Pyrazolyl-benzoxazole derivatives as protein kinase inhibitors. Design and validation of a combinatorial library

Article abstract of DOI:10.1016/j.tet.2005.08.070

The malfunctioning of protein kinases is a hallmark of numerous diseases, for which a satisfactory therapy is missing. We describe the design and synthesis of a kinase targeted library based on a novel 2-(3-phenyl-1H-pyrazol- 4-yl)-1,3-benzoxazole scaffold. Ethyl 3-(3-nitrophenyl)pyrazole-4-carboxylate and its 4-nitro regioisomer were bound to trityl chloride resin, saponified with NaOH in MeOH, and amidated with a choice of two o-aminophenols. The resulting N-(2-hydroxyphenyl)amides were cyclized by Mitsunobu reaction to form four variants of the pyrazolyl-benzoxazole core template. Straightforward stannous chloride reduction of the nitro group on solid phase allowed subsequent scaffold derivatization via acylation or sulfonylation of the obtained amino function. Cleavage with TFA gave rise to the final compounds (36 examples).

Full text of DOI:10.1016/j.tet.2005.08.070

Tetrahedron 61 (2005) 10801–10810
Pyrazolyl–benzoxazole derivatives as protein kinase inhibitors.
Design and validation of a combinatorial library
†
Daniela Berta, Marzia Villa, Anna Vulpetti and Eduard R. Felder
*
Department of Chemistry, Nerviano Medical Science, Viale Pasteur 10, I-20014 Nerviano (MI), Italy
Received 29 November 2004; revised 3 August 2005; accepted 18 August 2005
Available online 19 September 2005
Abstract—The malfunctioning of protein kinases is a hallmark of numerous diseases, for which a satisfactory therapy is missing. We
describe the design and synthesis of a kinase targeted library based on a novel 2-(3-phenyl-1H-pyrazol-4-yl)-1,3-benzoxazole scaffold. Ethyl
3-(3-nitrophenyl)pyrazole-4-carboxylate and its 4-nitro regioisomer were bound to trityl chloride resin, saponified with NaOH in MeOH, and
amidated with a choice of two o-aminophenols. The resulting N-(2-hydroxyphenyl)amides were cyclized by Mitsunobu reaction to form four
variants of the pyrazolyl–benzoxazole core template. Straightforward stannous chloride reduction of the nitro group on solid phase allowed
subsequent scaffold derivatization via acylation or sulfonylation of the obtained amino function. Cleavage with TFA gave rise to the final
compounds (36 examples).
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
new potent kinase inhibitors compound 1 (Fig. 1, X, YZH)
emerged as a binder of Cyclin dependent kinase 2 (CDK2).
Protein kinases (PKs) play a crucial role in the cellular
control of many different processes, including metabolic
pathways, cell growth and differentiation, membrane
transport, and apoptosis. A large share of the oncogenes
and proto-oncogenes involved in human cancers codes for
PKs. The anomalous activities of PKs are also implicated in
many non-malignant diseases, in inflammatory conditions
and in the multiplication of viruses and parasites. PKs may
also play a major role in the pathogenesis and development
of neurodegenerative disorders. Inhibitors of these enzymes
may arrest cell proliferation and trigger apoptosis. Their use
is being extensively evaluated for cancer chemotherapy and
other therapeutic areas. Flat heterocyclic hydrophobic
compounds, such as pyrazoles, have been reported to bind
to the hinge region of various kinase ATP pockets,
mimicking the adenine (purine) pharmacophore and
effectively competing with ATP.1 Searching for potent
and selective inhibitors of protein kinases has intensified
over the past few years1–4 culminating in the approval of
Imatinib5 (Gleevec) and Gefitinib6 (Iressa) for the oncology
drug market. In our internal high-throughput screening for
Figure 1. The pyrazolyl–benzoxazole scaffold (XZvariable from
aminophenol building blocks; YZvariable from derivatization of amino
group in either meta or para position.
In order to understand how 1 may interact in the ATP pocket
of the CDK2/Cyclin A complex an in silico docking
simulation was performed. The computational docking
experiment suggested that the pyrazole moiety could
interact with the hinge region in three different ways.
Figure 2a–c shows the three binding modes, which involve
two distinct tautomeric forms, differing by the presence of a
proton on either N1 or N2 of the pyrazole ring of the
inhibitor. The two binding modes A and C (reported,
respectively, in Fig. 2a and c) resemble the dual binding
modes observed by X-ray analysis on a 3-aryl-1H pyrazole
scaffold.7 In binding modes A and B the pyrazole ring is
making two hydrogen bond interactions with the carbonyl
Keywords: Solid-phase synthesis; Scaffold; Mitsunobu; Parallel synthesis;
Building blocks.
*
Corresponding author. Tel.: C39 331 581474; fax: C39 331 581347;
e-mail: eduard.felder@nervianoms.com
† Present address: Roche Palo Alto LLC MS R6 E3, 3431 Hillview Ave.
Palo Alto, CA 94304, USA.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.070

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D. Berta et al. / Tetrahedron 61 (2005) 10801–10810
Figure 2. Three binding modes of 1.
oxygen of Glu81 and the amide nitrogen of Leu83. In
binding mode C, both pyrazole nitrogens, N1 and N2–H,
interact, respectively, with the amide nitrogen and the
carbonyl oxygen of Leu83. Depending on the binding mode,
the phenyl ring at position 3 and the benzoxazole at position
4 can be oriented toward different regions of the ATP
pocket.
2. Results and discussion
The synthetic strategy is outlined in Scheme 1. The pyrazole
core 3 was synthesized starting from commercial para or
meta nitrobenzoylacetate, which was refluxed with triethyl-
orthoformate to give enolether 29 (Scheme 1). Cyclization
of 2 with hydrazine afforded 3 that was then linked to trityl
resin through one of the pyrazole nitrogens. The hydrolysis
of ethyl ester 4 to acid 5 required four treatments for a
complete conversion. The synthesis of amide 6 was
performed in the first instance according to Wang et al.10
by means of benzotriazol-1-yl-N-oxy tris (pyrrolidino)-
phosphonium hexafluorophosphate (PyBoP) as coupling
agent. This approach led to the desired product along with a
high percentage of a side product at m/z 564, to which we
assigned the hypothetical structure A (Fig. 3).
