4-(2-isothiocyanatoethyl)morpholine

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H). concentrated The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H). concentrated The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H). concentrated The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared by a modification of a procedure reported for related compounds: Henichart, J. P.; Bernier, J. L. Synthesis 1980, 4, 311. Acetic hydrazide (3.7 g, 50 mmol) in ethanol (50 mL) was placed in a 200 mL 3-necked round bottomed flask outfitted with a magnetic stir bar and a reflux condenser. 2-morpholinoethyl isothiocyanate (8.61 g, 500 mmol) in ethanol (50 mL) was added to the pot. The mixture was refluxed, under N2, for 6 h. The reaction was cooled to room temperature and the solvent removed on the rotovap. The resulting resin was dissolved in minimal ethanol and ether. A white solid precipitated out, was filtered and washed with cold ether. The filtrate, containing uncyclized intermediate, was concentrated and dissolved in xylenes. The mixture was refluxed under N2 for 8 h, then allowed to sit at room temperature, under N2. for 48 h. A white solid formed, was filtered and washed with cold ether. The first and second batches of white solid were combined to yield 7.33 g (64%) of the desired product. The title compound was prepared by a modification of a procedure Synthesis 1980, 4, 311 outfitted with a magnetic stir bar and a reflux condenser The mixture was refluxed, under N2, for 6 h the solvent removed on the rotovap The resulting resin was dissolved in minimal ethanol A white solid precipitated out was filtered washed with cold ether The filtrate, containing uncyclized intermediate was concentrated dissolved in xylenes The mixture was refluxed under N2 for 8 h to sit at room temperature, under N2 A white solid formed was filtered washed with cold ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared by a modification of a procedure reported for related compounds: Henichart, J. P.; Bernier, J. L. Synthesis 1980, 4, 311. Acetic hydrazide (3.7 g, 50 mmol) in ethanol (50 mL) was placed in a 200 mL 3-necked round bottomed flask outfitted with a magnetic stir bar and a reflux condenser. 2-morpholinoethyl isothiocyanate (8.61 g, 500 mmol) in ethanol (50 mL) was added to the pot. The mixture was refluxed, under N2, for 6 h. The reaction was cooled to room temperature and the solvent removed on the rotovap. The resulting resin was dissolved in minimal ethanol and ether. A white solid precipitated out, was filtered and washed with cold ether. The filtrate, containing uncyclized intermediate, was concentrated and dissolved in xylenes. The mixture was refluxed under N2 for 8 h, then allowed to sit at room temperature, under N2. for 48 h. A white solid formed, was filtered and washed with cold ether. The first and second batches of white solid were combined to yield 7.33 g (64%) of the desired product. The title compound was prepared by a modification of a procedure Synthesis 1980, 4, 311 outfitted with a magnetic stir bar and a reflux condenser The mixture was refluxed, under N2, for 6 h the solvent removed on the rotovap The resulting resin was dissolved in minimal ethanol A white solid precipitated out was filtered washed with cold ether The filtrate, containing uncyclized intermediate was concentrated dissolved in xylenes The mixture was refluxed under N2 for 8 h to sit at room temperature, under N2 A white solid formed was filtered washed with cold ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H). concentrated The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 19) (70 mg) and 4-(2-isothiocyanatoethyl)morpholine (50 mg) to give the title compound as beige solid (45 mg, 46%). LCMS (formate) Rt 0.56 min, MH+ 495

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and 4-(2-isothiocyanatoethyl)morpholine (50 mg) to give the title compound as beige solid (57 mg, 60%). LCMS (formate) Rt 0.51 min, MH+ 521

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H). concentrated The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred slurry of 25.8 g (0.15 mole) of 2-morpholinoethylisothiocyanate (S-7) in 250 ml ethanol under a nitrogen atmosphere was added in a slow stream 19.5 g (0.3 mole) of sodium azide dissolved in 600 ml water. The resultant solution was refluxed for 16 hrs, cooled to room temperature (20° C.) and filtered. The filtrate was extracted twice with ether, and then acidified to pH=1 with concentrated hydrochloric acid. The resultant solution was extracted three times with ether. The pH of the aqueous solution was adjusted to 4.5 using a 50% NaOH solution and a fine white precipitate formed. The precipitate was collected by filtration to yield 17.1 grams of intermediate S-8 with a melting point of 226°-8° C. filtered The filtrate was extracted twice with ether The resultant solution was extracted three times with ether a fine white precipitate formed The precipitate was collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared by a modification of a procedure reported for related compounds: Henichart, J. P.; Bernier, J. L. Synthesis 1980, 4, 311. Acetic hydrazide (3.7 g, 50 mmol) in ethanol (50 mL) was placed in a 200 mL 3-necked round bottomed flask outfitted with a magnetic stir bar and a reflux condenser. 2-morpholinoethyl isothiocyanate (8.61 g, 500 mmol) in ethanol (50 mL) was added to the pot. The mixture was refluxed, under N2, for 6 h. The reaction was cooled to room temperature and the solvent removed on the rotovap. The resulting resin was dissolved in minimal ethanol and ether. A white solid precipitated out, was filtered and washed with cold ether. The filtrate, containing uncyclized intermediate, was concentrated and dissolved in xylenes. The mixture was refluxed under N2 for 8 h, then allowed to sit at room temperature, under N2. for 48 h. A white solid formed, was filtered and washed with cold ether. The first and second batches of white solid were combined to yield 7.33 g (64%) of the desired product. 1H NMR (DMSO-d6): d 2.33 (s, 3H) 2.41 (m, 4H) 2.55 (m, 2H) 3.52 (m, 4H) 3.99 (t, 2H, J=6) 13.41 (s, 1H). MS (APCI) calcd for C9H16N4OS: 228.32; found (M+H+) 229.1. The title compound was prepared by a modification of a procedure Synthesis 1980, 4, 311 outfitted with a magnetic stir bar and a reflux condenser The mixture was refluxed, under N2, for 6 h the solvent removed on the rotovap The resulting resin was dissolved in minimal ethanol A white solid precipitated out was filtered washed with cold ether The filtrate, containing uncyclized intermediate was concentrated dissolved in xylenes The mixture was refluxed under N2 for 8 h to sit at room temperature, under N2 A white solid formed was filtered washed with cold ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H). concentrated The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane