Synthesis of 1,5-disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxamides

Article abstract of DOI:10.1016/j.tet.2014.11.034

1,5-Disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxamides functionalized at positions 1, 5, and 7 were prepared in six straightforward steps from cheap, commercially available dialkyl acetone-1,3-dicarboxylate. Due to the instability of methyl 1-benzyl-substituted pyrazolo[4,3-c]pyridine-7-carboxylates under basic hydrolytic conditions (LiOH/H₂O), a detour via the corresponding benzyl esters was introduced to deliver the final 1-benzyl-substituted-bicyclic carboxamides in seven steps. The designed synthetic route is suitable for the construction of a larger library of compounds. All the key compounds have been characterized by NMR spectroscopic techniques and X-ray analysis.

Full text of DOI:10.1016/j.tet.2014.11.034

Accepted Manuscript
Synthesis of 1,5-disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-
carboxamides
Uroš Grošelj , Eva Pušavec , Amalija Golobič , Georg Dahmann , Branko Stanovnik ,
Jurij Svete
PII:
S0040-4020(14)01606-8
10.1016/j.tet.2014.11.034
TET 26183
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 September 2014
Revised Date: 28 October 2014
Accepted Date: 10 November 2014
Please cite this article as: Grošelj U, Pušavec E, Golobič A, Dahmann G, Stanovnik B, Svete J,
Synthesis of 1,5-disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxamides,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.11.034.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of 1,5-disubstituted-4-oxo-4,5-
dihydro-1H-pyrazolo[4,3-c]pyridine-7-
carboxamides
Uroš Grošelja, , Eva Pušaveca, Amalija Golobiča, Georg Dahmannb, Branko Stanovnika, and Jurij Svetea
a)University of Ljubljana, Faculty of Chemistry and Chemical Technology, Aškerčeva cesta 5, P.O. Box 537, SI-
1000 Ljubljana, Slovenia
b)Medicinal Chemistry, Boehringer-Ingelheim Pharma GmbH&Co. KG, 88397 Biberach, Germany

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Synthesis of 1,5-disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-
c]pyridine-7-carboxamides
Uroš Grošelja, , Eva Pušaveca, Amalija Golobiča, Georg Dahmannb, Branko Stanovnika, and
Jurij Svetea
a)University of Ljubljana, Faculty of Chemistry and Chemical Technology, Aškerčeva cesta 5,
P.O. Box 537, SI-1000 Ljubljana, Slovenia
b)Medicinal Chemistry, Boehringer-Ingelheim Pharma GmbH&Co. KG, 88397 Biberach,
Germany
Keywords: pyrazolo[4,3-c]pyridine; enaminone methodology; cyclisation; amidation;
bis(pentafluorophenyl) carbonate (BPC); heterocycles
ABSTRACT
1,5-Disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-
carboxamides functionalized at positions 1, 5, and 7 were prepared in six straightforward
steps from cheap, commercially available dialkyl acetone-1,3-dicarboxylate. Due to the
instability of methyl 1-benzyl-substituted-pyrazolo[4,3-c]pyridine-7-carboxylates under basic
hydrolytic conditions (LiOH/H2O), a detour via the corresponding benzyl esters was
introduced to deliver the final 1-benzyl-substituted-bicyclic carboxamides in seven steps. The
designed synthetic route is suitable for the construction of a larger library of compounds. All
the key compounds have been characterized by NMR spectroscopic techniques and X-ray
analysis.
Introduction
Pyrazolo[4,3-c]pyridine derivatives exhibit various biological activities. 4,5,6,7-
Tetrahydro-1H-pyrazolo[4,3-c]pyridines are inhibitors of Mycobacterium tuberculosis
Corresponding author. Tel.: +386 1 2419 100; Fax: +386 1 2419 220; e-mail: uros.groselj@fkkt.uni-lj.si (U. Grošelj).

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pantothenate synthetase1, they exhibit in vitro antifungal and antibacterial activities2, are γ-
secretase inhibitors3, potent Catepsin S inhibitors4, and exhibit antihypertensive activity5. 3-
Aminopyrazolo[4,3-c]pyridin-4(5H)-ones show various kinase inhibitory activities.6,7,8
A literature search (SciFinder) for the preparation of pyrazolo[4,3-c]pyridines and their
partially saturated analogues revealed a large spectrum of approaches. Most of them are
summarized below.
A
tandem aza-Wittig/electrocyclic ring-closure reaction of
iminophosphorane, derived from 5-formylpyrazole derivatives, with isocyanates, ketones, and
aldehydes gave a variety of substituted pyrazolo[4,3-c]pyridines.9 1H-Pyrazolo[4,3-
c]pyridines were obtained from bis-acetylenic-N-benzoylhydrazones using aqueous
ammonia.10 Cyclisation of 4-alkoxy-8, 4-hydroxy-11, 4-(alkyl)amino-12,13, and 4-chloro-
piridine derivatives7,14,15,16,17,18 with acetyl, benzoyl, or cyano group in the meta position gave
the corresponding 3-substituted pyrazolo[4,3-c]pyridines. 3-(Phenylsulphonyloxy)pyrido[4,3-
c]pyrimidine-2,4-dione ring opens with sodium methoxide and rearranges to
hydrazinopyridine ester, which in refluxing acid yields 1H-pyrazolo[4,3-c]pyridin-3-one.19
One-pot multi-component reaction of 5-chloro-pyrazole-4-carbaldehyde, alkyne, and tert-
butylamine in the presence of PdCl2(PPh3)2 gave pyrazolo[4,3-c]pyridines.20 Treatment of N-
(3-methylpyridin-4-yl)acetamide derivative with isoamyl nitrite furnished in low yields the
corresponding pyrazolo[4,3-c]pyridine.21 On the other hand, cyclisation of diazonium salts,
generated from 5-alkyl-4-amino-2-(trifluoromethyl)pyridines, afforded trifluoromethylated
1H-pyrazolo[4,3-c]pyridines.22 α,β-Unsaturated nitrile derivatives were first reacted with S-
methylisothiourea and then with hydrazines to give various pyrazolo[4,3-c]pyridines and
pyrazolo[4,3-c]pyridin-4(5H)-ones.23 3-Amino-pyrazolo[4,3-c]pyridin-4(5H)-ones have been
prepared by condensation of 3-cyano-4-thiomethyl-2-pyridones, prepared from ketene
dithioacetals and 2-cyanoacetamides, with various hydrazines.6,24,25,26 In a similar way 3-
amino-pyrazolo[4,3-c]pyridin-6-ones have been prepared.27 Reaction of 5-aryl-2-
phenylpyrazolo[1,5-c]pyrimidine-7(6H)-thiones
with
potassium
cyclisation
hydroxide
yields
pyrazolo[4,3-c]pyridin-4(5H)-ones.28
Two-step
of 5-alkynyl-4-
(alkoxycarbonyl)pyrazoles with hydroxylamine or hydrazine furnished 5-hydroxy- and 5-
amino-pyrazolo[4,3-c]pyridin-4-ones, respectively.29,30 6-Amino-pyrazolo[4,3-c]pyridin-
4(5H)-one derivatives have been prepared from methyl 3-cyanomethyl-pyrazole-4-
carboxylates with ammonia.31,32 4-Hydrazinylisoxazolo[5,4-b]pyridine derivatives have been
transformed into pyrazolo[4,3-c]pyridin-4(5H)-ones with Mo(CO)633,34, by catalytic
hydrogenation35, or photochemically35. 4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridines were
synthesized from piperidin-4-one via 1,3-dicarbonyl intermediate followed by cyclisation

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with hydrazine.1,2,3,4,5 Instead of 1,3-dicarbonyl intermediates, piperidine derived
enaminoketones can be used.36,37 Acid or base treatment of 4-cyano-5-cyanomethyl-pyrazole
derivative leads to 4,5,6,7-tetrahydro-4,6-dioxopyrazolo[4,3-c]pyridines.38,39
The aim of this work was the preparation of 1,5-disubstituted-4-oxo-4,5-dihydro-1H-
pyrazolo[4,3-c]pyridine-7-carboxamides 1 in a synthesis which enables the easy introduction
of three different substituents at positions 1, 5, and 7. An efficient synthesis of such a template
would enable the preparation of a large library of compounds, suitable for screening for
various biological activities. The results of this study are reported herein (Figure 1).
Figure 1. Targeted library template 1.
Results and Discussion
The synthesis of 1,5-disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-
carboxamides 1 commenced from cheap, commercially available dimethyl acetone-1,3-
dicarboxylate (2a). Dialkyl acetone-1,3-dicarboxylates are very frequently used starting
materials for the construction of a broad spectrum of heterocyclic systems.40,41 4-
Hydroxypyridones 5a-c were prepared in a one-pot two step synthesis starting from 2a,
following the literature procedures.42,43 Treatment of 2a with N,N-dimethylformamide
dimethyl acetal (DMFDMA) in anhydrous MeOH at room temperature gave in situ
enaminone 3a42 in full conversion. The addition of primary amines 4a-c gave the
corresponding pyridones 5a-c in 20-60% yields. Reaction of 5a-c with excess DMFDMA in
refluxing toluene gave the respective crude enaminone intermediates 6a-c, which were
subsequently treated with monosubstituted hydrazines 7. We expected these reactions to yield
the corresponding cyclisation products, pyrazolo[4,3-c]pyridines 9. Much to our surprise, this
was not the case as reacting 6a-c with hydrazine monohydrate (7a) or phenylhydrazine
hydrochloride (7b) in MeOH or nPrOH resulted only in substitution of the dimethylamino

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group to give the enehydrazines 8a-c (R2 = H) and 8d-f (R2 = Ph). All efforts (acid and base
catalysis, elevated temperature, etc.) to cyclize intermediates 8a-f into 9a-f failed. Similarly,
the treatment of enaminone 6c with the 1,3-dinucleophile methyl 5-amino-1H-pyrazole-3-
carboxylate (10)44 stopped at the dimethylamino-substitution level, giving 11 as a mixture of
the (E)-, and the (Z)-geometrical isomers in 40% yield. Therefore, the first approach towards
pyrazolo[4,3-c]pyridine-7-carboxamides 1 via 4-hydroxypyridin-2-ones 5 failed (Scheme 1,
Table 1).
Scheme 1. First attempt to prepare methyl 1,5-disubstituted-4-oxo-4,5-dihydro-1H-
pyrazolo[4,3-c]pyridine-7-carboxylates 1.

