Pyridin-2(1H)one derivatives: A possible new class of therapeutics for mechanical allodynia

Article abstract of DOI:10.1016/j.ejmech.2019.111917

Mechanical Allodynia (MA), a frequent chronic pain symptom caused by innocuous stimuli, constitutes an unmet medical need, as treatments using analgesics available today are not always effective and can be associated with important side-effects. A series of 3,5-disubstituted pyridin-2(1H)-ones was designed, synthesized and evaluated in vivo toward a rat model of inflammatory MA. We found that the series rapidly and strongly prevented the development of MA. 3-(2-Bromophenyl)-5-(phenylamino)pyridin-2(1H)-one 69, the most active compound of the series, was also able to quickly reverse neuropathic MA in rats. Next, when 69 was evaluated toward a panel of 50 protein kinases (PK) in order to identify its potential biological target(s), we found that 69 is a p38α MAPK inhibitor, a PK known to contribute to pain hypersensitivity in animal models. 3,5-Disubstituted pyridin-2(1H)-ones thus could represent a novel class of analgesic for the treatment of MA.

Full text of DOI:10.1016/j.ejmech.2019.111917

Journal Pre-proof
Pyridin-2(1H)one derivatives: A possible new class of therapeutics for mechanical
allodynia
Alexia Visseq, Amélie Descheemaeker, Nicolas Pinto-Pardo, Lionel Nauton, Vincent
Théry, Francis Giraud, Isabelle Abrunhosa-Thomas, Alain Artola, Fabrice Anizon,
Radhouane Dallel, Pascale Moreau
PII:
S0223-5234(19)31069-4
DOI:
https://doi.org/10.1016/j.ejmech.2019.111917
EJMECH 111917
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 24 October 2019
Revised Date: 20 November 2019
Accepted Date: 25 November 2019
Please cite this article as: A. Visseq, Amé. Descheemaeker, N. Pinto-Pardo, L. Nauton, V. Théry, F.
Giraud, I. Abrunhosa-Thomas, A. Artola, F. Anizon, R. Dallel, P. Moreau, Pyridin-2(1H)one derivatives:
A possible new class of therapeutics for mechanical allodynia, European Journal of Medicinal Chemistry
(2019), doi: https://doi.org/10.1016/j.ejmech.2019.111917.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Masson SAS.

Graphical Abstract

Pyridin-2(1H)one derivatives: a possible new class of therapeutics
for mechanical allodynia
Alexia Visseq†, Amélie Descheemaeker‡, Nicolas Pinto-Pardo‡, Lionel Nauton†, Vincent
Théry†, Francis Giraud†, Isabelle Abrunhosa-Thomas†,*, Alain Artola‡, Fabrice Anizon†,*,
Radhouane Dallel‡,§,*, Pascale Moreau†
†
Université Clermont Auvergne, CNRS, SIGMA Clermont, Institut de Chimie de Clermont-
Ferrand, F-63000 Clermont-Ferrand, France
‡ Université Clermont Auvergne, Inserm, Neuro-Dol, F-63000 Clermont-Ferrand, France
§
Centre Hospitalier Universitaire Clermont-Ferrand, Service d'Odontologie, F-63000
Clermont-Ferrand, France
*Authors to whom correspondence should be addressed:
(FA) Tel: +33 (0) 4 73 40 53 64. E-mail: fabrice.anizon@uca.fr
(RD) Tel: +33 (0) 4 73 17 73 12. E-mail: radhouane.dallel@uca.fr
(IT) Tel: +33 (0) 4 73 40 71 31. E-mail: isabelle.thomas@sigma-clermont.fr
1

Abstract
Mechanical Allodynia (MA), a frequent chronic pain symptom caused by innocuous stimuli,
constitutes an unmet medical need, as treatments using analgesics available today are not
always effective and can be associated with important side-effects. A series of 3,5-
disubstituted pyridin-2(1H)-ones was designed, synthesized and evaluated in vivo toward a rat
model of inflammatory MA. We found that the series rapidly and strongly prevented the
development of MA. 3-(2-Bromophenyl)-5-(phenylamino)pyridin-2(1H)-one 69, the most
active compound of the series, was also able to quickly reverse neuropathic MA in rats. Next,
when 69 was evaluated toward a panel of 50 protein kinases (PK) in order to identify its
potential biological target(s), we found that 69 is a p38α MAPK inhibitor, a PK known to
contribute to pain hypersensitivity in animal models. 3,5-Disubstituted pyridin-2(1H)-ones
thus could represent a novel class of analgesic for the treatment of MA.
Keywords: Mechanical allodynia; pyridin-2(1H)-ones; p38 MAPK
2

1. Introduction
Chronic pain is a worldwide major health, social and economic problem. It has an important
impact on quality of life across all ages, and is the most common reason for seeking medical
care [1–5]. Global economic impact of pain is tremendous. Estimates show that chronic pain
affects more than 20% of Europeans and costs several hundred billion each year in medical
treatment and loss of productivity, with an expected increase due to population ageing.
Despite significant investments in research and development to study pain mechanisms and
discover new treatments, most of the analgesics available today are still based on old drug
classes: nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, opioids,
anticonvulsants or antidepressants [6,7]. Moreover, these therapies have strong side-effects or
abuse potentials, and are not always effective. Whereas most currently available treatments
can alleviate inflammatory pain (initiated by tissue damage/inflammation), they are only
partially effective for neuropathic pain (caused by nervous system lesion) [7]. Thus, chronic
pain still constitutes an unmet medical need with a strong demand of the market for new
efficient treatments.
Chronic pain syndromes, whether inflammatory or neuropathic, are characterized by
persistent pain hypersensitivity such as spontaneous pain, hyperalgesia and allodynia. It is
now well established that each of these pain symptoms relies on different cellular and
molecular mechanisms. Thus a drug against spontaneous pain will not necessarily have an
effect on allodynia and vice versa. Therefore, it is pivotal to discover drugs that specifically
target the fundamental mechanisms causing the various pain symptoms.
Mechanical allodynia (MA), or touch-evoked pain, is one of the most prevalent pain
symptoms, being present in almost half of neuropathic patients [8,9]. It was recently shown
that it is associated with the activation, in the spinal dorsal horn (SDH) or medullary dorsal
horn (MDH) (SDH trigeminal homologue in the brainstem), of a polysynaptic pathway
whereby tactile inputs can gain access to the pain circuitry in superficial SDH/MDH. MA thus
results from a miscoding, with cells that normally transmit and respond to noxious stimuli
being activated by tactile inputs.
Activation of several neuronal protein kinases (PK) within the superficial SDH/MDH, such as
extracellular signal-regulated protein kinases (ERK), the γ isoform of protein kinase C
(PKCγ) or p38 mitogen-activated protein kinase (p38 MAPK), was shown to contribute to
pain hypersensitivity in animal models of chronic inflammatory and neuropathic pain. Thus,
inhibitors of ERK phosphorylation reduce mechanical allodynia and hyperalgesia [10].
Genetic [11] or pharmacological inactivation of PKCγ [12–15] prevents inflammatory MA
whereas its activation is sufficient to produce MA [14]. Finally, inhibition of SDH/MDH p38
MAPK attenuates inflammatory [16–18] as well as neuropathic pain [18–20]. Therefore, PKs
are possible cellular targets to alleviate MA.
Consequently, our goal was to design new ATP-competitive inhibitors of the catalytic domain
of PKCγ for the treatment of MA. Based on the structures of two potent PKC inhibitors,
bisindolylmaleimides BIM-1 and (2-methyl-indolyl)BIM-1 [21], we envisaged the preparation
of 3,5-disubstituted pyridin-2(1H)-one derivatives: the central core pyridinone nucleus
3

features H-bond donor/acceptor atoms that could mimic maleimide (or ATP adenine) H-bond
interactions with the hinge region of the targeted kinase. For the substitution of 3- and 5-
positions, we considered aryl/heteroaryl(amino) groups. In order to assess the ability of this
scaffold to interact the ATP-binding pocket of PKCγ, we performed a molecular modeling
study using a PKCγ model generated by sequence homology from an X-ray crystal structure
of highly homologous PKCβ available in the Protein Data Bank (PDB ID: 2I0E; no crystal
structure of PKCγ available in the PDB). Then, we used an automated docking protocol of a
virtual library of 255 pyridin-2(1H)-ones. This work led us to foresee the general structure A
depicted in Figure 1, of a pyridin-2(1H)-one core substituted at the 3- and 5-positions by
aryl/heteroaryl and phenylamino groups, respectively. This article reports the synthesis of a
series of pyridin-2(1H)-one derivatives and their identification as potent anti-allodynic agents
in rodent models of MA.
Figure 1. Comparison between the general structure A of 3,5-disubstituted pyridin-2(1H)-one
derivatives and structure of (2-methylindolyl)BIM-1. Hydrogen bonds with the protein kinase
hinge region are represented by dashed lines.
2. Results and discussion
2.1. Synthesis of 3,5-disubstituted pyridin-2(1H)-one derivatives
A series of 7 compounds of general structure A was initially prepared to work out the
synthetic pathway as well as evaluate the potency of these compounds toward MA and PKCγ.
The general synthetic pathway is indicated in Scheme 1. The synthesis started from
commercially available 3-bromo-5-nitropyridin-2(1H)-one 1, functionalized in such way that
desired substituents could be easily introduced at the 3- and 5–positions. First, compound 1
was regioselectively O-benzylated in the presence of benzyl bromide and silver carbonate
leading to pyridine 2 [22]. After reduction of the nitro group, Buchwald-Hartwig amination
with iodobenzene afforded compound 4 in good yield.
4

Scheme 1. Synthesis of compounds 2–4 and 12–25.
From intermediate 4, aryl and heteroaryl substituents were then introduced at the 3-position
using a Suzuki cross-coupling with the boronic acids 5–11 (Scheme 1, Table 1) leading to
intermediates 12–18. Finally, cleavage of the benzyl group using BBr3 yielded final
compounds 19–25 (Table 1). Compounds 19–25 were substituted by different aryl/heteroaryl
groups leading to a preliminary library of pyridinone derivatives showing structural diversity
at the 3-position.
Table 1. Isolated yields for compounds 12–25.
Boronic acidsa
Products 12–18
Cpd Ar/HetAr
Products 19–25
Cpd Ar/HetAr
% yield
94
Cpd
19
20
21
22
23
24
25
Ar/HetAr
% yield
90
Phenyl
Phenyl
Phenyl
5
6
12
13
14
15
16
17
18
4-Fluorophenyl
Pyridin-4-yl
4-Fluorophenyl
Pyridin-4-yl
95
4-Fluorophenyl
Pyridin-4-yl
97
93
80
7
1-TIPS-1H-indol-3-yl
Quinolin-8-yl
Pyrimidin-5-yl
Isoquinolin-5-yl
1H-Indolyl-3-yl
Quinolin-8-yl
Pyrimidin-5-yl
Isoquinolin-5-yl
88
1H-Indolyl-3-yl
Quinolin-8-yl
Pyrimidin-5-yl
Isoquinolin-5-yl
73
8
83
19
9
94
80
10
11
95
44
aBoronic acids were either commercially available or prepared according to literature procedures (8 [23], 9 [24],
11 [25]).
2.2. Preliminary evaluation of compounds 19–25
5

