Synthesis and Antiviral Evaluation of 6-(Trifluoromethylbenzyl)

I:/3B2/Jobs/archiv/2007/Heft11/1.3d 22. 10. 2007 Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 N. R. El-Brollowsy et al. 1 Full Paper Synthesis and Antiviral Evaluation of 6-(Trifluoromethylbenzyl) and 6-(Fluorobenzyl) Analogues of HIV Drugs Emivirine and GCA-186 Nasser R. El-Brollosy 1, 2, Esben R. Sørensen 1, Erik B. Pedersen 1, Giuseppina Sanna 3, Paolo La Colla 3, and Roberta Loddo 3 1 Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Odense M, Denmark 2 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia 3 Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Microbiologia e Virologia Generale e Biotecnologie Microbiche, Universita di Cagliari, Monserrato, Italy The present study describes the synthesis and antiviral evaluation of a series of novel 6-(3-trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of the HIV drugs emivirine and GCA-186. The objective was to investigate whether the fluoro or trifluoromethyl substituents could lead to an improved antiviral activity against HIV-1 wild type and mutants resistant to non-nucleoside RT inhibitors. The biological test results showed that the most of theses compounds showed good activity against wild type HIV-1. Among them, compound 1-(ethoxymethyl)-6-(3-fluorobenzyl)-5-isopropyluracil (9i) showed the largest inhibitory potency (EC 50 = 0.02 lm), resulting equally potent than Emivirine against wild type HIV-1. Furthermore, compound 9i showed marginal better activity against resistant mutants than Emivirine. The key steps in the synthesis of the target compounds were either reaction of an appropriate b-keto ester with thiourea or a cross-coupling reaction of 6-chloro-2,4-dimethoxypyrimidines with benzylic Grignard reagents. Keywords: Alkenyloxymethyluracils / Grignard reaction / HIV-1 / Non-nucleoside reverse transcriptase inhibitors / Received: May 30, 2007; accepted: August 24, 2007 DOI 10.1002/ardp.2007001 Introduction Correspondence: Erik B. Pedersen, Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. E-mail: ebp@ifk.sdu.dk Fax: +45 6615 8780 Abbreviations: reverse transcriptase (RT); human immunodeficiency virus type 1 (HIV-1); non-nucleoside RT inhibitors (NNRTIs); 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT); N,O-bis(trimethylsilyl)acetamide (BSA); trimethylsilyl trifluoro-methanesulfonate (TMS triflate); 3- (4,5-dimethylthiazol-1-yl)-2,5-diphenyltetrazolium bromide (MTT) The reverse transcriptase (RT) enzyme of the human immunodeficiency virus type 1 (HIV-1) is an important target for development of anti-aids drugs. It is responsible for the conversion of a single-stranded RNA viral genome into a double-stranded DNA chain that subsequently is incorporated into the DNA of the infected host cell [1, 2]. In recent years, much effort has been put into the design and synthesis of HIV-1 non-nucleoside RT inhibitors (NNRTIs) [3]. The NNRTIs are highly specific as their binding site is a hydrophobic pocket located approximately 10 Š from the polymerease active site [4] forcing the RT subunit into an inactive conformation [5]. One of the first NNRTIs was 1-[(2-hydroxyethoxy)methyl]- 6-(phenylthio)thymine (HEPT) [6, 7]. Although HEPT did not show very high activity against HIV-1, it was considered an interesting lead compound for the synthesis of new analogues. Among them 6-benzyl-1-(ethoxymethyl)- 5-isopropyluracil (Emivirine, formerly MKC-442) [8], 6- (3,5-dimethylbenzyl)-5-isopropyluracil (GCA-186) [9], and the corresponding N-1 allyloxymethyl analogues [10] (BED-60 and AMB-A10) showed high potent activity against HIV-1 (Fig. 1).

2 N. R. El-Brollowsy et al. Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 wildtype and mutants resistant to non-nucleoside RT inhibitors (NNRTIs). Results and discussion Figure 1. Structures of the lead molecules HEPT, MKC-442, GCA-186, BED-60, and AMB-A10. During NNRTI mono therapy for HIV-1 infected patients [11] and in-vitro culture [12], rapid emergence of highly drug-resistant viruses is often observed. The primary cause of drug resistance is the substitution of tyrosine by cysteine at position 181 in the HIV-1 RT (Y181C). Furthermore, the RT mutation of the lysine at position 103 to asparagine (K103N) is frequently observed on treatment with retroviral regimens containing many NNRTIs [] including the FDA-(U.S. Food and Drug Administration) approved drugs (nevirapine [14], delavirdine [15], and efavirenz [16]). Therefore, it is of importance to find novel NNRTIs that may be able to overcome such resistance issue. GCA-186 (Fig. 1) differs structurally from emivirine only in the introduction of two methyl substituents in 3- and 5-position at the C-6 benzyl group. It performed better in tolerating the presence of the Y181C and K103N mutations than did emivirine itself. The increase of potency of GCA-186 over emivirine against the wildtype HIV and mutants has been correlated with an overall tighter and/or more complete fit in the hydrophobic pocket due to the presence of 3,5-dimethyl groups [9]. On the other hand, the two methyl substituents on GCA-186 were thought to undergo metabolism, e.g. by the cytochrome P 450 family in the liver. Recently, we synthesized a series of 6-(3,5-dichlorobenzyl) derivatives as isosteric analogues of GCA-186 [17] on a trial to avoid rapid metabolism in the liver. In an effort to improve the activity against HIV-1 wild type and resistant mutants, and as a part of our continuing interest in the chemistry of NNRTIs [10, 17 21], the present study describes the synthesis and antiviral evaluation of 6-(trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of emivirine and GCA-186. The objective was to investigate whether the fluoro- or trifluoromethyl substituents could lead to an improved antiviral activity against HIV-1 Chemistry The required key intermediate the 5,6-disubstituted uracil derivatives 4a i were synthesized via two independent routes based on the commercial availability of the starting materials (Scheme 1 & Fig. 2 renamed to scheme 1, please check following renumbering &). With the nitriles commercially available for compound 1a, b, we choose the b-keto ester strategy, developed by one of us [22], for the synthesis of the corresponding uracil derivatives 4a d (Scheme 2). However, with the fluoro-substituted benzylic bromide commercially available for compounds 7a d, we choose another strategy based on a Grignard reaction followed by a cross-coupling reaction for the synthesis of the uracil derivatives 4e i (Scheme 3). This method was chosen despite the fact that it is known that benzylic-type Grignard reagents can be difficult to prepare via the classical method with the treatment of magnesium powder. (Trifluoromethylphenyl)acetonitriles 1a, b were reacted with the zinc organometallic reagent from ethyl 2-bromobutyrate or methyl 2-bromoisovalerate in anhydrous THF [22] to give the corresponding b-keto esters 2ad which were condensed with thiourea in the presence of sodium ethoxide to afford the 2-thiouracils 3a d. The NMR spectra of the crude compounds 2a, c showed an impurity identified as another b-keto ester resulting from self-condensation of ethyl 2-bromobutyrate. On reaction with thiourea, the b-keto ester impurity also formed a pyrimidine compound as an impurity in the Scheme 1. Synthetis route for uracils 4a i.

Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 New Emivirine and GCA-186 Analogues 3 Scheme 2. Synthetis route of compounds 1 4. raw materials of 3a, c which were easily purified according to usual work-up procedures [23]. De-sulfurization of compounds 3a d with boiling aqueous chloroacetic acid gave the corresponding uracils 4a d (Scheme 2). The fluoro-substituted uracil analogues 4e i were synthesized in analogy to literature procedures [24, 25]. The appropriate Grignard reagents synthesized in situ in a standard way from the corresponding bromide as described by Wakefield [24] for benzyl bromide, were added to the methoxy-protected uracil derivatives 6a [26] or 6b [25] in the presence of an appropriate catalyst. A systematic investigation (including use of different catalysts, solvents, reaction time, and temperature) showed that the best results were obtained when Fe(acac) 3 was used as a catalyst in the cross-coupling reaction and the subsequent hydrolysis for the compounds with the following aromatic substitution pattern: 3-F (8a/4e, 61%), 2,5-F (8b/4f, 24%), and 2,3,5,6-F (8d/4h, 18%). The significant drop in yields, corresponding to the number and positions, was occupied by the fluoro group on the aromat with the highest yield for the mono-substituted aromat. Surprisingly, it was not possible to synthesize compound 8c using Fe(acac) 3 as a catalyst. However, we succeeded to synthesize compound 8c in 10% yield using commercially available catalyst NiCl 2 (dppe). It is noteworthy that the catalyst used by Adriane et al. [25] NiCl 2 (tpp) [27] was not successful in our hands. It was not possible to isolate the pure compounds 8a e due to a complex mixture. Nevertheless, compounds 4e i were easily obtained as solid compounds after hydrolysis of the corresponding methoxy-protected compounds 8a e in boiling aqueous HCl following evaporation and adition of water with overall yields of 8 61% (Scheme 3). The low yield for the synthesis of 4i (8%) compared to the corresponding 5-ethyl derivative 4e obtained in 61% yield is presumably due to steric hindrance of the larger isopropyl at the 5-position of the uracil ring. However, the (a) Ref. [25, 26]; (b) 4 equiv. Mg powder, dry Et2O; (c) 6a or 6b, cat., dry Et2O; (d) aq. HCl (4M).Scheme 3. Synthetis route of compounds 5 8. Scheme 4. Synthetis route of compounds 9 12. (a) BSA, H3CCH2OCH2Cl, CsI, CHCl3, 19 95%; (b) BSA, TMS-triflate, R 2 CH2O- CH2OCH2R 2,H3CCN, 38 89%. Scheme 4. Synthetis route of compounds 9 12. cross-coupling reaction was responsible for the overall low yield as the Grinard reagents were obtained in quantitative yield according to TLC analysis showing disappearance of the benzyl bromide.