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Table 1. Yields of isolated products 5, 6, 8, and 9.
Yield (%)
Compound
R1
R2
5
6
8
9
5a45, 6a
5b43, 6b
5c43, 6c
8a, 9a
8b, 9b
8c, 9c
Bn
20
100
100
100
4-MeO-C6H4
CH2-CH2-OMe
Bn
6043
4643
H
29
68
59
62
74
72
-
-
-
-
-
-
4-MeO-C6H4
CH2-CH2-OMe
Bn
H
H
8d, 9d
8e, 9e
Ph
Ph
Ph
4-MeO-C6H4
CH2-CH2-OMe
8f, 9f
The second strategy towards pyrazolo[4,3-c]pyridine-7-carboxamides 1 was based on the
initial preparation of the substituted pyrazole ring. Following the literature procedures,42 ethyl
1-substituted-5-(2-ethoxy-2-oxoethyl)-1H-pyrazole-4-carboxylates 13a and 13b were
prepared by a one-pot two step synthesis from diethyl acetone-1,3-dicarboxylate (2b),
DMFDMA, using methylhydrazine (7c) and benzylhydrazine dihydrochloride (7d),
respectively. First, 2b was reacted with DMFDMA, followed by the addition of hydrazine 7c
as the free base. The BnNHNH2·2HCl (7d) was separately neutralized with tBuOK in
anhydrous EtOH (cf. Experimental part) and then added to the in situ formed enaminone 3b
to afford the desired pyrazoles 13a and 13b,42 together with the pyridone by-products 14a and
14b, respectively. Pyrazoles 13 were then separated from the pyridones 14 by column
chromatography (CC). Interestingly, reaction between 3b and dihydrochloride 7d (without
prior neutralization) furnished the pyrazole 13b in 15% yield together with 1-benzyl-3-(3-
ethoxy-3-oxo-1-phenylprop-1-en-2-yl)-1H-pyrazole-4-carboxylate (15) in 17% yield. The
formation of both pyrazoles 13 and pyridones 14 can be explained by the initial substitution of
the dimethylamino group by the unsubstituted part of hydrazine 7, thus giving the
enehydrazine intermediate 12. Subsequent cyclocondensation via the N(2) nucleophilic
position yields the pyrazoles 13 (path A), whereas reaction via the N(1) nucleophilic position
furnishes pyridones 14 (path B). Literature reports the reaction of ethoxymethylene analogue
of 3a with hydrazine 7a, which resulted primarily in the formation of the corresponding
pyridone.31 The formation of the product 15 could be explained by condensation of the

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ACCEPTED MANUSCRIPT
regioisomer 13'b with benzaldehyde, which, in turn, could be formed by aerobic oxidation of
benzylhydrazine (7d) (Scheme 2).
Scheme 2. Synthesis of pyrazoles 13, 15, and pyridones 14.
The structures of compounds 14a, 14b, and 15 were confirmed by single crystal X-ray
analysis (Figures 2-4).
Figure 2. Single crystal X-ray analysis of compound 14a.

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Figure 3. Single crystal X-ray analysis of compound 14b.
Figure 4. Single crystal X-ray analysis of compound 15.
Next, ethyl 2-(1-substituted-1H-pyrazol-5-yl)acetates 13a and 13b were transformed by
treatment with tert-butoxy bis(dimethylamino)methane (TBDMAM) in refluxing toluene into
the corresponding enaminones 16a and 16b in 64% and 51% yield, respectively. Nucleophilic
substitution of the dimethylamino group of 16a and 16b with excess methylamine (4d) and
benzylamine (4a) in refluxing AcOH yielded products 17a-d in 78-91% yield as mixtures of

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ACCEPTED MANUSCRIPT
the (E)- and the (Z)-isomers. Apparently, the isomer composition of enamines 17 did not
affect the following cyclisation, probably due to the configurational lability of the exocyclic
double bond.46,47 Cyclisation of 17a-d in anhydrous THF in the presence of catalytic amounts
of tBuOK smoothly furnished the corresponding ethyl pyrazolo[4,3-c]pyridine-7-carboxylates
18a-d in 76-89% yields. Hydrolysis of the 1-methyl substituted esters 18a and 18b with
excess LiOH in a mixture of H2O, MeOH, and THF delivered the desired carboxylic acids
19a and 19b in 80% and 69% yield, respectively. On the other hand, hydrolysis of the 1-
benzyl substituted pyrazolopyridines 18c and 18d led to the decomposition of the bicyclic
system giving a mixture of products (Scheme 3, Table 2).
Scheme 3. Synthesis of carboxylic acids 19a and 19b from pyrazoles 13a and 13b.
Table 2. Yields of isolated products 17-19.
Yield (%)
Compound
R1
R2
17
18
19
80
17a, 18a, 19a
17b, 18b, 19b
17c, 18c, 19c
17d, 18d, 19d
Me
Bn
Me
Bn
Me
Me
Bn
Bn
78
88
89
91
83
89
76
77
69
a)
a)
a) Decomposition took place under basic hydrolytic conditions.
The structure of compound 18b was confirmed by single crystal X-ray analysis (Figure 5).

10
ACCEPTED MANUSCRIPT
Figure 5. Single crystal X-ray analysis of compound 18b.
For the preparation of 1-benzyl substituted pyrazolo[4,3-c]pyridine-7-carboxamides, a
modification of the existing methodology was needed. Most importantly, catalytic
hydrogenation (Pd-C) of 1,5-dibenzyl-substituted bicycle 18d resulted in complete recovery
of the starting material (Scheme 4, top). Therefore, transesterification of dimethyl acetone-1,3-
dicarboxylate (2a) with BnOH was used for the preparation of dibenzyl acetone-1,3-
dicarboxylate (2c) following the literature procedure.48 Reaction of 2c with DMFDMA gave
the enaminone 3c in 51% isolated yields. A short optimization of the reaction between
BnNHNH2·2HCl (7d) and 3c revealed that the best conversion into the desired pyrazole 20
(70% conversion) is achieved by treating the solution/suspension of BnNHNH2·2HCl (7d) in
AcOH with two equivalents of NaOAc, followed by the addition of 3c. In this manner, the
pyrazole 20 was prepared in 45% yield, while the regioisomer 21 was also isolated in 1%
yield. Reaction of 20 with TBDMAM gave the enaminone 22 in 65% yield. Next, acid
catalyzed treatment of 22 with excess propylamine (4e) or aniline (4f) in refluxing AcOH
furnished the respective dimethylamine substitution products 23a and 23b in full conversion.
In the reaction with aniline (4f), N-phenylacetamide was observed as the side-product. Base-
catalyzed (10 mol% tBuOK) cyclisation of 23a and 23b in anhydrous THF yielded bicycles
24a and 24b in 73% and 59% yield, respectively. Product 24a was isolated as a 1:1 solvate
with BnOH. Finally, catalytic hydrogenation (Pd-C) of the benzyl esters 24a and 24b gave the
carboxylic acids 25a and 25b in 88% and 57% yield, respectively (Scheme 4, bottom).

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Bn
O
MeOH
Pd-C 10%
N
r.t., 1 h, 50 psi
complete recovery of the
starting material
N
CO2Et
N
Bn
18d
O
DMFDMA
EtOH, r.t., 2 h
BnOH
180 °C, 4 h
O
O
BnO2C
CO2Bn
MeO2C
CO2Me
BnO2C
CO2Bn
Ref. 48
NMe2
2a
2c
3c
7d
BnNHNH2•2HCl (
AcOH, NaOAc
r.t. 90 °C
)
CO2Bn
CO2Bn
CO2Bn
tBuOCH(NMe2)2
NMe2
PhMe,
and
CO2Bn
N
N
N
N
N
CO2Bn
CO2Bn
N
Bn
Bn
Bn
21
20
22
R1
R1
O
O
MeOH
Pd-C 10%
r.t., 1 h, 50 psi
CO2Bn
R1NH2
AcOH,
4e f
( , )
tBuOK, THF
Ar, r.t., 20 min
N
N
NHR1
N
N
CO2Bn
N
N
CO2Bn
CO2H
N
N
Bn
Bn
Bn
23a; R1 = nPr
23b; R1 = Ph
24a; R1 = nPr
24b; R1 = Ph
25a; R1 = nPr
25b; R1 = Ph
Scheme 4. Synthesis of carboxylic acids 25 from dibenzyl acetone-1,3-dicarboxylate (2c).
A final modification of the developed methodology for the preparation of pyrazolo[4,3-
c]pyridine-7-carboxamides included the late stage DBU catalyzed transesterification of ethyl
1-benzyl-5-substituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylates 18c and
18d with excess BnOH. The corresponding benzyl esters 26a and 26b were prepared in 91%
and 95% yield, respectively. Catalytic hydrogenation (Pd-C) of 26a and 26b gave the
carboxylic acids 27a and 27b in 60% and 83% yield, respectively. The synthesis concluded
with amidation of carboxylic acids in a one-pot two step synthesis in DMF, thus introducing
variable substituents at position 7 of the pyrazolo[4,3-c]pyridine skeleton. Carboxylic acids
19a,b, 25a,b, and 27a,b were first transformed in situ into the pentafluorophenyl esters 28
using bis(pentafluorophenyl) carbonate49 (BPC) as the activating agent in the presence of one
equivalent of Et3N, followed by the addition of the desired amine 4a,g-l to form the final
amides 1a-j. Only amidation of 25a with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl amine
(4m)50 did not take place, instead the corresponding active ester 29 was isolated in 71% yield

12
ACCEPTED MANUSCRIPT
(Scheme 5, Table 3). The structure of amide 1g was confirmed by single crystal X-ray
analysis (Figure 6).
Scheme 5. Synthesis of carboxylic acids 27a,b, amides 1a-j, and active ester 29.

