the h and c  nmr spectra were recorded on a bruker spectrometer ( billerica , ma , usa ) operating at 500  mhz for h and 125  mhz for c. cdcl3 was used as the solvent for nmr experiments , unless otherwise stated . h chemical shift values (  ) are referenced to the residual nondeuterated components of the nmr solvents ( =7.26  ppm for chcl3 , etc . ) . the c chemical shifts (  ) column chromatography was performed using silica gel ( 3575  mesh ) or on an isolera biotage system ( uppsala , sweden ) . purity of prepared compounds was determined to be>95  % by highperformance liquid chromatography ( hplc)uv analysis ( thermo hplc connected with uv detector ; varian pursuit xs , 4.6  mm150  mm , 5.0  m , palo alto , ca , usa ) . a mixture of a nucleoside ( 1.0  eq  mol ) , an appropriate trityl chloride ( 2.2  eq  mol ) , and 4dimethylaminopyridine ( dmap , 2.8  mol  eq , unless stated otherwise ) in anhydrous pyridine ( 4.5  ml  mmol ) was heated at 80  c under an argon atmosphere for 18  h. the reaction was quenched by addition of meoh ( 2  ml  mmol ) at rt , and kept stirring at rt for 30  min . the organic solution was washed with saturated solution of nahco3 ( 320  ml ) , and the combined aqueous layers were extracted with ch2cl2 . the residue was purified by column chromatography on silica gel ( eluent system gradient meoh in ch2cl2=13  % containing 0.5  % triethylamine ) . experimental data for all active compounds are reported below and for inactive compounds in the supporting information . tritylated derivatives of ribavirin ( 5 ) were prepared according to the general procedure 1 from 5 ( 0.500  g , 2.05  mmol ) and trityl chloride ( 1.6  g , 5.74  mmol ) . column purification with a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as eluent yielded 5,3,2triotritylribavirin ( 5  a ) , 5,3bisotritylribavirin ( 5  b ) and 5,2bisotritylribavirin ( 5  c ) . b ) was obtained as a white solid ( 0.268  g , 18  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) :  
 = 8.21 ( s , 1  h , h3 ) , 7.437.38 ( m , 6  h , hph ) , 7.347.18 ( m , 24  h , hph ) , 6.64 ( br s , 1  h , nh 
 2 ) , 5.89 ( d , j=3.08  hz , 1  h , h1 ) , 5.66 ( br s , 1  h , nh 
 2 ) , 4.434.39 ( m , 1  h , h3 ) , 4.194.14 ( m , 1  h , h4 ) , 3.613.56 ( m , 1  h , h2 ) , 3.473.43 ( m , 1  h , h5 ) , 3.00 ( dd , j=10.9 , 5.5  hz , 1  h , h5 ) , 2.85  ppm ( d , j=4.5  hz , 1  h , oh2 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =160.4 ( c = o ) , 156.9 ( c5 ) , 144.1 ( c3 ) , 143.5 , 143.3 ( cph ) , 128.7 , 128.6 , 128.3 , 127.8 , 127.1 ( chph ) , 92.4 ( c1 ) , 88.1 , 87.1 ( c(ph)3 ) , 83.5 ( c4 ) , 74.3 ( c2 ) , 74.1 ( c3 ) , 64.0  ppm ( c5 ) ; ms ( es+ ) found : m / z 751.3 [ m+na ] , calcd for [ c46h40n4o5 ] : m / z 728.83 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=28.10  min . tritylated derivatives of 5fluorouridine ( 6 ) were prepared according to the general procedure 1 from 6 ( 0.30  g , 1.14  mmol ) and trityl chloride ( 1.02  g , 3.66  mmol ) in pyridine ( 6  ml ) . column chromatography purification using a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as an eluent yielded 5,3bisotrityl5fluorouridine ( 6  b ) , 5,2bisotrityl5fluorouridine ( 6  c ) , and 5otrityl5fluorouridine ( 6  d ) . d ) was obtained as a white solid ( 0.183  g , 32  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 , ) : =7.42 ( d , j 
 hf=6.0  hz , 1  h , h6 ) , 7.227.20 ( m , 6  h , hph ) , 7.057.02 ( m , 6  h , hph ) , 6.986.95 ( m , 6  h , hph ) , 5.72 ( dd , j=4.5 , 1.5  hz , 1  h , h1 ) , 4.04 ( t , j=5.0  hz , 1  h , h3 ) , 3.96 ( t , j=5.0  hz , 1  h , h2 ) , 3.903.87 ( m , 1  h , h4 ) , 3.30 ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) , 3.25  ppm ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso , ) : =161.0 ( d , j 
 cf=22.5  hz , c2 ) , 152.7 ( c4 ) , 144.4 ( d , j 
 cf=241.5  hz , c5 ) , 143.3 ( cph ) , 128.6 , 128.3 , 127.3 ( chph ) , 123.4 ( d , j 
 cf=33.75  hz , c6 ) , 90.1 ( c1 ) , 87.5 ( c(ph)3 ) , 84.4 ( c4 ) , 75.8 ( c2 ) , 71.0 ( c3 ) , 63.2  ppm ( c5 ) ; ms ( es+ ) found : m / z 527.10 [ m+na ] , calcd for [ c28h25fn2o6 ] : m / z 504.50 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=17.52  min . dimethoxytritylated derivatives of 5fluorouridine ( 6 ) were prepared according to the general procedure 1 from 6 ( 0.30  g , 1.14  mmol ) and 4,4dimethoxytrityl chloride ( 1.24  g , 3.66  mmol , 3.2  equiv / mol ) in pyridine ( 6  ml ) . column chromatography purification using a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as an eluent yielded three products , which were further repurified by preparative tlc using meoh / triethylamine ( 2:0.5  % ) in ch2cl2 to yield : 5,3bisodimethoxytrityl5fluorouridine ( 6  f ) , 5,2bisodimethoxytrityl5fluorouridine ( 6  g ) , and 5odimethoxytrityl5fluorouridine ( 6  h ) . h ) was obtained as a yellowish solid ( 0.17  g , 26  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso , ) : =7.91 ( d , j 
 hf=7.0  hz , 1  h , h6 ) , 7.40 ( dd , j=8.5 , 2.5  hz , 2  h , hph ) , 7.337.23 ( m , 7  h , hph ) , 6.90 ( apparent d , j=8.5  hz , 4  h , hph ) , 5.73 ( dd , j=4.0 , 1.5  hz , 1  h , h1 ) , 5.48 ( d , j=5.0  hz , 1  h , c2oh ) , 5.14 ( d , j=5.0  hz , 1  h , c3oh ) , 4.14 ( apparent q , j=5.0  hz , 1  h , h2 ) , 4.08 ( apparent q , j=5.0  hz , 1  h , h3 ) , 3.983.96 ( m , 1  h , h4 ) , 3.75 ( s , 6  h , 2 x och 
 3 ) , 3.29 ( dd , j=11.0 , 3.5  hz , 1  h , h5 ) , 3.19  ppm ( dd , j=11.0 , 3.5  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso , ) : =158.2 , 158.1 ( ch3ocph ) , 156.9 ( d , 
 j 
 cf=26.0  hz , c4 ) , 149.8 ( c2 ) , 144.7 ( cph ) , 139.9 ( d , 
 j 
 cf=230.5  hz , c5 ) , 135.4 , 135.2 ( cph ) , 129.7 , 128.9 , 128.2 , 127.9 , 127.6 , 126.7 , 125.3 ( chph ) , 124.6 ( d , 
 j 