We first assessed the in vivo efficacy of compounds 19–24 on the face Complete Freund’s
Adjuvant (CFA) model (Fig. 2) [26]. Compound 25 was not tested due to its insufficient
solubility. After receiving a subcutaneous injection of 25 µL of CFA (2.5 mg/kg) into the
right vibrissa pad, rats develop a MA that lasts days. We found that intracisternally applied
compounds prevented the development of inflammatory MA, particularly 19–21, 23 and 24.
The most active compound was 21, bearing a pyridin-4-yl moiety, with a rapid, strong and
persistent anti-allodynic effect for the duration of the assay (90% inhibition at 120 min after
CFA injection). The evaluation of this first series showed that the substituent at the 3-position
of the pyridinone nucleus had an important impact on the anti-allodynic effect, and that
changing its nature could lead to higher or lower activity.
Figure 2. Intracisternal application of compounds 19–24, 66–72 and 74–82 prevents face MA
in a rat model of inflammatory pain (Complete Freund’s Adjuvant (CFA), n=4–6 rats for each
compound). For this assay, compounds (5 µL at 100 µM) or control vehicle were intra-
cisternally administred 30 min before CFA injection. Compounds 67 and 69 (0.15 µg and
0.17 µg, respectively) induced 98% and 99% inhibition of inflammatory MA, respectively.
Compound series (19–25) was also tested toward PKCγ at 10 µM concentration at the
International Centre for Kinase Profiling (ICKP, Dundee, Scotland) according to previously
reported procedure [27]. Unfortunately, these compounds were not active toward this PK
(≥85% mean residual kinase activity at 10 µM in duplicate assays). This indicated that the in
vivo activity was due to an effect toward at least one other molecular target than PKCγ,
possibly another PK. However, due to the promising anti-allodynic effect of compounds 19–
24, we aimed to prepare more efficient anti-allodynic drugs in this series, before identification
of the potential molecular target. Thus, new products were synthesized and then evaluated on
the rat model of inflammatory MA.
2.3. Identification of compound 69 as a potent anti-allodynic drug
According to the results presented above, we decided to synthesize other analogues of
compounds 19–24, bearing at the 3-position diversely substituted phenyl rings or
6

heteroaromatic moieties. Thus, using the same synthetic pathway presented in Scheme 1,
intermediates 46–65 were prepared from compound 4 and debenzylation afforded final
products 66–82 in modest to good yields (Table 2). Deprotection of compounds 63–65 led to
products that could not be purified (83–85).
Table 2. Structure and isolated yields of compounds 46–85.
Boronic acids/boronatea,b
Cpd Ar/HetAr
Products 46–65
Cpd Ar/HetAr
Quinolin-4-yl
Products 66–85
% yield
90
Cpd
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
Ar/HetAr
% yield
69
Quinolin-4-yl
1H-Indol-4-ylb
2-Cl-C6H4
Quinolin-4-yl
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
1H-Indol-4-yl
2-Cl-C6H4
quant.
85
1H-Indol-4-yl
2-Cl-C6H4
67
50
c
2-Br-C6H4
2-Br-C6H4
–
2-Br-C6H4
18d
78
2-(CO2Et)C6H4
2-CNC6H4
2-(CO2Et)C6H4
2-CNC6H4
75
2-(CO2Et)C6H4
2-(CONH2)C6H4
2-NO2-C6H4
(1,1'-biphenyl)-4-yl
3-Cl-C6H4
c
–
32d
89
2-NO2-C6H4
(1,1'-biphenyl)-4-yl
3-Cl-C6H4
2-NO2-C6H4
(1,1'-biphenyl)-4-yl
3-Cl-C6H4
37
91
80
95
92
3-AcetylC6H4
4-HOC6H4
3-AcetylC6H4
4-HOC6H4
quant.
75
3-AcetylC6H4
4-HOC6H4
70e
91
4-CH3C6H4
4-CH3C6H4
86
4-CH3C6H4
96
4-CF3C6H4
4-CF3C6H4
83
4-CF3C6H4
95
4-CF3OC6H4
4-(CO2Me)C6H4
4-(CONH2)C6H4
2,4-diF-C6H3
4-CF3OC6H4
4-(CO2Me)C6H4
4-(CONH2)C6H4
2,4-diF-C6H3
91
4-CF3OC6H4
4-(CO2Me)C6H4
4-(CONH2)C6H4
2,4-diF-C6H3
91
60
90
c
–
74d
62d
c
–
7

f
f
f
1H-Indol-7-yl
3-NH2C6H4
1H-Indol-7-yl
3-NH2C6H4
49
96
86
1H-Indol-7-yl
3-NH2C6H4
3-HOC6H4
–
–
–
43
44
45
63
64
65
83
84
85
3-CH3OC6H4
3-CH3OC6H4
aBoronic acids/boronates were commercially available except 43 which was prepared according to literature
b
c
procedures [28]. Compound 27 was a pinacol boronate. Compounds could not be fully purified by column
d
chromatography and were engaged in the next step without further purification. Yield over 2 steps from 4.
eCompound 55 was debenzylated using TMSI. fCompounds could not be purified.
The in vivo efficacy of all new compounds, except 73 which was not soluble enough for in
vivo assays, was evaluated on the rat model of inflammatory MA (Fig. 2). We found that all
the new compounds had an anti-allodynic activity. Interestingly, four 3,5-disubstituted
pyridin-2(1H)-ones (67, 69, 70 and 77) were either as potent or even more effective than
compound 21. The most active pyridinones were 67 and 69 (Fig. 2), bearing at the 3-position
an indol-4-yl or a 2-bromophenyl substituent, respectively. In this model of inflammatory
MA, static MA was suppressed in compound 69 treated rats, in comparison to animals treated
with vehicle (Fig. 3A). The results showed that the 3-position of the pyridinone moiety
tolerated aryl/heteroaryl groups, including more sterically demanding groups such as indolyl
group. However, the manner in which these groups are connected to the pyridinone moiety
influenced the anti-allodynic activity (compare 22 and 67). In addition, compared to phenyl
substituted 19, introduction of a nitrogen atom (21, bearing a pyridine-4-yl moiety) or a
methyl group (77) at the 4-position led to comparable gains of activity. Similarly, substitution
at the 2-position by a bromine atom (69) or an ethoxycarbonyl group (70) was favorable, with
high activities similar to the one of compound 67 bearing an 1H-indol-4-yl substituent.
The most effective compound (69) was also evaluated in a rat model of facial neuropathic MA
produced by the constriction injury of the rat infraorbital nerve (Fig. 3B) [29]. Rats develop
MA within 2 weeks after constriction which then lasts for several weeks thereafter.
Intracisternal administration of compounds 69 on day 14 reversed MA. The effect was fast
(Fig. 3B), confirming the potential of this compound series in neuropathic pain management.
8

Figure 3. Intracisternal application of compound 69 both prevents inflammatory (A) and
reverses neuropathic static MA (B). Time courses of changes in behavioral responses
(allodynic score) evoked by static mechanical stimuli (6-g von Frey filament) applied on the
face of rats intracisternally treated with 0.17 µg of compound 69 (5 µL at 100 µM) or vehicle.
In A, compound 69 or vehicle was preemptively applied 30 min before subcutaneous injection
of Complete Freund’s Adjuvant (at time 0). In B, compound 69 or vehicle was applied (at
time 0) 14 days after IoN-CCI; that is, once a stable MA was established. Static MA was
completely suppressed (A) or quickly reversed (B) in compound 69-treated rats. Results are
presented as mean ± s.e.m.; n = 4 (A) and n = 5 (B) in each group. Allodynic score (from 0 to
4) according to Vos et al. [29].
2.4. Compounds 69 is a selective p38α MAPK inhibitor
Next, we undertook studies to identify the possible biological target(s) of the most active
compound 69. As previously indicated, the activation in neurons of PK such as PKCγ, ERK
or p38 MAPK can contribute to pain hypersensitivity. Therefore, we decided to screen
compound 69 toward a panel of 50 PKs that provide a representative sampling of the human
kinome (Fig. 4, Table S1) [27]. In this panel, we identified p38α MAPK as the privileged
target, with 19% of kinase residual activity at 10 µM compound concentration. Compound 69
was highly selective over the other protein kinases, as none of them showed a mean residual
activity < 65% at the same concentration. IC50 toward p38α MAPK was determined and found
to be in the micromolar range, with a value of 1.5 ± 0.7 µM (mean ± SD).
9

Figure 4. Compound 69 was evaluated at the International Center For Kinase Profiling
(ICKP, Dundee, Scotland) toward a panel of 50 protein kinases that provide a representative
sampling of the human kinome. The results were expressed as the mean percentage of residual
activity at 10 µM concentration (duplicate assays). Blue disks: ≥ 65%, red disk: 19%. See
Table S1 for screening values. The black square indicates the kinome region containing
protein kinases evaluated in a second screening (Fig. 5, Table S2). The tree was generated
using the Kinome Render software, and the illustration reproduced courtesy of Cell Signaling
Technology, Inc. (www.cellsignal.com) [30].
10

Next, we evaluated the selectivity of compound 69 toward another panel containing all four
p38 MAPK isoforms, ERK1, ERK2 as well as other protein kinases close to p38α MAPK in
the kinome phylogenetic tree (Fig. 5, Table S2). In addition, compound 67 that also exhibited
strong anti-allodynic activity was also evaluated in this screening. The results showed that 69
was selective of p38α MAPK over the other protein kinases tested in this panel, including p38
MAPK isoforms. Compound 67 exhibited the same selectivity profile. Its IC50 toward p38α
MAPK was determined and found to be in the micromolar range with a value of 3.0 ± 0.1 µM
(mean ± SD).
Figure 5. Compounds 67 and 69 were evaluated at the International Center For Kinase
Profiling (ICKP, Dundee, Scotland) toward a panel of 13 protein kinases. The results were
expressed as the mean percentage of residual activity at 1 µM concentration (duplicate
assays). Blue disks: ≥ 90%, red disk: 59%, for both compounds. See Table S2 for screening
values. The tree was generated using the Kinome Render software, and the illustration
reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com) [30].
Hence, compound 69 appears as a highly selective inhibitor of p38α MAPK when considering
the panel of 62 protein kinases evaluated. According to these results, besides not yet identified
other biological targets, p38α MAPK could be reasonably considered as a target for this series
of pyridin-2(1H)one derivatives, leading to the observed analgesia in the inflammatory and
neuropathic rat models of MA.
3. Conclusion
In summary, we synthesized a series of pyridin-2(1H)-one derivatives in 5 steps from 3-
bromo-5-nitropyridin-2(1H)-one 1. The heterocyclic core was substituted at the 5-position by
a phenylamino group whereas the 3-position was substituted by various aryl/heteroaryl
moieties. These compounds were evaluated in vivo toward a rat model of inflammatory MA.
We found that the series rapidly and strongly prevented the development of MA. Compound
69, the most active of the series, was also able to quickly reverse facial neuropathic MA in
rats. Next, when 69 was evaluated toward a panel of 50 protein kinases in order to identify its
potential biological target(s), we found that 69 is a p38α MAPK inhibitor, a PK known to
11

