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

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 synthesized 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 methyl phenylacetates were reduced with LiAlH₄^[23] 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, DCM; (c) 9, NaOH, DMSO; (d) mCPBA, THF; (e) (i) con.H₂SO₄, 100 °C; (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, DCE; (b) LiAlH₄, THF; (c) PCC, DCM; (d) 9, NaOH, DMSO; (e) mCPBA, THF; (f) substituted benzyl bromide, hydroxyphenylacetic ester derivative, K₂CO₃, NaI, DMF.

Biological assays

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]

Table 1.

The MtbTMPK enzymatic activity, antimycobacterial activity (H37Rv) and cytotoxicity against MRC-5 fibroblasts of representative compounds.

				M. tuberculosis MICa (μM)
Comp.	R	X	MtbTMPK IC50 (μM)	7H9/glucose	GAST/Fe	MRC-5 (μM)
5			28	19	19	-
10a	H	S	206	100	≥100	64
11a	H	SO	NI	25	37	>64
22a	2-PhO	SO	NI	50	9.4	30
22b	3-PhO	SO	NI	37	6.25	32
22g	4-PhO	SO	NI	25	3.13	>64

^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

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.

Further substitution of the phenyl ring of 11a indicated that electron withdrawing substituents contribute favourably to the whole-cell activity (Table 2). On the other hand, the position 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	Comp.	7H9/glucose	GAST /Fe	MRC-5 (μM)
	R1 = H	11a	25	37	>64
	R1 = 2-Cl	11e	12.5	37	>64
	R1 = 3-Cl	11f	19	37	>64
	R1 = 4-Cl	11c	19	25	>64
	R1 = 4-Br	11g	12.5	19	>64
	R1 = 4-CF3	11h	37	19	>64
	R1 = 3,4-Cl2	11d	19	12.5	>64
	R1 = 4-OMe	11b	>100	>100	>64
	X = SO	13	50	≥50	16.44
	X = SO2	14	37	19	>64
	R2 = 2-Cl	12e	37	>50	>64
	R2 = 3-Cl	12f	>50	>50	>64
	R2 = 4-CF3	12h	>50	>50	>64

^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. Interestingly, biphenyl analogue 11i was the most potent antimycobacterial analogue in both media without showing noticeable cytotoxicity against MRC-5 fibroblasts.

Table 3.

The antimycobacterial activity (H37Rv) and cytotoxicity against MRC-5 fibroblasts of compounds.

			M. tuberculosis MICa (μM)
Structure	Substituent	Comp.	7H9/glucose	GAST /Fe	MRC-5 (μM)
	R1 = Ph	22b	37	6.25	32
	R1 = 4-ClPh	22c	12.5	9.5	24
	R1 = 4-CH3Ph	22d	25	6.25	30
	R1 = 4-OMePh	22e	25	6.25	30
	R1 = 3,4-Cl2Ph	22f	12.5	19	8
	R1 = PhCH2	27a	19	6.25	25
	R1 = 4-ClPhCH2	27b	9.4	9.4	31
	R1 = 3,4-Cl2PhCH2	27c	9.4	9.4	>64
	R1 = 2-ClPhCH2	27d	9.4	4.7	25
	R1 = 3-ClPhCH2	27e	9.4	9.4	>64
	R1 = 2-NO2PhCH2	27f	37	19	64
	R2 = PhO	22g	25	3.13	>64
	R2 = 4-ClPhO	22h	9.4	9.4	25
	R2 = 4-MePhO	22i	9.4	4.7	28
	R2 = 4-OMePhO	22j	19	9.4	23
	R2 = 3,4-Cl2PhO	22k	9.4	19	28
	R2 = PhCH2O	27g	9.4	4.7	25
	R2 = Ph	11i	1.2	2.3	>64

^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. Structure activity relationships analysis revealed that the cyanopyridone moiety and sulfoxide group were indispensable for antimycobacterial 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. Importantly, removal of the ether linkage between the phenyl rings of 22g afforded biphenyl analogue 11i 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 ligand 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 Mycobacterium 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 OD_650nm 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 °C 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 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 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.).