Combining structural considerations and chemical feasi-
bility we therefore, planned a scaffold expansion based on
three diversity points given by the substituents and their
position on the benzoxazole ring, as well as the substituents
on the phenyl ring (Fig. 1). In this article, we describe a solid
phase synthetic route, which builds up the 2-(3-phenyl-1H-
pyrazol-4-yl)-1,3-benzoxazole scaffold from variably inter-
changeable building blocks. The synthesis of 36 examples
reported here allowed us to validate the method for the
subsequent production of a much larger kinase targeted
library.8
Upon replacing PyBOP with N-[1H-benzotriazol-1-yl)
(dimethylamino) methylene]-N-methyl methanaminium
Scheme 1. Reagents and conditions: (a) (EtO)3CH, Ac2O reflux, 3 h; (b) NH2NH2, EtOH 22 8C, 3 h; (c) Trityl-Cl resin, DIEA, DCM/DMF 22 8C, 16 h;
(d) NaOH, DMF/H2O, 70 8C, 64 h, four times; (e) II{1-2}, HOBt, TBTU, DMF, 22 8C, 16 h; (f) TBP, DEAD, THF, 22 8C, 16 h; (g) SnCl2$2H2O, DMF, 22 8C,
16 h.

D. Berta et al. / Tetrahedron 61 (2005) 10801–10810
10803
tetrafluoroborate N-oxide (TBTU) both aminophenol
II{1}as well as o-amino-p-cresol II{2}coupled with resin
5 to give resin 6 as the only product. The intramolecular
dehydrative cyclization of the 2-acylaminophenol 6
employing an excess of tri-n-butylphosphine (TBP) and
diethyl azodicarboxylate (DEAD) in THF was used to
provide resin 7. The traditional conditions for the
Mitsunobu reaction (triphenylphosphine TPP; DEAD)
were not suitable for substrate 6 due to an incomplete
conversion of the amide to the benzoxazole ring and the
recovery of a high amount of the aminophenoxy-triphenyl-
phosphonium salt (Fig. 3, structure B). Simple variations of
the ratio of reagents, the reaction time and the number of
treatments did not give satisfactory results. A dramatic
improvement was achieved when replacing triphenyl-
phosphine with tributylphosphine, which led to derivative
7 in a complete conversion. Reduction of the nitro group
cleanly proceeded with stannous chloride (SnCl2) in DMF
and the obtained aromatic amine 8 was then functionalized
with six acyl chlorides, two isocyanates and one sulfonyl
chloride (Fig. 4) to give resins 9, 10 and 11 (Scheme 2).
Formation of amides was also performed by coupling resin 8
with carboxylic acids in the presence of PyBop. The
outcome was similar for both methods. Cleavage with
trifluoroacetic acid (TFA) in DCM afforded the final
products.
Figure 3. Assumed structures of principal side products eliminated during
method development. Structure A is linked to PyBOP promoted
aminophenol coupling. Structure B is linked to TPP use in the cyclization
reaction.
All building blocks selected for aniline substitution showed
a good reactivity leading to desired products with an
Figure 4. Utilized monomer sets (building blocks).
Scheme 2. Reagents and conditions: (a) (i) DIEA, DCM, rt, 16 h (ii) TFA 10% in DCM, rt, 1 h; (b) (i) DCM, rt, 16 h, (ii) TFA 10% DCM, rt, 1 h; (c) (i) DIEA,
DCM, rt, 16 h, (ii) TFA 10% in DCM, rt, 1 h.

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D. Berta et al. / Tetrahedron 61 (2005) 10801–10810
Table 1. Overall qualitative assessment of the validation library (36 examples)
Crude (mg)
Purified (mg)
Chromatographic
recovery (%)a
LC–MS purity crudeb
LC–MS purity
purifiedb
Average
Max
Min
27
31.7
21.2
11
21
2.5
60
94.4
18.8
67.3
70.2
62.7
94
100
83.8
a Weight purified/weight crude (theoretical based on 254 nm HPLC purity).
b Percent peak area by UV (254 nm).
average yield of 46% and an average purity of crudes of
67.3% (Table 1). All the crude mixtures from the cleavage
were purified by preparative HPLC leading to compounds
with high purity (Table 2).
provided the rationale to develop this chemical class as a
source of kinase inhibitors. The validated synthetic
methodology described here can be applied to the
production of a large kinase targeted library comprising
thousands of molecules.8
3. Conclusion
4. Experimental
We have developed a highly effective route for the synthesis
of 2-(3-aryl-1H-pyrazol-4-yl)-1,3-benzoxazoles using a
stepwise solid phase path with a dehydrative Mitsunobu
cyclization as the key step. The preliminary docking
analysis performed on the identified screening hit in its
potential role as a combinatorial chemistry scaffold
4.1. Docking calculation of 1 into CDK2/Cyclin A
The crystal structure of CDK2/Cyclin A co-crystallized
with a proprietary compound was taken from in-house
X-ray data. The docking study was performed with QXP
(the docking module of the FloCprogram, Thistlesoft,
version 2003),12 using the docking algorithm, referred to as
MCdock. The MCdock algorithm employs a user-defined
number of repeated cycles of Monte Carlo followed by
energy minimisation to generate and refine an ensemble of
docked ligands. The ensemble is initiated with a single pose
and is allowed to grow to 50 poses. For each search cycle the
ligand pose is randomly chosen from the ensemble, and
subjected to 1000 steps of Monte Carlo searching. The
Monte Carlo variables are dihedrals of rotatable bonds,
Cartesian coordinates of ring atoms, and molecular ligand
rotation and translation. In each search cycle the best result
is energy minimized, using a modified Amber force field.13
Table 2. Purity data of the validation library members
Entry
MW
LC–MS purity
(purified)a
NMR purityb
9{I,II,III}
9{1,1,1}
9{1,1,2}
9{1,1,3}
9{1,1,4}
9{1,1,5}
9{1,1,6}
9{1,2,1}
9{1,2,2}
9{1,2,3}
9{1,2,4}
9{1,2,5}
9{1,2,6}
9{2,1,1}
9{2,1,2}
9{2,1,3}
9{2,1,4}
9{2,1,5}
9{2,1,6}
9{2,2,1}
9{2,2,2}
9{2,2,3}
9{2,2,4}
9{2,2,5}
9{2,2,6}
10{I,II,IV}
10{1,1,1}
10{1,1,2}
10{1,2,1}
10{1,2,2}
10{2,1,1}
10{2,1,2}
10{2,2,1}
10{2,2,2}
11{I,II,V}
11{1,1,1}
11{1,2,1}
11{2,1,1}
11{2,2,1}
346.4
344.4
380.4
410.4
394.4
428.9
360.4
358.4
394.4
424.5
408.5
442.9
346.4
344.4
380.4
410.4
408.5
428.9
360.4
358.4
394.4
424.5
408.5
442.9
94.6
97.1
95
95.9
100
83
86
97
88
84
92
94
85
81
81
99
94
86
73
91
86
94
66
87
83
80
87
89
92
97.8
96.6
98.8
92.9
97.7
97.6
100
96.5
87.1
88.6
92.4
93.2
78.2
95.3
94.2
91.1
90.6
97.1
94.6
QXP allows the user to define parts of the binding site as
flexible. These sections can move under the influence of the
molecular mechanics force field during energy minimiz-
ation. The sections designated for movement can be made
fully flexible or partially flexible (using distance-based
constraints). We made the CDK2 glycine-rich loop region
(Gly11, Glu12, Gly16 and Val17) and Glu8 partially
flexible and Lys33, Lys89, Tyr15 and Gln85 completely
flexible.
