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\DOI{10.5802/crchim.403}
\datereceived{2025-03-05}
\daterevised{2025-04-14}
\dateaccepted{2025-05-07}
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\dateposted{2025-06-20}
\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{research-article}

\title{Synthesis of C5-arylated pyrazoles from a pyrazole-4-carboxylate
by a palladium-catalyzed C5--H bond  activation/C4-decarboxylation
sequence}

\alttitle{Synth\`{e}se de pyrazoles C5-aryl\'{e}s \`{a} partir d'un
pyrazole-4-carboxylate par activation de la liaison C5--H catalys\'{e}e
par le palladium suivie d'une d\'{e}carboxylation en C4}

\author{\firstname{Ahlem} \lastname{Rahali}}
\address{Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes, France}
\address{Laboratoire de Chimie M\'{e}dicinale et Environnementale,
Institut Sup\'{e}rieur de Biotechnologie, Route de la Soukra km 4, 3038
Sfax, Tunisia}

\author{\firstname{Norman} \lastname{Le Floch}}
\addressSameAs{1}{Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes,
France}

\author{\firstname{Fatma} \lastname{Allouche}\IsCorresp}
\addressSameAs{2}{Laboratoire de Chimie M\'{e}dicinale et
Environnementale, Institut Sup\'{e}rieur de Biotechnologie, Route de la
Soukra km 4, 3038 Sfax, Tunisia}
\email[F. Allouche]{fatmaallouch@yahoo.fr}

\author{\firstname{Henri} \lastname{Doucet}\CDRorcid{0000-0002-1410-3663}\IsCorresp}
\addressSameAs{1}{Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes,
France}
\email[H. Doucet]{henri.doucet@univ-rennes1.fr}

\keywords{\kwd{C--H bond functionalization}\kwd{Direct
arylation}\kwd{Homogeneous catalysis}\kwd{Palladium}\kwd{Pyrazoles}}

\altkeywords{\kwd{Fonctionnalisation de liaisons
C--H}\kwd{Arylation directe}\kwd{Catalyse
homog\`{e}ne}\kwd{Palladium}\kwd{Pyrazoles}}

\begin{abstract}
In the context of palladium-catalyzed C--H bond arylation, it has been 
well-established that pyrazoles, with both C4 and C5 available
positions,  typically result in the formation of mixtures of C4-,
C5-arylated, and also  C4, C5-diarylated products. In this study, the
reactivity of ethyl  1-methylpyrazole-4-carboxylate in
palladium-catalyzed C--H arylation was  investigated. The objective was
to determine the effectiveness of the  presence of an ester substituent
at the C4 position of the pyrazole as a  blocking group in controlling
the regioselectivity of such C--H bond  arylations. It was observed
that the presence of such an ester substituent  acted as a convenient
blocking group, thereby enabling the control of  regioselectivity in
the arylation process at the C5 position of the  pyrazole. The reaction
exhibits a high degree of tolerance to a wide variety  of aryl
bromides, including a diverse array of functional groups at the 
\textit{para}, \textit{meta}, and \textit{ortho} positions of the aryl
bromides. Heteroarylation is also possible.  In the course of these
couplings, no decarboxylation of the pyrazole unit  was observed, and
the reaction requires only 2 mol{\%} of an air-stable  phosphine-free
palladium catalyst and KOAc as an inexpensive base.  Furthermore, the
removal of the pyrazole ester substituent was found to be  easy, which
demonstrates the potential of such an ester substituent as a  removable
blocking group.
\end{abstract}

\begin{altabstract}
Dans le contexte de l'arylation des liaisons C--H catalys\'{e}e par le 
palladium, il a \'{e}t\'{e} \'{e}tabli que les pyrazoles, dont les
positions  C4 et C5 sont libres, conduisent g\'{e}n\'{e}ralement la
formation de  m\'{e}langes de produits monoaryl\'{e}s en C4 et
\'{e}galement en C5 et de produits diaryl\'{e}s en C4, C5. Dans cette
\'{e}tude, la r\'{e}activit\'{e} du 1-m\'{e}thylpyrazole-4-carboxylate
d'\'{e}thyle en arylation C--H catalys\'{e}e par le palladium a
\'{e}t\'{e} d\'{e}termin\'{e}e. L'objectif \'{e}tait d'\'{e}valuer
l'efficacit\'{e} de la pr\'{e}sence d'un substituant ester en position
C4 du pyrazole en tant que groupement bloquant pour contr\^{o}ler la
r\'{e}gios\'{e}lectivit\'{e} de ces arylations de liaisons C--H. Il a
\'{e}t\'{e} observ\'{e} que la pr\'{e}sence de ce substituant ester en
position C4 du pyrazole est un groupement bloquant efficace pour 
contr\^{o}ler la r\'{e}gios\'{e}lectivit\'{e} de ces arylations. La 
pr\'{e}sence d'un tel substituant ester permettant ainsi le
contr\^{o}le de la r\'{e}gios\'{e}lectivit\'{e} en faveur de
l'arylation en position C5 du pyrazole. La r\'{e}action pr\'{e}sente un
degr\'{e} \'{e}lev\'{e} de tol\'{e}rance \`{a} une grande
vari\'{e}t\'{e} de bromures d'aryle, qui comprennent un large
\'{e}ventail de groupes fonctionnels en  positions \textit{para}-,
\textit{m\'{e}ta}- et \textit{ortho}-. Elle est \'{e}galement
compatible avec les bromures  d'h\'{e}t\'{e}roaryle. Au cours de ces
couplages, aucune  d\'{e}carboxylation de l'unit\'{e} pyrazole n'a
\'{e}t\'{e}  observ\'{e}e. La r\'{e}action ne n\'{e}cessite que 2
mol{\%} d'un  catalyseur au palladium sans phosphine et stable \`{a}
l'air et du KOAc comme base peu co\^{u}teuse. En outre,
l'\'{e}limination du substituent ester du pyrazole s'est av\'{e}r\'{e}e
facile, ce qui d\'{e}montre le potentiel de ce type de substituent en
tant que groupement bloquant temporaire. 
\end{altabstract}

