Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents

Article abstract of DOI:10.1016/j.ejmech.2020.112450

Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (MtbTMPK) for the synthesis of thymidine triphosphates and thus also DNA synthesis. Therefore, this enzyme constitutes a potential Achilles heel of the pathogen. Based on a previously reported MtbTMPK 6-aryl-substituted pyridone inhibitor and guided by two co-crystal structures of MtbTMPK with pyridone- and thymine-based inhibitors, we report the synthesis of a series of aryl-shifted cyanopyridone analogues. These compounds generally lacked significant MtbTMPK inhibitory potency, but some analogues did exhibit promising antitubercular activity. Analogue 11i demonstrated a 10-fold increased antitubercular activity (MIC H37Rv, 1.2 μM) compared to literature compound 5. Many analogues with whole-cell antimycobacterial activity were devoid of significant cytotoxicity.

Full text of DOI:10.1016/j.ejmech.2020.112450

Journal Pre-proof
Synthesis and structure activity relationships of cyanopyridone based anti-
tuberculosis agents
Yanlin Jian, Fabian Hulpia, Martijn D.P. Risseeuw, He Eun Forbes, Héle
̀ne Munier-
Lehmann, Guy Caljon, Helena I.M. Boshoff, Serge Van Calenbergh
PII:
S0223-5234(20)30421-9
DOI:
https://doi.org/10.1016/j.ejmech.2020.112450
EJMECH 112450
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 26 March 2020
Revised Date: 8 May 2020
Accepted Date: 10 May 2020
Please cite this article as: Y. Jian, F. Hulpia, M.D.P. Risseeuw, H.E. Forbes, Hé
G. Caljon, H.I.M. Boshoff, S. Van Calenbergh, Synthesis and structure activity relationships of
cyanopyridone based anti-tuberculosis agents, European Journal of Medicinal Chemistry (2020), doi:
https://doi.org/10.1016/j.ejmech.2020.112450.
̀. Munier-Lehmann,
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Synthesis and structure activity relationships of cyanopyridone based
anti-tuberculosis agents
Yanlin Jiana, Fabian Hulpiaa, Martijn D. P. Risseeuwa, He Eun Forbesb, Hélène
Munier-Lehmannc, Guy Caljond, Helena I. M. Boshoffb, and Serge Van Calenbergha, *
aLaboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460,
B-9000 Gent, Belgium
bTuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology,
National Institute of Allergy and Infectious Disease, National Institutes of Health, 9000
Rockville Pike, Bethesda, Maryland 20892, United States
cUnit of Chemistry and Biocatalysis, Department of Structural Biology and Chemistry, Institut
Pasteur, CNRS UMR3523, 28 Rue du Dr. Roux, Cedex 15 75724 Paris, France
dLaboratory for Microbiology, Parasitology and Hygiene, University of Antwerp,
Universiteitsplein 1 (S7), B-2610 Wilrijk, Belgium
* Corresponding author. Tel.: +32 9 264 81 24; fax: +32 9 264 81 46.
E-mail address: serge.vancalenbergh@ugent.be (S. van Calenbergh).

Abstract
Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase
(MtbTMPK) for the synthesis of thymidine triphosphates and thus also DNA synthesis.
Therefore, this enzyme constitutes a potential Achilles heel of the pathogen. Based on a
previously reported MtbTMPK 6-aryl-substituted pyridine inhibitor and guided by two co-crystal
structures of MtbTMPK with pyridone- and thymine-based inhibitors, we report the synthesis of
a series of aryl-shifted cyanopyridone analogues. These compounds generally lacked
significant MtbTMPK inhibitory potency, but some analogues did exhibit promising
antitubercular activity. Analogue 11i demonstrated a 10-fold increased antitubercular activity
(MIC H37Rv, 1.2 μM) compared to literature compound 5. Many analogues with whole-cell
antimycobacterial activity were devoid of significant cytotoxicity.
Graphical abstract

Introduction
Tuberculosis (TB), a communicable disease caused by the infectious agent Mycobacterium
tuberculosis (Mtb), still ranks as one of the top 10 causes of death worldwide with around 10
million people contracting TB every year.[1] Though a 27% reduction of TB-related death rate
was achieved since 2000 due to improved control, more than 1.2 million TB deaths were
reported in 2018.[1] In particular, the emergence of multidrug-resistant (MDR) and extensively
drug-resistant (XDR) tuberculosis threatens global efforts to combat TB.[2]
The first-line treatment of TB consists of a 6-month combination regimen, comprised of
isoniazid, ethambutol, pyrazinamide and rifampicin, while for resistant TB, the treatment
duration is longer and the employed drugs have a narrow therapeutic index, leading to poor
patient adherence and high economic burden.[2-4] The newly approved antitubercular drugs
bedaquiline,[5] delamanid[6] and pretomanid[7] open new prospects for the cure of MDR TB.
Nevertheless, the first bedaquiline-resistant Mtb isolate was already observed in 2014,[8] and
resistance to delamanid related to the poor bio-activation by mutations of the deazaflavin
(F420)-dependent nitroreductase (Ddn) was also reported.[9] Thus, there remains a pressing
need for new antitubercular chemical entities.
Thymidylate kinase (TMPK) catalyzes the phosphorylation of thymidine 5’-monophosphate to
the corresponding 5’-diphosphate in Mtb and is indispensable for Mtb growth and survival,[10]
earmarking this enzyme as an attractive target to develop inhibitors as potential anti-TB agents.
Additionally, several co-crystal structures of MtbTMPK with substrates/inhibitors have been
published,[11-14] enabling rational drug design.
Previously reported MtbTMPK inhibitors mainly arose from either substrate modifications[15-18]
or derivatisation of the thymine base.[19-21] Nevertheless, none of these derivatives displayed
adequate whole-cell activity (Figure 1, analogues 1-3).[18-21]

Figure 1. Structures of thymidine-like and non-nucleoside MtbTMPK inhibitors.
In 2015 AstraZeneca reported on a series of non-nucleoside MtbTMPK inhibitors featuring a
cyanopyridone moiety as a potential thymine isostere.[22] Their work resulted in the
identification of several analogues with reasonable antitubercular activity (Figure 1, 4 and 5).
Comparison of the co-crystal structure of MtbTMPK with our previously reported inhibitor 2
(PBD: 5NQ5[20]) to that with compound 4 (PDB:4UNQ[22]), shows that the thymine and pyridine
rings superimpose in such a way that key interactions with the enzyme are conserved (Figure
2A). This marks the cyanopyridone ring as a suitable thymine bioisostere. Although the phenyl
ring of 4 and the substituted piperidine ring of 2 protrude in different directions, the latter fits
perfectly in the big groove surrounded by helix α2, α3 and α5 through a bent conformation of
the biphenylether tail. This led us to explore a shift of the phenyl ring from the 6 position of the
cyanopyridone ring to the 5 position. First, compound 11a, featuring such aryl shift, was
docked into the catalytic pocket of enzyme to gain insight in the putative binding mode (Figure
2B). As expected, the cyanopyridone ring adopts an identical pose to that observed with
compound 4, with the aromatic tail pointing to a different direction, reminiscent of the piperidine
ring of compound 2.

Figure 2. A. Structure overlay of compound 2 (PDB 5NQ5) and compound 4 (PDB 4UNQ) in
the MtbTMPK active site. MtbTMPK is shown in a blue (PDB 5NQ5) and yellow (PDB 4UNQ)
cartoon representation with selected side chains labelled and shown as sticks with carbon
atoms colored grey. Ligands are drawn in stick representation with carbon atoms in pink
(ligand 2) and green (ligand 4), hydrogen-bonding interactions are shown as red lines. B.
Structure overlay of compound 4 and docking pose of compound 11a in the MtbTMPK (PDB
4UNQ) active site. MtbTMPK is shown in a yellow cartoon representation with selected side
chains labelled and shown as sticks with carbon atoms colored grey. Ligands are drawn in
stick representation with carbon atoms in green (ligand 4) and blue (ligand 11a),
hydrogen-bonding interactions are shown as red lines.
In this manuscript, we describe our optimization efforts starting from the designed aryl-shifted
cyanopyridone analogue 11a, arriving at compounds with whole cell activity, which surprisingly
failed to elicit enzyme inhibitory potency. An overview of the synthesized analogues is
presented in Figure 3.

Figure 3. An overview of synthesized compounds in this study.

Chemistry
To obtain the envisioned 5-aryl-substituted cyanopyridones, commercially available substituted
[23]
methyl phenylacetates were reduced with LiAlH4
and re-oxidized by PCC to the
corresponding aldehyde,[24,25] followed by condensation[22] with 9[26] to give intermediate
10a-10i (Scheme 1). Next, oxidation[27] of the resulting methylthiopyridones with 1 eq. of
mCPBA afforded the precipitate sulfoxides, while further oxidation of the resulting sulfoxides
with another 1 eq. of mCPBA furnished the sulfone analogues. For the synthesis of sulfoxide
13 and sulfone 14 analogues, intermediate 10d was first hydrolyzed with aq. sulfuric acid[28] to
give the corresponding 3-carboxamide thioether, which was then oxidized by mCPBA to yield
the desired analogues.
Scheme 1.
Reagents and conditions: (a) LiAlH4, THF; (b) PCC, CH2Cl2; (c) 9, NaOH, DMSO; (d)
mCPBA, THF; (e) (i) con.H2SO4, 100 ; (ii) mCPBA, THF.
The synthesis of substituted phenoxy- or benzyloxyaryl analogues 22a-22k and 27a-27g was
achieved from commercially available hydroxyphenylacetic ester derivatives (Scheme 2). First,
the phenolic group of hydroxyphenylacetates was functionalized by either Chan-Lam coupling
with boronic acids.[29] Alternatively, it was alkylated with benzyl bromides under basic
conditions.[30] Then, reduction of the ester to the corresponding alcohol, followed by
re-oxidation resulted in the desired arylacetaldehyde intermediate, which was subsequently
condensed with 9 to enable cyanopyridone ring formation. Finally, mCPBA-mediated oxidation
afforded analogues 22a-22k and 27a-27g.