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 °C 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 DCM (5-10 mL).^[24,25] The reaction mixture was filtered through short silica column to remove brown side-product. The collected filter 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, Ph), 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, Ph), 128.4 (2 C, Ph), 129.8 (2 C, Ph), 134.9 (1 C, Ph), 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, Ph), 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, Ph), 130.2 (2 C, Ph), 132.6 (1 C, Ph), 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 DCM (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), 7.20 - 7.37 (m, 2 H, Ph), 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, Ph), 116.9 (1 C, C-5), 124.5 (1 C, Ph), 131.5 (2 C, Ph), 140.4 (1 C, C-6), 159.4 (1 C, Ph), 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 DCM (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), 7.26 - 7.60 (m, 4 H, Ph), 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, Ph), 131.5 (1 C, Ph), 132.2 (2 C, Ph), 133.5 (1 C, Ph), 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 DCM (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, Ph), 7.68 (d, J = 8.2 Hz, 1 H, Ph), 7.74 (d, J = 2.1 Hz, 1 H, Ph), 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, Ph), 130.8 (1 C, Ph), 131.1 (1 C, Ph), 131.4 (1 C, Ph), 132.3 (1 C, Ph), 133.3 (1 C, Ph), 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 DCM (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, Ph), 7.47 - 7.52 (m, 1 H, Ph), 7.57 - 7.64 (m, 1 H, Ph), 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 Hz, 1 C, Ph), 129.35 (d, J = 20 Hz, 1 C, Ph), 131.0 (1 C, Ph), 131.1 (1 C, Ph), 133.21 (d, J = 16 Hz, 1 C, Ph), 133.80 (d, J = 7.5 Hz, 1 C, Ph), 141.65 (d, J = 71 Hz, 1 C, C-6), 160.4 (1 C, C-2), 166.3 (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 DCM (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, Ph), 7.43 - 7.52 (m, 2 H, Ph), 7.54 (t, J = 1.6 Hz, 1 H, Ph), 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, Ph), 129.2 (1 C, Ph), 130.1 (1 C, Ph), 130.3 (1 C, Ph), 133.1 (1 C, Ph), 134.7 (1 C, Ph), 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 DCM (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, Ph), 7.61 - 7.67 (m, 2 H, Ph), 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, Ph), 131.4 (2 C, Ph), 131.9 (1 C, Ph), 132.5 (2 C, Ph), 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 DCM (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, Ph), 7.81 (d, J = 8.3 Hz, 2 H, Ph), 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 (d, J = 273 Hz, 1 C, CF₃), 125.30 (d, J = 3.7 Hz, 2 C, Ph), 128.86 (q, J = 32 Hz, 1 C, Ph), 131.3 (2 C, Ph), 137.0 (1 C, Ph), 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 DCM (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, Ph), 7.71 (t, J = 7.5 Hz, 4 H, Ph), 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 (3 C, Ph), 127.8 (1 C, Ph), 129.0 (2 C, Ph), 130.8 (3 C, Ph), 131.7 (1 C, Ph), 139.2 (1 C, Ph), 140.1 (1 C, C-6), 140.8 (1 C, Ph), 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, Ph), 7.48 - 7.53 (m, 1 H, Ph), 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-4), 126.7 (1 C, Ph), 128.7 (1 C, Ph), 130.3 (1 C, Ph), 132.5 (1 C, Ph), 133.3 (1 C, Ph), 134.3 (1 C, Ph), 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 system: 5% methanol in CH₂Cl₂, 20 mg, 0.065 mmol, 23% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.16 (s, 3 H, SCH₃), 7.34 (dt, J = 7.5, 1.4 Hz, 1 H), 7.38 - 7.51 (m, 3 H, Ph), 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, C-3), 116.2 (1 C, C-5), 128.2 (1 C, Ph), 129.6 (2 C, Ph), 130.5 (1 C, Ph), 132.3 (1 C, Ph), 136.5 (1 C, Ph), 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, Ph), 7.77 (d, J = 8.1 Hz, 2 H, Ph), 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 Hz, 1 C, CF₃), 124.59 (q, J = 3.8 Hz, 2 C, Ph), 128.58 (q, J = 31 Hz, 1 C, Ph), 131.6 (2 C, Ph), 139.0 (Ph), 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 DCM (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 °C for 2 h to afford amide intermediate.^[28] Oxidation of the intermediated 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, 9.0 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, Ph), 7.45 (s, 1 H, H-6), 7.54 - 7.61 (m, 2 H, Ph), 7.63 (br. s., 1 H, NH₂), 8.36 (br. s., 1 H, NH₂), 12.59 (br. s., 1 H, NH). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 42.4 (1 C, SCH₃), 115.9 (1 C, C-5), 124.2 (1 C, C-3), 129.9 (1 C, Ph), 130.5 (1 C, Ph), 130.6 (1 C, Ph), 131.5 (1 C, Ph), 132.8 (1 C, Ph), 136.3 (1 C, Ph), 139.2 (1 C, C-6), 158.7 (1 C, C-4), 160.4 (1 C, C-2), 165.5 (1 C, CONH₂). 