Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase II inhibitors and cytotoxic agents

Article abstract of DOI:10.1016/j.bioorg.2016.04.007

A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU

Full text of DOI:10.1016/j.bioorg.2016.04.007

Accepted Manuscript
Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyri-
dines as topoisomerase II inhibitors and cytotoxic agents
Pritam Thapa, Tara Man Kadayat, Seojeong Park, Somin Shin, Til Bahadur
Thapa Magar, Ganesh Bist, Aarajana Shrestha, Younghwa Na, Youngjoo Kwon,
Eung-Seok Lee
PII:
S0045-2068(16)30040-2
DOI:
http://dx.doi.org/10.1016/j.bioorg.2016.04.007
YBIOO 1905
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
7 March 2016
25 April 2016
26 April 2016
Please cite this article as: P. Thapa, T.M. Kadayat, S. Park, S. Shin, T.B.T. Magar, G. Bist, A. Shrestha, Y. Na, Y.
Kwon, E-S. Lee, Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase
II inhibitors and cytotoxic agents, Bioorganic Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bioorg.2016.04.007
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Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as
topoisomerase II inhibitors and cytotoxic agents
[
a], #
[a], #
[b]
[b]
Pritam Thapa
, Tara Man Kadayat
, Seojeong Park , Somin Shin , Til Bahadur
[
a]
[a]
[a]
[c]
,[b]
Thapa Magar , Ganesh Bist , Aarajana Shrestha , Younghwa Na , Youngjoo Kwon * ,
,
[a]
Eung-Seok Lee *
[
a]
b]
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
[
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans
University, Seoul 120-750, Republic of Korea
[
c]
College of Pharmacy, Cha University, Pochon 487-010, Republic of Korea
#
Authors are equal contributors.
*
Corresponding Authors:
Tel: +82 53 810-2827, fax: +82 53 810-4654, email: eslee@yu.ac.kr (E.-S.L.)
Tel: +82 2 3277-4653, fax: +82 2 3277-2851, email: ykwon@ewha.ac.kr (Y.K.)

Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as
topoisomerase II inhibitors and cytotoxic agents
[
a], #
[a], #
[b]
[b]
Pritam Thapa
, Tara Man Kadayat
, Seojeong Park , Somin Shin , Til Bahadur
[
a]
[a]
[a]
[c]
,[b]
Thapa Magar , Ganesh Bist , Aarajana Shrestha , Younghwa Na , Youngjoo Kwon * ,
,
[a]
Eung-Seok Lee *
[
a]
b]
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
[
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans
University, Seoul 120-750, Republic of Korea
[
c]
College of Pharmacy, Cha University, Pochon 487-010, Republic of Korea
Abstract
A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and
evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity
against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most
of the tested compounds exhibited stronger topo II inhibitory activity at 100 µM as compared
to etoposide. All the compounds, except 39, did not show topo I inhibitory activity.
Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or
para-chlorophenyl at 4-position of central pyridine, and none of the compounds possess
meta-chlorophenyl. SAR study revealed the importance of ortho- or para-chlorophenyl at 4-
position of the central pyridine for selective topo II inhibitory activity. Similarly, all
compounds possessing meta- or para-hydroxyphenyl moieties showed moderate to
significant cytotoxic effects. Particularly, compounds 27-37, and 39 which showed excellent
cytotoxicity (IC = 0.68-1.25 M) against T47D breast cancer cells suggest the importance
5
0

of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of
anticancer agents with related scaffolds.
Keywords: 2-Phenol-4-chlorophenyl-6-aryl pyridines; Cytotoxicity; Topoisomerase I and II
inhibition; Synthesis
1
. Introduction
DNA topoisomerases (topos), first discovered by J. C. Wang in 1971 (the omega protein, ,
from E. coli.) [1], are the ubiquitous enzymes that solve the topological problems of DNA.
They either break one strand (topo I) [2] or both strands (topo II) [3] of DNA to release the
torsional stress that is buildup during several vital cellular processes like replication,
transcription, recombination, chromosome segregation etc. and reseal it [4-7]. Due to their
important role in maintenance and replication of DNA during proliferation, they have been a
good target for the development of anticancer agents [8-11]. As a result of intensive research
on topo targets, several topo inhibitors are now available in clinic for the treatment of several
cancers for decades [12-16]. Camptothecin and etoposide, topo I and II inhibitor, respectively,
are one of the most commonly used anticancer drugs. Similarly, there have been reports on
high expression of topo IIα in rapidly proliferative cancer cells [17-19]. In addition, recent
advancements in the structure of DNA-bound human topo IIα has provided an opportunity for
rational design and development of novel anticancer agents [20]. Drugs targeting topo II are
categorized into two broad classes namely topo II poison and topo II catalytic inhibitors
based on different mechanism of action [20, 21].
Over last decade our research group has focused on synthesis and evaluation of various
terpyridine derivatives as novel topo inhibitors as well as cytotoxic agents [22-31]. We

selected 2,2':6',2"-terpyridine because of its ability to form metal complexes, and act as
RNA/DNA binding agents [32-35]. Since then, we have accomplished modification on 2,4,6-
position of central pyridine, substituting either with flexible aryl groups or conformationally
constrained fused rings. While developing flexible 2,4,6-trisubstituted analogues, we
introduced several substituents such as methyl, chloro, or hydroxyls on aryl moieties. In one
of the studies [27], we have prepared the 2,4,6-triaryl derivatives with chlorophenyl and
phenol, respectively, at 2- and 4- position of central pyridine (Fig. 1) and evaluated for their
topo I and II inhibitory activity as well as cytotoxicity against several cancer cell lines.
Among them, compounds with para-chlorophenyl moiety were found to possess strong topo
II inhibitory activity.
In continuation of the work, herein, we have designed and synthesized several 2,4,6-triaryl
pyridine derivatives by interchanging chlorophenyl and phenol group at 4-and 2- position,
respectively, of central pyridine as shown in Figure 1. This study provided valuable
information on topo inhibition and cytotoxic effect by small change in position of
chlorophenyl and phenolic moieties of central pyridine for the development of novel
anticancer agents with related scaffolds.
(Figure 1)
2
. Results and discussion
2
.1. Chemistry
We designed and synthesized thirty-six 2-phenol-4-chlorophenyl-6 aryl pyridine derivatives
13-48) as shown in Scheme 1 and Figure 2. The final compounds were obtained in three
steps. At first, several pyridinium iodide salts 2 (R = a-d) were synthesized by reacting
(

appropriate aryl methyl ketones 1 (R = a-d) with iodine and pyridine for 3-5 h at 140 °C. In
1
1
1
parallel, propenone intermediates 7 (R = e-g), 8 (R = e-g), and 9 (R = e-g) were prepared
1
efficiently by the condensation of various aldehydes 3 (R = e-g) (1.0 equiv.), and
hydroxyacetophenone 4 or 5 or 6 (1.0 equiv.) in the presence of aqueous NaOH (3.0 equiv.).
We obtained propenone intermediates in the yield of 52.1-83.1%. Finally, using Kröhnke
pyridine synthesis method [36], 2-phenol-4-chlorophenyl-6-aryl pyridines 13-48 (Fig. 2)
1
1
1
were prepared. In brief, propenone intermediates 7 (R = e-g) or 8 (R = e-g) or 9 (R = e-g)
1.0 equiv.) were reacted with appropriate pyridinium iodide salts 2 (R = a-d) (1.5 equiv.) in
the presence of anhydrous ammonium acetate (10.0 equiv.) and glacial acetic acid at 100-
10 °C for 12-19 h. After workup and purification by silica gel column chromatography, we
(
1
obtained final compounds 13-48 in the yield of 36.0-90.6%. HPLC data for the prepared final
compounds showed high purity of >96%. Yields (%), HPLC purities (%), and melting point
(°C) of the prepared compounds are shown in Table S1 of Supplementary Information.
(
Scheme 1)
Figure 2)
(
2
. 2. Topo I and II inhibitory activity
We evaluated the synthesized thirty-six 2-phenol-4-chlorophenyl-6 aryl pyridine derivatives
13-48) for the topo I and II inhibitory activity as shown in Figure 3, Table 1, 2 and 3). We
(
studied the conversion of supercoiled plasmid DNA to relaxed DNA by topo I and II in the
presence of our synthesized final pyridine derivatives (13-48) as shown in Figure 3. All
compounds (13-48) were evaluated for topo II inhibitory activities at 100 M and 20 M
concentration. For topo I inhibitory activity only compound 39 showing moderate activity at
1
00 M was tested at 20 M concentration. We used camptothecin and etoposide, well-

known topo I and II inhibitors, respectively, as positive controls.
Figure 3 and Table 1-3 summarize the topo I and II inhibitory activity of the synthesized
compounds (13-48). From the results, it clearly indicates that the evaluated compounds are
specific to topo II except for compound 39. Compound 39 showed moderate topo I inhibitory
activity of 58.4% at 100 M concentration (as compared to 76.5% of camptothecin). On the
other hand, most of the compounds showed moderate to significant topo II inhibitory activity
at 100 M. Some compounds such as 35 (69.9% and 30.8% at 100 and 20 M, respectively)
and 36 (70.8% and 33.0% at 100 and 20 M, respectively) showed higher topo II inhibitory
activity than positive control etoposide (63.2% and 30.8% at 100 M and 20 M,
respectively) at both concentrations. Moreover, compounds 24 (72.1% as compared to 68.6%
of etoposide) and 26 (65.4% as compared to 63.2% of etoposide) showed better topo II
inhibition than etoposide at 100 M concentration. Similarly, compound 27 (60.1% as
compared to 63.2% of etoposide), 37 and 39 (60.9% and 60.8%, respectively, as compared to
6
6.3% of etoposide) showed comparable topo II inhibitory activity with positive control,
etoposide.
(Figure 3)
2
. 3. Cytotoxicity
We tested cytotoxicity of prepared thirty-six compounds (13-48) in four different human
cancer cell lines: HCT15; human colorectal adenocarcinoma, T47D; Human breast ductal
carcinoma, DU145; human prostate tumor, and Hela; human cervix tumor. The inhibitory
activity (IC ) values of evaluated compounds is expressed in micromolar concentration as
5
0

