethane was added 10 g of compound 9 in 92 . 8 g of dichloromethane at room temperature . after the reaction mixture was stirred for 6 . 5 h , the reaction mixture was added to the solution of 2 . 0 g na2so3 and 40 . 3 g of water . the organic layer was washed with diluted naoh solution and water , dichloromethane was concentrated and was displaced by methanol . the mixture was cooled to − 5 ° c . and filtered and the wet crystal was washed and dryed to give 10 . 3 g of compound 10 ( 84 %). 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 69 - 7 . 63 ( m , 2h ), 7 . 59 ( s , 1h ), 7 . 38 - 7 . 24 ( m , 3h ), 5 . 33 ( d , j = 10 . 2 hz , 1h ), 5 . 25 ( d , j = 9 . 9 hz , 1h ), 5 . 12 ( dd , j = 3 . 9 , 5 . 7 hz , 1h ), 5 . 05 - 4 . 90 ( m , 1h ), 4 . 11 ( dd , j = 3 . 9 , 13 . 2 hz , 1h ), 4 . 02 - 3 . 88 ( m , 3h ), 2 . 21 - 2 . 06 ( m , 1h ), 1 . 49 ( ddd , j = 2 . 4 , 4 . 5 , 14 . 1 hz , 1h ), 1 . 31 ( d , j = 6 . 9 hz , 3h ). under carbon mono - oxide atmosphere , a mixture of 25 . 0 g of compound 10 , 11 . 6 g of i - pr 2 net , 12 . 8 g of 2 , 4 - difluorobenzylamine , 335 mg of pd ( oac ) 2 and 1 . 9 g of 1 , 4 - bis ( diphenylphosphino ) butane in 188 ml of dma was stirred at 85 ° c . for 4 h . after cooling , the reaction mixture was divided and 10 / 25 of mixture was used for next step . 6 . 6 g of acoet , 29 . 9 g of water and 3 mg of seed crystal were added to the reaction mixture at 40 ° c . after stirring for 7 min , 29 . 9 g of water was added and cooled to room temperature . the crystal was filtered at room temperature and washed by 47 . 2 g of ethanol to give 10 . 1 g of compound 11 ( 83 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 10 . 40 ( t , j = 6 . 0 hz , 1h ), 8 . 35 ( s , 1h ), 7 . 66 - 7 . 58 ( m , 2h ), 7 . 42 - 7 . 24 ( m , 5h ), 6 . 78 - 6 . 74 ( m , 2h ), 5 . 30 ( d , j = 9 . 9 hz , 1h ), 5 . 26 ( d , j = 10 . 2 hz , 1h ), 5 . 15 ( dd , j = 3 . 9 , 5 . 7 hz , 1h ), 5 . 05 - 4 . 90 ( m , 1h ), 4 . 64 ( d , j = 5 . 4 hz , 2h ), 4 . 22 ( dd , j = 3 . 9 , 13 . 5 , 1h ), 4 . 09 ( dd , j = 6 . 0 , 13 . 2 hz , 1h ), 4 . 02 - 3 . 88 ( m , 2h ), 2 . 24 - 1 . 86 ( m , 1h ), 1 . 50 ( ddd , j = 2 . 4 , 4 . 5 , 14 . 1 hz , 1h ), 1 . 33 ( d , j = 7 . 2 hz , 3h ). under hydrogen atmosphere , a mixture of 4 . 0 g of compound 11 and 0 . 8 g of 50 % wet 5 % pd — c in 67 . 6 ml of thf and 1 . 6 ml of h 2 o was stirred for 1 . 5 h at 50 ° c . after mixture of 80 mg of nahso 3 and 2 . 0 ml of purified water was added to the reaction mixture and the reaction mixture was stirred for 1 h , precipitate was filtered , washed with 20 ml of thf , and the filtrate was concentrated to 11 . 97 g . after adding 6 . 7 ml of ethanol and 33 . 6 ml of purified water over 1 h , reaction mixture was cooled to 25 ° c . filtration , washing with 26 . 9 ml of etoh and drying provided 2 . 33 g of compound 12 ( 82 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 12 . 51 ( s , 1h ), 10 . 36 ( t , j = 5 . 7 hz , 1h ), 8 . 50 ( s , 1h ), 7 . 39 ( td , j = 8 . 7 , 6 . 3 hz , 1h ), 7 . 24 ( ddd , j = 2 . 6 , 9 . 5 , 10 . 8 hz , 1h ), 7 . 12 - 7 . 00 ( m , 1h ), 5 . 44 ( dd , j = 3 . 9 , 5 . 7 hz , 1h ), 4 . 90 - 4 . 70 ( m , 1h ), 4 . 65 - 4 . 50 ( m , 1h ), 4 . 54 ( d , j = 5 . 1 hz , 2h ), 4 . 35 ( dd , j = 6 . 0 , 13 . 8 hz , 1h ), 4 . 10 - 3 . 98 ( m , 1h ), 3 . 96 - 3 . 86 ( m , 1h ), 2 . 10 - 1 . 