contribute to pain hypersensitivity in animal models. In conclusion, 3,5-disubstituted pyridin-
2(1H)-ones thus could represent a novel class of analgesic for the treatment of MA.
4. Experimental section
4.1. Chemistry
4.1.1. General. Starting materials were obtained from commercial suppliers and used without
further purification. IR spectra were recorded on a Perkin-Elmer Spectrum 65 FT-IR
spectrometer ( in cm-1). NMR spectra, performed on a Bruker AVANCE 400 III HD (1H:
13
400 MHz, C: 101 MHz) are reported in ppm using the solvent residual peak as an internal
standard; the following abbreviations are used: singlet (s), doublet (d), triplet (t), quadruplet
(q), doublet of doublets (dd), doublet of doublet of doublets (ddd), doublet of triplets (dt),
triplet of doublets (td), triplet of triplets (tt), multiplet (m), broad signal (br s). Coupling
constants are expressed in Hertz. Experiments under microwave irradiation were performed
using a CEM Discover Benchmate apparatus. High resolution mass spectra were determined
on a high-resolution Waters Micro Q-Tof or Thermo Scientific Q Exactive Q-Orbitrap
apparatus (UCA START, Université Clermont Auvergne, Clermont-Ferrand, France).
Chromatographic purifications were performed by column chromatography using 40–63 µm
silica gel. Reactions were monitored by TLC using fluorescent silica gel plates (60 F254 from
Macherey Nagel). Melting points were measured on a Stuart SMP3 apparatus and are
uncorrected.
The purity of compounds 19–25 and 66–82 was established by HPLC analysis using a Agilent
infinity 1260 chromatograph with DAD detector and an Agilent Zorbax SB-Phenyl column
(4.6 mm x150 mm, 3.5 µm). Flow rate was 0.8 mL/min and the analysis was performed at 25
°C. Detection wavelength is indicated for each compound. Solvents were (A) water/0.1%
formic acid, (B) Acetonitrile. Gradient was 100:0 A/B to 30:70 A/B in 8 min and then 30:70
A/B for 3 min.
4.1.2. 2-(Benzyloxy)-3-bromo-5-nitropyridine (2).
To a solution under argon of crushed 3-bromo-5-nitropyridin-2(1H)-one 1 (1.90 g, 8.68
mmol, 1 eq.) in anhydrous toluene (26 mL), benzyl bromide (2.2 mL, 18.5 mmol, 2.1 eq.) was
added. The mixture was stirred at room temperature for 5 min. Then, the mixture was stirred
at 70 °C and crushed Ag2CO3 was added in three portions of 0.35 eq. every hour (3x840 mg,
3x3.05 mmol, 3x0.35 eq.). After 3 h 30 min at 70 °C, the mixture was filtered through a pad
of Celite and washed with ethyl acetate. The obtained yellow solid was purified by column
chromatography (SiO2, cyclohexane to EtOAc/cyclohexane 95:5) to give the desired product
2 with a residual impurity which was eliminated by washing with cyclohexane, to give 2 (2.51
g, 8.12 mmol, 94%) as a white solid. Rf = 0.40 (EtOAc/cyclohexane 2:98); Mp 128 °C; IR
(ATR) 3075, 1593, 1571, 1518, 1435, 1337, 1318, 1050, 1008, 725 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 9.10 (d, J = 2.5, 1H), 8.85 (d, J = 2.5, 1H), 7.50 (d, J = 7.3, 2H), 7.45–7.34 (m,
3H), 5.57 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 162.3 (C), 142.8 (CH), 139.6 (C), 137.1
(CH), 135.7 (C), 128.50 (2CH), 128.22 (CH), 127.9 (2CH), 106.3 (C), 69.7 (CH2); HRMS
(ESI+) calcd for C12H10BrN2O3 (M+H)+ 308.9869, found 308.9869.
4.1.3. 6-(Benzyloxy)-5-bromopyridin-3-amine (3).
12

To a solution of compound 2 (5.4 g, 17.5 mmol, 1 eq.) in a 10:1 propan-2-ol/water mixture
(375 mL) were added Fe powder (5.89 g, 105 mmol, 6 eq.) and NH4Cl (380 mg, 7.10 mmol,
0.4 eq.). The mixture was refluxed for 4 h. Then, the mixture was filtered through a pad of
Celite which was then washed with ethyl acetate. The filtrate was washed with water, and the
aqueous phase was extracted with ethyl acetate. The organic phase was dried over MgSO4,
filtered and then evaporated. The obtained orange oil was purified by column chromatography
(SiO2, EtOAc/cyclohexane 3:7 + 0.5% NEt3) to give the desired product 3 (4.64 g, 16.6
mmol, 95%) as a brown oil which crystalized in beige solid. Rf = 0.38 (EtOAc/cyclohexane
1
3:7); Mp 81 °C; IR (ATR) 3390, 3305, 3208, 1625, 1452, 1356, 1216, 1046, 982 cm-1; H
NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 2.5, 1H), 7.42 (d, J = 7.4, 2H), 7.37 (t, J = 7.4,
2H), 7.32 (d, J = 2.5, 1H), 7.32–7.27 (m, 1H), 5.26 (s, 2H), 5.04 (s, 2H); 13C NMR (101 MHz,
DMSO-d6) δ 150.4 (C), 141.2 (C), 137.6 (C), 130.1 (CH), 128.3 (2CH), 128.2 (CH), 127.6
(CH), 127.4 (2CH), 105.8 (C), 67.3 (CH2); HRMS (ESI+) calcd for C12H12BrN2O (M+H)+
279.0128, found 279.0124.
4.1.4. 6-(Benzyloxy)-5-bromo-N-phenylpyridin-3-amine (4).
A 5 mL screw-cap tube under argon was charged with compound 3 (444 mg, 1.59 mmol,
1eq.), Pd(OAc)2 (17.8 mg, 0.08 mmol, 0.05 eq.), Xantphos (46.2 mg, 0.08 mmol, 0.05 eq.)
and Cs2CO3 (1.04 g, 3.19 mmol, 2 eq.). Then, anhydrous 1,4-dioxane degassed with argon (8
mL) and iodobenzene (180 µL, 1.61 mmol, 1 eq.) were added. The tube was sealed and the
mixture was stirred at 100 °C for 4 h. The resulting suspension was filtered through a pad of
Celite which was then washed with ethyl acetate. After evaporation of the filtrate, the brown
residue was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane
1:9) to give a yellow-orange oil 4 (444 mg, 1.25 mmol, 79%) which solidify into a light
brown solid after some days in freezer. Rf = 0.31 (EtOAc/cyclohexane 1:9); Mp 49 °C; IR
(ATR) 3394, 1602, 1502, 1462, 1444, 1356, 1292, 1230, 1050, 738, 694 cm-1; 1H NMR (400
MHz, DMSO-d6) δ 8.14 (s, 1H, NH), 7.97 (d, J = 2.5, 1H), 7.78 (d, J = 2.5, 1H), 7.48–7.44
(m, 2H), 7.42–7.37 (m, 2H), 7.35–7.30 (m, 1H), 7.22 (dd, J = 8.6, 7.4, 2H), 6.96 (dd, J = 8.6,
1.1, 2H), 6.82 (tt, J = 7.4, 1.1, 1H), 5.37 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 153.3 (C),
143.7 (C), 137.2 (C), 135.4 (C), 135.2 (CH), 132.7 (CH), 129.4 (2CH), 128.4 (2CH), 127.8
(CH), 127.5 (2CH), 119.8 (CH), 115.7 (2CH), 106.0 (C), 67.7 (CH2); HRMS (ESI+) calcd for
C18H16BrN2O (M+H)+ 355.0441, found 355.0440.
4.1.5. General Procedures for the preparation of compounds 12–18, 46–51 and 53–65.
Procedure A (conventional heating): To a solution under argon of brominated derivative in
1,4-dioxane (0.1–0.6 mmol, 1 eq., 0.1 M) were added the boronic acid or boronic ester (1.5
eq.) and a 2 M Na2CO3 aqueous solution (5 eq.). The mixture was degassed with argon for 10
min before the addition of PdCl2(PPh3)2 (0.05 eq.). The solution was refluxed overnight. Ethyl
acetate was added and the resulting mixture was washed with water. The organic phase was
dried over MgSO4 and filtered. After evaporation under reduced pressure, the crude was
purified by column chromatography.
Procedure B (microwave irradiation): A 10 mL microwave tube under argon was charged
with brominated derivative (0.2–0.4 mmol, 1 eq.). 1,4-dioxane (0.1 M), boronic acid or
boronic ester (1.5 eq.) and a 2 M Na2CO3 aqueous solution (5 eq.) were added. The solution
was degassed with argon for 10 min before the addition of PdCl2(PPh3)2 (0.05 eq.). The tube
was sealed and the mixture was irradiated for 1 h (Discover mode, Dynamic control type, Pmax
13