shown in Table 1, Table 2, and Table 3 with adriamycin, etoposide, and camptothecin as
standards or positive controls. All of the compounds from series 1 (compound 13-24), except
1
6 (IC of 2.36 M against DU145), are not effective as cytotoxic agents (IC >50 M). In
5
0
50
comparison, compounds from series 2 (25-36) and series 3 (37-48) showed moderate to
significant cytotoxicity against all tested cancer cell lines. Interestingly, among the
compounds tested against T47D breast cancer cell lines, most compounds 27-37, 39 exhibited
stronger cytotoxicity than adriamycin (IC <1.34 M).
5
0
(Table 1)
(Table 2)
(Table 3)
2
.4. Structure-activity relationship study
From the results of topo I and II inhibitory activity, we can clearly notify that all of the
prepared compounds exhibited weaker topo II inhibitory activity indicating selectivity to topo
II inhibition. It was difficult to determine or specify the particular structural importance for
the topo inhibitory activity. However, during observation of the structure of those compounds
(24, 26, 27, 35, 36, 37, 39) having better topo II inhibitory activity than etoposide (Figure 4),
we found that none of the compound possess meta-chlorophenyl at 4-position of central
pyridine. From this result, to some extent, we can predict that ortho or para-chlorophenyl at
4
-position is likely an important moiety compared to meta-chlorophenyl for better topo II
inhibitory activity as observed in our previous study [27]. In addition, from in vitro study, we
found that most of the compounds with ortho-hydroxyphenyl (series 1; 13-24) did not show
cytotoxicity against all tested cancer cell lines. However, compounds 25-48 possessing meta-

or para-hydroxyphenyl group showed moderate to strong cytotoxicity. This indicates that
meta- or para-hydroxyphenyl at 2-position of central pyridine would be a better choice
compared to ortho-hydroxyphenyl for cytotoxic effects.
(Figure 4)
3
. Conclusion
We systematically designed and synthesized thirty-six 2-phenol-4-chlorophenyl-6-aryl
pyridines efficiently. These prepared compounds were evaluated for topo I and II inhibitory
activity and cytotoxicity against four different human cancer cell lines. From the results of
biological test, we found that evaluated compounds are selective for topo II inhibition. Most
of the compounds showed strong topo II inhibitory activity at 100 µM and some compounds
also showed considerable topo II inhibitory activity at 20 µM. Although we could not draw
the concrete SAR study, it is likely that ortho- or para-chlorophenyl at 4-position is important
for topo II inhibitory activity. Compounds 27-37, and 39 with meta- or para-hydroxyphenyl
at 2-position of the central pyridine is important for displaying potent antiproliferative effect
against T47D breast cancer cells. Further experiment to study the anticancer mechanistic
pathway of these compounds is ongoing to discover novel anticancer agents.
4
. Experimental
We obtained chemicals and reagents from Aldrich Chemical Co., Junsei or other chemical
companies, and utilized them without further purification. HPLC grade solvents such as
acetonitrile (ACN) and methanol were purchased from Burdick and Jackson, USA. Thin-
layer chromatography (TLC) and column chromatography (CC) were performed with
Kieselgel 60 F254 (Merck) and silica gel (Kieselgel 60, 230-400 mesh, Merck), respectively.

Compounds were visualized and detected on TLC plates with UV light (short wave, long
1
wave or both). NMR spectra were recorded on a Bruker AMX 250 (250 MHz, FT) for H
1
3
NMR and 62.5 MHz for C NMR. Chemical shifts (δ) were calibrated according to TMS and
recorded as ppm. Similarly, coupling constants (J) was recorded in hertz (Hz). Melting points
were determined in open capillary tubes on electrothermal 1A 9100 digital melting point
apparatus without correction.
HPLC analyses were performed using two Shimadzu LC-10AT pumps gradient-controlled
HPLC system equipped with Shimadzu system controller (SCL-10A VP) and photo diode
array detector (SPD-M10A VP) utilizing Shimadzu Class VP program. Sample volume of 10
®
μL was injected in Waters X-Terra 5 μM reverse-phase C column (4.6×250 mm) with a
1
8
gradient elution of 75% to100% of B in A for 10 min followed by 100% to 75% of B in A for
0 min at a flow rate of 1.0 mL/min at 254 nm UV detection, where mobile phase A was
1
doubly distilled water with 20 mM ammonium formate (AF) and B was 100% ACN. Purity of
compound is described as percent (%) and retention time was given in minutes.
®
ESI LC/MS analyses were performed with a Finnigan LCQ Advantage LC/MS/MS
®
spectrometry utilizing Xcalibur program. For ESI LC/MS, LC was performed on a Waters
Atlantis T3, 3 μm reverse-phase C column (2.1×50 mm) with an 8 μL injection volume of
1
8
sample. The mobile phase was gradient elution from 70% to 100% of B in A for 5.0 min
followed by 100% to 70% of B in A for 5.0 min and 70% of B in A for 5.0 min at a flow rate
of 200 μL/min, where mobile phase A was distilled water with 0.1% formic acid and B was
1
00% acetonitrile (ACN). MS ionization conditions were: Sheath gas flow rate: 40 arb, aux
gas flow rate: 0 arb, I spray voltage: 5.3 KV, capillary temperature: 275°C, capillary voltage:
7 V, tube lens offset: 45 V.
2

4
. 1. General method for preparation of 2 (R=a-d)
Aryl methyl ketone 1 (R=a-d) was treated with pyridine (15.0 equiv.) and iodine (1.0 equiv.).
The mixture was refluxed at 140 °C for 3-5 h to get the precipitate. It was cooled to room
temperature, filtered and washed with cold pyridine. The solid compound was dried to get 2
(R=a-d) in quantitative yield. Compounds were used without further purification.
4
. 2. General method for the preparation of 7e-g, 8e-g, and 9e-g
1
To a stirred solution of aldehydes 3 (R = e-g) (1.0 equiv.), and hydroxyacetophenone 4 or 5
or 6 (1.0 equiv.) in methanol, aqueous solution of NaOH (3.0 equiv.) was added dropwise at
room temperature. The reaction mixture was stirred at room temperature for 3-24 h. After that,
ice was added to reaction mixture and neutralized with 4N HCl. The resulted precipitate was
filtered off and washed with excess H O to get solid residue. In case of no precipitation after
2
neutralization with 4N HCl, the reaction mixture was extracted with EtOAc, washed with
H O and saturated NaCl. The organic phase was dried over MgSO , filtered, and concentrated.
2
4
Further purification was done by silica gel column chromatography using ethyl acetate and n-
hexane as eluents to yield 52.1-83.1% solid compound of 7e-g, 8e-g or 9e-g.
4
.2.1. Synthesis of 3-(2-Chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (7e)
Using general method 4.2 with 2-chlorobenzaldehyde (3e, 2.81 g, 20.00 mmol, 1.0 equiv.)
and 2-hydroxyacetophenone (4, 2.72 g, 20.00 mmol, 1.0 equiv.), 3.56 g (68.8 %, 13.76 mmol)
of 7e was obtained as a yellow solid.
R = 0.42 (ethyl acetate/n-hexane =1 : 5), mp : 109.8-110.2°C.
f
1
H NMR (250 MHz, CDCl ) δ 12.73 (s, 1H, phenolic OH), 8.30 (d, J = 15.5 Hz, 1H, -CO-
3
CH=CH-), 7.92 (dd, J = 9.6, 1.7 Hz, 1H, phenolic H-6), 7.78-7.74 (m, 1H, chlorophenyl H-6),

