(1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloropyridazin-3-amine (200 mg, 1.54 mmol, Eq: 1.00) and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (693 mg, 6.18 mmol, Eq: 4.00) were combined in a small round bottom flask and heated at 200° C. for 2 hours. The dark glassy residue was dissolved in DCM and purified by chromatography using a gradient of 0% to 25% methanol (with 2.5% ammonium hydroxide) in DCM to give about 100 mg (31.6%) of a brown, viscous oil. purified by chromatography to give about 100 mg (31.6%) of a brown, viscous oil

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloropyridazin-3-amine (200 mg, 1.54 mmol, Eq: 1.00) and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (693 mg, 6.18 mmol, Eq: 4.00) were combined in a small round bottom flask and heated at 200° C. for 2 hours. The dark glassy residue was dissolved in DCM and purified by chromatography using a gradient of 0% to 25% methanol (with 2.5% ammonium hydroxide) in DCM to give about 100 mg (31.6%) of a brown, viscous oil. purified by chromatography to give about 100 mg (31.6%) of a brown, viscous oil

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

Procedure: The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane according to Method 1 to give 25 mg (19%) of a white solid: 1H NMR (CD3OD) δ 7.91–6.44 (m, 9H), 4.67–4.63 (m, 1H), 4.35–4.33 (m, 1H), 4.09–4.07 (m, 1H), 3.99–3.95 (m, 1H), 3.72–3.70 (m, 1H), 3.21–3.17 (m, 1H), 2.95 (s, 3H), 2.33–2.31 (m, 2H); MS (ESI) 382.1 (M+H)+; Purity (HPLC) >95%.

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

Procedure: The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane according to Method 1 to give 25 mg (19%) of a white solid: 1H NMR (CD3OD) δ 7.91–6.44 (m, 9H), 4.67–4.63 (m, 1H), 4.35–4.33 (m, 1H), 4.09–4.07 (m, 1H), 3.99–3.95 (m, 1H), 3.72–3.70 (m, 1H), 3.21–3.17 (m, 1H), 2.95 (s, 3H), 2.33–2.31 (m, 2H); MS (ESI) 382.1 (M+H)+; Purity (HPLC) >95%.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Intermediate 167b (0.15 mmol) in THF (20 mL) was added (1S,4S)-2-methyl-2,5-diaza-bicyclo[2.2.1]heptane (366 mg, 3.3 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, then further purified by HPLC (C18 X-select column, 10-75% MeCN in H2O, 0.1% formic acid) to give the title compound (11 mg, 9%). LCMS (Method 5): Rt 3.45 min, m/z 743 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H, m), 1.54-1.66 (4H, m), 1.72-1.84 (3H, m), 1.84-1.92 (1H, m), 1.95-2.15 (2H, m), 2.22 (3H, s), 2.46-2.48 (1H, m), 2.52 (1H, dd, J=9.6, 2.4 Hz), 2.59 (1H, d, J=9.7 Hz), 2.71 (1H, d, J=9.6 Hz), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.09-3.13 (2H, m), 3.22 (1H, s), 3.28-3.32 (1H, m), 3.63 (1H, d, J=13.9 Hz), 3.70 (1H, d, J=13.9 Hz), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.47 (1H, t, J=4.2 Hz), 6.28 (1H, s), 7.04 (1H, d, J=8.6 Hz), 7.14 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.25 (2H, m), 7.26-7.36 (4H, m), 7.36-7.41 (2H, m), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.11 (1H, s), 8.25 (0.7H, s). The crude reaction mixture was cooled partitioned between EtOAc and water The aqueous phase was extracted with EtOAc (×3) the combined organic layers were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was purified by FCC on silica further purified by HPLC (C18 X-select column, 10-75% MeCN in H2O, 0.1% formic acid)

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

Procedure: A solution of 1.04 g of 5-chloro-3-methyl-1,2,4-thiadiazole, prepared by the procedure of J. Goerdeler, Chim. Ber., 1957, 90, 182, in 2 ml of tetrahydrofuran is added over one hour to a solution of 0.825 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane and 0.77 g of potassium carbonate in 10 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature overnight, diluted with methylene chloride and the organic layer is washed with water. The methylene chloride solution is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5: 2% methyl alcohol/methylene chloride) to give 0.56 g of the desired product: the organic layer is washed with water The methylene chloride solution is dried concentrated in vacuo to dryness The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5: 2% methyl alcohol/methylene chloride)