 cf=33.8  hz , c6 ) , 113.3 , 113.2 ( chph ) , 89.0 ( c1 ) , 85.8 ( c(ph)3 ) , 82.6 ( c4 ) , 73.2 ( c2 ) , 69.5 ( c3 ) , 63.1 ( c5 ) , 55.0  ppm ( och3 ) ; f  nmr ( 470  mhz , 25  c , [ d6]dmso , ) : =167.25  ppm ; ms ( es+ ) found : m / z 587 [ m+na ] , calcd for [ c30h29fn2o8 ] : m / z 564.55 [ m ] ; reversephase hplc ( h2o / ch3cn 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=14.85  min . dimethoxytritylated derivatives of uridine ( 9 ) were prepared according to the general procedure 1 from 9 ( 0.150  g , 0.61  mmol ) , 4,4dimethoxytrityl chloride ( 0.578  g , 1.71  mmol ) , and dmap ( 0.209  g , 1.71  mmol ) in anhydrous pyridine ( 10  ml ) . column chromatography eluting with a gradient of meoh / triethylamine ( 1:0.5  % to 3.5:0.5  % ) in ch2cl2 as an eluent gave 5,2bisodimethoxytrityluridine ( 9  g ) and 5dimethoxytrityluridine ( 9  h ) . h ) was obtained as a yellowish solid ( 0.16  g , 48  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : =8.01 ( d , j=8.0  hz , h6 ) , 7.437.38 ( m , 2  h , hph ) , 7.337.28 ( m , 6  h , hph ) , 7.267.22 ( m , 1  h , hph ) , 6.896.82 ( m , 4  h , hph ) , 5.92 ( d , j=2.5  hz , h1 ) , 5.38 ( d , j=8.0  hz , h5 ) , 4.44 ( dd , j=6.0 , 5.5  hz , h3 ) , 4.36 ( dd , j=5.0 , 2.5  hz , h2 ) , 4.224.18 ( m , 1  h , h4 ) , 3.80 ( s , 3  h , och 
 3 ) , 3.79 ( s , 3  h , och 
 3 ) , 3.55 ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) , 3.50  ppm ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =163.7 ( c2 ) , 158.7 , 158.6 ( ch3ocph ) 151.1 ( c4 ) , 144.4 ( cph ) , 140.3 ( c6 ) , 135.5 ( cph ) , 135.2 ( cph ) , 130.3 , 130.2 , 130.1 , 129.2 , 128.1 , 127.9 , 127.8 , 127.1 , 113.4 , 113.3 , 113.2 ( chph ) , 102.3 ( c5 ) , 90.6 ( c1 ) , 83.8 ( c4 ) , 87.0 ( c(ph)3 ) , 75.5 ( c2 ) , 69.7 ( c3 ) , 61.9 ( c5 ) , 55.2  ppm ( och3 ) ; ms ( es+ ) found : m / z 569.2 [ m+na ] , calcd for [ c30h30n2o8 ] : m / z 546.57 [ m ] ; reversephase hplc ( h2o / ch3cn from 80:20 to 10:90 in 15  min , then to ch3cn 100  % in 25  min ) , flow=1  ml  min , =245  nm , t 
 r=10.56  min . h ) was prepared according to the general procedure 1 from nacetyllamivudine ( 12 ) ( 0.80  g , 2.95  mmol ) , 4,4dimethoxytrityl chloride ( 1.2  g , 2.95  mmol ) , and dmap ( 0.036  g , 0.295  mmol ) in anhydrous pyridine ( 5  ml ) . column chromatography with a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as an eluent yielded 12  h as a white solid ( 0.55  g , 33  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : = 9.73 ( bs , 1  h , nh ) , 8.43 ( d , j=7.5  hz , 1  h , h6 ) , 7.497.47 ( m , 2  h , hph ) , 7.387.29 ( m , 7  h , hph ) , 7.21 ( d , j=7.5  hz , h5 ) , 6.906.88 ( m , 4  h , hph ) , 6.37 ( dd , j=5.5 , 2.0  hz , 1  h , h1 ) , 5.34 ( t , j=5.0  hz , 1  h , h4 ) , 3.84 ( s , 6  h , och 
 3 ) , 3.68 ( dd , j=12.5 , 2.5  hz , 1  h , h5a ) , 3.643.60 ( m , 2  h , h5b and h2a ) , 3.29 ( d , j=12.5  hz , h2b ) , 2.27  ppm ( s , 3  h , ch 
 3 ) ; c  nmr ( 125  mhz , 25  c , cdcl , ) : =170.5 ( coch3 ) , 163.0 ( c2 ) , 158.7 ( ch3ocph ) , 154.9 ( c4 ) , 145.7 ( c5 ) , 145.3 ( cph ) , 135.3 , 135.1 ( cph ) , 128.4 , 128.1 , 113.7 , ( chph ) , 87.9 ( c5 ) , 87.6 ( ch1 ) , 87.3 ( c(ph)3 ) , 63.5 ( ch25 ) , 55.3 ( och3 ) , 39.7 ( ch22 ) , 24.9  ppm ( coch3 ) ; ms ( es+ ) found : m / z 596.2 [ m+na ] , calcd for [ c31h31n3o6s ] : m / z 573.1974 [ m ] ; reversephase hplc ( h2o / ch3cn from 80:20 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=21.59  min . 
 5otrityl5iodo2deoxyuridine ( 14 d ) was prepared according to the general procedure 1 from 5iodo2deoxyuridine ( 14 ) ( 0.5  g , 1.41  mmol ) , trityl chloride ( 1.26  g , 4.52  mmol ) , and dmap ( 0.172  g , 1.41  mmol ) in anhydrous pyridine ( 10  ml ) . column chromatography eluting with a gradient of meoh ( 1  % to 4  % ) in ch2cl2 gave 5otrityl5iodo2deoxyuridine ( 14  d ) as a white solid ( 0.46  g , 55  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : =9.34 ( bs , 1  h , nh ) , 8.16 ( s , 1  h , h6 ) , 7.477.46 ( m , 6  h , hph ) , 7.367.33 ( m , 6  h , hph ) , 7.297.26 ( m , 3  h , hph ) , 6.34 ( dd , j=6.0 , 8.0  hz , 1  h , h1 ) , 4.584.57 ( m , 1  h , h3 ) , 4.154.13 ( m , 1  h , h4 ) , 3.453.39 ( m , 2  h , h5 ) , 2.562.52 ( m , 1  h , h2a ) , 2.322.28  ppm ( m , 1  h , h2b ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =160.0 ( c2 ) , 149.7 ( c4 ) , 144.2 ( c6 ) , 143.3 ( cph ) , 128.6 , 128.1 , 127.4 ( chph ) , 88.3 ( c5 ) , 87.7 ( c(ph)3 ) , 86.3 ( c4 ) , 85.5 ( c1 ) , 72.3 ( c3 ) , 63.6 ( c5 ) , 49.5  ppm ( c2 ) ; ms ( es+ ) found : m / z 619.2 [ m+na ] , calcd for [ c28h25in2o5 ] m / z 596.4130 [ m ] ; reversephase hplc ( h2o / ch3cn from 80:20 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=20.71  min . dimethoxytritylated derivatives of 5fluoro2deoxyuridine ( 15 ) were prepared according to the general procedure 1 from 15 ( 0.30  g , 1.22  mmol ) and 4,4dimethoxytrityl chloride ( 0.90  g , 2.68  mmol ) in pyridine ( 6  ml ) . column chromatography purification using gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as an eluent followed by preparative tlc purification with meoh / triethylamine ( 2:0.5  % ) in ch2cl2 yielded 5,3bisodimethoxytrityl5fluoro2deoxyuridine ( 15  f ) and 5odimethoxytrityl5fluoro2deoxyuridine ( 15  h ) . h ) was obtained as a yellowish solid ( 0.135  g , 20  % ) ; h  nmr ( 500  mhz , 25  c , meod ) : =7.92 ( d , j 
 hf=6.5  hz , 1  h , h6 ) , 7.45 ( dd , j=9.0 , 1.5  hz , 2  h , hph ) , 7.357.29 ( m , 6  h , hph ) , 7.257.23 ( m , 1  h , hph ) , 6.896.87 ( m , 4  h , hph ) , 6.256.22 ( m , 1  h , h1 ) , 4.524.49 ( m , 1  h , h3 ) , 4.054.03 ( m , 1  h , h4 ) , 3.80 ( s , 6  h , 2 x och 
 3 ) , 3.42 ( dd , j=10.5 , 4.0  hz , 1  h , h5 ) , 3.35 ( dd , j=10.5 , 4.0  hz , 1  h , h5 ) , 2.432.38 ( m , 1  h , h2 ) , 2.352.29  ppm ( m , 1  h , h2 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =160.6 ( c2 ) , 158.7 ( ch3ocph ) , 156.7 ( c4 ) , 144.8 ( cph ) , 143.4 ( d , 
 j 
 cf=239.5  hz , c5 ) , 129.8 , 128.8 , ( chph ) , 124.3 ( d , 
 j 
 cf=32.8  hz , c6 ) , 113.7 ( chph ) , 88.7 ( c(ph)3 ) , 87.8 ( c1 ) , 87.0 ( c4 ) , 72.3 ( c3 ) , 63.9 ( c5 ) , 55.3 ( och3 ) , 40.7  ppm ( c2 ) ; ms ( es+ ) found : m / z 571.6 [ m+na ] , calcd for [ c30h29fn2o7 ] : m / z 548.55 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=18.44  min . tritylated derivatives of 2fluoro2deoxyuridine ( 16 ) were prepared according to the general procedure 1 from 16 ( 0.50  g , 2.03  mmol ) and trityl chloride ( 1.60  g , 5.69  mmol ) in anhydrous pyridine ( 10  ml ) . after workup , the crude sample was purified by column chromatography using gradient of meoh / triethylamine ( 1:0.5  % to 2.5:0.5  % ) in ch2cl2 to give 5,3bisotrityl2fluoro2deoxyuridine 16  b and 5otrityl2fluoro2deoxyuridine 16  d. 