7
.64 (d, J = 15.5 Hz, 1H, -CO-CH=CH-), 7.54-7.44 (m, 2H, phenolic H-4 and chlorophenyl
H-4), 7.39-7.32 (m, 2H, chlorophenyl H-3, H-5), 7.03 (dd, J = 8.4, 0.9 Hz, 1H, phenolic H-3),
1
3
6
1
1
.94 (td, J = 8.1, 1.1 Hz, 1H, phenolic H-5); C NMR (62.5 MHz, CDCl ) δ 193.49 (C),
3
63.61 (C), 141.15 (CH), 136.58 (CH), 135.71 (C), 132.92 (C), 131.51 (CH), 130.40 (CH),
29.70 (CH), 127.91 (CH), 127.11 (CH), 122.73 (CH), 119.87 (C), 118.90 (CH), 118.67 (CH).
4
.2.2. Synthesis of 3-(3-Chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (7f)
Using general method 4.2 with 3-chlorobenzaldehyde (3f, 1.40 g, 10.00 mmol, 1.0 equiv.)
and 2-hydroxyacetophenone (4, 1.36 g, 10.00 mmol, 1.0 equiv.), 1.59 g (61.4 %, 6.14 mmol)
of 7f was obtained as a yellow solid.
R = 0.51 (ethyl acetate/n-hexane =1:5), mp : 115.9-116.9°C.
f
1
H NMR (250 MHz, CDCl ) δ 12.71 (s, 1H, phenolic OH), 7.92 (dd, J = 8.1, 1.4 Hz, 1H,
3
phenolic H-6), 7.84 (d, J = 15.5 Hz, 1H, -CO-CH=CH-), 7.67 (d, J = 15.5 Hz, 1H, -CO-
CH=CH-), 7.65 (br s, 1H, chlorophenyl H-2), 7.55-7.48 (m, 2H, phenolic H-4 and
chlorophenyl H-6), 7.42-7.34 (m, 2H, chlorophenyl H-4, H-5), 7.03 (d, J = 8.3 Hz, 1H,
13
phenolic H-3), 6.96 (td, J = 8.1, 0.9 Hz, 1H, phenolic H-5); C NMR (62.5 MHz, CDCl ) δ
3
1
1
93.36 (C), 163.61 (C), 143.64 (CH), 136.63 (C), 136.38 (CH), 135.05 (C), 130.68 (CH),
30.27 (CH), 129.65 (CH), 128.00 (CH), 127.02 (CH), 121.40 (CH), 119.85 (C), 118.94 (CH),
118.68 (CH).
4
.2.3. Synthesis of 3-(4-Chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (7g)
Using general method 4.2 with 4-chlorobenzaldehyde (3g, 2.81 g, 20.00 mmol, 1.0 equiv.)
and 2-hydroxyacetophenone (4, 2.72 g, 20.00 mmol, 1.0 equiv.), 2.70 g (52.15 %, 10.43
mmol) of 7g was obtained as a yellow solid.
R = 0.51 (ethyl acetate/n-hexane =1:5), mp : 159.0-159.9°C.
f

1
H NMR (250 MHz, CDCl ) δ 7.91 (dd, J = 6.7, 1.2 Hz, 1H, phenolic H-6), 7.86 (d, J = 15.1
3
Hz, 1H, -CO-CH=CH-), 7.62 (d, J = 15.7 Hz, 1H, -CO-CH=CH-), 7.59 (d, J = 8.42 Hz, 2H,
chlorophenyl H-2, H-6), 7.50 (td, J = 8.4, 1.40 Hz, 1H, phenolic H-4), 7.40 (d, J = 8.5 Hz, 2H,
chlorophenyl H-3, H-5), 7.02 (d, J = 8.3 Hz, 1H, phenolic H-3), 6.94 (t, J = 7.9 Hz, 1H,
1
3
phenolic H-5); C NMR (62.5 MHz, CDCl ) δ 193.46 (C), 163.65 (C), 143.89 (CH), 136.87
3
(
CH), 136.52 (C), 133.13 (C), 129.76 (CH), 129.59 (CH), 129.35 (CH), 120.67 (CH), 119.96
C), 118.88 (CH), 118.71 (CH).
(
4
.2.4. Synthesis of 3-(2-Chlorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one (8e)
Using general method 4.2 with 2-chlorobenzaldehyde (3e, 1.40 g, 10.00 mmol, 1.0 equiv.)
and 3-hydroxyacetophenone (5, 1.36 g, 10.00 mmol, 1.0 equiv.), 2.09 g (80.7 %, 8.07 mmol)
of 8e was obtained as a light yellow solid.
R = 0.40 (ethyl acetate/n-hexane =1:2), mp : 115.9-117.2°C.
f
1
H NMR (250 MHz, CDCl ) δ 8.18 (d, J = 15.8 Hz, 1H, -CO-CH=CH-), 7.72-7.68 (m, 1H,
3
chlorophenyl H-6), 7.62 (s, 1H, phenolic H-2), 7.55 (d, J = 7.7 Hz, 1H, phenolic H-6), 7.48 (d,
J = 15.8 Hz, 1H, -CO-CH=CH-), 7.43-7.25 (m, 4H, phenolic H-5 and chlorophenyl H-3, H-4,
13
H-5), 7.12 (ddd, J = 8.1, 2.5, 0.8 Hz, 1H, phenolic H-4), 6.62 (s, 1H, phenolic OH); C NMR
(
(
(
62.5 MHz, CDCl ) δ 190.90 (C), 156.52 (C), 141.22 (CH), 139.18 (CH), 135.60 (C), 133.09
3
C), 131.30 (CH), 130.30 (CH), 129.93 (CH), 127.85 (CH), 127.07 (CH), 124.66 (C), 121.10
CH), 120.70 (CH), 115.35 (CH).
4
.2.5. Synthesis of 3-(3-Chlorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one (8f)
Using general method 4.2 with 3-chlorobenzaldehyde (3f, 1.40 g, 10.00 mmol, 1.0 equiv.)
and 3-hydroxyacetophenone (5, 1.36 g, 10.00 mmol, 1.0 equiv.), 2.06 g (79.6 %, 7.96 mmol)
of 8f was obtained as a light yellow solid.

R = 0.51 (ethyl acetate/n-hexane =1:2), mp : 125.8-126.2°C.
f
1
H NMR (250 MHz, CDCl ) δ 7.74 (d, J = 15.7 Hz, 1H, -CO-CH=CH-), 7.62-7.57 (m, 3H,
3
phenolic H-2, H-6 and chlorophenyl H-2), 7.50 (d, J = 15.6 Hz, 1H, -CO-CH=CH-), 7.51-
7
7
1
1
.48 (m, 1H, chlorophenyl H-6), 7.42-7.34 (m, 3H, phenolic H-5 and chlorophenyl H-4, H-5),
1
3
.15-7.10 (m, 1H, phenolic H-4); C NMR (62.5 MHz, CDCl ) δ 190.20 (C), 156.34 (C),
3
43.56 (CH), 139.24 (CH), 136.57 (C), 135.00 (C), 130.49 (CH), 130.22 (CH), 130.01 (CH),
27.98 (CH), 126.86 (CH), 123.05 (C), 121.10 (CH), 120.61 (CH), 115.13 (CH).
4
.2.6. Synthesis of 3-(4-Chlorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one (8g)
Using general method 4.2 with 4-chlorobenzaldehyde (3g, 1.40 g, 10.00 mmol, 1.0 equiv.)
and 3-hydroxyacetophenone (5, 1.36 g, 10.00 mmol, 1.0 equiv.), 2.15 g (83.1 %, 8.31 mmol)
of 8g was obtained as a light yellow solid.
R = 0.40 (ethyl acetate/n-hexane =1:2), mp : 132.8-134.0°C.
f
1
H NMR (250 MHz, CDCl ) δ 7.75 (d, J = 15.7 Hz, 1H, -CO-CH=CH-), 7.63 (br s, 1H,
3
phenolic H-2), 7.57-7.52 (m, 1H, phenolic H-6), 7.55 (d, J = 8.5 Hz, 2H, chlorophenyl H-2,
H-6), 7.45 (d, J = 15.7 Hz, 1H, -CO-CH=CH-), 7.40-7.32 (m, 3H, phenolic H-5 and
chlorophenyl H-3, H-5), 7.13 (dd, J = 8.1, 2.5 Hz, 1H, phenolic H-4), 6.54 (s, 1H, phenolic
1
3
OH); C NMR (62.5 MHz, CDCl ) δ 190.59 (C), 156.51 (C), 143.94 (CH), 139.31 (CH),
3
1
1
36.66 (C), 133.22 (C), 129.96 (CH), 129.66 (CH), 129.26 (CH), 122.34 (C), 120.98 (CH),
20.64 (CH), 115.23 (CH).
4
.2.7. Synthesis of 3-(2-Chlorophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (9e)
Using general method 4.2 with 2-chlorobenzaldehyde (3e, 2.81 g, 20.00 mmol, 1.0 equiv.)
and 4-hydroxyacetophenone (6, 2.72 g, 20.00 mmol, 1.0 equiv.), 4.20 g (81.3 %, 16.26 mmol)
of 9e was obtained as a light yellow solid.

R = 0.31 (ethyl acetate/n-hexane =1:2), mp : 177.9-178.4°C.
f
1
H NMR (250 MHz, DMSO-d ) δ 10.48 (br s, 1H, phenolic OH), 8.20-8.17 (m, 1H,
6
chlorophenyl H-6), 8.10 (d, J = 8.6 Hz, 2H, phenolic H-2, H-6), 7.96 (br s, 2H, -CO-
CH=CH-), 7.56-7.42 (m, 3H, chlorophenyl H-3, H-4, H-5), 6.90 (d, J = 8.5 Hz, 2H, phenolic
1
3
H-3, H-5); C NMR (62.5 MHz, DMSO-d ) δ 187.05 (C), 162.69 (C), 137.54 (CH), 134.41
6
(
C), 132.70 (C), 131.93 (CH), 131.61 (C), 130.21 (CH), 129.01 (CH), 128.70 (CH), 127.88
CH), 125.07 (CH), 115.68 (CH).
(
4
.2.8. Synthesis of 3-(3-Chlorophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (9f)
Using general method 4.2 with 3-chlorobenzaldehyde (3f, 1.40 g, 10.00 mmol, 1.0 equiv.)
and 4-hydroxyacetophenone (6, 1.36 g, 10.00 mmol, 1.0 equiv.), 1.42 g (54.8 %, 5.48 mmol)
of 9f was obtained as a light yellow solid.
R = 0.42 (ethyl acetate/n-hexane =1:2), mp : 187.6-188.9°C.
f
1
H NMR (250 MHz, DMSO-d ) δ 10.45 (br s, 1H, phenolic OH), 8.11 (d, J = 8.7 Hz, 2H,
6
phenolic H-2, H-6), 8.05 (br s, 1H, chlorophenyl H-2), 7.98 (d, J = 15.6 Hz, 1H, -CO-
CH=CH-), 7.80-7.77 (m, 1H, chlorophenyl H-6), 7.63 (d, J = 15.6 Hz, 1H, -CO-CH=CH-),
1
3
7
.49-7.41 (m, 2H, chlorophenyl H-4, H-5), 6.89 (d, J = 8.7 Hz, 2H, phenolic H-3, H-5); C
NMR (62.5 MHz, DMSO-d ) δ 187.15 (C), 162.57 (C), 141.20 (CH), 137.38 (C), 133.97 (C),
6
1
31.56 (CH), 130.84 (C), 130.05 (CH), 129.13 (CH), 127.99 (CH), 127.94 (CH), 123.86
(CH), 115.59 (CH).
4
.2.9. Synthesis of 3-(4-Chlorophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (9g)
Using general method 4.2 with 4-chlorobenzaldehyde (3g, 0.70 g, 5.00 mmol, 1.0 equiv.) and
-hydroxyacetophenone (6, 0.68 g, 5.00 mmol, 1.0 equiv.), 0.73 g (56.6 %, 2.83 mmol) of 9g
was obtained as a light yellow solid.
4