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Table 3. Yields of isolated amides 1a-j.
Acid
19a
Amine
Me2NH
nBuNH2
Product R1
R2
Me
Bn
Bn
R3
Me
nBu
R4 Yield (%)
Me
Me
Me
Me
H
97
67
70
1a
1b
1c
19b
19b
H
L-Phe-OMe·HCl
L-Phe-OMe·HCl
Me
Me
Bn
Bn
Bn
nPr
H
H
H
30
35
91
19b
19b
25a
1d
1e
1f
Bn
Bn
Bn
Bn
Ph
Me
Bn
Bn
H
H
H
H
89
82
84
73
25b
27a
27b
27b
1g
1h
1i
nBuNH2
nBu
BnNH2
Bn
1j
Figure 6. Single crystal X-ray analysis of compound 1g.

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The structures of novel compounds 3c, 6a-c, 8a-f, 11, 14a,b, 15, 16a,b, 17a-d, 18a-d,
19a,b, 20-22, 23a,b-27a,b, 1a-j, and 29 were determined by spectroscopic methods (IR,
NMR spectroscopy (1H- and 13C-NMR, DEPT 90 and 135, COSY, HSQC, HMBC and
NOESY experiments), and MS-HRMS) and by elemental analyses for C, H, and N.
Compounds 3c, 6a-c, 16a,b, 17a-d, 19a,b, 21, 22, 23a,b, 24a,b, 25b, 1a,c,d,e,g, and 29 were
not prepared in analytically pure form. Their identities were confirmed by MS-HRMS and
13C-NMR. Identities of compounds 6a-c, 17a,c,d, and 23a,b were confirmed only by MS-
HRMS. Crude compounds 6a-c were used in the following transformation without any
purification. Due to the very low solubility of enehydrazines 8a and 8b, not all signals are
present in the respective 13C-NMR spectra.
Dimethylamino-substitution products 17a-d and 23a,b were characterized as mixtures of
the (E)- and the (Z)-geometrical isomers. In the 1H-NMR spectra, the NH-protons (vinylogous
amide) of the (Z)-isomers resonate at lower field compared to their (E)-counterparts due to the
presence of an intramolecular hydrogen bond (for details cf. Experimental part).
Conclusions
A
synthesis of 1,5-disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-
carboxamides 1 has been developed which enables the easy introduction of three different
substituents at positions 1, 5, and 7, suitable for the preparation of a large library of
compounds. Starting from cheap, commercially available dialkyl acetone-1,3-dicarboxylate
2a,b the target compounds have been prepared in six straightforward steps (Schemes 2, 3, 5).
For the preparation of 1-benzyl substituted amides, a modification of the synthetic
methodology was necessary due to the decomposition of methyl 1-benzyl-substituent-
pyrazolo[4,3-c]pyridine-7-carboxylates 18c,d under basic hydrolytic conditions (LiOH/H2O).
The introduction of the late stage transesterification enabled the synthesis of the final 1-
benzyl-substituted amides in seven steps (Schemes 4, 5). Starting from 2, the first substituent
(R2) at position 1 was introduced in the first/second step with the monosubstituted hydrazine
7, the second substituent (R1) at position 5 was embedded in the third/fourth step with the
amine 4, while the third substituent (R3/R4) at position 7 was introduced in the last step
(sixth/seventh step) via amidation with amines 4.

15
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EXPERIMENTAL
Materials and Methods
All reactions were performed under argon in dried glassware using anhydrous solvents
except when using aqueous reagents. Solvents for extractions and chromatography were of
technical grade and were distilled prior to use. Extracts were dried over technical grade
Na2SO4. Melting points were determined on a Kofler micro hot stage and on SRS OptiMelt
MPA100 - Automated Melting Point System (Stanford Research Systems, Sunnyvale,
California, United States). The NMR spectra were obtained on a Bruker Avance DPX 300 at
1
300 MHz for H and 75.5 MHz for 13C nucleus, and on a Bruker UltraShield 500 plus
1
13
(Bruker, Billerica, Massachusetts, United States) at 500 MHz for H and 126 MHz for C
nucleus, using DMSO-d6 and CDCl3 with TMS as the internal standard, as solvents. Mass
spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies,
Santa Clara, California, United States), IR spectra on a Perkin-Elmer Spectrum BX FTIR
spectrophotometer (PerkinElmer, Waltham, Massachusetts, United States). Microanalyses
were performed on a Perkin-Elmer CHN Analyzer 2400 II (PerkinElmer, Waltham,
Massachusetts, United States). Column chromatography (CC) was performed on silica gel
(Silica gel 60, particle size: 0.035-0.070 mm (Sigma-Aldrich, St. Louis, Missouri, United
States)). Catalytic hydrogenation was performed on a Parr Pressure Reaction Hydrogenation
Apparatus (Moline, Illinois, United States). Medium-pressure liquid chromatography (MPLC)
was performed with Büchi Flash Chromatography System (BUCHI Labortechnik AG, Flawil,
Switzerland) (Büchi Fraction Collector C-660, Büchi Pump Module C-605, Büchi Control
Unit C-620) on silica gel (LiChrosphere® Si 60 (12 µm) and/or LiChroprep® Si 60 (15-25
µm) (Merck, KGaA, Darmstadt, Germany)); column dimensions (wet filled): 22×460 mm,
36×460 mm and 40×460 mm; backpressure: 10–20 Bar; detection: UV 254 nm.
Dimethyl acetone-1,3-dicarboxylate (2a), diethyl acetone-1,3-dicarboxylate (2b), N,N-
dimethylformamide dimethyl acetal (DMFDMA), tert-butoxy bis(dimethylamino)methane
(TBDMAM), tBuOK, amines 4a-l, hydrazines 7a-d, nPrOH, BnOH, anhydrous DMF,
anhydrous THF, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), Pd-C, Et3N, LiOH·H2O, and
bis(pentafluoropheny) carbonate (BPC) are commercially available (Sigma-Aldrich, St. Louis,
Missouri, United States). Compounds 2c48, 5b43, 5c43, 1044, and 2,3,4,6-tetra-O-acetyl-β-
glucopyranosyl amine (4m)50 were prepared following the literature procedures.
D-

16
ACCEPTED MANUSCRIPT
Syntheses
Synthesis of dibenzyl 2-((dimethylamino)methylene)-3-oxopentanedioate (3c).
To a solution of 2c (10.5 g, 32.2 mmol) in anhydrous EtOH (40 mL) under argon DMFDMA
(4.5 mL, 32.2 mmol) was added and the resulting mixture was stirred at room temperature for
1 h. Volatile components were evaporated in vacuo and the residue was purified by column
chromatography (EtOAc/petroleum ether = 1:1). Fractions containing the product were
combined and volatile components evaporated in vacuo to give 3c. Yield: 6.24 g (51%) of red
oil; νmax 3063, 3032, 2932, 1734, 1683, 1637, 1576, 1497, 1454, 1421, 1375, 1324, 1276,
1205, 1141, 1093, 1040, 995, 914, 847, 747, 697 cm-1; δH (500 MHz, DMSO-d6) 7.85 (1 H, s,
CH), 7.41 – 7.28 (10 H, m, 2 · Ph), 5.12 (2 H, s, CH2Ph), 5.06 (2 H, s, CH2Ph), 3.74 (2 H, s,
CH2CO2Bn), 3.26 (3 H, s, NMe2), 2.73 (3 H, s, NMe2); δC (126 MHz, DMSO-d6) 187.5,
168.5, 166.8, 158.8, 136.7, 136.1, 128.41, 128.36, 128.0, 127.94, 127.87, 127.84, 99.7, 65.6,
65.0, 47.5, 47.2, 42.0; HRMS (EI): MH+, found 382.1646. [C22H24NO5]+ requires 382.1649.
Synthesis of methyl 1-benzyl-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (5a)45.
To a solution of dimethyl acetone-1,3-dicarboxylate (2a) (722 ꢀL, 4.8 mmol) in anhydrous
MeOH (10 mL) DMFDMA (735 ꢀL, 5.2 mmol) was added and the resulting mixture was
stirred at room temperature for 2 h to form in situ enaminone 3a. Then BnNH2·HCl (4a) (661
mg, 4.6 mmol) was added and the resulting mixture was stirred for additional 20 h at room
temperature and for 2 h under reflux. Volatile components were evaporated in vacuo, the
residue was suspended in CH2Cl2 (100 mL) and washed with HCl (1 M in H2O, 20 mL) and
brine (30 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile
components evaporated in vacuo. The residue was purified by column chromatography
(EtOAc/petroleum ether = 1:5). Fractions containing the product were combined and volatile
components evaporated in vacuo to give 5a. Yield: 240 mg (20%) of yellow oil; νmax 3061,
2954, 1736, 1685, 1656, 1555, 1469, 1318, 1215, 1028, 835, 782, 740, 695, 661 cm-1; δH (500
MHz, CDCl3) 10.48 (1 H, br s, OH), 8.11 (1 H, s, CH), 7.38 – 7.29 (5 H, m, Ph), 5.99 (1 H, s,
CH), 5.14 (2 H, s, CH2), 3.87 (3 H, s, CO2Me); δC (126 MHz, CDCl3) 168.2, 165.9, 163.6,
143.8, 135.8, 129.2, 128.5, 128.2, 100.1, 99.9, 52.6, 52.0; HRMS (EI): MH+, found 260.0918.
[C14H14NO4]+ requires 260.0917.
Synthesis of enaminones 6a-c – General procedure 1 (GP1).