The results were evaluated in terms of total estimated
binding energy, internal strain energy of the ligand, van der
Waals and electrostatic interaction energies. The calculation
was performed on a 225 MHz Octane SGI workstation.
395.4
409.4
409.4
423.5
395.4
409.4
409.4
423.5
95.7
100
100
92.7
90.1
92.4
93.7
97.6
89
82
95
88
93
85
92
76
4.2. Synthetic procedures
Parallel reactions were run using an Argonaut Quest 210
430.5
444.5
430.5
444.5
97
81
80
81
86
All reagents and solvents were purchased from commercial
suppliers of the best grade and used without further
purification. Melting points were determined in open glass
capillaries with a Bu¨chi 535 melting point apparatus and are
uncorrected. Flash chromatography was performed on silica
82.1
83.8
84.6
a Percent peak area by UV (254 nm).
b 1H NMR quantitative purity determined using 1,4-bis-(trimethylsilyl)
benzene as the standard Ref.11.
˚
gel (Merck grade 9385, 60 A). Thin-layer chromatography

D. Berta et al. / Tetrahedron 61 (2005) 10801–10810
10805
was performed on Whatman silica gel 60 plates coated with
250 mm layer with fluorescent indicator. Components were
visualized either by UV light (l: 254 nm) or by iodine vapor
HPLC/MS was performed on a Waters X Terra RP 18
(4.6!50 mm, 3.5 mm) column using a Waters 2790 HPLC
system equipped with a 996 Waters PDA detector and a
Micromass mod. ZQ single quadrupole mass spectrometer,
equipped with an electrospray (ESI) ion source. Mobile
phase A was ammonium acetate 5 mm buffer (pH 5.5 with
acetic acid/acetonitrile 95:5), and mobile phase B was H2O–
acetonitrile (5/95). Gradient from 10 to 90%B in 8 min, hold
90%B 2 min. UV detection at 220 and 254 nm. Flow rate
1 ml/min. Injection volume 10 ml. Full scan, mass range
from 100 to 800 amu. Capillary voltage was 2.5 KV; source
temperature was 120 8C; Cone was 10 V. Mass are given as
m/z ratio.
4.2.3. Ethyl 3-(nitrophenyl)-1-trityl polystyrene-1H-
pyrazole-4-carboxylate (4). DIEA (3.26 ml, 19.5 mmol)
and a solution of the pyrazole 3 (2.5 g, 9.5 mmol) in DMF
(12 ml) were added to a slurry of trityl chloride resin (5 g,
1.27 mmol/g loading, 6.35 mmol) in DCM (35 ml). The
mixture was gently stirred at rt for 16 h and then filtered
under reduced pressure. The resin was suspended in a
mixture of DCM/MeOH/DIEA 85:10:5 (100 ml), stirred for
20 min and filtered. After washing consecutively with
DCM, MeOH and Et2O it was dried overnight in the oven
at 35 8C under reduced pressure.
Both resins 4{1} and 4{2} gave rise to a loading of 1 mmol/g
measured by weight increase.
4.2.4. 3-(3-(Nitrophenyl)-1-trityl polystyrene-1H-
pyrazole-4-carboxylic acid (5). To a suspension of resin
4 (6.4 g, 1 mmol/g loading, 6.4 mmol) in 77 ml MeOH was
added NaOH 35% (6.4 ml) and stirred at 70 8C for 16 h.
After cooling, the slurry was filtered under reduced pressure
and washed abundantly with MeOH to dissolve the NaOH
precipitated during the reaction. The treatment was repeated
three more times till starting material disappearance on LC–
MS of a cleaved sample. The resin was afterwards washed
with MeOH, DCM, Et2O and dried at 35 8C under vacuum.
All compounds have been purified by preparative HPLC on
a Waters X-Terra RP18 (19!100 mm, 5 mm) column using
a Waters preparative HPLC 2525 equipped with a 996
Waters PDA detector and a Micromass mod. ZQ single
quadrupole mass spectrometer, electrospray ionisation,
positive mode. Mobile phase A was water 0.01% formic
acid, and mobile phase B was acetonitrile. Gradient from 10
to 90%B in 8 min, hold 90% B 2 min. Flow rate 20 ml/min.
1H NMR spectroscopy was recorded on a Mercury VX 400
operating at 400.45 MHz equipped with a 5 mm double
resonance probe (1H {15N–31P} ID_PFG Varian), using 1,
4-bis-(trimethylsilyl)benzene as internal standard; chemical
shifts are expressed in ppm (d).
4.2.5. N-(2-Hydroxyphenyl)-3-(nitrophenyl)-1-trityl
polystyrene-1H-pyrazole-4-carboxamide (6). A solution
of HOBt (1.35 g, 10 mmol) and TBTU (3.2 g, 10 mmol) in
15 ml of dry DMF was added to a slurry of resin 6 (2 g,
1 mmol/g loading, 2 mmol, 1 equiv) in 5 ml of dry DMF.
The mixture was stirred for 30 min then o-aminophenol
(10 equiv) was added and the final suspension was stirred at
rt for 20 h. The slurry was filtred under reduced pressure, the
resin washed abundantly with DMF, DCM, MeOH and Et2O
and dried at 35 8C under vacuum.
The high resolution mass analyses were performed on a
Micromass Q-TOF Ultima (Manchester, UK) hybrid
quadrupole/orthogonal acceleration time of flight mass
spectrometer equipped with an ESI ion source as described
previously.14 A Reserpine solution 250 pg/ml (about
100 counts/s) was used as the reference compound for
TOF Lock Mass correction ([MCH]C ion 609.2806 m/z).
4.2.6. 2-[3-(Nitrophenyl)-1-trityl polystyrene-1H-pyra-
zol-4-yl]-1,3-benzoxazole (7). Tributylphosphine (2.5 ml,
10 mmol) followed by DEAD (1.6 ml, 10 mmol) were
added dropwise to a slurry of resin 6 (2.1 g, 2 mmol) in
20 ml of dry THF. The brown suspension was stirred at rt for
16 h. After filtering under reduced pressure the resin was
washed with DMF (3!), DCM (3!), MeOH (3!) and
Et2O (3!) and dried at 35 8C under vacuum.