R = 0.30 (ethyl acetate/n-hexane =1:2), mp : 204.1-205.5°C.
f
1
H NMR (250 MHz, DMSO-d ) δ 10.45 (br s, 1H, phenolic OH), 8.08 (d, J = 8.7 Hz, 2H,
6
phenolic H-2, H-6), 7.93 (d, J = 15.5 Hz, 1H, -CO-CH=CH-), 7.90 (d, J = 8.5 Hz, 2H,
chlorophenyl H-2, H-6), 7.65 (d, J = 15.6 Hz, 1H, -CO-CH=CH-), 7.50 (d, J = 8.47 Hz, 2H,
1
3
chlorophenyl H-3, H-5), 6.88 (d, J = 8.7 Hz, 2H, phenolic H-3, H-5); C NMR (62.5 MHz,
DMSO-d ) δ 187.20 (C), 162.50 (C), 141.45 (CH), 134.97 (C), 134.08 (C), 131.47 (CH),
6
1
30.62 (C), 129.20 (CH), 129.11 (CH), 123.07 (CH), 115.60 (CH).
4
. 3. General method for the preparation of pyridine 13-48
2
-Phenol-4-Chlorophenyl-6-aryl pyridines (13-48) were synthesized on the basis of Kröhnke
synthesis, where propenone intermediates 7e-g, or 8e-g, or 9e-g (1.0 equiv.) were reacted
with appropriate pyridinium iodide salts 2 (R = a-d) (1.5 equiv.) in the presence of anhydrous
ammonium acetate (10.0 equiv.) and glacial acetic acid (AcOH). The reaction mixture was
heated at 100-110 °C for 12-19 h. After that the reaction mixture was extracted with ethyl
acetate (70 mL), washed with H O (50 mL× 3) and saturated NaCl (30 mL). The organic
2
phase was dried over MgSO and filtered off. The filtrate collected was concentrated to get
4
viscous or solid compound which was further purified by silica gel column chromatography
using ethyl acetate and n-hexane as eluents. Compounds 13-48 were obtained in the yield of
3
6.0-90.6%.
4
.3.1. Synthesis of 2-(4-(2-Chlorophenyl)-6-(furan-2-yl)pyridin-2-yl) phenol (13)
General method in section 4.3 was followed with 7e (0.39 g, 1.50 mmol, 1.0 equiv.), 2a (0.71
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 14 h. We obtained 328 mg (62.8%, 0.94 mmol) of 13 as a light
yellow solid.

R = 0.41 (ethyl acetate/n-hexane 1:5 v/v), mp: 164.1-164.7°C, HPLC: Retention time: 10.4
f
+
min, purity:99.4 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 348.07; found 348.25.
2
1
15
2
1
H NMR (250 MHz, CDCl ) δ 14.48 (br s, 1H, 2-phenyl 2-OH), 7.85 (dd, J = 7.90, 1.52 Hz,
3
1
H, 2-phenyl H-6), 7.84 (d, J = 1.17 Hz, 1H, pyridine H-3), 7.69 (d, J = 1.25 Hz, 1H,
pyridine H-5), 7.58-7.53 (m, 2H, 4-phenyl H-6 and 6-furan H-5), 7.42-7.39 (m, 3H, 4-phenyl
H-3, H-4, H-5), 7.33 (td, J = 6.82, 1.55 Hz, 1H, 2-phenyl H-4), 7.11 (d, J = 3.45 Hz, 1H, 6-
furan H-3), 7.05 (dd, J = 8.30, 1.10 Hz, 1H, 2-phenyl H-3), 6.92(td, J = 8.35, 1.25 Hz, 1H, 2-
1
3
phenyl H-5), 6.58 (dd, J = 3.47, 1.80 Hz, 1H, 6-furan H-4); C NMR (62.5 MHz, CDCl ) δ
3
1
60.03 (C), 157.31 (C), 151.98 (C), 149.61 (C), 145.84 (C), 144.03 (CH), 137.87 (C), 132.16
C), 131.70 (CH), 130.71 (CH), 130.34 (CH), 130.07 (CH), 127.25 (CH), 126.43 (CH),
18.87 (C), 118.75 (CH), 118.59 (CH), 118.04 (CH), 117.02 (CH), 112.29 (CH), 109.67 (CH).
(
1
4
.3.2. Synthesis of 2-(4-(2-Chlorophenyl)-6-(thiophen-2-yl)pyridin-2-yl) phenol (14)
General method in section 4.3 was followed with 7e (0.39 g, 1.50 mmol, 1.0 equiv.), 2b (0.74
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 14 h. We obtained 398 mg (72.9%, 1.09 mmol) of 14 as a light
yellow solid.
R = 0.40 (ethyl acetate/n-hexane 1:5 v/v), mp: 147.9-148.5 °C, HPLC: Retention time: 11.1
f
+
min, purity:99.6 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.26.
2
1
15
1
H NMR (250 MHz, CDCl ) δ 14.00 (br s, 1H, 2-phenyl 2-OH), 7.84-7.82 (m, 2H, 2-phenyl
3
H-6 and pyridine H-3), 7.67-7.65 (m, 2H, pyridine H-5 and 6-thiophene H-3), 7.57-7.52 (m,
H, 4-phenyl H-6), 7.47-7.37 (m, 4H, 6-thiophene H-5 and 4-phenyl H-3, H-4, H-5), 7.34 (td,
J = 8.45, 1.45 Hz, 1H, 2-phenyl H-4), 7.15 (dd, J = 5.02, 3.77 Hz, 1H, 6-thiophene H-4), 7.07
1
1
3
(
dd, J = 8.22, 0.70 Hz, 1H, 2-phenyl H-3), 6.92 (td, J = 8.12, 1.07 Hz, 1H, 2-phenyl H-5); C
NMR (62.5 MHz, CDCl ) δ 159.76 (C), 157.42(C), 149.62 (C), 149.47 (C), 142.76 (C),
3

1
1
37.79 (C), 132.18 (C), 131.73 (CH), 130.69 (CH), 130.37 (CH), 130.11(CH), 128.40 (CH),
27.97 (CH), 127.29(CH), 126.57 (CH), 125.69 (CH), 118.98 (C), 118.80 (CH), 118.59 (CH),
118.28 (CH), 117.65 (CH).
4
.3.3. Synthesis of 2-(4-(2-Chlorophenyl)-6-(thiophen-3-yl)pyridin-2-yl) phenol (15)
General method in section 4.3 was followed with 7e (0.39 g, 1.50 mmol, 1.0 equiv.), 2c (0.74
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 16 h. We obtained 388 mg (71.1%, 1.09 mmol) of 15 as a light
yellow solid.
R = 0.45 (ethyl acetate/n-hexane 1:5 v/v), mp: 133.1-133.8 °C, HPLC: Retention time: 11.1
f
+
min, purity:100 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.27.
2
1
15
1
H NMR (250 MHz, CDCl ) δ 14.70 (br s, 1H, 2-phenyl 2-OH), 7.93 (dd, J = 2.92, 1.27 Hz,
3
1
1
1
H, 6-thiophene H-2), 7.86 (d, J = 1.00 Hz, 1H, pyridine H-3), 7.84 (dd, J = 8.10, 1.37 Hz,
H, 2-phenyl H-6), 7.67 (dd, J = 5.07, 1.25 Hz, 1H, 6-thiophene H-4), 7.62 (d, J = 1.12 Hz,
H, pyridine H-5), 7.57-7.52 (m, 1H, 4-phenyl H-6), 7.45 (dd, J = 5.10, 2.97 Hz, 1H, 6-
thiophene H-5), 7.43-7.38 (m, 3H, 4-phenyl H-3, H-4, H-5), 7.33 (td, J = 6.67, 1.52 Hz, 1H,
2
1
1
1
-phenyl H-4), 7.07 (dd, J = 8.20, 1.00 Hz, 1H, 2-phenyl H-3), 6.92 (td, J = 8.15, 1.17 Hz,
1
3
H, 2-phenyl H-5); C NMR (62.5 MHz, CDCl ) δ 160.04 (C), 157.49 (C), 150.25 (C),
3
49.71 (C), 140.32 (C), 137.92 (C), 132.17 (C), 131.67 (CH), 130.71 (CH), 130.36 (CH),
30.07 (CH), 127.28 (CH), 127.00 (CH), 126.46 (CH), 125.92 (CH), 124.40 (C), 119.05
(CH), 118.87 (CH), 118.86 (CH), 118.51 (CH), 118.03 (CH).
4
.3.4. Synthesis of 2-(4-(2-Chlorophenyl)-6-phenylpyridin-2-yl) phenol (16)
General method in section 4.3 was followed with 7e (0.39 g, 1.50 mmol, 1.0 equiv.), 2d (0.73
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4