4 N. R. El-Brollowsy et al. Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 Table 1. Antiviral activity and cytotoxicity of compounds 9 12 against HIV-1 in MT-4 cells. a) Compound Wild type N119 (Y181C) A17 (K103N + Y181C) EFV R (K103R + V179D + P225H) EC 50 b) (lm) CC 50 c) (lm) SI d) EC 50 b) (lm) EC 50 b) (lm) EC 50 b) (lm) 9a 9b 9c 9d 9e 9f 9g 9h 9i 10a 10b 10c 10d 10e 10f 10h 11a 11b 11c 11e 11f 11h 12e 12f 12h MKC-442 BED-60 AMB-A10 GCA-186 Efavirenz 0.4 l 0.1 0.1 l 0.08 1.9 l 0.7 0.9 l 0.5 0.05 l 0.01 0.05 l 0.001 0.08 l 0.02 0.09 l 0.005 0.02 l 0.005 0.2 l 0.1 0.05 l 0.03 1.7 l 0.7 1.3 l 0.1 0.03 l 0.005 0.04 l 0.02 0.07 l 0.01 0.2 l 0.1 0.05 l 0.03 3 l 1 0.05 l 0.01 0.05 l 0.005 0.09 l 0.005 0.1 l 0.01 0.2 l 0.05 0.4 l 0.05 0.03 l 0.005 0.004 l 0.005 0.009 l 0.001 0.0006 [8] 0.002 l 0.0005 54 l 3 77 l 5 39 l 0.5 68 l 5 46 l 4 5 l 1 56 l 2 38 l 1 85 55 43 [8] 30 l 1 A250 240 A52 A111 A2000 A2000 A1250 A1111 A5000 385 780 A59 A77 A3333 A2500 A1428 340 920 33 A2000 A2000 56 0 280 95 A3333 21250 6111 72000 15000 4.5 l 0.3 1.5 l 0.5 80 17 l 3 18 l 2 11 l 0.5 35 23 14 l 3 3.2 l 0.5 1.3 l 0.2 l 1 10 l 1 14 l 6 40 5.5 l 0.5 2.6 l 0.8 100 l 3 A20 17 l 3 A5 24 25 l 5 A38 A20 0.3 l 0.01 0.4 l 0.06 0.008 l 0.0009 45 l 15 12 l 2 68 50 87 54 42 19 l 9 12 l 4 42 14 l 6 44 A68 10 l 0.5 56 53 A5 A56 A38 56 2.0 l 0.3 6.3 l 1.4 0.3 l 0.05 A54 56 A77 A39 60 70 A68 A46 A5 A56 A38 6.2 l 0.3 6.1 l 0.7 3.0 l 1 a) Data represent mean values of at least two separate experiments. b) Compound dose required to achieve 50% protection of MT-4 cells from HIV-1 induced cytopathogenicity, as determined by the MTT method. c) Compound dose required to reduce the viability of mock-infected cells by 50%, as determined by the MTT method. d) Selectivity index: ratio CC 50 /ED 50. The symbol (>) indicates that CC 50 was not reached at the highest concentration tested. For description of assay see Experimental, section 4. The 1-ethoxymethyluracils 9a i were prepared from 4a i via silylation in situ with N,O-bis(trimethylsilyl)acetamide (BSA) in anhydrous chloroform followed by treatment with chloromethyl ethyl ether in the presence of cesium iodide to give the MKC-442 analogues 9a-i in 19 95% yields (Scheme 4). For the synthesis of compounds 10 12, the method was modified. The appropriate uracils 4a f or 4h were silylated in situ with BSA in anhydrous acetonitrile and alkylated at the N-1 position with bis(allyloxy)methane [10, 28] (for compounds 4a f, and 4h) or bis(propargyloxy)methane [10] (for compounds 4a c, 4e, f, and 4h) or bis(2-methylallyoxy)methane [10] (for compounds 4e, f and 4h) in the presence of trimethylsilyl trifluoro-methanesulfonate (TMS triflate) [29] as a Lewis acid catalyst to give the target molecules; 1-(allyoxymethyl)uracils 10a f, and 10h, 1-(propargyloxymethyl)uracils 11a c, 11e, f, and 11h and 1-(2-methylallyoxymethyl)uracils 12e, f, and 12h, respectively (Scheme 4). The yield for the alkylation reactions varied in a range from 38 to 89%. Especially, the propynyloxymethyl alkylation proceeded badly, even though the reaction time was extended to three days. However, we succeeded to increase the yield up to 81% by using four equivalents of TMS triflate, and the reaction was finished after about 4 h. The compounds were identified by comparison of similar NMR data [10, 18 23]. MS and elemental analysis are in full agreement with the proposed structures.

Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 New Emivirine and GCA-186 Analogues 5 Biological screening Compounds 9a i and 10 12 were tested for biological activity against wildtype HIV-1 strain IIIB in MT-4 cells. Results were compared with the antiviral activity of emivirine, a well examined HEPT analogues and efavirenz, the most active anti-hiv drug used in therapy today. Compounds were also tested against NNRTI-resistant mutants [Y181C, K103N + Y181C, and triple mutant (K103R + V179D + P225H), highly resistant to efavirenz]. Results are listed in Table 1. As seen from the results listed in Tabel 1, most of the tested compounds showed good activity against wildtype HIV-1 with a wide range of EC 50 values from 3 0.02 lm. Generally, the majority of the novel compounds were not cytotoxic for MT-4 cells at the maximum concentration tested (100 lm). The only exception is compound 11h, which was surprisingly cytotoxic (5 lm). In general, the 3-fluoro-substituted uracil series (9e, 10e, and 11e) were 10-times more potent than the corresponding CF 3 -series (9a, 10a, and 11a). Compound 9i, the most active compound tested against HIV-1, substituted at R by a fluorine atom was in our study marginally more potent than MKC-442 (20 nm versus 30 nm). Increasing the electronegativity by the replacements of hydrogen atoms with up to four fluorine atoms on the benzyl ring, is well tolerated (9f h, 10h, and 11f, h). However, replacement of the 3,5-dimethyl groups in BED-60, with the strong withdrawing group CF 3 (9c, 10c, and 11c) resulted in the least active among the synthesized compounds. In fact, the activity was about 100-times lower when compared with the corresponding 3,5-dichloro derivatives which have previously been synthesized in our laboratory as isosteric analogues of GCA-186 and BED-60. Furthermore, the introduction of different unsaturated N-1 substituents had no effect on the anti-hiv-1 activity, except, when increasing the bulkiness around the double bond of 9e with methyl moieties (12e h), leads to a significant drop in activity compared to 9e (2-, 4-, and 8-fold, respectively) which is in in accordance with our previous observations [10]. It is well known that introduction of an isopropyl group instead of an ethyl group at C-5 leads to a rise in biologic activity. Surprisingly, only the emivirine analogues having an allyloxymethyl or a propynyloxymethyl at the N-1 position, and substitution with one CF 3 group on the aromatic ring leads to an up to 4-fold increase in activity (11a vs. 11b and 10a vs. 10b). Unfortunately, only a marginally improvement in activity compared to the clinically important mutants (N119, A17 or EFV R ) was observed for compounds 9a, b, 10a, b and 11a, b when compared with MKC-442. Conclusion In summary, we have described the synthesis and anti- HIV activity of novel 6-(3-trifluoromethylbenzyl) and 6- (fluoromethylbenzyl) analogues of emivirine, GCA-186, and BED-60. The most active compounds 9i and 10e showed activity against wild-type HIV-1 in the nanomolar range with a selective index of greater than 3333. This work received funding from the European Community's Sixth Framework Programme undercontractnumberlshp- CT-2004-503162 (Selection and development of microbicides for mucosal use to prevent sexual HIV transmission/acquisition) [31]. The authors have declared no conflict of interest. Experimental Chemistry NMR spectra were recorded on a Varian Gemini 2000 NMR spectrometer (Varian Inc., Palo Alto, CA, USA ) at 300 MHz for 1 H and 75 MHz for C with TMS as internal standard. Due to complexity of C-NMR spectra for polyfluorinated benzylic groups, only strong peaks are reported for the benzylic group. MALDI spectra were recorded on a Fourier Transform (FT) Ion Cyclotron Resonance Mass Spectrometer (IonSpec Corporation, Lake Forest, CA, USA). Melting points were determined on a Büchi melting point apparatus (Büchi Labortechnik, Flawil, Switzerland). Elementary analyses were performed at H.C. Ørsted Institute, University of Copenhagen. Silica gel (0.040-0.063 mm) used for column chromatography and