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140.2 (C), 138.0 (C), 135.1 (C), 133.0 (CH), 129.5 (CH), 128.9 (CH),
128.1 (CH), 127.7 (CH), 123.5 (C), 110.4 (CH), 48.6 (CH2), 21.1
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(CH3) ppm. IR (neat): ν = 3959.7 (w), 2928.9 (w), 1740.1 (w), 1665.8
˜
(s), 1607.0 (s), 1585.7 (m), 1492.0 (m), 1383.8 (w), 1373.4 (w), 1326.7
(w), 1288.7 (w), 1209.3 (w), 1144.5 (w), 1071.3 (w), 1013.7 (w), 856.8
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(ESI): calculated for C19H16BrN4O, 395.0507, found 395.0516 (M + H,
Δ = +0.9 mDa).
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5-(4-Bromophenyl)-2-cyclohexyl-6-methyl-2H-pyrazolo[4,3-c]-
pyridazin-3(5H)-one (30): Yield 32 %, brown solid, m.p. 278.6–
279.9 °C. 1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.6 Hz, 2 H),
7.27 (s, 2 H), 6.95 (s, 1 H), 4.58–4.95 (m, 1 H), 2.27 (s, 3 H), 2.00–1.79
(m, 6 H), 1.77–1.68 (m, 1 H) 1.55–1.38 (m, 2 H), 1.34–1.19 (m, 1
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 157.4 (C), 142.0 (C), 141.3
(C), 134.0 (C), 132.8 (CH), 128.2 (CH), 124.0 (C), 110.4 (CH), 53.3 (CH),
31.5 (CH ), 25.6 (CH ), 25.3 (CH ), 21.5 (CH ) ppm. IR (neat): ν =
˜
2
2
2
3
3036.8 (w), 2926.1 (w), 2852.4 (w), 1664.5 (s), 1615.7 (s), 1559.5 (m),
1483.1 (w), 1447.7 (w), 1379.1 (w), 1347.9 (w), 1310.8 (w), 1288.5
(w), 1208.4 (w), 1142.2 (w), 1069.8 (w), 1011.1 (w), 893.2 (w), 835.8
(m), 794.9 (w), 733.7 (w), 712.7 (w), 693.21 (w), 660.6 (w), 655.1 (w),
624.5 (w), 569.7 (w), 491.8 (w), 451.6 (w) cm–1. LC-MS (ESI): 409.1
[M + Na]+. HRMS (ESI): calculated for C18H20BrN4O, 387.0820, found
387.0826 (M + H, Δ = +0.6 mDa).
5-(4-Bromophenyl)-2-(2-ethylhexyl)-6-methyl-2H-pyrazolo[4,3-
c]pyridazin-3(5H)-one (31): Yield 73 %, brown solid, m.p. 99.8–
102.3 °C. 1H NMR (700 MHz, [D6]DMSO): δ = 7.86 (d, J = 7.6 Hz, 2
H), 7.65 (d, J = 7.8 Hz, 2 H), 7.29 (s, 1 H), 3.84–3.72 (m, 2 H), 2.24 (s,
3 H), 1.95–1.85 (m, 1 H), 1.41–1.20 (m, 8 H), 0.90 (s, 6 H) ppm. 13C
NMR (101 MHz, [D6]DMSO): δ = 158.2 (C), 143.7 (C), 142.3 (C), 140.4
(C), 134.6 (C), 133.0 (CH), 129.5 (CH), 123.4 (C), 110.2 (CH), 48.1 (CH2),
38.8 (CH), 30.5 (CH2), 28.5 (CH2), 23.8 (CH2), 22.9 (CH2), 21.1 (CH3),
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14.4 (CH3), 10.9 (CH3) ppm. IR (neat): ν = 2956.3 (w), 2930.2 (w),
˜
2870.7 (w), 1666.6 (s), 1606.0 (s), 1584.5 (w), 1485.5 (w), 1375.0 (w),
1279.6 (w), 1208.6 (w), 1167.2 (w), 1142.14 (w), 1066.6 (w), 1010.8
(m), 842.4 (m), 803.0 (w), 722.9 (w), 691.3 (m), 619.4 (w), 505.0 (w),
463.2 (w), 417.1 (w) cm–1. LC-MS (ESI): 439.1 [M + Na]+. HRMS (ESI):
calculated for C20H26BrN4O, 417.1290, found 417.1291 (M + H, Δ =
0.1 mDa).
Acknowledgments
The authors would like to thank AM Technology for the kind
loan of their Coflore ATR 1 L Agitated Cell Reactor and for their
invaluable technical support during the project. Financial sup-
port from the Royal Society of Chemistry (RSC) is also gratefully
acknowledged. Furthermore, the authors are very grateful to
A. S. Batsanov, D. S. Yufit (Department of Chemistry, Durham
University) for solving the X-ray crystal structures of 2, 6, 7, 16a,
27a and to A. Kenwright and J. A. Aguilar Malavia (Department
of Chemistry, Durham University) for their technical contribu-
tion in the NMR study reported in Table 1.
Keywords: Synthetic methods · Flow reactors · Solids in
flow · Protein–protein interactions · Nitrogen heterocycles ·
Structure–activity relationships · Medicinal chemistry
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