Scheme 2
Reagents and conditions: (a) substituted phenylboronic acid, pyridine, molecular sieves,
Cu(OAc)2, 1,2-dichloroethane; (b) LiAlH4, THF; (c) PCC, CH2Cl2; (d) 9, NaOH, DMSO; (e)
mCPBA, THF; (f) substituted benzyl bromide, hydroxyphenylacetic ester derivative, K2CO3,
NaI, DMF.
Biological results
To validate our design strategy, representative analogues 10a, 11a, 22a, 22b and 22g were
evaluated for their capacity to inhibit MtbTMPK activity. As shown in Table 1,
methylthiopyridone analogue 10a was 7-fold less active than reported compound 5.
Surprisingly, the sulfoxide-modified analogues 11a, 22a, 22b and 22g failed to exhibit any
enzyme inhibitory potency, contradicting our docking result and the remarkable inhibitory
activity observed for several 5,6-disubstituted analogues reported earlier by AstraZeneca.[22]
The inconsistency of the experimental results with the in-silico model are likely attributable to
the 5-phenyl ring, which unlike the 3-functionalized piperidine in 2 is unable to adapt a chair
conformation, which favours hydrophobic interactions with the relevant residues in the active
site of MtbTMPK (Figure 2A).
Despite the lack of enzyme inhibitory potency, these compounds do exert significant
antimycobacterial activity in vitro (Table 1), suggesting that they might interact with another

protein. Methylthiopyridone analogue 10a did not display in vitro antimycobacterial activity, but
oxidation to the sulfoxide 11a resulted in modest activity, comparable to the 6-substitued
analogue 5.[22] Interestingly, the phenoxy analogues of 11a (22a, 22b and 22g) retained
antimycobacterial activity, regardless of the position of the phenoxy substituent on the phenyl
ring. These analogues proved more potent in minimal (GAST/Fe) medium possibly reflecting
increased metabolic dependence of the cells on the activity of the putative target under these
growth conditions. Importantly, the active compounds 11a, 22a, 22b and 22g did not display
severe cytotoxicity with compound 22g showing selectivity index (SI) over 20 for minimal
(GAST/Fe) condition.
Table 1. The MtbTMPK enzymatic activity, antimycobacterial activity (H37Rv) and cytotoxicity
against MRC-5 fibroblasts of representative compounds.
M. tuberculosis MICa (μM)
Comp.
5
R
X
S
MtbTMPK IC50 (μM) 7H9/glucose
GAST/Fe MRC-5 (μM)
28
19
19
-
10a
H
H
206
100
25
≥100
37
64
>64
30
32
>64
-
11a
SO NI
22a
2-PhO SO NI
3-PhO SO NI
4-PhO SO NI
50
9.4
22b
37
6.25
3.13
0.2
22g
25
Isoniazid
0.15
aMinimum inhibitory concentration (MIC) is the minimum concentration required to inhibit >99%
growth of M. tuberculosis H37Rv in liquid culture. NI: no inhibition at 0.2 mM
Further substitution of the phenyl ring of 11a indicated that sterically demanding and
moderately electron withdrawing substituents, such as the 4-bromo substituent in 11g,

contribute favourably to the whole-cell activity (Table 2), while strongly electron withdrawing
substituents negatively affected the activity (11h). In addition, the use of polar electron
donating groups such as a methoxy group as found in analogue 11b appears to have a
negative effect on the activity. On the other hand, the position (o, m, p) of the substituent only
had a small effect on the in vitro activity against the organism. None of the analogues (11b-11h)
displayed appreciable cytotoxicity against human fibroblasts.
Table 2. Antimycobacterial activity (H37Rv) and cytotoxicity against MRC-5 fibroblasts of
compounds.
M. tuberculosis MICa (μM)
Structure
Substituent
R1 = H
Comp.
7H9/glucose
25
GAST/Fe
37
MRC-5 (μM)
11a
>64
R1 = 2-Cl
11e
12.5
37
>64
R1 = 3-Cl
R1 = 4-Cl
R1 = 4-Br
R1 = 4-CF3
R1 = 3,4-Cl2
R1 = 4-OMe
X = SO
11f
19
37
>64
>64
>64
>64
>64
>64
16.44
11c
11g
11h
11d
11b
13
19
25
12.5
37
19
19
19
12.5
>100
≥50
>100
50
X = SO2
14
37
19
>64
>64
>64
R2 = 2-Cl
R2 = 3-Cl
R2 = 4-CF3
12e
12f
12h
37
>50
>50
>50
>50
>50
0.2
>64
-
Isoniazid 0.15
aMinimum inhibitory concentration (MIC) is the minimum concentration required to inhibit >99%
growth of M. tuberculosis H37Rv in liquid culture.

Hydrolysing the cyano group of 11d into a carboxyamide (13) was at the expense of
antimycobacterial activity and selectivity, which could be partially restored by oxidation of the
sulfoxide to a sulfone (14), suggesting that a sulfone moiety could be a favourable factor for
the whole-cell activity. However, the favourable influence of a sulfone was found not to be a
general rule since oxidation of sulfoxides 11e, 11f and 11h to their corresponding sulfones
(12e, 12f and 12h), resulted in loss of antimycobacterial activity.
Since modification on both cyanopyridone core and phenyl ring of compound 11a failed to
afford substantial improvements in antimycobacterial activity, we shifted our attention to
scaffolds 22b and 22g (Table 3). Introduction of different substituents on the distal phenyl ring
of 22b, resulted in analogues with improved antimycobacterial activity (e.g. 22c and 22f). Also,
replacing the phenoxy substituent of 22b by a benzyloxy was found to be beneficial for the
whole-cell activity, with several analogues exhibiting MIC values below 10 μM upon further
substitution (27b-27e). Also, several substituted p-aryloxy analogues (derived from 22g)
showed promising activity. These results indicated that p-aryloxy analogues (22g) slightly
higher activity than their meta congeners (22b). Moreover, in agreement with our previous
statement, polar and electron rich moieties have a negative impact on antimycobacterial
activity (22j). Interestingly, a further increase of the lipophilicity by elimination of the oxygen of
the diarylether motif of 22g led to biphenyl analogue 11i, which showed significantly improved
activity and was the most potent antimycobacterial analogue in both media. Additionally, the
switch from a diphenylether to a biphenyl motif reduced cytotoxicity with selectivity indices of
27.8 and 50 depending on the assay conditions.
Table 3. The antimycobacterial activity (H37Rv) and cytotoxicity against MRC-5 fibroblasts of
compounds.
M. tuberculosis MICa (μM)
Structure
Substituent
R1 = Ph
Comp.
7H9/glucose
37
GAST/Fe
6.25
MRC-5 (μM)
22b
32
R1 = 4-ClPh
22c
12.5
9.5
24
R1 = 4-CH3Ph
R1 = 4-OMePh
22d
22e
25
25
6.25
6.25
30
30

R1 = 3,4-Cl2Ph
R1 = PhCH2
22f
12.5
19
19
8
27a
27b
27c
27d
27e
27f
6.25
9.4
9.4
4.7
9.4
19
25
R1 = 4-ClPhCH2
R1 = 3,4-Cl2PhCH2
R1 = 2-ClPhCH2
R1 = 3-ClPhCH2
R1 = 2-NO2PhCH2
R2 = PhO
9.4
9.4
9.4
9.4
37
31
>64
25
>64
64
22g
25
3.13
>64
R2 = 4-ClPhO
22h
9.4
9.4
25
R2 = 4-MePhO
R2 = 4-OMePhO
R2 = 3,4-Cl2PhO
R2 = PhCH2O
R2 = Ph
22i
22j
22k
27g
11i
9.4
19
4.7
9.4
19
28
23
28
25
>64
-
9.4
9.4
1.2
4.7
2.3
0.2
Isoniazid 0.15
aMinimum inhibitory concentration (MIC) is the minimum concentration required to inhibit >99%
growth of M. tuberculosis H37Rv in liquid culture.
Conclusion
Guided by the co-crystal structures of MtbTMPK with compounds 2 and 4, 33 readily
synthesized pyridone analogues were prepared and evaluated for their antimycobacterial
activity. Despite the fact that a first subset of analogues showed no inhibition of the MtbTMPK
enzyme, these compounds displayed cellular activity against M. tuberculosis, implying a
different or additional mode of action of these compounds. Structure activity relationships
analysis revealed that the cyanopyridone moiety and sulfoxide group were indispensable for
antimycobacterial activity. Lipophilic and moderately electron withdrawing substituents on the
phenyl ring positively influence the whole-cell activity. Substitution of the phenyl ring of 11a or
the distal phenyl rings of 22b or 22g afforded analogues with MIC-values just above or under
10 µM. Moreover, these results showed that p-aryloxy scaffold is superior to m-aryloxy scaffold.

