2-oxopropanethioamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(6-Bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)-2-methylpropane-2-sulfinamide (Example 47 Step 1, 0.5 g, 1.21 mmol) and 2-oxopropanethioamide (Intermediate 2, 0.373 g, 3.62 mmol) were dissolved in dry acetonitrile (4.0 mL) in a dry microwave vial. The vial was sealed and heated with MW for 20 min. at 130° C. The solvent was evaporated to give the crude title compound that was used directly in the next reaction. MS (ES+) m/z 395 [M+H]+. The vial was sealed The solvent was evaporated

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

Procedure: 2-Oxopropanethioamide (Intermediate 2, 289 mg, 2.80 mmol) and 6-bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-imine (Example 45 Step 2, 331.4 mg, 1.12 mmol) were dissolved in acetonitrile (3 mL) and heated using MW for 20 min to 120° C. The solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in heptane but co-eluted with byproducts. The not completely pure product was used as a mixture in the next step. heated The solvent was evaporated under reduced pressure The crude product was purified by flash chromatography

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

Procedure: 2-Oxopropanethioamide (Intermediate 2, 289 mg, 2.80 mmol) and 6-bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-imine (Example 45 Step 2, 331.4 mg, 1.12 mmol) were dissolved in acetonitrile (3 mL) and heated using MW for 20 min to 120° C. The solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using a gradient of 0-50% EtOAc in heptane but co-eluted with byproducts. The not completely pure product was used as a mixture in the next step. heated The solvent was evaporated under reduced pressure The crude product was purified by flash chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-imine (Example 29 Step 2, 1.37 g, 4.41 mmol) and 2-oxopropanethioamide (Intermediate 2, 0.909 g, 8.81 mmol) were dissolved in dry MeOH (25 mL) and the resulting orange solution was heated at 60° C. under a nitrogen atmosphere overnight. More 2-oxopropanethioamide (400 mg) was added and stirring continued. After 24 h the mixture was allowed to cool to r.t. and the solvent was evaporated. Purification by flash chromatography using a gradient of 0-100% EtOAc in heptane afforded 373 mg of the title compound (21% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (m, 1 H), 1.47 (m, 3 H), 1.87 (m, 2 H), 1.97 (m, 2 H), 2.29 (s, 3 H), 3.13 (s, 3 H), 4.11 (m, 1 H), 6.99 (d, 1 H), 7.16 (d, 1 H), 7.48 (dd, 1 H); MS (ES+) m/z 396 [M+H]+. to cool to r.t. the solvent was evaporated Purification by flash chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example 27 Step 2, 418 mg, 1.33 mmol) and 2-oxopropanethioamide (Intermediate 2, 412 mg, 3.99 mmol) were dissolved in dry MeOH (6 mL) and the resulting solution was heated at 60° C. under N2(g) overnight. The reaction mixture was allowed to cool to r.t. A precipitate formed which was filtered off and dried in vacuo, yielding the title compound (387 mg, 73% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.29-1.47 (m, 2 H), 1.49-1.62 (m, 2 H), 1.81-2.08 (m, 4 H), 2.28 (s, 3 H), 3.09 (d, 1 H), 3.15 (d, 1 H), 7.02 (d, 1 H), 7.33 (d, 1 H), 7.53 (d, 1 H), 12.42 (s, 1 H); MS (ES+) m/z 399.0 [M+H]|. to cool to r.t A precipitate formed which was filtered off dried in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example 27 Step 2, 418 mg, 1.33 mmol) and 2-oxopropanethioamide (Intermediate 2, 412 mg, 3.99 mmol) were dissolved in dry MeOH (6 mL) and the resulting solution was heated at 60° C. under N2(g) overnight. The reaction mixture was allowed to cool to r.t. A precipitate formed which was filtered off and dried in vacuo, yielding the title compound (387 mg, 73% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.29-1.47 (m, 2 H), 1.49-1.62 (m, 2 H), 1.81-2.08 (m, 4 H), 2.28 (s, 3 H), 3.09 (d, 1 H), 3.15 (d, 1 H), 7.02 (d, 1 H), 7.33 (d, 1 H), 7.53 (d, 1 H), 12.42 (s, 1 H); MS (ES+) m/z 399.0 [M+H]|. to cool to r.t A precipitate formed which was filtered off dried in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-imine (Example 25 Step 2, 235 mg, 0.84 mmol) and 2-oxopropanethioamide (Intermediate 2, 173 mg, 1.68 mmol) were taken up in anhydrous MeOH (5 mL) and the resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 3 h. When cooled to r.t. the mixture was concentrated and purified on a silica gel column eluted with 0-50% EtOAc in heptane to give 385 mg (95% yield) of the title compound; 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.40 (br. s, 1 H), 7.53 (dd, 1 H), 7.36 (d, 1 H), 7.03 (d, 1 H), 3.71 (td, 2 H), 3.44 (m, 2 H), 3.15 (m, 2 H), 2.29 (s, 3 H), 1.64 (s, 1 H), 1.55 (s, 1 H), 1.27 (m, 2 H); MS (ES+) m/z 365 [M+H]+. When cooled to r.t. the mixture was concentrated purified on a silica gel column eluted with 0-50% EtOAc in heptane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example 20v, Step 2, 204 mg, 0.67 mmol), trimethyl orthoformate (0.193 mL, 1.76 mmol) and 2-propanol (5 mL) was added to a MW vial. The vial was sealed and the mixture was heated at 60° C. (oil bath). 2-Oxopropanethioamide (Intermediate 2, 138 mg, 1.34 mmol) in MeOH (15 mL) was added and the resulting mixture was stirred overnight at 60° C. and was then concentrated in vacuo. The product was isolated using flash chromatography (0-50% EtOAc in heptane) to give the title compound (167 mg, 64% yield): MS (ES+) m/z 391 [M+H]+. The vial was sealed was then concentrated in vacuo The product was isolated