 5otrityl2fluoro2deoxyuridine ( 16  d ) was obtained as a white solid ( 0.79  g , 80  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso ) : =11.43 ( bs , 1  h , nh ) , 7.77 ( d , j=8.1  hz , 1  h , h6 ) , 7.417.29 ( m , 15  h , hph ) , 5.915.87 ( m , 1  h , h1 ) , 5.705.69 ( m , 1  h , oh3 ) , 5.31 ( d , j=8.1  hz , 1  h , h5 ) , 5.185.07 ( m , 1  h , h2 ) , 4.414.32 ( m , 1  h , h3 ) , 4.034.00 ( m , 1  h , h4 ) , 3.343.28  ppm ( m , 2  h , h5 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso ) : =163.1 ( c4 ) , 150.0 ( c2 ) , 143.3 ( ipso cph ) , 140.8 ( c6 ) , 128.3 , 127.9 , 127.2 ( chph ) , 101.4 ( c5 ) , 93.4 ( d , j 
 cf=184.5  hz , c2 ) , 88.6 ( d , j 
 cf=35.7  hz , c1 ) , 86.3 ( c(ph)3 ) , 80.8 ( c4 ) , 67.9 ( d , j 
 cf=16.6  hz , c3 ) , 62.2  ppm ( c5 ) ; f  nmr ( [ d6]dmso , 470  mhz ) : =199.47  ppm ; ms ( es+ ) found : m / z 511.14 [ m+na ] , calcd for [ c28h25fn2o5 ] : m / z 488.51 [ m ] ; reversephase hplc ( h2o / ch3cn from 50:50 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=6.35  min . dimethoxytritylated derivatives of 2fluoro2deoxyuridine ( 16 ) were prepared according to the general procedure 1 from 16 ( 0.200  g , 0.81  mmol ) , 4,4dimethoxytrityl chloride ( 0.769  g , 2.27  mmol ) , and dmap ( 0.278  g , 2.27  mmol ) in anhydrous pyridine ( 10  ml ) . after workup , the crude sample was purified by column chromatography using gradient of meoh / triethylamine ( 1:0.5  % to 2.5:0.5  % ) in ch2cl2 to give 5,3bisodimethoxytrityl2fluoro2deoxyuridine ( 16  f ) and 5odimethoxytrityl2fluoro2deoxyuridine ( 16  h ) . h ) was obtained as a white solid ( 0.053  g , 12  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) :  
 = 7.91 ( d , j=8.5  hz , 1  h , h6 ) , 7.417.38 ( m , 2  h , ar ) , 7.357.25 ( m , 8  h , hph ) , 6.896.85 ( m , 3  h , hph ) , 6.09 ( dd , j=16.5 , 1.5  hz , 1  h , h1 ) , 5.36 ( d , j=8.5  hz , 1  h , h5 ) , 5.05 ( dddd , j=52.5 , 4.5 , 1.5  hz , 1  h , h2 ) , 4.55 ( dddd , j=20.0 , 8.0 , 4.0 , hz , 1  h , h3 ) , 4.134.08 ( m , 1  h , h4 ) , 3.83 ( s , 3  h , och 
 3 ) , 3.82 ( s , 3  h , och 
 3 ) , 3.66 ( dd , j=11.5 , 2.5  hz , 1  h , h5 ) , 3.55  ppm ( dd , j=11.5 , 2.5  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =162.4 ( c2 ) , 158.8 , 158.7 ( ch3ocph ) , 149.7 ( c4 ) , 144.2 ( cph ) , 139.8 ( c6 ) , 135.1 , 135.0 ( cph ) , 130.2 , 130.1 , 128.2 , 128.1 , 127.2 , 113.4 ( chph ) , 102.5 ( c5 ) , 93.9 ( d , 
 j 
 cf=185.7  hz , c2 ) , 87.6 ( d , 
 j 
 cf=33.6  hz , c1 ) , 82.3 ( c4 ) , 87.0 ( c(ph)3 ) , 69.1 ( d , 
 j 
 cf=17.0  hz , c3 ) , 61.1 ( c5 ) , 55.3  ppm ( och3 ) ; ms ( es+ ) found : m / z : 571.2 [ m+na ] , calcd for [ c30h29fn2o7 ] : m / z 548.56 [ m ] ; reversephase hplc ( h2o / ch3cn from 80:20 to 10:90 in 15  min , then to ch3cn 100  % in 25  min , flow=1  ml  min , =245  nm , t 
 r=11.64  min . tritylated derivatives of 5methyluridine ( 19 ) were prepared according to general procedure 1 from 19 ( 0.50  g , 1.94  mmol ) and trityl chloride ( 1.50  g , 5.42  mmol ) in anhydrous pyridine ( 8.0  ml ) . column chromatography using a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as eluent yielded 5,3bisotrityl5methyluridine ( 19  b ) , 5,2bisotrityl5methyluridine ( 19  c ) and 5otrityl5methyluridine ( 19  d ) . d ) was obtained as a white solid ( 0.36  g , 37  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso ) : =11.38 ( bs , 1  h , nh ) , 7.507.27 ( m , 16  h , hph , h6 ) , 5.81 ( d , j=5.2  hz , 1  h , h1 ) , 5.49 ( d , j=5.7  hz , 1  h , oh2 ) , 5.19 ( d , j=5.6  hz , 1  h , oh3 ) , 4.214.17 ( m , 1  h , h2 ) , 4.144.11 ( m , 1  h , h3 ) , 3.983.96 ( m , 1  h , h4 ) , 3.283.16 ( m , 2  h , h5 ) , 1.44  ppm ( d , j=1.1  hz , 3  h , ch 
 3 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso ) : =163.6 ( c4 ) , 150.6 ( c2 ) , 143.4 (  ipso cph ) , 135.8 ( c6 ) , 128.2 , 128.0 , 127.1 ( chph ) , 109.4 ( c5 ) , 88.0 ( c1 ) , 86.4 ( c(ph)3 ) , 82.7 ( c4 ) , 73.0 ( c2 ) , 70.0 ( c3 ) , 63.7 ( c5 ) , 11.6  ppm ( ch3 ) ; ms ( es+ ) found : m / z 523.16 [ m+na ] , calcd for [ c29h28n2o6 ] : m / z 500.54 [ m ] ; reversephase hplc ( h2o / ch3cn from 95:5 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=20.36  min . tritylated derivatives of fludarabine ( 20 ) were prepared according to the standard procedure 1 from 20 ( 0.30  g , 1.05  mmol ) and trityl chloride ( 0.64  g , 2.31  mmol ) in pyridine ( 6  ml ) . column chromatography purification using a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as eluent gave two products which were further repurified by preparative tlc with meoh / triethylamine ( 2:0.5  % ) in ch2cl2 to yield 5 , 3bisotritylfludarabine ( 20  b ) and 5o , ntritylfludarabine ( 20  dnhtr ) . 