Importantly, removal of the ether linkage between the phenyl rings of 22g afforded more
lipophilic biphenyl analogue 11i with reduced cytotoxicity, showing 10-fold more potent
antimycobacterial activity than the literature compound 5, and therefore represents a
promising lead compound for further investigation.
Experimental part
Molecular modelling
Starting from publicly available complex crystal structure of MtbTMPK (PDB entry
4UNQ[22]), the molecular modelling was conducted using AutoDock vina and
AutodockTools-1.5.6.[31] After having minimized the energy in ChemDraw 3D 16.0, PDB files of
ligands were generated. All PDBQT files of receptor and ligands were generated in
AutodockTools-1.5.6. Centered on MtbTMPK active site PHE70 CE2 (the coordinates x, y, z
were 24.089, 33.504, −4.478 correspondingly), the prepared PDBQT files of ligands and
receptor were docked using a default grid spacing of 0.375 and 60 x 60 x 60 number of grid
points. Through Lamarckian 4.2 method, each ligand was docked 3 times in autodock vina,
affording total 60 possible conformations. All vinadock results were viewed and analyzed in
Chimera and LigPlus.
MtbTMPK assay
Mycobacterium tuberculosis thymidylate kinase (MtbTMPK) was expressed and purified as
previously reported[20]. The synthesized compounds were dissolved in DMSO and evaluated
by serial dilution at fixed concentration of dTMP (0.05 mM) and ATP (0.5 mM) according to the
spectrophotometric assay reported by Blondin et al.[32] The components of the reaction
medium were 50 mM Tris-HCl, pH 7.4, 50 mM KCl, 2 mM MgCl2, 0.2 mM NADH, 1 mM
phosphoenol pyruvate, and 2 units each of coupling enzymes (lactate dehydrogenase,
pyruvate kinase and nucleoside diphosphate kinase). IC50 value of each compound was
calculated with KaleidaGraph.
In vitro cytotoxicity assay
In vitro cytotoxicity on the MRC-5 Homo sapiens long fibroblast cell line (ATCC CCL-171) was
assessed for each analogue by a resazurin assay. The assay was conducted as previously
reported.[20]

Whole cell activity against M. tuberculosis
MIC values were determined as previously described.[33] Briefly, compounds were dissolved in
DMSO as 10 mM stocks. Isoniazid was used as a positive control, and DMSO as negative
control. M. tuberculosis H37Rv cells (ATCC 27294) were cultured to OD650nm 0.2-0.3 in the
respective medium and diluted 1000-fold in the medium for the MIC determination.
Compounds were 2-fold serially diluted in the required medium in clear, sterile round-bottom
96-well plates (Nunclon) at 50 mL per well in duplicates in a concentration range spanning
100-0.049 mM. An equal volume of the diluted cells equating to approximately 1× 104 bacteria
per well was added to each well. Plates were incubated at 37 for 1 week after which plates
were read with enlarging inverted mirror plate reader. The MIC was taken as the lowest
concentration that completely inhibited growth. The media was either GAST/Fe or
7H9/glucose/casitone/Tyloxapol. GAST/Fe medium (per liter) consisted of 0.3 g of Bacto
Casitone (Difco), 4.0 g of dibasic potassium phosphate, 2.0 g of citric acid, 1.0 g of L-alanine,
1.2 g of magnesium chloride hexahydrate, 0.6 g of potassium sulfate, 2.0 g of ammonium
chloride, 1.80 mL of 10 N sodium hydroxide, 10.0 mL of glycerol, 0.05% Tween 80, and 0.05 g
of ferric ammonium citrate adjusted to pH 6.6. The 7H9/glucose/casitone/Tyloxapol medium
(per liter) consisted of 4 g glucose, 4.7 g Middlebrook 7H9 broth base, 0.8 g NaCl, 0.3 g Bacto
casitone and 0.5 mL Tyloxapol.
Chemistry
All reagents and solvents were purchased from standard commercial sources and were of
analytical grade. All synthetic compounds described in this study were checked with analytical
TLC (Machery−Nagel precoated F254 aluminum plates), visualized under UV light at 254 nm,
and purified by column chromatography (CC) on a Reveleris X2 (Grace) automated flash unit.
All compounds were measured with Varian Mercury 300/75 MHz or a Bruker Avance Neo®
400/101 MHz spectrometer at 298.15 K using TMS as an internal standard. The analysis and
confirmation of final compounds were conducted with 1H, 13C, HSQC and HMBC NMR spectral
data, in assistant with high resolution mass spectrometry which was performed on a Waters
LCT Premier XETM time of flight (TOF) mass spectrometer equipped with a standard
electrospray ionization (ESI) and modular LockSpray TM interface. The purity of the tested
compounds was determined by LC - MS analysis (Waters AutoPurification system: a Waters

Cortecs C18 column (2.7 μm, 100 × 4.6 mm); a gradient system of formic acid in H2O (0.2%,
v/v)/MeCN; a flow rate of 1.44 mL/min; a gradient of 95:5 to 0:100 in 10 min.).
Atom numbering throughout the NMR follows the scheme below, atoms in the aryl ring of ester
intermediates are not explicitly assigned:
General procedure for the synthesis of aldehyde intermediates. To a solution of methyl phenyl
acetates (1.0 eq.) in dry THF (5 mL) was added LiAlH4 (2 eq.) at 0
under N2 atmosphere,
and the resulting mixture was stirred at room temperature for 1 h.[23] After complete
consumption of starting material, the reaction mixture was quenched with Na+/K+ tartrate
solution (~10 mL), and the mixture was filtered after being stirred at room temperature
overnight. The collected filtrate was dried and concentrated to afford crude alcohol
intermediate, which was oxidized by PCC (2 eq.) for 2 h in CH2Cl2 (5-10 mL).[24,25] The reaction
mixture was filtered through short silica column to remove brown side-product. The collected
filtrate was concentrated in vacuo for next step without any purification.
General procedure for the synthesis of final compounds. The obtained aldehyde intermediate
was treated with NaOH (2 eq.) and 9 in DMSO (1 mL) for 2 h to furnish key intermediate
methylthiopyridones,[22] which was oxidized by mCPBA in THF (4 mL) for 2-4 h to afford
desired compounds.
4-(Methylthio)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (10a) The suspension of
2-phenylacetaldehyde (0.2 g, 1.1 mmol) and NaOH (85 mg, 2.1 mmol) in DMSO (1 mL) was
added 9 (0.13 g, 1.1 mmol), and the reaction mixture was stirred at room temperature for 2 h to
give 10a (eluent system: 5% methanol in CH2Cl2, 0.16 g, 0.66 mmol, 62% yield). 1H NMR (300
MHz, DMSO-d6) δ ppm 2.37 (s, 3 H, SCH3), 7.32 - 7.46 (m, 5 H, H-2’, H-3’, H-4’, H-5’, H-6’),
7.52 (s, 1 H, H-6), 12.58 (br. s., 1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ ppm 17.5 (1 C,
SCH3), 102.6 (1 C, C-3), 115.8 (1 C, CN), 120.8 (1 C, C-5), 128.0 (1 C, C-4’), 128.4 (2 C, C-3’,
C-5’), 129.8 (2 C, C2’, C-6’), 134.9 (1 C, C-1’), 138.1 (1 C, C-6), 159.7 (1 C, C-2), 161.2 (1 C,
C-4). HRMS (ESI): m/z [M - H]- Calcd. for [C13H10N2OS - H]- 241.0441, found 241.0431.

4-(Methylsulfinyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (11a) To a solution of 10a
(0.13 g, 0.54 mmol) in dry THF (5 mL) was added mCPBA (75%, 0.12 g, 0.54 mmol), and the
reaction mixture was stirred at room temperature for 3 h to afford 11a (eluent system: 5%
methanol in CH2Cl2, 89 mg, 0.34 mmol, 64% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.75
(s, 3 H, SCH3), 7.25 - 7.51 (m, 5 H, H-2’, H-3’, H-4’, H-5’, H-6’), 7.75 (s, 1 H, H-6), 13.13 (br. s.,
1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ ppm 39.6 (1 C, SCH3), 112.4 (1 C, CN), 117.2 (1 C,
C-5), 128.5 (3 C, C-3’, C-4’, C-5’), 130.2 (2 C, C-2’, C-6’), 132.6 (1 C, C-1’), 140.6 (1 C, C-6),
160.4 (1 C, C-2), 165.7 (1 C, C-4), C (C-3) could not be observed. HRMS (ESI): m/z [M - H]-
Calcd. for [C13H10N2O2S - H]- 257.0390, found 257.0392.
5-(4-Methoxyphenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
(11b)
Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(4-methoxyphenyl)acetate (0.80 g, 4.4 mmol) was treated with LiAlH4
(0.34 g, 8.8 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with
PCC (1.2 g, 5.3 mmol) in CH2Cl2 (10 mL) to yield aldehyde. The suspension of aldehyde and
NaOH (0.13 g, 3.3 mmol) in DMSO (1 mL) was added 9 (0.31 g, 1.7 mmol) to give
methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 0.26 g, 1.2 mmol)
to afford 11b (eluent system: 5% methanol in CH2Cl2, 0.12 g, 0.42 mmol, 10% yield). 1H NMR
(300 MHz, DMSO-d6) δ ppm 2.75 (s, 3 H, SCH3), 3.79 (s, 3 H, OCH3), 6.91 - 7.05 (m, 2 H, Ph,
H-3’, H-5’), 7.20 - 7.37 (m, 2 H, H-2’, H-6’), 7.70 (s, 1 H, H-6), 13.07 (br. s., 1 H, NH). 13C NMR
(75 MHz, DMSO-d6) δ ppm 39.6 (1 C, SCH3), 55.2 (1 C, OCH3), 99.2 (1 C, C-3), 112.4 (1 C,
CN), 113.9 (2 C, C-3’, C-5’), 116.9 (1 C, C-5), 124.5 (1 C, C-1’), 131.5 (2 C, C-2’, C-6’), 140.4
(1 C, C-6), 159.4 (1 C, (CH3O)C-4’), 160.4 (1 C, C-2), 166.1 (1 C, C-4). HRMS (ESI): m/z [M -
H]- Calcd. for [C14H12N2O3S - H]- 287.0496, found 287.0495.
5-(4-Chlorophenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (11c) Following
the General procedure for the synthesis of aldehyde intermediates and final compounds,
methyl 2-(4-chlorophenyl)acetate (0.6 g, 3.3 mmol) was treated with LiAlH4 (0.25 g, 6.5 mmol)
in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.99 g, 4.6 mmol)
in CH2Cl2 (10 mL) to yield aldehyde. The suspension of aldehyde and NaOH (0.14 mg, 3.7