94 ( m , 1h ), 1 . 60 - 1 . 48 ( m , 1h ), 1 . 33 ( d , j = 6 . 9 hz , 3h ). after dissolution of 18 . 0 g of compound 12 ( 1 . 0 eq .) in 54 ml of etoh by heating , followed by filtration , 21 . 5 ml of 2n naohaq . ( 1 . 0 eq .) was added to the solution at 80 ° c . the solution was gradually cooled to room temperature . filtration , washing with 80 ml of etoh and drying provided 18 . 8 g of compound 13 ( 99 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 10 . 70 ( t , j = 6 . 0 hz , 1h ), 7 . 89 ( s , 1h ), 7 . 40 - 7 . 30 ( m , 1h ), 7 . 25 - 7 . 16 ( m , 1h ), 7 . 06 - 6 . 98 ( m , 1h ), 5 . 22 - 5 . 12 ( m , 1h ), 4 . 87 - 4 . 74 ( m , 1h ), 4 . 51 ( d , j = 5 . 4 hz , 2h ), 4 . 35 - 4 . 25 ( m , 1h ), 4 . 16 ( dd , j = 1 . 8 , 14 . 1 hz , 1h ), 4 . 05 - 3 . 90 ( m , 1h ), 3 . 86 - 3 . 74 ( m , 1h ), 2 . 00 - 1 . 72 ( m , 1h ), 1 . 44 - 1 . 32 ( m , 1h ), 1 . 24 ( d , j = 6 . 9 hz , 3h ). the starting material of example a is compound 8 , which is identical to formula ( ia ) of the process of the present invention . thus , example a depicts a utility for the invention process in providing an intermediate for the compound of formula 17 below which is isomeric to the compound zz - 2 at page 237 of wo 2006 / 116764 to brian johns et al . after dissolution of mixture of 320 g of compound 8 ( 1 . 0 eq .) in 3 . 20 l of meoh by heating , the solution was concentrated . to the residue , 1 . 66 l of mecn , 5 . 72 ml of acoh ( 0 . 1 eq .) and 82 . 6 g of ( s )- 2 - amino - propan - 1 - ol ( 1 . 1 eq .) were added and the mixture was heated to 70 ° c ., stirred at 70 ° c . for 4 h and concentrated . to the residue , 1 . 67 l of 2 - propanol was added and the mixture was concentrated ( twice ). after cooling of the residue , filtration , washing with 500 ml of cold 2 - propanol and drying provided 167 g of compound 14 ( 52 % yield ) as a crystal . 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 61 - 7 . 55 ( m , 2h ), 7 . 40 - 7 . 20 ( m , 4h ), 6 . 53 ( d , j = 7 . 2 , 1h ), 5 . 46 ( d , j = 10 . 5 hz , 1h ), 5 . 23 ( d , j = 10 . 2 hz , 1h ), 5 . 20 ( dd , j = 3 . 9 , 9 . 6 hz , 1h ), 4 . 46 - 4 . 34 ( m , 1h ), 4 . 31 ( dd , j = 6 . 6 , 8 . 7 hz , 1h ), 4 . 14 ( dd , j = 3 . 9 , 12 . 3 hz , 1h ), 3 . 79 ( dd , j = 9 . 9 , 12 . 3 hz , 1h ), 3 . 62 ( dd , j = 6 . 9 , 8 . 7 hz , 1h ), 1 . 38 ( d , j = 6 . 3 hz , 3h ). to slurry of 156 g of compound 14 ( 1 . 0 eq .) in 780 ml of nmp was added 93 . 6 g of nbs ( 1 . 1 eq .) and the mixture was stirred at room temperature for 2 . 5 h . the reaction mixture was added to 3 . 12 l of h 2 o . filtration , washing with 8 . 0 l of h 2 o and drying provided 163 g of compound 15 ( 84 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 8 . 37 ( s , 1h ), 7 . 55 - 7 . 50 ( m , 2h ), 7 . 42 - 7 . 25 ( m , 3h ), 5 . 34 ( dd , j = 3 . 6 , 9 . 9 hz , 1h ), 5 . 18 ( d , j = 10 . 8 hz , 1h ), 5 . 03 ( d , j = 10 . 5 hz , 1h ), 4 . 53 ( dd , j = 3 . 6 , 12 . 0 hz , 1h ), 4 . 40 - 4 . 20 ( m , 2h ), 3 . 99 ( dd , j = 9 . 9 , 11 . 7 hz , 1h ), 3 . 64 ( dd , j = 5 . 7 , 8 . 1 hz , 1h ), 1 . 27 ( d , j = 6 . 3 hz , 3h ). under carbon mono - oxide atmosphere , a mixture of 163 g of compound 15 ( 1 . 0 eq . ), 163 ml of i - pr 2 net ( 2 . 5 eq . ), 68 . 4 ml of 2 , 4 - difluorobenzylamine ( 1 . 5 eq .) and 22 . 5 g of pd ( pph 3 ) 4 ( 0 . 