(3.00 mL) at 100 °C for 15 h. We obtained 326 mg (60.7%, 0.91 mmol) of 16 as a light
yellow solid.
R = 0.45 (ethyl acetate/n-hexane 1:5 v/v), mp: 108.1-108.7 °C, HPLC: Retention time: 11.2
f
+
min, purity:100 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 358.09; found 358.30.
2
3
17
1
H NMR (250 MHz, CDCl ) δ 14.74 (br s, 1H, 2-phenyl 2-OH), 7.99 (dd, J = 7.80, 1.25 Hz,
3
2
7
7
7
H, 6-phenyl H-2, H-6), 7.93 (s, 1H, pyridine H-3), 7.86 (d, J = 8.02 Hz, 1H, 2-phenyl H-6),
.72 (s, 1H, pyridine H-5), 7.57-7.45 (m, 4H, 4-phenyl H-6 and 6-phenyl H-3, H-4, H-5),
.43-7.37 (m, 3H, 4-phenyl H-3, H-4, H-5), 7.34 (td, J = 6.90, 1.40 Hz, 1H, 2-phenyl H-4),
1
3
.07 (d, J = 8.20 Hz, 1H, 2-phenyl H-3), 6.93 (td, J = 7.15 Hz, 1H, 2-phenyl H-5); C NMR
62.5 MHz, CDCl ) δ 160.06 (C), 157.67 (C), 154.72 (C), 149.69 (C), 137.97 (C), 137.90 (C),
(
3
1
32.19 (C), 131.67 (CH), 130.77 (CH), 130.38 (CH), 130.07 (CH), 129.69 (CH), 129.11
CH), 127.29 (CH), 126.98 (CH), 126.47 (CH), 119.62 (C), 118.92 (CH), 118.88 (CH),
18.54 (CH), 118.29 (CH).
(
1
4
.3.5. Synthesis of 2-(4-(3-Chlorophenyl)-6-(furan-2-yl)pyridin-2-yl) phenol (17)
General method in section 4.3 was followed with 7f (0.39 g, 1.50 mmol, 1.0 equiv.), 2a (0.71
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 14 h. We obtained 366 mg (70.0%, 1.05 mmol) of 17 as a yellow
solid.
R = 0.45 (ethyl acetate/n-hexane 1:5 v/v), mp: 150.9-151.4 °C, HPLC: Retention time: 11.3
f
+
min, purity:99.7 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 348.07; found 348.25.
2
1
15
2
1
H NMR (250 MHz, CDCl ) δ 14.41 (br s, 1H, 2-phenyl 2-OH), 7.90 (dd, J = 7.82, 1.50 Hz,
3
1
H, 2-phenyl H-6), 7.88 (d, J = 1.35 Hz, 1H, pyridine H-3), 7.75 (d, J = 1.40 Hz, 1H,
pyridine H-5), 7.71-7.69 (m, 1H, 4-phenyl H-2), 7.62-7.58 (m, 2H, 4-phenyl H-6 and 6-furan
H-5), 7.47-7.45 (m, 2H, 4-phenyl H-4, H-5), 7.34 (td, J = 8.42, 1.57 Hz, 1H, 2-phenyl H-4),

7
6
.11 (dd, J = 3.45, 0.57 Hz, 1H, 6-furan H-3), 7.05 (dd, J = 8.25, 1.12 Hz, 1H, 2-phenyl H-3),
.94 (td, J = 8.15, 1.25 Hz, 1H, 2-phenyl H-5), 6.58 (dd, J = 3.47, 1.77 Hz, 1H, 6-furan H-4);
1
3
C NMR (62.5 MHz, CDCl ) δ 160.04 (C), 157.97 (C), 151.91 (C), 149.60 (C), 146.48 (C),
3
1
1
1
44.06 (CH), 140.12 (C), 135.20 (C), 131.81 (CH), 130.45 (CH), 129.44 (CH), 127.29 (CH),
26.35 (CH), 125.35 (C), 118.88 (CH), 118.65 (CH), 115.20 (CH), 114.33 (CH), 112.34 (CH),
09.80 (CH).
4
.3.6. Synthesis of 2-(4-(3-Chlorophenyl)-6-(thiophen-2-yl)pyridin-2-yl) phenol (18)
General method in section 4.3 was followed with 7f (0.26 g, 1.00 mmol, 1.0 equiv.), 2b (0.49
g, 1.50 mmol, 1.5 equiv.), NH OAc (0.77 g, 10.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 14 h. We obtained 197 mg (54.1%, 0.54 mmol) of 18 as a white solid.
R = 0.45 (ethyl acetate/n-hexane 1:5 v/v), mp: 139.2-139.7 °C, HPLC: Retention time: 11.9
f
+
min, purity: %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.26.
2
1
15
1
H NMR (250 MHz, CDCl ) δ 13.96 (br s, 1H, 2-phenyl 2-OH), 7.88 (dd, J = 7.52, 1.32 Hz,
3
1
4
H, 2-phenyl H-6), 7.87 (d, J = 1.15 Hz, 1H, pyridine H-3), 7.69-7.68 (m, 3H, pyridine H-5,
-phenyl H-2 and 6-thiophene H-3), 7.59-7.54 (m, 1H, 4-phenyl H-6), 7.47-7.45 (m, 3H, 4-
phenyl H-4, H-5 and 6-thiophene H-5), 7.34 (td, J = 8.42, 1.45 Hz, 1H, 2-phenyl H-4), 7.15
(dd, J = 4.97, 3.77 Hz, 1H, 6-thiophene H-4), 7.05 (dd, J = 8.20, 1.05 Hz, 1H, 2-phenyl H-3),
1
3
6
1
.94 (td, J = 8.15, 1.10 Hz, 1H, 2-phenyl H-5); C NMR (62.5 MHz, CDCl ) δ 159.76 (C),
3
58.02 (C), 150.11 (C), 149.70 (C), 142.62 (C), 140.11 (C), 135.21 (C), 131.83 (CH), 130.48
(CH), 129.45 (CH), 128.42 (CH), 128.06 (CH), 127.29 (CH), 126.48 (CH), 125.75 (CH),
1
25.36 (CH), 118.99 (C), 118.68 (CH), 118.64 (CH), 115.55 (CH), 115.02 (CH).
4
.3.7. Synthesis of 2-(4-(3-Chlorophenyl)-6-(thiophen-3-yl)pyridin-2-yl) phenol (19)

General method in section 4.3 was followed with 7f (0.26 g, 1.00 mmol, 1.0 equiv.), 2c (0.49
g, 1.50 mmol, 1.5 equiv.), NH OAc (0.77 g, 10.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 16 h. We obtained 205 mg (56.3%, 0.56 mmol) of 19 as a yellow
solid.
R = 0.46 (ethyl acetate/n-hexane 1:5 v/v), mp: 121.6-122.1 °C, HPLC: Retention time: 11.9
f
+
min, purity: 99.5 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.26
2
1
15
1
H NMR (250 MHz, CDCl ) δ 14.66 (br s, 1H, 2-phenyl 2-OH), 7.94 (dd, J = 2.97, 1.32 Hz,
3
1
1
7
7
3
H, 6-thiophene H-2), 7.93 (d, J = 1.30 Hz, 1H, pyridine H-3), 7.88 (dd, J = 8.15, 1.47 Hz,
H, 2-phenyl H-6), 7.69-7.66 (m, 3H, pyridine H-5, 4-phenyl H-2 and 6-thiophene H-4),
.60-7.54 (m, 1H, 4-phenyl H-6), 7.50-7.44 (m, 3H, 4-phenyl H-4, H-5 and 6-thiophene H-5),
.34 (td, J = 8.50, 1.50 Hz, 1H, 2-phenyl H-4), 7.05 (dd, J = 8.22, 1.10 Hz, 1H, 2-phenyl H-
1
3
), 6.94 (td, J = 8.15, 1.20 Hz, 1H, 2-phenyl H-5); C NMR (62.5 MHz, CDCl ) δ 160.06
3
(
C), 158.10 (C), 150.95 (C), 149.80 (C), 140.27 (C), 140.22 (C), 135.21 (C), 131.78 (CH),
30.48 (CH), 129.40 (CH), 127.32 (CH), 127.07 (CH), 126.39 (CH), 125.89 (CH), 125.38
CH), 124.51 (C), 118.90 (CH), 118.75 (CH), 118.57 (CH), 116.44 (CH), 115.34 (CH).
1
(
4
.3.8. Synthesis of 2-(4-(3-Chlorophenyl)-6-phenylpyridin-2-yl) phenol (20)
General method in section 4.3 was followed with 7f (0.26 g, 1.00 mmol, 1.0 equiv.), 2d (0.49
g, 1.50 mmol, 1.5 equiv.), NH OAc (0.77 g, 10.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 15 h. We obtained 237 mg (66.2%, 0.66 mmol) of 20 as a light
yellow solid.
R = 0.46 (ethyl acetate/n-hexane 1:5 v/v), Mp: 138.1-138.6 °C, HPLC: Retention time: 11.9
f
+
min, purity: 96.1 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 358.09; found 358.30.
2
3
17
1
H NMR (250 MHz, CDCl ) δ 14.70 (br s, 1H, 2-phenyl 2-OH), 8.00-7.99 (m, 2H, 6-phenyl
3
H-2, H-6), 7.97 (d, J = 1.45 Hz, 1H, pyridine H-3), 7.93 (dd, J = 8.05, 1.47 Hz, 1H, 2-phenyl