 5biso , n 
 tritylfludarabine ( 20  dnhtr ) was obtained as a white solid ( 0.05  g , 6  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : =8.16 ( s , 1  h , h8 ) , 7.457.33 ( m , 8  h , hph ) , 7.387.36 ( m , 8  h , hph ) , 7.387.36 ( m , 14  h , hph ) , 6.18 ( d , j=3.5  hz , 1  h , h1 ) , 4.36 ( apparent broad d , j=2.5  hz , 1  h , h3 ) , 4.254.20 ( m , 2  h , h2 , nh ) , 4.05 ( q , j=3.5  hz , 1  h , h4 ) , 3.89 ( bs , 1  h , 3oh ) , 3.62 ( dd , j=11.0 , 3.0  hz , 1  h , h5 ) , 3.42  ppm ( dd , j=11.0 , 3.0  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =159.9 ( 
 j 
 cf=209.0  hz , c2 ) , 155.7 ( 
 j 
 cf=20.8  hz , c6 ) , 149.3 ( 
 j 
 cf=18.0  hz , c4 ) , 144.2 , 142.9 ( cph ) , 140.1 ( ch8 ) , 129.0 , 128.6 , 128.1 , 127.9 , 127.5 , 127.1 ( chph ) , 118.8 ( 
 j 
 cf=3.8  hz , c5 ) , 88.2 , 88.1 ( c(ph)3 ) , 85.1 ( c1 ) , 83.0 ( c4 ) , 76.7 ( c3 ) , 76.6 ( c2 ) , 63.6  ppm ( c5 ) ; f  nmr ( 470  mhz , 25  c , cdcl3 ) : =49.84 ; ms ( es+ ) found : m / z 792.3 [ m+na ] , calcd for [ c48h40fn5o4 ] : m / z 769.86 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=27.40  min . tritylated derivatives of thymidine ( 21 ) were prepared according to the general procedure 1 from 21 ( 0.30  g , 1.24  mmol ) and trityl chloride ( 0.75  g , 2.72  mmol ) in pyridine ( 6  ml ) . column chromatography using a gradient of meoh / triethylamine ( 1:0.5  % to 3:0.5  % ) in ch2cl2 as an eluent gave 5,3bisotritylthymidine ( 21  b ) and 5otritylthymidine ( 1 ) . b ) was obtained as a white solid ( 0.147  g , 16  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : =7.53 ( d , j=1.0  hz , 1  h , h6 ) , 7.417.39 ( m , 6  h , hph ) , 7.277.23 ( m , 24  h , hph ) , 6.47 ( t , j=7.5  hz , 1  h , h1 ) , 4.454.42 ( m , 1  h , h3 ) , 3.873.85 ( m , 1  h , h4 ) , 3.24 ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) , 2.86 ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) , 1.971.94 ( m , 2  h , h2 ) , 1.41  ppm ( d , j=1.0  hz , 3  h , ch 
 3 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =163.3 ( c = o , c2 ) , 150.1 ( c = o , c4 ) , 144.0 , 143.3 ( cph ) , 135.8 ( c6 ) , 129.0 , 128.7 , 128.5 , 128.2 , 128.0 , 127.9 , 127.4 , 127.3 , 125.3 ( chph ) , 111.0 ( c5 ) , 87.8 , 87.4 ( c(ph)3 ) , 85.4 ( c4 ) , 84.9 ( c1 ) , 75.4 ( c3 ) , 63.8 ( c5 ) , 39.7 ( c2 ) , 11.7  ppm ( ch3 ) ; ms ( es+ ) found : m / z 749.38 [ m+na ] , calcd for [ c48h42n2o5 ] : m / z 726.85 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=24.56  min . 5otritylthymidine ( 1 ) was obtained as a white solid ( 0.19  g , 33  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso ) : =7.50 ( d , j=1.0  hz , 1  h , h6 ) , 7.417.38 ( m , 6  h , hph ) , 7.367.33 ( m , 6  h , hph ) , 7.307.26 ( m , 3  h , hph ) , 6.21 ( t , j=6.5  hz , 1  h , h1 ) , 5.30 ( d , j=4.5  hz , c3oh ) , 4.354.31 ( m , 1  h , h3 ) , 3.903.88 ( m , 1  h , h4 ) , 3.24 ( dd , j=10.5 , 3.0  hz , 1  h , h5 ) , 3.17 ( dd , j=10.5 , 3.0  hz , 1  h , h5 ) , 2.29 2.23 ( m , 1  h , h2 ) , 2.182.13 ( m , 1  h , h2 ) , 1.47  ppm ( d , j=1.0  hz , 3  h , ch 
 3 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso ) : =163.6 ( c = o , c2 ) , 150.3 ( c = o , c4 ) , 143.4 , ( cph ) , 135.6 ( c6 ) , 128.2 , 127.9 , 127.1 ( chph ) , 109.5 ( c5 ) , 86.3 ( c(ph)3 ) , 85.3 ( c4 ) , 83.6 ( c1 ) , 70.4 ( c3 ) , 63.9 ( c5 ) , 40.0 ( c2 ) , 11.7  ppm ( ch3 ) ; ms ( es+ ) found : m / z 507.54 [ m+na ] , calcd for [ c29h28n2o5 ] : m / z 484.54 [ m ] ; reversephase hplc ( h2o / ch3cn 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=6.29  min . tritylated derivatives of penciclovir ( 22 ) were prepared according to general procedure 1 from 22 ( 0.57  g , 2.25  mmol ) and trityl chloride ( 1.86  g , 6.75  mmol ) in anhydrous pyridine ( 10  ml ) . column chromatography eluting using a gradient of meoh / triethylamine ( 1:0.5  % to 3:0.5  % ) in ch2cl2 yielded 5,3bisotritylpenciclovir ( 22  b ) and 2n,5,3otritrityl penciclovir ( 22  bnhtr ) . 2n5,3otritrityl penciclovir ( 22  bnhtr ) was obtained as a white solid ( 0.47  g , 21  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso ) : =10.51 ( bs , 1  h , nh ) , 7.26 ( s , 1  h , h8 ) , 7.317.28 ( m , 31  h , hph , nh ) , 7.197.17 ( m , 6  h , hph ) , 7.077.04 ( m , 6  h , hph ) , 6.976.96 ( m , 3  h , hph ) , 3.243.21 ( m , 2  h , h1 ) , 2.912.85 ( m , 4  h , h4 , h5 ) , 1.621.58 ( m , 1  h , h3 ) , 1.131.09  ppm ( m , 2  h , h2 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso ) : =156.5 ( c6 ) , 150.3 ( c2 ) , 149.3 ( c4 ) , 144.6 , 143.8 (  ipso cph ) , 137.2 ( c8 ) , 128.7 , 128.4 , 128.1 , 127.8 , 127.4 , 126.9 , 126.3 ( chph ) , 117.0 ( c5 ) , 85.8 ( c(ph)3 ) , 62.7 ( c4 , c5 ) , 41.3 ( c1 ) , 37.3 ( c3 ) , 28.4  ppm ( c2 ) ; ms ( es+ ) found : m / z 1003.39 [ m+na ] , calcd for [ c67h57n5o3 ] m / z : 980.20 [ m ] ; reversephase hplc ( h2o / ch3cn from 50:50 to 0:100 in 40  min ) , flow=1  ml  min , =254  nm , t 
 r=36.64  min . antiviral assay : trityl compounds were prepared as stock solution of 100  mm in dimethyl sulfoxide ( dmso ) and then were diluted to a final assay concentration of 20 , 10 , 5  m . dilutions were made by adding the appropriate amount of dmso to lyophilized compound to achieve stock concentrations of 10 to 100  mm . dissolved compounds were stored at 20  c and brought to rt prior to assay . all compounds were well dissolved in dmso , and precipitates were not observed upon thawing . 
 cell culture : vero cells were grown in dulbeccos modified eagles medium ( dmem , sigmaaldrich ) with 10  % fbs ( sigmaaldrich ) . cells were plated into 96well plates at a density of 10 cells per well . virus culture : cells were then infected with dengue virus ( serotype d2 ( strain new guinea c ) , atcc number : vr1584 ) , and yellow fever vaccine ( 17  d strain asibi ; grown from a dose of sanofi pasteur stamaril ( 1000iu from embryonated chicken eggs ) and adapted to vero cells ( farleigh and bugert , 2014 , unpublished results ) at a moi of 1 , or left uninfected to determine compound toxicity . 
