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celite pad. The filtrate was washed with saturated NH4Cl aqueous
solution and brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by NH silica gel column chromatography
(25–50% CHCl3 in hexane) to give a free form of the title compound,
which was dissolved in EtOH (2 mL) and treated with 4 M HCl/
EtOAc (0.2 mL). The mixture was diluted with Et2O (5 mL) and stir-
red at room temperature for 1 h. The precipitate was collected by
filtration and washed with Et2O to give 6a (30 mg, 18%) as a color-
less solid. 1H NMR (DMSO-d6) d 3.83 (s, 3H), 5.48 (s, 2H), 7.54 (br s,
1H), 7.68 (d, 2H, J = 8.4 Hz), 8.07–8.16 (m, 6H), 8.69 (s, 1H), 8.71–
8.75 (m, 3H); MS (ESI) m/z 343 [M+H]+; Anal. Calcd for
5.1.6. [4-(3-Methylpyridin-2-yl)phenyl]methanol (11a)
Under argon gas atmosphere, to a mixture of 2-bromo-3-
methylpyridine (9a; 860 mg, 5.00 mmol) and [4-(hydroxymethyl)
phenyl]boronic acid (10; 836 mg, 5.50 mmol) in 1,2-dimethox-
yethane (DME; 30 mL) were added Pd(PPh3)4 (289 mg, 0.25 mmol)
and 1 M Na2CO3 aqueous solution (12.5 mL, 12.5 mm ol), and the
mixture was stirred at 90 °C for 8 h. The mixture was diluted with
water and extracted with EtOAc. The organic layer was concen-
trated in vacuo and purified by silica gel column chromatography
(0–5% MeOH in CHCl3) to give 11a (906 mg, 91%) as a pale yellow
solid. 1H NMR (DMSO-d6) d 2.32 (s, 3H), 4.56 (d, 2H, J = 5.7 Hz), 5.23
(t, 1H, J = 5.7 Hz), 7.28 (dd, 1H, J = 7.6, 4.7 Hz), 7.40 (d, 2H,
J = 8.3 Hz), 7.50 (d, 2H, J = 8.3 Hz), 7.69–7.73 (m, 1H), 8.45–8.48
(m, 1H); MS (ESI) m/z 200 [M+H]+.
C21H18N4Oꢀ2.2HClꢀ3.1H2O: C, 52.72; H, 5.56; N, 11.71; Cl, 16.30.
Found: C, 52.57; H, 5.60; N, 11.69; Cl, 16.30.
5.1.3. 4-(1-Methyl-3-{[4-(4,4,5,5-tetramethyl-1,3,2-
5.1.7. [4-(3,5-Dimethylpyridin-2-yl)phenyl]methanol (11b)
Compound 11b was prepared from 2-bromo-3,5-dimethylpyri-
dine (9b) and 10 in a manner similar to that described for com-
pound 11a, with a yield of 68% as a brown syrup. 1H NMR
(DMSO-d6) d 2.29 (s, 3H), 2.30 (s, 3H), 4.55 (d, 2H, J = 5.7 Hz),
5.21 (t, 1H, J = 5.7 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.47 (d, 2H,
J = 8.3 Hz), 7.52 (br s, 1H), 8.30 (br s, 1H); MS (ESI) m/z 214 [M+H]+.
dioxaborolan-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)pyridine (7)
Under argon gas atmosphere, to a mixture of 5 (292 mg,
0.85 mmol) and bis(pinacolato)diboron (259 mg, 1.02 mmol) and
potassium acetate (250 mg, 2.55 mmol) in dioxane (3.0 mL) was
added
[1,10-bis(diphenylphosphino)ferrocene]dichloropalladiu
m(II) complex with dichloromethane (Pd(dppf)Cl2ꢀCH2Cl2; 69
mg, 0.085 mmol), and the mixture was stirred at 100 °C for 3 h.
After cooling at room temperature, the insoluble material was
removed by filtration through celite pad and washed with
CHCl3/EtOAc, and the filtrate was concentrated in vacuo. The resi-
due was purified by silica gel column chromatography (0–3%
MeOH in CHCl3) to give 7 (135 mg, 41%) as a pale brown oil. 1H
NMR (CDCl3) d 1.35 (s, 12H), 3.81 (s, 3H), 5.37 (s, 2H), 7.47–
7.53 (m, 4H), 7.58 (s, 1H), 7.85 (d, 2H, J = 8.1 Hz), 8.47 (brd, 2H,
J = 4.4 Hz); MS (ESI) m/z 392 [M+H]+.
5.1.8. [4-(Isoquinolin-1-yl)phenyl]methanol (11c)
Compound 11c was prepared from 1-chloroisoquinoline (9c)
and 10 in a manner similar to that described for compound 11a,
with a quantitative yield as a yellow solid. 1H NMR (DMSO-d6) d
4.63 (d, 2H, J = 5.8 Hz), 5.31 (t, 1H, J = 5.8 Hz), 7.51 (2H, d,
J = 8.3 Hz), 7.62–7.68 (m, 3H), 7.77–7.82 (m, 1H), 7.84 (1H, d,
J = 5.6 Hz), 8.02–8.07 (m, 2H), 8.58 (d, 1H, J = 5.6 Hz); MS (ESI) m/
z 236 [M+H]+.
