Supplementary Materials. Table of contents

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1 Supplementary Materials Microwave- Assisted Multicomponent Ecofriendly Synthesis of 3-Bihetaryl-2-oxindole Derivatives Grafted with Phenothiazine Moiety A. S. Al-Bogami 1 and A. S. El-Ahl 1,2 * 1 Chemistry Department, faculty of Science, University of Jeddah, Jeddah, 21589, Saudi Arabia 2 Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt Address correspondence to A. S. El-Ahl, Chemistry Department, Faculty of Science, University of Jeddah, Jeddah 21589, Saudi Arabia, P.O.B , Mobile: , elahl2002@yahoo.com Table of contents Content page General experimental methods 3 Figure S1. 1 H NMR of compound 1a 20 Figure S2. 13 C of compound 1a 20 Figure S3. 1 H NMR of compound 1b 21 Figure S4. 13 C NMR of compound 1b 21 Figure S5. Mass spectrum of compound 1b 22 Figure S6. 1 H NMR of compound 1c 22 Figure S7. 13 C NMR of compound 1c 23 Figure S8. 1 H NMR of compound 2a 23 Figure S9. 13 C NMR of compound 2a 24 Figure S10. Mass spectrum of compound 2a 25 Figure S11. 1 H NMR of compound 2b 26 Figure S C NMR of compound 2b 26 Figure S13. Mass spectrum of compound 2b 27 Figure S14. 1 H NMR of compound 2c 28 Figure S C NMR of compound 2c 28 Figure S16. 1 H NMR of compound 2d 29 Figure S C NMR of compound 2d 29 Figure S18. 1 H NMR of compound 2e 29 Figure S C NMR of compound 2e 30 Figure S20. 1 H NMR of compound 2f 30 Figure S C NMR of compound 2f 30 Figure S22. Mass spectrum of compound 2f 31 Figure S23. 1 H NMR of compound 3a 32 Figure S C NMR of compound 3a 32 1

2 Figure S25. Mass spectrum of compound 3a 33 Figure S26. 1 H NMR of compound 3b 34 Figure S C NMR of compound 3b 34 Figure S28. 1 H NMR of compound 3c 34 Figure S C NMR of compound 3c 35 Figure S30. Mass spectrum of compound 3c 36 Figure S31. Mass spectrum of compound 4 37 Figure S32. Mass spectrum of compound 5 38 Figure S33. 1 H NMR of compound 6 39 Figure S C NMR of compound 6 39 Figure S35. HMBC spectrum of compound 6 39 Figure S36. 1 H NMR of compound 8 40 Figure S37. HMBC spectrum of compound 8 40 Figure S38. 1 H NMR of compound 9 41 Figure S C NMR of compound 9 41 Figure S40. HMBC spectrum of compound 9 41 Figure S N HMBC spectrum of compound 9 42 Figure S42. 1 H NMR of compound Figure S C NMR of compound Figure S44. Mass spectrum of compound

3 4 EXPERIMENTAL Melting points were determined on a Stuart melting point apparatus and are uncorrected. IR spectra were recorded on Nicolet is10 FT-IR spectrometer. The NMR spectra were recorded on a Bruker Avance III 400 (9.4 T, MHz for 1 H and MHz for 13 C) spectrometer and on a Varian Mercury VX-300 NMR spectrometer (Varian, Palo Alto, CA, USA). HMBC-gs was acquired and processed using standard Bruker NMR software (Topspin 3.2). Elemental analyses were carried out on a EuroVector instrument C, H, N, S analyzer EA3000 Series. Mass spectra were measured using Shimadzu GCMS-QP 1000 EX mass spectrometer (Shimadzu) at 70 ev. Microwave experiments were performed using CEM Discover and Explorer SP microwave apparatus (300 W), utilizing 35 ml capped glass reaction vessels and automated power control based on temperature feedback. The chemicals and solvents were purchased from Merck, Aldrich or Acros. Thin-layer chromatography (TLC) was performed on precoated Merck 60 GF254 silica gel plates with a fluorescent indicator. Compounds 1a-c were prepared following standard literature procedures. [27] 4.1 Synthesis of 3-(2-(phenothiazin-2-yl)-2-oxoethylidene)-2-oxindoles1ac: The hitherto unknown compounds 1a-c was synthesized according to the reported procedure. [27] The structure of the compounds was confirmed by IR, 1 H NMR, and Mass spectroscopy. General Procedure: [27] Popp, F. D. J. Heterocycl. Chem. 1982, 19,