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, 33 mg, 0.091 mmol, 79% yield). ¹H NMR (300 MHz, DMSO-d6) δ ppm 3.15 (s, 3 H, SCH₃), 7.30 (dd, J=8.4, 1.6 Hz, 1 H, Ph), 7.44 - 7.62 (m, 4 H, NH₂, Ph, H-6), 7.71 (br. s., 1 H, 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, Ph), 130.1 (1 C, Ph), 130.4 (1 C, Ph), 131.0 (1 C, Ph), 132.3 (1 C, Ph), 136.9 (1 C, Ph), 138.1 (1 C, C-6), 145.2 (1 C, C-4), 159.7 (1 C, C-2), 165.5 (1 C, CONH₂), 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, CH₃), 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, CH₃), 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 DCM (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, Ph), 6.95 (d, J = 7.9 Hz, 2 H, Ph), 7.12 (t, J = 8.0 Hz, 1 H, Ph), 7.21 (t, J = 7.4 Hz, 1 H, Ph), 7.27 - 7.48 (m, 4 H, Ph), 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, Ph), 118.8 (2 C, Ph), 123.6 (1 C, Ph), 123.8 (1 C, Ph), 123.9 (1 C, Ph), 130.1 (2 C, Ph), 131.0 (1 C, Ph), 132.7 (1 C, Ph), 141.4 (1 C, C-6), 154.4 (1 C, Ph), 155.8 (1 C, Ph), 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, CH₃), 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, CH₃), 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 DCM (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, Ph), 7.09 - 7.19 (m, 2 H, Ph), 7.34 - 7.48 (m, 3 H, Ph), 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, Ph), 118.8 (2 C, Ph), 120.3 (1 C, Ph), 123.7 (1 C, Ph), 125.2 (1 C, Ph), 130.1 (2 C, Ph), 130.3 (1 C, Ph), 134.4 (1 C, Ph), 140.7 (1 C, C-6), 156.3 (1 C, Ph), 156.6 (1 C, Ph), 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 (0.60g, 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% ethylacetate in petroleum ether, 0.40 g, 1.4 mmol, 33% yield). ¹H NMR (300 MHz, CDCl3) δ ppm 3.62 (s, 2 H, CH₂), 3.71 (s, 3 H, CH₃), 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, CH₃), 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 DCM (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, Ph), 7.14 (dt, J = 7.6, 1.3 Hz, 1 H, Ph), 7.36 - 7.49 (m, 3 H, Ph), 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, Ph), 120.4 (2 C, Ph), 120.5 (1 C, Ph), 125.7 (1 C, Ph), 127.4 (1 C, Ph), 130.0 (2 C, Ph), 130.4 (1 C, Ph), 134.5 (1 C, Ph), 140.7 (1 C, C-6), 155.3 (1 C, Ph), 156.2 (1 C, Ph), 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, 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, 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 DCM (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, CH₃), 2.76 (s, 3 H, SCH₃), 6.92 - 7.05 (m, 4 H, Ph), 7.10 (d, J = 7.6 Hz, 1 H, Ph), 7.15 - 7.26 (m, 2 H, Ph), 7.42 (t, J = 7.7 Hz, 1 H, Ph), 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, 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, Ph), 119.1 (2 C, Ph), 119.7 (1 C, Ph), 124.8 (1 C, Ph), 130.2 (1 C, Ph), 130.5 (2 C, Ph), 133.0 (1 C, Ph), 134.3 (1 C, Ph), 140.6 (1 C, C-6), 153.7 (1 C, Ph), 157.2 (1 C, Ph), 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, 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, 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 DCM (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, Ph), 7.38 (t, J = 7.7, 1.3 Hz, 1 H, Ph), 7.74 (s, 1 H, H-6), 13.09 (br. s., 1 H, NH). ¹³C 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, Ph), 116.6 (1 C, C-5), 117.3 (1 C, Ph), 118.9 (1 C, Ph), 120.9 (2 C, Ph), 124.4 (1 C, Ph), 130.1 (1 C, Ph), 134.3 (1 C, Ph), 140.6 (1 C, C-6), 148.9 (1 C, Ph), 155.8 (1 C, Ph), 158.0 (1 C, Ph), 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, CH₃), 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, CH₃), 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 DCM (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, Ph), 7.16 (br. s., 2 H, Ph), 7.21 (d, J = 7.5 Hz, 1 H, Ph), 7.34 (d, J = 2.6 Hz, 1 H, Ph), 7.50 (t, J = 8.2 Hz, 1 H, Ph), 7.66 (d, J = 8.9 Hz, 1 H, Ph), 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, Ph), 119.3 (1 C, Ph), 120.5 (1 C, Ph), 120.9 (1 C, Ph), 125.6 (1 C, Ph), 126.3 (1 C, Ph), 130.5 (1 C, Ph), 131.6 (1 C, Ph), 132.1 (1 C, Ph), 134.7 (1 C, Ph), 141.0 (1 C, C-6), 155.6 (1 C, Ph), 156.1 (1 C, Ph), 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, CH₃), 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, CH₃), 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 DCM (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 2.77 (s, 3 H, SCH₃), 7.06 (d, J = 8.4 Hz, 4 H, Ph), 7.11 - 7.20 (m, 2 H, Ph), 7.38 - 7.49 (m, 3 H, Ph), 7.79 (s, 1 H, H-6), 13.14 (br. s., 1 H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 40.2 (1 C, SCH₃), 99.4 (1 C, C-3), 112.3 (1 C, CN), 116.4 (1 C, C-5), 118.6 (1 C, Ph), 118.8 (2 C, Ph), 120.3 (1 C, Ph), 123.7 (1 C, Ph), 125.3 (1 C, Ph), 130.1 (2 C, Ph), 130.3 (1 C, Ph), 134.4 (1 C, Ph), 140.7 (1 C, C-6), 156.3 (1 C, Ph), 156.6 (1 C, Ph), 160.4 (1 C, C-2), 165.7 (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 DCM (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, Ph), 7.36 - 7.43 (m, 2 H, Ph), 7.45 - 7.51 (m, 2 H, Ph), 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, Ph), 120.9 (2 C, Ph), 127.8 (1 C, Ph), 127.8 (1 C, Ph), 130.0 (2 C, Ph), 132.2 (2 C, Ph), 140.7 (1 C, C-6), 154.9 (1 C, Ph), 156.7 (1 C, Ph), 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, 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, 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 DCM (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, PhCH₃), 2.79 (s, 3 H, SCH₃), 6.98 (d, J = 8.5 Hz, 4 H, Ph), 7.24 (d, J = 8.1 Hz, 2 H, Ph), 7.35 (d, J = 8.6 Hz, 2 H, Ph), 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, 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, Ph), 119.5 (2 C, Ph), 126.8 (1 C, Ph), 130.6 (2 C, Ph), 132.0 (2 C, Ph), 133.4 (1 C, Ph), 140.7 (1 C, C-6), 153.4 (1 C, Ph), 157.8 (1 C, Ph), 160.4 (1 C, C-2), 154.9 (1 C, C-4). HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₂₀H₁₆N₂O₃S-H]⁻ 363.0809, found 363.0810.