5.1.4. 2-[4-({[1-Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-
yl]oxy}methyl)phenyl]quinoxaline dihydrochloride (8)
5.1.9. [4-(1-Methyl-1H-benzimidazol-4-yl)phenyl]methanol
(11d)
Under argon gas atmosphere, to a mixture of 7 (130 mg,
0.33 mmol), 2-chloroquinoxaline (109 mg, 0.66 mmol) and K2CO3
(115 mg, 0.83 mmol) in dioxane (3.0 mL) and water (0.60 mL)
was added Pd(PPh3)4 (77 mg, 0.067 mmol), and the mixture was
stirred at 100 °C for 2 h. After cooling at room temperature, the
insoluble material was removed by filtration through celite pad
and washed with EtOAc, and the filtrate was concentrated in
vacuo. The residue was purified by flash column chromatography
(silica gel; 0–5% MeOH in CHCl3, then NH silica gel; 50–100%
EtOAc in hexane) to give colorless solid. To this solid in EtOH
(2 mL) and CHCl3 (1 mL) was added 4 M HCl/EtOAc (0.33 mL),
and the mixture was diluted with Et2O (5 mL). After the mixture
was stirred at room temperature for 2 h, the precipitate was col-
lected by filtration and washed with Et2O to give 8 (68 mg, 44%)
as a yellow solid. 1H NMR (DMSO-d6) d 3.84 (s, 3H), 5.52 (s, 2H),
7.76 (d, 2H, J = 8.3 Hz), 7.84–7.93 (m, 2H), 8.12–8.18 (m, 4H),
8.41 (d, 2H, J = 8.3 Hz), 8.70 (s, 1H), 8.74 (d, 2H, J = 7.0 Hz), 9.62
(s, 1H); MS (ESI) m/z 394 [M+H]+; Anal. Calcd for
C24H19N5Oꢀ1.9HClꢀ2.2H2O: C, 57.38; H, 5.08; N, 13.94; Cl, 13.41.
Found: C, 57.59; H, 4.99; N, 13.86; Cl, 13.17.
Compound 11d was prepared from 4-bromo-1-methyl-1H-ben-
zimidazole (9d) and 10 in a manner similar to that described for
compound 11a, with a yield of 69% as a colorless solid. 1H NMR
(DMSO-d6) d 3.88 (s, 3H), 4.56 (d, 2H, J = 5.7 Hz), 5.20 (t, 1H,
J = 5.7 Hz), 7.35 (dd, 1H, J = 7.8 Hz), 7.39–7.47 (m, 3H), 7.54 (dd,
1H, J = 8.0, 1.0 Hz), 8.05–8.08 (m, 2H), 8.24 (s, 1H); MS (ESI) m/z
239 [M+H]+.
5.1.10. 3-Methyl-2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-
3-yl]oxy}methyl)phenyl]pyridine dihydrochloride (12a)
To a mixture of 4 (350 mg, 2.00 mmol) and 11a (478 mg,
2.40 mmol) in toluene was added CMBP (724 mg, 3.00 mmol),
and the mixture was stirred at 90 °C for 8 h. The mixture was con-
centrated in vacuo, and the residue was purified by silica gel col-
umn chromatography (0–5% MeOH in CHCl3) to give a free form
of the title compound, which was diluted with EtOH (25 mL) and
treated with 4 M HCl/EtOAc (2.0 mL). After the mixture was stirred
at room temperature for 30 min, the mixture was concentrated in
vacuo and washed with EtOAc to give 12a (464 mg, 54%) as a beige
solid. 1H NMR (DMSO-d6) d 2.44 (s, 3H), 3.84 (s, 3H), 5.55 (s, 2H),
7.75 (s, 4H), 7.90–7.95 (m, 1H), 8.16 (d, 2H, J = 7.0 Hz), 8.48 (d,
1H, J = 7.8 Hz), 8.73–8.77 (m, 4H); MS (ESI) m/z 357 [M+H]+;
Anal. Calcd for C22H20N4Oꢀ2.2HClꢀ2.9H2O: C, 54.05; H, 5.77; N,
11.46; Cl, 15.95. Found: C, 54.23; H, 5.93; N, 11.34; Cl, 16.26.
5.1.5. 8-[4-({[1-Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-
yl]oxy}methyl)phenyl]quinoline dihydrochloride (6b)
Compound 6b was prepared from 5 and quinolin-8-ylboronic
acid in a manner similar to that described for compound 8, with
a yield of 84% as a beige solid. 1H NMR (DMSO-d6) d 3.85 (3H, s),
5.50 (2H, s), 7.59–7.75 (6H, m), 7.81 (dd, 1H, J = 7.2, 1.4 Hz), 8.06
(dd, 1H, J = 8.1, 1.4 Hz), 8.16 (d, 2H, J = 7.0 Hz), 8.50–8.55 (m, 1H),
8.71 (s, 1H), 8.74 (d, 2H, J = 7.0 Hz), 8.92 (dd, 1H, J = 4.3, 1.8 Hz);
MS (ESI) m/z 393 [M+H]+; Anal. Calcd for C25H20N4Oꢀ2.05H
Clꢀ0.25C4H8O2ꢀ3.5H2O: C, 56.54; H, 5.67; N, 10.14; Cl, 13.16.
Found: C, 56.75; H, 5.55; N, 9.88; Cl, 13.04.
5.1.11. 3,5-Dimethyl-2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-
pyrazol-3-yl]oxy}methyl)phenyl]pyridine dihydrochloride
(12b)
Compound 12b was prepared from 4 and 11b in a manner sim-
ilar to that described for compound 12a, with a yield of 28% as a
colorless solid. 1H NMR (DMSO-d6) d 2.37 (s, 3H), 2.43 (s, 3H),
3.83 (s, 3H), 5.51 (s, 2H), 7.63–7.72 (m, 4H), 8.07 (br s, 1H), 8.12