4 A mixture of appropriate isatin (0.01 mol) and 2-acetylphenothiazine (0.01 mol, 2.41 g) was suspended in 50 ml absolute ethanol containing 5 drops of diethylamine The reaction mixture was refluxed for 30 minutes and left to stand overnight at room temperature. The formed yellow precipitate was collected by filtration and washed several times by ethanol and suspended in 50 ml ethanol containing 0.5 ml of concentrated hydrochloric acid. The reaction mixture was refluxed for 1h, and cooled to room temperature. The formed violet precipitate was collected by filtration, washed with ethanol and recrystallized from acetone to give compounds 1a-c. 3-(2-Oxo-2-(10H-phenothiazin-2-yl)ethylidene)indolin-2-one 1a: Yield: 80%, violet solid. Mp o C, IR (V, thin film, cm -1 ): 3316, 2972, 1700, 1646, 1619, 1597, 1459, 1433, 1307, 1215, 1127, 1076, 1046, HNMR (DMSO-d 6 ): δ (dd, J 1 = 8 Hz, J 2 = 1 Hz, 1H, ArH), (td, J 1 = 8 Hz, J 2 = 1 Hz, 1H, ArH), (m, 2H, ArH), 6.98 (t, J = 8 Hz, 1H, ArH),7.03 (t, J= 8 Hz, 1H, ArH), 7.08 (d, J = 8 Hz, 1H, ArH), 7.31 (d, J = 1 Hz, 1H, ArH), 7.35 (t, J = 8 Hz, 1H, ArH), (dd, J 1 = 8 Hz, J 2 = 1.8 Hz, 1H, ArH), 7.62 (s, 1H, ArH), 8.00 (d, J = 8 Hz, 1H, ArH), 8.86 (s, 1H, NH), (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. For C 22 H 14 N 2 O 2 S: C, 71.33; H, 3.81; N, 7.56; S, Found: C, 71.15; H, 3.56; N, 7.35; S, Methyl-3-(2-oxo-2-(10H-phenothiazin-2-yl)ethylidene)indolin-2-one 1b: Yield: 85%, violet solid. Mp o C, IR: 3279, 2987, 1693, 1669, 1617, 1595, 1448, MS, M/Z (%): 384 (M +, 23), 370 (100), 342 (8), 325 (23), 4

5 309 (11), 293 (10), 198 (46), 186 (11), 172 (9), 116 (16), 89 (17). 1 H NMR (DMSO-d 6 ): δ 2.23 (s, 3H, 5-CH 3 ), 6.64 (d, J = 8 Hz,1H, ArH), (m, 2H, ArH), 6.91 (d, J = 8 Hz, 1H, ArH), 7.01 (t, J = 8 Hz, 1H, ArH), 7.08 (d, 2H, J = 8Hz, ArH), 7.16 (d, J = 8Hz, 1H, ArH), 7.32 (s, 1H, ArH), 7.41 (d, J = 8 Hz, 1H, ArH), 7.58 (s, 1H, =CH), 7.87(s, 1H, NH), 8.85 (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 21.18, , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. for C 23 H 16 N 2 O 2 S: C, 71.85; H, 4.19; N, 7.29; S, Found: C, 71.97; H, 4.32; N, 7.51; S, Bromo-3-(2-oxo-2-(10H-phenothiazin-2-yl)ethylidene)indolin-2-one 1c: Yield: 78%, violet Solid. Mp o C, IR: 3270, 2980, 1685, 1660, 1620, 1590, 1445, 1320.! H NMR(DMSO-d 6 ): δ 6.63 (d, J = 8Hz,1H, ArH), 6.76 (t, J = 8 Hz, 1H, ArH), 6.85 (d, J = 8 Hz, 1H, ArH), 6.90 (d, J = 8 Hz, 1H, ArH), 7.00 (t, J = 8 Hz, 1H, ArH), 7.07 (d, J = 8 Hz, 1H, ArH), 7.31 (s, 1H, ArH), 7.42 (d, J = 8 Hz, 1H, ArH), (dd, J 1 = 8 Hz, J 2 = 1.12, 1H, ArH), 7.68 ( s, 1H, ArH), 8.26 (s, 1H, =CH), 8.85 (s, 1H, NH), (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. for C 22 H 13 BrN 2 O 2 S: C, 58.81; H, 2.92; N, 6.23; S, Found: C, 58.97; H, 2.75; N, 6.45; S, Reaction of 3-(2-(phenothiazin-2-yl)-2-oxoethylidene)-2-oxindole derivatives 1a-c with 1,3-dicarbonyl compounds: General Procedure Conventional method: 5

6 A mixture of 3-(2-(phenothiazin-2-yl)-2-oxoethylidene)-2-oxindole derivatives 1a-c (3 mmol; 1a, 1.11g; 1b, g and 1c, g), 1,3-dicarbonyl compound (3 mmol; ethyl acetoacetate, 0.39 g; methyl acetoacetate, g; acetylacetone, 0.3 g; 2-hydroxynaphthalene-1,4-dione, g and indan-1,3- dione, g) and ammonium acetate (9 mmol, g) was suspended in glacial acetic acid (20 ml) and the reaction mixture was refluxed until TLC showed disappearance of the starting materials. The formed precipitate was collected by suction filtration and washed several times with cold ethanol. The collected solid materials were recrystallized from ethanol/dimethylformamide (2/1) mixture and oven dried at 120 o C to afford compounds 2a-f, 3a-c, 4 and 5 (Table 1) Microwave method: A mixture of 3-(2-(phenothiazin-2-yl)-2-oxoethylidene)-2-oxindole derivatives 1a-c (3 mmol; 1a, 1.11g; 1b, g and 1c, g), 1,3-dicarbonyl compound (3 mmol; ethyl acetoacetate, 0.39 g; methyl acetoacetate, g; acetylacetone, 0.3 g; 2-hydroxynaphthalene-1,4-dione, g and indan-1,3- dione, g) and ammonium acetate (9 mmol, g) was charged into a 35 ml glass reaction vessel (CEM, Discover and Explorer SP Vessels) and glacial acetic acid (5 ml) was added and the vessel was sealed with a control cap. The reaction was subjected to microwave irradiation, stirred and heated at 120 o C and power of 200 W, until completion of the reaction (TLC monitoring, Table 1). The reaction mixture was cooled and the formed precipitate was collected by filtration, washed several times with cold ethanol and recrystallized from ethanol/dimethylformamide (2/1) mixture to give compounds 2a-f, 3a-c, 4 and 5. 6

