3-iodo-4-methoxyaniline

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

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

Procedure: Following the General Procedure of Description 15 (Part A), the zinc insertion product of (5c) was used in situ to cross couple with commercial 3-iodo-4-methoxy-aniline (249 mg, 1.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (23 mg, 0.025 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (30 mg, 0.10 mmol, 10 mol-%) in anhydrous degassed DMF (3 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with ethyl acetate (EtOAc)/hexane and dichloromethane(DCM)/EtOAc mixtures (EtOAc/hexane=1:1, v/v→DCM/EtOAc=1:1, v/v) furnished ˜280 mg (66% yield; ˜80% purity by AUC) of the title compound (7a) as a yellow viscous oil. Rf˜0.23 (EtOAc/hexane=1:1, v/v). 1H NMR (300 MHz, CDCl3): δ 6.90 (br s, 1H), 6.78 (br. d, J=8.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 5.28 (br. d, J=8.1 Hz, 1H), 4.40-4.10 (m, 1H), 3.37 (s, 3H), 2.90-2.80 (br. m, 1H), 2.75 (dd, J=12.6, 6.3 Hz, 1H), 2.50 (d, J=5.1 Hz, 2H), 1.35 (s, 9H) ppm. LC/MS: Rt=0.908 min; ESI (pos.) m/z=339.15 (M+H+)+, 677.40 (2M+H+)+, 699.35 (2M+Na+)+. in anhydrous degassed DMF (3 mL) Filtration, aqueous work-up, and purification by silica gel column chromatography with ethyl acetate (EtOAc)/hexane and dichloromethane(DCM)/EtOAc

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

Procedure: Following the General Procedure of Description 15 (Part A), the zinc insertion product of (5c) was used in situ to cross couple with commercial 3-iodo-4-methoxy-aniline (249 mg, 1.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (23 mg, 0.025 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (30 mg, 0.10 mmol, 10 mol-%) in anhydrous degassed DMF (3 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with ethyl acetate (EtOAc)/hexane and dichloromethane(DCM)/EtOAc mixtures (EtOAc/hexane=1:1, v/v→DCM/EtOAc=1:1, v/v) furnished ˜280 mg (66% yield; ˜80% purity by AUC) of the title compound (7a) as a yellow viscous oil. Rf˜0.23 (EtOAc/hexane=1:1, v/v). 1H NMR (300 MHz, CDCl3): δ 6.90 (br s, 1H), 6.78 (br. d, J=8.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 5.28 (br. d, J=8.1 Hz, 1H), 4.40-4.10 (m, 1H), 3.37 (s, 3H), 2.90-2.80 (br. m, 1H), 2.75 (dd, J=12.6, 6.3 Hz, 1H), 2.50 (d, J=5.1 Hz, 2H), 1.35 (s, 9H) ppm. LC/MS: Rt=0.908 min; ESI (pos.) m/z=339.15 (M+H+)+, 677.40 (2M+H+)+, 699.35 (2M+Na+)+. in anhydrous degassed DMF (3 mL) Filtration, aqueous work-up, and purification by silica gel column chromatography with ethyl acetate (EtOAc)/hexane and dichloromethane(DCM)/EtOAc

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

Procedure: A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (203 g, 1.4 mol) and trimethoxymethane (1.51) was heated to reflux for 1 h, then the 3-iodo-4-methoxy-aniline (349.2 g, 1.402mol) was added portionwise. The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature. The resulting precipitate was filtered off, washed with diisopropyl ether and dried to give the title compound as a beige powder (485 g, 85.9%) was heated to reflux for 1 h at reflux for 1 h The resulting precipitate was filtered off washed with diisopropyl ether dried

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

Procedure: To a suspension of 3-iodo-4-methoxyaniline (8.0 g, 0.021 mol) and 2,4,5-trichloropyrimidine (4.13 g, 0.0225 mol) in N,N-dimethylformamide (57 mL) was added potassium carbonate (7.40 g, 0.0536 mol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove K2CO3 and concentrated to give the residue (10 grams). The residue was triturated with EtOAc, and filtered under vacuum. The residue was purified by silica gel column chromatography to give the desired product (2.54 g, 30%). LCMS for C11H9Cl21N3O (M+H)+: m/z=396.0, 398.0. The reaction mixture was filtered to remove K2CO3 concentrated