17
ACCEPTED MANUSCRIPT
To a solution of methyl 1-substituted-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate 5a-
c (1 equivalent) in anhydrous PhMe (5 mL) under argon DMFDMA (2.50-3.25 equivalents)
was added and the resulting mixture was heated under reflux for 1-7 h. Volatile components
were evaporated in vacuo and the residue (product) was used in the following transformation
without any purification.
Methyl 1-benzyl-5-((dimethylamino)methylene)-4,6-dioxo-1,4,5,6-tetrahydropyridine-3-
carboxylate (6a).
Following GP1: Prepared from 5a (240 mg, 0.926 mmol), DMFDMA (424 ꢀL, 3.00 mmol), t
= 7 h. Yield: full conversion; δH (500 MHz, CDCl3) 8.30 (1 H, s, CH), 8.19 (1 H, s, CH), 7.34
– 7.28 (5 H, m, Ph), 5.00 (2 H, s, CH2), 3.82 (3 H, s, CO2Me), 3.47 (3 H, s, NMe), 3.36 (3 H,
s, NMe); HRMS (EI): MH+, found 315.1334. [C17H19N2O4]+ requires 315.1339.
Methyl
5-((dimethylamino)methylene)-1-(4-methoxyphenyl)-4,6-dioxo-1,4,5,6-
tetrahydropyridine-3-carboxylate (6b).
Following GP1: Prepared from 5b (273 mg, 0.992 mmol), DMFDMA (353 ꢀL, 2.50 mmol), t
= 1 h. Yield: full conversion; δH (300 MHz, CDCl3) 8.32 (1 H, s, CH), 8.22 (1 H, s, CH), 7.23
(2 H, d, J 9.0 Hz, 2H of Arl), 6.97 (2 H, d, J 9.0 Hz, 2H of Arl), 3.84 (3 H, s, OMe), 3.83 (3
H, s, OMe), 3.48 (3 H, d, J 0.3 Hz, NMe), 3.39 (3 H, d, J 0.6 Hz, NMe); HRMS (EI): MH+,
found 331.1283. [C17H19N2O5]+ requires: 331.1288.
Methyl
5-((dimethylamino)methylene)-1-(2-methoxyethyl)-4,6-dioxo-1,4,5,6-
tetrahydropyridine-3-carboxylate (6c).
Following GP1: Prepared from 5c (227 mg, 1.00 mmol), DMFDMA (353 ꢀL, 2.50 mmol), t =
3 h. Yield: full conversion; δH (500 MHz, CDCl3) 8.28 (1 H, s, CH), 8.19 (1 H, s, CH), 3.98
(2 H, t, J 5.0 Hz, 2H of CH2), 3.84 (3 H, s, CO2Me), 3.60 (2 H, t, J 5.0 Hz, 2H of CH2), 3.48
(3 H, s, NMe), 3.37 (3 H, s, NMe), 3.34 (3 H, s, CH2CH2OMe); HRMS (EI): MH+, found
283.1288. [C13H19N2O5]+ requires: 283.1288.
Synthesis of enehydrazines 8a-f – General procedure 2 (GP2).
To a solution of methyl 1-substituted-5-((dimethylamino)methylene)-4,6-dioxo-1,4,5,6-
tetrahydropyridine-3-carboxylate 6a-c (1 equivalent) in MeOH or nPrOH (10 mL)
NH2NH2·H2O (7a) or PhNHNH2·HCl (7b) (1.05 equivalents) was added and the resulting
mixture was stirred at room temperature for 24 h. The precipitate 8 was collected by filtration

18
ACCEPTED MANUSCRIPT
and washed with Et2O (20 mL). For further purification, if needed, the precipitate was re-
suspended in EtOH (5 mL), the resulting mixture was heated under reflux for 30 minutes,
cooled to room temperature, the precipitate collected by filtration, and washed with Et2O (10
mL).
Methyl
1-benzyl-5-(hydrazinylmethylene)-4,6-dioxo-1,4,5,6-tetrahydropyridine-3-
carboxylate (8a).
Following GP2: Prepared from 6a (0.464 mmol), NH2NH2·H2O (7a) (24 ꢀL, 0.487 mmol),
MeOH. Yield: 41 mg (29%) of yellow solid, m.p. 212-219 °C; [Found: C, 59.67; H, 5.00; N,
13.77. C15H15N3O4 requires C, 59.79; H, 5.02; N, 13.95%]; νmax 3316, 3183, 1718, 1619,
1526, 1464, 1440, 1378, 1321, 1190, 1103, 1026, 861, 799, 737, 699 cm-1; δH (500 MHz,
DMSO-d6) 14.07 (1 H, br s, NHNH2), 8.37 (1 H, s, CH), 8.21 (1 H, s, CH), 7.36 – 7.33 (2 H,
m, 2H of Ph), 7.29 – 7.26 (3 H, m, 3H of Ph), 6.48 (2 H, br s, NHNH2), 5.09 (2 H, s, CH2),
3.69 (3 H, s, CO2Me); δC (126 MHz, DMSO-d6) 137.4, 128.6, 127.5, 127.4, 51.3 (not all
signals are present due to very low solubility); HRMS (EI): MH+, 302.1132. [C15H16N3O4]+
requires 302.1135.
Methyl
5-(hydrazinylmethylene)-1-(4-methoxyphenyl)-4,6-dioxo-1,4,5,6-
tetrahydropyridine-3-carboxylate (8b).
Following GP2: Prepared from 6b (0.480 mmol), NH2NH2·H2O (7a) (25 ꢀL, 0.504 mmol),
MeOH. Yield: 105 mg (68%) of yellow solid, m.p. 229-231 °C; [Found: C, 56.49; H, 4.58; N,
13.00. C15H15N3O5 requires C, 56.78; H, 4.76; N, 13.24%]; νmax 3205, 1726, 1690, 1652,
1615, 1514, 1463, 1430, 1332, 1315, 1290, 1260, 1239, 1217, 1188, 1114, 1026, 928, 832,
815 cm-1; δH (500 MHz, DMSO-d6) 13.90 (1 H, br s, NHNH2), 8.24 (1 H, br s, CH), 8.02 (1
H, s, CH), 7.33 (2 H, d, J 8.8 Hz, 2H of Arl), 7.02 (2 H, d, J 8.9 Hz, 2H of Arl), 6.43 (2 H, br
s, NHNH2), 3.80 (3 H, s, CO2Me), 3.68 (3 H, s, OMe); δC (126 MHz, DMSO-d6) 158.9,
148.8, 146.9, 132.9, 128.2, 114.1, 55.5, 51.3 (not all signals are present due to very low
solubility); HRMS (EI): MH+, 318.1082. [C15H16N3O5]+ requires 318.1084.
Methyl
5-(hydrazinylmethylene)-1-(2-methoxyethyl)-4,6-dioxo-1,4,5,6-
tetrahydropyridine-3-carboxylate (8c).
Following GP2: Prepared from 6c (0.603 mmol), NH2NH2·H2O (7a) (31 ꢀL, 0.633 mmol),
nPrOH. Yield: 97 mg (59%) of yellow solid, m.p. 188-202 °C; [Found: C, 49.06; H, 5.46; N,
15.37. C11H15N3O5 requires 49.07; H, 5.62; N, 15.61%]; νmax 3315, 3232, 2894, 1713, 1663,

19
ACCEPTED MANUSCRIPT
1623, 1466, 1437, 1298, 1180, 1116, 1063, 1010, 866, 835, 797, 623 cm-1; δH (500 MHz,
DMSO-d6) 14.03 (1 H, br s, NHNH2), 8.21 (1 H, s, CH), 8.17 (1 H, s, CH), 6.49 (2 H, br s,
NHNH2), 4.03 (2 H, t, J 5.1 Hz, 2H of CH2), 3.70 (3 H, s, CO2Me), 3.51 (2 H, t, J 5.2 Hz, 2H
of CH2), 3.23 (3 H, s, CH2CH2OMe); δC (126 MHz, DMSO-d6) 172.2, 164.1, 161.7, 147.5,
105.2, 101.4, 69.7, 62.5, 58.2, 51.3, 47.8; HRMS (EI): MH+, 270.1088. [C11H16N3O5]+
requires 270.1089.
Methyl
1-benzyl-4,6-dioxo-5-((2-phenylhydrazinyl)methylene)-1,4,5,6-
tetrahydropyridine-3-carboxylate (8d).
Following GP2: Prepared from 6a (0.508 mmol), PhNHNH2·HCl (7b) (77 mg, 0.533 mmol),
MeOH. Yield: 120 mg (62%) of yellow solid, m.p. 210-216 °C; [Found: C, 66.57; H, 5.11; N,
10.96. C21H19N3O4 requires C, 66.83; H, 5.07; N, 11.13%]; νmax 3253, 3032, 1695, 1632,
1597, 1491, 1456, 1434, 1324, 1296, 1256, 1220, 1152, 1112, 981, 786, 740, 687 cm-1; δH
(500 MHz, DMSO-d6) 13.65 (1 H, s, NHNHPh), 10.59 (1 H, s, NHNHPh), 8.53 (1 H, s, CH),
8.31 (1 H, s, CH), 7.37 – 7.34 (2 H, m, 2H of Ph), 7.30 – 7.26 (5 H, m, 5H of Ph), 6.87 – 6.80
(3 H, m, 3H of Ph), 5.21 (2 H, s, CH2), 3.78 (3 H, s, CO2Me); δC (126 MHz, DMSO-d6)
163.9, 163.2, 160.6, 144.9, 143.8, 138.0, 136.9, 129.5, 128.7, 127.7, 127.6, 119.6, 111.6,
103.7, 103.0, 51.8, 51.3; HRMS (EI): MH+, 378.1441. [C21H20N3O4]+ requires 378.1448.
Methyl
1-(4-methoxyphenyl)-4,6-dioxo-5-((2-phenylhydrazinyl)methylene)-1,4,5,6-
tetrahydropyridine-3-carboxylate (8e).
Following GP2: Prepared from 6b (0.501 mmol), PhNHNH2·HCl (7b) (76 mg, 0.526 mmol),
nPrOH. Yield: 147 mg (74%) of yellow solid, m.p. 231-238 °C; [Found: 64.03; H, 4.58; N,
10.66. C21H19N3O5 requires C, 64.12; H, 4.87; N, 10.68%]; νmax 3259, 1701, 1641, 1599,
1569, 1511, 1495, 1437, 1299, 1281, 1237, 1147, 1025, 957, 831, 785, 742, 685 cm-1; δH (500
MHz, DMSO-d6) 13.75 (1 H, s, NHNHPh), 10.62 (1 H, s, NHNHPh), 8.33 (1 H, s, CH), 8.14
(1 H, s, CH), 7.39 (2 H, d, J 8.8 Hz, 2H of Arl), 7.29 (2 H, t, J 7.8 Hz, 2H of Ph), 7.06 (2 H, d,
J 8.9 Hz, 2H of Arl), 6.87 (2 H, d, J 7.9 Hz, 2H of Ph), 6.83 (1 H, t, J 7.3 Hz, 1H of Ph), 3.82
(3 H, s, CO2Me), 3.77 (3 H, s, OCH3); δC (126 MHz, DMSO-d6) 164.2, 163.1, 160.7, 159.2,
144.9, 143.8, 138.2, 132.6, 129.6, 128.2, 119.6, 114.2, 111.6, 103.7, 103.2, 55.5, 51.9; HRMS
(EI): MH+, 394.1393. [C21H20N3O5]+ requires 394.1397.