mmol) in DMSO (1 mL) was added 9 (0.35 g, 1.8 mmol) to give methylthiopyridone
intermediate, followed by oxidation with mCPBA (75%, 0.33 g, 1.4 mmol) to afford 11c (eluent
system: 5% methanol in CH2Cl2, 0.27 g, 0.92 mmol, 29% yield). 1H NMR (300 MHz, DMSO-d6)
δ ppm 2.75 (s, 3 H, SCH3), 7.39 (d, J = 7.4 Hz, 2 H, H-2’, H-6’), 7.48 (d, J = 7.4 Hz, 2 H, H-3’,
H-5’), 7.76 (s, 1 H, H-6), 13.14 (br. s., 1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ ppm 39.7 (1 C,
SCH3), 99.4 (1 C, C-3), 112.3 (1 C, CN), 115.9 (1 C, C-5), 128.5 (2 C, C-3’, C-5’), 131.5 (1 C,
C-1’), 132.2 (2 C, C-2’, C-6’), 133.5 (1 C, (Cl)C-4’), 140.9 (1 C, C-6), 160.3 (1 C, C-2), 165.6 (1
C, C-4). HRMS (ESI): m/z [M - H]- Calcd. for [C13H9ClN2O2S - H]- 291.0000, found 291.0007.
5-(3,4-Dichlorophenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
(11d)
Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(3,4-dichlorophenyl)acetate (0.54 g, 2.5 mmol) was treated with LiAlH4
(0.19 g, 4.9 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with
PCC (0.63 g, 2.9 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and
NaOH (88 mg, 2.2 mmol) in DMSO (1 mL) was added 9 (0.21 g, 1.1 mmol) to give
methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 0.13 g, 0.58 mmol)
to afford 11d (eluent system: 5% methanol in CH2Cl2, 89 mg, 0.27 mmol, 11% yield). 1H NMR
(300 MHz, DMSO-d6) δ ppm 2.77 (s, 3 H, SCH3), 7.39 (dd, J = 8.2, 2.1 Hz, 1 H, H-6’), 7.68 (d,
J = 8.2 Hz, 1 H, H-5’), 7.74 (d, J = 2.1 Hz, 1 H, H-2’), 7.82 (s, 1 H, H-6), 13.19 (br. s., 1 H, NH).
13C NMR (75 MHz, DMSO-d6) δ ppm 39.5 (1 C, SCH3), 99.3 (1 C, C-3), 112.2 (1 C, CN), 114.7
(1 C, C-5), 130.4 (1 C, C-5’), 130.8 (1 C, C-6’), 131.1 (1 C, (Cl)C-3’), 131.4 (1 C, (Cl)C-4’),
132.3 (1 C, C-2’), 133.3 (1 C, C-1’), 141.3 (1 C, C-6), 160.3 (1 C, C-2), 165.6 (1 C, C-4). HRMS
(ESI): m/z [M - H]- Calcd. for [C13H8Cl2N2O2S - H]- 324.9611, found 324.9604.
5-(2-Chlorophenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (11e) Following
the General procedure for the synthesis of aldehyde intermediates and final compounds,
methyl 2-(2-chlorophenyl)acetate (0.3 g, 1.6 mmol) was treated with LiAlH4 (0.12 g, 3.3 mmol)
in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.63 g, 2.9 mmol)
in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (0.12 g, 2.9 mmol)
in DMSO (1 mL) was added 9 (0.27 g, 1.5 mmol) to give methylthiopyridone intermediate,

followed by oxidation with mCPBA (75%, 0.21 g, 0.92 mmol) to afford 11e (eluent system: 5%
methanol in CH2Cl2, 0.16 g, 0.55 mmol, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.75
(d, J = 9.9 Hz, 3 H, SCH3), 7.41 - 7.47 (m, 2 H, H-3’, H-6’), 7.47 - 7.52 (m, 1 H, H-4’), 7.57 -
7.64 (m, 1 H, H-5’), 7.85 (d, J = 10 Hz, 1 H, H-6), 13.25 (br. s., 1 H, NH). 13C NMR (101 MHz,
DMSO-d6) δ ppm 39.7 (1 C, SCH3), 99.4 (1 C, C-3), 111.9 (1 C, CN), 113.7 (1 C, C-5), 127.46
(d, J = 47.0 Hz, 1 C, C-3’), 129.35 (d, J = 20.0 Hz, 1 C, C-5’), 131.0 (1 C, C-1’), 131.1 (1 C,
C-4’), 133.21 (d, J = 16.1 Hz, 1 C, C-6’), 133.80 (d, J = 7.5 Hz, 1 C, (Cl)C-2’), 141.65 (d, J =
71.2 Hz, 1 C, C-6), 160.4 (1 C, C-2), 166.0 (d, J = 59.9 Hz, 1 C, C-4). HRMS (ESI): m/z [M - H]-
Calcd. for [C13H9ClN2O2S - H]- 291.0000, found 291.0006.
5-(3-Chlorophenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (11f) Following
the General procedure for the synthesis of aldehyde intermediates and final compounds,
methyl 2-(3-chlorophenyl)acetate (0.3 g, 1.6 mmol) was treated with LiAlH4 (0.12 g, 3.3 mmol)
in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.70 g, 3.3 mmol)
in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (0.13 g, 3.2 mmol)
in DMSO (1 mL) was added 9 (0.30 g, 1.6 mmol) to give methylthiopyridone intermediate,
followed by oxidation with mCPBA (75%, 0.31 g, 1.3 mmol) to afford 11f (eluent system: 5%
methanol in CH2Cl2, 0.15 g, 0.51 mmol, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.79
(s, 3 H, SCH3), 7.36 (dt, J = 7.1, 1.6 Hz, 1 H, H-6’), 7.43 - 7.52 (m, 2 H, H-4’, H-5’), 7.54 (t, J =
1.6 Hz, 1 H, H-2’), 7.83 (s, 1 H, H-6), 13.20 (br. s.,1 H, NH). 13C NMR (101 MHz, DMSO-d6) δ
ppm 39.7 (1 C, SCH3), 99.4 (1 C, C-3), 112.3 (1 C, CN), 115.7 (1 C, C-5), 128.5 (1 C, C-4’),
129.2 (1 C, C-6’), 130.1 (1 C, C-2’), 130.3 (1 C, C-5’), 133.1 (1 C, (Cl)C-3’), 134.7 (1 C, C-1’),
141.1 (1 C, C-6), 160.3 (1 C, C-2), 165.6 (1 C, C-4). HRMS (ESI): m/z [M - H]- Calcd. for
[C13H9ClN2O2S - H]- 291.0000, found 290.9987.
5-(4-Bromophenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (11g) Following
the General procedure for the synthesis of aldehyde intermediates and final compounds,
methyl 2-(4-bromophenyl)acetate (0.3 g, 1.3 mmol) was treated with LiAlH4 (99 mg, 2.6 mmol)
in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.56 g, 2.6 mmol)
in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (90 mg, 2.2 mmol)

in DMSO (1 mL) was added 9 (0.21 g, 1.1 mmol) to give methylthiopyridone intermediate,
followed by oxidation with mCPBA (75%, 0.13 g, 0.58 mmol) to afford 11g (eluent system: 5%
methanol in CH2Cl2, 0.14 g, 0.42 mmol, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78
(s, 3 H, SCH3), 7.32 - 7.39 (m, 2 H, H-2’, H-6’), 7.61 - 7.67 (m, 2 H, H-3’, H-5’), 7.78 (s, 1 H,
H-6), 13.18 (br. s., 1 H, NH). 13C NMR (101 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH3), 99.4 (1 C,
C-3), 112.3 (1 C, CN), 116.0 (1 C, C-5), 122.2 (1 C, (Br)C-4’), 131.4 (2 C, C-3’, C-5’), 131.9 (1
C, C-1’), 132.5 (2 C, C-2’, C-6’), 140.8 (1 C, C-6), 160.3 (1 C, C-2), 165.6 (1 C, C-4). HRMS
(ESI): m/z [M + H]+ Calcd. for [C13H9BrN2O2S + H]+ 336.9641, found 336.9644.
4-(Methylsulfinyl)-2-oxo-5-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carbonitrile (11h)
Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(4-(trifluoromethyl)phenyl)acetate (0.3 g, 1.4 mmol) was treated with
LiAlH4 (0.10 g, 2.8 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized
with PCC (0.59 g, 2.8 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde
and NaOH (0.11 g, 2.7 mmol) in DMSO (1 mL) was added 9 (0.26 g, 1.4 mmol) to give
methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 0.21 g, 0.93 mmol)
to afford 11h (eluent system: 5% methanol in CH2Cl2, 0.15 g, 0.46 mmol, 35% yield). 1H NMR
(400 MHz, DMSO-d6) δ ppm 2.81 (s, 3 H, SCH3), 7.64 (d, J = 8.1 Hz, 2 H, H-2’, H-6’), 7.81 (d, J
= 8.3 Hz, 2 H, H-3’, H-5’), 7.86 (s, 1 H, H-6), 13.24 (br. s., 1 H, NH). 19F NMR (377 MHz,
DMSO-d6) δ ppm -61.1. 13C NMR (101 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH3), 99.6 (1 C,
C-3), 112.3 (1 C, CN), 115.9 (1 C, C-5), 124.11 (q, J = 273.0 Hz, 1 C, CF3), 125.30 (d, J = 3.7
Hz, 2 C, C-3’, C-5’), 128.86 (q, J = 32.0 Hz, 1 C, (CF3)C-4’), 131.3 (2 C, C-2’, C-6’), 137.0 (1 C,
C-1’), 141.2 (1 C, C-6), 160.3 (1 C, C-2), 165.4 (1 C, C-4). HRMS (ESI): m/z [M - H]- Calcd. for
[C14H9F3N2O2S - H]- 325.0264, found 325.0256.
5-([1,1'-Biphenyl]-4-yl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
(11i)
Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-([1,1'-biphenyl]-4-yl)acetate (0.3 g, 1.3 mmol) was treated with LiAlH4
(0.10 g, 2.7 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with
PCC (0.56 g, 2.6 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and

