1-tert-butyl-4-iodobenzene

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one, 1-tert-butyl-4-iodobenzene (0.071 mL, 0.40 mmol), N,N′-dimethylethylenediamine (0.022 mL, 0.20 mmol), potassium phosphate tribasic (170 mg, 0.80 mmol), copper (I) iodide (15 mg, 0.080 mmol) in 1.0 mL NMP was heated at 70° C. for 17 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3, then CHCl3/EtOAc (1:1), and then gradient 3% to 6% MeOH in CHCl3/EtOAc (1:1). The solid obtained was then precipitated from an EtOAc/hexane mixture to give a pale yellow solid (44 mg, 57%). 1H NMR (DMSO) δ: 7.94 (s, 1H), 7.48-7.53 (m, 2H), 7.43 (d, J=6.7 Hz, 1H), 7.27-7.33 (m, 2H), 6.30 (s, 2H), 6.19 (d, J=7.0 Hz, 1H), 3.98 (br. s, 2H), 3.31 (br. s, 2H), 2.68 (t, J=5.3 Hz, 2H), 2.19 (s, 3H), 1.32 (s, 9H) The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution the EtOAc layer washed with H2O, brine dried with anhydrous Na2SO4 and rotary evaporated The resulting oil was chromatographed eluting with CHCl3 The solid obtained was then precipitated from an EtOAc/hexane mixture

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one, 1-tert-butyl-4-iodobenzene (0.071 mL, 0.40 mmol), N,N′-dimethylethylenediamine (0.022 mL, 0.20 mmol), potassium phosphate tribasic (170 mg, 0.80 mmol), copper (I) iodide (15 mg, 0.080 mmol) in 1.0 mL NMP was heated at 70° C. for 17 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3, then CHCl3/EtOAc (1:1), and then gradient 3% to 6% MeOH in CHCl3/EtOAc (1:1). The solid obtained was then precipitated from an EtOAc/hexane mixture to give a pale yellow solid (44 mg, 57%). 1H NMR (DMSO) δ: 7.94 (s, 1H), 7.48-7.53 (m, 2H), 7.43 (d, J=6.7 Hz, 1H), 7.27-7.33 (m, 2H), 6.30 (s, 2H), 6.19 (d, J=7.0 Hz, 1H), 3.98 (br. s, 2H), 3.31 (br. s, 2H), 2.68 (t, J=5.3 Hz, 2H), 2.19 (s, 3H), 1.32 (s, 9H) The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution the EtOAc layer washed with H2O, brine dried with anhydrous Na2SO4 and rotary evaporated The resulting oil was chromatographed eluting with CHCl3 The solid obtained was then precipitated from an EtOAc/hexane mixture

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyridin-2(1H)-one (52 mg, 0.20 mmol), 1-tert-butyl-4-iodobenzene (0.071 mL, 0.40 mmol), N,N′-dimethylethylenediamine (0.022 mL, 0.20 mmol), potassium phosphate tribasic (170 mg, 0.80 mmol), copper (I) iodide (15 mg, 0.080 mmol) in 1.0 mL NMP was heated at 80° C. for 6 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3, then CHCl3/EtOAc (1:1), and then 5% MeOH in CHCl3/EtOAc (1:1). The solid obtained was then triturated with an EtOAc/hexane mixture to give a pale greenish-beige solid (46 mg, 61%). 1H NMR (DMSO) δ: 8.03 (s, 1H), 7.48-7.54 (m, 2H), 7.28-7.33 (m, 2H), 7.27 (dd, J=6.7, 1.8 Hz, 1H), 6.87 (dd, J=7.3, 1.8 Hz, 1H), 6.37 (s, 2H), 6.27 (t, J=7.0 Hz, 1H), 4.07 (s, 2H), 3.46 (t, J=6.0 Hz, 2H), 2.69 (t, J=5.9 Hz, 2H), 1.33 (s, 9H). The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution the EtOAc layer washed with H2O, brine dried with anhydrous Na2SO4 and rotary evaporated The resulting oil was chromatographed eluting with CHCl3 The solid obtained was then triturated with an EtOAc/hexane mixture

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyridin-2(1H)-one (52 mg, 0.20 mmol), 1-tert-butyl-4-iodobenzene (0.071 mL, 0.40 mmol), N,N′-dimethylethylenediamine (0.022 mL, 0.20 mmol), potassium phosphate tribasic (170 mg, 0.80 mmol), copper (I) iodide (15 mg, 0.080 mmol) in 1.0 mL NMP was heated at 80° C. for 6 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3, then CHCl3/EtOAc (1:1), and then 5% MeOH in CHCl3/EtOAc (1:1). The solid obtained was then triturated with an EtOAc/hexane mixture to give a pale greenish-beige solid (46 mg, 61%). 1H NMR (DMSO) δ: 8.03 (s, 1H), 7.48-7.54 (m, 2H), 7.28-7.33 (m, 2H), 7.27 (dd, J=6.7, 1.8 Hz, 1H), 6.87 (dd, J=7.3, 1.8 Hz, 1H), 6.37 (s, 2H), 6.27 (t, J=7.0 Hz, 1H), 4.07 (s, 2H), 3.46 (t, J=6.0 Hz, 2H), 2.69 (t, J=5.9 Hz, 2H), 1.33 (s, 9H). The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution the EtOAc layer washed with H2O, brine dried with anhydrous Na2SO4 and rotary evaporated The resulting oil was chromatographed eluting with CHCl3 The solid obtained was then triturated with an EtOAc/hexane mixture