20
ACCEPTED MANUSCRIPT
Methyl
1-(2-methoxyethyl)-4,6-dioxo-5-((2-phenylhydrazinyl)methylene)-1,4,5,6-
tetrahydropyridine-3-carboxylate (8f).
Following GP2: Prepared from 6c (1.00 mmol), PhNHNH2·HCl (7b) (0.152 mg, 1.05 mmol),
nPrOH. Yield: 250 mg (72%) of yellow solid, m.p. 187-194 °C; [Found: C, 59.29; H, 5.58; N,
12.39. C17H19N3O5 requires C, 59.12; H, 5.55; N, 12.17%]; νmax 3237, 1702, 1643, 1604,
1577, 1496, 1447, 1309, 1292, 1266, 1215, 1086, 996, 863, 785, 79, 678 cm-1; δH (500 MHz,
DMSO-d6) 13.59 (1 H, s, NHNHPh), 10.57 (1 H, s, NHNHPh), 8.31 (1 H, s, CH), 8.30 (1 H,
s, CH), 7.28 (2 H, t, J 7.9 Hz, 1H of Ph), 6.86 (2 H, d, J 7.8 Hz, 2H of Ph), 6.82 (1 H, t, J 7.3
Hz, 1H of Ph), 4.15 (2 H, t, J 5.1 Hz, 2H of CH2), 3.79 (3 H, s, CO2Me), 3.57 (2 H, t, J 5.1
Hz, 2H of CH2), 3.24 (3 H, s, CH2CH2OMe); δC (126 MHz, DMSO-d6) 164.0, 163.3, 160.6,
145.8, 143.8, 138.0, 129.5, 119.5, 111.5, 103.3, 102.1, 69.3, 58.2, 51.8, 48.5; HRMS (EI):
MH+, 346.1393. [C17H20N3O5]+ requires 346.3397.
Synthesis of methyl (E,Z)-5-(((3-(methoxycarbonyl)-1H-pyrazol-5-yl)amino)methylene)-
1-(2-methoxyethyl)-4,6-dioxo-1,4,5,6-tetrahydropyridine-3-carboxylate (11).
To a solution of 6c (0.528 mmol) in MeOH (10 mL) methyl 5-amino-1H-pyrazole-3-
carboxylate (10)44 was added (78 mg, 0.554 mmol) and the resulting mixture was stirred at
room temperature for 24 h. The precipitate was collected by filtration and washed with Et2O
(20 mL) to give 11. Ratio of geometrical isomers: 2.4:1. Yield: 81 mg (40%) of yellow solid,
m.p. 237-251 °C; [Found: C, 50.52; H, 4.59; N, 14.59. C16H18N4O7 requires C, 50.79; H, 4.80;
N, 14.81%]; νmax 3140, 2955, 1695, 1654, 1616, 1595, 1584, 1464, 1435, 1394, 1352, 1312,
1287, 1226, 1094, 1066, 1019, 806, 772 cm-1; δH (500 MHz, DMSO-d6) for the major isomer:
14.02 (1 H, d, J 13.2 Hz, CHNH), 13.58 (1 H, br s, NH), 8.98 (1 H, d, J 13.1 Hz, CHNH),
8.45 (1 H, s, H), 8.33 (1 H, s, CH), 4.03 (2 H, t, J 5.0 Hz, 2 H of CH2), 3.85 (3 H, s, CO2Me),
3.73 (3 H, s, CO2Me), 3.54 (2 H, t, J 5.0 Hz, 2H of CH2), 3.26 (3 H, s, CH2CH2OMe); δH (500
MHz, DMSO-d6) for the minor isomer 13.58 (1 H, br s, NH), 12.88 (1 H, d, J 13.9 Hz,
CHNH), 8.99 (1 H, d, J 14.0 Hz, CHNH), 8.45 (1 H, s, CH), 8.30 (1 H, s, CH), 4.06 (2 H, t, J
5.0 Hz, 2H of CH2), 3.83 (3 H, s, CO2Me), 3.70 (3 H, s, CO2Me), 3.57 (2 H, t, J 5.0 Hz, 2H of
CH2), 3.27 (3 H, s, CH2CH2OMe); δC (126 MHz, DMSO-d6) for both isomers 179.6, 176.1,
165.0, 164.4, 164.3, 163.6, 162.9, 162.7, 151.9, 151.8, 151.6, 151.1, 147.5, 147.4, 134.1,
134.0, 109.0, 107.7, 105.2, 104.9, 101.5, 101.4, 69.7, 69.6, 58.24, 58.22, 51.63, 51.61, 51.4,
51.3, 47.6, 47.0; HRMS (EI): MH+, 379.1245. [C16H19N4O7]+ requires 379.1248.

21
ACCEPTED MANUSCRIPT
Synthesis of ethyl 5-(2-ethoxy-2-oxoethyl)-1-methyl-1H-pyrazole-4-carboxylate (13a)42
and ethyl 4-hydroxy-1-(methylamino)-6-oxo-1,6-dihydropyridine-3-carboxylate (14a).
To a solution of 2b (3.78 mL, 20 mmol) in anhydrous EtOH (40 mL) under argon DMFDMA
(2.80 mL, 20 mmol) was added and the resulting mixture was stirred at room temperature for
2 h to form in situ enaminone 3b. Then, MeNHNH2 (7c) (1.07 mL, 20 mmol) was added and
the resulting mixture was stirred at room temperature for 30 minutes and heated under reflux
for 1 h. Volatile components were evaporated in vacuo and the residue was purified/separated
by column chromatography (EtOAc/petroleum ether = 1:3). Fractions containing the
separated products were combined, respectively, and volatile components evaporated in vacuo
to give 13a and 14a. Product 14a was additionally recrystallized from a mixture of n-heptane,
EtOAc, and CH2Cl2.
Compound 13a42. Elutes first from the column. Yield: 2.76 g (57%) of yellowish solid; δH
(500 MHz, DMSO-d6) 7.80 (1 H, s, CH), 4.18 (2 H, q, J 7.1 Hz, OCH2CH3), 4.15 (2 H, s,
CH2), 4.11 (2 H, q, J 7.1 Hz, OCH2CH3), 3.79 (3 H, s, Me), 1.24 (3 H, t, J 7.1 Hz, OCH2CH3),
1.19 (3 H, t, J 7.1 Hz, OCH2CH3).
Compound 14a. Elutes second from the column. Yield: 640 mg (15%) of white solid, m.p.
117-119 °C; [Found: C, 51.03; H, 5.42; N, 13.19. C9H12N2O4 requires C, 50.94; H, 5.70; N,
13.20%]; νmax 3282, 3049, 2986, 1687, 1658, 1615, 1550, 1513, 1445, 1400, 1371, 1342,
1280, 1235, 1180, 1152, 1079, 1020, 1002, 949, 907, 868, 853, 781, 763, 748, 737, 677 cm-1;
δH (500 MHz, CDCl3) 10.79 (1 H, s, OH), 8.35 (1 H, s, CH), 6.13 (1 H, q, J 6.0 Hz, NH), 5.99
(1 H, s, CH), 4.39 (2 H, q, J 7.1 Hz, OCH2CH3), 2.81 (3 H, d, J 6.0 Hz, Me), 1.41 (3 H, t, J
7.2 Hz, OCH2CH3); δC (126 MHz, CDCl3) 167.8, 166.3, 162.1, 143.0, 99.13, 99.12, 62.0,
40.2, 14.2; HRMS (EI): MH+, 213.0870. [C9H13N2O4]+ requires 213.0870.
Synthesis of ethyl 1-benzyl-5-(2-ethoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate (13b)42
and ethyl 1-(benzylamino)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (14b).
To a solution of 2b (3.78 mL, 20 mmol) in anhydrous EtOH (40 mL) under argon DMFDMA
(2.80 mL, 20 mmol) was added and the resulting mixture was stirred at room temperature for
2 h to form in situ enaminone 3b. Separately, BnNHNH2·2HCl (7d) (4.02 g, 20 mmol) was
suspended in anhydrous EtOH (40 mL) and neutralized by the addition of tBuOK (4.48 g, 40
mmol) at room temperature. The resulting mixture was stirred for additional 30 minutes at
room temperature followed by the addition of the in situ formed 3b. The flask containing 3b
was washed with anhydrous EtOH (2·10 mL) to ensure quantitative transfer of 3b into the
solution of BnNHNH2. The resulting mixture was stirred at room temperature for 30 minutes