05 eq .) in 816 ml of dmso was stirred at 90 ° c . for 7 h . after cooling , removal of precipitate , washing with 50 ml of dmso and addition of 11 . 3 g of pd ( pph 3 ) 4 ( 0 . 025 eq . ), the reaction mixture was stirred at 90 ° c . for 2 h under carbon mono - oxide atmosphere again . after cooling , removal of precipitate and addition of 2 . 0 l of acoet and 2 . 0 l of h 2 o , the organic layer was washed with 1 . 0 l of 1n hclaq . and 1 . 0 l of h 2 o ( twice ) and the aqueous layer was extracted with 1 . 0 l of acoet . the organic layers were combined and concentrated . silica gel column chromatography of the residue provided 184 g of compound 16 ( 96 % yield ) as foam . 1 h nmr ( 300 mhz , cdcl 3 ) δ 10 . 38 ( t , j = 6 . 3 hz , 1h ), 8 . 39 ( s , 1h ), 7 . 75 - 7 . 25 ( m , 7h ), 6 . 90 - 6 . 70 ( m , 2h ), 5 . 43 ( d , j = 10 . 2 hz , 1h ), 5 . 24 ( d , j = 10 . 2 hz , 1h ), 5 . 19 ( dd , j = 3 . 9 , 9 . 9 hz , 1h ), 4 . 63 ( d , j = 6 . 0 hz , 2h ), 4 . 50 - 4 . 25 ( m , 3h ), 3 . 86 ( dd , j = 9 . 9 , 12 . 3 hz , 1h ), 3 . 66 ( dd , j = 6 . 9 , 8 . 4 hz , 1h ), 1 . 39 ( d , j = 6 . 0 hz , 3h ). under hydrogen atmosphere , a mixture of 184 g of compound 16 ( 1 . 0 eq .) and 36 . 8 g of 10 % pd — c in 3 . 31 l of thf and 0 . 37 l of meoh was stirred for 3 h . after filtration of precipitate ( pd — c ), washing with thf / meoh ( 9 / 1 ) and addition of 36 . 8 g of 10 % pd — c , the mixture was stirred for 20 min under hydrogen atmosphere . after filtration of precipitate ( pd — c ) and washing with thf / meoh ( 9 / 1 ), the filtrate was concentrated . after 200 ml of acoet was added to the residue , filtration afforded crude solid of compound 17 . the precipitates were combined and extracted with 4 . 0 l of chcl 3 / meoh ( 5 / 1 ). after concentration of the chcl 3 / meoh solution and addition of 250 ml of acoet to the residue , filtration afforded crude solid of compound 17 . the crude solids were combined and dissolved in 8 . 2 l of mecn / h 2 o ( 9 / 1 ) by heating . after filtration , the filtrate was concentrated . to the residue , 1 . 5 l of etoh was added and the mixture was concentrated ( three times ). after cooling of the residue , filtration and drying provided 132 g of compound 17 ( 88 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 11 . 47 ( brs , 1h ), 10 . 31 ( t , j = 6 . 0 hz , 1h ), 8 . 46 ( s , 1h ), 7 . 40 ( td , j = 8 . 6 , 6 . 9 hz , 1h ), 7 . 24 ( ddd , j = 2 . 6 , 9 . 4 , 10 . 6 , 1h ), 7 . 11 - 7 . 01 ( m , 1h ), 5 . 39 ( dd , j = 4 . 1 , 10 . 4 hz , 1h ), 4 . 89 ( dd , j = 4 . 2 , 12 . 3 hz , 1h ), 4 . 55 ( d , j = 6 . 0 hz , 2h ), 4 . 40 ( dd , j = 6 . 8 , 8 . 6 hz , 1h ), 4 . 36 - 4 . 22 ( m , 1h ), 4 . 00 ( dd , j = 10 . 2 , 12 . 3 hz , 1h ), 3 . 67 ( dd , j = 6 . 7 , 8 . 6 hz , 1h ), 1 . 34 ( d , j = 6 . 3 hz , 3h ). after dissolution of 16 . 0 g of compound 17 ( 1 . 0 eq .) in 2 . 56 l of etoh and 0 . 64 l of h 2 o by heating , followed by filtration , 39 ml of 1n naohaq . ( 1 . 0 eq .) was added to the solution at 75 ° c . the solution was gradually cooled to room temperature . filtration , washing with 80 ml of etoh and drying provided 13 . 5 g of compound 18 ( 80 % yield ) as a crystal . 1 h nmr ( 300 mhz , dmso - d 6 ) δ 10 . 73 ( t , j = 6 . 0 hz , 1h ), 7 . 89 ( s , 1h ), 7 . 40 - 7 . 30 ( m , 1h ), 7 . 25 - 7 . 16 ( m , 1h ), 7 . 07 - 6 . 98 ( m , 1h ), 5 . 21 ( dd , j = 3 . 8 , 10 . 