H-6), 7.78 (d, J = 1.35 Hz, 1H, pyridine H-5), 7.71-7.70 (m, 1H, 4-phenyl H-2), 7.63-7.56 (m,
H, 4-phenyl H-6), 7.54-7.46 (m, 5H, 6-phenyl H-3, H-4, H-5 and 4-phenyl H-4, H-5), 7.34
td, J = 8.40, 1.57 Hz, 1H, 2-phenyl H-4), 7.06 (dd, J = 8.25, 1.12 Hz, 1H, 2-phenyl H-3),
1
(
1
3
6
1
.95 (td, J = 6.92, 1.25 Hz, 1H, 2-phenyl H-5); C NMR (62.5 MHz, CDCl ) δ 160.08 (C),
3
58.29 (C), 155.53 (C), 149.82 (C), 140.35 (C), 137.85 (C), 135.23 (C), 131.79 (CH), 130.50
(CH), 129.80 (CH), 129.41 (CH), 129.15 (CH), 127.38 (CH), 126.97 (CH), 126.41 (CH),
1
25.43 (CH), 118.91 (C), 118.83 (CH), 118.61 (CH), 117.03 (CH), 115.64 (CH).
4
.3.9. Synthesis of 2-(4-(4-Chlorophenyl)-6-(furan-2-yl)pyridin-2-yl) phenol (21)
General method in section 4.3 was followed with 7g (0.39 g, 1.50 mmol, 1.0 equiv.), 2a (0.71
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 110 °C for 15 h. We obtained 188 mg (36.0%, 0.54 mmol) of 21 as a yellow
solid.
R = 0.49 (ethyl acetate/n-hexane 1:5 v/v), mp: 185.1-185.7°C, HPLC: Retention time: 11.4
f
+
min, purity:99.2 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 348.07; found 348.25.
2
1
15
2
1
H NMR (250 MHz, CDCl ) δ 14.37 (br s, 1H, 2-phenyl 2-OH), 7.87 (s, 1H, pyridine H-3),
3
7
4
.86 (d, J = 6.07 Hz, 1H, 2-phenyl H-6), 7.74 (s, 1H, pyridine H-5), 7.65 (d, J = 8.57 Hz, 2H,
-phenyl H-2, H-6), 7.57 (d, J = 0.90 Hz, 1H, 6-furan H-5), 7.49 (d, J = 8.57 Hz, 2H, 4-
phenyl H-3, H-5), 7.33 (td, J = 8.22, 1.32 Hz, 1H, 2-phenyl H-4), 7.09 (d, J = 3.37 Hz, 1H, 6-
furan H-3), 7.05 (d, J = 8.17 Hz, 1H, 2-phenyl H-3), 6.88 (td, J = 7.27, 0.55 Hz, 1H, 2-phenyl
13
H-5), 6.57 (dd, J = 3.40, 1.75 Hz, 1H, 6-furan H-4); C NMR (62.5 MHz, CDCl ) δ 160.11
3
(
C), 158.00 (C), 152.03 (C), 149.78 (C), 146.50 (C), 144.02 (CH), 136.73 (C), 135.78 (C),
31.77 (CH), 129.43 (CH), 128.43 (CH), 126.32 (CH), 118.85 (C), 118.75 (CH), 118.68 (CH),
15.06 (CH), 114.20 (CH), 112.33 (CH), 109.74 (CH).
1
1

4
.3.10. Synthesis of 2-(4-(4-Chlorophenyl)-6-(thiophen-2-yl)pyridin-2-yl) phenol (22)
General method in section 4.3 was followed with 7g (0.39 g, 1.50 mmol, 1.0 equiv.), 2b (0.71
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 110 °C for 12 h. We obtained 220 mg (40.0%, 0.60 mmol) of 22 as a light
yellow solid.
R = 0.41 (ethyl acetate/n-hexane 1:5 v/v), mp: 165.6-165.9 °C, HPLC: Retention time: 12.2
f
+
min, purity: 100 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.26
2
1
15
1
H NMR (250 MHz, CDCl ) δ 13.93 (br s, 1H, 2-phenyl 2-OH), 7.85 (s, 1H, pyridine H-3),
3
7
.83 (dd, J = 6.67, 1.25 Hz, 1H, 2-phenyl H-6), 7.67-7.63 (m, 2H, pyridine H-5 and 6-
thiophene H-3), 7.62 (d, J = 8.47 Hz, 2H, 4-phenyl H-2, H-6), 7.49 (d, J = 8.52 Hz, 2H, 4-
phenyl H-3, H-5), 7.43 (dd, J = 5.05, 0.90 Hz, 1H, 6-thiophene H-5), 7.32 (td, J = 8.50, 1.40
Hz, 1H, 2-phenyl H-4), 7.13 (dd, J = 4.95, 3.75 Hz, 1H, 6-thiophene H-4), 7.05 (dd, J = 8.20,
1
3
0
.90 Hz, 1H, 2-phenyl H-3), 6.89 (td, J = 8.17, 1.07 Hz, 1H, 2-phenyl H-5); C NMR (62.5
MHz, CDCl ) δ 159.83 (C), 158.03 (C), 150.11 (C), 149.87 (C), 142.71 (C), 136.70 (C),
3
1
35.78 (C), 131.79 (CH), 129.44 (CH), 128.42 (CH), 128.39 (CH), 127.98 (CH), 126.45
(CH), 125.69 (CH), 118.96 (C), 118.77 (CH), 118.66 (CH), 115.40 (CH), 114.91 (CH).
4
.3.11. Synthesis of 2-(4-(4-Chlorophenyl)-6-(thiophen-3-yl)pyridin-2-yl) phenol (23)
General method in section 4.3 was followed with 7g (0.39 g, 1.50 mmol, 1.0 equiv.), 2c (0.71
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 12 h. We obtained 296 mg (54.0%, 0.81 mmol) of 23 as a light
yellow solid.
R = 0.44 (ethyl acetate/n-hexane 1:5 v/v), mp: 170.8-171.3 °C, HPLC: Retention time: 12.3
f
+
min, purity: 100 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.26
2
1
15
1
H NMR (250 MHz, CDCl ) δ 14.62 (br s, 1H, 2-phenyl 2-OH), 7.92 (dd, J = 2.90, 1.25 Hz,
3

1
1
1
H, 6-thiophene H-2), 7.90 (d, J = 1.32 Hz, 1H, pyridine H-3), 7.86 (dd, J = 8.60, 1.37 Hz,
H, 2-phenyl H-6), 7.67-7.63 (m, 2H, pyridine H-5 and 6-thiophene H-4), 7.62 (dd, J = 8.72,
.97 Hz, 2H, 4-phenyl H-2, H-6), 7.49 (dd, J = 8.55, 1.80 Hz, 2H, 4-phenyl H-3, H-5), 7.45
(dd, J = 5.05, 2.97 Hz, 1H, 6-thiophene H-5), 7.33 (td, J = 6.97, 1.52 Hz, 1H, 2-phenyl H-4),
7
5
.05 (dd, J = 8.22, 1.02 Hz, 1H, 2-phenyl H-3), 6.93 (td, J = 8.00, 1.12 Hz, 1H, 2-phenyl H-
1
3
); C NMR (62.5 MHz, CDCl ) δ 160.13 (C), 158.12 (C), 150.97 (C), 149.99 (C), 140.34
3
(
C), 136.90 (C), 135.74 (C), 131.75 (CH), 129.45 (CH), 128.46 (CH), 127.04 (CH), 126.36
CH), 125.91 (CH), 124.44 (C), 118.87 (CH), 118.84 (CH), 118.60 (CH), 116.32 (CH),
(
115.21 (CH).
4
.3.12. Synthesis of 2-(4-(4-Chlorophenyl)-6-phenylpyridin-2-yl) phenol (24)
General method in section 4.3 was followed with 7g (0.39 g, 1.50 mmol, 1.0 equiv.), 2d (0.73
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 12 h. We obtained 273 mg (50.6%, 0.76 mmol) of 24 as a yellow
solid.
R = 0.46 (ethyl acetate/n-hexane 1:5 v/v), mp: 179.1-179.6 °C, HPLC: Retention time: 12.2
f
+
min, purity: 98.9 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 358.09; found 358.30.
2
3
17
1
H NMR (250 MHz, CDCl ) δ 14.72 (br s, 1H, 2-phenyl 2-OH), 7.97 (d, J = 1.22 Hz, 1H,
3
pyridine H-3), 7.96 (d, J = 8.05 Hz, 2H, 6-phenyl H-2, H-6), 7.89 (dd, J = 8.05, 1.42 Hz, 1H,
-phenyl H-6), 7.76 (d, J = 1.27 Hz, 1H, pyridine H-5), 7.65 (dd, J = 8.60, 1.97 Hz, 2H, 4-
2
phenyl H-2, H-6), 7.56-7.45 (m, 5H, 4-phenyl H-3, H-5 and 6-phenyl H-3, H-4, H-5), 7.34 (td,
J = 8.30, 1.25 Hz, 1H, 2-phenyl H-4), 7.05 (dd, J = 8.15 Hz, 1H, 2-phenyl H-3), 6.94 (td, J =
1
3
8
1
1
.00, 0.90 Hz, 1H, 2-phenyl H-5); C NMR (62.5 MHz, CDCl ) δ 160.09 (C), 158.21 (C),
3
55.43 (C), 149.93 (C), 137.89 (C), 136.88 (C), 135.69 (C), 131.74 (CH), 129.75 (CH),
29.44 (CH), 129.12 (CH), 128.48 (CH), 126.94 (CH), 126.35 (CH), 118.86 (C), 118.83 (CH),