\thanks{Scientific Ministry of Higher Education and Research of Tunisia}

\shortrunauthors

\maketitle

{\vspace*{6pt}}

\twocolumngrid

\end{noXML}

\section{Introduction} \label{sec1}

{\vspace*{-2pt}}

Several pharmaceutical compounds possess a 5-(hetero)arylpyrazole
unit~\cite{1}. Examples include celecoxib, a nonsteroidal
anti-inflammatory drug, and nidufexor, an experimental treatment for
non-alcoholic steatohepatitis (Figure~\ref{fig1}). Other examples
include rimonabant, a 5-(4-chlorophenyl)pyrazole, which has been shown
to have anti-obesity properties, and voxelotor, a
2-(pyrazol-5-yl)pyridine, which has been found to be beneficial in the
treatment of sickle cell disease (Figure~\ref{fig1}). While numerous
approaches have been reported for the synthesis of substituted
pyrazoles~\cite{2,3}, there remains a need for the development of
simple and straightforward methods for the synthesis of
5-arylpyrazoles.

\begin{figure}
\includegraphics{fig01}
\caption{\label{fig1}Selected drugs containing an arylpyrazole unit.}
\end{figure}

Direct C--H bond functionalization of (hetero)arenes by palladium
catalysis is an important research topic in organic 
chemistry~\cite{4,5,6,7,8,9,10,11,12,13,14,15,16,17,18}, and a number
of methods for controlling the regioselectivity of such a C--H bond
functionalization have been reported over the past few decades.
\mbox{Palladium-catalyzed} C--H bond arylation of five-membered ring
heteroarenes has emerged as an increasingly reliable method for
one-step access to (poly)arylated heteroarenes. This method 
constitutes a promising alternative to existing methods, particularly
the Stille, the Suzuki, or the Negishi coupling reactions~\cite{19}.
The palladium-catalyzed C--H bond arylation approach exhibits a notable
advantage as it circumvents the need for preliminary synthesis of
organometallic derivatives. In the case of five-membered ring
heteroarenes, the positions that exhibit the greatest reactivity in
Pd-catalyzed C--H bond activation are generally C2 and C5, as evidenced
by studies involving furan, thiophene, and pyrrole rings~\cite{20}.
However, this approach is not without limitations when it comes to
certain substrates, as the regioselectivity of the coupling process can
be sometimes challenging to control~\cite{20}. The pyrazole scaffold
has been identified as one of the most challenging  substrates, as
demonstrated in the seminal study by Sames and colleagues~\cite{21}.
They reported that the reaction of 1-SEM-pyrazole (SEM ${=}$\ 
2-(trimethylsilyl)ethoxymethyl) with bromobenzene resulted in the
formation of 5-phenylpyrazole, 4-phenylpyrazole, and
4,5-diphenylpyrazole in a 4:1:3 ratio. As a result, due to the presence
of the C4 and C5 free positions in a significant number of pyrazoles,
several groups obtained mixtures of arylated
products~\cite{22,23,24,25,26}. At present, the most reliable method
for controlling the regioselectivity of Pd-catalyzed pyrazoles
arylation at the C5 position is the introduction of a formyl~\cite{27,28},
chloro~\cite{29,30}, or bromo~\cite{31,32}
blocking group at the C4 position of the pyrazole (Scheme~\ref{sch1},
Equation~(1)). The introduction of an ester substituent as a blocking
group has the potential to be a highly practical approach, primarily
due to the ease with which it can be removed following arylation and
also due to its considerable potential in organic synthesis. However,
the use of such ester  substituents on pyrazoles as a blocking groups
remains limited. Sames and coworkers described a single example of the
C5-arylation of ethyl  1-SEM-pyrazole-4-carboxylate with bromobenzene
as coupling partner using Pd(OAc)\tsub{2} (5~mol{\%}) associated to
expensive and air-sensitive ligand P($n$Bu)Ad\tsub{2} (7.5~mol{\%}) as
the catalytic system (Scheme~\ref{sch1}, Equation~(2))
(for a study on the regioselectivity of the Pd-catalyzed CH
arylation of pyrazoles~\cite{21}). Very
recently, an enantioselective palladium-catalyzed C--H arylation of
ethyl 1-methyl-3-(trifluoromethyl)pyrazole-4-carboxylate was reported,
using Pd(OCOCF\tsub{3})\tsub{2} associated to a sophisticated phosphine
ligand as the catalyst (Scheme~\ref{sch1}, Equation (3))~\cite{27}. 
The objective of the present study was to provide more robust evidence
for the potential of an ester substituent as a blocking group at the C4
position of pyrazoles in Pd-catalyzed direct arylation. To achieve this
objective, our study focused on the reactivity of ethyl
1-methylpyrazole-4-carboxylate (Scheme~\ref{sch1}, Equation~(4)). 
Herein we describe: (1) the conditions for the Pd-catalyzed 
regioselective C--H C5-arylation of ethyl
1-methylpyrazole-4-carboxylate without decarboxylation; (2) the
spectrum of aryl bromides in this process; and (3) the conditions for
the decarboxylation  of a prepared 5-arylpyrazole derivative.

\begin{scheme*}
{\vspace*{-3pt}}
\includegraphics{sc01}
{\vspace*{4pt}}
\caption{\label{sch1}Pd-catalyzed direct C5-arylation of 4-substituted
pyrazoles.}
{\vspace*{-10pt}}
\end{scheme*}

%tab1
\begin{table*}
\caption{\label{tab1}Influence of the reaction conditions on the
Pd-catalyzed arylation of ethyl 1-methylpyrazole-4-carboxylate with 
1-bromo-4-(trifluoromethyl)benzene
\vspace*{4pt}\tpar{\protect\inlinefig{fx01}}\vspace*{-9pt}}
\tabcolsep6.5pt\begin{tabular}{ccccccc}
\thead
Entry &amp; Catalyst &amp; Solvent &amp; Base &amp; Temp. (\textdegree C) &amp; Conv.
({\%}) &amp; Yield in \textbf{1} ({\%}) \\
\endthead
\01 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; DMA &amp; KOAc  &amp; 150 &amp; 100 &amp; 88 \\
\02 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; DMA &amp; KOPiv &amp; 150 &amp; 100 &amp; 87 \\
\03 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; DMA &amp; CsOAc &amp; 150 &amp; 100 &amp; 71 \\
\04 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; DMA &amp; NaOAc &amp; 150 &amp; 100 &amp; 23 \\
\05 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; DMA &amp; K\tsub{2}CO\tsub{3} &amp; 150 &amp; 100 &amp; 35 \\
\06 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; DMA &amp; Cs\tsub{2}CO\tsub{3}&amp; 150 &amp; 100 &amp; \09 \\
\07 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; DMA &amp; KOAc &amp; 130 &amp; \095 &amp; 84 \\
\08 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; DMF &amp; KOAc &amp; 150 &amp; 100 &amp; 80 \\
\09 &amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; NMP &amp; KOAc &amp; 150 &amp; 100 &amp; 67 \\
10&amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; Xylene &amp; KOAc &amp; 150 &amp; 100 &amp; 38 \\
11&amp; PdCl(C\tsub{3}H\tsub{5})(dppb) &amp; 3-methyl-butan-1-ol &amp; KOAc &amp; 150 &amp; 100 &amp; 12 \\
12&amp; Pd(OAc)\tsub{2} &amp; DMA &amp; KOAc &amp; 150 &amp; 100 &amp; 85
\botline
\end{tabular}
\tabnote{Conditions: [Pd] (0.05~mmol),
1-bromo-4-(trifluoromethyl)benzene (1~mmol), ethyl
1-methylpyrazole-4-carboxylate (1.5~mmol), base (2~mmol), 16~h, 
conversion of 1-bromo-4-(trifluoromethyl)benzene, isolated yields.}
{\vspace*{-2pt}}
\end{table*}