7 Ethyl Ethyl 4-(2-oxoindolin-3-yl)-2-methyl-5-(10H-phenothiazin-2-yl)-1H-pyrrole -3-carboxylate 2a: Colorless solid. Mp > 300 o C, IR (v, thin layer, cm -1 ): 3345 (NH), 3315 (NH), 3248 (NH), 1710 (CO 2 Et), 1658 (C=O, 2-oxindol), 1600, 1585, 1462, 1440, 1340, 1318, 1293, 1142, MS, M/Z (%): 481(M +, 35), 435 (100), 407 (70), 391(25), 362 (25), 323 (20), 309 (25), 218 (30), 201 (35), 154 (38), 127(37), 77(27). 1 H-NMR (DMSO-d 6 ): δ 0.85 (t, J =7Hz, 3H, OCH 2 CH 3 ), 2.41(s, 3H, 2'- CH 3 ), (dq, 2H, OCH 2 CH 3 ), 4.57 (s, 1H, H-3), (t, J = 7 Hz, 2H, ArH) (m, 4H, ArH), (m, 2H, ArH), (m, 2H, ArH), l1 (m, 1H, ArH), 8.70 (s, 1H, NH), (s, 1H, NH), (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 13.63, 14.37, 45.12, 58.32, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. for C 28 H 23 N 3 O 3 S: C, 69.83; H, 4.81; N, 8.73; S, Found: C, 69.65; H, 4.93; N, 8.62; S, (5-methyl-2-oxoindolin-3-yl)-2-methyl-5-(10H-phenothiazin-2-yl)- 1H-pyrrole-3-carboxylate 2b: Colorless solid. Mp o C, IR (v, thin layer, cm -1 ): 3361 (NH), 3270 (NH), 3229 (NH), 2994 (C-H aliphatic), 1708 (CO 2 Et), 1652 (C=O, oxindole), 1625, 1601, 1588, 1487, 1469, 1439, 1391, 1346, 1296, 1271, 1148, 1111, 1096, 1077, 960. MS, M/Z (%): 495 (M +, 40), 446 (50), 467(30), 448 (40), 439 (30), 409 (30), 398 (46), 377(42), 345 (50), 290 (45), 269(45), 197(50), 155 (48).128 (40), 64 (100). 1 H NMR (DMSO-d 6 ): δ 0.87 (t, J = 7.5 Hz, 3H, OCH 2 CH 3 ), 2.18 (s, 3H, 5- CH 3 ), 2.43 (s, 3H, 2'-CH 3 ), (dq, 2H, OCH 2 CH 3 ), 4.56 (s, 1H, H-3), 6.62 (s, 1H, ArH), (m, 2H, ArH),

8 (d, J = 7.5 Hz, 1H, ArH), 6.81 (s, 1H, ArH), (m, 3H, ArH), ( m, 2H, ArH), 8.77 (s, 1H, NH), (s, 1H, NH), (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 13.66, 14.39, 21.16, 45.14, 58.34, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. for C 29 H 25 N 3 O 3 S: C, 70.28; H, 5.08; N, 8.48; S, Found: C, 70.05; H, 4.89; N, 8.57; S, Ethyl 4-(5-bromo-2-oxoindolin-3-yl)-2-methyl-5-(10H-phenothiazin-2-yl)- Methyl 1H-pyrrole-3-carboxylate 2c: Colorless solid. Mp o C, IR (v, thin layer, cm -1 ): 3354 (NH), 3305 (NH), 3241(NH), 1712 (CO 2 Et), 1655 (C=O, 2-oxindol), 1600, 1588, 1467, 1440, 1346, 1313, 1296, 1147, 1133, 1111, 1097, 1078, 920, H NMR (DMSOd 6 ): δ 0.92 (t, J = 7 Hz, 3H, OCH 2 CH 3 ), 2.43 (s, 3H, 2'-CH 3 ), (dq, 2H, OCH 2 CH 3 ), 4.65 (s, 1H, H-3), (m, 1H, ArH), (m, 3H, ArH), 6.78 (s, 1H ArH), (m, 2H, ArH), (m, 2H, ArH), (dd, J 1 = 0.8 Hz, J 2 = 4Hz, 1H, ArH), 8.76 (s,1h, NH), (s, 1H, NH), (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 13.72, 14.44, 45.15, 58.48, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. for C 28 H 22 BrN 3 O 3 S: C, 60.00; H, 3.96; N, 7.50; S, Found: C, 60.22; H, 3.85; N, 7.62; S, (2-oxoindolin-3-yl)-2-methyl-5-(10H-phenothiazin-2-yl)-1Hpyrrole-3-carboxylate 2d: Colorless solid. Mp > 300 o C, IR (v, thin layer, cm -1 ): 3353 (NH), 3301 (NH), 3244 (NH), 2988 (C-H aliphatic), 1710, (CO 2 Me), 1666 (C=O, 2-oxindole), 8