4.2.1. 3-(3-Nitro-phenyl)-1H-pyrazole-4-carboxylic acid
ethyl ester 3{2}. A solution of hydrazine monohydrate
(3.2 ml, 66 mmol) in dry ethanol (25 ml) was added
dropwise at 0 8C to a solution of I{2} (17.9 g, 61 mmol)
in ethanol (150 ml). The reaction mixture was stirred at rt
for 3 h and the resulting solid was filtered, washed with
water and cold ethanol, and dried to afford 11.5 g (72%) of
3{2} as a pale yellow solid. Mp 160–161 8C.
4.2.7. [4-(1,3-Benzoxazol-2-yl)-1-trityl polystyrene-1H-
pyrazol-3-yl]aniline (8). A solution of SnCl2$H2O (6.6 g,
30 mmol,) in DMF (10 ml) was added to a slurry of the resin
7 (2 g, 2 mmol) in DMF (10 ml). The suspension was stirred
at rt for 16 h. After filtering under reduced pressure the resin
was washed with DMF (3!), DCM (3!), MeOH (3!) and
Et2O (3!) and dried at 35 8C under vacuum.
1H NMR (DMSO-d6), (ppm): 13.69 (br s, 1H), 8.63 (t, JZ
1.8 Hz, 1H), 8.45 (d, JZ2.0 Hz, 1H), 8.23 (m, 2H), 7.70 (t,
JZ8.0 Hz, 1H), 4.19 (q, JZ7.1 Hz, 2H), 1.21 (t, JZ7.1 Hz,
3H).
4.2.2. 3-(4-Nitro-phenyl)-1H-pyrazole-4-carboxylic acid
ethyl ester 3{1}. Using the above procedure the treatment of
I{1} with hydrazine monohydrate afforded 3{1} as a yellow
solid (75%). Mp 191–192 8C.
4.3. Acylation with acyl chlorides
DIEA (137 mL, 0.08 mmol) and the appropriate acyl
chloride (0.04 mmol) were added to the resin 8 (100 mg,
0.01 mmol), swelled in DCM (3 ml). The resulting
suspension was stirred for 20 h at 22 8C, filtered, washed
with DCM, MeOH and Et2O, dried under nitrogen flux and
used in the next step.
1H NMR (DMSO-d6), ppm: 13.72 (br s, 1H), 8.44 (s, 1H),
8.25 (d, JZ8.8 Hz, 2H), 8.02 (s, JZ8.8 Hz, 2H), 4.18 (q,
JZ7.2 Hz, 2H), 1.22 (t, JZ7.1 Hz, 3H).

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D. Berta et al. / Tetrahedron 61 (2005) 10801–10810
4.4. Acylation with carboxylic acids
4.7.3. N-[4-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-benzamide 9{1,1,3}. HPLC (254 nm): tR
5.93 min (95%).
A solution of NMM (55 mL, 0.05 mmol), PyBOP (260 mg,
and the appropriate carboxylic acid (0.05 mmol) in 2 ml of
DCM was stirred for 30 min and then added to a suspension
of the resin 8 (100 mg, 0.01 mmol, 1 equiv) in DCM (1 ml).
The obtained suspension was stirred for 20 h at 22 8C,
filtered, washed with DCM (3!), MeOH (3!) and Et2O
(3!), dried under nitrogen flux and used in the next step.
1H NMR (DMSO-d6), ppm: 13.65 (br s, 1H), 10.39 (br s,
1H), 8.32 (br s, 1H), 7.97 (d, JZ6.8 Hz, 2H), 7.88 (m, 3H),
7.69 (m, 1H), 7.64 (m, 1H), 7.59 (m, 1H), 7.54 (t, JZ7.5 Hz,
2H), 7.33 (m, 2H).
HRMS (ESI) calcd for C2H16N4O2 [MCH]C381.1346,
found 381.13273.
4.5. Acylation with isocyanates
4.7.4.
phenyl]-3-methoxy-benzamide
(254 nm): tR 6.01 min (95.9%).
N-[4-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
9{1,1,4}.
The appropriate isocyanate (0.04 mmol) was added to the
resin 8 (100 mg, 0.01 mmol), swelled in DCM (3 ml) in the
Quest vessel. The resulting suspension was stirred for 20 h
at 22 8C, filtered, washed with DCM, MeOH and Et2O, dried
under nitrogen flux and used in the next step.
HPLC
1H NMR (DMSO-d6), ppm: 13.64 (br s, 1H), 10.36 (br s,
1H), 8.35 (s, 1H), 7.88 (m, 4H), 7.69 (m, 1H), 7.64 (m, 1H),
7.56 (d, JZ7.7 Hz, 1H), 7.50 (t, JZ1.6 Hz, 1H), 7.45 (t, JZ
7.7 Hz, 1H), 7.33 (m, 2H), 7.17 (m, 1H), 3.84 (s, 3H).
4.6. Sulfonylation
A solution of DIEA (103 mL, 0.06 mmol) and the
appropriate sulfonyl chlorides (0.06 mmol) in 2 ml of
DCM was added to a suspension of the resin 8 (100 mg,
0.01 mmol) in DCM (1 ml). The obtained suspension was
stirred for 20 h at 22 8C, filtered, washed with DCM, MeOH
and Et2O, dried under nitrogen flux and used in the next
step.
HRMS (ESI) calcd for C24H18N4O3 [MCH]C411.1452,
found 411.1441.
4.7.5.
N-[4-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-2-phenyl-acetamide 9{1,1,5}. HPLC (254 nm):
tR 5.48 min (100%).
1H NMR (DMSO-d6), ppm: 13.66 (br s, 1H), 10.38 (br s,
1H), 8.63 and 8.23 (2s, 1H, tautomers), 7.83 (m, 2H), 7.71
(m, 2H),7.65(m, 2H), 7.36(m, 5H), 7.28(m, 2H), 3.71(s, 2H).
4.7. Cleavage
A solution of 2 ml of TFA 10% in DCM were added to
100 mg of the resins obtained after the derivatization of 8 in
the Quest vessels. The red suspension was stirred for 1 h
then filtered and the resin washed twice with 1 ml of DCM.
The filtered solution was evaporated under nitrogen flux to
give the products (9, 10, 11) as a crude solid or an oil, which
was purified by preparative HPLC.
HRMS (ESI) calcd for C24H17ClN4O2 [MCH]C395.1502,
found 395.1502.
4.7.6.
N-[4-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-2-(4-chloro-phenyl)-acetamide 9{1,1,6}. HPLC
(254 nm): tR 6.50 min (97.8%).
1H NMR (DMSO-d6), ppm: 13.64 and 13.57 (2br s, 1H,
tautomers), 10.37 and 10.27 (2br s, 1H, tautomers), 8.18 (s,
1H), 7.79 (m, 2H), 7.72 (m, 2H), 7.64 (m, 4H), 7.38 (m, 2H),
7.32 (m, 2H), 3.68 (s, 2H).
4.7.1. N-[4-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-isobutyramide 9{1,1,1}. HPLC (254 nm): tR
4.87 min (94.6%).
1H NMR (DMSO-d6), ppm: 13.63 and 13.56 (2br s, 1H,
tautomers), 10.01 and 9.90 (2br s, 1H, tautomers), 8.60
and 8.18 (2s, 1H, tautomers), 7.76 (m, 3H) 7.67 (m, 2H),
7.62 (m, 1H), 7.32 (m, 2H), 2.62 (m, 1H), 1.12 (d, JZ
6.6 Hz, 6H).
HRMS (ESI) calcd for C24H17ClN4O2 [MCH]C429.1113,
found 429.1104.
4.7.7. N-{4-[4-(5-Methyl-benzooxazol-2-yl)-1H-pyrazol-
3-yl]-phenyl}-isobutyramide 9{1,2,1}. HPLC (254 nm):
tR 5.71 min (96.6%).
HRMS (ESI) calcd for C20H16N4O2 [MCH]C347.1502,
found 347.1500.
1H NMR (DMSO-d6), ppm: 13.59 and 13.53 (2br s, 1H,
tautomers), 10.00 and 9.89 (2br s, 1H, tautomers), 8.15 (s,
1H), 7.71 (m, 4H), 7.53 (d, JZ8.1 Hz, 1H), 7.44 (m, 1H),
7.14 (d, JZ8.0 Hz, 1H), 2.62 (m, 1H), 2.42 (s, 3H), 1.12, (d,
JZ6.8 Hz, 6H).
4.7.2. Cyclopropanecarboxylic acid [4-(4-benzooxazol-2-
yl-1H-pyrazol-3-yl)-phenyl]-amide 9{1,1,2}. HPLC
(254 nm): tR 5.14 min (97.1%).
1H NMR (DMSO-d6), ppm: 13.65 (br s, 1H), 10.38 (br s,
1H), 8.27 (br s, 1H), 7.82 (d, JZ8.7 Hz, 2H), 7.73 (m, 2H),
7.71 (m, 1H), 7.66 (m, 1H), 7.36 (m, 2H), 1.92 (m, 1H), 0.85
(m, 4H).
HRMS (ESI) calcd for C21H20N4O2 [MCH]C361.1659,
found 361.1652.
4.7.8. Cyclopropanecarboxylic acid {4-[4-(5-methyl-
benzooxazol-2-yl)-1H-pyrazol-3-yl]-phenyl}-amide 9{1,
2,2}. HPLC (254 nm): tR 5.55 min (98.8%).
HRMS (ESI) calcd for C20H16N4O2 [MCH]C345.1346,
found 345.1330.

D. Berta et al. / Tetrahedron 61 (2005) 10801–10810
10807
1H NMR (DMSO-d6), ppm: 13.55 (s, 1H), 10.32 (s, 1H),
8.31 (s, 1H), 7.78 (d, JZ8.8 Hz, 2H), 7.68 (d, JZ8.8 Hz,
2H), 7.53 (d, JZ8.0 Hz, 1H), 7.43 (m, 1H), 7.13 (d, JZ
8.0 Hz, 1H), 2.41 (s, 3H), 1.8 (m, 1H), 0.82 (m, 4H).
8.43 (s, 1H), 8.03 (s, 1H), 7.73 (d, JZ7.8 Hz, 1H), 7.67 (m,
1H), 7.62, (m, 1H), 7.48 (d, JZ7.3 Hz, 1H), 7.89 (t, JZ
7.8 Hz, 1H), 7.33 (m, 2H), 2.59 (m, 1H), 1.10 (d, JZ6.9 Hz,
6H).
HRMS (ESI) calcd for C21H18N4O2 [MCH]C359.1501,
found 359.1492.
HRMS (ESI) calcd for C20H18N4O2 [MCH]C347.1502,
found 347.1499.
4.7.9. N-{4-[4-(5-Methyl-benzooxazol-2-yl)-1H-pyrazol-
3-yl]-phenyl}-benzamide 9{1,2,3}. HPLC (254 nm): tR
6.28 min (92.9%).
4.7.14. Cyclopropanecarboxylic acid [3-(4-benzooxazol-
2-yl-1H-pyrazol-3-yl)-phenyl]-amide 9{2,1,2}. HPLC
(254 nm): tR 5.15 min (87.1%).
1H NMR (DMSO-d6), ppm: 13.65 and 13.55 (2br s, 1H,
tautomers), 10.43 and 10.33 (2br s, 1H, tautomers), 8.17 (s,
1H), 7.97 (m, 2H), 7.92 (m, 1H), 7.85 (m, 2H), 7.60 (m, 1H),
7.54 (m, 4H), 7.45 (m, 1H), 7.15 (d, JZ8.0 Hz, 1H), 2.42 (s,
3H).
1H NMR (DMSO-d6), ppm: 13.70 and 13.61 (2br s, 1H,
tautomers), 10.32 and 10.21 (2br s, 1H, tautomers), 8.61
and 8.20 (2s, 1H, tautomers), 7.98 (s, 1H), 7.66 (m, 3H),
3.45 (m, 2H), 7.32 (m, 2H), 1.78 (m, 1H), 0.78 (d, JZ
4.6 Hz, 4H).
HRMS (ESI) calcd for C24H18N4O2 [MCH]C395.1502,
found 395.1500.
HRMS (ESI) calcd for C20H16N4O2 [MCH]C345.1346,
found 345.1341.
4.7.10. 3-Methoxy-N-{4-[4-(5-methyl-benzooxazol-2-yl)-
1H-pyrazol-3-yl]-phenyl}-benzamide 9{1,2,4}. HPLC
(254 nm): tR 5.94 min (97.7%).
4.7.15. N-[3-(4-Benzoxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-benzamide 9{2,1,3}. HPLC (254 nm): tR
5.84 min (88.6%).
1H NMR (DMSO-d6), ppm: 13.65 (br s, 1H), 10.38 (br s,
1H), 8.38 (s, 1H), 7.88 (m, 4H), 7.51 (m, 5), 7.17 (m, 2H),
3.86 (s, 3H), 2.42 (s, 3H).