Conditions: temp:74.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 19 Step 3, 22.7 g, 57.7 mmol) and ammonia (7 M in MeOH, 180 mL, 1.26 mol) was put in a pressure reactor and heated to 74° C. overnight. The residue was allowed to reach r.t. and the mixture was concentrated. The residue was partitioned between 2 M citric acid (400 mL) and EtOAc (400 mL). Any insoluble material was filtered off and was determined to be unreacted starting material. The organic phase (org 1) was concentrated in vacuo to give additional unreacted starting material. To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The resulting organic phase (org 2) was saved. The residue from org 1, and the solid filtered off were combined and suspended in ammonia (7 M in MeOH, 180 mL, 1.26 mmol) and put in a pressure reactor and heated 100° C. overnight. The obtained solution was concentrated in vacuo. The residue was partitioned between 2 M citric acid (300 mL) and EtOAc (300 mL). To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The organic phase was combined with org 2 from above. Activated charcoal was added to the organic phase and the mixture was stirred for 30 min before it was filtered through diatomaceous earth. The organic phase was concentrated and dried in vacuo overnight to give a solid. To the solid was diisopropyl ether (125 mL) added and the mixture was refluxed overnight. The mixture was allowed to reach r.t. and the solid was filtered off to give the title compound (equivalent to Example 19 Isomeric Mixture 2 above) (15 g, 69% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (m, 1 H) 1.1-1.25 (m, 2 H) 1.35-1.45 (m, 3 H) 1.81 (br. d, 2 H) 2.16 (s, 3 H) 2.87-3.03 (m, 3 H) 3.18 (s, 3 H) 6.59 (br. s., 2 H), 6.64 (d, 1 H), 7.25 (d, 1 H), 7.34 (dd, 1 H); ES+) m/z 376 [M+H]+. to reach r.t. the mixture was concentrated The residue was partitioned between 2 M citric acid (400 mL) and EtOAc (400 mL) Any insoluble material was filtered off The organic phase (org 1) was concentrated in vacuo to give additional added The residue from org 1, and the solid filtered off put in a pressure reactor heated 100° C. overnight The obtained solution was concentrated in vacuo The residue was partitioned between 2 M citric acid (300 mL) and EtOAc (300 mL) added 50% NaOH was added until pH ˜12 the mixture was stirred for 10 min Activated charcoal was added to the organic phase the mixture was stirred for 30 min before it was filtered through diatomaceous earth The organic phase was concentrated dried in vacuo overnight to give a solid added the mixture was refluxed overnight to reach r.t. the solid was filtered off