\section{Results and discussion}\label{sec2}

The reactivity of ethyl 1-methylpyrazole-4-carboxylate (1.5 equiv.)
using 1-bromo-4-(trifluoromethyl)benzene (1 equiv.) as reaction
partners in the presence of 5~mol{\%} PdCl(C\tsub{3}H\tsub{5})(dppb)
catalyst~\cite{33} and a set of bases in DMA as the solvent, at
150~\textdegree C, was established (Table~\ref{tab1}). This catalyst
and solvent system had previously  demonstrated its potential for
Pd-catalyzed C--H bond arylation of  five-membered ring
heteroarenes~\cite{28}. Under these conditions, by using KOAc as the
base, the desired C5-arylated pyrazole \textbf{1} was obtained in
88{\%} yield (Table~\ref{tab1}, entry~1). It should be mentioned that
no trace of products coming from the decarboxylation of the pyrazole
ring was detected during the course of this reaction. A very similar
yield of 87{\%} in product \textbf{1} was obtained using KOPiv as the
base (Table~\ref{tab1}, entry~2). The CsOAc base was also very
effective, as \textbf{1} was isolated in 71{\%} yield
(Table~\ref{tab1}, entry~3). Conversely, NaOAc resulted in the
production of \textbf{1} in only 23{\%} yield (Table~\ref{tab1},
entry~4). The carbonate bases, namely K\tsub{2}CO\tsub{3} and
Cs\tsub{2}CO\tsub{3}, were less effective compared to KOAc or KOPiv,
affording \textbf{1} in only 35{\%} and 9{\%} yields, respectively
(Table~\ref{tab1},  entries~5 and~6). These results are consistent with
the Coordinated  Metalation Deprotonation (CMD) mechanism, where the
base coordinates to the palladium complex to activate the C--H bond.
The most effective bases in this CMD process have been shown to be
acetates and pivalates~\cite{34,35,36}. Lowering the reaction
temperature to  130~\textdegree C instead of 150~\textdegree C slightly
decreased the yield in product \textbf{1} due to an incomplete
conversion of 1-bromo-4-(trifluoromethyl)benzene (Table~\ref{tab1},
entry~7). The effect of different solvents on the reaction yield was
then evaluated. Both DMF and NMP resulted in slightly lower yields in
\textbf{1} compared to the reaction carried out in DMA, while xylene
and 3-methylbutan-1-ol were found to be much less effective than DMA
(Table~\ref{tab1},  entries 8--11). Finally, the desired product
\textbf{1} was obtained in a very good yield (85{\%}) using a
phosphine-free catalyst, namely  Pd(OAc)\tsub{2} (Table~\ref{tab1},
entry~12).

Ethyl 1-methylpyrazole-4-carboxylate was then subjected to a series of 
Pd-catalyzed direct arylation reactions with a variety of
\textit{ortho}-, \textit{meta}-, and \textit{para}-substituted aryl
bromides (Scheme~\ref{sch2}). The reactions were carried out using the
phosphine-free Pd(OAc)\tsub{2} catalyst (2 mol{\%}), in the presence of
KOAc as an inexpensive base, in DMA at 150~\textdegree C. 
Electron-deficient aryl bromides substituted at the \textit{para}
position with nitrile, acetyl, propionyl, formyl, ester, or
trifluoromethoxy groups were selected as the reactant for the synthesis
of C5-arylated pyrazoles. All these electron-deficient aryl bromides
afforded the target compounds \textbf{2}--\textbf{8} in yields ranging
from 76 to 81{\%}. The presence of a fluorine substituent at the
\textit{para} position of the aryl bromide, which does not exert a
significant electronic influence, resulted in a yield of product 
\textbf{9} comparable to that observed in the previous experiments. By
using 4-bromo-1-chlorobenzene, the desired product \textbf{10} was
obtained in 75{\%} yield. It is noteworthy that the C--Cl bond remained
intact during the course of this reaction, thereby enabling subsequent
transformations. It is also worth noting that the electron-rich
4-\textit{tert}-butylbromobenzene afforded \textbf{11} in a low yield
of 23{\%}, which is due to the low conversion of the aryl bromide. From
the electron-deficient nitrile, formyl and  trifluoromethyl
\textit{meta}-substituted aryl bromides, the C5-arylated pyrazoles
\textbf{12}--\textbf{14} were obtained in good yields. In a similar
manner, 3-fluorobromobenzene and 3-bromo-1-chlorobenzene were converted
into the target products \textbf{15} and \textbf{16} in 77{\%} and
81{\%} yield, respectively. In addition, when less activated
3-bromoanisole was used as the starting material, the target product
\textbf{17} was produced in 66{\%} yield. The reactivity of the
\textit{ortho}-substituted 2-bromobenzonitrile was also investigated.
Again, the reaction was successful, and compound \textbf{18} was
obtained in 73{\%} yield. The disubstituted
1,3-bis(trifluoromethyl)-5-bromobenzene and 1-bromo-3,5-difluorobenzene
also afforded the expected products \textbf{19} and \textbf{20} in good
yields. In addition, the N-containing \mbox{heteroaromatics} \mbox{3-~and}
\mbox{4-bromopyridines} were found to be effective reagents in the synthesis
of the desired heteroarylated pyrazoles \textbf{21} and \textbf{22},
with isolated yields of 74 and 71{\%}, respectively. Therefore, a
comparison of our method with  previous ones employing an ester
blocking group~\cite{21,27} (Scheme~\ref{sch1}, b and c), reveals
several advantages: our procedure is phosphine-free, a cost-effective
base is employed, and several functional groups at the \textit{para},
\textit{meta}, and \textit{ortho} positions of the aryl bromide are
tolerated. 

