# Three Component Reaction: An Efficient Synthesis and Reactions of 3,4-Dihydropyrimidin-2(1H)-Ones and Thiones Using New Natural Catalyst

Authors: A. M. Elmaghraby; I. A. Mousa; A. A. Harb; M. Y. Mahgoub
Journal: ISRN Organic Chemistry
 (2013)

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## Abstract

Synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidin-2(1H)-thione derivatives from aldehydes, 1,3-dicarbonyl derivatives and urea or thiourea using granite and quartz as new, natural and reusable catalysts. Some of the 3,4-dihydropyrimidin-2(1H)-thione derivatives were used to prepare new heterocyclic compounds. The antimicrobial activity of selected examples of the synthesized compounds was tested and showed moderate activity.


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## Body

## 1. Introduction

Aryl-3,4-dihydropyrimidines derivatives have recently received great attention because of their wide range of therapeutic and pharmacological properties, such as antiviral [1], antitumor, antibacterial and antifungal [2], anti-inflammatory [3], antihypertensive agents, and neuropeptide Y (NPY) antagonists [4]. Furthermore, these compounds have emerged as the integral backbones of several calcium-channel blockers [5]. Also, several alkaloids containing the dihydropyrimidine were isolated from marine sources, for example, of these are the batzelladine alkaloids, which are found to be potent HIVgp-120-CD4 inhibitors [6, 7].In general, the classic Biginelli approach to 3,4-dihydropyrimidinones is based on the condensation of ethyl acetoacetate, aromatic aldehyde, and urea under strong acidic conditions; this suffers, however, from low yields of products, particularly in case of substituted aromatic and aliphatic aldehydes [8, 9]. This problem has led to the development of multistep synthetic strategies that produce relatively higher yields, but lack the simplicity of the original one-pot-Biginelli protocol. Thus, the Biginelli reaction has received renewed interest from researchers interested in discovering milder and more efficient procedures that are applicable to a wide range of substituents in all three components and proceed in better yields. So, the one-pot-Biginelli protocol for 3,4-dihydropyrimidines synthesis was explored by varying all components and catalysts [10–18] in protic, aprotic solvents, and solvent free conditions [19] using either classical heating, microwave [20, 21], ultrasound [22, 23], and visible light (100 W Lamp, THF) irradiations [24]. Also several improved procedures have been reported recently using not only acidic media such as Lewis acids, protic acids, and ionic liquids as promoters [25, 26] but also nonacidic substances such as baker’s yeast [27], graphite [28], and iodine [29, 30]. Heterogeneous solid acids are used also; however, these are advantageous over conventional homogeneous acid catalysts as they can be easily recovered from the reaction mixture by simple filtration and can be reused after activation or without activation, thereby making the process economically viable [31]. Bakibaev and Filimonov [32] reported that piperidine as a base catalyst can promote the Biginelli protocol also, to afford the corresponding 3,4-dihydropyrimidines along with Hantzsch 1,4-dihydropyridines which may form in spite of urea decomposition in the reaction media, releasing ammonia. We would like to propose a new naturally and very cheap catalysts granite and quartz for the synthesis of 3,4-dihydropyrimidinones and 3,4-dihydropyrimidenthiones, using one-pot-Biginelli protocol, in refluxing ethanol.


## 2. Result and Discussion

It is interesting to report that the one pot reaction of a mixture of benzaldehyde, ethyl acetoacetate, and urea in the presence of granite or quartz as a catalyst in refluxing ethanol resulted in the formation of 4-phenyl-3,4-dihydropyrimidinoneIa, Table 1 in 64% or 68% yield according to the catalyst (Scheme 1). In a similar way, urea was condensed smoothly with variety of aromatic or heterocyclic aldehydes and variety of 1,3-dicarbonyl compounds in the presence of granite or quartz in refluxing ethanol as one pot reaction to afford the corresponding 3,4-dihydropyrimidines Ib–q (Table 1) whose composition and structures were confirmed by elemental analysis, Mass, IR, and 1H NMR spectra of the isolated products (cf. experimental section).Table 1
3,4-Dihydropyrimidin-2(1H)ones (I).
Entry
R1
R2
Time (h)
MP. [Reference]
Yielda
Quartz
Granite
Found
Reported
Quartz
Granite
Ia
C6H5
OEt
3
3.5
201-202
200–202 [33]
68
64
Ib
2-(OH)-C6H4
OEt
3.5
5
202–204
200–202 [34]
62
60
Ic
4-(OCH3)-C6H4
OEt
3
3
199-200
201-202 [35]
64
60
Id
Ph-CH=CH
OEt
3
4
232–234
232–235 [36]
58
55
Ie
2,5-(OCH3)-C6H3
OEt
4
5
210–212
212–214 [37]
61
58
If
3,4,5-(OCH3)-C6H2
OEt
3
4.5
180-181
180–182 [25]
60
56
Ig
2-furyl
OEt
3
4
205-206
203–205 [38]
66
61
Ih
2-(Cl)-C6H4
OEt
3
4
214-215
215-216 [39]
65
62
Ii
4-(OCH3)-C6H4
CH3
3
4
165–167
166–168 [40]
69
65
Ij
4-N(CH3)2-C6H4
OEt
3
4
233–235
230–232 [25]
62
58
Ik
4-(CH3)-C6H4
OEt
2
3
210–212
214-215 [35]
65
62
Il
2,6-(Cl)-C6H3
OEt
4
4.5
302-303
305 [41]
57
61
Im
2-thienyl
OEt
2
3
214–216
215–217 [42]
66
63
In
4-(F)-C6H4
OEt
2
3
175–177
175–177 [43]
71
68
Io
3-(OCH2Ph)-C6H4
OEt
3
3.5
178–180
New
65
62
Ip
3-(OCH2Ph)-C6H4
CH3
3.5
4
192–194
New
40
63
Iq
2,3-(OCH3)-C6H3
OEt
3
4
178–180
New
63
60
aIsolated yield.Scheme 1On the other hand, carrying out of the above reaction using of 3-benzyloxybenzaldehyde, acetyl acetone, and urea in refluxing ethanol using granite as catalyst, the corresponding 5-acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one Io was isolated. However, on carrying the above reaction using quartz as a catalyst, beside the proposed 3,4-dihydropyrimidinone Io, another product with molecular formula (C16H16N4O2), m/z=296 was isolated from the reaction media in 25% yield. This product can be identified as 4-amino-6-(3-(benzyloxy)phenyl)-5,6-dihydro-1,3,5-triazin-2(1H)-one III based on the analytical and the spectral data of the isolated product, which revealed the presence of characteristic stretching vibrations due to NH, NH2, and amidic CO at ν=3450, 3300, and 1640 cm−1 regions, respectively, in the IR spectrum. Also, the 1H-NMR spectrum of the isolated product shows signals at δ=5.07 (s, 2H, –CH2–), 5.43 (s, 1H, –CH–), 5.68 (s, 2H, –NH2), 6.70–7.46 (m, 9H, Ar), and 10.0 (s, 1H, NH) ppm. The 13C-NMR spectrum of the isolated product shows signals at δ=51.2 (CH aliphatic), 62.32 (CH2 aliphatic), 165.3 (C triazine ring), 190.4 (C=O amidic), and 111–160 (Benzene rings). This expectation is based on the observation that the 3-benzyloxybenzaldehyde condensed with two moles of urea to give the corresponding bis-ureide II as key intermediate which cyclized via elimination of H2O to give the extremely low yield triazine derivative III [44] (Scheme 2).Scheme 2In generality of this process, various 1,3-diketones and aldehydes were reacted with thiourea in refluxing ethanol using granite or quartz as the reaction catalyst to give the corresponding 3,4-dihydropyrimidin-2(1H)-thione derivatives IV (Table 2) which their structures were confirmed on the bases of the analytical and spectral data of the isolated products (cf. experimental section) (Scheme 3).Table 2
3,4-Dihydropyrimidin-2(1H)-thiones (IV).
Entry
R1
R2
R3
Time (h)
MP. [Reference]
Yielda
Quartz
Granite
Found
Reported
Quartz
Granite
IVa
C6H5
OEt
Ph
3
3
183-184
183–185 [45]
63
60
IVb
4-(OCH3)-C6H4
CH3
CH3
3.5
4
181-182
183-184 [46]
67
65
IVc
2,3-(OCH3)-C6H3
OEt
CH3
3.5
4
181–183
New
64
63
IVd
4-(OCH3)-C6H4
OEt
CH3
3
4
152-153
150–152 [43]
59
56
IVe
2-(OH)-C6H4
OEt
CH3
3
4
210-211
206–208 [47]
63
59
IVf
2,6-(Cl)-C6H3
OEt
CH3
4
5
222–224
New
55
60
IVg
3-(OCH2Ph)-C6H4
OEt
CH3
3
4
180–182
New
66
60
IVh
2,5-(OCH3)-C6H3
OEt
CH3
4.5
5
188–190
New
64
60
aIsolated yield.Scheme 3On reading of the experimental results, we noted that aromatic aldehydes carrying either electron-donating or electron-withdrawing substituents reacted well under the reaction conditions to give the corresponding products in moderate to good yields high purity in case of granite or quartz. However, the obtained yields on using quartz are higher than granite either in case of urea or thiourea. This may be due to the high percentage of SiO2 in quartz. This procedure not only preserves the simplicity of the Biginelli reaction but also produces good yields of the products with high purity. Also, the catalyst was recovered by simple filtration and reused in subsequent reactions with consistent activity.We can use the prepared 3,4-dihydropyrimidenthionesIVa–c to synthesize newly derivatives. Thus, heating of IVa–cwith methyl iodide in dry acetone in the presence of anhydrous potassium carbonate afforded the S–CH3 derivatives Va–c which was confirmed by using elemental analysis and spectral data. The 1H NMR illustrated the presence of singlet S–CH3 protons.On the other hand, heating ofIVa–cin acetic anhydride afforded the corresponding 3-N-acetyl derivatives VIa–c. Structure VIc was deduced from elemental and spectral data. The mass spectrum showed the molecular ion peak at m/z (%) = 378 (M+, 48.03), for molecular formula C18H22N2O5S. The 1H NMR illustrated the presence singlet N–COCH3 protons at δ=2.60 ppm, in addition to other singlet peaks at δ=2.27, 3.67, and 3.77 ppm for methyl and two methoxy groups, respectively, and the absence of the NH proton at δ=7.27.In the same time, we can use the same conditions to prepareVIa,b which was elucidated by correct elemental analysis and spectral data (cf. experimental data). Also VIa–c was synthesized by the reaction of IVa–c with acetyl chloride in DMF (melting and mixed melting point) (Scheme 4).Scheme 4In the same time, the pyrimidine derivativesVIIa,b can be synthesized via acetylation of the corresponding S–CH3 derivatives Va,b using acetic anhydride. Also, it can be prepared via methylation of the N-acetyl derivatives VIa,b. Structures VIIa,b were elucidated by elemental analysis and spectral data. The mass spectrum for VIIa showed the molecular ion peak at m/z (%) = 394 (M+, 12.51), while VIIb illustrated the molecular ion peak at m/z (%) = 332 (M+, 43.22). The 1H NMR revealed the presence of singlet peak at δ=2.50 ppm for COCH3 protons and the absence of the singlet peak at δ=7.27 ppm for NH proton. Also IR spectrum showed the absence of NH peak (Scheme 4).Methylation ofVa was carried out in methyl iodide in DMF in the presence of K2CO3 anhydrous that yielded VIIIa which was confirmed by correct elemental analysis as well as spectral data. The 1H NMR showed the absence of singlet peak at δ=7.27 ppm for NH proton and the appearance of a singlet peak at δ=3.33 ppm for N–CH3 protons (Scheme 4).Heating ofIVa with ethylchloroacetate in ethanol and sodium acetate afforded ethyl 3-oxo-5,7-diphenyl-3,5,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate Xaover the unisolated intermediate ethyl 2-(2-ethoxy-2-oxoethylthio)-4,6-diphenyl-1,6 dihydropyrimidine-5-carboxylate IXa as shown in elemental analysis as well as spectral data. The mass spectrum showed the molecular ion peak at m/z (%) = 378 (M+, 60.03) for molecular formula C21H18N2O3S. The 1H NMR revealed also the presence of one only ethyl ester group, at δ=0.85 for CH3 protons (t) and 3.85 for CH2 (q), and also the absence of NH proton at δ=7.27 ppm. The IR spectrum showed absorption bands at 1752, 1675, and 1589 cm−1 for carbonyl ester, amidic carbonyl groups, and C=N, respectively. Also, the isolated product Xa was obtained via the reaction of IVa with chloroacetyl chloride or bromoacetyl bromide in benzene and drops of triethylamine as catalyst. In the same time, compound Xa can be isolated from the reaction of IVa with chloro- or bromoacetic acid in acetic acid and acetic anhydride mixture in presence of anhydrous sodium acetate. Similarly, compound Xbwas prepared from the reaction of IVb with ethylchloroacetate, chloroacetic acid, or chloroacetyl-chloride as shown in previous conditions (Scheme 5).Scheme 5CompoundXa was condensed with different aromatic aldehydes in refluxing ethanolic pipredine solution to give the corresponding arylidene derivatives XIa–c. Structures XIa–cwere deduced from its elemental analysis and spectral data. The 1H NMR showed the absence of singlet peak for CH2 protons at δ=3.88 ppm and the appearance of singlet peak for =CH proton at δ=7.74 ppm (Scheme 5).Aiming to the synthesizing of thiazolopyrimidineXII, we refluxed IVb with chloroacetone in ethanolic piperidine solution. However the corresponding 1-(5-acetyl-6-(4-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-ylthio)propan-2-one XIIIwas formed which was identified by elemental analysis as well as spectral data. The mass spectrum showed the molecular ion peak at m/z (%) = 332 (M+, 5.30) for molecular formula C17H20N2O3S. The 1H NMR confirmed the presence of only one NH proton at δ=7.11 ppm and singlet peak at δ=2.46 ppm due to CH2 protons (Scheme 6).Scheme 6On the other hand, compoundVa,b was reacted with thiosemicarbazide in refluxing ethanol to give the corresponding carbazide XIVa,b instead of the corresponding fused pyrimidinotriazoles XV and XVI. Structures XIVa,b were established by elemental analysis and spectral data where the mass spectrum showed the molecular ion peak at m/z (%) = 395 (M+, 24.13) for XIVa and at m/z (%) = 333 (M+, 12.18) for XIVb (Scheme 7).Scheme 7On the other hand, refluxing ofIVa,bin methyl alcohol in the presence of acetic acid and water (4 : 1 : 1) afforded 3,4-dihydropyrimidinone derivatives XVIIa,b. Compound XVIIa was confirmed by compare mp. (Found) = 160°C, mp. (Reported) = 158°C [48]. Also, compound XVIIb was established by compare mp. (Found) = 164–166°C; mp. (Reported) = 166-167°C [48] (Scheme 8).Scheme 8