NaOH (91 mg, 2.3 mmol) in DMSO (1 mL) was added 9 (0.22 g, 1.1 mmol) to give
methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 0.11 g, 0.47 mmol)
to afford 11i (eluent system: 5% methanol in CH2Cl2, 77 mg, 0.23 mmol, 17% yield). 1H NMR
(300 MHz, DMSO-d6) δ ppm 2.80 (s, 3 H, SCH3), 7.33 - 7.52 (m, 5 H, H-2’, H-6’, H-3’’, H-4’’,
H-5’’), 7.71 (t, J = 7.5 Hz, 4 H, H-3’, H-5’, H-2’’, H-6’’), 7.80 (s, 1 H, H-6), 13.15 (br. s., 1 H, NH).
13C NMR (75 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH3), 99.4 (1 C, C-3), 112.4 (1 C, CN), 116.8
(1 C, C-5), 126.7 (4 C, C-3’, C-5’, C-2’’, C-6’’), 127.8 (1 C, C-4’’), 129.0 (2 C, C-3’’, C-5’’), 130.8
(2 C, C-2’, C-6’), 131.7 (1 C, C-1’), 139.2 (1 C, C-1’’), 140.1 (1 C, C-4’), 140.8 (1 C, C-6), 160.4
(1 C, C-2), 165.7 (1 C, C-4). HRMS (ESI): m/z [M - H]- Calcd. For [C19H14N2O2S - H]- 333.0703,
found 333.0702.
5-(2-Chlorophenyl)-4-(methylsulfonyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (12e) To
a
solution of 11e (90 mg, 0.31 mmol) in dry THF (5 mL) was added mCPBA (75%, 71 mg, 0.31
mmol), and the reaction mixture was stirred at room temperature for 2 h to afford 12e (eluent
system: 5% methanol in CH2Cl2, 32 mg, 0.10 mmol, 34% yield). 1H NMR (400 MHz, DMSO-d6)
δ ppm 3.25 (s, 3 H, SCH3), 7.34 - 7.47 (m, 3 H, H-3’, H-4’, H-6’), 7.48 - 7.53 (m, 1 H, H-5’), 7.98
(s, 1 H, H-6), 13.66 (br. s., 1 H, NH). 13C NMR (101 MHz, DMSO-d6) δ ppm 43.4 (1 C, SCH3),
102.7 (1 C, C-3), 113.5 (1 C, CN), 114.7 (1 C, C-5), 126.7 (1 C, C-3’), 128.7 (1 C, C-5’), 130.3
(1 C, C-4’), 132.5 (1 C, C-6’), 133.3 (1 C, C-1’), 134.3 (1 C, (Cl)C-2’), 144.9 (1 C, C-6), 155.1 (1
C, C-4), 160.3 (1 C, C-2). HRMS (ESI): m/z [M - H]- Calcd. for [C13H9ClN2O3S - H]- 306.9949,
found 306.9952.
5-(3-Chlorophenyl)-4-(methylsulfonyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (12f) To
a
solution of 11f (80 mg, 0.27 mmol) in dry THF (5 mL) was added mCPBA (75%, 62 mg, 0.27
mmol), and the reaction mixture was stirred at room temperature for 4 h to afford 12f (eluent
1
system: 5% methanol in CH2Cl2, 20 mg, 0.065 mmol, 23% yield). H NMR (400 MHz,
DMSO-d6) δ ppm 3.16 (s, 3 H, SCH3), 7.34 (dt, J = 7.5, 1.4 Hz, 1 H, H-6’), 7.38 - 7.51 (m, 3 H,
H-2’, H-4’, H-5’), 7.93 (s, 1 H, H-6), 13.61 (s, 1 H, NH). 13C NMR (101 MHz, DMSO-d6) δ ppm
43.9 (1 C, SCH3), 113.4 (1 C, CN), 116.2 (1 C, C-5), 128.2 (1 C, C-2’), 129.6 (2 C, C-5’, C-6’),
130.5 (1 C, C-4’), 132.3 (1 C, (Cl)C-3’), 136.5 (1 C, C-1’), 144.6 (1 C, C-6), 155.0 (1 C, C-4),

160.2 (1 C, C-2). C (C-3) could not be observed. HRMS (ESI): m/z [M - H]- Calcd. for
[C13H9ClN2O3S - H]- 306.9949, found 306.9934.
4-(Methylsulfonyl)-2-oxo-5-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carbonitrile (12h)
To a solution of 11h (60 mg, 0.18 mmol) in dry THF (5 mL) was added mCPBA (75%, 42 mg,
0.18 mmol), and the reaction mixture was stirred at room temperature for 4 h to afford 12h
(eluent system: 5% methanol in CH2Cl2, 20 mg, 0.058 mmol, 23% yield). 1H NMR (400 MHz,
DMSO-d6) δ ppm 3.20 (s, 3 H, SCH3), 7.59 (d, J = 8.0 Hz, 2 H, H-2’, H-6’), 7.77 (d, J = 8.1 Hz,
2 H, H-3’, H-5’), 7.95 (br. s., 1 H, H-6), 13.59 (br. s., 1 H, NH). 19F NMR (377 MHz, DMSO-d6) δ
ppm -61.1. 13C NMR (101 MHz, DMSO-d6) δ ppm 44.0 (1 C, SCH3), 103.6 (1 C, C-3), 113.5 (1
C, CN), 116.2 (1 C, C-5), 124.22 (q, J = 273.0 Hz, 1 C, CF3), 124.59 (q, J = 3.8 Hz, 2 C, C-3’,
C-5’), 128.58 (q, J = 31.0 Hz, 1 C, (CF3)C-4’), 131.6 (2 C, C-2’, C-6’), 139.0 (1 C, C-1’), 144.5
(1 C, C-6), 154.9 (1 C, C-4), 160.3 (1 C, C-2). HRMS (ESI): m/z [M - H]- Calcd. for
[C14H9F3N2O3S - H]- 341.0213, found 341.0217.
5-(3,4-Dichlorophenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
(13)
Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(3,4-dichlorophenyl)acetate (0.54 g, 2.5 mmol) was treated with LiAlH4
(0.19 g, 4.9 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with
PCC (0.63 g, 2.9 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and
NaOH (88 mg, 2.2 mmol) in DMSO (1 mL) was added 9 (0.21 g, 1.1 mmol) to give
methylthiopyridone intermediate, followed by hydrolysis in con. H2SO4 (10 mL) at 100 for 2 h
to afford amide intermediate.[28] Oxidation of the intermediate with mCPBA (75%, 82 mg, 0.36
mmol) in dry THF (4 mL) for 2 h afforded compound 13 (eluent system: 5% methanol in CH2Cl2,
79 mg, 0.23 mmol, 9% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.87 (s, 3 H, SCH3), 7.31
(dd, J = 8.2, 2.1 Hz, 1 H, H-6’), 7.45 (s, 1 H, H-6), 7.54 - 7.61 (m, 2 H, H-2’, H-5’), 7.63 (br. s., 1
H, (CO)NH2), 8.36 (br. s., 1 H, (CO)NH2), 12.59 (br. s., 1 H, NH). 13C NMR (75 MHz, DMSO-d6)
δ ppm 42.4 (1 C, SCH3), 115.5 (1 C, C-5), 123.7 (1 C, C-3), 129.4 (1 C, C-5’), 130.0 (1 C,
(Cl)C-3’), 130.1 (1 C, (Cl)C-4’), 131.0 (1 C, C-6’), 132.4 (1 C, C-2’), 135.9 (1 C, C-1’), 138.7 (1

C, C-6), 158.2 (1 C, C-4), 169.9 (1 C, C-2), 165.1 (1 C, CO(NH2)). HRMS (ESI): m/z [M - H]-
Calcd. for [C13H10Cl2N2O3S - H]- 342.9716, found 342.9702.
5-(3,4-Dichlorophenyl)-4-(methylsulfonyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (14) To a
solution of 13 (40 mg, 0.12 mmol) in dry THF was added mCPBA (75%, 27 mg, 0.12 mmol),
and the reaction mixture was stirred for 3 h to afford 14 (eluent system: 5% methanol in CH2Cl2,
1
33 mg, 0.091 mmol, 79% yield). H NMR (300 MHz, DMSO-d6) δ ppm 3.15 (s, 3 H, SCH3),
7.30 (dd, J = 8.4, 1.6 Hz, 1 H, H-6’), 7.44 - 7.62 (m, 4 H, (CO)NH2, H-6, H-2’, H-5’), 7.71 (br. s.,
1 H, (CO)NH2), 12.55 (br. s., 1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ ppm 45.4 (1 C, SCH3),
114.1 (1 C, C-5), 129.6 (1 C, C-5’), 130.1 (1 C, (Cl)C-3’), 130.4 (1 C, (Cl)C-4’), 131.0 (1 C,
C-6’), 132.3 (1 C, C-2’), 136.9 (1 C, C-1’), 138.1 (1 C, C-6), 145.2 (1 C, C-4), 159.7 (1 C, C-2),
165.5 (1 C, CO(NH2)), C (C-3) could not be observed. HRMS (ESI): m/z [M - H]- Calcd. for
[C13H10Cl2N2O4S - H]- 358.9665, found 358.9662.
4-(Methylsulfinyl)-2-oxo-5-(2-phenoxyphenyl)-1,2-dihydropyridine-3-carbonitrile
(22a)
According to a literature report,[29] methyl 2-(2-hydroxyphenyl)acetate (1.1 g, 8.1 mmol),
phenylboronic acid (2.9 g, 24 mmol), Cu(OAc)2 (2.9 g, 16 mmol), molecular sieves (1.5 g) and
pyridine (1.9 mL, 24 mmol) in 1,2-dichloroethane (50 mL) afforded the ester intermediate
methyl 2-(2-phenoxyphenyl)acetate 18a (eluent system: 10% ethylacetate in petroleum ether,
0.40 g, 1.6 mmol, 21% yield). 1H NMR (300 MHz, CDCl3) δ ppm 3.63 (s, 3 H, OCH3), 3.72 (s, 2
H, CH2), 6.90 (dd, J = 8.1, 1.0 Hz, 1 H, Ph), 6.95 - 7.01 (m, 2 H, Ph), 7.06 - 7.15 (m, 2 H, Ph),
7.21 - 7.37 (m, 4 H, Ph). 13C NMR (75 MHz, CDCl3) δ ppm 35.6 (1 C, CH2), 51.8 (1 C, OCH3),
118.3 (2 C, Ph), 118.8 (1 C, Ph), 123.0 (1 C, Ph), 123.6 (1 C, Ph), 125.8 (1 C, Ph), 128.6 (1 C,
Ph), 129.6 (2 C, Ph), 131.4 (1 C, Ph), 155.0 (1 C, Ph), 157.2 (1 C, Ph), 171.7 (1 C, CO).
Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(2-phenoxyphenyl)acetate (0.2 g, 0.83 mmol) was treated with LiAlH4
(63 mg, 1.7 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with
PCC (0.34 g, 1.6 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and
NaOH (57 mg, 1.4 mmol) in DMSO (1 mL) was added 9 (0.13 g, 0.71 mmol) to give
methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 0.10 g, 0.46 mmol)