118.60 (CH), 116.87 (CH), 115.43 (CH).
4
.3.13. Synthesis of 3-(4-(2-Chlorophenyl)-6-(furan-2-yl)pyridin-2-yl) phenol (25)
General method in section 4.3 was followed with 8e (0.39 g, 1.50 mmol, 1.0 equiv.), 2a (0.71
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 110 °C for 12 h. We obtained 324 mg (62.1%, 0.93 mmol) of 25 as a white solid.
R = 0.53 (ethyl acetate/n-hexane 1:2 v/v), mp: 127.8-128.5 °C, HPLC: Retention time: 8.0
f
+
min, purity:99.7 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 348.07; found 348.25.
2
1
15
2
1
H NMR (250 MHz, CDCl ) δ 7.72 (s, 1H, pyridine H-3), 7.68 (s, 1H, 2-phenyl H-2), 7.65 (s,
3
1
H, pyridine H-5), 7.58 (d, J = 7.74 Hz, 1H, 2-phenyl H-6), 7.54-7.49 (m, 2H, 4-phenyl H-6
and 6-furan H-5), 7.44-7.35 (m, 3H, 4-phenyl H-3, H-4, H-5), 7.32 (t, J = 7.79 Hz, 1H, 2-
phenyl H-5), 7.22 (d, J = 3.38 Hz, 1H, 6-furan H-3), 6.88 (dd, J = 8.04, 2.53 Hz, 1H, 2-
phenyl H-4), 6.54 (dd, J = 3.37, 1.76 Hz, 1H, 6-furan H-4), 5.55 (br s, 1H, 2-phenyl 3-OH);
1
3
C NMR (62.5 MHz, CDCl ) δ 156.73 (C), 156.17 (C), 153.77 (C), 149.23 (C), 148.67 (C),
3
1
1
43.37 (CH), 140.72 (C), 138.21 (C), 132.27 (C), 130.82 (CH), 130.27 (CH), 129.93 (CH),
29.75 (CH), 127.14 (CH), 119.74 (CH), 119.45 (CH), 117.82 (CH), 116.31 (CH), 114.25
(CH), 112.11 (CH), 109.23 (CH).
4
.3.14. Synthesis of 3-(4-(2-Chlorophenyl)-6-(thiophen-2-yl)pyridin-2-yl) phenol (26)
General method in section 4.3 was followed with 8e (0.39 g, 1.50 mmol, 1.0 equiv.), 2b (0.74
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 12 h. We obtained 496 mg (90.6%, 1.36 mmol) of 26 as a light
yellow solid.
R = 0.52 (ethyl acetate/n-hexane 1:2 v/v), mp: 125.8-126.1 °C, HPLC: Retention time: 8.9
f
+
min, purity: 99.5 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.26
2
1
15

1
H NMR (250 MHz, CDCl ) δ 7.71-7.70 (m, 1H, 2-phenyl H-2), 7.67-7.63 (m, 4H, 6-
3
thiophene H-3, 2-phenyl H-6 and pyridine H-3, H-5), 7.55-7.50 (m, 1H, 4-phenyl H-6), 7.44-
.35 (m, 4H, 6-thiophene H-5 and 4-phenyl H-3, H-4, H-5), 7.34 (t, J = 7.88 Hz, 1H, 2-
phenyl H-5), 7.12 (dd, J = 5.03, 3.68 Hz, 1H, 6-thiophene H-4), 6.90 (dd, J = 8.03, 1.82 Hz,
7
1
3
1
H, 2-phenyl H-4), 5.05 (br s, 1H, 2-phenyl 3-OH); C NMR (62.5 MHz, CDCl ) δ 156.19
3
(
C), 156.03 (C), 152.26 (C), 148.64 (C), 145.17 (C), 140.51 (C), 138.23 (C), 132.29 (C),
30.79 (CH), 130.29 (CH), 129.94 (CH), 129.77 (CH), 127.97 (CH), 127.79 (CH), 127.17
CH), 124.83 (CH), 119.46 (CH), 119.32 (CH), 117.95 (CH), 116.28 (CH), 114.03 (CH).
1
(
4
.3.15. Synthesis of 3-(4-(2-Chlorophenyl)-6-(thiophen-3-yl)pyridin-2-yl) phenol (27)
General method in section 4.3 was followed with 8e (0.39 g, 1.50 mmol, 1.0 equiv.), 2c (0.74
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 110 °C for 14 h. We obtained 415 mg (76.0%, 1.14 mmol) of 27 as an off-white
solid.
R = 0.51 (ethyl acetate/n-hexane 1:2 v/v), mp: 127.1-127.6 °C, HPLC: Retention time: 8.7
f
+
min, purity: 99.5 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.26.
2
1
15
1
H NMR (250 MHz, CDCl ) δ 8.04 (dd, J = 2.98, 1.14 Hz, 1H, 6-thiophene H-2), 7.80 (dd, J
3
=
5.04, 1.13 Hz, 1H, 6-thiophene H-4), 7.70-7.69 (m, 1H, 2-phenyl H-2), 7.67 (d, J = 1.09 Hz,
1
H, pyridine H-3), 7.65 (d, J = 8.87 Hz, 1H, 2-phenyl H-6), 7.63 (d, J = 1.18 Hz, 1H,
pyridine H-5), 7.55-7.50 (m, 1H, 4-phenyl H-6), 7.44-7.34 (m, 4H, 6-thiophene H-5 and 4-
phenyl H-3, H-4, H-5), 7.34 (t, J = 7.85 Hz, 1H, 2-phenyl H-5), 6.90 (dd, J = 7.44, 1.87 Hz,
1
3
1
H, 2-phenyl H-4), 5.03 (br s, 1H, 2-phenyl 3-OH); C NMR (62.5 MHz, CDCl ) δ 156.36
3
(
C), 156.01 (C), 153.15 (C), 148.64 (C), 142.31 (C), 140.98 (C), 138.38 (C), 132.30 (C),
30.83 (CH), 130.29 (CH), 129.92 (CH), 129.72 (CH), 127.17 (CH), 126.48 (CH), 126.19
CH), 123.96 (CH), 119.54 (CH), 119.50 (CH), 119.32 (CH), 116.15 (CH), 114.08 (CH).
1
(

4
.3.16. Synthesis of 3-(4-(2-Chlorophenyl)-6-phenylpyridin-2-yl) phenol (28)
General method in section 4.3 was followed with 8e (0.39 g, 1.50 mmol, 1.0 equiv.), 2d (0.73
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 110 °C for 16 h. We obtained 419 mg (78.0%, 1.17 mmol) of 28 as a white solid.
R = 0.52 (ethyl acetate/n-hexane 1:2 v/v), mp: 129.2-129.7 °C, HPLC: Retention time: 9.1
f
+
min, purity: 99.8 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 358.09; found 358.31.
2
3
17
1
H NMR (250 MHz, CDCl ) δ 8.17 (dd, J = 8.27, 1.34 Hz, 2H, 6-phenyl H-2, H-6), 7.76 (s,
3
1
H, 2-phenyl H-2), 7.72 (s, 2H, pyridine H-3, H-5), 7.65 (dd, J = 7.74, 0.66 Hz, 1H, 2-phenyl
H-6), 7.55-7.50 (m, 1H, 4-phenyl H-6), 7.48-7.45 (m, 3H, 6-phenyl H-3, H-4, H-5), 7.44-7.34
(m, 3H, 4-phenyl H-3, H-4, H-5), 7.34 (t, J = 7.86 Hz, 1H, 2-phenyl H-5), 6.88 (dd, J = 8.03,
1
3
2
1
.56 Hz, 1H, 2-phenyl H-4), 5.19 (br s, 1H, 2-phenyl 3-OH); C NMR (62.5 MHz, CDCl ) δ
3
56.97 (C), 156.39 (C), 156.04 (C), 148.65 (C), 141.01 (C), 139.32 (C), 138.43 (C), 132.30
(C), 130.88 (CH), 130.30 (CH), 129.92 (CH), 129.71 (CH), 129.11 (CH), 128.70 (CH),
1
27.16 (CH), 119.77 (CH), 119.60 (CH), 119.52 (CH), 116.17 (CH), 114.13 (CH).
4
.3.17. Synthesis of 3-(4-(3-Chlorophenyl)-6-(furan-2-yl)pyridin-2-yl) phenol (29)
General method in section 4.3 was followed with 8f (0.39 g, 1.50 mmol, 1.0 equiv.), 2a (0.71
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 16 h. We obtained 397 mg (76.1%, 1.14 mmol) of 29 as a white solid.
R = 0.54 (ethyl acetate/n-hexane 1:2 v/v), mp: 142.5-143.1 °C, HPLC: Retention time: 8.9
f
+
min, purity: 100 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 348.07; found 348.25.
2
1
15
2
1
H NMR (250 MHz, CDCl ) δ 7.82 (d, J = 1.12 Hz, 1H, pyridine H-3), 7.69-7.66 (m, 3H,
3
pyridine H-5, 2-phenyl H-2 and 4-phenyl H-2), 7.60-7.56 (m, 3H, 2-phenyl H-6, 4-phenyl H-
and 6-furan H-5), 7.44-7.42 (m, 2H, 4-phenyl H-4, H-5), 7.32 (t, J = 7.90 Hz, 1H, 2-phenyl
6