## 3. Antimicrobial Activity

There are 5 compounds (III,IVg,IVf,IVh, andIVc) that were tested and showed promising positive antibacterial activity.All the compounds showed activity against bacteria such asStaphylococcus aureusandEscherichia coli. The IVh & IVc compounds showed positive antibacterial against S. aureuswhich are 14.5 mm and 14 mm, respectively, which are 0.25 and 0.75 mm less than the zone around Streptomphenicol disc. This may be due the presence of sulfur atomand pyrimidine ring.The other three most active compounds tested are compoundsIVg, IVf, and III. The activity of these compounds against Staphylococcus aureusshowed positive reactions, 12.75, 12.5, and 12 mm of inhibition zones, respectively, compared to the inhibition zone of antibiotic used, as indicated in (Table 3); this may be due to sulfur atom, two chlorine atoms, and triazine ring, respectively.Table 3
Inhibition zone resulted from the effect of the antibiotic (Streptophenicol) and tested compounds onEscherichia  coli and Staphylococcus  aureus.
Compounds no.(1 × 10−2)
Escherichia  coli
Staphylococcus  aureus
Zone of inhibition
Antibiotic (Streptophenicol)
25
14.75
12
12
11
12.75
11
12.5
12
14.5
10.5
14All the compounds have approximately the same effect againstEscherichia coli bacteria as indicated by the zone of inhibition (Table 3). In case of using these compounds as antimicrobial cytotoxicity, effect of these compounds must be examined.


## 4. Conclusion

In summary, we have found that quartz and granite are extremely useful and highly efficient new natural, solids for the synthesis of biologically potent aryl 3,4-dihydropyrimidines by means of three-component condensations of an aldehyde, 1,3-dicarbonyl compound, and urea or thiourea in a one-pot operation. This method is applicable to a wide range of substrates, including aromatic and heterocyclic aldehydes, and provides a variety of biologically relevant 3,4-dihydropyrimidinones and 3,4-dihydropyrimidinthiones in high yields after short reaction times.


## 5. Experimental Section

### 5.1. General

All melting points were measured with a Gallenkamp apparatus. The IR spectra of samples were recorded in KBr via a Shimadzu FT-IR 8101 PC infrared spectrophotometer.1H NMR spectra were run at 300 MHz and recorded in CDCl3/[D6] DMSO using TMS as the internal standard. Chemical shifts were related to that of the solvent. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 eV. TLC was conducted on 0.25 mm precoated silica gel plates (60F-254). Elemental analyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. The catalyst is ground until it became fine powder.


#### 5.1.1. General Procedure for the Synthesis of the Newly 3,4-Dihydropyrimidinones(Io,p,q) and 3,4-Dihydropyrimidinthiones (IVc,h,g,f)

A mixture of aldehyde (1 mmol), 1,3-dicarbonyl compounds (1 mmol), urea or thiourea (1 mmol), and granite or quartz (0.5 g) in ethanol (15 mL) was heated under reflux for the required time. After completion of the reaction as monitored by T.L.C., the reaction mixture was filtered to separate the catalyst. Keep the reaction mixture overnight. The solid product was filtered under suction then recrystallized from ethanol to afford pure product.Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(Io). mp. = 178–180°C. I.R (KBr): ν=3300, 3100, 2950, 1700, 1630 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.16 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.33 (s, 3H, CH3), 4.08 (q, 2H, –O–CH2–CH3), 5.03 (s, 2H, –O–CH2–Ph), 5.37 (s, 1H, –CH–), 5.92 (s, 1H, –NH), 6.85–6.94 (m, 4H, Ar), 7.19–7.39 (m, 5H, Ar), 8.31 (s, 1H, –NH) ppm. Mass: m/z (%): 366 (M+, 6.31), 275 (22.72), 183 (24.94), 91 (100.0). C21H22N2O4 (366): calculated, %: C 68.84, H 6.05, N 7.65, O 17.47; found, %: C 68.82, H 6.10, N 7.55, O 17.46. Yield quartz (65%), granite (62%).5-Acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(Ip). mp. = 192–194°C. I.R (KBr): ν=3450, 3200, 2950, 1640, 1590 cm−1. 1H NMR (300 MHz, DMSO): δ=2.08 (s, 3H, CH3), 2.27 (s, 3H, –COCH3), 5.05 (s, 2H, –O–CH2–Ph), 5.20 (s, 1H, –CH–), 6.81–6.92 (m, 4H, Ar), 7.21–7.45 (m, 5H, Ar), 7.81 (s, 1H, –NH), 9.17 (s, 1H, –NH) ppm. Mass: m/z (%): 336 (M+, 1.6), 293 (1.9), 245 (33), 153 (14.6), 91 (100.0). C20H20N2O3 (336): calculated, %: C 71.41, H 5.99, N 8.33, O 14.27; found, %: C 71.40, H 6.0, N 8.30, O 14.21. Yield quartz (40%), granite (63%).Ethyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(Iq). mp. = 178–180°C. I.R (KBr): ν=3250, 3100, 2950, 1700, 1640 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.11 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.40 (s, 3H, CH3), 3.87 (s, 3H, –OCH3), 3.92 (s, 3H, –OCH3), 4.06 (q, 2H, –O–CH2–CH3), 5.71 (s, 1H, –CH–), 5.72 (s, 1H, –NH), 6.73 (d, 1H, Ar), 6.87 (d, 1H, Ar), 6.98 (t, 1H, Ar), 7.27 (s, 1H, –NH) ppm. Mass: m/z (%): 320 (M+, 13.7), 288 (100.0), 243 (55.2), 183 (94.9), 155 (68.9), 137 (60.1), 77 (47.3). C16H20N2O5 (320): calculated, %: C 59.99, H 6.29, N 8.74, O 24.97; found, %: C 59.95, H 6.22, N 8.70, O 24.99. Yield quartz (63%), granite (60%).Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVg). mp. = 180–182°C. I.R (KBr): ν=3400, 3150, 2950, 1650 cm−1. 1H NMR (300 MHz, DMSO): δ=1.10 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.27 (s, 3H, CH3), 4.01 (q, 2H, –O–CH2–CH3), 5.05 (s, 2H, –O–CH2–Ph), 5.15 (s, 1H, –CH–), 6.80 (m, 4H, Ar), 7.23–7.42 (m, 5H, Ar), 9.60 (s, 1H, –NH), 10.30 (s, 1H, –NH) ppm. Mass: m/z (%): 382 (M+, 17.6), 199 (12.2), 91 (100.0). C21H22N2O3S (382): calculated, %: C 65.95, H 5.80, N 7.32, O 12.55, S 8.38; found, %: C 65.89, H 5.60, N 7.35, O 17.46, S 8.36. Yield quartz (66%), granite (60%).Ethyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVc). mp. = 181–183°C. I.R (KBr): ν=3200, 3100, 2950, 1705 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.10 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.42 (s, 3H, CH3), 3.86 (s, 3H, –OCH3), 3.93 (s, 3H, –OCH3), 4.05 (q, 2H, –O–CH2–CH3), 5.71 (s, 1H, –CH–), 6.68 (d, 1H, Ar), 6.88 (d, 1H, Ar), 6.99 (t, 1H, Ar), 7.26 (s, 1H, –NH), 8.10 (s, 1H, –NH) ppm. Mass: m/z (%): 336 (M+, 76.4), 305 (86.1), 289 (81.5), 263 (100.0), 199 (87.7), 171 (63.3), 153 (31.5), 77 (44.6). C16H20N2O4S (336): calculated, %: C 57.12, H 5.99, N 8.33, O 19.02, S 9.53; found, %: C 57.13, H 5.96, N 8.35, O 19.06, S 9.51. Yield quartz (64%), granite (63%).Ethyl-4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVh). mp. = 188–190°C. I.R (KBr): ν=3200, 3100, 2940, 1700 cm−1. 1H NMR (300 MHz, DMSO): δ=1.05 (t, J=8.2 Hz, 3H, –O–CH2–CH3), 2.27 (s, 3H, CH3), 3.65 (s, 3H, –OCH3), 3.72 (s, 3H, –OCH3), 3.96 (q, 2H, –O–CH2–CH3), 5.44 (s, 1H, –CH–), 6.57 (s, 1H, Ar), 6.83 (d, 1H, Ar), 6.94 (d, 1H, Ar), 9.24 (s, 1H, –NH), 10.24 (s, 1H, –NH) ppm. Mass: m/z (%): 338 (M+, 10.97), 279 (10.49), 256 (19.23), 166 (45.38), 149 (100.0), 105 (28.13), 69 (90.57). C16H20N2O4S (336): calculated, %: C 57.12, H 5.99, N 8.33, O 19.02, S 9.53; found, %: C 57.14, H 5.96, N 8.30, O 19.04, S 9.56. Yield quartz (64%), granite (60%).Ethyl-4-(2,6-dichlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVf). mp. = 222–224°C. I.R (KBr): ν=3150, 3000, 2900, 1750, 1640 cm−1. 1H NMR (300 MHz, CDCl3): δ=0.94 (t, J=6.6 Hz, 3H, –O–CH2–CH3), 2.23 (s, 3H, CH3), 3.91 (q, 2H, –O–CH2–CH3), 6.28 (s, 1H, –CH–), 7.05–7.23 (m, 3H, Ar), 7.94 (s, 1H, –NH), 8.32 (s, 1H, –NH) ppm. Mass: m/z (%): 344 (M+, 23.9), 348 (M+4, 7.6), 315 (34.5), 199 (100.0), 171 (36.4), 153 (16.2). C14H14Cl2N2O2S (344): calculated, %: C 48.70, H 4.09, Cl 20.54, N 8.11, O 9.27, S 9.29; found, %: C 48.72, H 4.04, Cl 20.50, N 8.13, O 9.29, S 9.30. Yield quartz (55%), granite (60%).4-Amino-6-(3-(benzyloxy)phenyl)-5,6-dihydro-1,3,5-triazin-2(1H)-one
(III). mp. = 172–174°C I.R (KBr): ν=3450, 3300, 1640 cm−1. 1H NMR (300 MHz, DMSO): δ=5.07 (s, 2H, –CH2–), 5.43 (s, 1H, –CH–), 5.68 (s, 2H, –NH2), 6.70–6.92 (m, 4H, Ar), 6.98 (s, 1H, NH), 7.23–7.46 (m, 5H, Ar), 10.0 (s, 1H, NH) ppm. The 13C-NMR (300 MHz, DMSO) δ=51.2 (CH aliphatic), 62.32 (CH2 aliphatic), 165.3 (C triazine ring), 190.4 (C=O amidic), 111–160 (benzene rings). Mass: m/z (%): 296 (M+, 54.58), 294 (82.76), 253 (57.20), 227 (63.30), 203 (100.0), 182 (31.01), 171 (55.77), 131 (99.09), 104 (29.73). C16H16N4O2 (296): calculated, %: C 64.85, H 5.44, N 18.91, O 10.80; found, %: C 64.82, H 5.40, N 18.93, O 10.82. Yield quartz (25%).