= 75 W, T = 100 °C). The mixture was then filtered through a pad of Celite which was then
washed with ethyl acetate. The organic phase was washed with water and then dried over
MgSO4 and filtered. After evaporation under reduced pressure, the crude was purified by
column chromatography.
4.1.6. General Procedure for the preparation of compounds 19–21, 23–25, 66–74 and 76–
82.
Procedure C: To a solution under argon and cooled to 0 °C of benzylated compound in
anhydrous dichloromethane (0.1–0.5 mmol, 1 eq., 0.02 M) was added dropwise a 1 M BBr3
solution in dichloromethane (4 eq.). The mixture was stirred at room temperature for 1 h. The
reaction mixture was then quenched by addition of methanol, or by addition of NEt3 and
methanol when indicated. After evaporation under reduced pressure, EtOAc was added. The
mixture was washed with water, dried over MgSO4, and filtered. After evaporation under
reduced pressure, the crude was purified by column chromatography.
4.1.7. 6-(Benzyloxy)-N,5-diphenylpyridin-3-amine (12).
Compound 12 was prepared according to general procedure B, starting from 4 (95 mg, 0.267
mmol). The crude oil was purified by column chromatography (SiO2, cyclohexane to
EtOAc/cyclohexane 1:9) to give 12 (89 mg, 0.253 mmol, 94%). Rf = 0.70
(EtOAc/cyclohexane 3:7); Mp 118 °C; IR (ATR) 3380, 1601, 1514, 1497, 1466, 1424, 1359,
1
1298, 1255, 1218, 1022, 753, 728, 657, 695 cm-1; H NMR (400 MHz, DMSO-d6) δ 8.07 (s,
1H), 7.99 (d, J = 2.7, 1H), 7.62–7.59 (m, 2H), 7.53 (d, J = 2.8, 1H), 7.46–7.32 (m, 7H), 7.31–
7.26 (m, 1H), 7.20 (t, J = 7.8, 2H), 6.98 (d, J = 8.0, 2H), 6.77 (t, J = 7.3, 1H), 5.37 (s, 2H); 13C
NMR (101 MHz, DMSO-d6) δ 154.3 (C), 144.4 (C), 137.7 (C), 136.1 (C), 135.7 (CH), 134.6
(C), 130.5 (CH), 129.3 (2CH), 129.0 (2CH), 128.32 (2CH), 128.27 (2CH), 127.6 (CH), 127.5
(CH), 127.4 (2CH), 123.8 (C), 119.1 (CH), 115.2 (2CH), 67.1 (CH2); HRMS (ESI+) calcd for
C24H21N2O (M+H)+ 353.1648, found 353.1641.
4.1.8. 6-(Benzyloxy)-5-(4-fluorophenyl)-N-phenylpyridin-3-amine (13).
Compound 13 was prepared according to general procedure A, starting from 4 (154 mg, 0.434
mmol) and the corresponding boronic acid. The mixture was refluxed for 18 h. The crude oil
was purified by column chromatography (SiO2, cyclohexane + 0.5% NEt3 to
EtOAc/cyclohexane 1:9 + 0.5% NEt3) to give 13 (152 mg, 0.410 mmol, 95%) as a beige solid.
Rf = 0.70 (EtOAc/cyclohexane 3:7); Mp 104 °C; IR (ATR) 3383, 1599, 1500, 1438, 1223,
843, 757, 734, 697 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.99 (d, J = 2.7, 1H),
7.68–7.62 (m, 2H), 7.53 (d, J = 2.7, 1H), 7.42–7.17 (m, 9H), 6.98 (d, J = 7.9, 2H), 6.77 (t, J =
13
7.3, 1H), 5.37 (s, 2H); C NMR (101 MHz, DMSO-d6) δ 161.6 (d, JCF = 245, C), 154.2 (C),
144.3 (C), 137.6 (C), 135.7 (CH), 134.6 (C), 132.4 (d, JCF = 3, C), 131.0 (d, JCF = 8, 2CH),
130.4 (CH), 129.3 (2CH), 128.3 (2CH), 127.5 (CH), 127.4 (2CH), 122.8 (C), 119.1 (CH),
115.2 (2CH), 115.1 (d, JCF = 21.5, 2CH), 67.1 (CH2); HRMS (ESI+) calcd for C24H20FN2O
(M+H)+ 371.1554, found 371.1562.
4.1.9. 2-(Benzyloxy)-N-phenyl-[3,4'-bipyridin]-5-amine (14).
Compound 14 was prepared according to general procedure B, starting from 4 (103 mg, 0.290
mmol) and the corresponding boronic acid. The mixture was irradiated for 45 min at 100 °C.
The crude product was purified as above to give 14 (95.7 mg, 0.271 mmol, 93%). Rf = 0.30
(EtOAc/cyclohexane 5:5); Mp 129 °C; IR (ATR) 3261, 3189, 1594, 1443, 1262, 1229, 996,
1
829, 748, 698 cm-1; H NMR (400 MHz, DMSO-d6) δ 8.63–8.60 (m, 2H), 8.14 (s, 1H), 8.06
14

(d, J = 2.8, 1H), 7.66–7.63 (m, 3H), 7.43–7.40 (m, 2H), 7.39–7.34 (m, 2H), 7.32–7.27 (m,
1H), 7.21 (dd, J = 8.5, 7.4, 2H), 6.99 (dd, J = 8.6, 1.0, 2H), 6.79 (t, J = 7.3, 1H), 5.40 (s, 2H);
13C NMR (101 MHz, DMSO-d6) δ 154.2 (C), 149.6 (2CH), 144.2 (C), 143.7 (C), 137.4 (C)
137.1 (CH), 134.7 (C), 130.3 (CH), 129.4 (2CH), 128.4 (2CH), 127.6 (CH), 127.5 (2CH),
123.7 (2CH), 121.0 (C), 119.3 (CH), 115.3 (2CH), 67.3 (CH2); HRMS (ESI+) calcd for
C23H20N3O (M+H)+ 354.1601, found 354.1602.
4.1.10. 6-(Benzyloxy)-5-(1H-indol-3-yl)-N-phenylpyridin-3-amine (15).
1-(Triisopropylsilyl)-1H-indol-3-yl)boronic acid was prepared from 3-bromo-1-
(triisopropylsilyl)-1H-indole according to literature procedure [23]. A solution under argon of
3-bromo-1-(triisopropylsilyl)-1H-indole (500 mg, 1.42 mmol, 1 eq.) in anhydrous THF (5
mL) was cooled to –60 °C. A 2.42 M n-butyllithium solution in hexane (0.73 mL, 1.77 mmol,
1.25 eq.) was added dropwise. The mixture was stirred at –60 °C for 1 h. Triisopropyl borate
(0.4 mL, 1.73 mmol, 1.22 eq.) was added dropwise and the mixture was stirred at –60 °C for 1
h and at room temperature for 20 h. A saturated aqueous NH4Cl solution (1.5 mL) and toluene
(1.5 mL) were added and the mixture was washed with water. The organic phase was dried
over MgSO4, filtered and evaporated giving 1:1 mixture of 1-(triisopropylsilyl)-1H-indol-3-
yl)boronic acid and 1-(triisopropylsilyl)-1H-indole (427 mg, ratio evaluated by 1H NMR). The
crude was used without purification.
Compound 15 was prepared according to general procedure A, starting from 4 (47.8 mg,
0.135 mmol) and the mixture of 1-(triisopropylsilyl)-1H-indol-3-yl)boronic acid and 1-
(triisopropylsilyl)-1H-indole (128 mg). The reaction mixture was refluxed for 18 h. The
obtained crude (170 mg) was directly engaged in the next step due to partial deprotection of
the indolic part. To a solution of the crude product in THF (1 mL) was added a tetra-n-
butylammonium fluoride solution in THF (1 M, 0.36 mL, 0.36 mmol, 2.7 eq.). The mixture
was stirred for 1 h 30 min. EtOAc was added and the solution was washed with water and
brine. The organic phase was dried over MgSO4 and filtered. After evaporation, the solid was
purified by column chromatography (SiO2, cyclohexane + 0.5 % NEt3 to EtOAc/cyclohexane
25:75 + 0.5 % NEt3) to give 15 (46.4 mg, 0.119 mmol, 88%) as a mauve solid. Rf = 0.31
(EtOAc/cyclohexane 2:8); Mp 85 °C; IR (ATR) 3388, 3308, 1593, 1441, 1234, 1019, 740,
1
733, 693 cm-1; H NMR (400 MHz, DMSO-d6) δ 11.42 (br s, 1H), 8.06 (s, 1H), 7.90 (d, J =
2.7, 1H), 7.84 (d, J = 2.7, 1H), 7.78–7.74 (m, 2H), 7.47 (d, J = 7.4, 2H), 7.44 (d, J = 8.4, 1H),
7.39–7.34 (m, 2H), 7.33–7.28 (m, 1H), 7.22 (t, J = 7.8, 2H), 7.14 (t, J = 7.4, 1H), 7.06 (t, J =
7.5, 1H), 7.01 (d, J = 7.9, 2H), 6.77 (t, J = 7.3, 1H), 5.42 (s, 2H); 13C NMR (101 MHz,
DMSO-d6) δ 154.3 (C), 144.7 (C), 137.8 (C), 136.2 (C), 134.1 (C), 132.8 (CH), 129.3 (2CH),
128.8 (CH), 128.4 (2CH), 127.8 (2CH), 127.6 (CH), 126.4 (CH), 125.5 (C), 121.5 (CH),
119.6 (CH), 119.2 (CH), 118.91 (C), 118.89 (CH), 115.1 (2CH), 112.0 (CH), 109.1 (C), 67.2
(CH2); HRMS (ESI+) calcd for C26H22N3O (M+H)+ 392.1757, found 392.1765.
4.1.11. 6-(Benzyloxy)-N-phenyl-5-(quinolin-8-yl)pyridin-3-amine (16) .
Quinolin-8-ylboronic acid was prepared from 8-iodoquinoline according to literature
procedure [24]. To a solution under argon of 8-iodoquinoline (434 mg, 1.70 mmol, 1 eq.) in
anhydrous THF (1.35 mL) was added N,N,N′,N′-tetramethylethylenediamine (0.26 mL, 1.73
mmol, 1 eq.). The mixture was cooled to –78 °C a 2.5 M n-butyllithium solution in hexane
(0.68 mL, 1.70 mmol, 1 eq.) was added dropwise. The mixture was stirred at –78 °C for 4 h.
Trimethyl borate (0.57 mL, 5.11 mmol, 3 eq.) was added dropwise and the mixture was
15

stirred at room temperature for 2 h. A 3 M aqueous HCl solution (4 mL) was added and the
aqueous layer was washed with diethyl ether and neutralized by solid NaHCO3. The resulting
precipitate was filtered and washed with acetone to give quinolin-8-ylboronic acid (112 mg)
which was used without further purification.
Compound 16 was prepared according to general procedure A, starting from 4 (145 mg, 0.408
mmol) and the quinolin-8-ylboronic acid (114 mg). The mixture was refluxed for 21 h. The
crude solid was purified by column chromatography (SiO2, cyclohexane + 0.5% NEt3 to
EtOAc/cyclohexane 3:7 + 0.5% NEt3) to give 16 (137 mg, 0.340 mmol, 83%) as a yellow
solid. Rf = 0.41 (EtOAc/cyclohexane 3:7); Mp 162 °C; IR (ATR) 3252, 3180, 1592, 1497,
1
1461, 1228, 1003, 796, 736, 694 cm-1; H NMR (400 MHz, DMSO-d6) δ 8.90 (dd, J = 4.1,
1.8, 1H), 8.42 (dd, J = 8.3, 1.8, 1H), 8.05 (s, 1H), 8.03–8.00 (m, 2H), 7.81 (dd, J = 7.1, 1.5,
1H), 7.67 (dd, J = 8.1, 7.2, 1H), 7.56 (dd, J = 8.3, 4.1, 1H), 7.56 (d, J = 2.7, 1H), 7.24–7.12
(m, 7H), 7.01 (dd, J = 8.6, 1.0, 2H), 6.74 (tt, J = 7.3, 1.1, 1H), 5.27 (s, 2H); 13 C NMR (101
MHz, DMSO-d6) δ 155.3 (C), 150.2 (CH), 145.7 (C), 144.6 (C), 137.8 (C), 136.3 (CH), 135.8
(CH), 135.4 (C), 133.6 (C), 132.6 (CH), 130.6 (CH), 129.2 (2CH), 128.3 (CH), 128.0 (2CH +
C), 127.1 (CH), 126.9 (2CH), 126.1 (CH), 122.7 (C), 121.4 (CH), 118.8 (CH), 114.9 (2CH),
66.59 (CH2); HRMS (ESI+) calcd for C27H22N3O (M+H)+ 404.1757, found 404.1755.
4.1.12. 6-(Benzyloxy)-N-phenyl-5-(pyrimidin-5-yl)pyridin-3-amine (17).
Compound 17 was prepared according to general procedure A, starting from 4 (122 mg, 0.343
mmol) and the corresponding boronic acid. The mixture was refluxed for 18 h. The crude oil
was purified by column chromatography (SiO2, EtOAc/cyclohexane 1:9 to 65:35) to give 17
(115 mg, 0.324 mmol, 94%) as a yellow solid. Rf = 0.20 (EtOAc/cyclohexane 3:7); Mp 115
1
°C; IR (ATR) 3299, 1595, 1536, 1408, 1261, 1228, 1015, 747, 722, 692 cm-1; H NMR (400
MHz, DMSO-d6) δ 9.15 (s, 1H), 9.05 (s, 2H), 8.17 (s, 1H), 8.07 (d, J = 2.7, 1H), 7.75 (d, J =
2.8, 1H), 7.43–7.40 (m, 2H), 7.39–7.34 (m, 2H), 7.33–7.28 (m, 1H), 7.21 (t, J = 7.8, 2H), 7.01
13
(d, J = 7.9, 2H), 6.79 (t, J = 7.3, 1H), 5.38 (s, 2H); C NMR (101 MHz, DMSO-d6) δ 157.2
(CH), 156.5 (2CH), 154.3 (C), 144.2 (C), 137.3 (CH), 137.2 (C), 134.8 (C), 130.3 (CH),
130.0 (C), 129.3 (2CH), 128.4 (2CH), 127.68 (CH), 127.65 (2CH), 119.2 (CH), 117.2 (C),
115.3 (2CH), 67.5 (CH2); HRMS (ESI+) calcd for C22H19N4O (M+H)+ 355.1553, found
355.1560.
4.1.13. 6-(Benzyloxy)-5-(isoquinolin-5-yl)-N-phenylpyridin-3-amine (18).
Isoquinolin-5-ylboronic acid was prepared from 5-bromoisoquinoline according to literature
procedure [25]. Anhydrous THF (19 mL) was cooled to –78 °C then a 2.5 M n-butyllithium
solution in hexane (1.2 mL, 3.0 mmol, 1.25 eq.) was added under argon. A solution of 5-
bromoisoquinoline (502 mg, 2.41 mmol, 1 eq.) in anhydrous THF (5 mL) was added. The
mixture was stirred at –78 °C for 1 h. Triisopropyl borate (0.70 mL, 3.0 mmol, 1.25 eq.) was
added dropwise and the mixture was stirred at room temperature for 2 h. A 5% aqueous
NaOH solution (1 mL) was slowly added to quench the reaction. Aqueous phase was acidified
to pH 5 at 0 °C with a 10% aqueous HCl solution, then was extracted with EtOAc. The
organic phase was dried over MgSO4 and filtered. After evaporation, the obtained solid was
washed with diethyl ether to give isoquinolin-5-ylboronic acid (135.5 mg, 0.783 mmol, 32%).
Compound 18 was prepared according to general procedure A, starting from 4 (161 mg, 0.453
mmol) and isoquinolin-5-ylboronic acid. The mixture was refluxed for 18 h. The crude solid
was purified by column chromatography (SiO2, EtOAc/cyclohexane 1:9 to 65:35) to give 18
16