analytical silica gel TLC plates 60 F 254 were purchased from Merck (Darmstadt, Germany). Solvents used for column chromatography were distilled prior to use. The fluoro-benzyl bromides were purchased from Fluorochem,8 Old Glossop, Derbyshire, UK) Mg powder was purchased from Riedel-De Ha n (Seelze, Germany). Reagents were used as purchased. General procedure for synthesis of 2-alkyl-4-aryl-3- oxobutyrates 2a d Zn dust 25 30 g was activated by stirring with 4 M HCl (100 ml) for 5 min. The zinc dust was filtered and washed sequentially with water, ethyl alcohol, and ether. Dried by evaporation under reduced pressure at 808C for five hours, and kept in vacuo overnight. The activated Zn was suspended in anhydrous THF (35 ml) and heated to reflux. A few drops of ethyl 2-bromobutyrate or methyl 2-bromoisovalerate were added and the mixture was refluxed for 10 min. The appropriate nitrile; (3-trifluoromethylphenyl)acetonitrile 1a or [3,5-bis(trifluoromethyl)phenyl]acetonitrile 1b (0.015 mol) was added in one portion and ethyl 2- bromobutyrate or methyl 2-bromoisovalerate (0.03 mol) was added dropwise. After the addition was completed, the mixture was refluxed for 30 min. The reaction mixture was diluted with THF (100 ml) and saturated aqueous K 2 CO 3 (30 ml) was added. The mixture was stirred for 1 h and the THF layer was decanted

6 N. R. El-Brollowsy et al. Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 off. The residue was washed with THF (3620 ml) and the combined THF fractions were stirred with 10% aqueous HCl (20 ml) for 30 min. The solution was concentrated under reduced pressure and diluted with CH 2 Cl 2 (75 ml). The organic phase was washed with saturated aqueous NaHCO 3 (2650 ml), dried (Na 2 SO 4 ), and evaporated under reduced pressure to give 2a d as pale yellow oils. Ethyl-2-ethyl-3-oxo-4-(3-trifluoromethylphen-yl)butyrate 2a Yield 4.1 g (91%). 1 (CDCl 3 ): d (ppm) = 0.80 (t, 3H, J = 7.2 Hz, CH 3 ), 1.16 (t, 3H, J = 7.1 Hz, CH 3 ), 1.78 (m, 2H, CH 2 ), 3.37 (t, 1H, J = 7.3 Hz, CH), 3.81 (s, 2H, CH 2 ), 4.07 (q, 2H, J = 7.2 Hz, CH 2 ), 7.30 7.47 (m, 4H, H arom ). C-NMR (CDCl 3 ): d (ppm) = 11.77 (CH 3 ), 14.01 (CH 3 ), 21.51 (CH 2 ), 48.21 (CH 2 ), 60.06 (CH), 61.45 (CH 2 ), 123.98, 124.03, 126.32, 126.37, 128.99, 3.07, 4.25 (CF 3,C arom ), 169.43 (CO), 201.80 (CO). HRMS MALDI: m/z = 325.1022 [M+Na + ] (C 15 H 17 F 3 O 3 Na + ); requires 325.1030. Methyl-2-isopropyl-3-oxo-4-(3-trifluoromethylphenyl)butyrate 2b Yield 4.3 g (94%). 1 (CDCl 3 ): d (ppm) = 0.89, 0.96 (26d, 6H, J = 6.9 Hz, 26CH 3 ), 2.43 2.49 (m, 1H, CH), 3.31 (d, 1H, J = 7.3 Hz, CH), 3.69 (s, 3H, OCH 3 ), 3.87 (s, 2H, CH 2 ), 7.36 7.54 (m, 4H, H arom ). C-NMR (CDCl 3 ): d (ppm) = 20.35 (CH 3 ), 20.53 (CH 3 ), 28.70 (CH), 48.61 (CH 2 ), 52.24 (OCH 3 ), 66.15 (CH), 124.02, 124.07, 126.37, 126.42, 128.99, 3., 4.09 (CF 3,C arom ), 169.27 (CO), 201.44 (CO). HRMS MALDI: m/z = 325.1022 [M+Na + ](C 15 H 17 F 3 O 3 Na + ); requires 325.1025. Ethyl-4-[3,5-bis(trifluoromethyl)phenyl]-2-ethyl-3- oxobutyrate 2c Yield 5.1 g (92%). 1 (CDCl 3 ): d (ppm) = 0.92 (t, 3H, J = 7.4 Hz, CH 3 ), 1.25 (t, 3H, J = 7.1 Hz, CH 3 ), 1.90 (m, 2H, CH 2 ), 3.46 (t, 1H, J = 7.4 Hz, CH), 3.96 (s, 2H, CH 2 ), 4.18 (q, 2H, J = 7.1 Hz, CH 2 ), 7.64 (s, 2H, H arom ), 7.79 (s, 1H, H arom ). C-NMR (CDCl 3 ): d (ppm) = 11.82 (CH 3 ), 14.03 (CH 3 ), 21.55 (CH 2 ), 47.54 (CH 2 ), 60.45 (CH), 61.65 (CH 2 ), 121.20, 129.95, 1.52, 1.97, 5.79 (CF 3,C arom ), 169.35 (CO), 201.01 (CO). Methyl-4-[3,5-bis(trifluoromethyl)phenyl]-2-iso-propyl-3- oxobutyrate 2d Yield 5.0 g (90%). 1 (CDCl 3 ): d (ppm) = 0.94, 0.99 (26d, 6H, J = 6.9 Hz, 26CH 3 ), 1.97 (m, 1H, CH), 3.33 (d, 1H, J = 7.3 Hz, CH), 3.73 (s, 3H, OCH 3 ), 3.97 (s, 2H, CH 2 ), 7.63 (s, 2H, H arom ), 7.79 (s, 1H, H arom ). C-NMR (CDCl 3 ): d (ppm) = 20.38 (CH 3 ), 20.56 (CH 3 ), 28.87 (CH), 47.79 (CH 2 ), 52.37 (OCH 3 ), 66.52 (CH), 121.22, 129.97, 1.52, 1.96, 5.65 (CF 3,H arom ), 169.24 (CO), 200.73 (CO). General procedure for synthesis of 5-alkyl-6- (trifluoromethyl)benzyl-2-thiouracils 3a d Na (4.92 g, 0.217 mol) was dissolved in absolute ethanol (100 ml). Thiourea (11.42 g, 0.15 mol) was added and the reaction mixture was heated to reflux. The b-keto ester 2a d (0.01 mol) was added dropwise and the mixture was refluxed for two hours. The mixture was evaporated to dryness under reduced pressure and the residue was redissolved in H 2 O (100 ml). The solution was acidified with HCl to ph 4. The precipitate thus formed was filtered off, washed with H 2 O, then with Et 2 O, and dried to give 3a d as white solids. 5-Ethyl-6-(3-trifluoromethylbenzyl)-2-thiouracil 3a Yield 1.88 g (60%); mp. 182 1848C. 1 (DMSO-d 6 ): d (ppm) = 0.80 (t, 3H, J = 7.2 Hz, CH 3 ), 2.28 (q, 2H, J = 7.2 Hz, CH 2 ), 3.97 (s, 2H, CH 2 ), 7.53 7.67 (m, 4H, H arom ), 12.29, 12.41 (26s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) = 12.77 (CH 3 ), 17.69 (CH 2 ), 34. (CH 2 ), 117.41 (C-5), 123.47, 123.52, 124.95, 125.00, 129.71, 2.09, 8.21 (CF 3,C arom ), 148.27 (C-6), 161.35 (C-4), 174.24 (C-2). MS-EI: m/z (%) = 314 [M + ] (100). 5-Isopropyl-6-(3-trifluoromethylbenzyl)-2-thiouracil 3b Yield 1.9 g (58%); mp. 189-1918C. 1 (DMSO-d 6 ): d (ppm) = 0.85 (d, 6H, J = 6.6 Hz, 26CH 3 ), 2.85 (hept. 1H, J = 6.6 Hz, CH), 4.01 (s, 2H, CH 2 ), 7.50 7.64 (m, 4H, H arom ), 12.23, 12.36 (26s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) = 19.45 (26CH 3 ), 26.57 (CH), 34.25 (CH 2 ), 119.85 (C-5), 123.34, 123.48, 124.68, 124.73, 129.73, 2.09, 8.31 (CF 3,C arom ), 148.02 (C-6), 160.61 (C-4), 174.20 (C-2). MS-EI: m/z (%) = 328 [M + ] (100). 6-[3,5-Bis(trifluoromethyl)benzyl]-5-ethyl-2-thiouracil 3c Yield 1.75 g (46%); mp. 223 2258C. 1 (DMSO-d 6 ): d (ppm) = 0.80 (t, 3H, J = 7.4 Hz, CH 3 ), 2.14 (q, 2H, J = 7.4 Hz, CH 2 ), 4.08 (s, 2H, CH 2 ), 8.01 (s, 2H, H arom ), 8.03 (s, 1H, H arom ), 12.28, 12.47 (26s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) = 12.76 (CH 3 ), 17.68 (CH 2 ), 33.90 (CH 2 ), 117.83 (C-5), 120.68, 124.99, 129.20, 0.12, 140.21 (CF 3,C arom ), 147.23 (C-6), 161.33 (C-4), 174.33 (C-2). MS-EI: m/z (%) = 382 [M + ] (29). 6-[3,5-Bis(trifluoromethyl)benzyl]-5-isopropyl-2-thiouracil 3d Yield 0.75 g (19%); mp. 210 212 C. 1 (DMSO-d 6 ): d (ppm) = 1.09 (d, 6H, J = 6.6 Hz, CH 3 ), 2.94 (hept. 1H, J = 6.6 Hz, CH), 4.10 (s, 2H, CH 2 ), 7.99 (s, 2H, H arom ), 8.02 (s, 1H, H arom ), 12.22, 12.37 (26s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) = 19.43 (CH 3 ), 26.56 (CH), 34.01 (CH 2 ), 120.57 (C-5), 120.66, 125.03, 129.09, 0.61, 140.32 (CF 3,C arom ), 147.05 (C-6), 160.58 (C-4), 174.29 (C-2). MS-EI: m/z (%) = 396 [M + ] (58). General procedure for synthesis of 5-alkyl-6- (trifluoromethylbenzyl)uracils 4a d A suspension of 2-thiouracils (3a d, 0.01 mol) in 10% aqueous ClCH 2 CO 2 H (200 ml) was refluxed overnight. After cooling, the precipitate was filtered off, washed with cold EtOH, then Et 2 O, and dried to give 4a d as white solids. 5-Ethyl-6-(3-trifluoromethylbenzyl)uracil 4a Yield 2.1 g (70%); mp. 218-2198C. 1 (DMSO-d 6 ): d (ppm) = 0.91 (t, 3H, J = 6.5 Hz, CH 3 ), 2.46 (q, 2H, J = 6.5 Hz, CH 2 ), 3.87 (s, 2H, CH 2 ), 7.36 7.54 (m, 4H, H arom ), 10.79, 11.12 (26s, 2H, 26NH). C- NMR (DMSO-d 6 ): d (ppm) =.39 (CH 3 ), 17.55 (CH 2 ), 34.54 (CH 2 ), 111.63 (C-5), 123.41, 123.46, 124.89, 124.94, 129.64, 2.14, 8.35 (CF 3,C arom ), 147.73 (C-6), 150.86 (C-2), 164.38 (C-4). MS-EI: m/z (%) = 298 [M + ] (66). Anal. Calcd. for C 14 H F 3 N 2 O 2 60.25 H 2 O: C, 55.54; H, 4.49; N, 9.25. Found: C, 55.76; H, 4.24; N, 9.24.

Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 New Emivirine and GCA-186 Analogues 7 5-Isopropyl-6-(3-trifluoromethylbenzyl)uracil 4b Yield 2.27 g (73%); mp. 206 2088C. 1 (DMSO-d 6 ): d (ppm) = 1.07 (d, 6H, J = 6.7 Hz, 26CH 3 ), 2.83 (hept, 1H, J = 6.7 Hz, CH), 3.89 (s, 2H, CH 2 ), 7.58 7.64 (m, 4H, H arom ), 10.85 (br s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) = 19.99 (CH 3 ), 26.36 (CH), 34.78 (CH 2 ), 114.20 (C-5), 123.37, 123.43, 124.62, 124.68, 129.69, 2.11, 8.49 (CF 3,C arom ), 147.47 (C-6), 150.87 (C-2), 163.74 (C-4). MS-EI: m/z (%) = 312 [M + ] (47). Anal. calcd for C 15 H 15 F 3 N 2 O 2 60.25 H 2 O: C, 56.87; H, 4.93; N, 8.84. Found: C, 56.94; H, 4.67; N, 8.82. 6-[3,5-Bis(trifluoromethyl)benzyl]-5-ethyluracil 4c Yield 2.3 g (63%), mp. 250 2528C. 1 (DMSO-d 6 ): d (ppm) = 0.81 (t, 3H, J = 7.2 Hz, CH 3 ), 2.29 (q, 2H, J = 7.2 Hz, CH 2 ), 3.99 (s, 2H, CH 2 ), 8.02 8.03 (m, 3H, H arom ), 10.79, 11.08 (26s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) =.39 (CH 3 ), 17.52 (CH 2 ), 34.28 (CH 2 ), 112.01 (C-5), 120.62, 125.01, 129.19, 0.54, 140.37 (CF 3, C arom ), 146.78 (C-6), 150.84 (C-2), 164.32 (C-4). MS- EI: m/z (%) = 366 [M + ] (49). Anal. calcd for C 15 H 12 F 6 N 2 O 2 : C, 49.19; H, 3.30; N, 7.65. Found: C, 49.23; H, 3.16; N, 7.55. 6-[3,5-Bis(trifluoromethyl)benzyl]-5-isopropyluracil 4d Yield 2.3 g (61%); mp. 231 2338C. 1 (DMSO-d 6 ): d (ppm) = 1.10 (d, 6H, J = 6.8 Hz, 26CH 3 ), 2.91 (hept, 1H, J = 6.8 Hz, CH), 4.01 (s, 2H, CH 2 ), 8.01 (s, 2H, H arom ), 8.04 (s, 1H, H arom ), 10.77, 10.98 (26s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) = 19.92 (CH 3 ), 26.33 (CH), 34.47 (CH 2 ), 114.49 (C-5), 120.55, 125.03, 129.01, 0.59, 140.51 (CF 3,C arom ), 146.55 (C-6), 150.84 (C-2), 163.67 (C-4). MS-EI: m/z (%) = 380 [M + ] (58). Anal. calcd for C 16 H 14 F 6 N 2 O 2 :C, 50.53; H, 3.71; N, 7.37. Found: C, 50.92; H, 3.59; N, 7.35. General procedure for synthesis of 5-alkyl-6- (fluoromethylbenzyl)uracils 4e-i In-vacuo dried magnesium powder (4 equiv.) and anhydrous Et 2 O was stirred under a dry nitrogen atmosphere. A crystal of I 2 was added. Immediately after addition of the first few drops of the appropriate fluorobenzyl bromide (1 equiv in Et 2 O), the color turned from red/brown to white/green and the rest of the bromide was added dropwise during 10 min. The reaction mixture was stirred for one hour at room temperature and used in the next step without further purification. A mixture of the methoxy protected uracil chloride 6a or 6b (1 equiv.), Fe(acac) 3 (0.1 equiv.) or NiCl 2 (dppe) (30 mol% based on 6b) and Et 2 O was stirred under a dry nitrogen atmosphere. A solution of the appropriate fluorobenzylmagnesium bromide (1.33 equiv.) in anhydrous Et 2 O was added via a syringe. During the addition, the reaction mixture started to reflux and a color shift from red to brown was observed. The stirring was continued overnight at room temperature. The reaction mixture was quenched with saturated NH 4 Cl, and extracted with H 2 O. The aqueous layer was extracted with Et 2 O, and the combined ether phases were dried (MgSO 4 ) and evaporated in vacuo to give a yellow/brown oil. The crude products were deprotected in refluxed 4 M HCl overnight. Upon cooling to room temperature, white crystals precipitated. These were filtered off, washed with Et 2 O, and dried in vacuo to give 4e i. 5-Ethyl-6-(3-fluorobenzyl)uracil 4e Yield 798 mg (61%); mp. 224 2268C. 1 (DMSO-d 6 ): d (ppm) = 0.84 (t, 3H, J = 7.3 Hz, CH 3 ), 2.25 (q, 2H, J = 7.3 Hz, CH 2 ), 3.79 (s, 2H, CH 2 ), 7.07 7.43 (m, 4H, H arom ), 10.73, 11.04 (26s, 2H, General procedure for N-1 alkylation of 4a i Method A: To a suspension of compound 4a i (1 equiv.), in anhydrous CHCl 3 (20 ml), was added N,O-bis(trimethylsilyl)acetamide (BSA) (3.5 equiv.) and the mixture was stirred under a nitrogen atmosphere at room temperature. After a clear solution was obtained (10 min), chloromethyl ethyl ether (1.5 equiv.) and CsI (1 equiv.) were added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for three hours (for the synthesis of compounds 9a d) or overnight (for the synthesis of compounds 9e i). The reaction mixture was quenched with saturated aqueous NaHCO 3 (20 ml). The mixture was extracted with CH 2 Cl 2 (3650 ml). The organic phases were collected, dried (MgSO 4 ), and evaporated under reduced pressure. The products were purified by silica gel column chromatograi 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 26NH). C-NMR (DMSO-d 6 ): d (ppm) =.43 (CH 3 ), 17.53 (CH 2 ), 34.55 (CH 2 ), 111,49 (C-5), 1.37 (d, J = 20.3 Hz, C arom ), 115.00 (d, J = 21.8 Hz, C arom ), 124.14 (d, J = 3.0 Hz, C arom ), 0.46 (d, J = 9.0 Hz, C arom ), 9.67 (d, J = 10.0 Hz, C arom ), 147,91 (C-6), 150,85 (C-2), 162. (d, J = 242.20 Hz, C arom ), 164,40 (C-4). HRMS MALDI: m/z = 249.1034 [M + H + ](C H FN 2 O 2+ ); requires 249.1037. 5-Ethyl-6-(2,5-difluorobenzyl)uracil 4f Yield 308 mg (24%); mp. 223 2258C. 1 (DMSO-d 6 ): d (ppm) = 0.80 (t, 3H, J = 7.2 Hz, CH 3 ), 2.19 (q, 2H, J = 7.3 Hz, CH 2 ), 3.79 (s, 2H, CH 2 ), 7.09-7.31 (m, 3H, H arom ), 10.71, 11.06 (26s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) =.29 (CH 3 ), 17.44 (CH 2 ), 28.25 (CH 2 ), 112.17 (C-5), 114.91 116.91, 125.54 125.65 (C arom ), 146.42 (C-6), 150.82 (C-2), 156.34 (d, J = 239.3 Hz, C arom ), 158.11 (d, J = 241.5 Hz, C arom ), 164.31 (C-4). HRMS MALDI: m/z = 267.0940 [M+H + ](C H 12 F 2 N 2 O 2+ ); requires 267.0940. 5-Ethyl-6-(2,3,6-trifluorobenzyl)uracil 4g Yield 333 mg (10%); mp 215 2208C. 1 (DMSO-d 6 ): d (ppm) = 0.68 (t, 3H, J = 7.2 Hz, CH 3 ), 2.17 (q, 2H, J = 7.3 Hz, CH 2 ), 3.88 (s, 2H, CH 2 ), 7.12 7.52 (m, 2H, H arom ), 10.75, 11.05 (26s, 2H, 26NH). C- NMR (DMSO-d 6 ): d (ppm) = 12.66 (CH 3 ), 17.33 (CH 2 ), 23.95 (CH 2 ), 111.48 (C-5), 111.16 116.47 (C arom ), 146.68 (C-6), 150.69 (C-2), 164.18 (C-4). HRMS MALDI: m/z = 285.0845 [M+H + ] (C H 11 F 3 N 2 O 2+ ); requires 285.0848. 5-Ethyl-6-(2,3,5,6-tetrafluorobenzyl)uracil 4h Yield 690 mg (18%); mp. 205 2108C. 1 (DMSO-d 6 ): d (ppm) = 0.76 (t, 3H, J = 7.3 Hz, CH 3 ), 2.19 (q, 2H, J = 7.3 Hz, CH 2 ), 3.95 (s, 2H, CH 2 ), 7.86 (m, 1H, H arom ), 10.73, 11.09 (26s, 2H, 26NH). C- NMR (DMSO-d 6 ): d (ppm) = 12.79 (CH 3 ), 17.36 (CH 2 ), 23.98 (CH 2 ), 102.96 106.00 (C arom ), 111.75 (C-5), 145.89 (C-6), 150.68 (C-2), 164.10 (C-4). HRMS MALDI: m/z = 303.0751 [M+H + ] (C H 10 F 4 N 2 O 2+ ); requires 303.0758. 6-(3-Fluorobenzyl)-5-isopropyluracil 4i Yield 198 mg (8%). 1 (DMSO-d 6 ): d (ppm) = 1.06, 1.08 (d, 6H, J = 6 Hz, 26CH 3 ), 3.05 (sep, 1H, CH), 3.80 (s, 2H, CH 2 ), 7.08 7.39 (m, 4H, H arom ), 10.71, 10.90 (26s, 2H, 26NH). C-NMR (DMSO-d 6 ): d (ppm) = 19.32 (26CH 3 ), 20.02 (CH), 31.49 (CH 2 ), 1.41 (d, J = 20.2 Hz, C arom ), 114.86 (d, J = 21.0 Hz, C arom ), 124.00 (d, J = 3.0 Hz, C arom ), 0.47 (d, J = 8.2 Hz, C arom ), 9.84 (d, J = 7.5 Hz, C arom ), 162. (d, J = 204.9 Hz, C arom ), 114.10 (C-5), 147.64 (C-6), 150.84 (C- 2), 162.19 (C-4).