0 hz , 1h ), 4 . 58 ( dd , j = 3 . 8 , 12 . 1 hz , 1h ), 4 . 51 ( d , j = 5 . 4 hz , 2h ), 4 . 30 - 4 . 20 ( m , 2h ), 3 . 75 ( dd , j = 10 . 0 , 12 . 1 hz , 1h ), 3 . 65 - 3 . 55 ( m , 1h ), 1 . 27 ( d , j = 6 . 1 hz , 3h ). this example b utilizes a process to insert a ring nitrogen in place of oxygen in a pyrone ring and create an aldehyde equivalent by an osmium oxidation of a double bond . thus , this example is not within the scope of this invention and is provided to demonstrate the utility of the intermediates produced according to the process of the invention . in particular , the compound f below is a final product ( viii ) of the invention process and is here taken on to a product i below which is within the structure ( i - 7 ) where ( r ) m is 4 - f and r a is h at page 240 of wo 2006 / 116764 . to a bromobenzene ( 238 ml ) solution of compound a ( 23 . 8 g , 110 mmol ), selene dioxide ( 24 . 4 g , 220 mmol ) was added . the reaction mixture was stirred for 13 hours at 140 ° c . with removing water by dean - stark trap . insoluble particles were removed by filtration after cooling , and solvent was evaporated . toluene was added to the residue and precipitates were filtered off . after concentration in vaccuo , the residue was purified by silica gel column chromatography ( hexane / ethyl acetate ). compound b ( 16 . 5 g , 65 %) was obtained as yellow oil . 1 h - nmr ( cdcl 3 ) δ : 5 . 51 ( 2h , s ), 6 . 50 ( 1h , d , j = 5 . 4 hz ), 7 . 36 ( 5h , s ), 7 . 75 ( 1h , d , j = 5 . 4 hz ), 9 . 88 ( 1h , s ). to an ice cooled aqueous ( 465 ml ) solution of sodium chlorite ( 38 . 4 g , 424 mmol ) and sulfamic acid ( 54 . 9 g , 566 mmol ), acetone ( 465 ml ) solution of compound b ( 46 . 5 g , 202 mmol ) was added and the mixture was stirred for 40 minutes at room temperature . after removing acetone in vaccuo , precipitates were collected by filtration and washed with cold water . compound c ( 42 . 8 g , 86 %) was obtained as colorless crystal . 1 h - nmr ( dmso - d 6 ) δ : 5 . 12 ( 2h , s ), 6 . 54 ( 1h , d , j = 5 . 6 hz ), 7 . 33 - 7 . 46 ( 5h , m ), 8 . 20 ( 1h , d , j = 5 . 6 hz ). an ethanol ( 17 ml ) solution of allylamine ( 13 . 2 g 231 mmol ) was added to an ethanol ( 69 ml ) suspension of compound c ( 17 . 2 g , 70 mmol ), then the mixture was stirred for 4 . 5 hours at 50 ° c . and for 3 hours at 75 ° c . to the cooled reaction mixture , 2n hydrochloric acid and ice were added and precipitates were collected by filtration . compound d was obtained as colorless crystal . 1 h - nmr ( cdcl 3 ) δ : 4 . 37 ( 2h , brs ), 4 . 95 ( 2h , s ), 5 . 26 - 5 . 39 ( 2h , m ), 5 . 81 - 5 . 94 ( 1h , m ), 6 . 32 ( 1h , dd , j = 0 . 8 , 7 . 2 hz ), 7 . 29 - 7 . 37 ( 3h , m ), 7 . 48 - 7 . 51 ( 2h , m ), 7 . 99 ( 1h , dd , j = 0 . 8 , 7 . 6 hz ), 8 . 11 ( 1h , brs ). to an acetonitrile ( 146 ml ) suspension of compound d ( 14 . 6 g , 51 mmol ), 1 , 8 - diazabicyclo [ 5 . 4 . 0 ] undec - 7 - ene ( 15 . 5 g , 102 mmol ) and methyl iodide ( 18 . 2 g , 128 mmol ) were added and the mixture was stirred for 15 hours at room temperature . after evaporating solvent , the residue was purified by silica gel column chromatography ( chloroform / methanol ). compound e ( 14 . 2 g , 93 %) was obtained as colorless solid . 1 h - nmr ( cdcl 3 ) δ : 3 . 75 ( 3h , s ), 4 . 40 ( 2h , d , j = 5 . 7 hz ), 5 . 16 - 5 . 