(173 mg, 0.429 mmol, 95%) as a white solid. Rf = 0.22 (EtOAc/cyclohexane 3:7); Mp 162 °C;
1
IR (ATR) 3279, 1603, 1441, 1361, 1227, 995, 746 cm-1; H NMR (400 MHz, DMSO-d6) δ
9.37 (s, 1H), 8.46 (d, J = 5.9, 1H), 8.16 (dd, J = 7.5, 1.9, 1H), 8.14 (d, J = 2.7, 1H), 8.12 (s,
1H), 7.79–7.72 (m, 2H), 7.51 (d, J = 2.8, 1H), 7.43 (d, J = 5.9, 1H), 7.24–7.17 (m, 5H), 7.15–
7.11 (m, 2H), 7.02 (d, J = 7.9, 2H), 6.77 (t, J = 7.3, 1H), 5.38–5.22 (br s, 2H); 13C NMR (101
MHz, DMSO-d6) δ 154.7 (C), 152.7 (CH), 144.2 (C), 143.1 (CH), 137.3 (C), 136.4 (CH),
134.5 (C), 133.42 (C), 133.41 (C), 131.7 (CH), 131.6 (CH), 129.3 (2CH), 128.2 (C), 128.1
(2CH), 127.8 (CH), 127.39 (CH), 127.35 (2CH), 127.1 (CH), 121.4 (C), 119.3 (CH), 118.5
(CH), 115.4 (2CH), 66.90 (CH2); HRMS (ESI+) calcd for C27H22N3O (M+H)+ 404.1757,
found 404.1763.
4.1.14. 3-Phenyl-5-(phenylamino)pyridin-2(1H)-one (19).
Compound 19 was prepared according to general procedure C, starting from 12 (46.3 mg,
0.131 mmol). The mixture was stirred for 4 h and was quenched with NEt3 (12 eq.) and
MeOH (4 eq.). The crude was purified by column chromatography (SiO2, EtOAc/MeOH
99.9:0.1 to 99.2:0.8) to give 19 (31.0 mg, 0.118 mmol, 90%) as a yellow solid. Rf = 0.20
(CH2Cl2/MeOH 97:3); Mp > 153 °C (decomposition); IR (ATR) 3294, 1592, 1549, 1495,
1
1456, 1441, 863, 796, 784, 738 cm-1; H NMR (400 MHz, DMSO-d6) δ 11.64 (br s, 1H),
7.73–7.69 (m, 2H), 7.52 (d, J = 2.9, 1H), 7.51 (s, 1H), 7.41–7.36 (m, 2H), 7.34–7.28 (m, 1H),
7.19 (d, J = 2.8, 1H), 7.14 (dd, J = 8.4, 7.4, 2H), 6.75 (d, J = 8.0, 2H), 6.68 (t, J = 7.3, 1H);
13C NMR (101 MHz, DMSO-d6) δ 159.5 (C), 146.5 (C), 137.5 (CH), 136.5 (C), 129.9 (C),
129.2 (2CH), 128.2 (2CH), 127.9 (2CH), 127.5 (CH), 127.1 (CH), 122.8 (C), 117.9 (CH),
113.81 (2CH); HRMS (ESI+) calcd for C17H15N2O (M+H)+ 263.1179, found 263.1173;
HPLC purity ≥ 99 %, tR = 8.18 min, λ = 284 nm.
4.1.15. 3-(4-Fluorophenyl)-5-(phenylamino)pyridin-2(1H)-one (20).
Compound 20 was prepared according to general procedure C, starting from 13 (80.5 mg,
0.217 mmol). The mixture was stirred for 1 h. The crude was purified by column
chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5 to 97:3) to give 20 (58.9 mg, 0.210 mmol,
97%) as a yellow solid. Rf = 0.35 (CH2Cl2/MeOH 94:6); Mp > 198 °C (decomposition); IR
1
(ATR) 3276, 1593, 1549, 1451, 1226, 830 cm-1; H NMR (400 MHz, DMSO-d6) δ 11.69 (br
s, 1H), 7.81–7.75 (m, 2H), 7.53 (d, J = 2,9, 1H), 7,51 (s, 1H), 7.24–7,11 (m, 5H), 6.74 (d, J =
13
7.9, 2H), 6.68 (t, J = 7.3, 1H); C NMR (101 MHz, DMSO-d6) δ 161.6 (d, JCF = 245, C),
159.5 (C), 146.5 (C), 137.5 (CH), 132.8 (d, JCF = 3, C), 130.2 (d, JCF = 8, 2CH), 129.2 (2CH),
128.8 (C), 127.1 (CH), 122.8 (C), 117.9 (CH), 114.8 (d, JCF = 21, 2CH), 113.8 (2CH); HRMS
(ESI+) calcd for C17H14FN2O (M+H)+ 281.1085, found 281.1087; HPLC purity ≥ 99%, tR =
8.30 min, λ = 282 nm.
4.1.16. 5-(Phenylamino)-[3,4'-bipyridin]-2(1H)-one (21).
Compound 21 was prepared according to general procedure C, starting from 14 (59.2 mg,
0.168 mmol). The mixture was stirred for 2 h 30 min. The crude was purified by column
chromatography (SiO2, CH2Cl2/MeOH 99:1 to 95:5) to give 21 (35.5 mg, 0.135 mmol, 80%)
as a yellow solid. Rf = 0.37 (CH2Cl2/MeOH 94:6); Mp > 230 °C (decomposition); IR (ATR)
3220, 1661, 1631, 1596, 1460, 1325, 1258, 830 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 11.85
(br s, 1H), 8.56 (d, J = 5.4, 2H), 7.82–7.79 (m, 2H), 7.76 (d, J = 2.8, 1H), 7.54 (s, 1H), 7.30
13
(d, J = 2.8, 1H), 7.15 (t, J = 7.8, 2H), 6.75 (d, J = 7.9, 2H), 6.69 (t, J = 7.3, 1H); C NMR
(101 MHz, DMSO-d6) δ 159.2 (C), 149.4 (2CH), 146.4 (C), 143.6 (C), 138.9 (CH), 129.3
17