22
ACCEPTED MANUSCRIPT
and heated under reflux for 1 h. Volatile components were evaporated in vacuo, the residue
was suspended in EtOAc (300 mL) and washed with H2O (50 mL) and brine (50 mL). The
organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated
in vacuo. The residue was purified/separated by column chromatography (EtOAc/petroleum
ether = 1:3). Fractions containing the separated products were combined, respectively, and
volatile components evaporated in vacuo to give 13b and 14b.
Compound 13b42. Elutes first from the column. Yield: 3.81 g (60%) of yellowish solid; δH
(500 MHz, DMSO-d6) 7.89 (1 H, s, CH), 7.34 – 7.24 (3 H, m, 3H of Ph), 7.19 – 7.15 (2 H, m,
2H of Ph), 5.42 (2 H, s, CH2), 4.18 (2 H, q, J 7.1 Hz, OCH2CH3), 4.13 (2 H, s, CH2), 3.98 (2
H, q, J 7.1 Hz, OCH2CH3), 1.24 (3 H, t, J 7.1 Hz, OCH2CH3), 1.11 (3 H, t, J 7.1 Hz,
OCH2CH3).
Compound 14b. Elutes second from the column. Yield: 540 mg (9%) of yellow solid, m.p.
90-93 °C; [Found: C, 62.68; H, 5.43; N, 9.59. C15H16N2O4 requires C, 62.49; H, 5.59; N,
9.72%];
νmax 3305, 2982, 2933, 1734, 1683, 1615, 1545, 1511, 1452, 1400, 1374, 1335, 1224, 1181,
1152, 1072, 1015, 965, 926, 914, 836, 780, 748, 727, 699, 674 cm-1; δH (500 MHz, DMSO-d6)
10.79 (1 H, s, OH), 7.93 (1 H, s, CH), 7.37 – 7.27 (5 H, m, Ph), 7.08 (1 H, t, J 4.7 Hz, NH),
5.79 (1 H, s, CH), 4.18 (2 H, q, J 7.1 Hz, OCH2CH3), 4.08 (2 H, d, J 4.7 Hz, CH2), 1.21 (3 H,
t, J 7.1 Hz, OCH2CH3); δC (126 MHz, DMSO-d6) 165.1, 165.0, 161.2, 145.2, 136.7, 129.3,
128.4, 127.7, 99.0, 98.0, 60.8, 54.5, 14.0; HRMS (EI): MH+, 289.1182. [C15H17N2O4]+
requires 289.1183.
Synthesis of ethyl 1-benzyl-5-(2-ethoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate (13b)42
and
(Z)-ethyl
1-benzyl-3-(3-ethoxy-3-oxo-1-phenylprop-1-en-2-yl)-1H-pyrazole-4-
carboxylate (15).
To a solution of 2b (3.78 mL, 20 mmol) in anhydrous EtOH (40 mL) under argon DMFDMA
(2.80 mL, 20 mmol) was added and the resulting mixture was stirred at room temperature for
2 h to form in situ enaminone 3b. Then, BnNHNH2·2HCl (7d) (4.02 g, 20 mmol) was added
and resulting mixture was stirred at room temperature for 30 minutes and heated under reflux
for 1 h. Volatile components were evaporated in vacuo, the residue was suspended in EtOAc
(300 mL) and washed with NaHCO3 (aq. sat., 50 mL), H2O (30 mL), and brine (50 mL). The
organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated
in vacuo. The residue was purified by column chromatography (EtOAc/petroleum ether =

23
ACCEPTED MANUSCRIPT
1:3). Fractions containing the products were combined and volatile components evaporated in
vacuo to give a mixture of 13b and 15 in a ca. 1:1 ratio. Products 13b and 15 were partially
separated by MPLC (EtOAc/petroleum ether = 1:4). Fractions containing the separated
products were combined, respectively, and volatile components evaporated in vacuo to give
13b and 15. Mixed fractions were crystalized from n-heptane to give pure 13b.
Compound 15. Elutes first from the column. Yield: 1.38 g (17%) of yellow solid, m.p. 65-68
°C; [Found: C, 71.30; H, 6.06; N, 6.85. C24H24N2O4 requires C, 71.27; H, 5.98; N, 6.93%];
νmax 2980, 2929, 2853, 1708, 1618, 1532, 1496, 1455, 1379, 1269, 1214, 1149, 1107, 1077,
1026, 979, 925, 848, 774, 722, 694 cm-1; δH (500 MHz, DMSO-d6) 8.48 (1 H, s, CH), 7.42 –
7.30 (11 H, m, 10H of Ph, CH), 5.38 (2 H, s, CH2), 4.14 (2 H, q, J 7.1 Hz, OCH2CH3), 4.07 (2
H, q, J 7.0 Hz, OCH2CH3), 1.21 (3 H, t, J 7.1 Hz, OCH2CH3), 1.03 (3 H, t, J 7.1 Hz,
OCH2CH3); δC (126 MHz, DMSO-d6) 166.5, 162.1, 149.7, 137.5, 136.3, 135.5, 135.0, 128.9,
128.7, 128.6, 128.1, 128.00, 127.97, 126.1, 111.6, 60.3, 59.8, 55.2, 14.2, 13.5; HRMS (EI):
MH+, 405.1808. [C24H25N2O4]+ requires 405.1809.
Compound 13b42. Elutes second from the column. Yield: 957 mg (15%) of yellowish solid.
For 1H-NMR see above.
Synthesis of enaminones 16a, 16b, and 22 – General procedure 3 (GP3).
To a solution of alkyl 5-(2-alkoxy-2-oxoethyl)-1-substituted-1H-pyrazole-4-carboxylate 13a,b
or 20 (1 equivalent) in anhydrous PhMe under argon tert-butoxy bis(dimethylamino)methane
(TBDMAM) (1.5 equivalents) was added and the resulting mixture was heated under reflux
for 24 h. Volatile components were evaporated in vacuo and the residue was purified by
column chromatography (CC). Fractions containing the desired enaminone were combined
and volatile components evaporated in vacuo.
Ethyl
5-(1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl)-1-methyl-1H-pyrazole-4-
carboxylate (16a).
Following GP3: Prepared from 13a (1.38 g, 5.74 mmol), TBDMAM (1.78 mL, 8.61 mmol),
PhMe (15 mL), CC [1) EtOAc/petroleum ether = 1:2 to elute the nonpolar impurities; 2)
EtOAc/petroleum ether = 1:1 to elute the product 16a]. Yield: 1.10 g (64%) of yellow oil; νmax
2979, 2935, 2905, 2817, 1688, 1603, 1554, 1490, 1430, 1392, 1377, 1363, 1287, 1207, 1183,
1146, 1093, 1056, 1039, 980, 868, 837, 766, 738, 712, 697, 650 cm-1; δH (300 MHz, DMSO-

24
ACCEPTED MANUSCRIPT
d6) 7.80 (1 H, s, CH), 7.67 (1 H, s, CH), 4.18 – 4.06 (2 H, m, OCH2CH3), 4.05 – 3.92 (2 H, m,
OCH2CH3), 3.60 (3 H, s, Me), 2.69 (6 H, br s, NMe2), 1.20 (3 H, t, J 7.1 Hz, OCH2CH3), 1.08
(3 H, t, J 7.1 Hz, OCH2CH3); δC (75 MHz, DMSO-d6) 166.8, 162.3, 152.1, 141.2, 139.9,
114.1, 83.2, 59.0, 58.7, 36.3, 14.5, 14.1; HRMS (EI): MH+, 296.1610. [C14H22N3O4]+ requires
296.1605.
Ethyl
1-benzyl-5-(1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl)-1H-pyrazole-4-
carboxylate (16b).
Following GP3: Prepared from 13b (837 mg, 2.65 mmol), TBDMAM (820 ꢀL, 3.97 mmol),
PhMe (8 mL), CC [1) EtOAc/petroleum ether = 1:2 to elute the nonpolar impurities; 2)
EtOAc/petroleum ether = 1:2 to elute the product 16b]. Yield: 505 mg (51%) of yellow oil;
νmax 2979, 1688, 1603, 1555, 1486, 1455, 1430, 1401, 1379, 1363, 1283, 1212, 1181, 1119,
1087, 1041, 1000, 870, 839, 765, 732, 698 cm-1; δH (500 MHz, CDCl3) 7.96 (1 H, s, CH),
7.69 (1 H, s, CH), 7.31 – 7.23 (5 H, m, Ph), 5.22 (1 H, d, J 14.7 Hz, CHaHb), 5.08 (1 H, d, J
14.7 Hz, CHaHb), 4.22 (2 H, qd, J 2.1, 7.1 Hz, OCH2CH3), 4.04 (2 H, q, J 7.1 Hz, OCH2CH3),
2.50 (6 H, br s, NMe2), 1.27 (3 H, t, J 7.1 Hz, OCH2CH3), 1.11 (3 H, t, J 7.1 Hz, OCH2CH3);
δC (126 MHz, CDCl3) 168.2, 163.4, 152.2, 141.32, 141.27, 136.1, 128.6, 128.5, 128.0, 115.2,
84.4, 59.76, 59.85, 53.6, 14.6, 14.5; HRMS (EI): MH+, 372.1917. [C20H26N3O4]+ requires
372.1918.
Benzyl 1-benzyl-5-(3-(benzyloxy)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)-1H-pyrazole-
4-carboxylate (22).
Following GP3: Prepared from 20 (2.61 g, 5.93 mmol), TBDMAM (1.84 mL, 8.90 mmol),
PhMe (20 mL), CC (EtOAc/petroleum ether = 1:2). Yield: 1.92 g (65%) of orange oil; νmax
3031, 2944, 1688, 1602, 1554, 1487, 1454, 1429, 1401, 1365, 1279, 1207, 1172, 1118, 1085,
1013, 910, 872, 822, 781, 729, 694 cm-1; δH (500 MHz, CDCl3) 8.01 (1 H, s, CH), 7.63 (1 H,
s, CH), 7.34 – 7.15 (15 H, m, 3 · Ph), 5.24 (1 H, d, J 12.4 Hz, CHaHbPh), 5.16 (1 H, d, J 14.7
Hz, CHaHbPh), 5.12 (1 H, d, J 12.4 Hz, CHaHbPh), 5.04 (2 H, s, CH2Ph), 5.01 (1 H, d, J 14.7
Hz, CHaHbPh), 2.73 (3 H, br s, NMe), 2.01 (3 H, br s, NMe); δC (126 MHz, CDCl3) 167.8,
163.1, 152.7, 141.5, 141.1, 137.1, 136.4, 135.9, 128.6, 128.49, 128.48, 128.44, 128.40, 128.2,
128.1, 127.9, 127.7, 127.6, 115.0, 83.8, 65.6, 65.4, 53.7; HRMS (EI): MH+, 496.2228.
[C30H30N3O4]+ requires 496.2231.