#### 5.1.2. General Procedure of Methylation of CompoundsIVa–c

A mixture ofIVa–c (0.005 mol) and methyl iodide (0.005 mol) was dissolved in dry acetone in the presence of pot. Carbonate anhydrous was refluxed in water bath for 5 hours. The reaction mixture was filtered on hot then kept for overnight. The formed solid was filtered off and crystallized from an appropriate solvent to give Va,b,c.Ethyl-2-(methylthio)-4,6-diphenyl-1,6-dihydropyrimidine-5-carboxylate
(Va). The formed solid was crystallized from petroleum ether/benzene 2 : 1; mp. = 158–160°C; I.R (KBr): ν=3280, 2982, 2807, 1676, 1614, 1493 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 2.49 (s, 3H, –SCH3), 3.86 (q, 2H, –O–CH2–CH3), 5.74 (s, 1H, –CH–), 7.27 (s, 1H, NH), 7.28–7.48 (m, 10H, Ar) ppm; mass: m/z (%): 352 (M+, 23.35), 337 (33.58), 323 (68.32), 275 (100.0), 77 (25.52); C20H20N2O2S (352): calculated, %: C 68.16, H 5.72, N 7.95, O 9.08, S 9.10; Found, %: C 68.13, H 5.75, N 7.97, O 9.10, S 9.12; yield (77%).1-(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)-1,6-dihydropyrimidin-5-yl)ethanone
(Vb). The formed solid was crystallized from petroleum ether/ethanol 1 : 1; mp. = 126–128°C; I.R (KBr): ν=3285, 2950, 2928, 1639, 1594 cm−1; 1H NMR (300 MHz, DMSO): δ=2.09 (s, 3H, –CH3), 2.23 (s, 3H, –SCH3), 2.28 (s, 3H, –COCH3), 3.70 (s, 3H, –OCH3), 5.54 (s, 1H, –CH–), 6.82–7.15 (d, d, 4H, Ar), 9.57 (s, 1H, –NH) ppm; mass: m/z (%): 288 (M+, 29.40), 250 (22.10), 183 (19.10), 73 (67.60), 57 (100.0); C15H18N2O2S (290): calculated, %: C 62.04, H 6.25, N 9.65, O 11.02, S 11.04; found, %: C 62.03, H 6.26, N 9.65, O 11.04, S 11.03; yield (86%).Ethyl-6-(2,3-dimethoxyphenyl)-4-methyl-2-(methylthio)-1,6-dihydropyrimidine-5-carboxylate
(Vc). The solid product was crystallized from petroleum ether (60–80); mp. = 140°C; I.R (KBr): ν=3321, 2935, 2832, 1706, 1669, 1594 cm−1; 1H NMR (300 MHz, DMSO): δ=1.13 (t, J=7.5 Hz, 3H, CH3CH2O–), 2.39 (s, 3H, –CH3), 2.45 (s, 3H, –SCH3), 3.87 (s, 3H, –OCH3), 3.93 (s, 3H, –OCH3), 4.06 (q, 2H, CH3CH2O–), 5.85 (s, 1H, –CH), 6.77–7.02 (m, 3H, Ar), 7.27 (s, 1H, –NH) ppm; mass: m/z (%): 350 (M+, 20.56), 335 (36.97), 321 (64.29), 303 (40.44), 213 (100.0), 77 (23.14); C17H22N2O4S (350): calculated, %: C 58.27, H 6.33, N 7.99, O 18.26, S 9.15; found, %: C 58.26, H 6.33, N 7.97, O 18.27, S 9.16; yield (74%).


#### 5.1.3. Acylation of CompoundsIVa–c

Method (A). A mixture of IVa–c (0.005 mol) and acetyl chloride (0.01 mol) was refluxed in DMF (15 mL) as a solvent containing (5 drops) of triethylamine (TEA) for 1 hour and then stirred at room temperature for overnight, and then the solution was poured into ice with vigorous stirring, and then the solid product was filtered off and recrystallized from suitable solvent to afford compounds VIa,b,c.Method (B). A solution of IVa–c (0.01 mol) in 15 mL of acetic anhydride was heated under reflux for 1.30 hour. The solution was then poured into 150 mL of ice-water and stirred for several hours until crystallization was complete. The precipitate was filtered and crystallized from suitable solvent to afford compounds VIa,b,c.Ethyl 3-acetyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(VIc). The solid product was recrystallized from ethanol; method (A): yield (81%). method (B): yield (78%); mp. = 186°C; I.R (KBr): ν=3237, 2996, 2944, 2837, 1702, 1671 cm−1; 1H NMR (300 MHz, DMSO): δ=1.17 (t, J=6.6 Hz, 3H, CH3CH2O–), 2.27 (s, 3H, –CH3), 2.60 (s, 3H, –COCH3), 3.67 (s, 3H, –OCH3), 3.77 (s, 3H, –OCH3), 4.08 (q, 2H, CH3CH2O–), 5.50 (s, 1H, –CH), 6.68–7.0 (m, 3H, Ar), 11.6 (s, 1H, –NH) ppm; mass: m/z (%): 378 (M+, 48.03), 335 (96.81), 289 (100.0), 263 (45.57), 199 (33.62), 77 (22.44); C18H22N2O5S (378): calculated, %: C 57.13, H 5.86, N 7.40, O 21.14, S 8.47; found, %: C 57.14, H 5.85, N 7.41, O 21.13, S 8.45.Ethyl  3-acetyl-4,6-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(VIa). The solid product was recrystallized from benzene; method (A): yield (80%); method (B): yield (85%). mp. = 136°C; I.R (KBr): ν=3215, 2986, 1642, 1599, 1494 cm−1; mass: m/z (%): 380 (M+, 37.39), 337 (100.0), 307 (25.7), 265 (57.72), 104 (65.03); C21H20N2O3S (380): calculated, %: C 66.29, H 5.30, N 7.36, O 12.62, S 8.43; found, %: C 66.28, H 5.31, N 7.35, O 12.63, S 8.42.1,1
′
-(6-(4-Methoxyphenyl)-4-methyl-2-thioxo-2,3-dihydropyrimidine-1,5(6H)-diyl)diethanone(VIb). The solid product was recrystallized from ethanol; method (A): yield (65%); method (B): yield (70%). mp. = 130°C; I.R (KBr): ν=3243, 2962, 1698, 1609, 1509 cm−1.


#### 5.1.4. Synthesis of Compounds(VIIa,b)

A solution ofVa,b(0.01 mol) in 15 mL of acetic anhydride was heated under reflux for one hour. The solution was then poured into 150 mL of ice-water and stirred for several hours until crystallization was complete. The precipitate was filtered off and washed with water then crystallized from an appropriate solvent to afford VIIa,b.Ethyl  1-acetyl-2-(methylthio)-4,6-diphenyl-1,6-dihydropyrimidine-5-carboxylate
(VIIa). The solid product crystallized from petroleum ether (60–80); yield (90%); mp. = 102°C; I.R (KBr): ν=2978, 1697, 1601, 1533 cm−1; 1H NMR (300 MHz,CDCl3): 0.97 (t, J=6.6 Hz, 3H, CH3CH2O–), 2.50 (s, 3H, –SCH3), 2.50 (s, 3H, –COCH3), 4.02 (q, 2H, CH3CH2O–), 6.66 (s, 1H, –CH), 7.27–7.60 (m, 10H, Ar) ppm; mass: m/z (%): 394 (M+, 12.51), 351 (100.0), 337 (10.86), 323 (28.06), 275 (84.24), 129 (18.40), 77 (29.31); C22H22N2O3S (394): calculated, %: C 66.98, H 5.62, N 7.10, O 12.17, S 8.13; found, %: C 66.97, H 5.63, N 7.09, O 12.18, S 8.12.1,1
′
-(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)pyrimidine-1,5(6H)-diyl)diethanone(VIIb). The precipitated product was crystallized from benzene; yield (86%); mp. = 180°C. I.R (KBr): ν=2990, 1675, 1568 cm−1; mass: m/z (%): 332 (M+, 43.22), 312 (39.56), 278 (51.28), 100 (100.0), 67 (50.55); C17H20N2O3S (332): calculated, %: C 61.42, H 6.06, N 8.43, O 14.44, S 9.65; found, %: C 61.43, H 6.04, N 8.46, O 14.45, S 9.66.Synthesis of Ethyl 1-Methyl-2-(methylthio)-4,6-diphenyl-1,6-dihydro-pyrimidine-5-carboxylate
(VIIIa). A mixture of Va (0.005 mol) and methyl iodide (0.005 mol) was dissolved in DMF in the presence of pot. Carbonate anhydrous was refluxed in water bath for 4 hours. The reaction mixture was filtered on hot then the filtrate was cooled and poured onto cold water with stirring; the formed solid was filtered off and crystallized from ethanol : benzene (3 : 1); mp. = 92°C; I.R (KBr): ν=3058, 2977, 2932, 1717, 1580 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.84 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 2.57 (s, 3H, –SCH3), 3.33 (s, 3H, –NCH3), 4.01 (q, 2H, –O–CH2–CH3), 5.74 (s, 1H, –CH–), 7.49–7.64 (m, 10H, Ar) ppm; mass: m/z (%): 366 (M+, 5.21), 350 (100.0), 321 (28.48), 129 (30.96), 77 (15.87); C21H22N2O2S (366): calculated, %: C 68.82, H 6.05, N 7.64, O 8.73, S 8.75; found, %: C 68.81, H 6.04, N 7.65, O 8.73, S 8.75; yield (25%).


#### 5.1.5. General Procedure for the Preparation of Compounds(Xa,b)

Method (A). A mixture of IVa,b (1 mmol) and chloroacetic acid (1 mmol) was dissolved in 40 mL of a mixture of (AC)2O/ACOH (1 : 3) in the presence of 3 gm anhydrous sodium acetate that was refluxed for 4 hours. The reaction mixture was cold and poured onto cold water with stirring; the solid formation was filtered off and crystallized from benzene/ethanol (3 : 1) to give Xa,b.Method (B). A mixture of IVa,b (0.005 mol) and chloroacetyl chloride with 2 drops of T.E.A was refluxed in benzene for 3 hours. Then the reaction mixture was filtered off through heating then dried and crystallized from benzene/ethanol (3 : 1) to give Xa,b.Method (C). A mixture of IVa,b (0.005 mol), ethylchloro acetate (0.005 mol), and sodium acetate trihydrate (1 gm) was refluxed in ethanol for 5 hours. The reaction mixture was filtered and kept for overnight. The solid formation was filtered off then dried and crystallized from benzene/ethanol 3/1 to afforded Xa,b.Ethyl 3-oxo-5,7-diphenyl-3,5,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(Xa). The formed solid was crystallized from benzene/ethanol (3 : 1); method (A): yield (72%); method (B): yield (75%); method (C): yield (84%). mp. = 136–8°C; I.R (KBr): ν=2976, 2931, 2900, 1752, 1675, 1589 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.85 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.85 (q, 2H, –O–CH2–CH3), 3.88 (s, 2H, –CH2CO–), 6.19 (s, 1H, –CH–), 7.27–7.51 (m, 10H, Ar) ppm; mass: m/z (%): 378 (M+, 60.03), 350 (16.30), 301 (100.0), 273 (35.62), 129 (25.11), 77 (35.57); C21H18N2O3S (378): calculated, %: C 66.65, H 4.79, N 7.40, O 12.68, S 8.47; found, %: C 66.65, H 4.78, N 7.41, O 12.67, S 8.47.6-Acetyl-5-(4-methoxyphenyl)-7-methyl-8,8a-dihydro-2H-thiazolo[3,2-a]pyrimidin-3(5H)-one
(Xb). The formed solid was crystallized from benzene and drops of ethanol; method (A): yield (42%). method (B): yield (34%). method (C): yield (40%). mp. = 160–162°C; I.R (KBr): ν=2983, 2936, 2876, 1756, 1655, 1612 cm−1; 1H NMR (300 MHz, DMSO): δ=2.16 (s, 3H, CH3), 2.34 (s, 3H, –COCH3), 3.70 (s, 3H, OCH3), 4.15 (s, 2H, –CH2CO–), 5.98 (s, 1H, –CH–), 6.86–7.21 (d, d, 4H, Ar) ppm; mass: m/z (%): 316 (M+, 35.08), 301 (5.32), 273 (100.0), 245 (28.08), 230 (4.72), 181 (19.36), 115 (25.14), 77 (26.0); C16H18N2O3S (316): calculated, %: C 60.36, H 5.70, N 8.80, O 15.08, S 10.07; found, %: C 60.35, H 5.70, N 8.81, O 15.06, S 10.08.