35 ( 2h , m ), 5 . 29 ( 2h , s ), 5 . 81 - 5 . 94 ( 1h , m ), 6 . 62 ( 1h , d , j = 7 . 5 hz ), 7 . 27 - 7 . 42 ( 6h , m ). to a diethyl ether ( 390 ml ) solution of compound e ( 13 . 3 g , 44 mmol ), potassium osmate ( vi ) dihydrate ( 1 . 62 g , 4 . 4 mmol ) and sodium metaperiodate ( 28 . 1 g , 132 mmol ) were added . the mixture was stirred for 2 . 5 hours at room temperature and precipitates were collected by filtration . collected solid was dissolved in chloroform - methanol and insoluble particles were filtered off . concentration in vaccuo gave crude product of compound f ( 14 . 3 g ). 1h nmr ( dmso - d6 ) δ : 3 . 23 ( 3h , s ), 3 . 82 ( 3h , s ), 3 . 87 ( 2h , t , j = 4 . 4 hz ), 4 . 62 ( 1h , dd , j = 11 . 7 , 4 . 8 hz ), 5 . 11 ( 2h , s ), 6 . 31 ( 1h , d , j = 7 . 5 hz ), 6 . 78 ( 1h , d , j = 6 . 6 hz ), 7 . 33 - 7 . 40 ( 5h , m ), 7 . 64 ( 1h , d , j = 7 . 5 hz ). to chloroform ( 108 ml ) and methanol ( 12 ml ) solution of compound f ( 11 . 7 g , crude product ), 3 - aminopropanol ( 2 . 77 g , 36 . 9 mmol ), and acetic acid ( 1 . 2 ml ) were added and the mixture was stirred for 90 minutes at 70 ° c . after concentrating in vaccuo , the residue was purified by silica gel column chromatography ( chloroform / methanol ). compound g ( 8 . 48 g , 72 % for 2 steps ) was obtained as colorless cryatal . 1 h - nmr ( cdcl 3 ) δ : 1 . 54 - 1 . 64 ( 1h , m ), 1 . 85 - 2 . 01 ( 1h , m ), 3 . 00 ( 1h , dt , j = 3 . 6 , 12 . 9 hz ), 3 . 74 ( 1h , dt , j = 2 . 7 , 12 . 3 hz ), 3 . 93 ( 1h , dd , j = 5 . 1 , 13 . 5 hz ), 4 . 07 - 4 . 21 ( 2h , m ), 4 . 63 - 4 . 69 ( 1h , m ), 4 . 94 ( 1h , t , j = 4 . 8 hz ), 5 . 25 ( 2h , dd , j = 10 . 2 , 24 . 6 hz ), 6 . 56 ( 1h , d , j = 7 . 5 hz ), 7 . 22 - 7 . 38 ( 5h , m ), 7 . 63 - 7 . 66 ( 2h , m ). to acetic acid ( 93 ml ) solution of compound g ( 6 . 1 g , 18 . 7 mmol ), acetic acid ( 31 ml ) solution of bromine ( 1 . 44 ml , 28 . 0 mmol ) was added dropwisely during 15 minutes . the mixture was stirred for 3 hours at room temperature . after addition of 5 % aqueous sodium hydrogen sulfite ( 8 ml ), 2n sodium hydroxide ( 500 ml ) was added dropwisely during 20 minutes . precipitates were collected by filtration and washed with mixture of dichloromethane and diisopropyl ether . compound h ( 6 . 02 g , 79 %) was obtained as colorless crystal . 1 h - nmr ( dmso - d 6 ) δ : 1 . 55 - 1 . 74 ( 2h , m ), 3 . 12 ( 1h , dt , j = 3 . 0 , 12 . 3 hz ), 3 . 84 ( 1h , dt , j = 2 . 7 , 11 . 7 hz ), 4 . 00 - 4 . 05 ( 1h , m ), 4 . 20 - 4 . 26 ( 1h , m ), 4 . 40 - 4 . 46 ( 2h , m ), 5 . 03 ( 2h , s ), 5 . 15 - 5 . 17 ( 1h , m ), 7 . 31 - 7 . 40 ( 3h , m ), 7 . 56 - 7 . 58 ( 2h , m ), 8 . 39 ( 1h , s ). to dimethyl sulfoxide ( 1 . 42 ml ) solution of compound h ( 71 mg , 0 . 175 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 25 mg , 0 . 035 mmol ), 4 - fluorobenzyl amine ( 0 . 06 ml , 0 . 525 mmol ) and diisopropyl amine ( 0 . 15 ml , 0 . 875 mmol ) were added , then the mixture was stirred under carbon monoxide atmosphere for 5 hours at 80 ° c . after cooling , saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate . the extract was washed with water and dried with anhydrous sodium sulfate . solvent was removed in vaccuo and the residue was purified with silica gel column chromatography ( ethyl acetate / methanol ). compound i ( 74 . 5 mg , 89 %) was obtained as colorless crystal . 