9 1626, 1602, 1588, 1536, 1486, 1467, 1444, 1392, 1376, 1315, 1297, 1271, 1193, 1145, 1135, 1104, 1046, 1035, 914, H NMR (DMSO-d 6 ): δ 2.41 (s, 3H, 2'-CH 3 ), 3.2 (s, 3H, CO 2 CH 3 ), 4.59 (s,1h, H-3), (m, 1H, ArH), (m, 2H, ArH), (m, 3H, ArH), (m, 2H, ArH), (m, 2H, ArH), (m, 1H, ArH), 8.73 (s, 1H, NH), (s, 1H, NH, (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 14.13, 45.02, 49.68, , , , , , , , , , , ,126.70, , , , , , , , , , , , Anal. Calcd. for: C 27 H 21 N 3 O 3 S. C, 69.36; H, 4.53; N, 8.99; S, Found: C, 69.61; H, 4.75; N, 8.71; S, Methyl 4-(5-bromo-2-oxoindolin-3-yl)-2-methyl-5-(10H-phenothiazin-2-yl)- 1H-pyrrole-3-carboxylate 2e: Colorless solid. Mp > 300 o C, IR (v, thin layer, cm -1 ): 3350 (NH), 3304 (NH), 3250 (NH), 2944 (CH), 1714 (C=O, ester), 1663 (C=O, 2-oxindole), 1605, 1588, 1466, 1445, 1313, 1297, 1277, 1265, 1161, 1145, 1133, 11045, 1133, 1105, 1080, H NMR (DMSO-d 6 ): δ 2.42 (s, 3H, 2'-CH 3 ), 3.26 (s, 3H, CO 2 Me), 4.65 (s, 1H, H-3), (m, 2H, ArH), (m, 2H, ArH,), 6.85 (s, 1H, ArH), (t, J = 8 Hz, 2H, ArH), (m, 2H, ArH), 7.30 (d, J = 8 Hz, 1H, H-6, ArH), 8.74 (s, 1H, NH), (s, 1H, NH), (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 13.51, 45.06, 49.83, , , , , , , , , , , , , , , , , , , , 142.2, , , , Anal. Calcd. for: C 27 H 20 BrN 3 O 3 S: C, 59.35; H, 3.69; N, 7.69; S, Found: C, 59.45; H, 3.51; N, 7.53; S,

10 Methyl 2-methyl-4-(5-methyl-2-oxoindolin-3-yl)-5-(10H-phenothiazin-2-yl)- 1H-pyrrole-3-carboxylate 2f: Colorless solid. Mp > 300 o C, IR (v, thin layer, cm -1 ): 3353 (NH), 3301(NH), 3244 (NH), 2988 (CH 3 ), 1710 (CO 2 Me), 1666 (C=O, 2-oxindole), 1626, 1602, 1588, 1536, 1486, 1467, 1444, 1392, 1376, 1315, 1297, 1271, 1218, 1193, 1145, 1135, MS, M/Z (%): 478 (M + - 3, 45), 458 (41), 437 (52), 422 (51), 412 (54), 402 (47), 390 (53), 365 (57), 319 (51), 256 (43), 207(48), 158 (53), 134 (49), 96 (59),80 (100). 1 H NMR (DMSO-d 6 ) δ 2.18 (s, 3H, 2'-CH 3 ), 2.42 (s, 3H, 5'-CH 3 ), 3.22 (s, 3H, CO 2 CH 3 ), 4.57 (s, 1H, H-3), 6.6 (s, 1H, ArH), (m, 3H, ArH), 6.82(d, J = 1.6 Hz, 1H, ArH), (m, 3H, ArH), (m, 2H, ArH), 8.77(s, 1H, NH), 10.25(s, 1H, NH), 11.61(s, 1H, NH). 13 C NMR(DMSO-d 6 ) δ 13.45, 21.17, 45.04, 49.68, , 109.8, , , , , , , , , , , , , , (2c), , , , , 142.8, , Anal. Calcd. for C 28 H 23 N 3 O 3 S: C, 69.83; H, 4.81; N, 8.73; S, Found: C, 69.62; H, 4.65; N, 8.94; S, (4-Acetyl-5-methyl-2-(10H-phenothiazin-2-yl)-1H-pyrrol-3-yl)indolin-2- one 3a: Colorless solid. Mp o C, IR (v, thin layer, cm -1 ): 3318 (NH), 2988 (C-H, aliphatic), 1705 (COCH 3 ), 1680 (C=O, 2-oxindol), 1561, 1464, 1393, 1356, 1330, 1298, 1279, 1253, 1213, 1128, 1074, 1018, 968, 928. MS, M/Z (%): 451(M +, 60), 409 (100), 380 (60), 277 (100), 167 (30), 128 (30), 77(25), 64(38). 1 H-NMR (DMSO-d 6 ): δ 2.09 (s, 3H, CH 3 ), 2.12 (s, 3H, CH 3 ), 4.5 (s, 1H, H-3), (m, 4H, ArH), 6.79 (d, J = 8 Hz, 2H, ArH), (m, 2H, ArH), (m, 2H, ArH), (m, 1H, ArH), 8.77 (s, 1H, NH),