5-(4-(4-Methoxyphenoxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (22j)

According to a literature report,^[29] methyl 2-(4-hydroxyphenyl)acetate (0.30 g, 2.2 mmol), (4-methoxyphenyl)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-methoxyphenoxy)phenyl)acetate 18j (eluent system: 10% ethylacetate in petroleum ether, 0.38 g, 1.4 mmol, 63% yield). ¹H NMR (400 MHz, CDCl3) δ ppm 3.60 (s, 2 H, CH₂), 3.71 (s, 3 H, OCH₃), 3.81 (s, 3 H, PhOCH₃), 6.86 - 6.93 (m, 4 H, Ph), 6.96 - 7.01 (m, 2 H, Ph), 7.19 - 7.24 (m, 2 H, Ph). ¹³C NMR (101 MHz, CDCl3) δ ppm 40.3 (1 C, CH₂), 52.0 (1 C, OCH₃), 55.6 (1 C, PhOCH₃), 114.8 (2 C, Ph), 117.6 (2 C, Ph), 120.8 (2 C, Ph), 127.9 (1 C, Ph), 130.4 (2 C, Ph), 150.0 (1 C, Ph), 155.9 (1 C, Ph), 157.7 (1 C, Ph), 172.2 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(4-(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 DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (37 mg, 0.93 mmol) in DMSO (1 mL) was added 9 (87 mg, 0.46 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 31 mg, 0.13 mmol) to afford 22j (eluent system: 5% methanol in CH₂Cl₂, 0.14 g, 0.37 mmol, 15% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (s, 3 H, SCH₃), 3.76 (s, 3 H, OCH₃), 6.91 - 6.96 (m, 2 H, Ph), 6.97 - 7.02 (m, 2 H, Ph), 7.03 - 7.09 (m, 2 H, Ph), 7.23 - 7.41 (m, 2 H, Ph), 7.74 (s, 1 H, H-6), 13.11 (br. s., 1 H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 39.6 (1 C, SCH₃), 55.4 (1 C, OCH₃), 99.4 (1 C, C-3), 112.4 (1 C, CN), 115.2 (2 C, Ph), 116.7 (3 C, Ph, C-5), 121.3 (2 C, Ph), 126.4 (1 C, Ph), 131.9 (2 C, Ph), 140.6 (1 C, C-6), 148.6 (1 C, Ph), 156.0 (1 C, Ph), 158.5 (1 C, Ph), 160.4 (1 C, C-2), 166.0 (1 C, C-4). HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₂₀H₁₆N₂O₄S-H]⁻ 379.0758, found 379.0739.

5-(4-(3,4-Dichlorophenoxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (22k)

According to a literature report,^[29] methyl 2-(4-hydroxyphenyl)acetate (0.30 g, 2.2 mmol), (3,4-dichlorophenyl)boronic acid (1.3 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-(3,4-dichlorophenoxy)phenyl)acetate 18k (eluent system: 10% ethylacetate in petroleum ether, 0.40 g, 1.3 mmol, 58% yield). ¹H NMR (400 MHz, CDCl3) δ ppm 3.63 (s, 2 H, CH₂), 3.73 (s, 3 H, OCH₃), 6.86 (dd, J = 8.8, 2.8 Hz, 1 H, Ph), 6.95 - 7.01 (m, 2 H, Ph), 7.09 (d, J = 2.9 Hz, 1 H, Ph), 7.27 - 7.31 (m, 2 H, Ph), 7.38 (d, J = 8.8 Hz, 1 H, Ph). ¹³C NMR (101 MHz, CDCl3) δ ppm 40.3 (1 C, CH₂), 52.1 (1 C, OCH₃), 117.9 (1 C, Ph), 119.4 (2 C, Ph), 120.3 (1 C, Ph), 126.5 (1 C, Ph), 129.9 (1 C, Ph), 130.9 (2 C, Ph), 131.0 (1 C, Ph), 133.2 (1 C, Ph), 155.2 (1 C, Ph), 156.5 (1 C, Ph), 171.9 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(4-(3,4-dichlorophenoxy)phenyl)acetate (0.2 g, 0.65 mmol) was treated with LiAlH₄ (49 mg, 1.3 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.24 g, 1.1 mmol) in DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (46 mg, 1.1 mmol) in DMSO (1 mL) was added 9 (0.11 g, 0.57 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 34 mg, 0.15 mmol) to afford 22k (eluent system: 5% methanol in CH₂Cl₂, 41 mg, 0.098 mmol, 15% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.80 (s, 3 H, SCH₃), 7.07 (dd, J = 8.9, 2.9 Hz, 1 H, Ph), 7.10 - 7.16 (m, 2 H, Ph), 7.38 (d, J = 2.8 Hz, 1 H, Ph), 7.40 - 7.45 (m, 2 H, Ph), 7.68 (d, J = 8.9 Hz, 1 H, Ph), 7.78 (s, 1 H, H-6), 13.14 (br. s., 1 H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH₃), 99.3 (1 C, C-3), 112.4 (1 C, CN), 116.4 (1 C, C-5), 118.7 (2 C, Ph), 119.2 (1 C, Ph), 120.9 (1 C, Ph), 125.9 (1 C, Ph), 128.4 (1 C, Ph), 131.7 (1 C, Ph), 132.1 (1 C, Ph), 132.3 (2 C, Ph), 140.8 (1 C, C-6), 155.7 (1 C, Ph), 156.1 (1 C, Ph), 160.4 (1 C, C-2), 165.8 (1 C, C-4). HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₁₉H₁₂Cl₂N₂O₃S-H]⁻ 416.9873, found 416.9865.

5-(3-(Benzyloxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (27a)

According to a literature report^[30] with minor revision, methyl 2-(3-hydroxyphenyl)acetate (0.30 g, 2.2 mmol), benzyl bromide (0.26 mL, 2.2 mmol), K₂CO₃ (0.61 g, 4.4 mmol), sodium iodide (33 mg, 0.22 mmol) in DMF (10 mL) afforded the ester intermediate methyl 2-(3-(benzyloxy)phenyl)acetate 23a (eluent system: 10% ethylacetate in petroleum ether, 0.33 g, 1.3 mmol, 58% yield). ¹H NMR (300 MHz, CDCl3) δ ppm 3.65 (s, 2 H, CH₂), 3.73 (s, 3 H, CH₃), 5.10 (s, 2 H, OCH₂), 6.83 - 7.05 (m, 3 H, Ph), 7.21 - 7.52 (m, 6 H, Ph). ¹³C NMR (75 MHz, CDCl3) δ ppm 41.1 (1 C, CH₂), 52.0 (1 C, CH₃), 69.8 (1 C, OCH₂), 113.4 (1 C, Ph), 115.8 (1 C, Ph), 121.8 (1 C, Ph), 127.5 (2 C, Ph), 127.9 (1 C, Ph), 128.5 (2 C, Ph), 129.5 (1 C, Ph), 135.4 (1 C, Ph), 136.9 (1 C, Ph), 158.9 (1 C, Ph), 171.8 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(3-(benzyloxy)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 (0.34 g, 1.6 mmol) in DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (48 mg, 1.2 mmol) in DMSO (1 mL) was added 9 (0.11 g, 0.60 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 69 mg, 0.30 mmol) to afford 27a (eluent system: 5% methanol in CH₂Cl₂, 92 mg, 0.25 mmol, 32% yield). ¹H NMR (300 MHz, DMSO-d6) δ ppm 2.73 (s, 3 H, SCH₃), 5.11 (s, 2 H, CH₂), 6.92 (dt, J = 7.6, 1.2 Hz, 1 H, Ph), 7.01 - 7.10 (m, 2 H, Ph), 7.26 - 7.48 (m, 6 H, Ph), 7.74 (s, 1 H, H-6), 13.12 (br. s., 1 H, NH). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 39.8 (1 C, SCH₃), 69.3 (1 C, CH₂), 99.3 (1 C, C-3), 112.3 (1 C, CN), 115.1 (1 C, Ph), 116.5 (1 C, Ph), 117.0 (1 C, C-5), 122.6 (1 C, Ph), 127.8 (2 C, Ph), 127.9 (1 C, Ph), 128.4 (2 C, Ph), 129.7 (1 C, Ph), 133.9 (1 C, Ph), 136.8 (1 C, Ph), 140.5 (1 C, C-6), 158.3 (1 C, Ph), 160.4 (1 C, C-2), 165.9 (1 C, C-4). HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₂₀H₁₆N₂O₃S-H]⁻ 363.0809, found 363.0821.

5-(3-((4-Chlorobenzyl)oxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (27b)

According to a literature report^[30] with minor revision, methyl 2-(3-hydroxyphenyl)acetate (0.40 g, 2.9 mmol), 4-chlorobenzyl bromide (0.60 g, 2.9 mmol), K₂CO₃ (0.81 g, 5.9 mmol), sodium iodide (44 mg, 0.29 mmol) in DMF (20 mL) afforded the ester intermediate methyl 2-(3-((4-chlorobenzyl)oxy)phenyl)acetate 23b (eluent system: 10% ethylacetate in petroleum ether, 0.50 g, 1.7 mmol, 5% yield). ¹H NMR (400 MHz, CDCl3) δ ppm 3.61 (s, 2 H, CH₂), 3.70 (s, 3 H, OCH₃), 5.03 (s, 2 H, CH₂), 6.85 - 6.93 (m, 3 H, Ph), 7.22 - 7.29 (m, 1 H, Ph), 7.36 - 7.39 (m, 4 H, Ph). ¹³C NMR (101 MHz, CDCl3) δ ppm 41.2 (1 C, CH₂), 52.1 (1 C, OCH₃), 69.1 (1 C, CH₂), 113.5 (1 C, Ph), 115.8 (1 C, Ph), 122.1 (1 C, Ph), 128.7(2 C, Ph), 128.8 (2 C, Ph), 129.6 (1 C, Ph), 133.7 (1 C, Ph), 135.4 (1 C, Ph), 135.5 (1 C, Ph), 158.7 (1 C, Ph), 171.9 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(3-((4-chlorobenzyl)oxy)phenyl)acetate (0.2 g, 0.69 mmol) was treated with LiAlH₄ (52 mg, 1.4 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.29 g, 1.3 mmol) in DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (48 mg, 1.2 mmol) in DMSO (1 mL) was added 9 (0.11 g, 0.60 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 58 mg, 0.25 mmol) to afford 27b (eluent system: 5% methanol in CH₂Cl₂, 84 mg, 0.21 mmol, 31% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.75 (s, 3 H, SCH₃), 5.13 (s, 2 H, CH₂), 6.95 (d, J = 7.5 Hz, 1 H, Ph), 7.07 (br. s., 2 H, Ph), 7.36 (t, J = 8.3 Hz, 1 H, Ph), 7.43 - 7.56 (m, 4 H, Ph), 7.76 (s, 1 H, H-6), 13.14 (br. s., 1 H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH₃), 68.5 (1 C, PhCH₂), 99.3 (1 C, C-3), 112.3 (1 C, CN), 115.2 (1 C, Ph), 116.5 (1 C, Ph), 116.9 (1 C, C-5), 122.8 (1 C, Ph), 128.5 (2 C, Ph), 129.6 (2 C, Ph), 129.8 (1 C, Ph), 132.5 (1 C, Ph), 133.9 (1 C, Ph), 135.9 (1 C, Ph), 140.4 (1 C, C-6), 158.1 (1 C, Ph), 160.4 (1 C, C-2), 165.9 (1 C, C-4). HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₂₀H₁₅ClN₂O₃S-H]⁻ 397.0419, found 397.0417.