\begin{scheme}
\includegraphics{sc02}
{\vspace*{8pt}}
\caption{\label{sch2}Scope of the Pd-catalyzed direct C5-arylation of
ethyl 1-methylpyrazole-4-carboxylate.}
{\vspace*{-12pt}}
\end{scheme}

The decarboxylation of pyrazole-4-carboxylates has previously been
described by several research groups~\cite{37,38,39}. In order to
further {demonstrate} the effectiveness of using an ester substituent as
a removable blocking group on pyrazoles, the decarboxylation of ethyl 
1-methyl-5-(4-(trifluoromethyl)phenyl)pyrazole-4-carboxylate \textbf{1}
was achieved (Scheme~\ref{sch3}).
Under basic conditions followed by acidification, in DMA
at 150~\textdegree C, a complete decarboxylation was observed,
resulting in the formation of the desired
1-methyl-5-(4-(trifluoromethyl)phenyl)pyrazole \textbf{23} in 76{\%}
yield. 

\begin{scheme}
\includegraphics{sc03}
{\vspace*{8pt}}
\caption{\label{sch3}Decarboxylation of ethyl 
1-methyl-5-(4-(trifluoromethyl)phenyl)pyrazole-4-carboxylate.}
{\vspace*{-6pt}}
\end{scheme}

In summary, the results of this study show that an ester function is an
effective and easily removable blocking group at the C4 position of a 
pyrazole, which enables a regioselective arylation at the C5 position.
The  reaction exhibits high tolerance to a wide array of functional
groups, at  the \textit{para}, \textit{meta}, and even \textit{ortho}
positions of the aryl bromides. It should be noted that  the ester
function remained unaltered by the reaction conditions. The  utility of
ester substituents in a variety of organic reactions, as well as  their
easy elimination has been well-documented. Therefore, using such 
blocking groups on pyrazoles is an attractive approach. Furthermore,
the use  of only 2 mol{\%} of an air-stable phosphine-free palladium
catalyst in  conjunction with KOAc as an inexpensive base renders this
one-step process  highly appealing for the synthesis of 5-arylpyrazole
derivatives.

\subsection{Experimental section}
\subsubsection{General}
Pd(OAc)\tsub{2} (98{\%}) was purchased from  Aldrich. DMA {(99${+}${\%})}
extra pure and KOAc (99{\%}) were purchased from Acros. Ethyl
1-methylpyrazole-4-carboxylate (95{\%}) was purchased from Doug 
Discovery. These compounds were not purified before use. All reagents
were weighed and handled in air. All reactions were carried out under
an inert atmosphere with standard Schlenk techniques. \tsup{1}H,
\tsup{19}F and \tsup{13}C NMR spectra were recorded on a Bruker Avance
III 400~MHz spectrometer. Melting points were determined with a Kofler
hot bench system. \mbox{High-resolution} mass spectra were measured on a
Thermo Fisher Q{-}Exactive spectrometer. Flash column chromatography
was performed using Macherey-Nagel silica 60~M (0.04--0.063~mm).

\subsubsection{General procedure for palladium-catalyzed direct
C5-arylations of ethyl 1-methylpyrazole-4-carboxylate}

To a 25~mL oven-dried Schlenk tube, aryl bromide (1~mmol, 1 equiv.),
ethyl 1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol, 1.5 equiv.),
KOAc (0.196~g, 2~mmol, 2 equiv.) and Pd(OAc)\tsub{2} (11.2~mg,
0.05~mmol, 0.05 equiv.) and DMA (4~mL) were successively added. The
reaction mixture was evacuated by vacuum-argon cycles (5 times) and
stirred at 150~\textdegree C (oil bath temperature) for 16~h. After
cooling the reaction at room temperature and concentration, the crude
mixture was purified by flash column chromatography on silica gel to 
afford the C5-arylated ethyl 1-methylpyrazole-4-carboxylate
derivatives.

\subsubsection{Ethyl
1-methyl-5-(4-(trifluoromethyl)phenyl){\ubreak}pyrazole-4-carboxylate
(\textbf{1})}

From 1-bromo-4-(trifluoromethyl)benzene (0.225 g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{1}
was obtained in 85{\%} yield (0.253~g) as a yellow solid: mp 
96--98~\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$ 
8.02 (s, 1H), 7.78 (d, $J=8.1$~Hz, 2H), 7.55 (d, $J=8.0$~Hz, 2H), 4.19
(q, $J=7.1$~Hz, 2H), 3.77 (s, 3H), 1.21 (t, $J=7.1$~Hz, 3H). \tsup{19}F
NMR (376~MHz, CDCl\tsub{3}) $\delta$\ ${-}$63.0. \tsup{13}C NMR
(101~MHz, CDCl\tsub{3}) $\delta$ 162.7, 144.4, 141.2, 132.8, 131.5 (q,
$J=32.8$~Hz),  130.5, 125.2 (q, $J=3.8$~Hz), 123.8 (q, $J=272.4$~Hz),
113.2, 60.0, 37.4, 14.1. HRMS calcd for  [M${+}$H]$^{+}$
C\tsub{14}H\tsub{14}N\tsub{2}O\tsub{2}F\tsub{3}  299.1002, found
299.1002.

\subsubsection{Ethyl 5-(4-cyanophenyl)-1-methylpyrazole-4-{\ubreak}carboxylate
(\textbf{2})}

From 4-bromobenzonitrile (0.182~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{2}
was obtained in 76{\%} yield (0.194~g) as a colorless solid: mp
117--119~\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$
8.02 (s, 1H), 7.81 (d, $J=8.5$~Hz, 2H), 7.55 (d, $J=8.5$~Hz, 2H), 4.19
(q, $J=7.1$~Hz, 2H), 3.77 (s, 3H), 1.22 (t, $J=7.1$~Hz, 3H). 
\tsup{13}C NMR (100~MHz, CDCl\tsub{3}) $\delta$  162.6, 143.8, 141.3,
133.8, 132.0, 130.9, 118.2, 113.4, 60.1, 37.5, 14.1. HRMS calcd for
[M${+}$H]$^{+}$ C\tsub{14}H\tsub{14}N\tsub{3}O\tsub{2}  256.1080, found
256.1080.