25
ACCEPTED MANUSCRIPT
Synthesis of dimethylamino-substitution products 17a-d and 23a,b – General procedure 4
(GP4).
To a solution of enaminone 16a,b or 22 (1 equivalent) in AcOH was added amine 4a,d,e,f (6
equivalents) and the resulting mixture was heated under reflux for 5 h. Volatile components
were evaporated in vacuo, the residue was dissolved in EtOAc, and carefully washed with
NaHCO3 (aq. sat.) till pH 8, and with brine (30 mL). The organic phase was dried over
anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was
purified by flash column chromatography (CC) (EtOAc). Fractions containing the products
were combined and volatile components evaporated in vacuo. The dimethylamino-
substitution products were isolated as mixtures of the (E)- and the (Z)-geometrical isomers,
and used in the following step without further purification/separation. The acid catalyzed
substitution of the dimethylamino group may be partially accompanied by the following
cyclization (evident in the case of product 17a) as well as the formation of the corresponding
acetamides (evident in the case of product 23b). 1H-NMR spectra were only partially assigned
i.e. only those signals unambiguously belonging to the (E)- or the (Z)-isomer are listed.
(E/Z)-Ethyl 5-(3-ethoxy-1-(methylamino)-3-oxoprop-1-en-2-yl)-1-methyl-1H-pyrazole-4-
carboxylate (17a).
Following GP4: Prepared from 16a (4.04 g, 13.68 mmol), MeNH2 (4d) (10.3 mL, c = 8 M,
82.08 mmol), AcOH (40 mL). Yield: 3.00 g (78%) of yellow oil, (E):(Z) = 1:1; δH (500 MHz,
CDCl3) for (E)-17a 7.72 (1 H, d, J 14.3 Hz, CH), 4.49 (1 H, br s, NH); δH (500 MHz, CDCl3)
for (Z)-17a 8.53 (1 H, br s, NH), 6.92 (1 H, d, J 13.5 Hz, CH); HRMS (EI): MH+, 282.1448.
[C13H20N3O4]+ requires 282.1448.
(E/Z)-Ethyl 5-(1-(benzylamino)-3-ethoxy-3-oxoprop-1-en-2-yl)-1-methyl-1H-pyrazole-4-
carboxylate (17b).
Following GP4: Prepared from 16a (760 mg, 2.57 mmol), BnNH2 (4a) (1.72 mL, 15.42
mmol), AcOH (9 mL). Yield: 811 mg (88%) of yellow oil, (E):(Z) = 1:1; νmax 3306, 3064,
3030, 2979, 2935, 2904, 2872, 1685, 1608, 1554, 1489, 1454, 1375, 1340, 1274, 1207, 1168,
1138, 1091, 1040, 987, 869, 839, 768, 734, 698, 649 cm-1; δH (500 MHz, CDCl3) for (E)-17b
7.85 (1 H, s, CH), 7.84 (1 H, d, J 14.6 Hz, CH), 7.37–7.21 (5 H, m, Ph), 5.05 (1 H, br s, NH),

26
ACCEPTED MANUSCRIPT
4.49–4.33 (2 H, m, CH2), 4.25–4.06 (4 H, m, OCH2CH3), 3.64 (3 H, s, Me), 1.26 (3 H, t, J 7.1
Hz, OCH2CH3), 1.19 (3 H, t, J 7.1 Hz, OCH2CH3); δH (500 MHz, CDCl3) for (Z)-17b 8.94 (1
H, br s, NH), 7.01 (1 H, d, J 13.4 Hz, CH), 3.66 (3 H, s, Me), 1.29 (3 H, t, J 7.1 Hz,
OCH2CH3); δC (126 MHz, CDCl3) for (E)-17b 166.8, 162.9, 151.1, 141.4, 139.2, 137.8,
129.0, 128.1, 127.4, 113.4, 88.2, 60.0, 59.9, 52.6, 37.0, 14.7, 14.5; HRMS (EI): MH+,
358.1745. [C19H24N3O4]+ requires 358.1761.
1
Additional column chromatography (EtOAc) yielded pure (E)-17b – the respective H- and
13C-NMR spectra are listed above (see also the Supporting Information). All the other
analyses refer to the mixture of isomers.
(E/Z)-Ethyl 1-benzyl-5-(3-ethoxy-1-(methylamino)-3-oxoprop-1-en-2-yl)-1H-pyrazole-4-
carboxylate (17c).
Following GP4: Prepared from 16b (1.26 g, 3.39 mmol), MeNH2 (4d) (2.54 mL, c = 8 M,
20.34 mmol), AcOH (10 mL). Yield: 1.08 g (89%) of yellow oil, (E):(Z) = 0.95:1; νmax 3322,
2979, 2935, 1672, 1615, 1552, 1479, 1455, 1407, 1369, 1344, 1267, 1207, 1178, 1143, 1105,
1032, 984, 870, 839, 782, 728, 696 cm-1; δH (500 MHz, CDCl3) for (E)-17c 7.99 (1 H, s, CH),
7.58 (1 H, d, J 14.4 Hz, CH), 2.78 (3 H, br s, Me); δH (500 MHz, CDCl3) for (Z)-17c 8.39 (1
H, s, NH), 7.96 (1 H, s, CH), 6.55 (1 H, d, J 13.4 Hz, CH), 2.94 (3 H, d, J 5.0 Hz, Me);
HRMS (EI): MH+, 358.1762. [C19H24N3O4]+ requires 358.1761.
(E/Z)-Ethyl 1-benzyl-5-(1-(benzylamino)-3-ethoxy-3-oxoprop-1-en-2-yl)-1H-pyrazole-4-
carboxylate (17d).
Following GP4: Prepared from 16b (1.22 g, 3.28 mmol), BnNH2 (4a) (2.19 mL, 19.68 mmol),
AcOH (10 mL). Yield: 1.29 g (91%) of yellow oil, (E):(Z) = 1:1.3; νmax 3307, 2979, 1671,
1611, 1552, 1482, 1454, 1372, 1345, 1275, 1208, 1174, 1112, 1091, 1029, 870, 839, 781, 728,
696 cm-1; δH (500 MHz, CDCl3) for (E)-17d 7.99 (1 H, s, CH), 7.74 (1 H, d, J 14.3 Hz, CH),
1.11 (3 H, t, J 7.1 Hz, OCH2CH3); δH (500 MHz, CDCl3) for (Z)-17d 8.81 (1 H, br s, NH),
7.97 (1 H, s, CH), 6.67 (1 H, d, J 13.3 Hz, CH), 1.15 (3 H, t, J 7.1 Hz, OCH2CH3); HRMS
(EI): MH+, 434.2071. [C25H28N3O4]+ requires 434.2074.
Benzyl 1-benzyl-5-(3-(benzyloxy)-3-oxo-1-(propylamino)prop-1-en-2-yl)-1H-pyrazole-4-
carboxylate (23a).

27
ACCEPTED MANUSCRIPT
Following GP4: Prepared from 22 (1.03 g, 2.08 mmol), nPrNH2 (4e) (1.05 mL, 12.48 mmol),
AcOH (6 mL). Yield: 1.02 g (96%) of colorless oil, (E):(Z) = 1:1.2; νmax 3305, 3064, 3033,
2962, 2874, 1710, 1670, 1614, 1550, 1496, 1481, 1455, 1407, 1381, 1350, 1266, 1209, 1175,
1143, 1105, 1078, 1014, 981, 911, 872, 783, 728, 695 cm-1; δH (300 MHz, CDCl3) for (E)-23a
8.07 (1 H, s, CH), 7.61 (1 H, d, J 14.6 Hz, CH), 5.52 (1 H, br s, NH); δH (300 MHz, CDCl3)
for (Z)-23a 8.50 (1 H, br s, NH), 8.02 (1 H, s, CH), 6.55 (1 H, d, J 13.6 Hz, CH); HRMS (EI):
MH+, 510.2381. [C31H32N3O4]+ requires 510.2387.
Benzyl 1-benzyl-5-(3-(benzyloxy)-3-oxo-1-(phenylamino)prop-1-en-2-yl)-1H-pyrazole-4-
carboxylate (23b).
Following GP4: Prepared from 22 (828 mg, 1.67 mmol), PhNH2 (4f) (912 ꢀL, 10.02 mmol),
AcOH (5 mL). Yield: 100% conversion, red oil, (E):(Z) = 1:1.67; δH (500 MHz, CDCl3) for
(E)-23b 8.11 (1 H, d, J 14.1 Hz, CH), 8.08 (1 H, s, CH), 6.29 (1 H, d, J 14.1 Hz, NH); δH (500
MHz, CDCl3) for (Z)-23b 10.35 (1 H, d, J 13.1 Hz, CH), 8.06 (1 H, s, CH); HRMS (EI):
MH+, 544.2231. [C34H30N3O4]+ requires 544.2231.
Cyclisation of dimethylamino-substitution products 17a-d and 23a,b – General procedure
5 (GP5).
To a solution of dimethylamino-substitution product 17a-d or 23a,b (1 equivalent) in
anhydrous THF under argon tBuOK (0.1 equivalents) was added and the resulting mixture
was stirred at room temperature for 20 minutes. Then, silica gel 60 (1 g/mmol) was added
followed by evaporation of volatile components. The residue (reaction mixture coated on
silica gel 60) was purified by column chromatography (CC). Fractions containing the products
were combined and volatile components evaporated in vacuo.
Ethyl 1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (18a).
Following GP5: Prepared from 17a (3.00 g, 10.66 mmol), tBuOK (120 mg, 1.07 mmol), THF
(55 mL), CC (EtOAc/petroleum ether = 1:1). Yield: 2.10 g (83%) of white solid, m.p. 142-
144 °C; [Found: C, 56.24; H, 5.33; N, 17.78. C11H13N3O3 requires C, 56.16; H, 5.57; N,
17.86%]; νmax 3105, 2962, 1698, 1667, 1598, 1538, 1458, 1443, 1396, 1359, 1293, 1256,
1219, 1198, 1175, 1096, 1051, 998, 981, 919, 903, 869, 775, 732, 704, 684, 636 cm-1; δH (500
MHz, CDCl3) 8.16 (1 H, s, CH), 8.03 (1 H, s, CH), 4.38 (2 H, q, J 7.1 Hz, OCH2CH3), 4.28 (3
H, s, Me), 3.63 (3 H, s, Me), 1.42 (3 H, t, J 7.1 Hz, OCH2CH3); δC (126 MHz, CDCl3) 163.5,