11 (s, 1H, NH), (s, 1H, NH). 13 C (DMSO-d 6 ): δ 15.16, 30.39, 45.05, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. for: C 27 H 21 N 3 O 2 S. C, 71.82; H, 4.69; N, 9.31; S, Found: C, 71.95; H, 4.81; N, 9.52; S, (4-Acetyl-5-methyl-2-(10H-phenothiazin-2-yl)-1H-pyrrol-3-yl)-5- methylindolin-2-one 3b: Colorless solid. Mp > 300 o C, IR (v, thin layer, cm -1 ): 3391, 3277, 1704, 1610, 1536, 1488, 1466, 1445, 1432, 1379, 1343, 1318, 1304, 1257, 1219, 1109, 973, 947, H NMR (DMSO-d 6 ): δ 2.12 (s, 3H, CH 3 ), 2.14 (s, 3H, CH 3 ), 2.16 (s, 3H, CH 3 ), 4.49 (s, 1H, H-3), 6.54 (s, 1H, ArH), (m, 4H, ArH), (M, 3H, ArH), (m, 2H, ArH) 8.79 (s, 1H, NH), (s, 1H, NH), (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 15.17, 21.18, 30.43, 45.28, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. for C 28 H 23 N 3 O 2 S: C, 72.23; H, 4.98; N, 9.03; S, Found: C, 72.15; H, 4.77; N, 9.31; S, (4-Acetyl-5-methyl-2-(10H-phenothiazin-2-yl)-1H-pyrrol-3-yl)-5- bromoindolin-2-one 3c: Colorless solid. Mp o C, IR (v, thin layer, cm -1 ): 3379 (NH), 3287 (NH), 3189 (NH), 1708 (C=O, ketonic), 1612, 1560, 1536, 1466, 1432, 1413, 1344, 1318, 1303, 1205, 1110, 1067, 972. MS, M/Z (%): 489 (M , 75), 473 (97), 454 (60), 432 (75), 324(90), 299 (90), 232 (100)178 (97), 143 (81), 137 (90), 93 (69) 1 H NMR (DMSO-d 6 ): δ 2.16 (s, 3H, 5'-CH 3 ), 2.53 (s, 3H, COCH 3 ),

12 (s, 1H, H-3), (m, 5H, ArH), (m, 1H, ArH), (m, 1H, ArH), (m, 2H, ArH), 7.26 (d, J= 8 Hz, 1H, H-6, ArH).8.76 (s, 1H, NH), 10.37(s, 1H, NH), (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 15.19, 30.41, 45.30, , , , , , , , , , , , , , , , , , , , , , , , Anal. Calcd. for C 27 H 20 BrN 3 O 2 S: C, 61.14; H, 3.80; N, 7.92; S, Found: C, 61.32; H, 4.01; N, 7.98; S, (2-Oxindolin-3-yl)-2-(10H-phenothiazin-2-yl)-1H-benzo[f]indole-4,9- dione 4: Violet solid. Mp > 300 o C, IR (v, thin layer, cm -1 ): 3328 (NH), 1680 (C=O), 1618, 1583, 1462, 1434, 1303, 1254, 1118, 1081, 1032, 870, 744, 725, 667. MS, M/Z ( %): 495 (M , 55), 490 (72), 481(77), 474(63), 368 (90), 300 (71), 261(100), 226 (69),186 (87), 177(66), 150 (64), 91(67). 1 H NMR (DMSOd 6 ): δ 5.4 (s, 1H, H-3), 6.78 (m, 2H, ArH), (m, 3H, ArH), (m, 2H, ArH), (m, 4H, ArH), 8.07(m, 2H, ArH), (m, 2H, ArH), 8.9 (s,1h, NH), 9.54 (s, 1H, NH), (s, 1H, NH). Anal. Calcd. for C 32 H 19 N 3 O 3 S: C, 73.13; H, 3.64; N, 8.00; S, Found: C, 73.24; H, 3.51; N, 7.83; S, (2-Oxoindolin-3-yl)-2-(10H-phenothiazin-2-yl)indeno[1,2-b]pyrrol-4(1H)- one 5: Violet solid. Mp o C, IR (v, thin layer, cm -1 ): 3280 (NH), 1685 (C=O), 1600, 1575, 1537, 1462, 1431, 1377, 1275, 1193, 1155, 1094, 1031, 994. MS, M/Z (%):497 (M +, 51), 469 (51), 450 (57), 438 (65), 421(42), 403 (51), 389 (58), 362 (52), 321 (47), 304 (69), 293 (62), 269 (60), 251 (60), 227 (44),