\subsubsection{Ethyl 5-(4-acetylphenyl)-1-methylpyrazole-4-carboxylate
(\textbf{3})}

From 4-bromoacetophenone (0.199 g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{3}
was obtained in 78{\%} yield (0.212~g) as a colorless solid: mp 
79--81~\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$
8.09 (d, $J=8.4$~Hz, 2H), 8.02 (s, 1H), 7.52 (d, $J=8.4$~Hz, 2H), 4.18
(q, $J=7.1$~Hz, 2H), 3.77 (s, 3H), 2.68 (s, 3H), 1.21 (t, $J=7.1$~Hz,
3H).  \tsup{13}C NMR (101~MHz, CDCl\tsub{3}) $\delta$ 197.4, 162.8,
144.8, 141.2, 137.6, 133.7, 130.4, 128.2, 113.2, 60.0, 37.4, 26.7,
14.1. HRMS calcd for [M${+}$H]$^{+}$ 
C\tsub{15}H\tsub{17}N\tsub{2}O\tsub{3} 273.1234, found 273.1233.

\subsubsection{Ethyl
1-methyl-5-(4-propionylphenyl)pyrazole-4-carboxylate 
(\textbf{4})}

From 4-bromopropiophenone (0.213~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{4}
was obtained in 81{\%} yield (0.232~g) as a colorless solid: mp 
77--78~\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$
8.10 (d, $J=8.5$~Hz, 2H), 8.02 (s, 1H), 7.52 (d, $J=8.4$~Hz, 2H), 4.18
(q, $J=7.1$~Hz, 2H), 3.77 (s, 3H), 3.08 (q, $J=7.2$~Hz, 2H), 1.28 (t,
$J=7.2$~Hz, 3H), 1.20 (t, $J=7.2$~Hz, 3H). \tsup{13}C NMR (75~MHz,
CDCl\tsub{3}) $\delta$ 200.1, 162.8, 144.8, 141.2, 137.4, 133.5, 130.3,
127.8, 113.1, 60.0, 37.4, 31.9, 14.1, 8.2. HRMS calcd for [M${+}$H]$^{+}$
C\tsub{16}H\tsub{19}N\tsub{2}O\tsub{3} 287.1390, found 287.1390.

\subsubsection{Ethyl 5-(4-formylphenyl)-1-methylpyrazole-4-carboxylate
(\textbf{5})}

From 4-bromobenzaldehyde (0.185~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{5}
was obtained in 80{\%} yield (0.206~g) as a yellow solid: mp 
107--109~\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$
10.13 (s, 1H), 8.04--8.02 (m, 3H), 7.60 (d, $J=8.2$~Hz, 2H), 4.18 (q,
$J=7.2$~Hz,  2H), 3.78 (s, 3H), 1.21 (t, $J=7.1$~Hz, 3H). \tsup{13}C
NMR (100~MHz,  CDCl\tsub{3}) $\delta$ 191.5, 162.7, 144.5, 141.3,
136.7, 135.1, 130.8, 129.4, 113.3, 60.1, 37.5, 14.1. HRMS calcd for
[M${+}$H]$^{+}$ C\tsub{14}H\tsub{15}N\tsub{2}O\tsub{3} 259.1077, found
259.1077.

\subsubsection{Ethyl
5-(4-(ethoxycarbonyl)phenyl)-1-{\ubreak}methylpyrazole-4-carboxylate 
(\textbf{6})}
{\vspace*{-1pt}}

From ethyl 4-bromobenzoate (0.229~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{6}
was obtained in 77{\%} yield (0.232~g) as a yellow solid: mp 69--71
\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$  8.18 (d,
$J=8.3$~Hz, 2H), 8.02 (s, 1H), 7.48 (d, $J=8.3$~Hz, 2H), 4.44 (q,
$J=7.1$~Hz, 2H), 4.17 (q, $J=7.1$~Hz, 2H), 3.75 (s, 3H), 1.44 (t,
$J=7.1$~Hz, 3H), 1.19 (t, $J=7.1$~Hz, 3H). \tsup{13}C NMR (100~MHz,
CDCl\tsub{3}) $\delta$ 166.0, 162.8, 144.8, 141.2, 133.5, 131.3, 130.1,
129.4, 113.1, 61.3, 60.0, 37.4, 14.3, 14.1. HRMS calcd for
[M${+}$H]$^{+}$ C\tsub{16}H\tsub{19}N\tsub{2}O\tsub{4} 303.1339, found
303.1339.{\vspace*{-2pt}}

\subsubsection{Ethyl
1-methyl-5-(4-(trifluoromethoxy)phenyl){\ubreak}pyrazole-4-carboxylate 
(\textbf{7})}
{\vspace*{-1pt}}

From 1-bromo-4-(trifluoromethoxy)benzene (0.241 g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{7}
was obtained in 78{\%} yield (0.245~g) as a yellow oil. \tsup{1}H NMR 
(400~MHz, CDCl\tsub{3}) $\delta$ 8.00 (s, 1H), 7.44 (d, $J=8.8$~Hz,
2H), 7.35 (d, $J=7.8$~Hz, 2H), 4.17 (q, $J=7.1$~Hz,  2H), 3.75 (s, 3H),
1.19 (t, $J=7.1$~Hz, 3H). \tsup{19}F NMR (376~MHz, CDCl\tsub{3})
$\delta$\ ${-}$57.8. \tsup{13}C NMR (101~MHz, CDCl\tsub{3}) $\delta$
162.8, 149.9 (q, $J=1.9$~Hz), 144.5, 141.2, 131.7, 127.7, 120.6, 120.2
(q, $J=258.1$~Hz), 113.07, 60.0, 37.4, 14.0. HRMS calcd for
[M${+}$H]$^{+}$ C\tsub{14}H\tsub{14}N\tsub{2}O\tsub{3}F\tsub{3}
315.0951, found 315.0950.{\vspace*{-2pt}}

\subsubsection{Ethyl
5-(4-(difluoromethoxy)phenyl)-1-{\ubreak}methylpyrazole-4-carboxylate 
(\textbf{8})}
{\vspace*{-2pt}}

From 1-bromo-4-(difluoromethoxy)benzene (0.223 g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{8}
was obtained in 81{\%} yield (0.240~g) as a colorless oil. \tsup{1}H
NMR (400~MHz, CDCl\tsub{3}) $\delta$ 8.01 (s, 1H), 7.42 (d, $J=8.7$~Hz,
2H), 7.26 (d, $J=8.7$~Hz, 2H), 6.61 (t, $J=73.4$~Hz, 1H), 4.19 (q,
$J=7.1$~Hz, 2H), 3.76 (s, 3H), 1.22 (t, $J=7.1$~Hz,  4H). \tsup{19}F
NMR (376~MHz, CDCl\tsub{3}) $\delta$\ ${-}$81.6. \tsup{13}C NMR (101~MHz,
CDCl\tsub{3}) $\delta$ 162.9, 151.9 (t, $J=3.0$~Hz), 144.8, 141.2,
131.7, 126.1, 119.2, 115.6 (t, $J=260.7$ ~Hz), 112.9, 59.9, 37.3, 14.1.
HRMS calcd for [M${+}$H]$^{+}$ 
C\tsub{14}H\tsub{15}F\tsub{2}N\tsub{2}O\tsub{3} 297.1045, found
297.1045.{\vspace*{-2pt}}