8 N. R. El-Brollowsy et al. Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 phy using 0-1% MeOH/CHCl 3 (9a d) or 42% EtOH/petroleum ether (9e i) as eluents. 1-(Ethoxymethyl)-5-ethyl-6-(3- trifluoromethylbenzyl)uracil 9a Yield 256 mg (72%) as white solid; mp. 1 28C. 1 (CDCl 3 ): d (ppm) = 1.04 (t, 3H, J = 7.4 Hz, CH 3 ), 1. (t, 3H, J = 7.0 Hz, CH 3 ), 2.42 (q, 2H, J = 7.4 Hz, CH 2 ), 3.57 (q, 2H, J = 7.0 Hz, CH 3 ), 4.22 (s, 2H, CH 2 ), 5.11 (s, 2H, CH 2 ), 7.23 7.56 (m, 4H, H arom ). C-NMR (CDCl 3 ): d (ppm) =.67 (CH 3 ), 14.94 (CH 3 ), 19.21 (CH 2 ), 33.23 (CH 2 ), 65.08 (CH 2 ), 72.82 (CH 2 ), 117.36 (C-5), 124.10, 124.18, 124.23, 124.29, 129.73, 0.44, 6.47 (CF 3,C arom ), 147.93 (C-6), 151.89 (C-2), 163.25 (C-4). MS-EI: m/z (%) = 356 [M + ] (25). Anal. calcd for C 17 H 19 F 3 N 2 O 3 : C, 57.30; H, 5.37; N, 7.86. Found: C, 57.16; H, 5.32; H, 7.76. 1-(Ethoxymethyl)-5-isopropyl-6-(3- trifluoromethylbenzyl)uracil 9b Yield 288 mg (78%) as white solid; mp. 8 98C. 1 (CDCl 3 ): d (ppm) = 1.14 (t, 3H, J = 7.1 Hz, CH 3 ), 1.28 (d, 6H, J = 6.9 Hz, 26CH 3 ), 2.75 (hept, 1H, J = 6.9 Hz, CH), 3.59 (q, 2H, J = 7.1 Hz, CH 2 ), 4.25 (s, 2H, CH 2 ), 5.14 (s, 2H, CH 2 ), 7.31 7.57 (m, 4H, H arom ), 9.41 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) = 14.93 (CH 3 ), 20.27 (CH 3 ), 28.47 (CH), 33.31 (CH 2 ), 65.09 (CH 2 ), 72.98 (CH 2 ), 120.14 (C-5), 124.06, 124.11, 124.14, 124.19, 129.67, 0.54, 6.61 (CF 3,C arom ), 147.36 (C-6), 151.84 (C-2), 162.23 (C-4). HRMS MALDI: m/z = 393.96 [M+Na + ] (C 18 H 21 F 3 N 2 O 3 Na + ); requires 393.1404. Anal. calcd for C 18 H 21 F 3 N 2 O 3 : C, 58.37; H, 5.72; N, 7.56. Found: C, 58.33; H, 5.66; N, 7.53. 6-[3,5-Bis(trifluoromethyl)benzyl]-1-(ethoxymethyl)-5- ethyluracil 9c Yield 300 mg (71%) as white solid; mp. 9 1408C. 1 (CDCl 3 ): d (ppm) = 1.04 (t, 3H, J = 7.4 Hz, CH 3 ), 1.10 (t, 3H, J = 7.1 Hz, CH 3 ), 2.41 (q, 2H, J = 7.4 Hz, CH 2 ), 3.56 (q, 2H, J = 7.1 Hz, CH 2 ), 4.29 (s, 2H, CH 2 ), 5.14 (s, 2H, CH 2 ), 7.58 (s, 2H, H arom ), 7.82 (s, 1H, H arom ), 9.53 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) =.57 (CH 3 ), 14.82 (CH 3 ), 19.27 (CH 2 ), 33.24 (CH 2 ), 65.19 (CH 2 ), 72.96 (CH 2 ), 117.81 (C-5), 121.15, 127.42, 127.46, 2.82, 8.31 (CF 3, C arom ), 146.75 (C-6), 151.67 (C-2), 162.92 (C-4). HRMS MALDI: m/z = 447.1114 [M+Na + ](C 18 H 18 F 6 N 2 O 3 Na + ); requires 447.1124. Anal. calcd for C 18 H 18 F 6 N 2 O 3 : C, 50.95; H, 4.28; N, 6.60. Found: C, 51.25; H, 4.28; N, 6.54. 6-[3,5-Bis(trifluoromethyl)benzyl]-1-(ethoxymethyl)-5- isopropyluracil 9d Yield 306 mg (70%) as white solid; mp. 160 1618C. 1 (CDCl 3 ): d (ppm) = 1.09 (t, 3H, J = 7.1 Hz, CH 3 ), 1.28 (d, 6H, J = 6.8 Hz, 26CH 3 ), 2.67 (hept, 1H, J = 6.8 Hz, CH), 3.58 (q, 2H, J = 7.1 Hz, CH 2 ), 4.31 (s, 2H, CH 2 ), 5.18 (s, 2H, CH 2 ), 7.60 (s, 2H, H arom ), 7.82 (s, 1H, H arom ), 9.40 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) = 14.81 (CH 3 ), 20.16 (CH 3 ), 28.66 (CH), 33.22 (CH 2 ), 65.18 (CH 2 ), 73.12 (CH 2 ), 120.56 (C-5), 121.33, 124.81, 127.45, 2.75, 8.39 (CF 3, C arom ), 146.17 (C-6), 151.70 (C-2), 161.99 (C-4). HRMS MALDI: m/z = 461.1270 [M+Na + ] (C 19 H 20 F 6 N 2 O 3 Na + ); requires 461.1280. 1-(Ethoxymethyl)-5-ethyl-6-(3-fluorobenzyl)uracil 9e Yield 117 mg (95%) as white solid; mp. 114 1168C. 1 (CDCl 3 ): d (ppm) = 1.05 (t, 3H, J = 7.5 Hz, CH 3 ), 1.16 (t, 3H, J = 7.2 Hz, CH 3 ), 2.44 (q, 2H, J = 7.5 Hz, CH 2 ), 3.59 (q, 2H, J = 7.2 Hz, CH 2 ), 4.14 (s, 2H, CH 2 ), 5.10 (s, 2H, CH 2 ), 6.81 7.33 (m, 4H, H arom ), 9.59 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.71 (CH 3 ), 14.98 (CH 3 ), 19.14 (CH 2 ), 33.11 (CH 2 ), 65.04 (CH 2 ), 72.73 (CH 2 ), 114.33 (d, J = 21.0 Hz, C arom ), 114.41 (d, J = 22.5 Hz, C arom ), 122.93 (d, J = 3.0 Hz, C arom ), 0.74 (d, J = 8.3 Hz, C arom ), 7.80 (d, J = 7.5 Hz, C arom ), 163.24 (d, J = 246.0 Hz, C arom ), 117.16 (C-5), 148.32 (C-6), 151.86 (C-2), 164.24 (C-4). HRMS MALDI: m/z = 329.1272 [M+Na + ] (C 16 H 19 FN 2 O 3 Na + ); requires 329,1273. Anal. calcd for C 16 H 19 FN 2 O 3 : C, 62,73; H, 6,25; N, 9,14. Found: C, 62,85; H, 6,31; N, 9,12. 6-(2,5-Difluorobenzyl)-1-(ethoxymethyl)-5-ethyluracil 9f Yield 206 mg (85%) as white solid; mp. 117-1208C. 1 (CDCl 3 ): d (ppm) = 1.05 (t, 3H, J = 7.2 Hz, CH 3 ), 1.15 (t, 3H, J = 7.2 Hz, CH 3 ), 2.44 (q, 2H, J = 7.2 Hz, CH 2 ), 3.58 (q, 2H, J = 7.2 Hz, CH 2 ), 4.12 (s, 2H, CH 2 ), 5.14 (s, 2H, CH 2 ), 6.62-7.12 (m, 3H, H arom ), 9.54 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.57 (CH 3 ), 14.87 (CH 3 ), 19.12 (CH 2 ), 29.71 (d, J = 4.5 Hz, CH 2 ), 64.96 (CH 2 ), 72.87 (CH 2 ), 114.45 116.94, 124.35 124,69, 156.36 (d, J = 220.8 Hz, C arom ), 158.95 (d, J = 242.3 Hz, C arom ), 117.63 (C-5), 147.31 (C-6), 151.71 (C-2), 162.99 (C-4). HRMS MALDI: m/z = 347.1178 [M+Na + ] (C 16 H 18 F 2 N 2 O 3 Na + ); requires 347.1171. Anal. calcd for C 16 H 18 F 2 N 2 O 3 : C, 59.25; H, 5.59; N, 8.64. Found: C, 59.25; H, 5.50; N, 8.60. 