13 (56), 191(87), 180 (58), 161(57), 144 (73), 134 (71), 120 (58), 109 (71), 97 (71), 57(100). 1 H NMR (DMSO-d 6 ): δ 5.41, (s, 1H, H-3), (m, 4H, ArH), (m, 5H, ArH), (m, 3H, ArH), (m, 1H, ArH),8.12 (d, J = 7.5 Hz, 1H, ArH), 8.51(d, J = 7.5 Hz, 1H, ArH), 8.82 (s,1h, NH),10.97(s, 1H, NH), (s, 1H, NH). Anal. Calcd. for C 31 H 19 N 3 O 2 S: C, 74.83; H, 3.85; N, 8.45; S, Found: C, 74.72; H, 3.64; N, 8.62; S, Synthesis of ethyl 5-(10-(2-chloroacetyl)-10H-phenothiazin-2-yl)-4-(1- (2-chloro-acetyl)-2-oxoindolin-3-yl)-2-methyl-1H-pyrrole-3-carboxylate 6: Conventional Method: A mixture of 3-pyrrolyl-2-oxindole 2a (3 mmol, g) and chloroacetyl chloride (3.1 mmol, g, ml) was suspended in toluene (25 ml) and the reaction mixture was refluxed for 3 h with extrusion of moisture (TLC monitoring). The solvent and excess reagent was removed under reduced pressure and the formed precipitate was crystallized from toluene to give 1.37 g of compound 6 as colorless crystals Microwave method: A mixture of 3- pyrrolyl-2-oxindole 2a (3 mmol, g) and chloroacetyl chloride (3.1 mmol, g, ml) was suspended in toluene (15 ml) and the reaction mixture was heated under microwave irradiation at 110 o C and power of 200 W for 1 h (TLC monitoring). The solvent and excess reagent was removed under reduced pressure and the formed precipitate was crystallized from toluene to give 1.62 g of compound 6. Colorless solid. Mp o C, IR ( v, thin layer, cm -1 ): 3305, 2960, 1753, 1694, 1672, 1552, 1525, 1464,1443, 1407, 1351, 1332, 1275, 1252, 1241,1189, 1169, 1137, 1096, 1086, 1047, 1015, 924, H NMR (DMSO- 13

14 d 6 ) 0.85 (t, J = 7.0 Hz, 3H, 2'-CH 3 ), 2.47(s, 3H, CH 3 ), (dq, 2H, CO 2 CH 2 CH 3 ), 3.79 (br, 2H, COCH 2 Cl, diastereotopic CH 2 ), 4.98 (d, J = 20 Hz, 1H, diastereotopic H),4.99 (s, 1H, H-3), 5.09 (d, J = 20 Hz,1H, diastereotopic H) 7.01 (d, J = 7Hz, 1H, ArH), 7.17 (t, 1H, J = 7 Hz, ArH), (m, 2H, ArH), (m, 2H, ArH), 7.62 (d, J = 7.5 Hz, 1H, ArH), (m, 2H, ArH), 7.81(s, 1H, ArH), 8.12 (d, J = 8.4 Hz,1H, ArH) 11.91(s, 1H, NH). 13 C NMR (DMSO-d 6 ) 13.82, 14.30, 43.34, 45.01, 46.41, 59.02, , , , , , , , , , (2C), , , , , , , , , , , , , , , Anal. Calcd. for C 32 H 25 Cl 2 N 3 O 5 S: C, 60.57; H, 3.97; N, 6.62; S, Found: C, 60.68; H, 4.11; N, 6.79; S, Ethyl 5-(10-(2-azidoacetyl)-10H-phenothiazin-2-yl)-2-methyl-4-(2- oxoindolin-3-yl)-1h-pyrrole-3-carboxylate 8: Conventional method A: A suspension of the dichloroacetyl 2-oxindole derivative 6 (3 mmol, g) and sodium azide (6.6 mmol, 0.43 g) in acetone (30 ml) was heated under reflux for 4 h (TLC monitoring). The solvent was removed under reduced pressure and the solid residue was crystalized from ethyl acetate to give 1.35 g of compound 8 as colorless solid Conventional Method B: To a solution of dichloroacetyl-2-oxindole 6 (3 mmol, g mmol) in chloroform (30 ml) were added sodium azide (6.6 mmol, 0.43 g), water (15 ml), and benzyltriethylammonium bromide (0.026 g, 0.10 mmol). The reaction mixture was stirred at reflux temperature for 48 h and the organic layer was separated. The organic layer was washed with water (3 x 20 ml), dried on 14