to afford 22a (eluent system: 5% methanol in CH2Cl2, 68 mg, 0.19 mmol, 23% yield). 1H NMR
(300 MHz, DMSO-d6) δ ppm 2.78 (br. s., 3 H, SCH3), 6.88 (d, J = 7.9 Hz, 1 H, H-5’), 6.95 (d, J
= 7.9 Hz, 2 H, H-2’’, H-6’’), 7.12 (t, J = 8.0 Hz, 1 H, H-4’’), 7.21 (t, J = 7.4 Hz, 1 H, H-3’), 7.27 -
7.48 (m, 4 H, H-4’, H-6’, H-3’’, H-5’’), 7.75 (br. s., 1 H, H-6), 13.10 (br. s., 1 H, NH). 13C NMR
(75 MHz, DMSO-d6) δ ppm 39.5 (1 C, SCH3), 99.1 (1 C, C-3), 112.2 (1 C, CN), 117.8 (1 C,
C-5’), 118.8 (2 C, C-2’’, C-6’’), 123.6 (1 C, C-1’), 123.8 (1 C, C-3’), 123.9 (1 C, C-4’’), 130.1 (2
C, C-3’’, C-5’’), 131.0 (1 C, C-6’), 132.7 (1 C, C-4’), 141.4 (1 C, C-6), 154.4 (1 C, C-2’), 155.8 (1
C, C-1’’), 160.3 (1 C, C-2), C (C-4) and C (C-5) could not be observed. HRMS (ESI): m/z [M -
H]- Calcd. for [C19H14N2O3S - H]- 349.0652, found 349.0638.
4-(Methylsulfinyl)-2-oxo-5-(3-phenoxyphenyl)-1,2-dihydropyridine-3-carbonitrile
(22b)
According to a literature report,[29] methyl 2-(3-hydroxyphenyl)acetate (1.1 g, 8.1 mmol),
phenylboronic acid (2.9 g, 24 mmol), Cu(OAc)2 (2.9 g, 16 mmol), molecular sieves (1.5 g) and
pyridine (1.9 mL, 24 mmol) in 1,2-dichloroethane (50 mL) afforded the ester intermediate
methyl 2-(3-phenoxyphenyl)acetate 18b (eluent system: 10 % ethylacetate in petroleum ether,
0.80 g, 3.3 mmol, 41% yield). 1H NMR (300 MHz, CDCl3) δ ppm 3.62 (s, 2 H, CH2), 3.71 (s, 3 H,
OCH3), 6.90 - 6.95 (m, 1 H, Ph), 6.98 (t, J = 2.1 Hz, 1 H, Ph), 7.01 - 7.07 (m, 3 H, Ph), 7.13 (tt,
J = 7.4, 1.14 Hz, 1 H, Ph), 7.26 - 7.40 (m, 3 H, Ph). 13C NMR (75 MHz, CDCl3) δ ppm 40.9 (1 C,
CH2), 52.0 (1 C, OCH3), 117.3 (1 C, Ph), 119.0 (2 C, Ph), 119.7 (1 C, Ph), 123.3 (1 C, Ph),
124.0 (1 C, Ph), 129.7 (3 C, Ph), 135.7 (1 C, Ph), 156.9 (1 C, Ph), 157.4 (1 C, Ph), 171.6 (1 C,
CO). Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(3-phenoxyphenyl)acetate (0.2 g, 0.83 mmol) was treated with LiAlH4
(63 mg, 1.7 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with
PCC (0.35 g, 1.6 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and
NaOH (60 mg, 1.5 mmol) in DMSO (1 mL) was added 9 (0.14 g, 0.74 mmol) to give
methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 87 mg, 0.38 mmol)
to afford 22b (eluent system: 5% methanol in CH2Cl2, 57 mg, 0.16 mmol, 20% yield). 1H NMR
(300 MHz, DMSO-d6) δ ppm 2.75 (s, 3 H, SCH3), 6.99 - 7.07 (m, 4 H, H-2’, H-4’, H-2’’, H-6’’),
7.09 - 7.19 (m, 2 H, H-6’, H-4’’), 7.34 - 7.48 (m, 3 H, H-5’, H-3’’, H-5’’), 7.77 (s, 1 H, H-6), 13.12
(br. s., 1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH3), 99.3 (1 C, C-3), 112.3

(1 C, CN), 116.4 (1 C, C-5), 118.6 (1 C, C-2’), 118.8 (2 C, C-2’’, C-6’’), 120.3 (1 C, C-4’), 123.7
(1 C, C-4’’), 125.2 (1 C, C-6’), 130.1 (2 C, C-3’’, C-5’’), 130.3 (1 C, C-5’), 134.4 (1 C, C-1’),
140.7 (1 C, C-6), 156.3 (1 C, C-3'), 156.6 (1 C, C-1’’), 160.4 (1 C, C-2), 165.6 (1 C, C-4).
HRMS (ESI): m/z [M - H]- Calcd. for [C19H14N2O3S - H]- 349.0652, found 349.0649.
5-(3-(4-Chlorophenoxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
(22c) According to a literature report,[29] methyl 2-(3-hydroxyphenyl)acetate (0.60 g, 4.4
mmol), (4-chlorophenyl)boronic acid (2.1 g, 13 mmol), Cu(OAc)2 (1.6 g, 8.8 mmol), molecular
sieves (0.82 g) and pyridine (1.1 mL, 13 mmol) in 1,2-dichloroethane (50 mL) afforded the
ester intermediate methyl 2-(3-(4-chlorophenoxy)phenyl)acetate 18c (eluent system: 10%
1
ethylacetate in petroleum ether, 0.40 g, 1.4 mmol, 33% yield). H NMR (300 MHz, CDCl3) δ
ppm 3.62 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3), 6.87 - 6.99 (m, 4 H, Ph), 7.05 (d, J = 7.3 Hz, 1 H,
Ph), 7.25 - 7.34 (m, 3 H, Ph). 13C NMR (75 MHz, CDCl3) δ ppm 40.9 (1 C, CH2), 52.1 (1 C,
OCH3), 117.4 (1 C, Ph), 119.8 (1 C, Ph), 120.2 (2 C, Ph), 124.5 (1 C, Ph), 128.4 (1 C, Ph),
129.8 (2 C, Ph), 129.9 (1 C, Ph), 136.0 (1 C, Ph), 155.7 (1 C, Ph), 157.1 (1 C, Ph), 171.6 (1 C,
CO). Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(3-(4-chlorophenoxy)phenyl)acetate (0.2 g, 0.72 mmol) was treated with
LiAlH4 (55 mg, 1.5 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized
with PCC (0.31 g, 1.5 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde
and NaOH (42 mg, 1.1 mmol) in DMSO (1 mL) was added 9 (99 mg, 0.53 mmol) to give
methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 55 mg, 0.24 mmol)
to afford 22c (eluent system: 5% methanol in CH2Cl2, 41 mg, 0.11 mmol, 15% yield). 1H NMR
(300 MHz, DMSO-d6) δ ppm 2.75 (s, 3 H, SCH3), 7.01 - 7.10 (m, 4 H, H-2’, H-4’, H-2’’, H-6’’),
7.14 (dt, J = 7.6, 1.3 Hz, 1 H, H-6’), 7.36 - 7.49 (m, 3 H, H-5’, H-3’’, H-5’’), 7.76 (s, 1 H, H-6),
13.12 (br. s., 1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH3), 99.3 (1 C, C-3),
112.3 (1 C, CN), 116.3 (1 C, C-5), 118.9 (1 C, C-2’), 120.4 (2 C, C-2’’, C-6’’), 120.5 (1 C, C-4’),
125.7 (1 C, C-6’), 127.4 (1 C, (Cl)C-4’’), 130.0 (2 C, C-3’’, C-5’’), 130.4 (1 C, C-5’), 134.5 (1 C,
C-1’), 140.7 (1 C, C-6), 155.3 (1 C, C-1’’), 156.2 (1 C, C-3’), 160.3 (1 C, C-2), 165.7 (1 C, C-4).
HRMS (ESI): m/z [M - H]- Calcd. for [C19H13ClN2O3S - H]- 383.0262, found 383.0248.