1H NMR (DMSO-d6), ppm: 13.79 and 13.69 (2br s, 1H,
tautomers), 10.43 and 10.33 (2br s, 1H, tautomers), 8.25 (s,
1H), 7.98 (d, JZ6.9 Hz, 2H), 7.90 (m, 1H), 7.66 (m, 4H),
7.55 (m, 3H), 7.45 (m, 1H), 7.35 (m, 2H).
HRMS (ESI) calcd for C24H18N4O2 [MCH]C425.1608,
found 425.1617.
HRMS (ESI) calcd for C23H16N4O2 [MCH]C381.1346,
found 381.1347.
4.7.11. N-{4-[4-(5-Methyl-benzooxazol-2-yl)-1H-pyra-
zol-3-yl]-phenyl}-2-phenyl-acetamide 9{1,2,5}. HPLC
(254 nm): tR 6.29 min (97.6%).
4.7.16.
N-[3-(4-Benzoxazol-2-yl-1H-pyrazol-3-yl)-
9{2,1,4}. HPLC
phenyl]-3-methoxy-benzamide
(254 nm): tR 5.98 min (92.4%). 1H NMR (DMSO-d6),
ppm: 13.78 and 13.69 (br s, 1H, tautomers), 10.39 and 10.29
(2br s, 1H, tautomers), 8.23 (m, 2H), 7.93 (m, 1H), 7.68 (m,
3H), 7.55 (m, 2H), 7.46 (t, JZ7.9 Hz, 2H), 7.36 (m, 2H),
7.18 (d, JZ8.9 Hz, 1H), 3.85 (s, 3H).
1H NMR (DMSO-d6), ppm: 13.61 (br s, 1H), 10.34 (br s,
1H), 8.29 (br s, 1H), 7.79 (d, JZ8.2 Hz, 2H), 7.70 (d, JZ
8.2 Hz, 2H), 7.54 (d, JZ8.2 Hz, 1H), 7.44 (s, 1H), 7.35 (m,
4H), 7.25 (m, 1H), 7.14 (d, JZ7.3 Hz, 1H), 3.68 (s, 2H),
2.42 (s, 3H).
HRMS (ESI) calcd for C24H18N4O3 [MCH]C411.1452,
found 411.1464.
HRMS (ESI) calcd for C25H20N4O2 [MCH]C409.1659,
found 409.1668.
4.7.17. N-[3-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-2-phenyl-acetamide 9{2,1,5}. HPLC (254 nm):
tR 5.52 min (93.2%).
4.7.12. 2-(4-Chloro-phenyl)-N-{4-[4-(5-methyl-benzo-
oxazol-2-yl)-1H-pyrazol-3-yl]-phenyl}-acetamide 9{1,2,
6}. HPLC (254 nm): tR 6.84 min (100%).
1H NMR (DMSO-d6), ppm: 13.76 and 13.68 (2br s, 1H,
tautomers), 10.36 and 10.25 (2br s, 1H, tautomers), 8.55 and
8.22 (2s, 1H, tautomers), 8.05 (s, 1H), 7.73 (m, 1H), 7.66
(m, 2H), 7.59 (m, 2H), 7.46 (m, 1H), 7.34 (m, 5H), 7.25 (m,
1H), 3.64 (d, JZ7.8 Hz, 2H).
1H NMR (DMSO-d6), ppm: 13.66 and 13.58 (2br s, 1H,
tautomers), 10.40 and 10.31 (2br s, 1H, tautomers), 8.20 (s,
1H), 7.82 (m, 2H), 7.72 (m, 2H), 7.52 (d, JZ8.2 Hz, 1H),
7.50 (s, 1H), 7.41 (m, 4H), 7.16 (dd, J1Z8.2 Hz, J2Z
1.1 Hz, 1H), 3.72 (s, 2H), 2.42 (s, 3H).
HRMS (ESI) calcd for C24 H18 N4 O2 [MCH]C395.1502,
found 395.1519.
HRMS (ESI) calcd for C25H19ClN4O2 [MCH]C443.1269,
found 443.1279.
4.7.18. N-[3-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-2-(4-chloro-phenyl)-acetamide 9{2,1,6}. HPLC
(254 nm): tR 6.41 min (78.2%).
4.7.13. N-[3-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-isobutyramide 9{2,1,1}. HPLC (254 nm): tR
5.25 min (96.5%).
1H NMR (DMSO-d6), ppm: 13.66 (br s, 1H), 10.26 (br s,
1H), 8.56 and 8.23 (2br s, 1H, tautomers), 8.03 (s, 1H), 7.64
1H NMR (DMSO-d6), ppm: 13.70 (br s, 1H), 9.93 (br s, 1H),

10808
D. Berta et al. / Tetrahedron 61 (2005) 10801–10810
(m, 3H), 7.58 (m, 1H), 7.50 (m, 1H), 7.34 (m, 6H), 3.64 (s,
2H).
tautomers), 10.34 and 10.24 (2br s, 1H, tautomers), 8.61 and
8.20 (2s, 1H, tautomers), 8.03 (s, 1H), 7.71 (m, 1H), 7.54 (d,
JZ8.5 Hz, 2H), 7.43 (m, 2H), 7.36 (m, 4H), 7.27 (m, 1H),
7.18 (d, JZ8.05 Hz, 1H), 3.67 (s, 2H), 2.44 (s, 3H).
HRMS (ESI) calcd for C24H17ClN4O2 [MCH]C429.1113,
found 429.1096.
HRMS (ESI) calcd for C25H20N4O2 [MCH]C409.1659,
found 409.1666.
4.7.19. N-{3-[4-(5-Methyl-benzooxazol-2-yl)-1H-pyra-
9{2,2,1}.
zol-3-yl]-phenyl}-isobutyramide
(254 nm): tR 5.66 min (95.3%).
HPLC
4.7.24. 2-(4-Chloro-phenyl)-N-{3-[4-(5-methyl-benzo-
oxazol-2-yl)-1H-pyrazol-3-yl]-phenyl}-acetamide 9{2,2,
6}. HPLC (254 nm): tR 6.77 min (94.6%).