#### 5.1.6. Synthesis of Compounds(XIa,b,c)

A mixture of compoundXa (1 mmol), aromatic aldehyde (1 mmol), and 2 drops of piperidine was refluxed in ethanol for 2 hours. The reaction mixture kept overnight, then the solid product was filtered off and crystallized from EtOH to afford compound XI.(E)-Ethyl 2-(4-chlorobenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIa). mp. = 164–6°C; I.R (KBr): ν=3446, 1721, 1620, 1559 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.89 (q, 2H, –O–CH2–CH3), 6.34 (s, 1H, –CH–), 7.27–7.54 (m, 14H, Ar), 7.74 (s, 1H, =CH–) ppm; mass: m/z (%): 500 (M+2, 45.80), 503 (M+4, 9.82), 423 (67.99), 168 (100.0), 77 (77.69); C28H21ClN2O3S (500): calculated, %: C 67.13, H 4.22, Cl 7.08, N 5.59, O 9.58, S 6.40; found, %: C 67.14, H 4.24, Cl 7.07, N 5.60, O 9.59, S 6.42; yield (88%).(E)-Ethyl 2-(2,3-dimethoxybenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIb). mp. = 148°C; I.R (KBr): ν=34454, 1712, 1630, 1581 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.6 Hz, 3H, –O–CH2–CH3), 3.77 (s, 3H, –OCH3), 3.85 (s, 3H, –OCH3), 6.34 (s, 1H, –CH–), 6.84 (d, 1H Ar), 6.96 (s, 1H, Ar), 6.98 (d, 1H, Ar), 7.35–7.55 (m, 10H, Ar), 8.09 (s, 1H, =CH–) ppm; mass: m/z (%): 526 (M+1, 42.98), 449 (100.0), 363 (27.0), 77 (5.37); C30H26N2O5S (526): calculated, %: C 68.42, H 4.98, N 5.32, O 15.19, S 6.09; found, %: C 68.43, H 4.99, N 5.33, O 15.20, S 6.10; Yield (85%).(E)-Ethyl2-(3-nitrobenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIc). mp. = 158–160°C; I.R (KBr): ν=3100, 2998, 1716, 1617, 1557, 1563, 1530 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.84 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.86 (q, 2H, –O–CH2–CH3), 6.31 (s, 1H, –CH–), 7.20–7.75 (m, 14H, Ar), 8.31 (s, 1H, =CH–) ppm; C28H21N3O5S (511): calculated, %: C 65.74, H 4.14, N 8.21, O 15.64, S 6.27; found, %: C 65.75, H 4.13, N 8.22, O 15.63, S 6.28; yield (92%).Synthesis of 1-[5-Acetyl-6-(4-methoxy-phenyl)-4-methyl-1,6-dihydro-pyrimidin-2-ylsulfanyl]-propan-2-one
(XIII). A mixture of IVb (0.005 mol), chloroacetone (0.005 mol), and 2 drops of piperidine was refluxed in ethanol for 6 hours. The reaction mixture was kept for overnight. The solid formation was filtered off then dried and crystallized from benzene/ethanol (1 : 1); mp. = 215°C; I.R (KBr): ν=3112, 3004, 1644, 1608, 1524 cm−1; 1H NMR (300 MHz, DMSO): δ=2.25 (s, 3H, –CH3), 2.26 (s, 3H, –COCH3), 2.30 (s, 3H, –COCH3), 2.46 (s, 2H, CH2), 3.71 (s, 3H, –OCH3), 6.44 (s, 1H, –CH), 6.90–7.28 (d, d, 4H, Ar), 7.11 (s, 1H, –NH); mass: m/z (%): 332 (M+, 5.30), 298 (5.30), 270 (33.60), 245 (25.7), 91 (100.0); C17H20N2O3S (332): calculated, %: C 61.42, H 6.06, N 8.43, O 14.44, S 9.65; found, %: C 61.43, H 6.05, N 8.43, O 14.42, S 9.66; yield (48%).


#### 5.1.7. Reaction of CompoundsVa,b with Thiosemicarbazide

A mixture ofVa,b (0.005 mol) and thiosemicarbazide (0.07 mol) was refluxed in ethanol (20 mL) for 7 hours in a water bath, then the reaction mixture was allowed to stand for several hours at room temperature, then the solid product was filtered off and recrystallized from ethanol to formed compounds XIVa,b.Ethyl 2-(2-carbamothioylhydrazinyl)-4,6-diphenyl-1,6-dihydro-pyrimidine-5-carboxylate
(XIVa). Method (A): yield (51%); method (B): yield (46%); mp. = 170–172°C I.R (KBr): ν=3370, 3262, 3175, 1644, 1620 cm−1. 1H NMR (300 MHz, DMSO): δ=0.71 (t, J=7.5 Hz, 3H, OCH2CH3), 3.74 (q, 2H, OCH2CH3), 4.50 (s, 2H, –NH2), 5.26 (s, –CH), 7.19–7.58 (m, 10H, Ar), 8.65 (s, 1H, –NH), 9.78 (s, 1H, –NH), 10.51 (s, 1H, –NH) ppm; mass: m/z (%): 395 (M+, 24.13), 379 (21.13), 368 (49.20), 352 (76.97), 105 (86.51), 55 (100.0); C20H21N5O2S (395): calculated, %: C 60.74, H 5.35, N 17.71, O 8.09, S 8.11; found, %: C 60.73, H 5.36, N 17.71, O 8.08.2-(5-Acetyl-6-(4-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-yl)hydrazinecarbothioamide
(XIVb). Method (A): yield (64%); method (B): yield (48%); mp. = 92°C; I.R (KBr): ν=3284, 3145, 2049, 1604, 1510 cm−1; mass: m/z (%): 333 (M+, 12.18), 274 (14.92), 233 (27.31), 215 (84.93), 178 (90.61), 136 (100.0), 76 (65.0), 51 (23.07); C15H19N5O2S (333): calculated, %: C 54.04, H 5.74, N 21.01, O 9.60, S 9.62; found, %: C 54.05, H 5.74, N 21.0, O 9.61, S 9.62.


#### 5.1.8. Synthesis of CompoundsXVIIa,b

CompoundIVa,b (0.005 mol) was heated under reflux in (10 mL) of methanol, containing acetic acid (2.5 mL) and water (2.5 mL). After reflux for 25 hours, methanol was distilled off and the remaining solution was treated portionwise with water until precipitation was completed. After standing for several hours at room temperature, the solid product was removed by filteration to yield XVIIa,b which crystallized from ethanol.Ethyl  2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(XVIIa). mp. (found) = 160°C, mp. (reported) = 158°C [48]; yield (77%).5-Acetyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(XVIIb). mp. (found) = 164–166°C; mp. (reported) = 166-167°C [48]; yield (71%).


## 5.1. General

All melting points were measured with a Gallenkamp apparatus. The IR spectra of samples were recorded in KBr via a Shimadzu FT-IR 8101 PC infrared spectrophotometer.1H NMR spectra were run at 300 MHz and recorded in CDCl3/[D6] DMSO using TMS as the internal standard. Chemical shifts were related to that of the solvent. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 eV. TLC was conducted on 0.25 mm precoated silica gel plates (60F-254). Elemental analyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. The catalyst is ground until it became fine powder.


### 5.1.1. General Procedure for the Synthesis of the Newly 3,4-Dihydropyrimidinones(Io,p,q) and 3,4-Dihydropyrimidinthiones (IVc,h,g,f)

A mixture of aldehyde (1 mmol), 1,3-dicarbonyl compounds (1 mmol), urea or thiourea (1 mmol), and granite or quartz (0.5 g) in ethanol (15 mL) was heated under reflux for the required time. After completion of the reaction as monitored by T.L.C., the reaction mixture was filtered to separate the catalyst. Keep the reaction mixture overnight. The solid product was filtered under suction then recrystallized from ethanol to afford pure product.Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(Io). mp. = 178–180°C. I.R (KBr): ν=3300, 3100, 2950, 1700, 1630 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.16 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.33 (s, 3H, CH3), 4.08 (q, 2H, –O–CH2–CH3), 5.03 (s, 2H, –O–CH2–Ph), 5.37 (s, 1H, –CH–), 5.92 (s, 1H, –NH), 6.85–6.94 (m, 4H, Ar), 7.19–7.39 (m, 5H, Ar), 8.31 (s, 1H, –NH) ppm. Mass: m/z (%): 366 (M+, 6.31), 275 (22.72), 183 (24.94), 91 (100.0). C21H22N2O4 (366): calculated, %: C 68.84, H 6.05, N 7.65, O 17.47; found, %: C 68.82, H 6.10, N 7.55, O 17.46. Yield quartz (65%), granite (62%).5-Acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(Ip). mp. = 192–194°C. I.R (KBr): ν=3450, 3200, 2950, 1640, 1590 cm−1. 1H NMR (300 MHz, DMSO): δ=2.08 (s, 3H, CH3), 2.27 (s, 3H, –COCH3), 5.05 (s, 2H, –O–CH2–Ph), 5.20 (s, 1H, –CH–), 6.81–6.92 (m, 4H, Ar), 7.21–7.45 (m, 5H, Ar), 7.81 (s, 1H, –NH), 9.17 (s, 1H, –NH) ppm. Mass: m/z (%): 336 (M+, 1.6), 293 (1.9), 245 (33), 153 (14.6), 91 (100.0). C20H20N2O3 (336): calculated, %: C 71.41, H 5.99, N 8.33, O 14.27; found, %: C 71.40, H 6.0, N 8.30, O 14.21. Yield quartz (40%), granite (63%).Ethyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(Iq). mp. = 178–180°C. I.R (KBr): ν=3250, 3100, 2950, 1700, 1640 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.11 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.40 (s, 3H, CH3), 3.87 (s, 3H, –OCH3), 3.92 (s, 3H, –OCH3), 4.06 (q, 2H, –O–CH2–CH3), 5.71 (s, 1H, –CH–), 5.72 (s, 1H, –NH), 6.73 (d, 1H, Ar), 6.87 (d, 1H, Ar), 6.98 (t, 1H, Ar), 7.27 (s, 1H, –NH) ppm. Mass: m/z (%): 320 (M+, 13.7), 288 (100.0), 243 (55.2), 183 (94.9), 155 (68.9), 137 (60.1), 77 (47.3). C16H20N2O5 (320): calculated, %: C 59.99, H 6.29, N 8.74, O 24.97; found, %: C 59.95, H 6.22, N 8.70, O 24.99. Yield quartz (63%), granite (60%).Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVg). mp. = 180–182°C. I.R (KBr): ν=3400, 3150, 2950, 1650 cm−1. 1H NMR (300 MHz, DMSO): δ=1.10 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.27 (s, 3H, CH3), 4.01 (q, 2H, –O–CH2–CH3), 5.05 (s, 2H, –O–CH2–Ph), 5.15 (s, 1H, –CH–), 6.80 (m, 4H, Ar), 7.23–7.42 (m, 5H, Ar), 9.60 (s, 1H, –NH), 10.30 (s, 1H, –NH) ppm. Mass: m/z (%): 382 (M+, 17.6), 199 (12.2), 91 (100.0). C21H22N2O3S (382): calculated, %: C 65.95, H 5.80, N 7.32, O 12.55, S 8.38; found, %: C 65.89, H 5.60, N 7.35, O 17.46, S 8.36. Yield quartz (66%), granite (60%).Ethyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVc). mp. = 181–183°C. I.R (KBr): ν=3200, 3100, 2950, 1705 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.10 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.42 (s, 3H, CH3), 3.86 (s, 3H, –OCH3), 3.93 (s, 3H, –OCH3), 4.05 (q, 2H, –O–CH2–CH3), 5.71 (s, 1H, –CH–), 6.68 (d, 1H, Ar), 6.88 (d, 1H, Ar), 6.99 (t, 1H, Ar), 7.26 (s, 1H, –NH), 8.10 (s, 1H, –NH) ppm. Mass: m/z (%): 336 (M+, 76.4), 305 (86.1), 289 (81.5), 263 (100.0), 199 (87.7), 171 (63.3), 153 (31.5), 77 (44.6). C16H20N2O4S (336): calculated, %: C 57.12, H 5.99, N 8.33, O 19.02, S 9.53; found, %: C 57.13, H 5.96, N 8.35, O 19.06, S 9.51. Yield quartz (64%), granite (63%).Ethyl-4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVh). mp. = 188–190°C. I.R (KBr): ν=3200, 3100, 2940, 1700 cm−1. 1H NMR (300 MHz, DMSO): δ=1.05 (t, J=8.2 Hz, 3H, –O–CH2–CH3), 2.27 (s, 3H, CH3), 3.65 (s, 3H, –OCH3), 3.72 (s, 3H, –OCH3), 3.96 (q, 2H, –O–CH2–CH3), 5.44 (s, 1H, –CH–), 6.57 (s, 1H, Ar), 6.83 (d, 1H, Ar), 6.94 (d, 1H, Ar), 9.24 (s, 1H, –NH), 10.24 (s, 1H, –NH) ppm. Mass: m/z (%): 338 (M+, 10.97), 279 (10.49), 256 (19.23), 166 (45.38), 149 (100.0), 105 (28.13), 69 (90.57). C16H20N2O4S (336): calculated, %: C 57.12, H 5.99, N 8.33, O 19.02, S 9.53; found, %: C 57.14, H 5.96, N 8.30, O 19.04, S 9.56. Yield quartz (64%), granite (60%).Ethyl-4-(2,6-dichlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVf). mp. = 222–224°C. I.R (KBr): ν=3150, 3000, 2900, 1750, 1640 cm−1. 1H NMR (300 MHz, CDCl3): δ=0.94 (t, J=6.6 Hz, 3H, –O–CH2–CH3), 2.23 (s, 3H, CH3), 3.91 (q, 2H, –O–CH2–CH3), 6.28 (s, 1H, –CH–), 7.05–7.23 (m, 3H, Ar), 7.94 (s, 1H, –NH), 8.32 (s, 1H, –NH) ppm. Mass: m/z (%): 344 (M+, 23.9), 348 (M+4, 7.6), 315 (34.5), 199 (100.0), 171 (36.4), 153 (16.2). C14H14Cl2N2O2S (344): calculated, %: C 48.70, H 4.09, Cl 20.54, N 8.11, O 9.27, S 9.29; found, %: C 48.72, H 4.04, Cl 20.50, N 8.13, O 9.29, S 9.30. Yield quartz (55%), granite (60%).4-Amino-6-(3-(benzyloxy)phenyl)-5,6-dihydro-1,3,5-triazin-2(1H)-one
(III). mp. = 172–174°C I.R (KBr): ν=3450, 3300, 1640 cm−1. 1H NMR (300 MHz, DMSO): δ=5.07 (s, 2H, –CH2–), 5.43 (s, 1H, –CH–), 5.68 (s, 2H, –NH2), 6.70–6.92 (m, 4H, Ar), 6.98 (s, 1H, NH), 7.23–7.46 (m, 5H, Ar), 10.0 (s, 1H, NH) ppm. The 13C-NMR (300 MHz, DMSO) δ=51.2 (CH aliphatic), 62.32 (CH2 aliphatic), 165.3 (C triazine ring), 190.4 (C=O amidic), 111–160 (benzene rings). Mass: m/z (%): 296 (M+, 54.58), 294 (82.76), 253 (57.20), 227 (63.30), 203 (100.0), 182 (31.01), 171 (55.77), 131 (99.09), 104 (29.73). C16H16N4O2 (296): calculated, %: C 64.85, H 5.44, N 18.91, O 10.80; found, %: C 64.82, H 5.40, N 18.93, O 10.82. Yield quartz (25%).