1-(Ethoxymethyl)-5-ethyl-6-(2,3,6-trifluorobenzyl)uracil 9g Yield 5 mg (11%) as white solid. 1 (CDCl 3 ): d (ppm) = 0.89 (t, 3H, J = 7.4 Hz, CH 3 ), 1.17 (t, 3H, J = 7.1 Hz, CH 3 ), 2.37 (q, 2H, J = 7.5 Hz, CH 2 ), 3.60 (q, 2H, J = 7.1 Hz, CH 2 ), 4.15 (s, 2H, CH 2 ), 5.35 (s, 2H, CH 2 ), 6.82 7.15 (m, 2H, H arom ), 8.53 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) = 12.78 (CH 3 ), 14.94 (CH 3 ), 19.21 (CH 2 ), 23.27 (CH 2 ), 64.88 (CH 2 ), 73.20 (CH 2 ), 110.87 111.34, 115.79 117.10 (C arom ), 117.05 (C-5), 147.54 (C-6), 151.54 (C-2), 162.86 (C-4). HRMS MALDI: m/z = 365.1084 [M+Na + ] (C 16 H 17 F 3 N 2 O 3 Na + ); requires 365.1078. 1-(Ethoxymethyl)-5-ethyl-6-(2,3,5,6- tetrafluorobenzyl)uracil 9h Yield 84 mg (36%). 1 (CDCl 3 ): d (ppm) = 0.92 (t, 3H, J = 7.5 Hz, CH 3 ), 1.15 (t, 3H, J = 7.2 Hz, CH 3 ), 2.38 (q, 2H, J = 7.5 Hz, CH 2 ), 3.60 (q, 2H, J = 7.2 Hz, CH 2 ), 4.20 (s, 2H, CH 2 ), 5.35 (s, 2H, CH 2 ), 6.82 7.15 (m, 1H, H arom ), 9.40 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) = 12.81 (CH 3 ), 14.89 (CH 3 ), 19.19 (CH 2 ), 23.47 (CH 2 ), 64.95 (CH 2 ), 73.19 (CH 2 ), 104.96 106.01 (C arom ), 117.37 (C-5), 146.68 (C- 6), 151.59 (C-2), 162.89 (C-4). HRMS MALDI: m/z = 383.0989 [M+Na + ](C 16 H 16 F 4 N 2 O 3 Na + ); requires 383.0989. 1-(Ethoxymethyl)-6-(3-fluorobenzyl)-5-isopropyluracil 9i Yield 23 mg (19%). 1 (CDCl 3 ): d (ppm) = 1.18 (t, 3H, J = 7.2 Hz, CH 3 ), 1.28 (d, 6H, J = 6.9 Hz, 26CH 3 ), 2.83 (sep, 1H, CH), 3.61 (q, 2H, J = 7.2 Hz, CH 2 ), 4.18 (s, 2H, CH 2 ), 5. (s, 2H, CH 2 ), 6.82 7.35 (m, 4H, H arom ), 9.45 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) = 14.97 (CH 3 ), 19.53 (CH), 20.33 (26CH 3 ), 33.19 (CH 2 ), 65.02 (CH 2 ), 72.88 (CH 2 ), 114.33 (d, J = 21.0 Hz, C arom ), 114.24 (d, J = 21.0 Hz, C arom ), 114.37 (d, J = 21.8 Hz, C arom ), 122.86 (d, J = 3.0 Hz, C arom ), 0.69 (d, J = 8.3 Hz, C arom ), 7.99 (d, J = 7.5 Hz, C arom ), 163.22 (d, J

Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 New Emivirine and GCA-186 Analogues 9 = 246.0 Hz, C arom ), 119.90 (C-5), 147.77 (C-6), 151.81 (C-2), 162.36 (C-4). HRMS MALDI: m/z = 343.1428 [M+Na + ](C 17 H 21 FN 2 O 3 Na + ); requires 343.1427. Anal. calcd for C 17 H 21 FN 2 O 3 60.5 H 2 O: C, 61.99; H, 6.73; N, 8.59. Found: C, 61.58; H, 6.97; N, 8.86. General procedure for N-1 alkylation of 4a-f, h Method B: The pyrimidine 4a f (1 equiv.) was stirred in anhydrous CH 3 CN (15 ml) under a nitrogen atmosphere and BSA (3.5 equiv.) was added. After a clear solution was obtained (10 min), the mixture was cooled to -508C, and TMS triflate (one equiv. for preparation of 10a f, 10h, and 12e, f, h; four equiv. for preparation of 11a c, 11e, f, and 11h) was added followed by dropwise addition of the appropriate acetal (2 equiv.). The reaction mixture was stirred at room temperature for 3 4 hours (for the synthesis of compounds 10a d and 11a c) or overnight (for the synthesis of compounds 10e, f, g, 11e, f, h, and 12e, f, h). The reaction was quenched with cold, satutated, aqueous NaHCO 3 solution (5 ml), and the solvent was evaporated under reduced pressure at room temperature. The residue was extracted with CH 2 Cl 2 (3650 ml). The organic phases were collected, dried (MgSO 4 ), and evaporated under reduced pressure. The products were purified by silica gel column chromatography using 0 1% MeOH/CHCl 3 (10a d and 11a c) or 42% EtOH/petroleum ether (10e, f, g, 11e, f, h, and 12e, f, h) as eluents. 1-(Allyloxymethyl)-5-ethyl-6-(3- trifluoromethylbenzyl)uracil 10a Yield 253 mg (69%) as white foams. 1 (CDCl 3 ): d (ppm) = 1.04 (t, 3H, J = 7.5 Hz, CH 3 ), 2.43 (q, 2H, J = 7.5 Hz, CH 2 ), 4.11 (dd, 2H, J = 1.3, 5.7 Hz, CH 2 ), 4.23 (s, 2H, CH 2 ), 5. (s, 2H, CH 2 ), 5.17 5.31 (m, 2H, CH 2 =), 5.77 5.90 (m, 1H, =CH), 7.26-7.57 (m, 4H, H arom ), 9.47 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) =.68 (CH 3 ), 19.21 (CH 2 ), 33.28 (CH 2 ), 70.59 (CH 2 ), 72.57 (CH 2 ), 117.45 (C-5), 117.99 (CH 2 =), 124.20, 124.25, 124.31, 124.36, 129.79, 0.45, 6.33 (CF 3,C arom ), 3.35 (=CH), 147.84 (C-6), 151.76 (C-2), 163.08 (C-4). HRMS MALDI: m/z = 391.1240 [M+Na + ](C 18 H 19 F 3 N 2 O 3 Na + ); requires 391.1235. 