(2CH), 129.2 (CH), 126.6 (C), 122.8 (C), 122.4 (2CH), 118.0 (CH), 113.8 (2CH); HRMS
(ESI+) calcd for C16H14N3O (M+H)+ 264.1131, found 264.1134; HPLC purity ≥ 97%, tR =
6.04 min, λ = 270 nm.
4.1.17. 3-(1H-Indol-3-yl)-5-(phenylamino)pyridin-2(1H)-one (22).
To a mixture under argon of 20% Pd(OH)2/C (13.61 mg, 0.019 mmol, 0.25 eq.) and ethyl
acetate (1 mL), previously degassed with argon, was added a solution of compound 15 (30.9
mg, 0.079 mmol, 1 eq.) in ethyl acetate (4.5 mL) previously degassed with argon. The mixture
was then hydrogenated at room temperature for 15 h. The mixture was filtered through a pad
of Celite which was then washed with ethyl acetate. The filtrate was evaporated under
reduced pressure and the obtained red solid was purified by column chromatography (SiO2,
EtOAc + 0.5 % NEt3 to EtOAc/MeOH 95:5 + 0.5% NEt3) to give 22 (17.4 mg, 0.058 mmol,
73%) a red powder. Rf = 0.37 (EtOAc/MeOH 95:5 + 0.5% NEt3); Mp > 181 °C
1
(decomposition); IR (ATR) 3450–3150, 1597, 1497, 1431, 734, 693 cm-1; H NMR (400
MHz, DMSO-d6) δ 11.51 (br s, 1H), 11.39 (br s, 1H), 8.32 (d, J = 2.6, 1H), 7.82–7.79 (m,
2H), 7.58 (s, 1H), 7.46 (d, J = 8.0, 1H), 7.21–7.11 (m, 3H), 7.10–7.04 (m, 2H), 6.82 (d, J =
8.0, 2H), 6.69 (t, J = 7.3, 1H); 13C NMR (101 MHz, DMSO-d6) δ 159.5 (C), 146.5 (C), 136.2
(C), 132.6 (CH), 129.3 (2CH), 127.5 (CH), 126.3 (C), 125.1 (C), 122.7 (C), 122.2 (CH),
121.4 (CH), 119.7 (CH), 119.2 (CH), 117.9 (CH), 113.9 (2CH), 112.1 (CH), 109.6 (C);
HRMS (ESI+) calcd for C19H16N3O (M+H)+ 302.1288, found 302.1292; HPLC purity ≥ 97 %,
tR = 8.19 min, λ = 280 nm.
4.1.18. 5-(Phenylamino)-3-(quinolin-8-yl)pyridin-2(1H)-one (23).
Compound 23 was prepared according to general procedure C, starting from 16 (80.3 mg,
0.199 mmol). The mixture was stirred for 2 h 40 min and was quenched with NEt3 (12 eq.)
and MeOH (4 eq.). After evaporation, EtOAc was added. The mixture was washed once with
water and twice with a saturated aqueous NaHCO3 solution, dried over MgSO4 and filtered.
After evaporation, the crude was purified by column chromatography (SiO2, CH2Cl2/MeOH
99:1 + 0.5% NEt3 to 96:4 + 0.5% NEt3). The residue was dissolved in EtOAc and washed
with water to eliminate the remaining triethylamine salts. After drying over MgSO4, filtration
and evaporation, 23 (11.9 mg, 0.0380 mmol, 19%) was obtained as a kaki powder. The poor
yield could be explained by the poor solubility of the final product.
Compound 23 was again prepared according to general procedure C, starting from 16 (133.8
mg, 0.332 mmol). The mixture was stirred for 3 h, quenched with NEt3 (12 eq.) and MeOH (4
eq.) and then concentrated. The crude was filtered and washed with water, acetone and
CH2Cl2. The compound 23 with important traces of CH2Cl2 was obtained (70 mg, containing
about 10.5% wt CH2Cl2).
Rf = 0.27 (CH2Cl2/MeOH 95:5); Mp > 255 °C (decomposition); IR (ATR) 3245, 1649, 1578,
1
1557, 1494, 1335, 1258, 795, 750, 705 cm-1; H NMR (400 MHz, DMSO-d6) δ 11.52 (br s,
1H), 8.88 (dd, J = 4.1, 1.8, 1H), 8.39 (dd, J = 8.3, 1.8, 1H), 7.97 (dd, J = 8.2, 1.5, 1H), 7.85
(dd, J = 7.1, 1.5, 1H), 7.63 (dd, J = 8.1, 7.2, 1H), 7.56–7.51 (m, 3H), 7.23 (br s, 1H), 7.15 (dd,
J = 8.5, 7.3, 2H), 6.83 (dd, J = 8.6, 1.0, 2H), 6.66 (tt, J = 7.3, 1.0, 1H); 13C NMR (101 MHz,
DMSO-d6) δ 159.8 (C), 150.0 (CH), 146.4 (C), 145.8 (C), 140.2 (CH), 136.3 (CH), 135.5 (C),
130.6 (CH), 129.3 (C), 129.2 (2CH), 128.1 (C), 127.9 (CH), 126.6 (CH), 125.9 (CH), 122.3
(C), 121.3 (CH), 117.8 (CH), 113.8 (2CH); HRMS (ESI+) calcd for C20H16N3O (M+H)+
314.1288, found 314.1291; HPLC purity ≥ 96%, tR = 6.77 min, λ = 282 nm.
18

4.1.19. 5-(Phenylamino)-3-(pyrimidin-5-yl)pyridin-2(1H)-one (24).
Compound 24 was prepared according to general procedure C, starting from 17 (80.5 mg,
0.227 mmol). The mixture was stirred for 3 h 20 min and was quenched with NEt3 (12 eq.)
and MeOH (4 eq.). After evaporation, EtOAc was added. The mixture was washed with a
saturated NaHCO3 solution, dried over MgSO4, and filtered. After evaporation, the crude was
purified by column chromatography (SiO2, CH2Cl2/MeOH 98:2 to 95:5) to give 24 (47.8 mg,
0.181 mmol, 80%) as a yellow solid. Rf = 0.12 (CH2Cl2/MeOH 95:5); Mp > 160 °C
(decomposition); IR (ATR) 3408, 3287, 1597, 1548, 1475, 742, 717, 694 cm-1; 1H NMR (400
MHz, DMSO-d6) δ 11.90 (br s, 1H), 9.15 (s, 2H), 9.10 (s, 1H), 7.82 (d, J = 2.9, 1H), 7.56 (s,
1H), 7.30 (d, J = 2.8, 1H), 7.14 (t, J = 7.8, 2H), 6.76 (d, J = 8.0, 2H), 6.68 (t, J = 7.3, 1H); 13C
NMR (101 MHz, DMSO-d6) δ 159.2 (C), 156.9 (CH), 155.7 (2CH), 146.4 (C), 138.8 (CH),
130.2 (C), 129.2 (2CH), 128.9 (CH), 123.8 (C), 123.0 (C), 118.0 (CH), 113.8 (2CH); HRMS
(ESI+) calcd for C15H13N4O (M+H)+ 265.1084, found 265.1090; HPLC purity ≥ 96%, tR =
7.61 min, λ = 284 nm.
4.1.20. 3-(Isoquinolin-5-yl)-5-(phenylamino)pyridin-2(1H)-one (25).
Compound 25 was prepared according to general procedure C, starting from 18 (172 mg,
0.426 mmol). The mixture was stirred for 2 h 30 min and was quenched with NEt3 (16 eq.)
and MeOH (6 eq.). After evaporation, EtOAc was added. The mixture was washed with a
saturated NaHCO3 solution, dried over MgSO4, and filtered. After evaporation, the crude was
purified by column chromatography (SiO2, CH2Cl2/MeOH 98:2 to 90:10) to give 25 (58.6 mg,
0.187 mmol, 44%) as a yellow solid. Rf = 0.16 (CH2Cl2/MeOH 94:6); Mp > 209 °C
1
(decomposition); IR (ATR) 3274, 1646, 1583, 1554, 1496, 1462, 745 cm-1; H NMR (400
MHz, DMSO-d6) δ 11.73 (br s, 1H), 9.34 (s, 1H), 8.47 (d, J = 5,9, 1H), 8.15–8.11 (m, 1H),
7.74–7.70 (m, 2H), 7.56–7.53 (m, 2H), 7.44 (d, J = 2.9, 1H), 7.35 (d, J = 2.9, 1H), 7.15 (dd, J
13
= 8.5, 7.4, 2H), 6.80 (dd, J = 8.6, 1.0, 2H), 6.68 (tt, J = 7.3, 1.0, 1H); C NMR (101 MHz,
DMSO-d6) δ 159.4 (C), 152.6 (CH), 146.3 (C), 142.8 (CH), 139.9 (CH), 134.3 (C), 133.6 (C),
131.5 (CH), 129.3 (C), 129.2 (2CH), 128.3 (C), 128.0 (CH), 127.6 (CH), 127.0 (CH), 122.8
(C), 118.7 (CH), 118.0 (CH), 114.0 (2CH); HRMS (ESI+) calcd for C20H16N3O (M+H)+
314.1288, found 314.1292; HPLC purity ≥ 96%, tR = 6.47 min, λ = 278 nm.
4.1.21. 6-(Benzyloxy)-5-(quinolin-4-yl)-N-phenylpyridin-3-amine (46).
Compound 46 was prepared according to general procedure A, starting from 4 (201 mg, 0.566
mmol) and the corresponding boronic acid. The mixture was refluxed for 16 h. The crude oil
was purified by column chromatography (SiO2, EtOAc/cyclohexane 1:9 to 3:7) to give 46
(205 mg, 0.508 mmol, 90%) as a yellow powder. Rf = 0.16 (EtOAc/cyclohexane 2:8); Mp 156
1
°C; IR (ATR) 3232, 3179, 1597, 1438, 1229, 1022, 730, 694 cm-1; H NMR (400 MHz,
DMSO-d6) δ 8.95 (d, J = 4.4, 1H), 8.17 (s, 1H), 8.16 (d, J = 2.8, 1H), 8.09 (d, J = 8.4, 1H),
7.79 (ddd, J = 8.4, 6.8, 1.6, 1H), 7.66 (dd, J = 8.4, 1.4, 1H), 7.58 (ddd, J = 8.3, 6.8, 1.4, 1H),
7.54 (d, J = 2.8, 1H), 7.52 (d, J = 4.4, 1H), 7.24–7.17 (m, 5H), 7.14–7.10 (m, 2H), 7.02 (dd, J
= 8.7, 1.1, 2H), 6.78 (tt, J = 7.3, 1.0, 1H), 5.39–5.21 (br s, 2H); 13C NMR (101 MHz, DMSO-
d6) δ 154.3 (C), 150.1 (CH), 147.7 (C), 144.0 (C), 142.9 (C), 137.3 (C), 136.9 (CH), 134.5
(C), 131.0 (CH), 129.5 (CH), 129.4 (CH), 129.3 (2CH), 128.1 (2CH), 127.4 (CH), 127.3
(2CH), 126.8 (CH), 126.2 (C), 125.9 (CH), 122.2 (CH), 120.3 (C), 119.4 (CH), 115.5 (2CH),
67.0 (CH2); HRMS (ESI+) calcd for C27H22N3O (M+H)+ 404.1757, found 404.1763.
4.1.22. 6-(Benzyloxy)-5-(1H-indol-4-yl)-N-phenylpyridin-3-amine (47).
19