1 h - nmr ( dmso - d 6 ) δ : 1 . 58 - 1 . 74 ( 2h , m ), 3 . 10 - 3 . 18 ( 1h , m ), 3 . 80 - 3 . 88 ( 1h , m ), 4 . 02 - 4 . 07 ( 1h , m ), 4 . 43 - 4 . 59 ( 5h , m ), 5 . 05 ( 2h , s ), 5 . 20 ( 1h , t , j = 3 . 9 hz ), 7 . 13 - 7 . 19 ( 2h , m ), 7 . 32 - 7 . 40 ( 5h , m ), 7 . 56 - 7 . 59 ( 2h , m ), 8 . 61 ( 1h , s ). this example c shows a refunctionalization of a compound 6 as shown above in example 1 ( of formula ( vi )), including a bromination at the r x position , to yield final products 20 and 21 ( of formula ( i )) of the invention . such compounds with br at the r x position can be reacted as in examples 1 and 2 to add the r 2 — x — nr 1 — c ( o )— sidechain . a reactor was charged with 1 -( 2 , 3 - dihydroxypropyl )- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylic acid 6 ( 4 . 302 kg , 13 . 47 mol ) followed by charging with nahco 3 ( 1 . 69 kg , 20 . 09 mol ) and 242 g of deionized water . to this was added 21 . 4 kg of nmp and the mixture was stirred and temperature brought to 28 - 35 ° c . dimethyl sulfate ( 2 . 34 kg , 18 . 30 mol ) was added dropwise via an addition funnel to the reaction mixture over 1 - 3 hours keeping the temperature at 28 - 33 ° c . the slurry was agitated at this temperature for 14 h . when deemed complete , the reaction mixture was cooled to 5 ° c . or below and the mixture was neutralized to ph 6 by the addition of hcl ( 561 ml of conc hcl in 2806 g of deionized water ). the reaction vessel was slowly charged with cold 20 % brine solution composed of 8 . 7 kg nacl , 20 kg of deionized water and 14 . 8 kg of ice at a maximum temperature of 10 ° c . the mixture was agitated at 0 - 10 ° c . for 2 . 5 h . the slurry was filtered under vacuum and the cake washed with 15 kg of deionized water two times . the wet solid product was dried at 45 - 55 ° c . under vacuum until constant weight was obtained . the desired product methyl 1 -( 2 , 3 - dihydroxypropyl )- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 7 was obtained as a light yellow solid ( 3 . 77 kg , 99 . 42 % purity by hplc , 84 %). 1 h nmr ( 300 mhz , dmso - d 6 ) δ 7 . 60 ( d , j = 7 . 5 hz , 1h ), 7 . 36 ( m , 5h ), 6 . 28 ( d , j = 7 . 5 hz , 1h ), 5 . 23 ( d , j = 5 . 4 hz , 1h ), 5 . 10 ( abq , j = 10 . 8 hz , 2h ), 4 . 85 ( m , 1h ), 3 . 98 ( dd , j = 14 . 3 , 2 . 4 hz , 1h ), 3 . 79 ( s , 3h ), 3 . 70 ( dd , j = 14 . 3 , 9 . 0 hz , 1h ), 3 . 58 ( m , 1h ), 3 . 23 ( m , 1h ). a reactor was charged with ( 3 . 759 kg , 11 . 27 mol ) of methyl 1 -( 2 , 3 - dihydroxypropyl )- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 7 and 18 . 8 l of dmf . to this agitated mixture at 18 - 20 ° c . was added n - bromosuccinimide ( 2 . 220 kg , 12 . 47 mol ) over 20 minutes via a powder funnel . the resultant mixture was stirred at rt for 16 h . at this time less than 1 % of starting material was present by hplc . the mixture was worked up in half batches by cooling to 10 ° c . and added an ice / water mixture ( 12 kg ice in 35 kg deionized water ) and the mixture was agitated , then filtered . this was repeated for the second half of the batch . the combined filter cake was washed with 14 l of water and dried in a vacuum oven to provide 4 . 033 kg of methyl 5 - bromo - 1 -( 2 , 3 - dihydroxypropyl )- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 19 ( 91 . 