5-(3-((3,4-Dichlorobenzyl)oxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (27c)

According to a literature report^[30] with minor revision, methyl 2-(3-hydroxyphenyl)acetate (0.40 g, 2.9 mmol), 3,4-dichlorobenzyl bromide (0.70 g, 2.9 mmol), K₂CO₃ (0.81 g, 5.9 mmol), sodium iodide (44 mg, 0.29 mmol) in DMF (20 mL) afforded the ester intermediate methyl 2-(3-((3,4-dichlorobenzyl)oxy)phenyl)acetate 23c (eluent system: 10% ethylacetate in petroleum ether, 0.75 g, 2.3 mmol, 84% yield). ¹H NMR (300 MHz, CDCl3) δ ppm 3.62 (s, 2 H, CH₂), 3.70 (s, 3 H, CH₃), 5.01 (s, 2 H, OCH₂), 6.87 (d, J = 8.2 Hz, 1 H, Ph), 6.93 (br. s., 2 H, Ph), 7.21 - 7.30 (m, 2 H, Ph), 7.41 - 7.48 (m, 1 H, Ph), 7.54 (s, 1 H, Ph). ¹³C NMR (75 MHz, CDCl3) δ ppm 41.1 (1 C, CH₂), 52.1 (1 C, CH₃), 68.4 (1 C, OCH₂), 113.4 (1 C, Ph), 115.8 (1 C, Ph), 122.3 (1 C, Ph), 126.5 (1 C, Ph), 129.2 (1 C, Ph), 129.7 (1 C, Ph), 130.5 (1 C, Ph), 131.8 (1 C, Ph), 132.6 (1 C, Ph), 135.6 (1 C, Ph), 137.3 (1 C, Ph), 158.4 (1 C, Ph), 171.7 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(3-((3,4-dichlorobenzyl)oxy)phenyl)acetate (0.2 g, 0.62 mmol) was treated with LiAlH₄ (47 mg, 1.2 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.26 g, 1.2 mmol) in DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (48 mg, 1.2 mmol) in DMSO (1 mL) was added 9 (0.11 g, 0.60 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 58 mg, 0.26 mmol) to afford 27c (eluent system: 5% methanol in CH₂Cl₂, 80 mg, 0.18 mmol, 30% yield). ¹H NMR (300 MHz, DMSO-d6) δ ppm 2.73 (s, 3 H, SCH₃), 5.13 (s, 2 H, CH₂), 6.94 (d, J = 7.3 Hz, 1 H, Ph), 7.00 - 7.09 (m, 2 H, Ph), 7.29 - 7.46 (m, 2 H, Ph), 7.64 (d, J = 8.5 Hz, 1 H, Ph), 7.69 (s, 1 H, Ph), 7.74 (s, 1 H, H-6), 13.14 (br. s., 1 H, NH). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 39.8 (1 C, SCH₃), 67.7 (1 C, CH₂), 99.3 (1 C, C-3), 112.3 (1 C, CN), 115.2 (1 C, Ph), 116.6 (1 C, Ph), 116.9 (1 C, C-5), 122.9 (1 C, Ph), 127.9 (1 C, Ph), 129.5 (1 C, Ph), 129.8 (1 C, Ph), 130.4 (1 C, Ph), 130.7 (1 C, Ph), 131.1 (1 C, Ph), 134.0 (1 C, Ph), 138.1 (1 C, Ph), 140.5 (1 C, C-6), 157.9 (1 C, Ph), 160.4 (1 C, C-2), 165.8 (1 C, C-4). HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₂₀H₁₄Cl₂N₂O₃S-H]⁻ 431.0029, found 431.0031.

5-(3-((2-Chlorobenzyl)oxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (27d)

According to a literature report^[30] with minor revision, methyl 2-(3-hydroxyphenyl)acetate (0.40 g, 2.9 mmol), 1-(bromomethyl)-2-chlorobenzene (0.60 g, 2.9 mmol), K₂CO₃ (0.81 g, 5.9 mmol), sodium iodide (44 mg, 0.29 mmol) in DMF (20 mL) afforded the ester intermediate methyl 2-(3-((2-chlorobenzyl)oxy)phenyl)acetate 23d (eluent system: 10% ethylacetate in petroleum ether, 0.26 g, 0.89 mmol, 30% yield). ¹H NMR (300 MHz, CDCl3) δ ppm 3.63 (s, 2 H, CH₂), 3.71 (s, 3 H, CH₃), 5.17 (s, 2 H, OCH₂), 6.86 - 7.01 (m, 3 H, Ph), 7.23 - 7.36 (m, 3 H, Ph), 7.41 (dd, J = 7.0, 2.1 Hz, 1 H, Ph), 7.53 - 7.63 (m, 1 H, Ph). ¹³C NMR (75 MHz, CDCl3) δ ppm 41.2 (1 C, CH₂), 52.1 (1 C, CH₃), 67.1 (1 C, OCH₂), 113.4 (1 C, Ph), 116.0 (1 C, Ph), 122.1 (1 C, Ph), 126.9 (1 C, Ph), 128.8 (1 C, Ph), 129.0 (1 C, Ph), 129.3 (1 C, Ph), 129.6 (1 C, Ph), 132.6 (1 C, Ph), 134.7 (1 C, Ph), 135.5 (1 C, Ph), 158.7 (1 C, Ph), 171.8 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(3-((2-chlorobenzyl)oxy)phenyl)acetate (0.2 g, 0.69 mmol) was treated with LiAlH₄ (52 mg, 1.4 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.25 g, 1.2 mmol) in DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (43 mg, 1.1 mmol) in DMSO (1 mL) was added 9 (0.10 g, 0.53 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 89 mg, 0.39 mmol) to afford 27d (eluent system: 5% methanol in CH₂Cl₂, 90 mg, 0.23 mmol, 33% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3 H, SCH₃), 5.19 (s, 2 H, PhCH₂), 6.97 (dd, J = 7.7, 1.2 Hz, 1 H, Ph), 7.06 - 7.13 (m, 2 H, Ph), 7.33 - 7.44 (m, 3 H, Ph), 7.49 - 7.56 (m, 1 H, Ph), 7.59 - 7.65 (m, 1 H, Ph), 7.79 (s, 1 H, H-6), 13.15 (br. s., 1 H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH₃), 67.0 (1 C, PhCH₂), 99.3 (1 C, C-3), 112.4 (1 C, C-5), 115.2 (1 C, Ph), 116.4 (1 C, Ph), 116.9 (1 C, C-5), 122.9 (1 C, Ph), 127.4 (1 C, Ph), 129.4 (1 C, Ph), 129.8 (1 C, Ph), 129.9 (1 C, Ph), 130.2 (1 C, Ph), 132.6 (1 C, Ph), 134.0 (1 C, Ph), 134.1 (1 C, Ph), 140.5 (1 C, C-6), 158.1 (1 C, Ph), 160.4 (1 C, C-2), 165.9 (1 C, C-4). HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₂₀H₁₅ClN₂O₃S-H]⁻ 397.0419, found 397.0411.