### 5.1.2. General Procedure of Methylation of CompoundsIVa–c

A mixture ofIVa–c (0.005 mol) and methyl iodide (0.005 mol) was dissolved in dry acetone in the presence of pot. Carbonate anhydrous was refluxed in water bath for 5 hours. The reaction mixture was filtered on hot then kept for overnight. The formed solid was filtered off and crystallized from an appropriate solvent to give Va,b,c.Ethyl-2-(methylthio)-4,6-diphenyl-1,6-dihydropyrimidine-5-carboxylate
(Va). The formed solid was crystallized from petroleum ether/benzene 2 : 1; mp. = 158–160°C; I.R (KBr): ν=3280, 2982, 2807, 1676, 1614, 1493 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 2.49 (s, 3H, –SCH3), 3.86 (q, 2H, –O–CH2–CH3), 5.74 (s, 1H, –CH–), 7.27 (s, 1H, NH), 7.28–7.48 (m, 10H, Ar) ppm; mass: m/z (%): 352 (M+, 23.35), 337 (33.58), 323 (68.32), 275 (100.0), 77 (25.52); C20H20N2O2S (352): calculated, %: C 68.16, H 5.72, N 7.95, O 9.08, S 9.10; Found, %: C 68.13, H 5.75, N 7.97, O 9.10, S 9.12; yield (77%).1-(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)-1,6-dihydropyrimidin-5-yl)ethanone
(Vb). The formed solid was crystallized from petroleum ether/ethanol 1 : 1; mp. = 126–128°C; I.R (KBr): ν=3285, 2950, 2928, 1639, 1594 cm−1; 1H NMR (300 MHz, DMSO): δ=2.09 (s, 3H, –CH3), 2.23 (s, 3H, –SCH3), 2.28 (s, 3H, –COCH3), 3.70 (s, 3H, –OCH3), 5.54 (s, 1H, –CH–), 6.82–7.15 (d, d, 4H, Ar), 9.57 (s, 1H, –NH) ppm; mass: m/z (%): 288 (M+, 29.40), 250 (22.10), 183 (19.10), 73 (67.60), 57 (100.0); C15H18N2O2S (290): calculated, %: C 62.04, H 6.25, N 9.65, O 11.02, S 11.04; found, %: C 62.03, H 6.26, N 9.65, O 11.04, S 11.03; yield (86%).Ethyl-6-(2,3-dimethoxyphenyl)-4-methyl-2-(methylthio)-1,6-dihydropyrimidine-5-carboxylate
(Vc). The solid product was crystallized from petroleum ether (60–80); mp. = 140°C; I.R (KBr): ν=3321, 2935, 2832, 1706, 1669, 1594 cm−1; 1H NMR (300 MHz, DMSO): δ=1.13 (t, J=7.5 Hz, 3H, CH3CH2O–), 2.39 (s, 3H, –CH3), 2.45 (s, 3H, –SCH3), 3.87 (s, 3H, –OCH3), 3.93 (s, 3H, –OCH3), 4.06 (q, 2H, CH3CH2O–), 5.85 (s, 1H, –CH), 6.77–7.02 (m, 3H, Ar), 7.27 (s, 1H, –NH) ppm; mass: m/z (%): 350 (M+, 20.56), 335 (36.97), 321 (64.29), 303 (40.44), 213 (100.0), 77 (23.14); C17H22N2O4S (350): calculated, %: C 58.27, H 6.33, N 7.99, O 18.26, S 9.15; found, %: C 58.26, H 6.33, N 7.97, O 18.27, S 9.16; yield (74%).


### 5.1.3. Acylation of CompoundsIVa–c

Method (A). A mixture of IVa–c (0.005 mol) and acetyl chloride (0.01 mol) was refluxed in DMF (15 mL) as a solvent containing (5 drops) of triethylamine (TEA) for 1 hour and then stirred at room temperature for overnight, and then the solution was poured into ice with vigorous stirring, and then the solid product was filtered off and recrystallized from suitable solvent to afford compounds VIa,b,c.Method (B). A solution of IVa–c (0.01 mol) in 15 mL of acetic anhydride was heated under reflux for 1.30 hour. The solution was then poured into 150 mL of ice-water and stirred for several hours until crystallization was complete. The precipitate was filtered and crystallized from suitable solvent to afford compounds VIa,b,c.Ethyl 3-acetyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(VIc). The solid product was recrystallized from ethanol; method (A): yield (81%). method (B): yield (78%); mp. = 186°C; I.R (KBr): ν=3237, 2996, 2944, 2837, 1702, 1671 cm−1; 1H NMR (300 MHz, DMSO): δ=1.17 (t, J=6.6 Hz, 3H, CH3CH2O–), 2.27 (s, 3H, –CH3), 2.60 (s, 3H, –COCH3), 3.67 (s, 3H, –OCH3), 3.77 (s, 3H, –OCH3), 4.08 (q, 2H, CH3CH2O–), 5.50 (s, 1H, –CH), 6.68–7.0 (m, 3H, Ar), 11.6 (s, 1H, –NH) ppm; mass: m/z (%): 378 (M+, 48.03), 335 (96.81), 289 (100.0), 263 (45.57), 199 (33.62), 77 (22.44); C18H22N2O5S (378): calculated, %: C 57.13, H 5.86, N 7.40, O 21.14, S 8.47; found, %: C 57.14, H 5.85, N 7.41, O 21.13, S 8.45.Ethyl  3-acetyl-4,6-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(VIa). The solid product was recrystallized from benzene; method (A): yield (80%); method (B): yield (85%). mp. = 136°C; I.R (KBr): ν=3215, 2986, 1642, 1599, 1494 cm−1; mass: m/z (%): 380 (M+, 37.39), 337 (100.0), 307 (25.7), 265 (57.72), 104 (65.03); C21H20N2O3S (380): calculated, %: C 66.29, H 5.30, N 7.36, O 12.62, S 8.43; found, %: C 66.28, H 5.31, N 7.35, O 12.63, S 8.42.1,1
′
-(6-(4-Methoxyphenyl)-4-methyl-2-thioxo-2,3-dihydropyrimidine-1,5(6H)-diyl)diethanone(VIb). The solid product was recrystallized from ethanol; method (A): yield (65%); method (B): yield (70%). mp. = 130°C; I.R (KBr): ν=3243, 2962, 1698, 1609, 1509 cm−1.


### 5.1.4. Synthesis of Compounds(VIIa,b)

A solution ofVa,b(0.01 mol) in 15 mL of acetic anhydride was heated under reflux for one hour. The solution was then poured into 150 mL of ice-water and stirred for several hours until crystallization was complete. The precipitate was filtered off and washed with water then crystallized from an appropriate solvent to afford VIIa,b.Ethyl  1-acetyl-2-(methylthio)-4,6-diphenyl-1,6-dihydropyrimidine-5-carboxylate
(VIIa). The solid product crystallized from petroleum ether (60–80); yield (90%); mp. = 102°C; I.R (KBr): ν=2978, 1697, 1601, 1533 cm−1; 1H NMR (300 MHz,CDCl3): 0.97 (t, J=6.6 Hz, 3H, CH3CH2O–), 2.50 (s, 3H, –SCH3), 2.50 (s, 3H, –COCH3), 4.02 (q, 2H, CH3CH2O–), 6.66 (s, 1H, –CH), 7.27–7.60 (m, 10H, Ar) ppm; mass: m/z (%): 394 (M+, 12.51), 351 (100.0), 337 (10.86), 323 (28.06), 275 (84.24), 129 (18.40), 77 (29.31); C22H22N2O3S (394): calculated, %: C 66.98, H 5.62, N 7.10, O 12.17, S 8.13; found, %: C 66.97, H 5.63, N 7.09, O 12.18, S 8.12.1,1
′
-(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)pyrimidine-1,5(6H)-diyl)diethanone(VIIb). The precipitated product was crystallized from benzene; yield (86%); mp. = 180°C. I.R (KBr): ν=2990, 1675, 1568 cm−1; mass: m/z (%): 332 (M+, 43.22), 312 (39.56), 278 (51.28), 100 (100.0), 67 (50.55); C17H20N2O3S (332): calculated, %: C 61.42, H 6.06, N 8.43, O 14.44, S 9.65; found, %: C 61.43, H 6.04, N 8.46, O 14.45, S 9.66.Synthesis of Ethyl 1-Methyl-2-(methylthio)-4,6-diphenyl-1,6-dihydro-pyrimidine-5-carboxylate
(VIIIa). A mixture of Va (0.005 mol) and methyl iodide (0.005 mol) was dissolved in DMF in the presence of pot. Carbonate anhydrous was refluxed in water bath for 4 hours. The reaction mixture was filtered on hot then the filtrate was cooled and poured onto cold water with stirring; the formed solid was filtered off and crystallized from ethanol : benzene (3 : 1); mp. = 92°C; I.R (KBr): ν=3058, 2977, 2932, 1717, 1580 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.84 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 2.57 (s, 3H, –SCH3), 3.33 (s, 3H, –NCH3), 4.01 (q, 2H, –O–CH2–CH3), 5.74 (s, 1H, –CH–), 7.49–7.64 (m, 10H, Ar) ppm; mass: m/z (%): 366 (M+, 5.21), 350 (100.0), 321 (28.48), 129 (30.96), 77 (15.87); C21H22N2O2S (366): calculated, %: C 68.82, H 6.05, N 7.64, O 8.73, S 8.75; found, %: C 68.81, H 6.04, N 7.65, O 8.73, S 8.75; yield (25%).