6 %) as an off - white powder of 99 . 2 % hplc purity . 1 h nmr ( 300 mhz , methanol - d 4 ) δ 8 . 21 ( s , 1h ), 7 . 41 - 7 . 33 ( m , 5h ), 5 . 16 ( s , 2h ), 4 . 17 ( dd , j = 14 . 3 , 2 . 4 hz , 1h ), 3 . 90 ( dd , j = 14 . 3 , 9 . 0 hz , 1h ), 3 . 81 ( s , 3h ), 3 . 78 ( m , 1 ), 3 . 52 ( dd , j = 11 . 3 , 4 . 8 hz , 1h ), 3 . 41 ( dd , j = 11 . 3 , 6 . 3 hz , 1h ). a reactor was charged with sodium periodate ( 1 . 67 kg , 7 . 8 mol ) and 44 l of deionized water . to the agitated mixture was added 8 . 5 kg of ice . this was stirred until all the ice melted and the mixture temperature was 1 . 4 ° c . to this was added methyl 5 - bromo - 1 -( 2 , 3 - dihydroxypropyl )- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 19 ( 2 . 73 kg , 6 . 62 mol ) via a powder addition funnel . the mixture was allowed to warm to rt and the slurry was stirred for 16 h . a sample was monitored by 1 h nmr and showed the disappearance of starting material . the mixture was filtered and the cake washed with 20 kg of deionized water . this was repeated until a negative starch / iodide paper result was obtained ( 4 × 20 l washes ). the solids were dried in a vacuum oven at 45 - 55 ° c . to provide methyl 5 - bromo - 1 -( 2 , 2 - dihydroxyethyl )- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 20 ( 2 . 176 kg , 88 %) as a mixture with the corresponding aldehyde form 21 . purity was determined to be 99 . 5 % by hplc . 1 h nmr ( 300 mhz , acetone - d 6 ) δ 8 . 12 ( s , 1h ), 7 . 49 - 7 . 30 ( m , 5h ), 5 . 56 ( dd , j = 6 . 0 , 2 . 4 hz , 1h ), 5 . 23 ( m , 1h ), 5 . 20 ( s , 2h ), 3 . 97 ( d , j = 5 . 1 hz , 2h ), 3 . 87 ( s , 3h ). this example shows a reaction of a compound 5 of formula ( ii ) with one of ( iii ) in step i ) and a refunctionalization step ii ) of compounds of formula ( v ) ( compounds 22 , 23 , 24 and 25 ) in producing compounds of formula ( i ) according to the process of the invention . to a flask ( 1 l ) charged with 500 ml of anhydrous ethanol was added 49 . 2 g ( 0 . 2 mol ) of 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 4h - pyran - 2 - carboxylic acid 5 . the suspension was slowly heated to 55 - 60 ° c . before addition of 2 - amino - acetaldehyde - dimethylacetal ( 84 . 1 g , 0 . 8 mole ). the reaction was then brought up to 65 ° c . and further stirred for 18 hours . the solvent was removed under reduced pressure to produce 1 -[ 2 , 2 - bis ( methyloxy ) ethyl ]- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylic acid 22 ( crude ) as brown oil , which was used for the next step directly . crude 1 -[ 2 , 2 - bis ( methyloxy ) ethyl ]- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylic acid 22 obtained as above was dissolved in dmf ( 500 ml ). to this solution was added nahco 3 ( 50 . 5 g , 0 . 6 mole ). the suspension was stirred vigorously with a mechanic stirrer while ch 3 i in tbme ( 2 . 0 m , 300 ml ) was introduced by addition funnel over 30 minutes . after addition , the reaction was stirred overnight at room temperature . the reaction mixture was then diluted with etoac (˜ 1 . 5 l ) and washed with water and brine . the organic layer was dried over anhydrous na 2 so 4 . evaporation of solvents gave methyl 1 -[ 2 , 2 - bis ( methyloxy ) ethyl ]- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 23 as brown oil , which was used directly for the next step . a 2 l flask equipped with a mechanic stirrer were charged with methyl 1 -[ 2 , 2 - bis ( methyloxy ) ethyl ]- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 23 as obtained above and 500 ml of dichloromethane . to this flask was added nbs ( 30 g , 0 . 