4-(Methylsulfinyl)-2-oxo-5-(3-(p-tolyloxy)phenyl)-1,2-dihydropyridine-3-carbonitrile
(22d)
According to a literature report,[29] methyl 2-(3-hydroxyphenyl)acetate (0.60g, 4.4 mmol),
p-tolylboronic acid (1.8 g, 13 mmol), Cu(OAc)2 (1.6 g, 8.8 mmol), molecular sieves (0.8 g) and
pyridine (1.1 mL, 13 mmol) in 1,2-dichloroethane (50 mL) afforded the ester intermediate
methyl 2-(3-(p-tolyloxy)phenyl)acetate 18d (eluent system: 10% ethylacetate in petroleum
ether, 0.34 g, 1.3 mmol, 30% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.37 (s, 3 H, (Ph)CH3),
3.62 (s, 2 H, CH2), 3.72 (s, 3 H, OCH3), 6.89 - 6.99 (m, 4 H, Ph), 7.00 - 7.05 (m, 1 H, Ph), 7.14
- 7.21 (m, 2 H, Ph), 7.25 - 7.32 (m, 1 H, Ph). 13C NMR (75 MHz, CDCl3) δ ppm 20.6 (1 C,
(Ph)CH3), 40.9 (1 C, CH2), 51.9 (1 C, OCH3), 116.7 (1 C, Ph), 119.1 (3 C, Ph), 123.5 (1 C, Ph),
129.6 (1 C, Ph), 130.1 (2 C, Ph), 132.9 (1 C, Ph), 135.6 (1 C, Ph), 154.4 (1 C, Ph), 157.9 (1 C,
Ph), 171.6 (1 C, CO). Following the General procedure for the synthesis of aldehyde
intermediates and final compounds, methyl 2-(3-(p-tolyloxy)phenyl)acetate (0.2 g, 0.78 mmol)
was treated with LiAlH4 (59 mg, 1.6 mmol) in dry THF (5 mL) to give alcohol intermediate,
which was oxidized with PCC (0.28 g, 1.3 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The
suspension of aldehyde and NaOH (46 mg, 1.2 mmol) in DMSO (1 mL) was added 9 (0.11 g,
0.58 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%,
78 mg, 0.34 mmol) to afford 22d (eluent system: 5% methanol in CH2Cl2, 54 mg, 0.15 mmol,
19% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H, (Ph)CH3), 2.76 (s, 3 H, SCH3),
6.92 - 7.05 (m, 4 H, H-2’, H-4’, H-2’’, H-6’’), 7.10 (d, J = 7.6 Hz, 1 H, H-6’), 7.15 - 7.26 (m, 2 H,
H-3’’, H-5’’), 7.42 (t, J = 7.7 Hz, 1 H, H-5’), 7.77 (s, 1 H, H-6), 13.12 (br. s., 1 H, NH). 13C NMR
(101 MHz, DMSO-d6) δ ppm 20.3 (1 C, (Ph)CH3), 39.7 (1 C, SCH3), 99.5 (1 C, C-3), 112.3 (1 C,
CN), 116.5 (1 C, C-5), 118.1 (1 C, C-2’), 119.1 (2 C, C-2’’, C-6’’), 119.7 (1 C, C-4’), 124.8 (1 C,
C-6’), 130.2 (1 C, C-5’), 130.5 (2 C, C-3’’, C-5’’), 133.0 (1 C, (CH3)C-4’’), 134.3 (1 C, C-1’),
140.6 (1 C, C-6), 153.7 (1 C, C-1’’), 157.2 (1 C, C-3’), 160.4 (1 C, C-2), 165.7 (1 C, C-4).
HRMS (ESI): m/z [M - H]- Calcd. for [C20H16N2O3S - H]- 363.0809, found 363.0810.
5-(3-(4-Methoxyphenoxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
(22e) According to a literature report,[29] methyl 2-(3-hydroxyphenyl)acetate (0.60 g, 4.4
mmol), (4-methoxyphenyl)boronic acid (2.0 g, 13 mmol), Cu(OAc)2 (1.6 g, 8.8 mmol),
molecular sieves (0.8 g) and pyridine (1.1 mL, 13 mmol) in 1,2-dichloroethane (50 mL)

afforded the ester intermediate methyl 2-(3-(4-methoxyphenoxy)phenyl)acetate 18e (eluent
system: 10% ethylacetate in petroleum ether, 0.33 g, 1.2 mmol, 28% yield). 1H NMR (300 MHz,
CDCl3) δ ppm 3.60 (s, 2 H, CH2), 3.70 (s, 3 H, OCH3), 3.82 (s, 3 H, (Ph)OCH3), 6.82 - 6.87 (m,
1 H, Ph), 6.88 - 6.94 (m, 3 H, Ph), 6.95 - 7.03 (m, 3 H, Ph), 7.22 - 7.29 (m, 1 H, Ph). 13C NMR
(75 MHz, CDCl3) δ ppm 41.0 (1 C, CH2), 52.0 (1 C, OCH3), 55.6 (1 C, (Ph)OCH3), 114.8 (2 C,
Ph), 116.0 (1 C, Ph), 118.4 (1 C, Ph), 120.9 (2 C, Ph), 123.2 (1 C, Ph), 129.6 (1 C, Ph), 135.6
(1 C, Ph), 149.8 (1 C, Ph), 155.9 (1 C, Ph), 158.6 (1 C, Ph), 171.7 (1 C, CO). Following the
General procedure for the synthesis of aldehyde intermediates and final compounds, methyl
2-(3-(4-methoxyphenoxy)phenyl)acetate (0.2 g, 0.74 mmol) was treated with LiAlH4 (56 mg,
1.5 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.32 g,
1.5 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (46 mg,
1.2 mmol) in DMSO (1 mL) was added 9 (0.11 g, 0.58 mmol) to give methylthiopyridone
intermediate, followed by oxidation with mCPBA (75%, 95 mg, 0.42 mmol) to afford 22e (eluent
system: 5% methanol in CH2Cl2, 0.12 g, 0.32 mmol, 42% yield). 1H NMR (300 MHz, DMSO-d6)
δ ppm 2.74 (s, 3 H, SCH3), 3.75 (s, 3 H, OCH3), 6.89 - 7.08 (m, 7 H, H-2’, H-4’, H-6’, H-2’’, H-3’’,
H-5’’, H-6’’), 7.38 (t, J = 7.7, 1.3 Hz, 1 H, H-5’), 7.74 (s, 1 H, H-6), 13.09 (br. s., 1 H, NH). 13
C
NMR (75 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH3), 55.4 (1 C, OCH3), 99.4 (1 C, C-3), 112.4 (1
C, CN), 115.2 (2 C, C-3’’, C-5’’), 116.6 (1 C, C-5), 117.3 (1 C, C-2’), 118.9 (1 C, C-4’), 120.9 (2
C, C-2’’, C-6’’), 124.4 (1 C, C-6’), 130.1 (1 C, C-5’), 134.3 (1 C, C-1’), 140.6 (1 C, C-6), 148.9 (1
C, C-1’’), 155.8 (1 C, (CH3O)C-4’’), 158.0 (1 C, C-3’), 160.4 (1 C, C-2), 165.6 (1 C, C-4). HRMS
(ESI): m/z [M - H]- Calcd. for [C20H16N2O4S - H]- 379.0758, found 379.0753.
5-(3-(3,4-Dichlorophenoxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
(22f) According to a literature report,[29] methyl 2-(3-hydroxyphenyl)acetate (0.60 g, 4.4
mmol), (3,4-dichlorophenyl)boronic acid (2.5 g, 13 mmol), Cu(OAc)2 (1.6 g, 8.8 mmol),
molecular sieves (0.8 g) and pyridine (1.1 mL, 13 mmol) in 1,2-dichloroethane (50 mL)
afforded the ester intermediate methyl 2-(3-(3,4-dichlorophenoxy)phenyl)acetate 18f (eluent
system: 10% ethylacetate in petroleum ether, 0.73 g, 2.3 mmol, 53% yield). 1H NMR (300 MHz,
CDCl3) δ ppm 3.63 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3), 6.86 (dd, J = 8.9, 2.8 Hz, 1 H, Ph), 6.90 -
6.99 (m, 2 H, Ph), 7.06 - 7.12 (m, 2 H, Ph), 7.31 (d, J = 7.9 Hz, 1 H, Ph), 7.37 (d, J = 8.8 Hz, 1

H, Ph). 13C NMR (75 MHz, CDCl3) δ ppm 40.8 (1 C, CH2), 52.1 (1 C, OCH3), 117.8 (1 C, Ph),
118.0 (1 C, Ph), 120.2 (1 C, Ph), 120.3 (1 C, Ph), 125.1 (2 C, Ph), 130.0 (1 C, Ph), 130.9 (1 C,
Ph), 133.1 (1 C, Ph), 136.1 (1 C, Ph), 156.1 (1 C, Ph), 156.3 (1 C, Ph), 171.5 (1 C, CO).
Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(3-(3,4-dichlorophenoxy)phenyl)acetate (0.2 g, 0.64 mmol) was treated
with LiAlH4 (49 mg, 1.3 mmol) in dry THF (5 mL) to give alcohol intermediate, which was
oxidized with PCC (0.23 g, 1.1 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of
aldehyde and NaOH (28 mg, 0.71 mmol) in DMSO (1 mL) was added 9 (0.11 g, 0.58 mmol) to
give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 32 mg, 0.14
mmol) to afford 22f (eluent system: 5% methanol in CH2Cl2, 41 mg, 0.098 mmol, 16% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3 H, SCH3), 7.05 (dd, J = 8.8, 2.6 Hz, 1 H, H-6’’),
7.16 (br. s., 2 H, H-2’, H-4’), 7.21 (d, J = 7.5 Hz, 1 H, H-6’), 7.34 (d, J = 2.6 Hz, 1 H, H-2’’), 7.50
(t, J = 8.2 Hz, 1 H, H-5’), 7.66 (d, J = 8.9 Hz, 1 H, H-5’’), 7.80 (br. s., 1 H, H-6), 13.12 (br. s., 1 H,
NH). 13C NMR (101 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH3), 99.1 (1 C, C-3), 112.4 (1 C, CN),
116.2 (1 C, C-5), 118.9 (1 C, C-6’’), 119.3 (1 C, C-2’), 120.5 (1 C, C-2’’), 120.9 (1 C, C-4’),
125.6 (1 C, (Cl)C-4’’), 126.3 (1 C, C-6’), 130.5 (1 C, C-5’), 131.6 (1 C, C-5’’), 132.1 (1 C,
(Cl)C-3’’), 134.7 (1 C, C-1’), 141.0 (1 C, C-6), 155.6 (1 C, C-3’), 156.1 (1 C, C-1’’), 160.5 (1 C,
C-2), 165.5 (1 C, C-4). HRMS (ESI): m/z [M - H]- Calcd. for [C19H12Cl2N2O3S - H]- 416.9873,
found 416.9875.
4-(Methylsulfinyl)-2-oxo-5-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carbonitrile
(22g)
According to a literature report,[29] methyl 2-(4-hydroxyphenyl)acetate (0.60 g, 4.4 mmol),
phenylboronic acid (1.6 g, 13 mmol), Cu(OAc)2 (1.6 g, 8.8 mmol), molecular sieves (0.8 g) and
pyridine (1.1 mL, 13 mmol) in 1,2-dichloroethane (50 mL) afforded the ester intermediate
methyl 2-(4-phenoxyphenyl)acetate 18g (eluent system: 10% ethylacetate in petroleum ether,
0.66 g, 2.7 mmol, 62% yield). 1H NMR (300 MHz, CDCl3) δ ppm 3.63 (s, 2 H, CH2), 3.72 (s, 3 H,
OCH3), 6.95 - 7.06 (m, 4 H, Ph), 7.08 - 7.15 (m, 1 H, Ph), 7.23 - 7.29 (m, 2 H, Ph), 7.31 - 7.39
(m, 2 H, Ph). 13C NMR (75 MHz, CDCl3) δ ppm 40.3 (1 C, CH2), 52.0 (1 C, OCH3), 118.8 (4 C,
Ph), 123.2 (1 C, Ph), 128.7 (1 C, Ph), 129.6 (2 C, Ph), 130.5 (2 C, Ph), 156.3 (1 C, Ph), 157.0
(1 C, Ph), 172.0 (1 C, CO). Following the General procedure for the synthesis of aldehyde