5-(3-((3-Chlorobenzyl)oxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (27e)

According to a literature report^[30] with minor revision, methyl 2-(3-hydroxyphenyl)acetate (0.40 g, 2.9 mmol), m-chlorobenzyl bromide (0.60 g, 2.9 mmol), K₂CO₃ (0.81 g, 5.9 mmol), sodium iodide (44 mg, 0.29 mmol) in DMF (20 mL) afforded the ester intermediate methyl 2-(3-((3-chlorobenzyl)oxy)phenyl)acetate 23e (eluent system: 10% ethylacetate in petroleum ether, 0.62 g, 2.1 mmol, 73% yield). ¹H NMR (400 MHz, CDCl3) δ ppm 3.61 (s, 2 H, CH₂), 3.70 (s, 3 H, OCH₃), 5.03 (s, 2 H, CH₂), 6.84 - 6.94 (m, 3 H, Ph), 7.23 - 7.28 (m, 1 H, Ph), 7.29 - 7.32 (m, 3 H, Ph), 7.35 - 7.48 (m, 1 H, Ph). ¹³C NMR (101 MHz, CDCl3) δ ppm 41.2 (1 C, CH₂), 52.1 (1 C, OCH₃), 69.1 (1 C, CH₂), 113.4 (1 C, Ph), 115.8 (1 C, Ph), 122.1 (1 C, Ph), 125.3 (1 C, Ph), 127.4 (1 C, Ph), 128.0 (1 C, Ph), 129.6 (1 C, Ph), 129.8 (1 C, Ph), 134.5 (1 C, Ph), 135.5 (1 C, Ph), 139.0 (1 C, Ph), 158.6 (1 C, Ph), 171.9 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(3-((3-chlorobenzyl)oxy)phenyl)acetate (0.2 g, 0.69 mmol) was treated with LiAlH₄ (52 mg, 1.4 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.26 g, 1.2 mmol) in DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (42 mg, 1.0 mmol) in DMSO (1 mL) was added 9 (98 mg, 0.52 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 58 mg, 0.26 mmol) to afford 27e (eluent system: 5% methanol in CH₂Cl₂, 74 mg, 0.19 mmol, 27% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.75 (s, 3 H, SCH₃), 5.15 (s, 2 H, PhCH₂), 6.95 (d, J = 7.6 Hz, 1 H, Ph), 7.02 - 7.12 (m, 2 H, Ph), 7.31 - 7.48 (m, 4 H, Ph), 7.52 (s, 1 H, Ph), 7.77 (s, 1 H, H-6), 13.15 (br. s., 1 H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 39.8 (1 C, SCH₃), 68.4 (1 C, PhCH₂), 99.4 (1 C, C-3), 112.3 (1 C, CN), 115.1 (1 C, Ph), 116.5 (1 C, Ph), 116.9 (1 C, C-5), 122.8 (1 C, Ph), 126.2 (1 C, Ph), 127.3 (1 C, Ph), 127.8 (1 C, Ph), 129.8 (1 C, Ph), 130.4 (1 C, Ph), 133.1 (1 C, Ph), 133.9 (1 C, Ph), 139.4 (1 C, Ph), 140.4 (1 C, C-6), 158.0 (1 C, Ph), 160.4 (1 C, C-2), 165.9 (1 C, C-4). HRMS (ESI): m/z [M + H]⁺ Calcd. for [C₂₀H₁₅ClN₂O₃S+H]⁺ 399.0565, found 399.0544.

4-(Methylsulfinyl)-5-(3-((2-nitrobenzyl)oxy)phenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (27f)