### 5.1.5. General Procedure for the Preparation of Compounds(Xa,b)

Method (A). A mixture of IVa,b (1 mmol) and chloroacetic acid (1 mmol) was dissolved in 40 mL of a mixture of (AC)2O/ACOH (1 : 3) in the presence of 3 gm anhydrous sodium acetate that was refluxed for 4 hours. The reaction mixture was cold and poured onto cold water with stirring; the solid formation was filtered off and crystallized from benzene/ethanol (3 : 1) to give Xa,b.Method (B). A mixture of IVa,b (0.005 mol) and chloroacetyl chloride with 2 drops of T.E.A was refluxed in benzene for 3 hours. Then the reaction mixture was filtered off through heating then dried and crystallized from benzene/ethanol (3 : 1) to give Xa,b.Method (C). A mixture of IVa,b (0.005 mol), ethylchloro acetate (0.005 mol), and sodium acetate trihydrate (1 gm) was refluxed in ethanol for 5 hours. The reaction mixture was filtered and kept for overnight. The solid formation was filtered off then dried and crystallized from benzene/ethanol 3/1 to afforded Xa,b.Ethyl 3-oxo-5,7-diphenyl-3,5,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(Xa). The formed solid was crystallized from benzene/ethanol (3 : 1); method (A): yield (72%); method (B): yield (75%); method (C): yield (84%). mp. = 136–8°C; I.R (KBr): ν=2976, 2931, 2900, 1752, 1675, 1589 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.85 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.85 (q, 2H, –O–CH2–CH3), 3.88 (s, 2H, –CH2CO–), 6.19 (s, 1H, –CH–), 7.27–7.51 (m, 10H, Ar) ppm; mass: m/z (%): 378 (M+, 60.03), 350 (16.30), 301 (100.0), 273 (35.62), 129 (25.11), 77 (35.57); C21H18N2O3S (378): calculated, %: C 66.65, H 4.79, N 7.40, O 12.68, S 8.47; found, %: C 66.65, H 4.78, N 7.41, O 12.67, S 8.47.6-Acetyl-5-(4-methoxyphenyl)-7-methyl-8,8a-dihydro-2H-thiazolo[3,2-a]pyrimidin-3(5H)-one
(Xb). The formed solid was crystallized from benzene and drops of ethanol; method (A): yield (42%). method (B): yield (34%). method (C): yield (40%). mp. = 160–162°C; I.R (KBr): ν=2983, 2936, 2876, 1756, 1655, 1612 cm−1; 1H NMR (300 MHz, DMSO): δ=2.16 (s, 3H, CH3), 2.34 (s, 3H, –COCH3), 3.70 (s, 3H, OCH3), 4.15 (s, 2H, –CH2CO–), 5.98 (s, 1H, –CH–), 6.86–7.21 (d, d, 4H, Ar) ppm; mass: m/z (%): 316 (M+, 35.08), 301 (5.32), 273 (100.0), 245 (28.08), 230 (4.72), 181 (19.36), 115 (25.14), 77 (26.0); C16H18N2O3S (316): calculated, %: C 60.36, H 5.70, N 8.80, O 15.08, S 10.07; found, %: C 60.35, H 5.70, N 8.81, O 15.06, S 10.08.


### 5.1.6. Synthesis of Compounds(XIa,b,c)

A mixture of compoundXa (1 mmol), aromatic aldehyde (1 mmol), and 2 drops of piperidine was refluxed in ethanol for 2 hours. The reaction mixture kept overnight, then the solid product was filtered off and crystallized from EtOH to afford compound XI.(E)-Ethyl 2-(4-chlorobenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIa). mp. = 164–6°C; I.R (KBr): ν=3446, 1721, 1620, 1559 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.89 (q, 2H, –O–CH2–CH3), 6.34 (s, 1H, –CH–), 7.27–7.54 (m, 14H, Ar), 7.74 (s, 1H, =CH–) ppm; mass: m/z (%): 500 (M+2, 45.80), 503 (M+4, 9.82), 423 (67.99), 168 (100.0), 77 (77.69); C28H21ClN2O3S (500): calculated, %: C 67.13, H 4.22, Cl 7.08, N 5.59, O 9.58, S 6.40; found, %: C 67.14, H 4.24, Cl 7.07, N 5.60, O 9.59, S 6.42; yield (88%).(E)-Ethyl 2-(2,3-dimethoxybenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIb). mp. = 148°C; I.R (KBr): ν=34454, 1712, 1630, 1581 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.6 Hz, 3H, –O–CH2–CH3), 3.77 (s, 3H, –OCH3), 3.85 (s, 3H, –OCH3), 6.34 (s, 1H, –CH–), 6.84 (d, 1H Ar), 6.96 (s, 1H, Ar), 6.98 (d, 1H, Ar), 7.35–7.55 (m, 10H, Ar), 8.09 (s, 1H, =CH–) ppm; mass: m/z (%): 526 (M+1, 42.98), 449 (100.0), 363 (27.0), 77 (5.37); C30H26N2O5S (526): calculated, %: C 68.42, H 4.98, N 5.32, O 15.19, S 6.09; found, %: C 68.43, H 4.99, N 5.33, O 15.20, S 6.10; Yield (85%).(E)-Ethyl2-(3-nitrobenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIc). mp. = 158–160°C; I.R (KBr): ν=3100, 2998, 1716, 1617, 1557, 1563, 1530 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.84 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.86 (q, 2H, –O–CH2–CH3), 6.31 (s, 1H, –CH–), 7.20–7.75 (m, 14H, Ar), 8.31 (s, 1H, =CH–) ppm; C28H21N3O5S (511): calculated, %: C 65.74, H 4.14, N 8.21, O 15.64, S 6.27; found, %: C 65.75, H 4.13, N 8.22, O 15.63, S 6.28; yield (92%).Synthesis of 1-[5-Acetyl-6-(4-methoxy-phenyl)-4-methyl-1,6-dihydro-pyrimidin-2-ylsulfanyl]-propan-2-one
(XIII). A mixture of IVb (0.005 mol), chloroacetone (0.005 mol), and 2 drops of piperidine was refluxed in ethanol for 6 hours. The reaction mixture was kept for overnight. The solid formation was filtered off then dried and crystallized from benzene/ethanol (1 : 1); mp. = 215°C; I.R (KBr): ν=3112, 3004, 1644, 1608, 1524 cm−1; 1H NMR (300 MHz, DMSO): δ=2.25 (s, 3H, –CH3), 2.26 (s, 3H, –COCH3), 2.30 (s, 3H, –COCH3), 2.46 (s, 2H, CH2), 3.71 (s, 3H, –OCH3), 6.44 (s, 1H, –CH), 6.90–7.28 (d, d, 4H, Ar), 7.11 (s, 1H, –NH); mass: m/z (%): 332 (M+, 5.30), 298 (5.30), 270 (33.60), 245 (25.7), 91 (100.0); C17H20N2O3S (332): calculated, %: C 61.42, H 6.06, N 8.43, O 14.44, S 9.65; found, %: C 61.43, H 6.05, N 8.43, O 14.42, S 9.66; yield (48%).


### 5.1.7. Reaction of CompoundsVa,b with Thiosemicarbazide

A mixture ofVa,b (0.005 mol) and thiosemicarbazide (0.07 mol) was refluxed in ethanol (20 mL) for 7 hours in a water bath, then the reaction mixture was allowed to stand for several hours at room temperature, then the solid product was filtered off and recrystallized from ethanol to formed compounds XIVa,b.Ethyl 2-(2-carbamothioylhydrazinyl)-4,6-diphenyl-1,6-dihydro-pyrimidine-5-carboxylate
(XIVa). Method (A): yield (51%); method (B): yield (46%); mp. = 170–172°C I.R (KBr): ν=3370, 3262, 3175, 1644, 1620 cm−1. 1H NMR (300 MHz, DMSO): δ=0.71 (t, J=7.5 Hz, 3H, OCH2CH3), 3.74 (q, 2H, OCH2CH3), 4.50 (s, 2H, –NH2), 5.26 (s, –CH), 7.19–7.58 (m, 10H, Ar), 8.65 (s, 1H, –NH), 9.78 (s, 1H, –NH), 10.51 (s, 1H, –NH) ppm; mass: m/z (%): 395 (M+, 24.13), 379 (21.13), 368 (49.20), 352 (76.97), 105 (86.51), 55 (100.0); C20H21N5O2S (395): calculated, %: C 60.74, H 5.35, N 17.71, O 8.09, S 8.11; found, %: C 60.73, H 5.36, N 17.71, O 8.08.2-(5-Acetyl-6-(4-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-yl)hydrazinecarbothioamide
(XIVb). Method (A): yield (64%); method (B): yield (48%); mp. = 92°C; I.R (KBr): ν=3284, 3145, 2049, 1604, 1510 cm−1; mass: m/z (%): 333 (M+, 12.18), 274 (14.92), 233 (27.31), 215 (84.93), 178 (90.61), 136 (100.0), 76 (65.0), 51 (23.07); C15H19N5O2S (333): calculated, %: C 54.04, H 5.74, N 21.01, O 9.60, S 9.62; found, %: C 54.05, H 5.74, N 21.0, O 9.61, S 9.62.


### 5.1.8. Synthesis of CompoundsXVIIa,b

CompoundIVa,b (0.005 mol) was heated under reflux in (10 mL) of methanol, containing acetic acid (2.5 mL) and water (2.5 mL). After reflux for 25 hours, methanol was distilled off and the remaining solution was treated portionwise with water until precipitation was completed. After standing for several hours at room temperature, the solid product was removed by filteration to yield XVIIa,b which crystallized from ethanol.Ethyl  2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(XVIIa). mp. (found) = 160°C, mp. (reported) = 158°C [48]; yield (77%).5-Acetyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(XVIIb). mp. (found) = 164–166°C; mp. (reported) = 166-167°C [48]; yield (71%).


## 5.1.1. General Procedure for the Synthesis of the Newly 3,4-Dihydropyrimidinones(Io,p,q) and 3,4-Dihydropyrimidinthiones (IVc,h,g,f)