1-(Allyloxymethyl)-5-isopropyl-6-(3- trifluoromethylbenzyl)uracil 10b Yield 290 mg (76%) as white solid; mp. 112 18C. 1 (CDCl 3 ): d (ppm) = 1.28 (d, 6H, J = 6.9 Hz, CH 3 ), 2.77 (hept, 1H, J = 6.9 Hz, CH), 4.11 (dd, 2H, J = 1.2, 4.4 Hz, CH 2 ), 4.25 (s, 2H, CH 2 ), 5.16 (s, 2H, CH 2 ), 5.17 5.31 (m, 2H, CH 2 =), 5.79 5.86 (m, 1H, =CH), 7.30 7.57 (m, 4H, H arom ), 9.41 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) = 20.29 (CH 3 ), 28.49 (CH), 33.36 (CH 2 ), 70.57 (CH 2 ), 72.74 (CH 2 ), 117.96 (C-5), 120.26 (CH 2 =), 124.08, 124., 124.21, 124.26, 129.73, 0.53, 6.48 (CF 3,C arom ), 3.36 (=CH), 147.25 (C-6), 151.83 (C-2), 162.20 (C-4). MS-EI: m/z (%) = 382 [M + ] (5). Anal. calcd for C 19 H 21 F 3 N 2 O 3 : C, 59.68; H, 5.54; N, 7.33. Found: C, 59.68; H, 5.48; N, 7.34. 1-(Allyloxymethyl)-6-[3,5-bis(trifluoromethyl)benzyl]-5- ethyluracil 10c Yield 296 mg (68%) as white solid; mp. 1 28C. 1 (CDCl 3 ): d (ppm) = 1.05 (t, 3H, J = 7.4 Hz, CH 3 ), 2.46 (q, 2H, J = 7.4 Hz, CH 2 ), 4.08 (d, 2H, J = 5.9 Hz, CH 2 ), 4.30 (s, 2H, CH 2 ), 5.16 (s, 2H, CH 2 ), 5.20-5.28 (m, 2H, CH 2 =), 5.74 5.87 (m, 1H, =CH), 7.58 (s, 2H, H arom ), 7.82 (s, 1H, H arom ), 9.66 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) =.59 (CH 3 ), 19.28 (CH 2 ), 33.27 (CH 2 ), 70.59 (CH 2 ), 72.66 (CH 2 ), 117.93 (C-5), 118.17 (CH 2 =), 121.56, 124.74, 127.41, 2.86, 8.15 (CF 3,C arom ), 3.06 (=CH), 146.63 (C-6), 151.68 (C-2), 162.94 (C-4). HRMS MALDI: m/z = 459.1114 [M+Na + ](C 19 H 18 F 6 N 2 O 3 Na + ); requires 459.1129. Anal. calcd for C 19 H 18 F 6 N 2 O 3 : C, 52.30; H, 4.16; N, 6.42. Found: C, 52.53; H, 4.; N, 6.33. 1-(Allyloxymethyl)-6-[3,5-bis(trifluoromethyl)benzyl]-5- isopropyluracil 10d Yield 298 mg (66%) as white solid; mp. 166-1678C. 1 (CDCl 3 ): d (ppm) = 1.28 (d, 6H, J = 6.9 Hz, 26CH 3 ), 2.70 (hept, 1H, J = 6.9 Hz, CH), 4.11 (d, 2H, J = 5.6 Hz, CH 2 ), 4.31 (s, 2H, CH 2 ), 5.16 5.26 (m, 2H, CH 2 =), 5.18 (s, 2H, CH 2 ), 5.74 5.84 (m, 1H, =CH), 7.59 (s, 2H, H arom ), 7.82 (s, 1H, H arom ), 9.29 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) = 20.18 (CH 3 ), 28.68 (CH), 33.35 (CH 2 ), 70.56 (CH 2 ), 72.82 (CH 2 ), 118.16 (C-5), 120.66 (CH 2 =), 121.41, 124.79, 127.43, 2.81, 8.21 (CF 3,C arom ), 3.06 (=CH), 146.06 (C-6), 151.61 (C-2), 161.91 (C-4). HRMS MALDI: m/z = 473.1270 [M+Na + ](C 20 H 20 F 6 N 2 O 3 Na + ); requires 473.1283. 1-(Allyloxymethyl)-5-ethyl-6-(3-fluorobenzyl)uracil 10e Yield 227 mg (89%) as white solid; mp. 60 628C. 1 (CDCl 3 ): d (ppm) = 1.07 (t, 3H, J = 7.4 Hz, CH 3 ), 2.45 (q, 2H, J = 7.2 Hz, CH 2 ), 4.10 (dt, 2H, J = 5.7, 1.5 Hz, CH 2 ), 4.16 (s, 2H, CH 2 ), 5. (s, 2H, CH 2 ), 5.17 5.32 (m, 2H, =CH 2 ), 5.79 5.90 (m, 1H, CH=), 6.82 7.35 (m, 4H, H arom ), 9.42 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.72 (CH 3 ), 19.16 (CH 2 ), 33.16 (CH 2 ), 70.56 (CH 2 ), 72.54 (CH 2 ), 117.87 (=CH 2 ), 3.45 (CH=), 114.40 (d, J = 21.0 Hz, C arom ), 122.94 (d, J = 3.0 Hz, C arom ), 0.75 (d, J = 8.3 Hz, C arom ), 7.64 (d, J = 6.8 Hz, C arom ), 163.26 (d, J = 246.0 Hz, C arom ), 117.24 (C-5), 148.23 (C-6), 151.77 (C-2), 163.12 (C-4). HRMS MALDI: m/z = 341,1277 [M+Na + ] (C 17 H 19 FN 2 O 3 Na + ); requires 341,10. Anal. calcd for C 17 H 19 FN 2 O 3 : C, 64.14; H, 6.02; N, 8.80. Found: C, 64.22; H, 6.05; N, 8.75. 1-(Allyloxymethyl)-6-(2,5-difluorobenzyl)-5-ethyluracil 10f Yield 165 mg (84%) as white solid; mp. 93 968C. 1 (CDCl 3 ): d (ppm) = 1.05 (t, 3H, J = 7.5 Hz, CH 3 ), 2.41 (q, 2H, J = 7.5 Hz, CH 2 ), 4.09 (dt, 2H, J = 5.4, 1.2 Hz, CH 2 ), 4. (s, 2H, CH 2 ), 5.15 (s, 2H, CH 2 ), 5.17 5.30 (m, 2H, =CH 2 ), 5.78 5.90 (m, 1H, CH=), 6.62 7.12 (m, 3H, H arom ), 9.42 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.59 (CH 3 ), 19.15 (CH 2 ), 26.77 (d, J = 3.8 Hz, CH 2 ), 70.48 (CH 2 ), 72.66 (CH 2 ), 117.89 (=CH 2 ), 3.29 (CH=), 114.52 117.00, 124.31 124.55, 156.37 (d, J = 243.8 Hz, C arom ), 159.00 (d, J = 243.0 Hz, C arom ), 117.71 (C-5), 147.23 (C-6), 151.61 (C-2), 162.85 (C- 4). HRMS MALDI: m/z = 359,1178 [M+Na + ](C 17 H 18 F 2 N 2 O 3 Na + ); requires 359,1180. Anal. calcd for C 17 H 18 F 2 N 2 O 3 : C, 60.71; H, 5.39; N, 8.33. Found: C, 60.73; H, 5.27; N, 8.25. 1-(Allyloxymethyl)-5-ethyl-6-(2,3,5,6- tetrafluorobenzyl)uracil 10h Yield 115 mg (48%). 1 (CDCl 3 ): d (ppm) = 1.04 (t, 3H, J = 7.5 Hz, CH 3 ), 2.49 (q, 2H, J = 7.5 Hz, CH 2 ), 4.15 (dt, 2H, J = 5.4, 1.2 Hz, CH 2 ), 4.20 (s, 2H, CH 2 ), 5.41 (s, 2H, CH 2 ), 5.14 5.34 (m, 2H, =CH 2 ), 5.76 5.95 (m, 1H, CH=), 7.00 7.15 (m, 1H, H arom ), 9.00 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.22 (CH 3 ), 18.77 (CH 2 ), 24.03 (CH 2 ), 69.92 (CH 2 ), 71.31 (CH 2 ), 117.85 (=CH 2 ), 3.25 (CH=), 105.02-106.09, 117.21 117.45 (C arom ), 114.14 (C-5), 146.56 (C-6), 151.45 (C-2), 162.75 (C-4). HRMS MALDI: m/z = 395,0989 [M+Na + ] (C 17 H 16 F 4 N 2 O 3 Na + ); requires 395,0971.