1H NMR (DMSO-d6), ppm: 13. 67 and 13.59 (2br s, 1H,
tautomers), 9.95 and 9.83 (br s, 1H), 8.16 (s, 1H), 8.01 (s,
1H), 7.71 (dd, J1Z23.6 Hz, J2Z8.5 Hz, 1H), 7.52 (d, JZ
8.0 Hz 1H), 7.41 (m, 2H), 7.33 (t, JZ8.5 Hz, 1H), 7.14 (d,
JZ7.7 Hz, 1H), 2.58 (m, 1H), 2.41 (s, 3H), 1.09 (d, JZ
6.8 Hz, 6H).
1H NMR (DMSO-d6), ppm: 13.68 and 13.60 (2br s, 1H,
tautomers), 10.32 and 10.21 (2br s, 1H, tautomers), 8.57 and
8.17 (2s, 1H, tautomers), 8.02 (s, 1H), 7.68 (m, 1H), 7.51
(m, 2H), 7.36 (m, 6H), 7.14 (d, JZ8.0 Hz, 1H) 3.64 (s, 2H),
2.41 (s, 3H).
HRMS (ESI) calcd for C21H20N4O2 [MCH]C361.1659,
found 361.1643.
HRMS (ESI) calcd for C25H19ClN4O2 [MCH]C443.1269,
found 443.1273.
4.7.20. Cyclopropanecarboxylic acid {3-[4-(5-methyl-
benzooxazol-2-yl)-1H-pyrazol-3-yl]-phenyl}-amide 9{2,
2,2}. HPLC (254 nm): tR 5.58 min (94.2%).
4.7.25. 1-[4-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-3-phenyl-urea 10{1,1,1}. HPLC (254 nm): tR
5.46 min (95.7%).
1H NMR (DMSO-d6), ppm: 13.71 and 13.63 (2br s, 1H,
tautomers), 10.35 and 10.24 (2br s, 1H, tautomers), 8.20 (s,
1H), 8.01 (s, 1H), 7.74 (m, 1H), 7.56 (d, JZ8.2 Hz, 1H),
7.45 (m, 1H), 7.36 (m, 1H), 7.17 (d, JZ8.0 Hz, 1H), 2.45 (s,
3H), 1.81 (m, 1H), 0.82 (d, JZ4.5 Hz, 4H).
1H NMR (DMSO-d6), ppm: 13.65 and 13.57 (2br s, 1H,
tautomers), 8.91 (br s, 1H), 8.77 (br s, 1H), 8.62 and 8.21
(2s, 1H), 7.82 (m, 2H), 7.70 (m, 1H), 7.63 (m, 3H), 7.53 (m,
2H), 7.30 (m, 4H), 6.99 (t, JZ7.4 Hz, 1H).
HRMS (ESI) calcd for C21H18N4O2 [MCH]C359.1502,
found 359.1509.
HRMS (ESI) calcd for C23H17N5O2 [MCH]C396.1455,
found 396.1469.
4.7.21. N-{3-[4-(5-Methyl-benzooxazol-2-yl)-1H-pyra-
zol-3-yl]-phenyl}-benzamide 9{2,2,3}. HPLC (254 nm):
tR 6.24 min (91.1%).
4.7.26. 1-[4-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-3-benzyl-urea 10{1,1,2}. HPLC (254 nm): tR
5.28 min (100%).
1H NMR (DMSO-d6), (ppm): 13.63 (br s, 1H), 10.36 and
10.29 (2br s, 1H, tautomers), 8.19 (s, 1H), 7.94 (m, 2H), 7.88
(m, 1H), 7.58 (m, 2H), 7.52 (m, 5H), 7.43 (m, 1H), 7.13 (d,
JZ8.0 Hz, 1H), 2.41 (s, 3H).
1H NMR (DMSO-d6), ppm: 8.78 (s, 1H), 8.36 (br s, 1H),
7.77 (m, 2H), 7.70 (m, 1H), 7.66 (m, 1H), 7.56 (d, JZ
8.8 Hz, 2H), 7.35 (m, 6H), 7.27 (m, 1H), 6.73 (t, JZ6.0 Hz,
1H), 4.35 (d, JZ5.6 Hz, 2H).
HRMS (ESI) calcd for C24H18N4O2 [MCH]C395.1502,
found 395.1493.
HRMS (ESI) calcd for C24 H19 N5 O2 [MCH]C410.1611,
found 410.1620.
4.7.22. 3-Methoxy-N-{3-[4-(5-methyl-benzooxazol-2-yl)-
1H-pyrazol-3-yl]-phenyl}-benzamide 9{2,2,4}. HPLC
(254 nm): tR 6.34 min (90.6%).
4.7.27. 1-{4-[4-(5-Methyl-benzooxazol-2-yl)-1H-pyrazol-
3-yl]-phenyl}-3-phenyl-urea 10{1,2,1}. HPLC (254 nm):
tR 6.43 min (100%).
1H NMR (DMSO-d6), ppm: 13.69 and 13.62 (2br s, 1H,
tautomers), 10.32 and 10.26 (2br s, 1H, tautomers), 8.18 (s,
1H), 7.88 (s, 1H), 7.58 (m, 1H), 7.53 (d, JZ7.7 Hz, 2H),
7.47 (m, 2H), 7.43 (t, JZ7.8 Hz, 2H), 7.14 (m, 2H), 3.82 (s,
3H), 2.41 (s, 3H).
1H NMR (DMSO-d6), ppm: 13.59 and 13.51 (2br s, 1H,
tautomers), 8.88 (br s, 1H), 8.74 (br s, 1H), 8.56 and 8. 15
(2s, 1H, tautomers), 7.78 (m, 2H), 7.56 (m, 3H), 7.45 (m,
3H), 7.28 (t, JZ7.5 Hz, 2H), 7.14 (d, JZ8.8 Hz, 1H), 6.97
(t, JZ7.5 Hz, 1H), 2.42 (s, 3H).
HRMS (ESI) calcd for C25H20N4O3 [MCH]C425.1608,
found 425.1601.
HRMS (ESI) calcd for C24H19N5O2 [MCH]C410.1611,
found 410.1616.
4.7.23. N-{3-[4-(5-Methyl-benzooxazol-2-yl)-1H-pyra-
zol-3-yl]-phenyl}-2-phenyl-acetamide 9{2,2,5}. HPLC
(254 nm): tR 5.92 min (97.1%).
4.7.28. 1-Benzyl-3-{4-[4-(5-methyl-benzooxazol-2-yl)-
1H-pyrazol-3-yl]-phenyl}-urea
(254 nm): tR 6.17 min (92.7%).
10{1,2,2}.