A mixture of aldehyde (1 mmol), 1,3-dicarbonyl compounds (1 mmol), urea or thiourea (1 mmol), and granite or quartz (0.5 g) in ethanol (15 mL) was heated under reflux for the required time. After completion of the reaction as monitored by T.L.C., the reaction mixture was filtered to separate the catalyst. Keep the reaction mixture overnight. The solid product was filtered under suction then recrystallized from ethanol to afford pure product.Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(Io). mp. = 178–180°C. I.R (KBr): ν=3300, 3100, 2950, 1700, 1630 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.16 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.33 (s, 3H, CH3), 4.08 (q, 2H, –O–CH2–CH3), 5.03 (s, 2H, –O–CH2–Ph), 5.37 (s, 1H, –CH–), 5.92 (s, 1H, –NH), 6.85–6.94 (m, 4H, Ar), 7.19–7.39 (m, 5H, Ar), 8.31 (s, 1H, –NH) ppm. Mass: m/z (%): 366 (M+, 6.31), 275 (22.72), 183 (24.94), 91 (100.0). C21H22N2O4 (366): calculated, %: C 68.84, H 6.05, N 7.65, O 17.47; found, %: C 68.82, H 6.10, N 7.55, O 17.46. Yield quartz (65%), granite (62%).5-Acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(Ip). mp. = 192–194°C. I.R (KBr): ν=3450, 3200, 2950, 1640, 1590 cm−1. 1H NMR (300 MHz, DMSO): δ=2.08 (s, 3H, CH3), 2.27 (s, 3H, –COCH3), 5.05 (s, 2H, –O–CH2–Ph), 5.20 (s, 1H, –CH–), 6.81–6.92 (m, 4H, Ar), 7.21–7.45 (m, 5H, Ar), 7.81 (s, 1H, –NH), 9.17 (s, 1H, –NH) ppm. Mass: m/z (%): 336 (M+, 1.6), 293 (1.9), 245 (33), 153 (14.6), 91 (100.0). C20H20N2O3 (336): calculated, %: C 71.41, H 5.99, N 8.33, O 14.27; found, %: C 71.40, H 6.0, N 8.30, O 14.21. Yield quartz (40%), granite (63%).Ethyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(Iq). mp. = 178–180°C. I.R (KBr): ν=3250, 3100, 2950, 1700, 1640 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.11 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.40 (s, 3H, CH3), 3.87 (s, 3H, –OCH3), 3.92 (s, 3H, –OCH3), 4.06 (q, 2H, –O–CH2–CH3), 5.71 (s, 1H, –CH–), 5.72 (s, 1H, –NH), 6.73 (d, 1H, Ar), 6.87 (d, 1H, Ar), 6.98 (t, 1H, Ar), 7.27 (s, 1H, –NH) ppm. Mass: m/z (%): 320 (M+, 13.7), 288 (100.0), 243 (55.2), 183 (94.9), 155 (68.9), 137 (60.1), 77 (47.3). C16H20N2O5 (320): calculated, %: C 59.99, H 6.29, N 8.74, O 24.97; found, %: C 59.95, H 6.22, N 8.70, O 24.99. Yield quartz (63%), granite (60%).Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVg). mp. = 180–182°C. I.R (KBr): ν=3400, 3150, 2950, 1650 cm−1. 1H NMR (300 MHz, DMSO): δ=1.10 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.27 (s, 3H, CH3), 4.01 (q, 2H, –O–CH2–CH3), 5.05 (s, 2H, –O–CH2–Ph), 5.15 (s, 1H, –CH–), 6.80 (m, 4H, Ar), 7.23–7.42 (m, 5H, Ar), 9.60 (s, 1H, –NH), 10.30 (s, 1H, –NH) ppm. Mass: m/z (%): 382 (M+, 17.6), 199 (12.2), 91 (100.0). C21H22N2O3S (382): calculated, %: C 65.95, H 5.80, N 7.32, O 12.55, S 8.38; found, %: C 65.89, H 5.60, N 7.35, O 17.46, S 8.36. Yield quartz (66%), granite (60%).Ethyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVc). mp. = 181–183°C. I.R (KBr): ν=3200, 3100, 2950, 1705 cm−1. 1H NMR (300 MHz, CDCl3): δ=1.10 (t, J=7.2 Hz, 3H, –O–CH2–CH3), 2.42 (s, 3H, CH3), 3.86 (s, 3H, –OCH3), 3.93 (s, 3H, –OCH3), 4.05 (q, 2H, –O–CH2–CH3), 5.71 (s, 1H, –CH–), 6.68 (d, 1H, Ar), 6.88 (d, 1H, Ar), 6.99 (t, 1H, Ar), 7.26 (s, 1H, –NH), 8.10 (s, 1H, –NH) ppm. Mass: m/z (%): 336 (M+, 76.4), 305 (86.1), 289 (81.5), 263 (100.0), 199 (87.7), 171 (63.3), 153 (31.5), 77 (44.6). C16H20N2O4S (336): calculated, %: C 57.12, H 5.99, N 8.33, O 19.02, S 9.53; found, %: C 57.13, H 5.96, N 8.35, O 19.06, S 9.51. Yield quartz (64%), granite (63%).Ethyl-4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVh). mp. = 188–190°C. I.R (KBr): ν=3200, 3100, 2940, 1700 cm−1. 1H NMR (300 MHz, DMSO): δ=1.05 (t, J=8.2 Hz, 3H, –O–CH2–CH3), 2.27 (s, 3H, CH3), 3.65 (s, 3H, –OCH3), 3.72 (s, 3H, –OCH3), 3.96 (q, 2H, –O–CH2–CH3), 5.44 (s, 1H, –CH–), 6.57 (s, 1H, Ar), 6.83 (d, 1H, Ar), 6.94 (d, 1H, Ar), 9.24 (s, 1H, –NH), 10.24 (s, 1H, –NH) ppm. Mass: m/z (%): 338 (M+, 10.97), 279 (10.49), 256 (19.23), 166 (45.38), 149 (100.0), 105 (28.13), 69 (90.57). C16H20N2O4S (336): calculated, %: C 57.12, H 5.99, N 8.33, O 19.02, S 9.53; found, %: C 57.14, H 5.96, N 8.30, O 19.04, S 9.56. Yield quartz (64%), granite (60%).Ethyl-4-(2,6-dichlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(IVf). mp. = 222–224°C. I.R (KBr): ν=3150, 3000, 2900, 1750, 1640 cm−1. 1H NMR (300 MHz, CDCl3): δ=0.94 (t, J=6.6 Hz, 3H, –O–CH2–CH3), 2.23 (s, 3H, CH3), 3.91 (q, 2H, –O–CH2–CH3), 6.28 (s, 1H, –CH–), 7.05–7.23 (m, 3H, Ar), 7.94 (s, 1H, –NH), 8.32 (s, 1H, –NH) ppm. Mass: m/z (%): 344 (M+, 23.9), 348 (M+4, 7.6), 315 (34.5), 199 (100.0), 171 (36.4), 153 (16.2). C14H14Cl2N2O2S (344): calculated, %: C 48.70, H 4.09, Cl 20.54, N 8.11, O 9.27, S 9.29; found, %: C 48.72, H 4.04, Cl 20.50, N 8.13, O 9.29, S 9.30. Yield quartz (55%), granite (60%).4-Amino-6-(3-(benzyloxy)phenyl)-5,6-dihydro-1,3,5-triazin-2(1H)-one
(III). mp. = 172–174°C I.R (KBr): ν=3450, 3300, 1640 cm−1. 1H NMR (300 MHz, DMSO): δ=5.07 (s, 2H, –CH2–), 5.43 (s, 1H, –CH–), 5.68 (s, 2H, –NH2), 6.70–6.92 (m, 4H, Ar), 6.98 (s, 1H, NH), 7.23–7.46 (m, 5H, Ar), 10.0 (s, 1H, NH) ppm. The 13C-NMR (300 MHz, DMSO) δ=51.2 (CH aliphatic), 62.32 (CH2 aliphatic), 165.3 (C triazine ring), 190.4 (C=O amidic), 111–160 (benzene rings). Mass: m/z (%): 296 (M+, 54.58), 294 (82.76), 253 (57.20), 227 (63.30), 203 (100.0), 182 (31.01), 171 (55.77), 131 (99.09), 104 (29.73). C16H16N4O2 (296): calculated, %: C 64.85, H 5.44, N 18.91, O 10.80; found, %: C 64.82, H 5.40, N 18.93, O 10.82. Yield quartz (25%).


## 5.1.2. General Procedure of Methylation of CompoundsIVa–c

A mixture ofIVa–c (0.005 mol) and methyl iodide (0.005 mol) was dissolved in dry acetone in the presence of pot. Carbonate anhydrous was refluxed in water bath for 5 hours. The reaction mixture was filtered on hot then kept for overnight. The formed solid was filtered off and crystallized from an appropriate solvent to give Va,b,c.Ethyl-2-(methylthio)-4,6-diphenyl-1,6-dihydropyrimidine-5-carboxylate
(Va). The formed solid was crystallized from petroleum ether/benzene 2 : 1; mp. = 158–160°C; I.R (KBr): ν=3280, 2982, 2807, 1676, 1614, 1493 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 2.49 (s, 3H, –SCH3), 3.86 (q, 2H, –O–CH2–CH3), 5.74 (s, 1H, –CH–), 7.27 (s, 1H, NH), 7.28–7.48 (m, 10H, Ar) ppm; mass: m/z (%): 352 (M+, 23.35), 337 (33.58), 323 (68.32), 275 (100.0), 77 (25.52); C20H20N2O2S (352): calculated, %: C 68.16, H 5.72, N 7.95, O 9.08, S 9.10; Found, %: C 68.13, H 5.75, N 7.97, O 9.10, S 9.12; yield (77%).1-(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)-1,6-dihydropyrimidin-5-yl)ethanone
(Vb). The formed solid was crystallized from petroleum ether/ethanol 1 : 1; mp. = 126–128°C; I.R (KBr): ν=3285, 2950, 2928, 1639, 1594 cm−1; 1H NMR (300 MHz, DMSO): δ=2.09 (s, 3H, –CH3), 2.23 (s, 3H, –SCH3), 2.28 (s, 3H, –COCH3), 3.70 (s, 3H, –OCH3), 5.54 (s, 1H, –CH–), 6.82–7.15 (d, d, 4H, Ar), 9.57 (s, 1H, –NH) ppm; mass: m/z (%): 288 (M+, 29.40), 250 (22.10), 183 (19.10), 73 (67.60), 57 (100.0); C15H18N2O2S (290): calculated, %: C 62.04, H 6.25, N 9.65, O 11.02, S 11.04; found, %: C 62.03, H 6.26, N 9.65, O 11.04, S 11.03; yield (86%).Ethyl-6-(2,3-dimethoxyphenyl)-4-methyl-2-(methylthio)-1,6-dihydropyrimidine-5-carboxylate
(Vc). The solid product was crystallized from petroleum ether (60–80); mp. = 140°C; I.R (KBr): ν=3321, 2935, 2832, 1706, 1669, 1594 cm−1; 1H NMR (300 MHz, DMSO): δ=1.13 (t, J=7.5 Hz, 3H, CH3CH2O–), 2.39 (s, 3H, –CH3), 2.45 (s, 3H, –SCH3), 3.87 (s, 3H, –OCH3), 3.93 (s, 3H, –OCH3), 4.06 (q, 2H, CH3CH2O–), 5.85 (s, 1H, –CH), 6.77–7.02 (m, 3H, Ar), 7.27 (s, 1H, –NH) ppm; mass: m/z (%): 350 (M+, 20.56), 335 (36.97), 321 (64.29), 303 (40.44), 213 (100.0), 77 (23.14); C17H22N2O4S (350): calculated, %: C 58.27, H 6.33, N 7.99, O 18.26, S 9.15; found, %: C 58.26, H 6.33, N 7.97, O 18.27, S 9.16; yield (74%).


## 5.1.3. Acylation of CompoundsIVa–c

Method (A). A mixture of IVa–c (0.005 mol) and acetyl chloride (0.01 mol) was refluxed in DMF (15 mL) as a solvent containing (5 drops) of triethylamine (TEA) for 1 hour and then stirred at room temperature for overnight, and then the solution was poured into ice with vigorous stirring, and then the solid product was filtered off and recrystallized from suitable solvent to afford compounds VIa,b,c.Method (B). A solution of IVa–c (0.01 mol) in 15 mL of acetic anhydride was heated under reflux for 1.30 hour. The solution was then poured into 150 mL of ice-water and stirred for several hours until crystallization was complete. The precipitate was filtered and crystallized from suitable solvent to afford compounds VIa,b,c.Ethyl 3-acetyl-4-(2,3-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(VIc). The solid product was recrystallized from ethanol; method (A): yield (81%). method (B): yield (78%); mp. = 186°C; I.R (KBr): ν=3237, 2996, 2944, 2837, 1702, 1671 cm−1; 1H NMR (300 MHz, DMSO): δ=1.17 (t, J=6.6 Hz, 3H, CH3CH2O–), 2.27 (s, 3H, –CH3), 2.60 (s, 3H, –COCH3), 3.67 (s, 3H, –OCH3), 3.77 (s, 3H, –OCH3), 4.08 (q, 2H, CH3CH2O–), 5.50 (s, 1H, –CH), 6.68–7.0 (m, 3H, Ar), 11.6 (s, 1H, –NH) ppm; mass: m/z (%): 378 (M+, 48.03), 335 (96.81), 289 (100.0), 263 (45.57), 199 (33.62), 77 (22.44); C18H22N2O5S (378): calculated, %: C 57.13, H 5.86, N 7.40, O 21.14, S 8.47; found, %: C 57.14, H 5.85, N 7.41, O 21.13, S 8.45.Ethyl  3-acetyl-4,6-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(VIa). The solid product was recrystallized from benzene; method (A): yield (80%); method (B): yield (85%). mp. = 136°C; I.R (KBr): ν=3215, 2986, 1642, 1599, 1494 cm−1; mass: m/z (%): 380 (M+, 37.39), 337 (100.0), 307 (25.7), 265 (57.72), 104 (65.03); C21H20N2O3S (380): calculated, %: C 66.29, H 5.30, N 7.36, O 12.62, S 8.43; found, %: C 66.28, H 5.31, N 7.35, O 12.63, S 8.42.1,1
′
-(6-(4-Methoxyphenyl)-4-methyl-2-thioxo-2,3-dihydropyrimidine-1,5(6H)-diyl)diethanone(VIb). The solid product was recrystallized from ethanol; method (A): yield (65%); method (B): yield (70%). mp. = 130°C; I.R (KBr): ν=3243, 2962, 1698, 1609, 1509 cm−1.