According to a literature report^[30] with minor revision, methyl 2-(3-hydroxyphenyl)acetate (0.40 g, 2.9 mmol), 2-nitrobenzyl bromide (0.64 g, 2.9 mmol), K₂CO₃ (0.81 g, 5.9 mmol), sodium iodide (44 mg, 0.29 mmol) in DMF (20 mL) afforded the ester intermediate methyl 2-(3-((2-nitrobenzyl)oxy)phenyl)acetate 23f (eluent system: 10% ethylacetate in petroleum ether, 0.60 g,2.0 mmol, 88% yield). ¹H NMR (300 MHz, CDCl3) δ ppm 3.62 (s, 2 H, CH₂), 3.71 (s, 3 H, OCH₃), 5.49 (s, 2 H, CH₂), 6.85 - 6.99 (m, 3 H, Ph), 7.27 (t, J = 7.8 Hz, 1 H, Ph), 7.42 - 7.55 (m, 1 H, Ph), 7.69 (td, J = 7.6, 1.2 Hz, 1 H, Ph), 7.85 - 7.96 (m, 1 H, Ph), 8.18 (dd, J = 8.2, 1.2 Hz, 1 H, Ph). ¹³C NMR (75 MHz, CDCl3) δ ppm 41.1 (1 C, CH₂), 52.1 (1 C, OCH₃), 66.7 (1 C, CH₂), 113.4 (1 C, Ph), 116.1 (1 C, Ph), 122.5 (1 C, Ph), 124.9 (1 C, Ph), 128.3 (1 C, Ph), 128.5 (1 C, Ph), 129.7 (1 C, Ph), 133.8 (1 C, Ph), 134.0 (1 C, Ph), 135.6 (1 C, Ph), 149.2 (1 C, Ph), 158.3 (1 C, Ph), 171.8 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(3-((2-nitrobenzyl)oxy)phenyl)acetate (0.2 g, 0.66 mmol) was treated with LiAlH₄ (50 mg, 1.3 mmol) in dry THF (5 mL) to give alcohol intermediate, which was oxidized with PCC (0.13 g, 0.61 mmol) in DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (20 mg, 0.49 mmol) in DMSO (1 mL) was added 9 (46 mg, 0.25 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 17 mg, 0.080 mmol) to afford 27f (eluent system: 5% methanol in CH₂Cl₂, 7.0 mg, 0.017 mmol, 3% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.72 (s, 3 H, SCH₃), 5.50 (s, 2 H, CH₂), 6.97 (d, J = 7.6 Hz, 1 H, Ph), 7.03 - 7.12 (m, 2 H, Ph), 7.37 (t, J = 8.1 Hz, 1 H, Ph), 7.58 - 7.67 (m, 1 H, Ph), 7.74 - 7.84 (m, 3 H, Ph, H-6), 8.14 (d, J = 7.9 Hz, 1 H, Ph), 12.98 - 13.32 (s, 1 H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 39.7 (1 C, SCH₃), 66.4 (1 C, CH₂), 99.3 (1 C, C-3), 112.3 (1 C, CN), 115.3 (1 C, Ph), 116.3 (1 C, Ph), 123.1 (1 C, Ph), 124.9 (1 C, Ph), 129.2 (1 C, Ph), 129.9 (1 C, Ph), 130.7 (1 C, Ph), 132.3 (1 C , Ph), 134.0 (2 C, Ph), 140.5 (1 C, C-6), 147.5 (1 C, Ph), 157.8 (1 C, Ph), 160.4 (1 C, C-2), 166.1 (1 C, C-4). C (C-5) could not be observed. HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₂₀H₁₅N₃O₅S-H]⁻ 408.0659, found 408.0661.

5-(4-(Benzyloxy)phenyl)-4-(methylsulfinyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (27g)

According to a literature report^[30] with minor revision, methyl 2-(4-hydroxyphenyl)acetate (0.30 g, 2.2 mmol), benzyl bromide (0.26 mL, 2.2 mmol), K₂CO₃ (0.61 g, 4.4 mmol), sodium iodide (33 mg, 0.22 mmol) in DMF (10 mL) afforded the ester intermediate methyl 2-(4-(benzyloxy)phenyl)acetate 23g (eluent system: 10% ethylacetate in petroleum ether, 0.38 g, 1.5 mmol, 67% yield). ¹H NMR (400 MHz, CDCl3) δ ppm 3.59 (s, 2 H, CH₂), 3.71 (s, 3 H, OCH₃), 5.07 (s, 2 H, CH₂), 6.93 - 6.98 (m, 2 H, Ph), 7.19 - 7.25 (m, 2 H, Ph), 7.31 - 7.37 (m, 1 H, Ph), 7.38 - 7.47 (m, 4 H, Ph). ¹³C NMR (101 MHz, CDCl3) δ ppm 40.3 (1 C, CH₂), 52.0 (1 C, OCH₃), 70.0 (1 C, CH₂), 114.9 (2 C, Ph), 126.3 (1 C, Ph), 127.4 (2 C, Ph), 127.9 (1 C, Ph), 128.5 (2 C, Ph), 130.3 (2 C, Ph), 137.0 (1 C, Ph), 157.9 (1 C, Ph), 172.3 (1 C, CO). Following the General procedure for the synthesis of aldehyde intermediates and final compounds, methyl 2-(4-(benzyloxy)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 (0.33 g, 1.5 mmol) in DCM (5 mL) to yield aldehyde. The suspension of aldehyde and NaOH (57 mg, 1.42 mmol) in DMSO (1 mL) was added 9 (0.13 g, 0.71 mmol) to give methylthiopyridone intermediate, followed by oxidation with mCPBA (75%, 48 mg, 0.21 mmol) to afford 27g (eluent system: 5% methanol in CH₂Cl₂, 29 mg, 0.080 mmol, 10% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 3 H, SCH₃), 5.14 (s, 2 H, CH₂), 7.04 - 7.09 (m, 2 H, Ph), 7.26 - 7.37 (m, 3 H, Ph), 7.38 - 7.44 (m, 2 H, Ph), 7.44 - 7.50 (m, 2 H, Ph), 7.70 (s, 1 H, H-6), 13.08 (br. s., 1 H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 39.6 (1 C, SCH₃), 69.3 (1 C, CH₂), 99.2 (1 C, C-3), 112.4 (1 C, CN), 114.7 (2 C, Ph), 116.9 (1 C, C-5), 124.8 (1 C, Ph), 127.8 (2 C, Ph), 127.9 (1 C, Ph), 128.5 (2 C, Ph), 131.5 (2 C, Ph), 136.8 (1 C, Ph), 140.5 (1 C, C-6), 158.5 (1 C, Ph), 160.4 (1 C, C-2), 166.1 (1 C, C-4). HRMS (ESI): m/z [M - H]⁻ Calcd. for [C₂₀H₁₆N₂O₃S-H]⁻ 363.0809, found 363.0796.