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

Procedure: Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-tert-butyl-4-iodobenzene. Obtained

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

Procedure: Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-tert-butyl-4-iodobenzene. Obtained

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

Procedure: Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-tert.-butyl-iodo-benzene. Obtained

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

Procedure: A degassed solution of 489.5 mg (0.156%) of copper(I) chloride and 906 mg (1%) mmol) of 1,10-phenanthroline in 100 ml of toluene were saturated with N2 for 1 hour and heated to 130° C. The solution was subsequently admixed with 16.2 g (50 mmol) of 2,7-dibromocarbazole and 13.2 g (50 mmol) of 1-iodo-4-tert-butylbenzene and heated at 180° C. for 2 hours. After cooling, the mixture was admixed with 180 ml of water, the organic phase was separated off and the solvent was removed under reduced pressure. The product was recrystallized from n-hexane. Yield: 13 g (59%). Purity according to HPLC: 99.5% heated at 180° C. for 2 hours After cooling the organic phase was separated off the solvent was removed under reduced pressure The product was recrystallized from n-hexane

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

Procedure: Copper iodide (74 mg) and bis(triphenylphosphine)palladium(II) dichloride (135 mg) were added to a solution of 4-tert-butyliodobenzene (3.0 g) in triethylamine (10 mL), and the mixture was stirred at room temperature for 15 minutes. (5R)-1-(2,4-Dimethoxybenzyl)-5-ethynylpyrrolidin-2-one (1.0 g) was added thereto over one hour, and the mixture was stirred at room temperature for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→1:1) to give (5R)-5-[(4-tert-butylphenyl)ethynyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless powder (1.25 g, 84%). over one hour the mixture was stirred at room temperature for three hours followed by extraction with ethyl acetate The organic layer was washed with brine dried over anhydrous magnesium sulfate filtered The solvent was then evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→1:1)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,3-bis(3-bromophenyl)azetidine (60 mg, 0.163 mmol), 1-tert-butyl-4-iodobenzene (85 mg, 0.327 mmol), xantphos (9.46 mg, 0.016 mmol), Pd2(dba)3 (3.74 mg, 4.09 μmol) and tert-butoxide (18.85 mg, 0.196 mmol) in dioxane (5 mL) was stirred at 110° C. for 12 h. After the reaction was cooled to room temperature, water (15 mL) and dichloromethane (15 mL) was added. The aqueous phase was extracted with dichloromethane (15 mL×3). The combined organic layers were dried and concentrated. The residue was purified by prep-HPLC (Instrument waters 2767 PHW004 Column YMC-Triart C18 150*20 mm S-5 um 12 nm Mobile Phase A: water (0.05% NH4HCO3) B: ACN Gradient 95-95% B in 8 min stop in 14 min Flow Rate(ml/min) 20.00 Detective Wavalength(nm) 214\254 Retention Time(min) 7.4 to afford 26 mg of the title compound (0.052 mmol, 31.8% yield). LC/MS: [M+1]=500. After the reaction was cooled to room temperature The aqueous phase was extracted with dichloromethane (15 mL×3) The combined organic layers were dried concentrated The residue was purified by prep-HPLC (Instrument waters 2767 PHW004 Column YMC-Triart C18 150*20 mm S-5 um 12 nm Mobile Phase A

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

Procedure: A degassed solution of 489.5 mg (0.156%) of copper(I) chloride and 906 mg (1%) mmol) of 1,10-phenanthroline in 100 ml of toluene were saturated with N2 for 1 hour and heated to 130° C. The solution was subsequently admixed with 16.2 g (50 mmol) of 2,7-dibromocarbazole and 13.2 g (50 mmol) of 1-iodo-4-tert-butylbenzene and heated at 180° C. for 2 hours. After cooling, the mixture was admixed with 180 ml of water, the organic phase was separated off and the solvent was removed under reduced pressure. The product was recrystallized from n-hexane. Yield: 13 g (59%). Purity according to HPLC: 99.5% heated at 180° C. for 2 hours After cooling the organic phase was separated off the solvent was removed under reduced pressure The product was recrystallized from n-hexane

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one, 1-tert-butyl-4-iodobenzene (0.071 mL, 0.40 mmol), N,N′-dimethylethylenediamine (0.022 mL, 0.20 mmol), potassium phosphate tribasic (170 mg, 0.80 mmol), copper (I) iodide (15 mg, 0.080 mmol) in 1.0 mL NMP was heated at 70° C. for 17 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3, then CHCl3/EtOAc (1:1), and then gradient 3% to 6% MeOH in CHCl3/EtOAc (1:1). The solid obtained was then precipitated from an EtOAc/hexane mixture to give a pale yellow solid (44 mg, 57%). 1H NMR (DMSO) δ: 7.94 (s, 1H), 7.48-7.53 (m, 2H), 7.43 (d, J=6.7 Hz, 1H), 7.27-7.33 (m, 2H), 6.30 (s, 2H), 6.19 (d, J=7.0 Hz, 1H), 3.98 (br. s, 2H), 3.31 (br. s, 2H), 2.68 (t, J=5.3 Hz, 2H), 2.19 (s, 3H), 1.32 (s, 9H) The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution the EtOAc layer washed with H2O, brine dried with anhydrous Na2SO4 and rotary evaporated The resulting oil was chromatographed eluting with CHCl3 The solid obtained was then precipitated from an EtOAc/hexane mixture