7- Hydroxymethyl-2- perhydropyrido

Treatment of perhydropyrido[2,l-c][l,4]oxazine-3,6-dione 232 with B2H6 yielded (—)-(2i )-[(2S)-hydroxymethyl)piperldin-1 -yl]-2-phenylethanol (233) (00T233). Reduction of ( )-(3i ,4i ,9aS)-4-methyl-3-phenylperhydropyr-ido[2,l-c][l,4]oxazin-3-ol (234) with NaBH4 yielded ring-opened product 235 (97JHC1813). 

Reduction of a 7-(2-oxoethyl) derivative with NaBH4 in EtOH at room temperature gave 7-(2-hydroxyethyl)-2-(2-pyrimidinyl)perhydropyrido[l, 2-u]pyrazine (99MIP6). Reduction of 7-formyl-8-[(4-cyanophenyl)methoxy]-1,3,4,6,11,1 lu-hexahydro-2//-pyrazino[l,2-A]isoquinoline-l,4-dione with NaBH4 yielded a 7-hydroxymethyl derivative (98MIP7). 

The bromine atom of 4-aryl-2-(4-bromobutyl)-2,3,5,6,7,8-hexahydro-177- ancj -perhydropyrido[l,2-c]pyrimidine-l,3-diones was displaced with 4-substituted piperazines <2002FES959, 2004APH139, 2004PHA99>. Heating 3-hydroxymethyl derivatives of epimeric 6-methyl-l,3,4,6,7,llb-hexahydro-277-pyrimido[6,l-,2]isoquinolin-2-ones 152 resulted in the formation of the 3-unsubstituted derivatives 153 by loss of CH20 (Equation 26) <1997LA1165>. 

Reaction of 4-aryl-3,4,6,7,8,9-hexahydro- and -perhydropyrido[2,l-c] [l,4]oxazin-6-ones with ( Pr)2NLi in THF at 0 °C, then with 3-methoxy-4-(4-methyl-l H-imidazol-1 -yl)benzaldehide afforded 7-( [3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl] hydroxymethyl derivatives, which were dehydrated by treatment first with MeSC Cl and NEt3, then with a solution of NaOMe in MeOH to provide (E)-7- [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]methylene -4-aryl-3,4,6,7,8,9-hexahydro- and -perhydropyrido[2,l-c][l,4]oxazin-6-ones (07USA2007/0117859). 

Boiling l-(4-aminophenyl)-2-[2-(hydroxymethyl)piperidin-l-yl]ethanol in 48% aqueous HBr for 3.5 h yielded 3-(4-aminophenyl)perhydropyrido [2,1 -c] [1,4]oxazine (08WOP2008 /026046). 

Perhydropyrido[l,2-c][l,3]oxazin-l-ones were prepared in the reaction of the appropriate 2-(2-piperidyl)ethanols and ethyl chloroformate (63AP38) in the presence of sodium ethylate in boiling benzene, or when 2-(2-piperidyl)ethanol was reacted with dimethyl carbonate in the presence of sodium methylate (91X1311). l-Hydroxymethyl-9,10-dimethoxy-l,2,4,6,7,llb-hexahydro-[l,3]oxazino[4,3-fl]isoquinoline-4-oneand 4-thione were prepared from l-[bis(hydroxymethyl)methyl]-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline with ethyl chloroformate in the presence of sodium methylate, and thiophosgene in the presence of NEts, respectively... 

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