 cell viability was determined after seven days using celltiterglo promega , following the manufacturer 's instructions . the h and c  nmr spectra were recorded on a bruker spectrometer ( billerica , ma , usa ) operating at 500  mhz for h and 125  mhz for c. cdcl3 was used as the solvent for nmr experiments , unless otherwise stated . h chemical shift values (  ) are referenced to the residual nondeuterated components of the nmr solvents ( =7.26  ppm for chcl3 , etc . ) . the c chemical shifts (  ) column chromatography was performed using silica gel ( 3575  mesh ) or on an isolera biotage system ( uppsala , sweden ) . purity of prepared compounds was determined to be>95  % by highperformance liquid chromatography ( hplc)uv analysis ( thermo hplc connected with uv detector ; varian pursuit xs , 4.6  mm150  mm , 5.0  m , palo alto , ca , usa ) . a mixture of a nucleoside ( 1.0  eq  mol ) , an appropriate trityl chloride ( 2.2  eq  mol ) , and 4dimethylaminopyridine ( dmap , 2.8  mol  eq , unless stated otherwise ) in anhydrous pyridine ( 4.5  ml  mmol ) was heated at 80  c under an argon atmosphere for 18  h. the reaction was quenched by addition of meoh ( 2  ml  mmol ) at rt , and kept stirring at rt for 30  min . the organic solution was washed with saturated solution of nahco3 ( 320  ml ) , and the combined aqueous layers were extracted with ch2cl2 . the residue was purified by column chromatography on silica gel ( eluent system gradient meoh in ch2cl2=13  % containing 0.5  % triethylamine ) . experimental data for all active compounds are reported below and for inactive compounds in the supporting information . tritylated derivatives of ribavirin ( 5 ) were prepared according to the general procedure 1 from 5 ( 0.500  g , 2.05  mmol ) and trityl chloride ( 1.6  g , 5.74  mmol ) . column purification with a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as eluent yielded 5,3,2triotritylribavirin ( 5  a ) , 5,3bisotritylribavirin ( 5  b ) and 5,2bisotritylribavirin ( 5  c ) . b ) was obtained as a white solid ( 0.268  g , 18  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) :  
 = 8.21 ( s , 1  h , h3 ) , 7.437.38 ( m , 6  h , hph ) , 7.347.18 ( m , 24  h , hph ) , 6.64 ( br s , 1  h , nh 
 2 ) , 5.89 ( d , j=3.08  hz , 1  h , h1 ) , 5.66 ( br s , 1  h , nh 
 2 ) , 4.434.39 ( m , 1  h , h3 ) , 4.194.14 ( m , 1  h , h4 ) , 3.613.56 ( m , 1  h , h2 ) , 3.473.43 ( m , 1  h , h5 ) , 3.00 ( dd , j=10.9 , 5.5  hz , 1  h , h5 ) , 2.85  ppm ( d , j=4.5  hz , 1  h , oh2 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =160.4 ( c = o ) , 156.9 ( c5 ) , 144.1 ( c3 ) , 143.5 , 143.3 ( cph ) , 128.7 , 128.6 , 128.3 , 127.8 , 127.1 ( chph ) , 92.4 ( c1 ) , 88.1 , 87.1 ( c(ph)3 ) , 83.5 ( c4 ) , 74.3 ( c2 ) , 74.1 ( c3 ) , 64.0  ppm ( c5 ) ; ms ( es+ ) found : m / z 751.3 [ m+na ] , calcd for [ c46h40n4o5 ] : m / z 728.83 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=28.10  min . tritylated derivatives of 5fluorouridine ( 6 ) were prepared according to the general procedure 1 from 6 ( 0.30  g , 1.14  mmol ) and trityl chloride ( 1.02  g , 3.66  mmol ) in pyridine ( 6  ml ) . column chromatography purification using a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as an eluent yielded 5,3bisotrityl5fluorouridine ( 6  b ) , 5,2bisotrityl5fluorouridine ( 6  c ) , and 5otrityl5fluorouridine ( 6  d ) . d ) was obtained as a white solid ( 0.183  g , 32  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 , ) : =7.42 ( d , j 
 hf=6.0  hz , 1  h , h6 ) , 7.227.20 ( m , 6  h , hph ) , 7.057.02 ( m , 6  h , hph ) , 6.986.95 ( m , 6  h , hph ) , 5.72 ( dd , j=4.5 , 1.5  hz , 1  h , h1 ) , 4.04 ( t , j=5.0  hz , 1  h , h3 ) , 3.96 ( t , j=5.0  hz , 1  h , h2 ) , 3.903.87 ( m , 1  h , h4 ) , 3.30 ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) , 3.25  ppm ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso , ) : =161.0 ( d , j 
 cf=22.5  hz , c2 ) , 152.7 ( c4 ) , 144.4 ( d , j 
 cf=241.5  hz , c5 ) , 143.3 ( cph ) , 128.6 , 128.3 , 127.3 ( chph ) , 123.4 ( d , j 
 cf=33.75  hz , c6 ) , 90.1 ( c1 ) , 87.5 ( c(ph)3 ) , 84.4 ( c4 ) , 75.8 ( c2 ) , 71.0 ( c3 ) , 63.2  ppm ( c5 ) ; ms ( es+ ) found : m / z 527.10 [ m+na ] , calcd for [ c28h25fn2o6 ] : m / z 504.50 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=17.52  min . dimethoxytritylated derivatives of 5fluorouridine ( 6 ) were prepared according to the general procedure 1 from 6 ( 0.30  g , 1.14  mmol ) and 4,4dimethoxytrityl chloride ( 1.24  g , 3.66  mmol , 3.2  equiv / mol ) in pyridine ( 6  ml ) . column chromatography purification using a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as an eluent yielded three products , which were further repurified by preparative tlc using meoh / triethylamine ( 2:0.5  % ) in ch2cl2 to yield : 5,3bisodimethoxytrityl5fluorouridine ( 6  f ) , 5,2bisodimethoxytrityl5fluorouridine ( 6  g ) , and 5odimethoxytrityl5fluorouridine ( 6  h ) . h ) was obtained as a yellowish solid ( 0.17  g , 26  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso , ) : =7.91 ( d , j 
 hf=7.0  hz , 1  h , h6 ) , 7.40 ( dd , j=8.5 , 2.5  hz , 2  h , hph ) , 7.337.23 ( m , 7  h , hph ) , 6.90 ( apparent d , j=8.5  hz , 4  h , hph ) , 5.73 ( dd , j=4.0 , 1.5  hz , 1  h , h1 ) , 5.48 ( d , j=5.0  hz , 1  h , c2oh ) , 5.14 ( d , j=5.0  hz , 1  h , c3oh ) , 4.14 ( apparent q , j=5.0  hz , 1  h , h2 ) , 4.08 ( apparent q , j=5.0  hz , 1  h , h3 ) , 3.983.96 ( m , 1  h , h4 ) , 3.75 ( s , 6  h , 2 x och 3 ) , 3.29 ( dd , j=11.0 , 3.5  hz , 1  h , h5 ) , 3.19  ppm ( dd , j=11.0 , 3.5  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso , ) : =158.2 , 158.1 ( ch3ocph ) , 156.9 ( d , 
 j 
 cf=26.0  hz , c4 ) , 149.8 ( c2 ) , 144.7 ( cph ) , 139.9 ( d , 
 j 
 cf=230.5  hz , c5 ) , 135.4 , 135.2 ( cph ) , 129.7 , 128.9 , 128.2 , 127.9 , 127.6 , 126.7 , 125.3 ( chph ) , 124.6 ( d , 
 j 
