The preparation procedure for compound 14b was similar to that of compound 14a, and tetrahydrofuran-3-carboxylic acid was substituted for 3-hydroxy-3-methylbutanoic acid.
A subtlety of our procedure for compound discovery is that it involves both parallel (A ) and antiparallel (B ) amyloid β-sheets.
To assess the performance of the proposed testing procedure for compound covariate, we conducted simulation studies under various scenarios to study type I error rate and power.
3-({[(1 R,2 S )-1-Hydroxy-1-phenylpropan-2-yl]amino}methyl -1-octylpyridin-1-ium Bromide (4): By following the procedure for compound 3, compound 2 (0.46 g, 1.89 mmol) and n-octyl bromide (0.33 mL, 1.89 mmol) afforded the crude product as a viscous brown oil, which was purified by preparative HPLC (MeOH/H2O, 50 50) to give 4 (0.35 g, 0.92 mmol, 49 % yield) as a light yellow oil.
1-Dodecyl-3({[(1 R,2 S )-1-hydroxy-1-phenylpropan-2-yl]amino}methyl pyridin-1-ium Bromide (5): By following the procedure for compound 3, compound 2 (1.14 g, 4.70 mmol) and n-dodecyl bromide (1.13 mL, 4.70 mmol) afforded the crude product as a viscous brown oil, which was purified by preparative HPLC (MeOH/H2O, 50 50) to give 5 (1.05 g, 2.77 mmol, 59%% yield) as a light yellow oil.
1-Butyl-3({[(1 S,2 R )-2-hydroxy-1,2-diphenylethyl]amino}methyl pyridin-1-ium Bromide (8): By following the procedure for compound 3, compound 7 (0.40 g, 1.31 mmol) and n-butyl bromide (0.14 mL, 1.31 mmol) gave the crude product as a viscous yellow oil, which was was purified by preparative HPLC (MeOH/H2O, 80 20) to yield product 8 (0.31 g, 0.79 mmol) as a light yellow liquid.
General procedure for compounds 7: A solution of 1 or 2 in THF (1 mL) was added to a solution of 1 equiv of ketene 3 or 4 in THF (5 mL) at 20 °C.
General procedure for compounds 5: A solution of 1 or 2 in THF (1 mL) was added to a solution of 1 equiv of ketene 3 or 4 in THF (5 mL) at 20 °C. 1 equiv of of DBU in THF (1 m) was added dropwise, and the resulting reaction mixture was stirred for 5 30 min, during which time it was monitored by P NMR spectroscopy.
Prepared using the same procedure described for compound 1, refluxing a mixture of anhydrous ZnCl2 (4.000 g, 29.35 mmol), isophthalonitrile (6.700 g, 52.29 mmol), and l-valinol (16.000 g, 15.51 mmol) in 80 mL of dry chlorobenzene for 72 h.
Prepared using the same procedure described for compound 1, using anhydrous ZnCl2 (3.340 g, 24.51 mmol), 2-cyanopyridine (2.095 g, 20.13 mmol) and l-phenylalaninol (3.992 g, 26.40 mmol) in 40 mL of dry chlorobenzene, and the reaction mixture was refluxed for 60 h.
Starting from ketone 22c (96 mg; 0.25 mmol) and using the same procedure as for compound 1l the desired compound was obtained (18 mg; 11%).