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

Procedure: A solution of 1.04 g of 5-chloro-3-methyl-1,2,4-thiadiazole, prepared by the procedure of J. Goerdeler, Chim. Ber., 1957, 90, 182, in 2 ml of tetrahydrofuran is added over one hour to a solution of 0.825 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane and 0.77 g of potassium carbonate in 10 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature overnight, diluted with methylene chloride and the organic layer is washed with water. The methylene chloride solution is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5: 2% methyl alcohol/methylene chloride) to give 0.56 g of the desired product: the organic layer is washed with water The methylene chloride solution is dried concentrated in vacuo to dryness The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5: 2% methyl alcohol/methylene chloride)

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

Procedure: A solution of 2.1 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane prepared by the procedure of U. Jordis et al, Synthesis, 1990, 925, and 1.8 ml of 2-chloropyrazine in 8 ml of diazabicyclo[3.6.0]undecene-5 is heated to approximately 80° C. for 2 hours. The reaction solution is cooled, diluted with 100 ml of methylene chloride and washed with 30 ml of 5N aqueous sodium hydroxide. The organic layer is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5; methylene chloride to 5% methyl alcohol/methylene chloride) to give 2.1 g of the desired product as a pale yellow oil: The reaction solution is cooled washed with 30 ml of 5N aqueous sodium hydroxide The organic layer is dried concentrated in vacuo to dryness The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5; methylene chloride to 5% methyl alcohol/methylene chloride)

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

Procedure: A solution of 2.1 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane prepared by the procedure of U. Jordis et al, Synthesis, 1990, 925, and 1.8 ml of 2-chloropyrazine in 8 ml of diazabicyclo[3.6.0]undecene-5 is heated to approximately 80° C. for 2 hours. The reaction solution is cooled, diluted with 100 ml of methylene chloride and washed with 30 ml of 5N aqueous sodium hydroxide. The organic layer is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5; methylene chloride to 5% methyl alcohol/methylene chloride) to give 2.1 g of the desired product as a pale yellow oil: The reaction solution is cooled washed with 30 ml of 5N aqueous sodium hydroxide The organic layer is dried concentrated in vacuo to dryness The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5; methylene chloride to 5% methyl alcohol/methylene chloride)

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

Procedure: The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane according to Method 1 to give 25 mg (19%) of a white solid: 1H NMR (CD3OD) δ 7.91-6.44 (m, 9H), 4.67-4.63 (m, 1H), 4.35-4.33 (m, 1H), 4.09-4.07 (m, 1H), 3.99-3.95 (m, 1H), 3.72-3.70 (m, 1H), 3.21-3.17 (m, 1H), 2.95 (s, 3H), 2.33-2.31 (m, 2H); MS (ESI) 382.1 (M+H)+; Purity (HPLC) >95%.

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloropyridazin-3-amine (200 mg, 1.54 mmol, Eq: 1.00) and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (693 mg, 6.18 mmol, Eq: 4.00) were combined in a small round bottom flask and heated at 200° C. for 2 hours. The dark glassy residue was dissolved in DCM and purified by chromatography using a gradient of 0% to 25% methanol (with 2.5% ammonium hydroxide) in DCM to give about 100 mg (31.6%) of a brown, viscous oil. purified by chromatography to give about 100 mg (31.6%) of a brown, viscous oil

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloropyridazin-3-amine (200 mg, 1.54 mmol, Eq: 1.00) and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (693 mg, 6.18 mmol, Eq: 4.00) were combined in a small round bottom flask and heated at 200° C. for 2 hours. The dark glassy residue was dissolved in DCM and purified by chromatography using a gradient of 0% to 25% methanol (with 2.5% ammonium hydroxide) in DCM to give about 100 mg (31.6%) of a brown, viscous oil. purified by chromatography to give about 100 mg (31.6%) of a brown, viscous oil