\subsubsection{Ethyl 5-(4-fluorophenyl)-1-methylpyrazole-4-carboxylate
(\textbf{9})}
{\vspace*{-2pt}}

From 1-bromo-4-fluorobenzene (0.175~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{9}
was obtained in 83{\%} yield (0.206~g) as a yellow oil. \tsup{1}H NMR
(400~MHz, CDCl\tsub{3}) $\delta$ 8.00 (s, 1H),  7.41--7.37 (m, 2H),
7.20 (t, $J=8.6$~Hz, 2H), 4.18 (q, $J=7.1$~Hz, 2H),  3.75 (s, 3H), 1.21
(t, $J=7.1$~Hz, 3H). \tsup{19}F NMR (376  MHz, CDCl\tsub{3}) $\delta$\ 
${-}$111.3. \tsup{13}C NMR (101~MHz, CDCl\tsub{3}) $\delta$ 163.3
($J=249.6$~Hz), 162.9, 144.9, 141.2, 139 (d, $J=8.5$~Hz), 125.0, 115.5
(d,~$J=22.0$~Hz), 112.9, 59.9, 37.3, 14.1. HRMS calcd for [M${+}$H]$^{+}$
C\tsub{13}H\tsub{14}N\tsub{2}O\tsub{2}F 249.1034, found 249.1033.

\subsubsection{Ethyl 5-(4-chlorophenyl)-1-methylpyrazole-4-carboxylate
(\textbf{10})~\cite{40}}

From 1-bromo-4-chlorobenzene (0.192~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{10}
was obtained in 75{\%} yield (0.199~g) as a colorless solid: mp
123--125 \textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$
8.01 (s, 1H), 7.80 (d, $J=8.4$~Hz, 2H), 7.54 (d, $J=8.4$ ~Hz, 2H), 4.17
(q, $J=7.2$~Hz, 2H), 3.76 (s, 3H), 1.20 (t, $J=7.2$ ~Hz, 3H).
\tsup{13}C NMR (101~MHz, CDCl\tsub{3}) $\delta$ 162.6, 143.8, 141.3,
133.8, 132.0, 130.9, 118.2, 113.4, 60.2, 37.5, 14.1. HRMS calcd for
[M${+}$H]$^{+}$ C\tsub{13}H\tsub{14}ClN\tsub{2}O\tsub{2}  265.0738, found
265.0738.

\subsubsection{Ethyl
5-(4-(\textit{tert}-butyl)phenyl)-1-{\ubreak}methylpyrazole-4-carboxylate
(\textbf{11})}

From 1-bromo-4-(\textit{tert}-butyl)benzene (0.213~g, 1~mmol) and ethyl
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{11}
was obtained in 23{\%} yield (0.066~g) as a colorless oil.  \tsup{1}H
NMR (400~MHz, CDCl\tsub{3}) $\delta$ 8.00 (s, 1H), 7.51 (d, $J=8.4$~Hz,
2H), 7.33 (d, $J=8.4$~Hz, 2H), 4.18 (q, $J=7.1$~Hz,  2H), 3.77 (s, 3H),
1.39 (s, 9H), 1.20 (t, $J=7.1$~Hz, 3H). \tsup{13}C NMR (75~MHz,
CDCl\tsub{3}) $\delta$ 163.1, 152.4, 146.2, 141.1, 129.6, 125.9, 125.2,
112.5, 59.8, 37.4, 34.8, 31.3, 14.1. HRMS calcd for [M${+}$H]$^{+}$
C\tsub{17}H\tsub{23}N\tsub{2}O\tsub{2} 287.1754, found 287.1753.

\subsubsection{Ethyl 5-(3-cyanophenyl)-1-methylpyrazole-4-carboxylate
(\textbf{12})}

From 3-bromobenzonitrile (0.182~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{12}
was obtained in 81{\%} yield (0.207~g) as a yellow solid: mp 137--139 
\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$ 8.02 (s,
1H), 7.80 (ddd, $J=6.5$, 2.5, 1.6~Hz, 1H), 7.72 (s, 1H), 7.68--7.61 (m,
2H), 4.18 (q, $J=7.1$~Hz, 2H), 3.77 (s, 3H), 1.21 (t, $J=7.1$~Hz, 3H).
\tsup{13}C NMR (101~MHz, CDCl\tsub{3}) $\delta$ 162.6, 143.3,  141.3,
134.4, 133.6, 132.9, 130.6, 129.3, 118.0, 113.4, 112.9, 60.1, 37.5,
14.1. HRMS calcd for [M${+}$H]$^{+}$ 
C\tsub{14}H\tsub{14}N\tsub{3}O\tsub{2} 256.1080, found 256.1080.

\subsubsection{Ethyl 5-(3-formylphenyl)-1-methylpyrazole-4-carboxylate
(\textbf{13})}

From 3-bromobenzaldehyde (0.185~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{13}
was obtained in 76{\%} yield (0.196~g) as a yellow solid: mp 94--96
\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$ 10.10 (s,
1H), 8.04--7.99 (m, 2H), 7.93 (s, 1H), 7.71--7.65 (m, 2H), 4.17 (q, 
$J=7.1$~Hz, 2H), 3.78 (s, 3H), 1.19 (t, $J=7.1$~Hz, 3H). \tsup{13}C NMR
(101~MHz, CDCl\tsub{3}) $\delta$ 191.4, 162.7, 144.4, 141.2, 136.4,
135.9, 131.1, 130.5, 130.2, 129.1, 113.2, 60.0,  37.4, 14.1. HRMS calcd
for [M${+}$H]$^{+}$  C\tsub{14}H\tsub{15}N\tsub{2}O\tsub{3} 259.1077,
found 259.1078.