Compound 47 was prepared according to general procedure A, starting from 4 (189 mg, 0.53
mmol) and the corresponding pinacol boronic ester. The mixture was refluxed for 16 h. The
crude oil was purified by column chromatography (SiO2, EtOAc/cyclohexane 5:95 to
EtOAc/cyclohexane 15:85) to give 47 (207 mg, 0.53 mmol, quant.) as a grey powder. Rf =
0.30 (EtOAc/cyclohexane 2:8); Mp 66 °C; IR (ATR) 3394, 1595, 1496, 1441, 1350, 1228,
748, 694 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.06 (s, 1H), 8.02 (d, J = 2.7,
1H), 7.58 (d, J = 2.7, 1H), 7.43–7.10 (m, 11H), 6.99 (d, J = 7.9, 2H), 6.76 (t, J = 7.3, 1H),
6.32–6.30 (m, 1H), 5.35 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 154.7 (C), 144.5 (C),
137.7 (C), 136.0 (C), 135.3 (CH), 134.1 (C), 131.3 (CH), 129.3 (2CH), 128.1 (2CH), 127.9
(C), 127.4 (2CH), 127.3 (CH), 126.5 (C), 125.5 (CH), 123.7 (C), 120.7 (CH), 120.0 (CH),
119.0 (CH), 115.2 (2CH), 111.1 (CH), 100.5 (CH), 66.9 (CH2); HRMS (ESI+) calcd for
C26H22N3O (M+H)+ 392.1757, found 392.1751.
4.1.23. 6-(Benzyloxy)-5-(2-chlorophenyl)-N-phenylpyridin-3-amine (48).
Compound 48 was prepared according to general procedure A, starting from 4 (125.2 mg,
0.352 mmol) and the corresponding boronic acid. The mixture was refluxed for 15 h 30 min.
The crude oil was purified by column chromatography (SiO2, pentane to EtOAc/pentane 1:9)
to give 48 (116 mg, 0.300 mmol, 85%) a red oil. Rf = 0.34 (EtOAc/cyclohexane 1:9); IR
(ATR) 3390, 1599, 1497, 1425, 1231, 736, 693 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.10
(s, 1H), 8.03 (d, J = 2.8, 1H), 7.58–7.53 (m, 1H), 7.47–7.38 (m, 4H), 7.33–7.23 (m, 5H), 7.20
13
(dd, J = 8.5, 7.3, 2H), 6.97 (d, J = 8.7, 1.1, 2H), 6.77 (tt, J = 7.3, 1.0, 1H), 5.30 (s, 2H); C
NMR (101 MHz, DMSO-d6) δ 154.4 (C), 144.2 (C), 137.6 (C), 136.4 (CH), 135.2 (C), 134.0
(C), 132.6 (C), 131.8 (CH), 131.2 (CH), 129.6 (CH), 129.32 (2CH), 129.28 (CH), 128.2
(2CH), 127.4 (CH), 127.3 (2CH), 127.1 (CH), 121.9 (C), 119.2 (CH), 115.2 (2CH), 67.0
(CH2); HRMS (ESI+) calcd for C24H20ClN2O (M+H)+ 387.1259, found 387.1248.
4.1.24. 6-(Benzyloxy)-5-(2-bromophenyl)-N-phenylpyridin-3-amine (49).
Compound 49 was prepared according to general procedure A, starting from 4 (114.7 mg,
0.323 mmol) and the corresponding boronic acid. The mixture was refluxed for 16 h. The
crude was chromatographed (SiO2, cyclohexane to EtOAc/cyclohexane 1:9) but some
impurity remained in the obtained orange oil (71 mg). Compound 49 was used for the next
step without further purification. Rf = 0.29 (EtOAc/cyclohexane 1:9).
4.1.25. Ethyl 2-(2-(benzyloxy)-5-(phenylamino)pyridin-3-yl)benzoate (50).
Compound 50 was prepared according to general procedure A, starting from 4 (123.5 mg,
0.348 mmol) and the corresponding boronic acid. The mixture was refluxed for 15 h. The
crude oil was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane
1:9) to give 50 (110 mg, 0.259 mmol, 75%) an orange-brown oil. Rf = 0.40
1
(EtOAc/cyclohexane 2:8); IR (ATR) 3372, 1708, 1598, 1430, 1253, 746, 693 cm-1; H NMR
(400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.98 (d, J = 2.7, 1H), 7.85 (dd, J = 7.7, 1.4, 1H), 7.65
(td, J = 7.6, 1.5, 1H), 7.50 (td, J = 7.6, 1.3, 1H), 7.41 (dd, J = 7.6, 1.3, 1H), 7.39 (d, J = 2.7,
1H), 7.33–7.22 (m, 5H), 7.20 (dd, J = 8.6, 7.3, 2H), 6.96 (dd, J = 8.6, 1.1, 2H), 6.76 (tt, J =
13
7.3, 1.1, 1H), 5.24 (s, 2H), 3.98 (q, J = 7.1, 2H), 0.95 (t, J = 7.1, 3H); C NMR (101 MHz,
DMSO-d6) δ 166.8 (C), 154.3 (C), 144.6 (C), 137.4 (C), 136.6 (C), 135.5 (CH), 134.1 (C),
132.1 (CH), 131.1 (CH), 131.0 (C), 130.4 (CH), 129.5 (CH), 129.3 (2CH), 128.1 (2CH),
128.0 (CH), 127.4 (CH), 127.3 (2CH), 124.9 (C), 118.9 (CH), 115.0 (2CH), 66.8 (CH2), 60.4
(CH2), 13.6 (CH3); HRMS (ESI+) calcd for C27H25N2O3 (M+H)+ 425.1860, found 425.1857.
20

4.1.26. 2-(2-(Benzyloxy)-5-(phenylamino)pyridin-3-yl)benzonitrile (51).
Compound 51 was prepared according to general procedure A, starting from 4 (152 mg, 0.428
mmol) and the corresponding boronic acid. The mixture was refluxed for 15 h. The crude was
chromatographed (SiO2, pentane to EtOAc/pentane) but some impurities remained in the
obtained white solid (131.6 mg). Compound 51 was used for the next step without further
purification. Rf = 0.35 (EtOAc/pentane 5:5).
4.1.27. 6-(Benzyloxy)-5-(2-nitrophenyl)-N-phenylpyridin-3-amine (52).
To a solution under argon of 4 (201.4 mg, 0.567 mmol, 1 eq.) in 1,4-dioxane (0.5 mL) were
added the 2-nitrophenylboronic acid (95.1 mg, 0.57, 1 eq.) and a 2 M aqueous K2CO3 solution
(4 eq.). The mixture was degassed with argon for 10 min before the addition of Pd(dppf)Cl2
(24.4 mg, 0.033 mmol, 0.06 eq.). The solution was stirred at 100 °C. Additional portions of
boronic acid were added after 2 h 30 min (47.3 mg, 0.283 mmol, 0.5 eq.), 17 h 30 min (31.6
mg, 0.189 mmol, 0.33 eq.) and 24 h (47.4 mg, 0.284 mmol, 0.5 eq.). The mixture was then
stirred at 100 °C overnight. Ethyl acetate was added and the resulting mixture was washed
with water. The organic phase was dried over MgSO4 and filtered. After evaporation under
reduced pressure, the crude was purified by column chromatography (SiO2, cyclohexane to
EtOAc/cyclohexane 1:9) to give the desired product 52 (83.1 mg, 0.209 mmol, 37%) as an
orange powder. Rf = 0.41 (EtOAc/cyclohexane 2:8); Mp 141 °C; IR (ATR) 3370, 1453, 1351,
1
1295, 1250, 1219, 990, 730, 693 cm-1; H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.05
(dd, J = 8.1, 1.2, 1H), 8.01 (d, J = 2.7, 1H), 7.80 (td, J = 7.6, 1.3, 1H), 7.64 (ddd, J = 8.1, 7.5,
1.5, 1H), 7.60 (dd, J = 7.6, 1.3, 1H), 7.55 (d, J = 2.7, 1H), 7.33–7.19 (m, 7H), 7.00 (dd, J =
13
8.6, 1.1, 2H), 6.79 (tt, J = 7.3, 1.1, 1H), 5.21 (br s, 2H); C NMR (101 MHz, DMSO-d6) δ
153.5 (C), 148.6 (C), 144.2 (C), 137.0 (C), 136.1 (CH), 134.7 (C), 133.8 (CH), 132.6 (CH),
130.6 (C), 129.9 (CH), 129.4 (CH), 129.3 (2CH), 128.2 (2CH), 127.5 (CH), 127.4 (2CH),
124.3 (CH), 121.3 (C), 119.3 (CH), 115.3 (2CH), 67.2(CH2); HRMS (ESI+) calcd for
C24H20N3O3 (M+H)+ 398.1499, found 398.1487.
4.1.28. 5-([1,1'-biphenyl]-4-yl)-6-(benzyloxy)-N-phenylpyridin-3-amine (53).
Compound 53 was prepared according to general procedure A, starting from 4 (119 mg, 0.335
mmol) and the corresponding boronic acid. The mixture was refluxed for 16 h. The crude oil
was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane 1:9) to
give 53 (30.8 mg) and a second fraction containing trace of 4-phenylphenol. CH2Cl2 was
added to the second fraction which was washed with a 0.5 M aqueous NaOH solution, and
then with water. The organic phase was dried over MgSO4, filtered and evaporated to give
pure 53 (99.8 mg). Compound 53 (130.6 mg, 0.305 mmol, 91%) was obtained as a light
brown solid. Rf = 0.27 (EtOAc/cyclohexane 1:9); Mp 109 °C; IR (ATR) 3304, 1595, 1437,
1
1232, 1006, 841, 721, 690 cm-1; H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 8.00 (d, J =
2.7, 1H), 7.76–7.69 (m, 6H), 7.60 (d, J = 2.8, 1H), 7.51–7.41 (m, 4H), 7.40–7.34 (m, 3H),
7.32–7.26 (m, 1H), 7.21 (dd, J = 8.6, 7.3, 2H), 7.00 (dd, J = 8.7, 1.1, 2H), 6.78 (tt, J = 7.3,
1.1, 1H), 5.41 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 154.3 (C), 144.4 (C), 139.6 (C),
139.3 (C), 137.7 (C), 135.7 (CH), 135.2 (C), 134.6 (C), 130.3 (CH), 129.5 (2CH), 129.3
(2CH), 129.0 (2CH), 128.3 (2CH), 127.6 (CH), 127.5 (CH), 127.4 (2CH), 126.6 (2CH), 126.5
(2CH), 123.3 (C), 119.1 (CH), 115.2 (2CH), 67.1 (CH2); HRMS (ESI+) calcd for C30H25N2O
(M+H)+ 429.1961, found 429.1972.
4.1.29. 6-(Benzyloxy)-5-(3-chlorophenyl)-N-phenylpyridin-3-amine (54).
21