15 anhydrous Na 2 SO 4 and concentrated in vacuum. The residue was recrystallized from ethyl acetate (15 ml) to give g of compound 8 (20% yield) Microwave method: A suspension of the dichloroacetyl 2-oxindole derivative 6 (1mmole, g) and sodium azide (2.2 mmol, g) in acetone (5 ml) was irradiated in CEM microwave apparatus at 56 o C and power of (200 W). The completion of the reaction was monitored by TLC. The reaction mixture was processed in the same manner in the conventional method to give 0.49 g of compound 8. Colorless solid. Mp o C, IR (v, thin layer, cm -1 ): 3266 (NH), 2105 (N 3 ), 1685 (C=O), 1680 (C=O), 1618, 1560, 1524, 1466, 1444, 1330, 1268, 1173, 704, H NMR (DMSO-d 6 ): δ 0.86 (t, J = 7 Hz, 3H, -CO 2 CH 2 CH 3 ), 2.45 (s, 3H, 2'-CH 3 ), 3.75 (dq, 2H, -CO 2 CH 2 CH 3 ) 4.26 (br, 2H, COCH 2 N 3, diastereotopic CH 2 ), 4.62 ( s, 1H, H-3), (m, 2H, ArH) (m, 1H, ArH), 7.36 (m, 1H, ArH), (m, 1H, ArH), 7.49 (d, J = 8 Hz, 1H, ArH), (dd, J 1 = 1.2 Hz, J 2 = 7.5 Hz, 1H, ArH), 7.67 (s, 1H, ArH), (m, 2H, ArH), 7.80 (m, 1H, ArH), (s, 1H, NH), 11.71(s, 1H, NH). 13 C NMR (DMSO-D 6 ): 13.58, 14.34, 45.04, 51.16, 58.45, , , , , , , (2C), (2C), , , , (2C), (2C), (2C), , , , , , Anal. Calcd. for C 30 H 24 N 6 O 4 S: C, 63.82; H, 4.28; N, ; S, Found: C, 63.59; H, 4.32; N, 14.95; S, Diethyl 1-(2-(2-(4-(ethoxycarbonyl)-3-(2-hydroxy-1H-indol-3-yl)-5- methyl-1h-pyrrol-2-yl)-10h-phenothiazin-10-yl)-2-oxoethyl)-1h-1,2,3- triazole-4,5-dicarboxylate 9: 15

16 4.5.1 Conventional method: Ethyl yl)-1h-pyrrole-3-carboxylate 8 (3 mmol, g) and diethyl- acetylene dicarboxylate (3.3 mmol, g, 0.49 ml) was dissolved in 25 ml acetone and refluxed for 2h until TLC showed the consuming of the starting material. The solvent was removed under reduced pressure and the solid residue was recrystallized from ethanol to give 1.87 g of compound Microwave method: Ethyl 5-(10-(2-azidoacetyl)-10H-phenothiazin-2-yl)-2-methyl-4-(2-oxoindolin-3-5-(10-(2-azidoacetyl)-10H-phenothiazin-2-yl)-2-methyl-4-(2-oxoindolin- 3-yl)-1H-pyrrole-3-carboxylate 8 (3 mmol, g) and diethyl acetylenedicarboxylate (3.3 mmol cap, g, 0.49 ml) was dissolved in 10 ml acetone and subjected to microwave irradiation at 56 o C (200 W) for 1h until TLC showed the disappearance of the starting material. The solvent was removed under reduced pressure and the solid residue was recrystallized from ethanol to give 2.02 g of compound 9. Colorless solid. Mp o C, IR (v, thin layer, cm -1 ): 3222 (NH), 2982 (C- H, aliphatic), 1694, 1665, 1619, 1560, 1523, 1465, 1299, 1272, 1248, 1212, 1171, 1143, 1096, 1059, 1017, 932, H NMR (DMSO-d 6 ) δ 0.83 (t, J = 7 Hz, 3H,-CO 2 CH 2 CH 3 ), 1.17 (t, J = 7 Hz, 3H,-CO 2 CH 2 CH 3 ), 1.25 ( t, J = 7 Hz, 3H,-CO 2 CH 2 CH 3 ), 2.41(s, 3H, 2'-CH 3 ), (m, 6H, 3 CH 2 ), 4.60 (d, J = 10 Hz, 2H, COCH 2 N 3 ), 6.74 (d, J = 7 Hz, 1H, ArH), (m, 3H, ArH), 7.11 (t, J= 7.5 Hz, 1H, ArH), (m, 3H, ArH), 7.62 (m, 1H, ArH), 7.68 (m, 2H, ArH), 7.79 (brs, 1H, enolic-oh), (s, 1H, NH)11.72 (s, 1H, NH). 13 C NMR (DMSO-d 6 ): δ 13.46, 14.05, 14.26, 14.68, 44.98, 52.95, 58.63, 62.33, 63.11, , , , , , , , 16

17 127.55, , (2C), , (2C), (2C), , , (2C), (2C), , , , , , , Anal. Calcd. for C 38 H 34 N 6 O 8 S: C, 62.11; H, 4.66; N, 11.44; S, Found: C, 62.23; H, 4.45; N, 11.61; S, Ethyl 5-(10-(2-chloroacetyl)-10H-phenothiazin-2-yl)-2-methyl-4-(3-oxo- 2,3-dihydrooxazolo[3,2-a]indol-9-yl)-1H-pyrrole-3-carboxylate10: Conventional method: Dichloroacetyl 2-oxindole derivative 6 (3 mmol, g) was added into a suspension of sodium hydride (60% in paraffin oil, 3 mmol, 0.12 g) in toluene (40 ml). The reaction mixture was heated with extrusion of moisture under reflux for 3h (TLC monitoring). The reaction mixture was cooled and the solvent was removed under reduced pressure. The solid residue was crystalized from toluene to give 1.49 g of compound Microwave method: Dichloroacetyl 2-oxindole derivative 6 (3 mmol, g) was added into a suspension of sodium hydride (60% in paraffin oil, 3 mmol, 0.12 g) in toluene (20 ml). The reaction mixture was subjected to microwave irradiation at 110 o C (200 W) for 1h (TLC monitoring). The reaction mixture was cooled and the solvent was removed under reduced pressure. The solid residue was crystalized from toluene to give 1.61 g of compound 10 as colorless solid. Colorless solid. Mp o C, IR (v, thin layer, cm -1 ): 3280 (NH), 2978 (C-H aliphatic), 1756 (C=O, 4-oxazolone), 1667(C=O, 2-oxindole), 1603, 1524, 1458, 1341, 1260, 1236, 1189, 1134, 1098, 1000, 784, 755. MS, M/Z( %): 493 ( M , 40), 485 (60), 470 (50), 420 (50), 378 (80), 353 (60), 274 (60), 229 (60), 198 (65), 123 (70), 92 (70), 80 (100). 1 H NMR (DMSO-d 6 ): 0.9 (t, J =