\subsubsection{Ethyl
1-methyl-5-(3-(trifluoromethyl)phenyl){\ubreak}pyrazole-4-carboxylate 
(\textbf{14})}

From 1-bromo-3-(trifluoromethyl)benzene (0.225 g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231 g, 1.5~mmol), product \textbf{14}
was obtained in 80{\%} yield (0.238 g) as a yellow solid: mp 85--87
\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$ 8.03 (s,
1H), 7.78 (d, $J=8.2$~Hz, 1H), 7.68 (s, 1H), 7.65--7.60 (m, 2H),  4.17
(q, $J=7.1$~Hz, 2H), 3.77 (s, 3H), 1.16 (t, $J=7.1$~Hz, 3H). \tsup{19}F
NMR (376~MHz, CDCl\tsub{3}) $\delta$\ ${-}$62.7. \tsup{13}C NMR (101~MHz,
CDCl\tsub{3}) $\delta$ 162.7, 144.1, 141.3, 133.4, 130.8 (q, $J=32.8$
Hz), 130.0, 128.9, 127.0 (q, $J=3.8$~Hz), 126.1 (q, $J=3.7$~Hz), 123.8
(q, $J=272.5$~Hz), 113.3, 60.1, 37.4, 14.0. HRMS calcd for
[M${+}$H]$^{+}$  C\tsub{14}H\tsub{14}N\tsub{2}O\tsub{2}F\tsub{3}
299.1002, found 299.1001.

\subsubsection{Ethyl 5-(3-fluorophenyl)-1-methylpyrazole-4-carboxylate
(\textbf{15})}

From 1-bromo-3-fluorobenzene (0.175~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{15}
was obtained in 77{\%} yield (0.191~g) as a colorless solid: mp 79--81
\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$ 8.01 (s,
1H), 7.51--7.45 (m, 1H), 7.23--7.12 (m, 3H), 4.19 (q, $J=7.1$~Hz, 2H),
3.76 (s, 3H), 1.20 (t, $J=7.1$~Hz, 3H). \tsup{19}F NMR (376~MHz,
CDCl\tsub{3}) $\delta$\ ${-}$112.5. \tsup{13}C NMR (101~MHz, CDCl\tsub{3})
$\delta$ 162.8, 162.2 (d, $J=247.3$~Hz), 144.5, 141.2, 131.1 (d,
$J=8.3$~Hz), 129.9 (d, $J=8.3$~Hz), 125.7 (d,  $J=3.2$~Hz), 117.2 (d,
$J=22.6$~Hz), 116.4 (d, $J=20.9$~Hz), 113.1, 59.9, 37.4, 14.1. HRMS
calcd  for [M${+}$H]$^{+}$  C\tsub{13}H\tsub{14}N\tsub{2}O\tsub{2}F
249.1034, found\break 249.1033.

\subsubsection{Ethyl 5-(3-chlorophenyl)-1-methylpyrazole-4-carboxylate 
(\textbf{16})}

From 1-bromo-3-chlorobenzene (0.192~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{16}
was obtained in 81{\%} yield (0.214~g) as a colorless oil. \tsup{1}H
NMR (400~MHz, CDCl\tsub{3}) $\delta$ 8.01 (s, 1H),  7.52--7.39 (m, 4H),
4.17 (q, $J=7.1$~Hz, 2H), 3.76 (s, 3H), 1.21 (t, $J=7.1$~Hz, 3H).
\tsup{13}C NMR (101~MHz, CDCl\tsub{3}) $\delta$ 162.8, 144.3, 141.2,
134.2, 130.8, 130.1, 129.6, 129.5, 128.2, 113.1, 60.00, 37.4, 14.1.
HRMS calcd for [M${+}$H]$^{+}$  C\tsub{13}H\tsub{14}ClN\tsub{2}O\tsub{2}
265.0738, found 265.0738.

\subsubsection{Ethyl 5-(3-methoxyphenyl)-1-methylpyrazole-4-carboxylate
(\textbf{17})}

From 1-bromo-3-methoxybenzene (0.187~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{17}
was obtained in 66{\%} yield (0.172~g) as a yellow solid: mp 87--89
\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$ 7.99 (s,
1H), 7.40 (dd, $J=8.4$, 7.5~Hz, 1H), 7.02 (ddd, $J=8.4$, 2.6, 1.0~Hz,
1H), 6.95 (dt, $J=7.5$, 1.2~Hz, 1H), 6.92 (dd, $J=2.6$, 1.5~Hz, 1H),
4.17 (q, $J=7.1$~Hz, 2H), 3.85 (s, 3H), 3.75 (s, 3H), 1.19 (t, $J=7.1$
Hz, 3H). \tsup{13}C NMR (75~MHz, CDCl\tsub{3}) $\delta$  162.9, 159.3,
145.7, 141.1, 130.3, 129.4, 122.2, 115.7, 114.8, 112.8, 59.8, 55.3,
37.4, 14.1. HRMS calcd for [M${+}$H]$^{+}$ 
C\tsub{14}H\tsub{17}N\tsub{2}O\tsub{3} 261.1234, found\break 261.1232.

\subsubsection{Ethyl 5-(2-cyanophenyl)-1-methylpyrazole-4-carboxylate
(\textbf{18})}

From 2-bromobenzonitrile (0.182~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{18}
was obtained in 73{\%} yield (0.186~g) as a yellow solid: mp 86--88
\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$ 8.05 (s,
1H), 7.85 (dd, $J=7.8$, 1.4~Hz, 1H), 7.75 (td, $J=7.7$, 1.4~Hz, 1H),
7.63 (td, $J=7.7$, 1.4~Hz, 1H), 7.48 (dd, $J=7.8$, 1.3~Hz, 1H), 4.18
(q, $J=7.1$~Hz, 2H), 3.77 (s, 3H), 1.19 (t, $J=7.1$~Hz, 3H). \tsup{13}C
NMR (101~MHz, CDCl\tsub{3}) $\delta$ 162.4, 141.7, 141.2, 133.1, 133.0,
132.6, 131.2, 129.9, 116.9, 114.4, 114.1, 60.1, 37.3, 14.0. HRMS calcd
for [M${+}$H]$^{+}$  C\tsub{14}H\tsub{14}N\tsub{3}O\tsub{2} 256.1080,
found 256.1083.

