(2-amino-6-chlorophenyl)methanol

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

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

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

Procedure: (2-Amino-6-chlorophenyl)methanol (16 g, 101 mmol), 5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (20.0 g, 111 mmol), RuCl2(PPh3)3 (0.971 g, 1.01 mmol), and KOH (5.7 g, 101 mmol) were refluxed in 200 mL of toluene for 12 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel plug and eluted with dichloromethane. The product was washed by methanol and recrystallized from hexane to obtain ˜20 gram of the desired product which was confirmed by GC-MS. Water was collected from the reaction filtered through a silica gel plug eluted with dichloromethane The product was washed by methanol recrystallized from hexane

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

Procedure: (2-Amino-6-chlorophenyl)methanol (16 g, 101 mmol), 5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (20.0 g, 111 mmol), RuCl2(PPh3)3 (0.971 g, 1.01 mmol), and KOH (5.7 g, 101 mmol) were refluxed in 200 mL of toluene for 12 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel plug and eluted with dichloromethane. The product was washed by methanol and recrystallized from hexane to obtain ˜20 gram of the desired product which was confirmed by GC-MS. Water was collected from the reaction filtered through a silica gel plug eluted with dichloromethane The product was washed by methanol recrystallized from hexane

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

Procedure: 2-Amino-6-chlorobenzoic acid (25.0 g, 143 mmol) was dissolved in 120 mL of anhydrous THF in a 500 mL 2 neck round bottom flask. The solution was cooled in an ice-water bath. 215 mL of 1.0 M lithium aluminum hydride (LAH) THF solution was then added dropwise. After all of the LAH was added, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for overnight. ˜10 mL of water was added to the reaction mixture followed by 7 g 15% NaOH. An additional 20 g of water was added to the reaction mixture. Decant the organic THF phase and the solid was added with ethyl acetate. ˜200 mL and stirring and combined ethyl acetate organic portion and THF portion and added Na2SO4 drying agent. The mixture was filtered and evaporated. ˜20 g yellow solid was obtained without further purification for next step reaction. The solution was cooled in an ice-water bath Decant the organic THF phase the solid was added with ethyl acetate ˜200 mL and stirring added Na2SO4 drying agent The mixture was filtered evaporated

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

Procedure: A mixture of [2-chloro-6-(isopropylamino)phenyl]methanol, 5-chloro-2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine (2.7 g, ratio; 1:1, step 2) and manganese dioxide (3.9 g, 33.8 mmol) in toluene (50 mL) was stirred at reflux temperature for 16 h. The mixture was filtrated through a pad of Celite and the filtrate was concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:30) to give 1.2 g (45% from (2-amino-6-chlorophenyl)methanol) of the title compound as a yellow solid. at reflux temperature for 16 h The mixture was filtrated through a pad of Celite the filtrate was concentrated in vacuo The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:30)

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

Procedure: To a mixture of (2-amino-6-chlorophenyl)methanol (2.3 g, 14.6 mmol, step 1), acetic acid (14 mL), sodium acetate hydrate (4.8 g, 58.5 mmol), acetone (7 mL), ethanol (4.8 mL), and water (14 mL) was added a solution of sodium borohydride (1.66 g, 43.9 mmol) in 2N aqueous sodium hydroxide solution (4.8 mL) at 0° C. over a period of 4 h. The mixture was basified with potassium carbonate (3 g) and added water (150 mL). The aqueous layer was extracted with n-hexane. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 2.74 g of the mixture of title compound and 5-chloro-2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine (1:1). The mixture was used next reaction without further purification. The aqueous layer was extracted with n-hexane The organic layer was dried over sodium sulfate concentrated in vacuo

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

Procedure: To a suspension of lithium aluminum hydride (1.1 g, 29.1 mmol) in tetrahydrofuran (150 mL) was added 2-amino-6-chlorobenzoic acid (5 g, 29.1 mmol) at 0° C. The mixture was stirred at room temperature for 16 h. Then, the reaction mixture was quenched with sodium sulfate decahydrate (3 g) and brine (10 ml) and filtrated through a pad of Celite. The organic layer was concentrated in vacuo and the residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:2) to give 2.4 g (52%) of the title compound as a colorless oil. Then, the reaction mixture was quenched with sodium sulfate decahydrate (3 g) and brine (10 ml) filtrated through a pad of Celite The organic layer was concentrated in vacuo the residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:2)

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

Procedure: To a suspension of lithium aluminum hydride (1.1 g, 29.1 mmol) in tetrahydrofuran (150 mL) was added 2-amino-6-chlorobenzoic acid (5 g, 29.1 mmol) at 0° C. The mixture was stirred at room temperature for 16 h. Then, the reaction mixture was quenched with sodium sulfate decahydrate (3 g) and brine (10 ml) and filtrated through a pad of Celite. The organic layer was concentrated in vacuo and the residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:2) to give 2.4 g (52%) of the title compound as a colorless oil. Then, the reaction mixture was quenched with sodium sulfate decahydrate (3 g) and brine (10 ml) filtrated through a pad of Celite The organic layer was concentrated in vacuo the residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:2)

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

Procedure: (2-Amino-6-chlorophenyl)methanol (16 g, 102 mmol), 3,5-dimethylacetophenone (22.6 g, 152 mmol), RuCl2(PPh3)3 (0.973 g, 1.015 mmol), and KOH (10.25 g, 183 mmol) were refluxed in 270 mL of toluene for 18 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature, filtered through a silica gel plug and eluted with 5% ethyl acetate in hexanes. The product was further purified by Kugelrohr distillation to give 23.5 g of crude product, which was crystallized from 60 mL of MeOH to give 8.6 g (32% yield) of the desired product. Water was collected from the reaction filtered through a silica gel plug eluted with 5% ethyl acetate in hexanes The product was further purified by Kugelrohr distillation to give 23.5 g of crude product, which was crystallized from 60 mL of MeOH

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

Procedure: (2-Amino-6-chlorophenyl)methanol (16 g, 102 mmol), 3,5-dimethylacetophenone (22.6 g, 152 mmol), RuCl2(PPh3)3 (0.973 g, 1.015 mmol), and KOH (10.25 g, 183 mmol) were refluxed in 270 mL of toluene for 18 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature, filtered through a silica gel plug and eluted with 5% ethyl acetate in hexanes. The product was further purified by Kugelrohr distillation to give 23.5 g of crude product, which was crystallized from 60 mL of MeOH to give 8.6 g (32% yield) of the desired product. Water was collected from the reaction filtered through a silica gel plug eluted with 5% ethyl acetate in hexanes The product was further purified by Kugelrohr distillation to give 23.5 g of crude product, which was crystallized from 60 mL of MeOH

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

Procedure: (2-Amino-6-chlorophenyl)methanol (16 g, 102 mmol), 3,5-dimethylacetophenone (22.6 g, 152 mmol), RuCl2(PPh3)3 (0.973 g, 1.015 mmol), and KOH (10.25 g, 183 mmol) were refluxed in 270 mL of toluene for 18 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature, filtered through a silica gel plug and eluted with 5% ethyl acetate in hexanes. The product was further purified by Kugelrohr distillation to give 23.5 g of crude product, which was crystallized from 60 mL of MeOH to give 8.6 g (32% yield) of the desired product. Water was collected from the reaction filtered through a silica gel plug eluted with 5% ethyl acetate in hexanes The product was further purified by Kugelrohr distillation to give 23.5 g of crude product, which was crystallized from 60 mL of MeOH