28
ACCEPTED MANUSCRIPT
158.8, 142.3, 140.1, 136.6, 114.3, 100.4, 61.3, 41.5, 36.7, 14.4; HRMS (EI): MH+, 236.1031.
[C11H14N3O3]+ requires 236.1030.
Ethyl
(18b).
5-benzyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylate
Following GP5: Prepared from 17b (1.07 g, 3 mmol), tBuOK (34 mg, 0.3 mmol), THF (15
mL), CC (EtOAc/petroleum ether = 1:1). Yield: 836 mg (89%) of white solid, m.p. 117-120
°C; [Found: C, 65.63; H, 5.56; N, 13.50. C17H17N3O3 requires C, 65.58; H, 5.50; N, 13.50%];
νmax 3108, 3060, 2979, 2933, 1718, 1656, 1588, 1532, 1499, 1473, 1452, 1439, 1401, 1365,
1346, 1297, 1250, 1184, 1149, 1058, 974, 941, 918, 842, 772, 738, 703, 635 cm-1; δH (500
MHz, CDCl3) 8.19 (1 H, s, CH), 8.03 (1 H, s, CH), 7.38 – 7.29 (5 H, m, Ph), 5.23 (2 H, s,
CH2), 4.34 (2 H, q, J 7.1 Hz, OCH2CH3), 4.27 (3 H, s, Me), 1.37 (3 H, t, J 7.1 Hz,
OCH2CH3); δC (126 MHz, CDCl3) 163.6, 158.6, 141.5, 140.0, 137.2, 136.3, 129.2, 128.4,
128.1, 114.6, 101.2, 61.5, 51.5, 41.6, 14.3; HRMS (EI): MH+, 312.1327. [C17H18N3O3]+
requires 312.1343.
Ethyl
(18c).
1-benzyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylate
Following GP5: Prepared from 17c (1.08 g, 3.02 mmol), tBuOK (34 mg, 0.302 mmol), THF
(15 mL), CC (EtOAc/petroleum ether = 1:1). Yield: 720 mg (76%) of white solid, m.p. 110-
114 °C; [Found: C, 65.57; H, 5.23; N, 13.41. C17H17N3O3 requires C, 65.58; H, 5.50; N,
13.50%]; νmax 2928, 1710, 1677, 1599, 1529, 1495, 1451, 1429, 1406, 1370, 1353, 1308,
1289, 1237, 1189, 1096, 1064, 1031, 922, 894, 831, 778, 734, 720, 693 cm-1; δH (500 MHz,
CDCl3) 8.27 (1 H, s, CH), 7.96 (1 H, s, CH), 7.27 – 7.19 (3 H, m, 3H of Ph), 7.05 – 7.02 (2 H,
m, 2H of Ph), 6.03 (2 H, s, CH2), 4.28 (2 H, q, J 7.1 Hz, OCH2CH3), 3.62 (3 H, s, Me), 1.30
(3 H, t, J 7.1 Hz, OCH2CH3); δC (126 MHz, CDCl3) 163.5, 158.8, 142.3, 140.1, 137.7, 137.5,
128.6, 127.6, 127.0, 114.8, 100.7, 61.4, 56.3, 36.8, 14.4; HRMS (EI): MH+, 312.1343.
[C17H18N3O3]+ requires 312.1343.
Ethyl 1,5-dibenzyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (18d).
Following GP5: Prepared from 17d (1.29 g, 2.98 mmol), tBuOK (33 mg, 0.298 mmol), THF
(15 mL), CC (EtOAc/petroleum ether = 2:3). Yield: 900 mg (77%) of white solid, m.p. 118-
121 °C; [Found: C, 71.24; H, 5.35; N, 10.74. C23H21N3O3 requires C, 71.30; H, 5.46; N,
10.85%]; νmax 3104, 3029, 2938, 1713, 1677, 1597, 1537, 1494, 1452, 1438, 1417, 1367,

29
ACCEPTED MANUSCRIPT
1302, 1284, 1226, 1187, 1174, 1092, 1072, 1044, 1029, 963, 927, 900, 832, 803, 777, 730,
716, 698, 649, 621, 611 cm-1; δH (500 MHz, CDCl3) 8.29 (1 H, s, CH), 7.96 (1 H, s, CH), 7.38
– 7.29 (5 H, m, 5H of Ph), 7.27 – 7.19 (3 H, m, 3H of Ph), 7.08 – 7.04 (2 H, m, 2H of Ph),
6.02 (2 H, s, CH2), 5.20 (2 H, s, CH2), 4.24 (2 H, q, J 7.1 Hz, OCH2CH3), 1.26 (3 H, t, J 7.1
Hz, OCH2CH3); δC (126 MHz, CDCl3) 163.5, 158.5, 141.4, 139.8, 137.9, 137.6, 136.1, 129.1,
128.6, 128.4, 128.2, 127.6, 127.1, 114.8, 101.3, 61.5, 56.3, 51.5, 14.3; HRMS (EI): MH+,
388.1652. [C23H22N3O3]+ requires 388.1656.
Benzyl 1-benzyl-4-oxo-5-propyl-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylate
(24a) and benzyl alcohol.
Following GP5: Prepared from 23a (994 mg, 1.95 mmol), tBuOK (21.9 mg, 0.195 mmol),
THF (10 mL), CC (EtOAc/petroleum ether = 1:2). Yield: 731 mg, 24a:BnOH = 1:1
(calculated for 24a: m = 574 mg, 73%) of colorless oil; νmax 3401, 3063, 3031, 2963, 2874,
1713, 1661, 1596, 1537, 1496, 1454, 1413, 1376, 1303, 1230, 1185, 1128, 1070, 1025, 907,
779, 730, 695 cm-1; δH (500 MHz, CDCl3): for 24a 8.25 (1 H, s, CH), 7.96 (1 H, s, CH), 7.41
– 7.32 (4 H, m, 4H of Ph), 7.31 – 7.26 (1 H, m, 1H of Ph), 7.23 – 7.19 (3 H, m, 3H of Ph),
7.03 – 6.99 (2 H, m, 2H of Ph), 6.01 (2 H, s, CH2Ph), 5.26 (2 H, s, CH2Ph), 3.96 – 3.91 (2 H,
m, CH3CH2CH2N), 1.81 – 1.72 (2 H, m, CH3CH2CH2N), 0.95 (3 H, t, J 7.4 Hz, CH3); δC (126
MHz, CDCl3) for 24a 163.5, 158.4, 142.0, 141.0, 137.70, 137.66, 135.6, 128.71, 128.67,
128.62, 127.7, 127.6, 127.1, 115.0, 100.3, 65.6, 56.3, 50.7, 23.1, 11.2; HRMS (EI): MH+,
402.1812. [C24H24N3O3]+ requires 402.1812.
Benzyl 1-benzyl-4-oxo-5-phenyl-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxylate
(24b).
Following GP5: Prepared from 23b (907 mg, 1.67 mmol), tBuOK (18.7 mg, 0.167 mmol),
THF (10 mL), CC (EtOAc/petroleum ether = 1:1). Yield: 427 mg (59%) of yellow solid, m.p.
111-115 °C; νmax 3291, 3259, 3194, 3135, 3060, 2947, 1719, 1692, 1663, 1598, 1558,1556,
1487, 1435, 1368, 1321, 1296, 1283, 1263, 1228, 1181, 1059, 1027, 962, 906, 838, 775, 752,
731, 706, 693, 606 cm-1; δH (500 MHz, CDCl3) 8.30 (1 H, s, CH), 8.05 (1 H, s, CH), 7.49 –
7.42 (5 H, m, 5H of Ph), 7.37 – 7.33 (5 H, m, 5H of Ph), 7.25 – 7.22 (3 H, m, 3H of Ph), 7.07
– 7.04 (2 H, m, 2H of Ph), 6.05 (2 H, s, CH2Ph), 5.25 (2 H, s, CH2Ph); δC (126 MHz, CDCl3)
163.3, 158.2, 142.2, 139.9, 139.7, 138.11, 138.06, 137.5, 135.4, 129.6, 129.1, 128.8, 128.74,
128.69, 127.7, 127.2, 127.1, 114.9, 101.1, 67.3, 56.5; HRMS (EI): MH+, 436.1654.
[C27H22N3O3]+ requires 436.1656.