\subsubsection{Ethyl 
5-(3,5-bis(trifluoromethyl)phenyl)-1-{\ubreak}methylpyrazole-4-carboxylate 
(\textbf{19})}

From 1-bromo-3,5-bis(trifluoromethyl)benzene (0.293~g, 1~mmol) and
ethyl 1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product
\textbf{19} was obtained in 83{\%} yield (0.304~g) as a colorless
solid: mp 119--121 \textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3})
$\delta$ 8.06 (s, 1H), 8.03 (s, 1H), 7.89 (s, 2H), 4.18 (q, $J=7.2$~Hz,
2H), 3.80 (s, 3H), 1.16 (t, $J=7.2$~Hz, 3H). \tsup{19}F NMR (376~MHz,
CDCl\tsub{3}) $\delta$\ ${-}$62.9. \tsup{13}C NMR (101~MHz, CDCl\tsub{3})
$\delta$ 162.3, 142.3, 141.5, 131.9 (q, $J=34.0$~Hz), 131.4, 130.5 (q,
$J=3.7$~Hz), 123.2 (m), 122.9 (q,~$J=273.1$~Hz), 113.9, 60.3, 37.5,
13.9. HRMS calcd for [M${+}$H]$^{+}$ 
C\tsub{15}H\tsub{13}F\tsub{6}N\tsub{2}O\tsub{2} 367.0876, found\break
367.0876.

\subsubsection{Ethyl
5-(3,5-difluorophenyl)-1-{\ubreak}methylpyrazole-4-carboxylate 
(\textbf{20})}

From 1-bromo-3,5-difluorobenzene (0.193~g, 1~mmol) and ethyl 
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{20}
was  obtained in 78{\%} yield (0.208~g) as a colorless solid: mp
110--112  \textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$
8.00 (s, 1H), 6.98--6.92 (m, 3H), 4.19 (q, $J=7.1$~Hz, 2H), 3.77  (s,
3H), 1.22 (t, $J=7.1$~Hz, 3H). \tsup{19}F NMR (376~MHz,  CDCl\tsub{3})
$\delta$\ ${-}$108.9. \tsup{13}C NMR (75  MHz, CDCl\tsub{3}) $\delta$
162.7 (dd, $J=249.9$, 12.8~Hz), 162.6,  143.3, 141.2, 132.0 (t, $J=8.0$
Hz), 113.3 (m), 105.0 (t, $J=24.9$~Hz),  60.1, 37.5, 14.1. HRMS calcd
for [M${+}$H]$^{+}$  C\tsub{13}H\tsub{13}F\tsub{2}N\tsub{2}O\tsub{2} 
267.0940, found 267.0940.

\subsubsection{Ethyl 1-methyl-5-(pyridin-3-yl)pyrazole-4-{\ubreak}carboxylate
(\textbf{21})}

From 3-bromopyridine (0.157~g, 1~mmol) and ethyl
1-methylpyrazole-4-carboxylate (0.231~g, 1.5~mmol), product \textbf{21}
was obtained in 74{\%} yield (0.171~g) as a yellow solid: mp
109--111~\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$
8.74 (dd, $J=4.9$, 1.7~Hz, 1H), 8.67--8.62 (m, 1H), 8.05 (s, 1H),
7.80.7.74 (m, 1H), 7.46 (ddd, $J=7.9$, 4.9, 0.9~Hz, 1H), 4.18 (q,
$J=7.2$~Hz, 2H), 3.80 (s, 3H), 1.20 (t, $J=7.2$~Hz, 3H). \tsup{13}C NMR
(101~MHz, CDCl\tsub{3}) $\delta$ 162.7, 150.4, 150.3, 142.5, 141.4,
137.7, 125.4, 123.0, 113.7, 60.1, 37.5, 14.1. HRMS calcd for
[M${+}$H]$^{+}$  C\tsub{12}H\tsub{14}N\tsub{3}O\tsub{2} 232.1080, found
232.1079.

\subsubsection{Ethyl 1-methyl-5-(pyridin-4-yl)pyrazole-4-{\ubreak}carboxylate
(\textbf{22})}

From 4-bromopyridine (0.157 g, 1~mmol) and ethyl
1-methylpyrazole-4-carboxylate (0.231 g, 1.5~mmol), product \textbf{22}
was obtained in 71{\%} yield (0.164~g) as a colorless solid: mp
97--99~\textdegree C. \tsup{1}H NMR (400~MHz, CDCl\tsub{3}) $\delta$
8.79 (d, $J=6.0$~Hz, 2H), 8.03 (s, 1H), 7.35 (d,  $J=6.0$~Hz, 2H), 4.19
(q, $J=7.1$~Hz, 2H), 3.78 (s, 3H), 1.21 (t,  $J=7.1$~Hz, 3H).
\tsup{13}C NMR (101~MHz, CDCl\tsub{3}) $\delta$ 162.5, 149.9, 143.0,
141.3, 137.3, 124.6, 113.4, 60.2, 37.5, 14.1. HRMS calcd for
[M${+}$H]$^{+}$ C\tsub{12}H\tsub{14}N\tsub{3}O\tsub{2} 232.1080, found\break
232.1080.

\subsubsection{1-Methyl-5-(4-(trifluoromethyl)phenyl){\ubreak}pyrazole
(\textbf{23})~\cite{23}}

A mixture of \textbf{1} (0.149~g, 0.5~mmol) and 2 N aqueous NaOH (1~mL,
2~mmol) in DMA (1~mL) was stirred at 100~\textdegree C for 1~h. After
cooling, the mixture was acidified by H\tsub{2}SO\tsub{4} (0.25~mL, 
5~mmol) and stirred at 150~\textdegree C for 10~h. The mixture was
basicified by 2 N aqueous NaOH and extracted with EtOAc three times.
The combined organic layers were dried over MgSO\tsub{4}, and the
solvent was evaporated under reduced pressure to yield \textbf{23}
(0.86~g, 76{\%}) as a colorless oil. \tsup{1}H NMR (400~MHz,
CDCl\tsub{3}) $\delta$ 7.75 (d, $J=7.8$~Hz, 2H), 7.57 (d, $J=7.8$~Hz,
2H), 7.56 (dd, $J=2.0$~Hz,  1H), 6.39 (d, $J=2.0$~Hz, 1H), 3.94 (s,
3H). \tsup{19}F NMR (376~MHz, CDCl\tsub{3}) $\delta$\ ${-}$62.7.
\tsup{13}C NMR (101~MHz, CDCl\tsub{3}) $\delta$ 142.1, 138.8, 134.3,
130.5 (q, $J=32.7$~Hz), 129.0, 125.7 (q, $J=3.8$~Hz), 124.0 (q, 
$J=272.3$~Hz), 106.7, 37.6.

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.

\section*{Acknowledgment}

We are grateful to the Scientific Ministry of Higher Education and
Research of Tunisia for providing financial support to AR.

\back{}

\section*{Supplementary data}

Supporting information for this article is available on the journal's
website under \printDOI\ or from the author.  

\CDRsupplementaryTwotypes{supplementary-material}{\cdrattach{crchim-403-suppl.pdf}}

\printbibliography
\refinput{crchim20250195-reference.tex}

\end{document}
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