Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7](SC)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][C@H:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1.C(O)(C(F)(F)F)=O.CS>C(#N)C.CC(O)C>[CH3:20][O:21][CH2:22][CH2:23][C@@H:24]1[NH:25][CH2:26][CH2:27][N:28]([C:7]2[C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:29]1
Reactant: COCC[C@H]1CNCCN1
Reactant: CSC1=Nc2ccccc2Nc2sc(C(C)C)nc21
Agent: CS
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1
Temperature: 45 °C
Reaction time: 0.03 h

Procedure:
Equip a 1 liter single necked round bottom flask with a condenser, magnetic stir bar, heating mantle, and nitrogen inlet. Charge the flask with 2-isopropyl-10-methylsulfanyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (44.9 g, 0.155 mol), (S)-2-(2-methoxyethyl)piperazine (27.98 g, 0.194 mol, 1.25 eqs.), and IPA (270 mL, 6 vols.). Heat the resulting slurry to reflux and monitor by HPLC: Column=Zorbax C-8, Flow=1 mL/min., A=ACN, B=0.1% aqueous TFA, Gradient=95% A/5% B to 5% A/95% B over 10 minutes, Hold at 5/95 A/B for 3 minutes, and return to 95/5 A/B over 2 minutes, Column temperature=30° C., Wavelength=250 nm. After 3 hours at relux, HPLC analysis indicates a product to starting material ratio (p/sm) of 2.9/1.0. Allow the reaction mixture to reflux overnight under a nitrogen purge. After 19.75 hours at reflux, HPLC analysis indicates a p/sm ratio of 16.1/1.0. Allow the mixture to reflux 2 hours longer and assay again by HPLC. Indications of this analysis show no change in the p/sm. ratio. Charge additional (S)-2-(2-methoxyethyl)piperazine (2.24 g, 0.0155 mol, 0.1 eq.) to the reaction vessel and continue to reflux for 5 hours. Indications of HPLC analysis shows 3% remaining starting material, 2-Isopropyl-10-methylsulfanyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene. Methyl mercaptan is evolved during the reaction. On this scale, the odors associated with that chemical were controlled by a nitrogen purge exhausted to the far back of the hood. For future, larger scale operations, a bleach scrubber should be considered. Stop the heating and allow the reaction mixture to cool to 40-50° C. Transfer the flask to the roto-vap and strip the IPA using a 40-50° C. bath. Dissolve the resulting thick, orange oil in ethyl acetate (1000 mL), transfer to a separatory funnel, and wash with deionized water (2×250 mL). After a brine wash (250 mL), dry the solution over Na2SO4, filter, and concentrate in vacuo. Allow the resulting oil to pull under vacuum overnight at ambient temperature. Solidification of the material overnight into a yellow mass (74.1 g, theory=59.84 g). HPLC analysis indicates 2.1% remaining 2-Isopropyl-10-methylsulfanyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene. Treat these solids with ligroin (500 mL) and ethyl acetate (50 mL). Place a magnetic stir bar in the flask and the mixture vigorously at ambient temperature until all of the solids were broken into small particles (6 hrs.). Filter the mixture and rinse the solids with 100/5 ligroin/ethyl acetate (105 mL), then ligroin (2×200 mL). Transfer the yellow solids to a tared dish and dry under vacuum at ambient temperature. Recover 53.67 grams of title compound (89.7%): 1H NMR (500 MHz, DMSO-d6): δ 1.23 (d, 6H), 1.49-1.53 (m, 2H), 2.20-2.39 (bm, 1H), 2.43-2.49 (m, 1H), 2.62-2.74 (m, 2H), 2.70-2.83 (m, 1H), 2.85-2.90 (m, 1H), 3.04-3.08 (m, 1H), 3.19 (s, 3H), 3.30-3.41 (m, 2H), 3.90-4.09 (bm, 2H), 6.67 (m, 1H), 6.69-6.79 (m, 2H), 6.79-6.86 (m, 1H). 13C NMR (100 MHz, DMSO-d6): δ 22.88, 22.91, 33.13, 33.85, 39.36, 40.61, 45.54, 52.88, 58.36, 69.67, 119.25, 123.43, 124.33, 127.96, 131.74, 141.41, 143.52, 151.04, 155.97, 165.59. MS (80:20 MeOH:H2O w/6.5 mM NH4OAc). Calculated: 385.53. Found: ES+ 386.2. ES− 384.2.