 cf=33.8  hz , c6 ) , 113.3 , 113.2 ( chph ) , 89.0 ( c1 ) , 85.8 ( c(ph)3 ) , 82.6 ( c4 ) , 73.2 ( c2 ) , 69.5 ( c3 ) , 63.1 ( c5 ) , 55.0  ppm ( och3 ) ; f  nmr ( 470  mhz , 25  c , [ d6]dmso , ) : =167.25  ppm ; ms ( es+ ) found : m / z 587 [ m+na ] , calcd for [ c30h29fn2o8 ] : m / z 564.55 [ m ] ; reversephase hplc ( h2o / ch3cn 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=14.85  min . dimethoxytritylated derivatives of uridine ( 9 ) were prepared according to the general procedure 1 from 9 ( 0.150  g , 0.61  mmol ) , 4,4dimethoxytrityl chloride ( 0.578  g , 1.71  mmol ) , and dmap ( 0.209  g , 1.71  mmol ) in anhydrous pyridine ( 10  ml ) . column chromatography eluting with a gradient of meoh / triethylamine ( 1:0.5  % to 3.5:0.5  % ) in ch2cl2 as an eluent gave 5,2bisodimethoxytrityluridine ( 9  g ) and 5dimethoxytrityluridine ( 9  h ) . 5odimethoxytrityluridine ( 9  h ) was obtained as a yellowish solid ( 0.16  g , 48  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : =8.01 ( d , j=8.0  hz , h6 ) , 7.437.38 ( m , 2  h , hph ) , 7.337.28 ( m , 6  h , hph ) , 7.267.22 ( m , 1  h , hph ) , 6.896.82 ( m , 4  h , hph ) , 5.92 ( d , j=2.5  hz , h1 ) , 5.38 ( d , j=8.0  hz , h5 ) , 4.44 ( dd , j=6.0 , 5.5  hz , h3 ) , 4.36 ( dd , j=5.0 , 2.5  hz , h2 ) , 4.224.18 ( m , 1  h , h4 ) , 3.80 ( s , 3  h , och 
 3 ) , 3.79 ( s , 3  h , och 
 3 ) , 3.55 ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) , 3.50  ppm ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =163.7 ( c2 ) , 158.7 , 158.6 ( ch3ocph ) 151.1 ( c4 ) , 144.4 ( cph ) , 140.3 ( c6 ) , 135.5 ( cph ) , 135.2 ( cph ) , 130.3 , 130.2 , 130.1 , 129.2 , 128.1 , 127.9 , 127.8 , 127.1 , 113.4 , 113.3 , 113.2 ( chph ) , 102.3 ( c5 ) , 90.6 ( c1 ) , 83.8 ( c4 ) , 87.0 ( c(ph)3 ) , 75.5 ( c2 ) , 69.7 ( c3 ) , 61.9 ( c5 ) , 55.2  ppm ( och3 ) ; ms ( es+ ) found : m / z 569.2 [ m+na ] , calcd for [ c30h30n2o8 ] : m / z 546.57 [ m ] ; reversephase hplc ( h2o / ch3cn from 80:20 to 10:90 in 15  min , then to ch3cn 100  % in 25  min ) , flow=1  ml  min , =245  nm , t 
 r=10.56  min . h ) was prepared according to the general procedure 1 from nacetyllamivudine ( 12 ) ( 0.80  g , 2.95  mmol ) , 4,4dimethoxytrityl chloride ( 1.2  g , 2.95  mmol ) , and dmap ( 0.036  g , 0.295  mmol ) in anhydrous pyridine ( 5  ml ) . column chromatography with a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as an eluent yielded 12  h as a white solid ( 0.55  g , 33  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : = 9.73 ( bs , 1  h , nh ) , 8.43 ( d , j=7.5  hz , 1  h , h6 ) , 7.497.47 ( m , 2  h , hph ) , 7.387.29 ( m , 7  h , hph ) , 7.21 ( d , j=7.5  hz , h5 ) , 6.906.88 ( m , 4  h , hph ) , 6.37 ( dd , j=5.5 , 2.0  hz , 1  h , h1 ) , 5.34 ( t , j=5.0  hz , 1  h , h4 ) , 3.84 ( s , 6  h , och 
 3 ) , 3.68 ( dd , j=12.5 , 2.5  hz , 1  h , h5a ) , 3.643.60 ( m , 2  h , h5b and h2a ) , 3.29 ( d , j=12.5  hz , h2b ) , 2.27  ppm ( s , 3  h , ch 
 3 ) ; c  nmr ( 125  mhz , 25  c , cdcl , ) : =170.5 ( coch3 ) , 163.0 ( c2 ) , 158.7 ( ch3ocph ) , 154.9 ( c4 ) , 145.7 ( c5 ) , 145.3 ( cph ) , 135.3 , 135.1 ( cph ) , 128.4 , 128.1 , 113.7 , ( chph ) , 87.9 ( c5 ) , 87.6 ( ch1 ) , 87.3 ( c(ph)3 ) , 63.5 ( ch25 ) , 55.3 ( och3 ) , 39.7 ( ch22 ) , 24.9  ppm ( coch3 ) ; ms ( es+ ) found : m / z 596.2 [ m+na ] , calcd for [ c31h31n3o6s ] : m / z 573.1974 [ m ] ; reversephase hplc ( h2o / ch3cn from 80:20 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=21.59  min . d ) was prepared according to the general procedure 1 from 5iodo2deoxyuridine ( 14 ) ( 0.5  g , 1.41  mmol ) , trityl chloride ( 1.26  g , 4.52  mmol ) , and dmap ( 0.172  g , 1.41  mmol ) in anhydrous pyridine ( 10  ml ) . column chromatography eluting with a gradient of meoh ( 1  % to 4  % ) in ch2cl2 gave 5otrityl5iodo2deoxyuridine ( 14  d ) as a white solid ( 0.46  g , 55  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : =9.34 ( bs , 1  h , nh ) , 8.16 ( s , 1  h , h6 ) , 7.477.46 ( m , 6  h , hph ) , 7.367.33 ( m , 6  h , hph ) , 7.297.26 ( m , 3  h , hph ) , 6.34 ( dd , j=6.0 , 8.0  hz , 1  h , h1 ) , 4.584.57 ( m , 1  h , h3 ) , 4.154.13 ( m , 1  h , h4 ) , 3.453.39 ( m , 2  h , h5 ) , 2.562.52 ( m , 1  h , h2a ) , 2.322.28  ppm ( m , 1  h , h2b ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =160.0 ( c2 ) , 149.7 ( c4 ) , 144.2 ( c6 ) , 143.3 ( cph ) , 128.6 , 128.1 , 127.4 ( chph ) , 88.3 ( c5 ) , 87.7 ( c(ph)3 ) , 86.3 ( c4 ) , 85.5 ( c1 ) , 72.3 ( c3 ) , 63.6 ( c5 ) , 49.5  ppm ( c2 ) ; ms ( es+ ) found : m / z 619.2 [ m+na ] , calcd for [ c28h25in2o5 ] m / z 596.4130 [ m ] ; reversephase hplc ( h2o / ch3cn from 80:20 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=20.71  min . dimethoxytritylated derivatives of 5fluoro2deoxyuridine ( 15 ) were prepared according to the general procedure 1 from 15 ( 0.30  g , 1.22  mmol ) and 4,4dimethoxytrityl chloride ( 0.90  g , 2.68  mmol ) in pyridine ( 6  ml ) . column chromatography purification using gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as an eluent followed by preparative tlc purification with meoh / triethylamine ( 2:0.5  % ) in ch2cl2 yielded 5,3bisodimethoxytrityl5fluoro2deoxyuridine ( 15  f ) and 5odimethoxytrityl5fluoro2deoxyuridine ( 15  h ) . h ) was obtained as a yellowish solid ( 0.135  g , 20  % ) ; h  nmr ( 500  mhz , 25  c , meod ) : =7.92 ( d , j 
 hf=6.5  hz , 1  h , h6 ) , 7.45 ( dd , j=9.0 , 1.5  hz , 2  h , hph ) , 7.357.29 ( m , 6  h , hph ) , 7.257.23 ( m , 1  h , hph ) , 6.896.87 ( m , 4  h , hph ) , 6.256.22 ( m , 1  h , h1 ) , 4.524.49 ( m , 1  h , h3 ) , 4.054.03 ( m , 1  h , h4 ) , 3.80 ( s , 6  h , 2 x och 
 3 ) , 3.42 ( dd , j=10.5 , 4.0  hz , 1  h , h5 ) , 3.35 ( dd , j=10.5 , 4.0  hz , 1  h , h5 ) , 2.432.38 ( m , 1  h , h2 ) , 2.352.29  ppm ( m , 1  h , h2 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =160.6 ( c2 ) , 158.7 ( ch3ocph ) , 156.7 ( c4 ) , 144.8 ( cph ) , 143.4 ( d , 
 j 
 cf=239.5  hz , c5 ) , 129.8 , 128.8 , ( chph ) , 124.3 ( d , 
 j 
 cf=32.8  hz , c6 ) , 113.7 ( chph ) , 88.7 ( c(ph)3 ) , 87.8 ( c1 ) , 87.0 ( c4 ) , 72.3 ( c3 ) , 63.9 ( c5 ) , 55.3 ( och3 ) , 40.7  ppm ( c2 ) ; ms ( es+ ) found : m / z 571.6 [ m+na ] , calcd for [ c30h29fn2o7 ] : m / z 548.55 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=18.44  min . tritylated derivatives of 2fluoro2deoxyuridine ( 16 ) were prepared according to the general procedure 1 from 16 ( 0.50  g , 2.03  mmol ) and trityl chloride ( 1.60  g , 5.69  mmol ) in anhydrous pyridine ( 10  ml ) . after workup , the crude sample was purified by column chromatography using gradient of meoh / triethylamine ( 1:0.5  % to 2.5:0.5  % ) in ch2cl2 to give 5,3bisotrityl2fluoro2deoxyuridine 16  b and 5otrityl2fluoro2deoxyuridine 16  d. 