HPLC
1H NMR (DMSO-d6), ppm: 13.73 and 13.64 (2br s, 1H,
1H NMR (DMSO-d6), ppm: 13.52 (br s, 1H), 8.84 (br s, 1H),

D. Berta et al. / Tetrahedron 61 (2005) 10801–10810
10809
8.28 (s, 1H), 7.72 (d, JZ8.8 Hz, 2H), 7.54 (d, JZ8 Hz, 2H),
7.50 (8s, 1H), 7.44 (m, 1H), 7.31 (m, 4H), 7.23 (m, 1H), 7.13
(m, 1H), 6.81 (br s, 1H), 4.31 (d, JZ5.8 Hz, 2H), 2.41 (s,
3H).
1H NMR (DMSO-d6), ppm: 13.61 (br s, 1H), 10.55 (br s,
1H), 8.58 and 8.20 (2s, 1H, tautomers), 7.74 (m, 4H), 7.67
(m, 1H),7.59(m, 1H),7.35(m, 4H), 7.20(m, 2H), 2.34(s, 3H).
HRMS (ESI) calcd for C23H18N4O3S [MCH]C431.1172,
found 431.1187.
HRMS (ESI) calcd for C25H21N5O2 [MCH]C424.1768,
found 424.1779.
4.7.34. 4-Methyl-N-{4-[4-(5-methyl-benzooxazol-2-yl)-
1H-pyrazol-3-yl]-phenyl}-benzenesulfonamide 11{1,2,
1}. HPLC (254 nm): tR 6.45 min (82.1%).
4.7.29. 1-[3-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-3-phenyl-urea 10{2,1,1}. HPLC (254 nm): tR
5.52 min (90.1%).
1H NMR (DMSO-d6), ppm: 13.54 (br s, 1H), 10.53 and
10.36 (2br s, 1H, tautomers), 8.54 and 8.13 (2s, 1H,
tautomers), 7.71 (m, 4H), 7.52 (d, JZ8 Hz, 1H), 7.39 (t, JZ
0.8 Hz, 1H), 7.36 (d, JZ8.1 Hz, 2H), 7.19 (m, 2H), 7.13 (d,
JZ8.0 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H).
1H NMR (DMSO-d6), ppm: 13.73 (br s, 1H), 9.00 (br s, 1H),
8.91 (br s, 1H), 8.53 (s, 1H), 7.88 (s, 1H), 7.69 (m, 1H), 7.64
(m, 1H), 7.61 (m, 1H), 7.45 (d, JZ7.8 Hz, 2H), 7.42 (m,
2H), 7.35 (m, 2H), 7.27 (t, JZ7.8 Hz, 2H), 6.96 (t, JZ
7.3 Hz, 1H).
HRMS (ESI) calcd for C24H20N4O3S [MCH]C445.1329,
found 445.1326.
HRMS (ESI) calcd for C23H17N5O2 [MCH]C396.1455,
found 396.1472.
4.7.35. N-[4-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-4-methyl-benzenesulfonamide 11{2,1,1}. HPLC
(254 nm): tR 5.73 min (83.8%).
4.7.30. 1-[3-(4-Benzooxazol-2-yl-1H-pyrazol-3-yl)-
phenyl]-3-benzyl-urea 10{2,1,2}. HPLC (254 nm): tR
5.78 min (92.4%).
1H NMR (DMSO-d6), ppm: 13.56 (br s, 1H), 10.50 (br s,
1H), 8.39 (s, 1H), 7.76 (m, 4H), 7.69 (m, 1H), 7.61 (m, 1H),
7.40 (d, JZ8.0 Hz, 2H), 7.35 (m, 2H), 7.22 (d, JZ8.4 Hz,
2H), 2.36 (s, 3H).
1H NMR (DMSO-d6), ppm: 13.68 (br s, 1H), 8.71 (s, 1H),
8.32 (br s, 1H), 7.84 (s, 1H), 7.69 (m, 1H), 7.64 (m,
1H), 7.58 (m, 1H), 7.35 (m, 7H), 7.26 (m, 2H), 6.68 (br s,
1H), 4.31 (d, JZ5.7 Hz, 2H).
HRMS (ESI) calcd for C23H18N4O3S [MCH]C431.1172,
found 431.1187.
HRMS (ESI) calcd for C24H19N5O2 [MCH]C410.1611,
found 410.1594.
4.7.36. 4-Methyl-N-{3-[4-(5-methyl-benzooxazol-2-yl)-
1H-pyrazol-3-yl]-phenyl}-benzenesulfonamide 11{2,2,
1}. HPLC (254 nm): tR 6.37 min (84.6%).
4.7.31. 1-{3-[4-(5-Methyl-benzooxazol-2-yl)-1H-pyrazol-
3-yl]-phenyl}-3-phenyl-urea 10{2,2,1}. HPLC (254 nm):
tR 6.42 min (93.7%).
1H NMR (DMSO-d6), ppm: 13.61 (br s, 1H), 10.28 (br s,
1H), 8.55 and 8.17 (2s, 1H, tautomers), 7.60 (d, JZ8.3 Hz,
2H), 7.58 (s, 1H), 7.51 (d, JZ8.1 Hz, 2H), 7.40 (s, 1H), 7.30
(s, 1H), 7.29 (d, JZ8.5 Hz, 2H), 7.15 (d, JZ8.1 Hz, 2H),
2.42 (s, 3H), 2.19 (s, 3H).
1H NMR (DMSO-d6), ppm: 13.64 (br s, 1H), 8.79 (br s, 1H),
8.69 (s, 1H), 7.86 (s, 1H), 7.56 (m, 3H), 7.42 (m, 4H), 7.25
(t, JZ7.3 Hz, 2H), 7.14 (d, JZ8.0 Hz, 2H), 6.95 (t, JZ
7.3 Hz, 1H), 2.41 (s, 3H).
HRMS (ESI) calcd for C24H20N4O3S [MCH]C445.1329,
found 445.1317.
HRMS (ESI) calcd for C24H19N5O2 [MCH]C410.1611,
found 410.1608.
4.7.32. 1-Benzyl-3-{3-[4-(5-methyl-benzooxazol-2-yl)-
1H-pyrazol-3-yl]-phenyl}-urea
(254 nm): tR 6.15 min (97.6%).
10{2,2,2}.
HPLC
References and notes
1H NMR (DMSO-d6), ppm: 13.64 and 13.56 (2br s, 1H,
tautomers), 8.70 and 8.59 (2br s, 1H, tautomers), 8.16 (s,
1H), 7.79 (d, JZ12.3 Hz, 1H), 7.52 (m, 3H), 7.42 (s, 1H),
7.37 (m, 1H), 7.29 (m, 4H), 7.22 (m, 1H), 7.14 (d, JZ
8.2 Hz, 1H), 6.61 (m, 1H), 4.29 (d, JZ5.8 Hz, 2H), 2.41 (s,
3H).
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(254 nm): tR 6.08 min (97.0%).

10810
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