17 mole ) portion - wise . the reaction was stirred at room temperature until its completion ( monitored by tlc , ˜ 6 hours ). the mixture was then diluted with dichloromethane and washed with nahco 3 ( ss ). the organic phase was dried over na 2 so 4 before evaporation of the solvents . the crude product was purified by column chromatography ( silica gel , etoh / dcm : 0 - 40 %) to afford methyl 1 -[ 2 , 2 - bis ( methyloxy ) ethyl ]- 5 - bromo - 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 24 as a light brown solid ( 50 g , 60 % over three steps ). 1 h nmr ( 400 mhz , chloroform - d ) δ ppm 7 . 7 ( s , 1h ), 7 . 4 ( m , 2h ), 7 . 3 ( d , j = 7 . 9 hz , 3h ), 5 . 3 ( s , 2h ), 4 . 4 ( s , 1h ), 3 . 8 ( d , j = 4 . 8 hz , 2h ), 3 . 8 ( s , 3h ), 3 . 4 ( s , 6h ). lc - ms ( m + h + ): calcd 426 , obsd 426 . a pressure vessel was charged with methyl 1 -[ 2 , 2 - bis ( methyloxy ) ethyl ]- 5 - bromo - 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 24 ( 6 . 4 g , 15 mmol ), 2 , 4 - difluorobenzylamine ( 3 . 2 g , 22 . 5 mmol ), k 3 po 4 ( 9 . 45 g , 45 mmol ), pd ( ococf 3 ) 2 ( 398 mg , 1 . 2 mmol ), xantophos ( 694 mg , 1 . 2 mmol ) and toluene ( 200 ml ). the mixture was purged by co ( 4 ×) before being heated to 100 ° c . for 22 hours under co atmosphere ( 60 psi ). after cooled down to the room temperature , the solids were filtered off through celite and washed with etoac . the filtrate was concentrated and the residual was purified by column chromatography ( silica gel , etoac / hexane 0 ˜ 80 %) to afford methyl 1 -[ 2 , 2 - bis ( methyloxy ) ethyl ]- 5 -({[( 2 , 4 - difluorophenyl ) methyl ] amino } carbonyl )- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 25 as a light brown oil ( 4 . 7 g , 61 %). 1h nmr ( 400 mhz , chloroform - d ) δ ppm 10 . 4 ( m , 1h ), 8 . 4 ( s , 1h ), 7 . 4 ( m , 6h ), 6 . 8 ( d , j = 9 . 3 hz , 2h ), 5 . 3 ( s , 2h ), 4 . 6 ( d , j = 5 . 7 hz , 2h ), 4 . 5 ( s , 1h ), 4 . 0 ( d , j = 4 . 8 hz , 2h ), 3 . 8 ( s , 3h ), 3 . 4 ( s , 6h ). lc - ms ( m + h + ): calcd 517 , obsd 517 . methyl 1 -[ 2 , 2 - bis ( methyloxy ) ethyl ]- 5 -({[( 2 , 4 - difluorophenyl ) methyl ] amino } carbonyl )- 4 - oxo - 3 -[( phenylmethyl ) oxy ]- 1 , 4 - dihydro - 2 - pyridinecarboxylate 25 ( 11 . 6 g ) was treated with 90 % formic acid ( 250 ml ) at 40 ° c . for ˜ 12 hours ( monitored by lc - ms ). after the solvents were evaporated at & lt ; 40 ° c ., the residue was re - dissolved in etoac (˜ 1 l ) and the resulting solution was washed with nahco 3 and brine . the organic phase was then dried over na 2 so 4 . after evaporation of solvents , the titled compounds 26 and 27 were obtained as an approximate 80 / 20 equilibrium mixture ( 10 . 57 g ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ ppm 10 . 3 ( m , 1h ), 9 . 47 ( s , aldehyde - h . ˜ 0 . 2h )), 8 . 4 ( m , 1h ), 7 . 3 ( s , 6h ), 7 . 2 ( m , 1h ), 7 . 0 ( m , 1h ), 6 . 3 ( m , 2h ), 5 . 1 ( s , 3h ), 4 . 9 ( m , 1h ), 4 . 5 ( m , 3h ), 3 . 9 ( m , 2h ), 3 . 8 ( s , 3h ). lc - ms , for 26 ( m + h + ), calcd 503 , obsd 503 ; for 27 ( m + h 2 o + h + ), cald 489 , obsd 489 .