 5otrityl2fluoro2deoxyuridine ( 16  d ) was obtained as a white solid ( 0.79  g , 80  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso ) : =11.43 ( bs , 1  h , nh ) , 7.77 ( d , j=8.1  hz , 1  h , h6 ) , 7.417.29 ( m , 15  h , hph ) , 5.915.87 ( m , 1  h , h1 ) , 5.705.69 ( m , 1  h , oh3 ) , 5.31 ( d , j=8.1  hz , 1  h , h5 ) , 5.185.07 ( m , 1  h , h2 ) , 4.414.32 ( m , 1  h , h3 ) , 4.034.00 ( m , 1  h , h4 ) , 3.343.28  ppm ( m , 2  h , h5 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso ) : =163.1 ( c4 ) , 150.0 ( c2 ) , 143.3 ( ipso cph ) , 140.8 ( c6 ) , 128.3 , 127.9 , 127.2 ( chph ) , 101.4 ( c5 ) , 93.4 ( d , j 
 cf=184.5  hz , c2 ) , 88.6 ( d , j 
 cf=35.7  hz , c1 ) , 86.3 ( c(ph)3 ) , 80.8 ( c4 ) , 67.9 ( d , j 
 cf=16.6  hz , c3 ) , 62.2  ppm ( c5 ) ; f  nmr ( [ d6]dmso , 470  mhz ) : =199.47  ppm ; ms ( es+ ) found : m / z 511.14 [ m+na ] , calcd for [ c28h25fn2o5 ] : m / z 488.51 [ m ] ; reversephase hplc ( h2o / ch3cn from 50:50 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=6.35  min . dimethoxytritylated derivatives of 2fluoro2deoxyuridine ( 16 ) were prepared according to the general procedure 1 from 16 ( 0.200  g , 0.81  mmol ) , 4,4dimethoxytrityl chloride ( 0.769  g , 2.27  mmol ) , and dmap ( 0.278  g , 2.27  mmol ) in anhydrous pyridine ( 10  ml ) . after workup , the crude sample was purified by column chromatography using gradient of meoh / triethylamine ( 1:0.5  % to 2.5:0.5  % ) in ch2cl2 to give 5,3bisodimethoxytrityl2fluoro2deoxyuridine ( 16  f ) and 5odimethoxytrityl2fluoro2deoxyuridine ( 16  h ) . h ) was obtained as a white solid ( 0.053  g , 12  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) :  
 = 7.91 ( d , j=8.5  hz , 1  h , h6 ) , 7.417.38 ( m , 2  h , ar ) , 7.357.25 ( m , 8  h , hph ) , 6.896.85 ( m , 3  h , hph ) , 6.09 ( dd , j=16.5 , 1.5  hz , 1  h , h1 ) , 5.36 ( d , j=8.5  hz , 1  h , h5 ) , 5.05 ( dddd , j=52.5 , 4.5 , 1.5  hz , 1  h , h2 ) , 4.55 ( dddd , j=20.0 , 8.0 , 4.0 , hz , 1  h , h3 ) , 4.134.08 ( m , 1  h , h4 ) , 3.83 ( s , 3  h , och 
 3 ) , 3.82 ( s , 3  h , och 
 3 ) , 3.66 ( dd , j=11.5 , 2.5  hz , 1  h , h5 ) , 3.55  ppm ( dd , j=11.5 , 2.5  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =162.4 ( c2 ) , 158.8 , 158.7 ( ch3ocph ) , 149.7 ( c4 ) , 144.2 ( cph ) , 139.8 ( c6 ) , 135.1 , 135.0 ( cph ) , 130.2 , 130.1 , 128.2 , 128.1 , 127.2 , 113.4 ( chph ) , 102.5 ( c5 ) , 93.9 ( d , 
 j 
 cf=185.7  hz , c2 ) , 87.6 ( d , 
 j 
 cf=33.6  hz , c1 ) , 82.3 ( c4 ) , 87.0 ( c(ph)3 ) , 69.1 ( d , 
 j 
 cf=17.0  hz , c3 ) , 61.1 ( c5 ) , 55.3  ppm ( och3 ) ; ms ( es+ ) found : m / z : 571.2 [ m+na ] , calcd for [ c30h29fn2o7 ] : m / z 548.56 [ m ] ; reversephase hplc ( h2o / ch3cn from 80:20 to 10:90 in 15  min , then to ch3cn 100  % in 25  min , flow=1  ml  min , =245  nm , t 
 r=11.64  min . tritylated derivatives of 5methyluridine ( 19 ) were prepared according to general procedure 1 from 19 ( 0.50  g , 1.94  mmol ) and trityl chloride ( 1.50  g , 5.42  mmol ) in anhydrous pyridine ( 8.0  ml ) . column chromatography using a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as eluent yielded 5,3bisotrityl5methyluridine ( 19  b ) , 5,2bisotrityl5methyluridine ( 19  c ) and 5otrityl5methyluridine ( 19  d ) . d ) was obtained as a white solid ( 0.36  g , 37  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso ) : =11.38 ( bs , 1  h , nh ) , 7.507.27 ( m , 16  h , hph , h6 ) , 5.81 ( d , j=5.2  hz , 1  h , h1 ) , 5.49 ( d , j=5.7  hz , 1  h , oh2 ) , 5.19 ( d , j=5.6  hz , 1  h , oh3 ) , 4.214.17 ( m , 1  h , h2 ) , 4.144.11 ( m , 1  h , h3 ) , 3.983.96 ( m , 1  h , h4 ) , 3.283.16 ( m , 2  h , h5 ) , 1.44  ppm ( d , j=1.1  hz , 3  h , ch 
 3 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso ) : =163.6 ( c4 ) , 150.6 ( c2 ) , 143.4 (  ipso cph ) , 135.8 ( c6 ) , 128.2 , 128.0 , 127.1 ( chph ) , 109.4 ( c5 ) , 88.0 ( c1 ) , 86.4 ( c(ph)3 ) , 82.7 ( c4 ) , 73.0 ( c2 ) , 70.0 ( c3 ) , 63.7 ( c5 ) , 11.6  ppm ( ch3 ) ; ms ( es+ ) found : m / z 523.16 [ m+na ] , calcd for [ c29h28n2o6 ] : m / z 500.54 [ m ] ; reversephase hplc ( h2o / ch3cn from 95:5 to 0:100 in 30  min ) , flow=1  ml  min , =254  nm , t 
 r=20.36  min . tritylated derivatives of fludarabine ( 20 ) were prepared according to the standard procedure 1 from 20 ( 0.30  g , 1.05  mmol ) and trityl chloride ( 0.64  g , 2.31  mmol ) in pyridine ( 6  ml ) . column chromatography purification using a gradient of meoh / triethylamine ( 1:0.5  % to 2:0.5  % ) in ch2cl2 as eluent gave two products which were further repurified by preparative tlc with meoh / triethylamine ( 2:0.5  % ) in ch2cl2 to yield 5 , 3bisotritylfludarabine ( 20  b ) and 5o , ntritylfludarabine ( 20  dnhtr ) . 