10 N. R. El-Brollowsy et al. Arch. Pharm. Chem. Life Sci. 2007, 340, 0000 0000 5-Ethyl-1-(prop-2-ynyloxymethyl)-6-(3- trifluoromethylbenzyl)uracil 11a Yield 297 mg (81%) as white solid; mp. 129 08C. 1 (CDCl 3 ): d(ppm) = 1.05 (t, 3H, J = 7.5 Hz, CH 3 ), 2.44 (t, 1H, J = 2.4 Hz, CH=), 2.45 (q, 2H, J = 7.5 Hz, CH 2 ), 4.22 (s, 2H, CH 2 ), 4.28 (d, 2H, J = 2.4 Hz, CH 2 ), 5.18 (s, 2H, CH 2 ), 7.27 7.58 (m, 4H, H arom ), 9.64 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) =.72 (CH 3 ), 19.19 (CH 2 ), 33.21 (CH 2 ), 57.16 (CH 2 ), 72.51(CH=), 74.92 (CH 2 ), 78.85 (=C), 117.59 (C-5), 124.25, 124.29, 124.35, 124.41, 129.82, 0.40, 6.16 (CF 3,C arom ), 147.66 (C-6), 151.84 (C-2), 163.09 (C-4). MS-EI: m/z (%) = 366 [M + ] (56). Anal. calcd for C 18 H 17 F 3 N 2 O 3 : C, 59.02; H, 4.68; N, 7.65. Found: C, 59.10; H, 4.66; N, 7.64. 5-Isopropyl-1-(prop-2-ynyloxymethyl)-6-(3- trifluoromethylbenzyl)uracil 11b Yield 308 mg (81%) as white solid; mp. 141 1428C. 1 (CDCl 3 ): d (ppm) = 1.30 (d, 6H, J = 6.9 Hz, 26CH 3 ), 2.45 (t, 1H, J = 2.4 Hz, CH=), 2.81 (hept, 1H, J = 6.9 Hz, CH), 4.25 (s, 2H, CH 2 ), 4.29 (d, 2H, J = 2.4 Hz, CH 2 ), 5.20 (s, 2H, CH 2 ), 7.27 7.58 (m, 4H, H arom ), 9.57 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) = 20.31 (CH 3 ), 28.48 (CH), 33.29 (CH 2 ), 57.15 (CH 2 ), 72.63 (CH=), 74.90 (CH 2 ), 78.88 (=C), 120.44 (C-5), 124.19, 124.23, 124.26, 124.31, 129.76, 0.48, 6.31 (CF 3,C arom ), 147.06 (C-6), 151.90 (C-2), 162.23 (C-4). MS-EI: m/z (%) = 380 [M + ] (34). Anal. calcd for C 19 H 19 F 3 N 2 O 3 : C, 60.00; H, 5.03; N, 7.36. Found: C, 59.95; H, 4.97; N, 7.25. 6-[3,5-Bis(trifluoromethyl)benzyl]-5-ethyl-1-(prop-2- ynyloxymethyl)uracil 11c Yield 342 mg (79%); mp. 155 1568C. 1 (CDCl 3 ): d (ppm) = 1.05 (t, 3H, J = 7.4 Hz, CH 3 ), 2.42 (q, 2H, J = 7.4 Hz, CH 2 ), 2.43 (t, 1H, J = 2.3 Hz, CH=), 4.27 (d, 2H, J = 2.3 Hz, CH 2 ), 4.29 (s, 2H, CH 2 ), 7.60 (s, 2H, H arom ), 7.83 (s, 1H, H arom ), 9.57 (s, 1H, NH). C-NMR (CDCl 3 ): d (ppm) =.63 (CH 3 ), 19.29 (CH 2 ), 33.19 (CH 2 ), 57.17 (CH 2 ), 72.59 (CH=), 75.08 (CH 2 ), 78.67 (=C), 118.04 (C-5), 121.61, 124.74, 127.48, 2.91, 7.93 (CF 3,C arom ), 146.48 (C-6), 151.62 (C-2), 162.86 (C-4). HRMS MALDI: m/z = 457.0957 [M+Na + ] (C 19 H 16 F 6 N 2 O 3 Na + ); requires 457.0954. Anal. calcd for C 19 H 16 F 6 N 2 O 3 : C, 52.54; H, 3.71; N, 6.45. Found: C, 52.60; H, 3.68; N, 6.38. 5-Ethyl-6-(3-fluorobenzyl)-1-(prop-2-ynyloxymethyl)uracil 11e Yield 168 mg (66%) as white solid; mp. 109 111 C. 1 (CDCl 3 ): d (ppm) = 1.08 (t, 3H, J = 7.5 Hz, CH 3 ), 2.46 (s, 1H, 0CH), 2.47 (q, 2H, J = 7.5 Hz, CH 2 ), 4.16 (s, 2H, CH 2 ), 4.29 (s, 2H, CH 2 C0), 5.19 (s, 2H, CH 2 ), 6.84 7.36 (m, 4H, H arom ), 9.50 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.76 (CH 3 ), 19.15 (CH 2 ), 33.11 (CH 2 ), 57.21 (CH 2 ), 72.52 (OCH), 74.82 (CH 2 ), 78.95 (CO), 114.47 (d, J = 21.0 Hz, C arom ), 122.94 (d, J = 3.0 Hz, C arom ), 0.83 (d, J = 8.3 Hz, C arom ), 7.53 (d, J = 7.5 Hz, C arom ), 163.26 (d, J = 246.0 Hz, C arom ), 117.38 (C-5), 148.08 (C-6), 151.85 (C-2), 163.09 (C-4). 6-(2,5-Difluorobenzyl)-5-ethyl-1-(prop-2- ynyloxymethyl)uracil 11f Yield 183 mg (73%) as white solid; mp. 108 1108C. 1 (CDCl 3 ): d (ppm) = 1.06 (t, 3H, J = 7.5 Hz, CH 3 ), 2.45 (s, 1H, 0CH), 2.42 (q, 2H, J = 7.5 Hz, CH 2 ), 4. (s, 2H, CH 2 ), 4.27 (s, 2H, CH 2 CO), 5.22 (s, 2H, CH 2 ), 6.64 7. (m, 3H, H arom ), 9.51 (s, H, NH). C- NMR (CDCl 3 ): d (ppm).62 (CH 3 ), 19.12 (CH 2 ), 26.80 (d, J = 3.0 Hz, CH 2 ), 57.15 (CH 2 ), 72.61 (OCH), 74.90 (CH 2 ), 78.69 (CO), 114.47 117.03, 124.06, 124.16, 124.30, 124.41, 156.38 (d, J = 243.8 Hz, C arom ), 158.99 (d, J = 240.00 Hz, C arom ), 117.89 (C-5), 147.04 (C-6), 151.76 (C-2), 162.89 (C-4). HRMS MALDI: m/z = 357.1021 [M+Na + ] (C 17 H 16 F 2 N 2 O 3 Na + ); requires 357.1016. 5-Ethyl-1-(prop-2-ynyloxymethyl)-6-(2,3,5,6- tetrafluorobenzyl)uracil 11h Yield 93 mg (38%). 1 (CDCl 3 ): d (ppm) = 0.94 (t, 3H, J = 7.2 Hz, CH 3 ), 2.41 (s, 1H, 3CH), 2.39 (q, 2H, J = 7.2 Hz, CH 2 ), 4.18 (s, 2H, CH 2 ), 4.27 (s, 2H, CH 2 C4.1.6.93), 5.43 (s, 2H, CH 2 ), 6.99-7.15 (m, 1H, H arom ), 9.11 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) = 12.89 (CH 3 ), 19.18 (CH 2 ), 23.49 (CH 2 ), 57.17 (CH 2 ), 72.98 (3CH), 74.83 (CH 2 ), 78.66 (C0), 105. 115.75 (C arom ), 117.63 (C-5), 146.39 (C-6), 151.55 (C-2), 162.66 (C-4). HRMS MALDI: m/z = 393.0833 [M+Na + ] (C 17 H 14 F 4 N 2 O 3 Na + ); requires 393.0837. 5-Ethyl-6-(3-fluorobenzyl)-1-(2- methylallyloxymethyl)uracil 12e Yield 219 mg (82%) as white solid; mp. 105 1078C. 1 (CDCl 3 ): d (ppm) = 1.07 (t, 3H, J = 7.5 Hz, CH 3 ), 1.71 (s, 3H, CH 3 ), 2.45 (q, 2H, J = 7.5 Hz, CH 2 ), 4.02 (s, 2H, CH 2 ), 4.18 (s, 2H, CH 2 ), 4.89, 4.95 (26s, 2H, =CH 2 ), 5.14 (s, 2H, CH 2 ), 6.82-7.35 (m, 4H, H arom ), 9.53 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.73 (CH 3 ), 19.14 (CH 2 ), 19.44 (CH 3 ), 33.10 (CH 2 ), 72.71 (CH 2 ), 73.59 (CH 2 ), 112.65 (=CH 2 ), 141.12 (C=), 114.27-114.55 (m, 26C arom ), 122.95 (d, J = 3.0 Hz, C arom ), 0.80 (d, J = 8.3 Hz, C arom ), 7.69 (d, J = 7.5 Hz, C arom ), 163.27 (d, J = 246.0 Hz, C arom ), 117.22 (C-5), 148.25 (C-6), 151.79 (C-2), 163.20 (C-4). HRMS MALDI: m/z = 355.1434 [M+Na + ] (C 18 H 21 FN 2 O 3 Na + ); requires 355.1400. Anal. calcd for C 18 H 21 FN 2 O 3 : C, 65.05; H, 6.37; N, 8.43. Found: C, 65.22; H, 6.37; N, 8.32. 6-(2,5-Difluorobenzyl)-5-ethyl-1-(2- methylallyloxymethyl)uracil 12f Yield 190 mg (72%) as white solid; mp. 96 998C. 1 (CDCl 3 ): d (ppm) = 1.05 (t, 3H, J = 7.5 Hz, CH 3 ), 1.70 (s, 3H, CH 3 ), 2.41 (q, 2H, J = 7,5 Hz, CH 2 ), 4.00 (s, 2H, CH 2 C=), 4.14 (s, 2H, CH 2 ), 4.87, 4.94 (26s, 2H, =CH 2 ), 5.15 (s, 2H, CH 2 ), 6.62-7,12 (m, 3H, H arom ), 9.44 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.60 (CH 3 ), 19.12 (CH 3 ), 19.38 (CH 2 ), 26.70 (d, J = 3.0 Hz, CH 2 ), 72.83 (CH 2 ), 73.54 (CH 2 ), 112.67 (=CH 2 ), 140.99 (C=), 114.48 117.01, 124.19 124.52, 156.37 (d, J = 243.8 Hz, C arom ), 158.98 (d, J = 243.00 Hz, C arom ), 117.69 (C-5), 147.25 (C-6), 151.63 (C-2), 162.95 (C-4). HRMS MALDI: m/z = 373.34 [M+Na + ] (C 18 H 20 F 2 N 2 O 3 Na + ); requires 373.31. Anal. calcd for C 18 H 20 F 2 N 2 O 3 : C, 61.71; H, 5.75; N, 8.00. Found: C, 61.77; H, 5.62; N, 7.92. 5-Ethyl-1-(2-methylallyloxymethyl)-6-(2,3,5,6- tetrafluorobenzyl)uracil 12h Yield 144 mg (56%). 1 (CDCl 3 ): d (ppm) = 1.04 (t, 3H, J = 7.5 Hz, CH 3 ), 2.49 (q, 2H, J = 7.5 Hz, CH 2 ), 4.15 (m, 2H, CH 2 ), 4.20 (s, 2H, CH 2 ), 5.41 (s, 2H, CH 2 ), 5.14 5.34 (m, 2H, =CH 2 ), 5.76 5.95 (m, 1H, CH=), 7.00 7.15 (m, 1H, H arom ), 9.00 (s, H, NH). C-NMR (CDCl 3 ): d (ppm) =.22 (CH 3 ), 18.77 (CH 2 ), 24.03 (CH 2 ), 69.92 (CH 2 ), 71.31 (CH 2 ), 117.85 (=CH 2 ), 3.25 (CH=), 105.02 106.09, 117.21 117.45 (C arom ), 114.14 (C-5), 146.56 (C-6), 151.45 (C-2), 162.75 (C-4). HRMS MALDI: m/z = 395.0989 [M+Na + ](C 18 H 18 F 4 N 2 O 3 Na + ); requires 395.0971.