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

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Iodo-4-methoxyaniline (0.670 g, 2.0 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.598 g, 2.4 mmol) in n-butanol (10 mL). The mixture was heated to 95° C. for 15 h. The solvent was removed and the residue was purified by silica gel chromatography (5% MeOH in dichloromethane) to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.46 (m, 2H), 3.56 (m, 2H), 3.80 (s, 3H), 4.03 (m, 2H), 6.38 (s, 1H), 6.72 (s, 1H), 7.00 (d, J=9.2 Hz, 1H), 7.85 (dd, J=2.8, 8.8 Hz, 1H), 8.34 (s, 1H), 9.27 (s, 1H), 11.93 (s, 1H). MS (ES+): m/z 547.91 [MH+]. HPLC: tR=3.39 min (ZQ2000, polar—5 min). The solvent was removed the residue was purified by silica gel chromatography (5% MeOH in dichloromethane)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Iodo-4-methoxyaniline (0.670 g, 2.0 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.598 g, 2.4 mmol) in n-butanol (10 mL). The mixture was heated to 95° C. for 15 h. The solvent was removed and the residue was purified by silica gel chromatography (5% MeOH in dichloromethane) to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.46 (m, 2H), 3.56 (m, 2H), 3.80 (s, 3H), 4.03 (m, 2H), 6.38 (s, 1H), 6.72 (s, 1H), 7.00 (d, J=9.2 Hz, 1H), 7.85 (dd, J=2.8, 8.8 Hz, 1H), 8.34 (s, 1H), 9.27 (s, 1H), 11.93 (s, 1H). MS (ES+): m/z 547.91 [MH+]. HPLC: tR=3.39 min (ZQ2000, polar—5 min). The solvent was removed the residue was purified by silica gel chromatography (5% MeOH in dichloromethane)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 3-neck 250 mL round-bottomed flask equipped with a stir bar, condenser and N2 lines was placed iron powder (3.50 g, 62.7 mmol), ammonium chloride (4.88 g, 91.3 mmol), ethanol (72 mL) and water (23 mL). The mixture was heated to 85° C. and then 2-iodo-1-methoxy-4-nitro-benzene (5.0 g, 17.9 mmol) was added portion wise over a period of about 2 minutes. The mixture was allowed to stir at 85° C. for 2 hours and then filtered through Celite. The Celite was washed with EtOH (100 mL) and the filtrate was concentrated. To the concentrated material was added water (100 mL) and ethyl acetate (150 mL). The organic portion was removed and the aqueous portion was re-extracted with ethyl acetate (150 mL). The organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The residue was purified by column chromatography utilizing 50% EtOAc/hexanes as the eluent to produce 3.92 g of I-252 as a brown semi-solid in 88% yield. MS (ESI+): 250.1 (M+1). In a 3-neck 250 mL round-bottomed flask equipped with a stir bar, condenser filtered through Celite The Celite was washed with EtOH (100 mL) the filtrate was concentrated To the concentrated material was added water (100 mL) and ethyl acetate (150 mL) The organic portion was removed the aqueous portion was re-extracted with ethyl acetate (150 mL) washed with brine (150 mL) dried (MgSO4) concentrated The residue was purified by column chromatography to produce 3.92 g of I-252 as a brown semi-solid in 88% yield

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 3-neck 250 mL round-bottomed flask equipped with a stir bar, condenser and N2 lines was placed iron powder (3.50 g, 62.7 mmol), ammonium chloride (4.88 g, 91.3 mmol), ethanol (72 mL) and water (23 mL). The mixture was heated to 85° C. and then 2-iodo-1-methoxy-4-nitro-benzene (5.0 g, 17.9 mmol) was added portion wise over a period of about 2 minutes. The mixture was allowed to stir at 85° C. for 2 hours and then filtered through celite. The celite was washed with EtOH (100 mL) and the filtrate was concentrated. To the concentrated material was added water (100 mL) and ethyl acetate (150 mL). The organic portion was removed and the aqueous portion was re-extracted with ethyl acetate (150 mL). The organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The crude material was purified by column chromatography utilizing 50% EtOAc/hexanes as the eluent to produce 3.92 g of 3-iodo-4-methoxy-phenylamine (I-45, X═I, Y═H, Z═NH2, R1═CH3) as a brown semi-solid in 88% yield. MS (ESI+): 250.1 (M+1) In a 3-neck 250 mL round-bottomed flask equipped with a stir bar, condenser filtered through celite The celite was washed with EtOH (100 mL) the filtrate was concentrated To the concentrated material was added water (100 mL) and ethyl acetate (150 mL) The organic portion was removed the aqueous portion was re-extracted with ethyl acetate (150 mL) washed with brine (150 mL) dried (MgSO4) concentrated The crude material was purified by column chromatography

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

Procedure: To a solution of 3-iodo-4-methoxyaniline (180 mg, 0723 mmol) in DCM (5 mL) 1-methyl-4-piperidone (0.116 mL, 106 mg, 0.940 mmol), TFA (0.290 mL, 429 mg, 3.760 mmol) and tetramethylammonium triacetoxyborohydride (285 mg, 1.084 mmol) were added in sequence. The reaction is completed in 30 min. The reaction mixture was diluted with DCM, washed with saturated solution of sodium hydrogen carbonate (3×5 mL), brine (3×5 mL), dried over sodium sulfate and the solvent was removed under vacuum. The solid crude so obtained was purified by flash chromatography (EtOAc/TEA 99/1) to afford a beige solid that was crystallized from diethylether to afford the title compound as a whitish solid (197 mg, 79%). washed with saturated solution of sodium hydrogen carbonate (3×5 mL), brine (3×5 mL) dried over sodium sulfate the solvent was removed under vacuum The solid crude so obtained was purified by flash chromatography (EtOAc/TEA 99/1) to afford a beige solid that was crystallized from diethylether

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

Procedure: To 2-iodo-1-methoxy-4-nitrobenzene (485 mg, 1.74 mmol) suspended in methanol (6 mL) a solution of NH4Cl (465 mg, 8.69 mmol) in water (4.9 mL) and powdered Fe (290 mg, 5.192 mmol) were added and the mixture was heated to reflux for 3 h. The precipitate formed was filtered off and the filtrate was evaporated until the methanol was eliminated. After diluting with water and alkalinization with sodium carbonate the mixture was extracted with EtOAc (4×20 mL). The combined organic extracts were washed with brine (3×10 mL), water (10 mL), dried over sodium sulfate and the solvent was removed under vacuum. The crude dark oil was purified by flash chromatography on silica gel (hexane/EtOAc 1/1) to afford 400 mg of solid that was crystallized from n-pentane and diethyl ether to yield the title compound (363 mg, 83%). were added the mixture was heated to reflux for 3 h The precipitate formed was filtered off the filtrate was evaporated until the methanol After diluting with water and alkalinization with sodium carbonate the mixture was extracted with EtOAc (4×20 mL) The combined organic extracts were washed with brine (3×10 mL), water (10 mL) dried over sodium sulfate the solvent was removed under vacuum The crude dark oil was purified by flash chromatography on silica gel (hexane/EtOAc 1/1)