 5biso , n 
 tritylfludarabine ( 20  dnhtr ) was obtained as a white solid ( 0.05  g , 6  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : =8.16 ( s , 1  h , h8 ) , 7.457.33 ( m , 8  h , hph ) , 7.387.36 ( m , 8  h , hph ) , 7.387.36 ( m , 14  h , hph ) , 6.18 ( d , j=3.5  hz , 1  h , h1 ) , 4.36 ( apparent broad d , j=2.5  hz , 1  h , h3 ) , 4.254.20 ( m , 2  h , h2 , nh ) , 4.05 ( q , j=3.5  hz , 1  h , h4 ) , 3.89 ( bs , 1  h , 3oh ) , 3.62 ( dd , j=11.0 , 3.0  hz , 1  h , h5 ) , 3.42  ppm ( dd , j=11.0 , 3.0  hz , 1  h , h5 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =159.9 ( 
 j 
 cf=209.0  hz , c2 ) , 155.7 ( 
 j 
 cf=20.8  hz , c6 ) , 149.3 ( 
 j 
 cf=18.0  hz , c4 ) , 144.2 , 142.9 ( cph ) , 140.1 ( ch8 ) , 129.0 , 128.6 , 128.1 , 127.9 , 127.5 , 127.1 ( chph ) , 118.8 ( 
 j 
 cf=3.8  hz , c5 ) , 88.2 , 88.1 ( c(ph)3 ) , 85.1 ( c1 ) , 83.0 ( c4 ) , 76.7 ( c3 ) , 76.6 ( c2 ) , 63.6  ppm ( c5 ) ; f  nmr ( 470  mhz , 25  c , cdcl3 ) : =49.84 ; ms ( es+ ) found : m / z 792.3 [ m+na ] , calcd for [ c48h40fn5o4 ] : m / z 769.86 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=27.40  min . tritylated derivatives of thymidine ( 21 ) were prepared according to the general procedure 1 from 21 ( 0.30  g , 1.24  mmol ) and trityl chloride ( 0.75  g , 2.72  mmol ) in pyridine ( 6  ml ) . column chromatography using a gradient of meoh / triethylamine ( 1:0.5  % to 3:0.5  % ) in ch2cl2 as an eluent gave 5,3bisotritylthymidine ( 21  b ) and 5otritylthymidine ( 1 ) . b ) was obtained as a white solid ( 0.147  g , 16  % ) ; h  nmr ( 500  mhz , 25  c , cdcl3 ) : =7.53 ( d , j=1.0  hz , 1  h , h6 ) , 7.417.39 ( m , 6  h , hph ) , 7.277.23 ( m , 24  h , hph ) , 6.47 ( t , j=7.5  hz , 1  h , h1 ) , 4.454.42 ( m , 1  h , h3 ) , 3.873.85 ( m , 1  h , h4 ) , 3.24 ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) , 2.86 ( dd , j=11.0 , 2.5  hz , 1  h , h5 ) , 1.971.94 ( m , 2  h , h2 ) , 1.41  ppm ( d , j=1.0  hz , 3  h , ch 
 3 ) ; c  nmr ( 125  mhz , 25  c , cdcl3 ) : =163.3 ( c = o , c2 ) , 150.1 ( c = o , c4 ) , 144.0 , 143.3 ( cph ) , 135.8 ( c6 ) , 129.0 , 128.7 , 128.5 , 128.2 , 128.0 , 127.9 , 127.4 , 127.3 , 125.3 ( chph ) , 111.0 ( c5 ) , 87.8 , 87.4 ( c(ph)3 ) , 85.4 ( c4 ) , 84.9 ( c1 ) , 75.4 ( c3 ) , 63.8 ( c5 ) , 39.7 ( c2 ) , 11.7  ppm ( ch3 ) ; ms ( es+ ) found : m / z 749.38 [ m+na ] , calcd for [ c48h42n2o5 ] : m / z 726.85 [ m ] ; reversephase hplc ( h2o / ch3cn from 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=24.56  min . 5otritylthymidine ( 1 ) was obtained as a white solid ( 0.19  g , 33  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso ) : =7.50 ( d , j=1.0  hz , 1  h , h6 ) , 7.417.38 ( m , 6  h , hph ) , 7.367.33 ( m , 6  h , hph ) , 7.307.26 ( m , 3  h , hph ) , 6.21 ( t , j=6.5  hz , 1  h , h1 ) , 5.30 ( d , j=4.5  hz , c3oh ) , 4.354.31 ( m , 1  h , h3 ) , 3.903.88 ( m , 1  h , h4 ) , 3.24 ( dd , j=10.5 , 3.0  hz , 1  h , h5 ) , 3.17 ( dd , j=10.5 , 3.0  hz , 1  h , h5 ) , 2.29 2.23 ( m , 1  h , h2 ) , 2.182.13 ( m , 1  h , h2 ) , 1.47  ppm ( d , j=1.0  hz , 3  h , ch 
 3 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso ) : =163.6 ( c = o , c2 ) , 150.3 ( c = o , c4 ) , 143.4 , ( cph ) , 135.6 ( c6 ) , 128.2 , 127.9 , 127.1 ( chph ) , 109.5 ( c5 ) , 86.3 ( c(ph)3 ) , 85.3 ( c4 ) , 83.6 ( c1 ) , 70.4 ( c3 ) , 63.9 ( c5 ) , 40.0 ( c2 ) , 11.7  ppm ( ch3 ) ; ms ( es+ ) found : m / z 507.54 [ m+na ] , calcd for [ c29h28n2o5 ] : m / z 484.54 [ m ] ; reversephase hplc ( h2o / ch3cn 90:10 to 0:50 in 30  min ) , flow=1  ml  min , =245  nm , t 
 r=6.29  min . tritylated derivatives of penciclovir ( 22 ) were prepared according to general procedure 1 from 22 ( 0.57  g , 2.25  mmol ) and trityl chloride ( 1.86  g , 6.75  mmol ) in anhydrous pyridine ( 10  ml ) . column chromatography eluting using a gradient of meoh / triethylamine ( 1:0.5  % to 3:0.5  % ) in ch2cl2 yielded 5,3bisotritylpenciclovir ( 22  b ) and 2n,5,3otritrityl penciclovir ( 22  bnhtr ) . 2n5,3otritrityl penciclovir ( 22  bnhtr ) was obtained as a white solid ( 0.47  g , 21  % ) ; h  nmr ( 500  mhz , 25  c , [ d6]dmso ) : =10.51 ( bs , 1  h , nh ) , 7.26 ( s , 1  h , h8 ) , 7.317.28 ( m , 31  h , hph , nh ) , 7.197.17 ( m , 6  h , hph ) , 7.077.04 ( m , 6  h , hph ) , 6.976.96 ( m , 3  h , hph ) , 3.243.21 ( m , 2  h , h1 ) , 2.912.85 ( m , 4  h , h4 , h5 ) , 1.621.58 ( m , 1  h , h3 ) , 1.131.09  ppm ( m , 2  h , h2 ) ; c  nmr ( 125  mhz , 25  c , [ d6]dmso ) : =156.5 ( c6 ) , 150.3 ( c2 ) , 149.3 ( c4 ) , 144.6 , 143.8 (  ipso cph ) , 137.2 ( c8 ) , 128.7 , 128.4 , 128.1 , 127.8 , 127.4 , 126.9 , 126.3 ( chph ) , 117.0 ( c5 ) , 85.8 ( c(ph)3 ) , 62.7 ( c4 , c5 ) , 41.3 ( c1 ) , 37.3 ( c3 ) , 28.4  ppm ( c2 ) ; ms ( es+ ) found : m / z 1003.39 [ m+na ] , calcd for [ c67h57n5o3 ] m / z : 980.20 [ m ] ; reversephase hplc ( h2o / ch3cn from 50:50 to 0:100 in 40  min ) , flow=1  ml  min , =254  nm , t 
 r=36.64  min . antiviral assay : trityl compounds were prepared as stock solution of 100  mm in dimethyl sulfoxide ( dmso ) and then were diluted to a final assay concentration of 20 , 10 , 5  m . dilutions were made by adding the appropriate amount of dmso to lyophilized compound to achieve stock concentrations of 10 to 100  mm . dissolved compounds were stored at 20  c and brought to rt prior to assay . all compounds were well dissolved in dmso , and precipitates were not observed upon thawing . 
 cell culture : vero cells were grown in dulbeccos modified eagles medium ( dmem , sigmaaldrich ) with 10  % fbs ( sigmaaldrich ) . cells were plated into 96well plates at a density of 10 cells per well . virus culture : cells were then infected with dengue virus ( serotype d2 ( strain new guinea c ) , atcc number : vr1584 ) , and yellow fever vaccine ( 17  d strain asibi ; grown from a dose of sanofi pasteur stamaril ( 1000iu from embryonated chicken eggs ) and adapted to vero cells ( farleigh and bugert , 2014 , unpublished results ) at a moi of 1 , or left uninfected to determine compound toxicity . 
 cell viability was determined after seven days using celltiterglo promega , following the manufacturer 's instructions . as a service to our authors and readers , this journal provides supporting information supplied by the authors . such materials are peer reviewed and may be reorganized for online delivery , but are not copyedited or typeset . technical support issues arising from supporting information ( other than missing files ) should be addressed to the authors .
abstracta series of tritylated and dimethoxytritylated analogues of selected pyrimidine and purine nucleosides were synthesized and evaluated for their in vitro inhibitory activity against two important members of the genus flavivirus in the flaviviridae family , the yellow fever ( yfv ) and dengue viruses ( denv ) . among all compounds tested , the 5otritylated and the 5odimethoxytritylated 5fluorouridine derivatives exerted potency against yfv . interestingly in the series of purine analogues , the 5o , nbistritylated fludarabine 
 derivative revealed strong inhibitory activity against denv at m concentrations , however significantly weaker potency against yfv .