H-5), 7.22 (d, J = 3.37 Hz, 1H, 6-furan H-3), 6.88 (dd, J = 8.00, 2.42 Hz, 1H, 2-phenyl H-4),
1
3
6
.53 (dd, J = 3.32, 1.72 Hz, 1H, 6-furan H-4), 6.13 (br s, 1H, 2-phenyl 3-OH); C NMR
(
(
(
62.5 MHz, CDCl ) δ 157.69 (C), 156.23 (C), 153.51 (C), 149.81 (C), 148.70 (C), 143.44
3
CH), 140.53 (C), 140.32 (C), 135.07 (C), 130.34 (CH), 129.96 (CH), 129.12 (CH), 127.22
CH), 125.26 (CH), 119.34 (CH), 117.09 (CH), 116.49 (CH), 115.16 (CH), 114.32 (CH),
112.20 (CH), 109.44 (CH).
4
.3.18. Synthesis of 3-(4-(3-Chlorophenyl)-6-(thiophen-2-yl)pyridin-2-yl) phenol (30)
General method in section 4.3 was followed with 8f (0.39 g, 1.50 mmol, 1.0 equiv.), 2b (0.74
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 17 h. We obtained 423 mg (77.3%, 1.16 mmol) of 30 as a white solid.
R = 0.55 (ethyl acetate/n-hexane 1:2 v/v), mp: 143.2-143.8 °C, HPLC: Retention time: 9.8
f
+
min, purity: 100 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.26.
2
1
15
1
H NMR (250 MHz, CDCl ) δ 7.72-7.66 (m, 6H, pyridine H-3, H-5, 2-phenyl H-2, H-6, 4-
3
phenyl H-2 and 6-thiophene H-3), 7.60-7.55 (m, 1H, 4-phenyl H-6), 7.46-7.42 (m, 3H, 4-
phenyl H-4, H-5 and 6-thiophene H-5), 7.37 (t, J = 7.77 Hz, 1H, 2-phenyl H-5), 7.15 (dd, J =
4
.70, 3.77 Hz, 1H, 6-thiophene H-4), 6.92 (dd, J = 7.97, 2.47 Hz, 1H, 2-phenyl H-4), 5.14 (br
1
3
s, 1H, 2-phenyl 3-OH); C NMR (62.5 MHz, CDCl ) δ 156.94 (C), 156.04 (C), 152.89 (C),
3
1
1
48.80 (C), 145.00 (C), 140.54 (C), 140.39 (C), 135.09 (C), 130.38 (CH), 129.99 (CH),
29.08 (CH), 128.02 (CH), 127.93 (CH), 127.26 (CH), 125.29 (CH), 124.89 (CH), 119.40
(CH), 116.72 (CH), 116.36 (CH), 115.36 (CH), 114.00 (CH).
4
.3.19. Synthesis of 3-(4-(3-Chlorophenyl)-6-(thiophen-3-yl)pyridin-2-yl) phenol (31)
General method in section 4.3 was followed with 8f (0.39 g, 1.50 mmol, 1.0 equiv.), 2c (0.74
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4

(3.00 mL) at 100 °C for 15 h. We obtained 473 mg (86.6%, 1.30 mmol) of 31 as a white solid.
R = 0.55 (ethyl acetate/n-hexane 1:2 v/v), mp: 148.8-149.3 °C, HPLC: Retention time: 9.7
f
+
min, purity: 100 %; ESI LC/MS: m/z calcd for C H ClNOS [MH] 364.05; found 364.27.
2
1
15
1
H NMR (250 MHz, CDCl ) δ 8.03 (dd, J = 3.00, 1.25 Hz, 1H, 6-thiophene H-2), 7.78 (dd, J
3
=
5.05, 1.25 Hz, 1H, 6-thiophene H-4), 7.71 (d, J = 1.40 Hz, 1H, pyridine H-3), 7.68 (d, J =
1
7
.45 Hz, 1H, pyridine H-5), 7.67-7.62 (m, 3H, 2-phenyl H-2, H-6 and 4-phenyl H-2), 7.58-
.52 (m, 1H, 4-phenyl H-6), 7.46-7.42 (m, 2H, 4-phenyl H-4, H-5), 7.39 (dd, J = 5.05, 3.00
Hz, 1H, 6-thiophene H-5), 7.33 (t, J = 7.80 Hz, 1H, 2-phenyl H-5), 6.89 (dd, J = 7.97, 2.47
1
3
Hz, 1H, 2-phenyl H-4), 5.58 (br s, 1H, 2-phenyl 3-OH); C NMR (62.5 MHz, CDCl ) δ
3
1
57.24 (C), 156.05 (C), 153.84 (C), 148.78 (C), 142.05 (C), 140.74 (C), 140.61 (C), 135.06
C), 130.36 (CH), 129.95 (CH), 129.02 (CH), 127.25 (CH), 126.43 (CH), 126.31 (CH),
25.29 (CH), 124.15 (CH), 119.43 (CH), 116.98 (CH), 116.84 (CH), 116.34 (CH), 114.15
CH).
(
1
(
4
.3.20. Synthesis of 3-(4-(3-Chlorophenyl)-6-phenylpyridin-2-yl) phenol (32)
General method in section 4.3 was followed with 8f (0.39 g, 1.50 mmol, 1.0 equiv.), 2d (0.73
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 100 °C for 15 h. We obtained 408 mg (76.0%, 1.14 mmol) of 32 as a white solid.
R = 0.57 (ethyl acetate/n-hexane 1:2 v/v), mp: 181.5-181.9 °C, HPLC: Retention time: 9.9
f
+
min, purity: 100 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 358.09; found 358.30.
2
3
17
1
H NMR (250 MHz, CDCl ) δ 8.14 (dd, J = 8.30, 1.65 Hz, 2H, 6-phenyl H-2, H-6), 7.82 (d, J
3
=
1.40 Hz, 1H, pyridine H-3), 7.78 (d, J = 1.40 Hz, 1H, pyridine H-5), 7.72-7.66 (m, 3H, 2-
phenyl H-2, H-6 and 4-phenyl H-2), 7.60-7.56 (m, 1H, 4-phenyl H-6), 7.53-7.43 (m, 5H, 6-
phenyl H-3, H-4, H-5 and 4-phenyl H-4, H-5), 7.35 (t, J = 7.80 Hz, 1H, 2-phenyl H-5), 6.89
1
3
(
dd, J = 8.05, 2.52 Hz, 1H, 2-phenyl H-4), 5.54 (br s, 1H, 2-phenyl 3-OH); C NMR (62.5

MHz, CDCl ) δ 157.75 (C), 157.18 (C), 156.06 (C), 148.81 (C), 140.84 (C), 140.72 (C),
3
1
1
39.19 (C), 135.07 (C), 130.37 (CH), 129.95 (CH), 129.22 (CH), 129.01 (CH), 128.73 (CH),
27.29 (CH), 127.15 (CH), 125.32 (CH), 119.44 (CH), 117.23 (CH), 117.07 (CH), 116.29
(CH), 114.13 (CH).
4
.3.21. Synthesis of 3-(4-(4-Chlorophenyl)-6-(furan-2-yl)pyridin-2-yl) phenol (33)
General method in section 4.3 was followed with 8g (0.39 g, 1.50 mmol, 1.0 equiv.), 2a (0.71
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4
(3.00 mL) at 105 °C for 18 h. We obtained 421 mg (80.6%, 1.21 mmol) of 33 as an off-white
solid.
R = 0.46 (ethyl acetate/n-hexane 1:2 v/v), mp: 162.5-162.9 °C, HPLC: Retention time: 8.8
f
+
min, purity: 100 %; ESI LC/MS: m/z calcd for C H ClNO [MH] 348.07; found 348.25.
2
1
15
2
1
H NMR (250 MHz, CDCl ) δ 7.81 (d, J = 1.42 Hz, 1H, pyridine H-3), 7.69 (d, J = 1.45 Hz,
3
1
H, pyridine H-5), 7.67-7.62 (m, 3H, 4-phenyl H-2, H-6 and 2-phenyl H-2), 7.57 (d, J = 7.86
Hz, 1H, 2-phenyl H-6), 7.54 (d, J = 1.03 Hz, 1H, 6-furan H-5), 7.47 (dd, J = 8.55, 1.82 Hz,
H, 4-phenyl H-3, H-5), 7.32 (t, J = 7.92 Hz, 1H, 2-phenyl H-5), 7.22 (d, J = 3.21 Hz, 1H, 6-
furan H-3), 6.88 (dd, J = 7.99, 1.90 Hz, 1H, 2-phenyl H-4), 6.54 (dd, J = 3.37, 1.76 Hz, 1H,
2
1
3
6
1
-furan H-4), 5.64 (br s, 1H, 2-phenyl 3-OH); C NMR (62.5 MHz, CDCl ) δ 157.58 (C),
3
56.19 (C), 153.71 (C), 149.84 (C), 148.85 (C), 143.38 (CH), 140.71 (C), 136.97 (C), 135.37
(C), 129.95 (CH), 129.31 (CH), 128.35 (CH), 119.40 (CH), 116.87 (CH), 116.40 (CH),
115.00 (CH), 114.29 (CH), 112.18 (CH), 109.36 (CH).
4
.3.22. Synthesis of 3-(4-(4-Chlorophenyl)-6-(thiophen-2-yl)pyridin-2-yl) phenol (34)
General method in section 4.3 was followed with 8g (0.39 g, 1.50 mmol, 1.0 equiv.), 2b (0.74
g, 2.25 mmol, 1.5 equiv.), NH OAc (1.15 g, 15.00 mmol, 10.0 equiv.) and glacial AcOH
4