18 Hz, 3H, CH 3 ), 2.38 (s, 3H, CH 3 ), 3.86 (brs, 2H, COCH 2 Cl), (dq, 2H, OCH 2 CH 3 ), 4.86 (d, J = 16 Hz, 1H, H a ), 5.03 (d, J = 16 Hz,1H, H b ) (d, J = 7.5 Hz, 1H, ArH), (m, 3H, ArH), (m, 4H, ArH), (m, 2H, ArH), 7.87(d, J = 6Hz, 1H, ArH), 8.96 (s, 1H, NH). 13 C NMR (DMSOd 6 ): 13.96, 21.46, 41.72, 59.37, 76.28, , (2C), , , , , , (2C), , , (2C), (2C), , , , , , , , , , , ; Anal. calcd. for C 32 H 24 ClN 3 O 5 S: C, 64.26; H, 4.04; N, 7.03; S, Found: C, 64.10; H, 4.19; N, 7.22; S,

19 Table 1. Comparison between conventional and microwave-assisted method of synthesis of compounds 2a-f, 3a-c, 4, 5, 6, 8-10 in terms of yield and time. Number Reaction conditions Conventional Yield (%) (time, min.) Microwave Yield (%) (time, min.) 2a 83 (20) a 92 (10) b 2b 87 (15) a 93 (5) b 2c 85 (30) a 91 (10) b 2d 87(20) a 92(10) b 2e 86 (20) a 93(10) b 2f 88(15) a 95(10) b 3a 82(20) a 90(10) b 3b 81(20) a 88(10) b 3c 82(30) a 87(10) b 4 75(30) a 85(15) b 5 70(40) a 85(15) b 6 72 (180) c 85(60) e 8 80 (240) d 87(90) f 9 85 (120) d 92(60) f 10 83(180) c 90(60 ) e a. AcOH, reflux; b. AcOH, MW (120 o C, 200 W); c. Toluene, reflux; d. acetone, reflux; e. Toluene, MW (110 o C, 200 W); f. Acetone, MW (56 o C, 200 W). 19

20 Figure S1. 1 H NMR of compound 1a Figure S2. 13 C NMR of compound 1a 21

21 Figure S3. 1 H NMR of compound 1b Figure S4. 13 C NMR of compound 1b 21

22 Figure S5. Mass Spectrum of compound 1b Figure S6. 1 H NMR of compound 1c 22

23 Figure S7. 13 C NMR of compound 1c Figure S8. 1 H NMR of compound 2a 23

24 Figure S9. 13 C NMR of compound 2a 24

25 Figure S10. Mass spectra of compound 2a 25

26 Figure S11. 1 H NMR spectrum of compound 2b Figure S C NMR spectrum of compound 2b. 26

27 Figure S13. Mass spectrum of compound 2b 27

28 Figure S14. 1 H NMR of compound 2c Figure S C NMR spectrum of compound 2c 28

29 Figure S16. 1 H NMR of compound 2d. Figure S C NMR of compound 2d. Figure S18. 1 H NMR of compound 2e 29

30 Figure S C NMR of compound 2e Figure S20. 1 H NMR spectrum of 2f Figure S C NMR spectrum of compound 2f 31

31 Figure S 22. Mass spectrum of compound 2f 31

32 Figure S23. 1 H NMR spectrum of compound3a Figure S C NMR spectrum of compound 3a 32

33 Figure S 25. Mass spectrum of compound 3a 33

34 Figure S26. 1 H NMR spectrum of compound 3b Figure S C NMR spectrum of compound 3b 34

35 Figure S H NMR spectrum of compound 3c Figure S C NMR spectrum of compound 3c 35

36 Figure S30. Mass spectrum of compound 3c 36

37 Figure S31. Mass spectrum of compound 4 37

38 Figure S32. Mass spectrum of compound 5 38

39 Figure S33. 1 H NMR of compound 6 Figure S C NMR spectrum of compound 6 Figure S35. HMBC spectrum of compound 6 39

40 Figure S36. 1 H NMR spectrum of compound 8 Figure S37. HMBC of compound 8 41

41 Figure S38. 1 H NMR spectrum of compound 9 Figure S C NMR spectrum of compound 9 Figure S40. HMBC spectrum of compound 9 41

42 Figure S N HMBC of compound 9 Figure S42. 1 H NMR of compound 10 Figure S C NMR of compound 10 42

43 Figure S44. Mass spectrum of compound 10 43