intermediates and final compounds, methyl 2-(4-phenoxyphenyl)acetate (0.2 g, 0.83 mmol)
was treated with LiAlH4 (63 mg, 1.6 mmol) in dry THF (5 mL) to give alcohol intermediate,
which was oxidized with PCC (0.3 g, 1.4 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The
suspension of aldehyde and NaOH (50 mg, 1.3 mmol) in DMSO (1 mL) was added 9 (0.12 g,
0.63 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%,
67 mg, 0.29 mmol) to afford 22g (eluent system: 5% methanol in CH2Cl2, 76 mg, 0.22 mmol,
26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.79 (s, 3 H, SCH3), 7.00 - 7.05 (m, 2 H, H-3’,
H-5’), 7.06 - 7.10 (m, 2 H, H-2’’, H-6’’), 7.20 (t, J = 7.2 Hz, 1 H, H-4’’), 7.35 - 7.40 (m, 2 H, H-2’,
H-6’), 7.41 - 7.46 (m, 2 H, H-3’’, H-5’’), 7.76 (s, 1 H, H-6), 13.13 (br. s., 1 H, NH). 13C NMR (101
MHz, DMSO-d6) δ ppm 39.6 (1 C, SCH3), 99.3 (1 C, C-3), 112.3 (1 C, CN), 116.6 (1 C, C-5),
117.9 (2 C, C-3’, C-5’), 119.3 (2 C, C-2’’, C-6’’), 124.1 (1 C, C-4’’), 127.3 (1 C, C-1’), 130.2 (2 C,
C-3’’, C-5’’), 132.0 (2 C, C-2’, C-6’), 140.6 (1 C, C-6), 155.9 (1 C, C-1’’), 157.2 (1 C, C-4’),
160.4 (1 C, C-2), 165.9 (1 C, C-4). HRMS (ESI): m/z [M - H]- Calcd. for [C19H14N2O3S - H]-
349.0652, found 349.0654.
5-(4-(4-Chlorophenoxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
(22h) According to a literature report,[29] methyl 2-(4-hydroxyphenyl)acetate (0.30 g, 2.2
mmol), (4-chlorophenyl)boronic acid (1.0 g, 6.6 mmol), Cu(OAc)2 (0.80 g, 4.4 mmol),
molecular sieves (0.40 g) and pyridine (0.53 mL, 6.6 mmol) in 1,2-dichloroethane (25 mL)
afforded the ester intermediate methyl 2-(4-(4-chlorophenoxy)phenyl)acetate 18h (eluent
system: 10% ethylacetate in petroleum ether, 0.30 g, 1.1 mmol, 49% yield). 1H NMR (400 MHz,
CDCl3) δ ppm 3.62 (s, 2 H, CH2), 3.72 (s, 3 H, OCH3), 6.92 - 6.98 (m, 4 H, Ph), 7.23 - 7.31 (m,
4 H, Ph). 13C NMR (101 MHz, CDCl3) δ ppm 40.3 (1 C, CH2), 52.1 (1 C, OCH3), 118.9 (2 C, Ph),
120.0 (2 C, Ph), 128.3 (1 C, Ph), 129.2 (1 C, Ph), 129.7 (2 C, Ph), 130.7 (2 C, Ph), 155.8 (1 C,
Ph), 156.0 (1 C, Ph), 172.0 (1 C, CO). Following the General procedure for the synthesis of
aldehyde intermediates and final compounds, methyl 2-(4-(4-chlorophenoxy)phenyl)acetate
(0.2 g, 0.72 mmol) was treated with LiAlH4 (55 mg, 1.5 mmol) in dry THF (5 mL) to give alcohol
intermediate, which was oxidized with PCC (0.26 g, 1.2 mmol) in CH2Cl2 (5 mL) to yield
aldehyde. The suspension of aldehyde and NaOH (39 mg, 0.97 mmol) in DMSO (1 mL) was
added 9 (91 mg, 0.48 mmol) to give methylthiopyridone intermediate, followed by oxidation

with mCPBA (75%, 61 mg, 0.27 mmol) to afford 22h (eluent system: 5% methanol in CH2Cl2,
91 mg, 0.24 mmol, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.79 (s, 3 H, SCH3), 7.04
- 7.13 (m, 4 H, H-3’, H-5’, H-2’’, H-6’’), 7.36 - 7.43 (m, 2 H, H-2’, H-6’), 7.45 - 7.51 (m, 2 H, H-3’’,
H-5’’), 7.77 (s, 1 H, H-6), 13.13 (br. s., 1 H, NH). 13C NMR (101 MHz, DMSO-d6) δ ppm 39.6 (1
C, SCH3), 99.3 (1 C, C-3), 112.3 (1 C, CN), 116.5 (1 C, C-5), 118.2 (2 C, C-3’, H-5’), 120.9 (2 C,
C-2’’, C-6’’), 127.7 (1 C, C-1’), 127.8 (1 C, (Cl)C-4’’), 130.0 (2 C, C-3’’, C-5’’), 132.2 (2 C, C-2’,
C-6’), 140.7 (1 C, C-6), 154.9 (1 C, C-1’’), 156.7 (1 C, C-4’), 160.4 (1 C, C-2), 165.9 (1 C, C-4).
HRMS (ESI): m/z [M - H]- Calcd. for [C19H13ClN2O3S - H]- 383.0262, found 383.0258.
4-(Methylsulfinyl)-2-oxo-5-(4-(p-tolyloxy)phenyl)-1,2-dihydropyridine-3-carbonitrile (22i)
According to a literature report,[29] methyl 2-(4-hydroxyphenyl)acetate (0.30 g, 2.2 mmol),
p-tolylboronic acid (0.90 g, 6.6 mmol), Cu(OAc)2 (0.80 g, 4.4 mmol), molecular sieves (0.40 g)
and pyridine (0.53 mL, 6.6 mmol) in 1,2-dichloroethane (25 mL) afforded the ester
intermediate methyl 2-(4-(p-tolyloxy)phenyl)acetate 18i (eluent system: 10% ethylacetate in
petroleum ether, 0.18 g, 0.70 mmol, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.35 (s, 3 H,
(Ph)CH3), 3.61 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3), 6.90 - 6.97 (m, 4 H, Ph), 7.15 (d, J = 8.1 Hz,
2 H, Ph), 7.23 (d, J = 8.8 Hz, 2 H, Ph). 13C NMR (101 MHz, CDCl3) δ ppm 20.7 (1 C, (Ph)CH3),
40.3 (1 C, CH2), 52.0 (1 C, OCH3), 118.3 (2 C, Ph), 119.1 (2 C, Ph), 128.3 (1 C, Ph), 130.2 (2 C,
Ph), 130.5 (2 C, Ph), 133.0 (1 C, Ph), 154.6 (1 C, Ph), 156.9 (1 C, Ph), 172.1 (1 C, CO).
Following the General procedure for the synthesis of aldehyde intermediates and final
compounds, methyl 2-(4-(p-tolyloxy)phenyl)acetate (0.2 g, 0.78 mmol) was treated with LiAlH4
(59 mg, 1.6 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with
PCC (0.29 g, 1.3 mmol) in CH2Cl2 (5 mL) to yield aldehyde. The suspension of aldehyde and
NaOH (54 mg, 1.4 mmol) in DMSO (1 mL) was added 9 (0.13 g, 0.67 mmol) to give
methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 72 mg, 0.32 mmol)
to afford 22i (eluent system: 5% methanol in CH2Cl2, 0.11 g, 0.30 mmol, 38% yield). 1H NMR
(400 MHz, DMSO-d6) δ ppm 2.31 (s, 3 H, (Ph)CH3), 2.79 (s, 3 H, SCH3), 6.98 (dx2, J = 8.5 Hz,
4 H, H-3’, H-5’, H-2’’, H-6’’), 7.24 (d, J = 8.1 Hz, 2 H, H-3’’, H-5’’), 7.35 (d, J = 8.6 Hz, 2 H, H-2’,
H-6’), 7.75 (s, 1 H, H-6), 13.12 (br. s., 1 H, NH). 13C NMR (101 MHz, DMSO-d6) δ ppm 20.3 (1
C, (Ph)CH3), 39.7 (1 C, SCH3), 99.3 (1 C, C-3), 112.4 (1 C, CN), 116.6 (1 C, C-5), 117.4 (2 C,