## 5.1.4. Synthesis of Compounds(VIIa,b)

A solution ofVa,b(0.01 mol) in 15 mL of acetic anhydride was heated under reflux for one hour. The solution was then poured into 150 mL of ice-water and stirred for several hours until crystallization was complete. The precipitate was filtered off and washed with water then crystallized from an appropriate solvent to afford VIIa,b.Ethyl  1-acetyl-2-(methylthio)-4,6-diphenyl-1,6-dihydropyrimidine-5-carboxylate
(VIIa). The solid product crystallized from petroleum ether (60–80); yield (90%); mp. = 102°C; I.R (KBr): ν=2978, 1697, 1601, 1533 cm−1; 1H NMR (300 MHz,CDCl3): 0.97 (t, J=6.6 Hz, 3H, CH3CH2O–), 2.50 (s, 3H, –SCH3), 2.50 (s, 3H, –COCH3), 4.02 (q, 2H, CH3CH2O–), 6.66 (s, 1H, –CH), 7.27–7.60 (m, 10H, Ar) ppm; mass: m/z (%): 394 (M+, 12.51), 351 (100.0), 337 (10.86), 323 (28.06), 275 (84.24), 129 (18.40), 77 (29.31); C22H22N2O3S (394): calculated, %: C 66.98, H 5.62, N 7.10, O 12.17, S 8.13; found, %: C 66.97, H 5.63, N 7.09, O 12.18, S 8.12.1,1
′
-(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)pyrimidine-1,5(6H)-diyl)diethanone(VIIb). The precipitated product was crystallized from benzene; yield (86%); mp. = 180°C. I.R (KBr): ν=2990, 1675, 1568 cm−1; mass: m/z (%): 332 (M+, 43.22), 312 (39.56), 278 (51.28), 100 (100.0), 67 (50.55); C17H20N2O3S (332): calculated, %: C 61.42, H 6.06, N 8.43, O 14.44, S 9.65; found, %: C 61.43, H 6.04, N 8.46, O 14.45, S 9.66.Synthesis of Ethyl 1-Methyl-2-(methylthio)-4,6-diphenyl-1,6-dihydro-pyrimidine-5-carboxylate
(VIIIa). A mixture of Va (0.005 mol) and methyl iodide (0.005 mol) was dissolved in DMF in the presence of pot. Carbonate anhydrous was refluxed in water bath for 4 hours. The reaction mixture was filtered on hot then the filtrate was cooled and poured onto cold water with stirring; the formed solid was filtered off and crystallized from ethanol : benzene (3 : 1); mp. = 92°C; I.R (KBr): ν=3058, 2977, 2932, 1717, 1580 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.84 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 2.57 (s, 3H, –SCH3), 3.33 (s, 3H, –NCH3), 4.01 (q, 2H, –O–CH2–CH3), 5.74 (s, 1H, –CH–), 7.49–7.64 (m, 10H, Ar) ppm; mass: m/z (%): 366 (M+, 5.21), 350 (100.0), 321 (28.48), 129 (30.96), 77 (15.87); C21H22N2O2S (366): calculated, %: C 68.82, H 6.05, N 7.64, O 8.73, S 8.75; found, %: C 68.81, H 6.04, N 7.65, O 8.73, S 8.75; yield (25%).


## 5.1.5. General Procedure for the Preparation of Compounds(Xa,b)

Method (A). A mixture of IVa,b (1 mmol) and chloroacetic acid (1 mmol) was dissolved in 40 mL of a mixture of (AC)2O/ACOH (1 : 3) in the presence of 3 gm anhydrous sodium acetate that was refluxed for 4 hours. The reaction mixture was cold and poured onto cold water with stirring; the solid formation was filtered off and crystallized from benzene/ethanol (3 : 1) to give Xa,b.Method (B). A mixture of IVa,b (0.005 mol) and chloroacetyl chloride with 2 drops of T.E.A was refluxed in benzene for 3 hours. Then the reaction mixture was filtered off through heating then dried and crystallized from benzene/ethanol (3 : 1) to give Xa,b.Method (C). A mixture of IVa,b (0.005 mol), ethylchloro acetate (0.005 mol), and sodium acetate trihydrate (1 gm) was refluxed in ethanol for 5 hours. The reaction mixture was filtered and kept for overnight. The solid formation was filtered off then dried and crystallized from benzene/ethanol 3/1 to afforded Xa,b.Ethyl 3-oxo-5,7-diphenyl-3,5,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(Xa). The formed solid was crystallized from benzene/ethanol (3 : 1); method (A): yield (72%); method (B): yield (75%); method (C): yield (84%). mp. = 136–8°C; I.R (KBr): ν=2976, 2931, 2900, 1752, 1675, 1589 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.85 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.85 (q, 2H, –O–CH2–CH3), 3.88 (s, 2H, –CH2CO–), 6.19 (s, 1H, –CH–), 7.27–7.51 (m, 10H, Ar) ppm; mass: m/z (%): 378 (M+, 60.03), 350 (16.30), 301 (100.0), 273 (35.62), 129 (25.11), 77 (35.57); C21H18N2O3S (378): calculated, %: C 66.65, H 4.79, N 7.40, O 12.68, S 8.47; found, %: C 66.65, H 4.78, N 7.41, O 12.67, S 8.47.6-Acetyl-5-(4-methoxyphenyl)-7-methyl-8,8a-dihydro-2H-thiazolo[3,2-a]pyrimidin-3(5H)-one
(Xb). The formed solid was crystallized from benzene and drops of ethanol; method (A): yield (42%). method (B): yield (34%). method (C): yield (40%). mp. = 160–162°C; I.R (KBr): ν=2983, 2936, 2876, 1756, 1655, 1612 cm−1; 1H NMR (300 MHz, DMSO): δ=2.16 (s, 3H, CH3), 2.34 (s, 3H, –COCH3), 3.70 (s, 3H, OCH3), 4.15 (s, 2H, –CH2CO–), 5.98 (s, 1H, –CH–), 6.86–7.21 (d, d, 4H, Ar) ppm; mass: m/z (%): 316 (M+, 35.08), 301 (5.32), 273 (100.0), 245 (28.08), 230 (4.72), 181 (19.36), 115 (25.14), 77 (26.0); C16H18N2O3S (316): calculated, %: C 60.36, H 5.70, N 8.80, O 15.08, S 10.07; found, %: C 60.35, H 5.70, N 8.81, O 15.06, S 10.08.


## 5.1.6. Synthesis of Compounds(XIa,b,c)

A mixture of compoundXa (1 mmol), aromatic aldehyde (1 mmol), and 2 drops of piperidine was refluxed in ethanol for 2 hours. The reaction mixture kept overnight, then the solid product was filtered off and crystallized from EtOH to afford compound XI.(E)-Ethyl 2-(4-chlorobenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIa). mp. = 164–6°C; I.R (KBr): ν=3446, 1721, 1620, 1559 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.89 (q, 2H, –O–CH2–CH3), 6.34 (s, 1H, –CH–), 7.27–7.54 (m, 14H, Ar), 7.74 (s, 1H, =CH–) ppm; mass: m/z (%): 500 (M+2, 45.80), 503 (M+4, 9.82), 423 (67.99), 168 (100.0), 77 (77.69); C28H21ClN2O3S (500): calculated, %: C 67.13, H 4.22, Cl 7.08, N 5.59, O 9.58, S 6.40; found, %: C 67.14, H 4.24, Cl 7.07, N 5.60, O 9.59, S 6.42; yield (88%).(E)-Ethyl 2-(2,3-dimethoxybenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIb). mp. = 148°C; I.R (KBr): ν=34454, 1712, 1630, 1581 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.87 (t, J=6.6 Hz, 3H, –O–CH2–CH3), 3.77 (s, 3H, –OCH3), 3.85 (s, 3H, –OCH3), 6.34 (s, 1H, –CH–), 6.84 (d, 1H Ar), 6.96 (s, 1H, Ar), 6.98 (d, 1H, Ar), 7.35–7.55 (m, 10H, Ar), 8.09 (s, 1H, =CH–) ppm; mass: m/z (%): 526 (M+1, 42.98), 449 (100.0), 363 (27.0), 77 (5.37); C30H26N2O5S (526): calculated, %: C 68.42, H 4.98, N 5.32, O 15.19, S 6.09; found, %: C 68.43, H 4.99, N 5.33, O 15.20, S 6.10; Yield (85%).(E)-Ethyl2-(3-nitrobenzylidene)-3-oxo-5,7-diphenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(XIc). mp. = 158–160°C; I.R (KBr): ν=3100, 2998, 1716, 1617, 1557, 1563, 1530 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.84 (t, J=6.9 Hz, 3H, –O–CH2–CH3), 3.86 (q, 2H, –O–CH2–CH3), 6.31 (s, 1H, –CH–), 7.20–7.75 (m, 14H, Ar), 8.31 (s, 1H, =CH–) ppm; C28H21N3O5S (511): calculated, %: C 65.74, H 4.14, N 8.21, O 15.64, S 6.27; found, %: C 65.75, H 4.13, N 8.22, O 15.63, S 6.28; yield (92%).Synthesis of 1-[5-Acetyl-6-(4-methoxy-phenyl)-4-methyl-1,6-dihydro-pyrimidin-2-ylsulfanyl]-propan-2-one
(XIII). A mixture of IVb (0.005 mol), chloroacetone (0.005 mol), and 2 drops of piperidine was refluxed in ethanol for 6 hours. The reaction mixture was kept for overnight. The solid formation was filtered off then dried and crystallized from benzene/ethanol (1 : 1); mp. = 215°C; I.R (KBr): ν=3112, 3004, 1644, 1608, 1524 cm−1; 1H NMR (300 MHz, DMSO): δ=2.25 (s, 3H, –CH3), 2.26 (s, 3H, –COCH3), 2.30 (s, 3H, –COCH3), 2.46 (s, 2H, CH2), 3.71 (s, 3H, –OCH3), 6.44 (s, 1H, –CH), 6.90–7.28 (d, d, 4H, Ar), 7.11 (s, 1H, –NH); mass: m/z (%): 332 (M+, 5.30), 298 (5.30), 270 (33.60), 245 (25.7), 91 (100.0); C17H20N2O3S (332): calculated, %: C 61.42, H 6.06, N 8.43, O 14.44, S 9.65; found, %: C 61.43, H 6.05, N 8.43, O 14.42, S 9.66; yield (48%).


## 5.1.7. Reaction of CompoundsVa,b with Thiosemicarbazide

A mixture ofVa,b (0.005 mol) and thiosemicarbazide (0.07 mol) was refluxed in ethanol (20 mL) for 7 hours in a water bath, then the reaction mixture was allowed to stand for several hours at room temperature, then the solid product was filtered off and recrystallized from ethanol to formed compounds XIVa,b.Ethyl 2-(2-carbamothioylhydrazinyl)-4,6-diphenyl-1,6-dihydro-pyrimidine-5-carboxylate
(XIVa). Method (A): yield (51%); method (B): yield (46%); mp. = 170–172°C I.R (KBr): ν=3370, 3262, 3175, 1644, 1620 cm−1. 1H NMR (300 MHz, DMSO): δ=0.71 (t, J=7.5 Hz, 3H, OCH2CH3), 3.74 (q, 2H, OCH2CH3), 4.50 (s, 2H, –NH2), 5.26 (s, –CH), 7.19–7.58 (m, 10H, Ar), 8.65 (s, 1H, –NH), 9.78 (s, 1H, –NH), 10.51 (s, 1H, –NH) ppm; mass: m/z (%): 395 (M+, 24.13), 379 (21.13), 368 (49.20), 352 (76.97), 105 (86.51), 55 (100.0); C20H21N5O2S (395): calculated, %: C 60.74, H 5.35, N 17.71, O 8.09, S 8.11; found, %: C 60.73, H 5.36, N 17.71, O 8.08.2-(5-Acetyl-6-(4-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-yl)hydrazinecarbothioamide
(XIVb). Method (A): yield (64%); method (B): yield (48%); mp. = 92°C; I.R (KBr): ν=3284, 3145, 2049, 1604, 1510 cm−1; mass: m/z (%): 333 (M+, 12.18), 274 (14.92), 233 (27.31), 215 (84.93), 178 (90.61), 136 (100.0), 76 (65.0), 51 (23.07); C15H19N5O2S (333): calculated, %: C 54.04, H 5.74, N 21.01, O 9.60, S 9.62; found, %: C 54.05, H 5.74, N 21.0, O 9.61, S 9.62.


## 5.1.8. Synthesis of CompoundsXVIIa,b

CompoundIVa,b (0.005 mol) was heated under reflux in (10 mL) of methanol, containing acetic acid (2.5 mL) and water (2.5 mL). After reflux for 25 hours, methanol was distilled off and the remaining solution was treated portionwise with water until precipitation was completed. After standing for several hours at room temperature, the solid product was removed by filteration to yield XVIIa,b which crystallized from ethanol.Ethyl  2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(XVIIa). mp. (found) = 160°C, mp. (reported) = 158°C [48]; yield (77%).5-Acetyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one
(XVIIb). mp. (found) = 164–166°C; mp. (reported) = 166-167°C [48]; yield (71%).



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*Source: 706437-2013-08-18.xml*