Compound 54 was prepared according to general procedure A, starting from 4 (117 mg, 0.329
mmol). The mixture was refluxed for 16 h. The crude oil was purified by column
chromatography (SiO2, cyclohexane to EtOAc/cyclohexane 1:9) to give 54 (121.3 mg, 0.314
mmol, 95%) as a red oil. Rf = 0.40 (EtOAc/cyclohexane 1:9); IR (ATR) 3378, 1602, 1589,
1
1439, 1409, 1359, 1298, 1256, 1217, 1013, 894, 754, 728, 692 cm-1; H NMR (400 MHz,
DMSO-d6) δ 8.09 (s, 1H), 8.02 (d, J = 2.7, 1H), 7.71 (t, J = 1.7, 1H), 7.58 (d, J = 2.7, 1H),
7.56 (dt, J = 7.5, 1.5, 1H), 7.46 (t, J = 7.7, 1H), 7.44–7.40 (m, 3H), 7.39–7.33 (m, 2H), 7.32–
7.27 (m, 1H), 7.21 (dd, J = 8.5, 7.4, 2H), 6.99 (dd, J = 8.6, 1.0, 2H), 6.78 (tt, J = 7.3, 1.1, 1H),
13
5.38 (s, 2H); C NMR (101 MHz, DMSO-d6) δ 154.1 (C), 144.3 (C), 138.2 (C), 137.5 (C),
136.3 (CH), 134.6 (C), 132.9 (C), 130.4 (CH), 130.2 (CH), 129.4 (2CH), 128.9 (CH), 128.3
(2CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 127.4 (2CH), 122.2 (C), 119.2 (CH), 115.2
(2CH), 67.2 (CH2); HRMS (ESI+) calcd for C24H20ClN2O (M+H)+ 387.1259, found
387.1268.
4.1.30. 1-(3-(2-(Benzyloxy)-5-(phenylamino)pyridin-3-yl)phenyl)ethan-1-one (55).
Compound 55 was prepared according to general procedure A, starting from 4 (117.5 mg,
0.331 mmol) and the corresponding boronic acid. The mixture was refluxed for 15 h. The
crude oil was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane
15:85) to give 55 (130.6 mg, 0.331 mmol, quant.) a brown oil. Rf = 0.41 (EtOAc/cyclohexane
2:8); IR (ATR) 3367, 1669, 1596, 1535, 1497, 1490, 1442, 1417, 1246, 1218, 1009, 734, 693
1
cm-1; H NMR (400 MHz, DMSO-d6) δ 8.21 (td, J = 1.8, 0.5, 1H), 8.10 (s, 1H), 8.04 (d, J =
2.7, 1H), 7.93 (ddd, J = 7.8, 1.8, 1.1, 1H), 7.86 (ddd, J = 7.7, 1.9, 1.1, 1H), 7.62 (d, J = 2.8,
1H), 7.59 (td, J = 7.8, 0.5, 1H), 7.45–7.41 (m, 2H), 7.38–7.32 (m, 2H), 7.32–7.26 (m, 1H),
7.21 (dd, J = 8.6, 7.3, 2H), 6.99 (dd, J = 8.7, 1.1, 2H), 6.78 (tt, J = 7.3, 1.1, 1H), 5.38 (s, 2H),
13
2.56 (s, 3H); C NMR (101 MHz, DMSO-d6) δ 197.7 (C), 154.3 (C), 144.4 (C), 137.5 (C),
136.8 (C), 136.4 (C), 136.2 (CH), 134.6 (C), 133.6 (CH), 130.6 (CH), 129.3 (2CH), 129.0
(CH), 128.7 (CH), 128.3 (2CH), 127.58 (2CH), 127.57 (CH), 127.2 (CH), 122.8 (C), 119.1
(CH), 115.2 (2CH), 67.2 (CH2), 26.7 (CH3); HRMS (ESI+) calcd for C26H23N2O2 (M+H)+
395.1754, found 395.1748.
4.1.31. 4-(2-(Benzyloxy)-5-(phenylamino)pyridin-3-yl)phenol (56).
Compound 56 was prepared according to general procedure A, starting from 4 (147 mg, 0.414
mmol) and the corresponding boronic acid. The mixture was refluxed for 15 h. The crude oil
was purified by column chromatography (SiO2, EtOAc/cyclohexane 5:95 to 2:8). The
obtained yellow solid was then dissolved in ethyl acetate and washed with water. The organic
phase was dried over MgSO4, filtered and evaporated to give 56 (115 mg, 0.312 mmol, 75%)
as a pale yellow solid. Rf = 0.24 (EtOAc/cyclohexane 8:2); Mp 172°C; IR (ATR) 3389, 1597,
1528, 1249, 1211, 1023, 725, 689 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.99
(s, 1H), 7.92 (d, J = 2.7, 1H), 7.47 (d, J = 2.7, 1H), 7.43 (d, J = 8.7, 2H), 7.43–7.39 (m, 2H),
7.38–7.33 (m, 2H), 7.31–7.26 (m, 1H), 7.20 (dd, J = 8.4, 7.4, 2H), 6.96 (dd, J = 8.6, 1.0, 2H),
6.80 (d, J = 8.7, 2H), 6.76 (tt, J = 7.3, 1.0, 1H), 5.36 (s, 2H); 13C NMR (101 MHz, DMSO-d6)
δ 157.0 (C), 154.3 (C), 144.5 (C), 137.8 (C), 134.8 (CH), 134.4 (C), 130.2 (2CH), 130.0
(CH), 129.3 (2CH), 128.3 (2CH), 127.4 (CH), 127.3 (2CH), 126.6 (C), 123.9 (C), 118.9 (CH),
115.10 (2CH), 115.06 (2CH), 67.0 (CH2); HRMS (ESI+) calcd for C24H21N2O2 (M+H)+
369.1598, found 369.1587.
4.1.32. 6-(Benzyloxy)-N-phenyl-5-(p-tolyl)pyridin-3-amine (57).
22

Compound 57 was prepared according to general procedure A, starting from 4 (120 mg, 0.338
mmol) and the corresponding boronic acid. The mixture was refluxed for 15 h. The crude oil
was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane 1:9) to
give 57 containing trace of 4-methylphenol. EtOAc was added and the organic phase washed
with a 0.5 M aqueous NaOH solution, and then with water. The organic phase was dried over
MgSO4, filtered and evaporated to give 57 (106 mg, 0.289 mmol, 86%) as an orange solid. Rf
= 0.37 (EtOAc/cyclohexane 1:9); Mp 72 °C; IR (ATR) 3313, 1594, 1440, 1231, 1025, 868,
822, 730, 692 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.97 (d, J = 2.7, 1H), 7.51
(d, J = 2.8, 1H), 7.50 (d, J = 8.2, 2H), 7.42–7.39 (m, 2H), 7.38–7.33 (m, 2H), 7.31–7.26 (m,
1H), 7.23 (d, J = 7.8, 2H), 7.20 (dd, J = 8.6, 7.3, 2H), 6.97 (dd, J = 8.7, 1.1, 2H), 6.76 (tt, J =
13
7.3, 1.1, 1H), 5.36 (s, 2H), 2.32 (s, 3H); C NMR (101 MHz, DMSO-d6) δ 154.3 (C), 144.5
(C), 137.7 (C), 137.0 (C), 135.4 (CH), 134.5 (C), 133.2 (C), 130.4 (CH), 129.3 (2CH), 128.85
(2×2CH), 128.3 (2CH), 127.49 (CH), 127.46 (2CH), 123.8 (C), 119.0 (CH), 115.1 (2CH),
67.1 (CH2), 20.8 (CH3); HRMS (ESI+) calcd for C25H23N2O (M+H)+ 367.1805, found
367.1797.
4.1.33. 6-(Benzyloxy)-N-phenyl-5-(4-(trifluoromethyl)phenyl)pyridin-3-amine (58).
Compound 58 was prepared according to general procedure A, starting from 4 (152 mg, 0.43
mmol) and the corresponding boronic acid. The mixture was refluxed for 18 h. The crude
green oil was purified by column chromatography (SiO2, EtOAc/cyclohexane 5:95 to 2:8) to
give 58 (149 mg, 0.35 mmol, 83%) as a pale yellow oil which solidified to a yellow solid.
Rf = 0.51 (EtOAc/cyclohexane 2:8); Mp 109 °C; IR (ATR) 3383, 3336, 1598, 1442, 1322,
1123, 1111, 1068, 845, 738, 693 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 8.05 (d,
J = 2.8, 1H), 7.84 (d, J = 8.2, 2H), 7.78 (d, J = 8.4, 2H), 7.61 (d, J = 2.8, 1H), 7.42–7.39 (m,
2H), 7.38–7.33 (m, 2H), 7,31–7,26 (m, 1H), 7.21 (dd, J = 8.5, 7.3, 2H), 7.00 (dd, J = 8.6, 1.1,
13
2H), 6.78 (tt, J = 7.3, 1.1, 1H), 5.40 (s, 2H); C NMR (101 MHz, DMSO-d6) δ 154.1 (C),
144.2 (C), 140.3 (C), 137.5 (C), 136.5 (CH), 134.7 (C), 130.5 (CH), 129.8 (2CH), 129.3
(2CH), 128.3 (2CH), 127.9 (q, JCF = 32, C), 127.52 (CH), 127.46 (2CH), 125.1 (q, JCF = 4,
2CH), 124.2 (q, JCF = 272, C), 122.2 (C), 119.2 (CH), 115.3 (2CH), 67.2 (CH2); HRMS
(ESI+) calcd for C25H20F3N2O (M+H)+ 421.1522, found 421.1539.
4.1.34. 6-(Benzyloxy)-N-phenyl-5-(4-(trifluoromethoxy)phenyl)pyridin-3-amine (59).
Compound 59 was prepared according to general procedure A, starting from 4 (115.1 mg,
0.324 mmol) and the corresponding boronic acid. The mixture was refluxed for 16 h. The
crude was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane
1:9) to give 59 (128.1 mg, 0.293 mmol, 91%) as a grey solid. Rf = 0.36 (EtOAc/cyclohexane
1:9); Mp 83 °C; IR (ATR) 3394, 1598, 1443, 1258, 1206, 1163, 1047, 1017, 734, 695 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 8.01 (d, J = 2.7, 1H), 7.74 (d, J = 8.9, 2H),
7.57 (d, J = 2.8, 1H), 7.45–7.33 (m, 6H), 7.31–7.26 (m, 1H), 7.20 (dd, J = 8.5, 7.4, 2H), 6.99
(dd, J = 8.6, 1.0, 2H), 6.78 (tt, J = 7.4, 1.0, 1H), 5.38 (s, 2H); 13C NMR (101 MHz, DMSO-d6)
δ 154.1 (C), 147.7 (q, J = 2, C), 144.3 (C), 137.6 (C), 136.1 (CH), 135.4 (C), 134.6 (C), 131.0
(2CH), 130.4 (CH), 129.3 (2CH), 128.3 (2CH), 127.5 (CH), 127.4 (2CH), 122.3 (C), 120.8
(2CH), 120,1 (q, J = 256, C), 119.2 (CH), 115.3 (2CH), 67.1 (CH2); HRMS (ESI+) calcd for
C25H20F3N2O2 (M+H)+ 437.1463, found 437.1471.
4.1.35. Methyl 4-(2-(benzyloxy)-5-(phenylamino)pyridin-3-yl)benzoate (60).
23

Compound 60 was prepared according to general procedure A, starting from 4 (98.9 mg,
0.278 mmol) and the corresponding boronic acid. The mixture was refluxed for 16 h. The
crude was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane
15:85) to give 60 (68.8 mg, 0.168 mmol, 60%) as a yellow powder. Rf = 0.46
(EtOAc/cyclohexane 2:8); Mp 139 °C; IR (ATR) 3374, 1707, 1695, 1598, 1280, 1261, 861,
729, 695 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.04 (d, J = 2.7, 1H), 8.00 (d, J
= 8.6, 2H), 7.77 (d, J = 8.6, 2H), 7.60 (d, J = 2.7, 1H), 7.43–7.39 (m, 2H), 7.39–7.33 (m, 2H),
7.32–7.26 (m, 1H), 7.21 (dd, J = 8.5, 7.3, 2H), 6.99 (dd, J = 8.6, 1.1, 2H), 6.78 (tt, J = 7.3,
13
1.1, 1H), 5.38 (s, 2H), 3.86 (s, 3H); C NMR (101 MHz, DMSO-d6) δ 166.0 (C), 154.2 (C),
144.3 (C), 141.0 (C), 137.5 (C), 136.5 (CH), 134.7 (C), 130.5 (CH), 129.39 (2CH), 129.35
(2CH), 129.1 (2CH), 128.6 (C), 128.4 (2CH), 127.6 (CH), 127.5 (2CH), 122.6 (C), 119.2
(CH), 115.3 (2CH), 67.3 (CH2), 52.2 (CH3); HRMS (ESI+) calcd for C26H23N2O3 (M+H)+
411.1703, found 411.1702.
4.1.36. 4-(2-(Benzyloxy)-5-(phenylamino)pyridin-3-yl)benzamide (61).
Compound 61 was prepared according to general procedure A, starting from 4 (115 mg, 0.324
mmol) and the corresponding boronic acid. The mixture was refluxed for 16 h. The crude was
purified by column chromatography (SiO2, EtOAc/cyclohexane 3:7 to 6:4) but some
impurities remained in the obtained white powder (133 mg). Compound 61 was used for the
next step without further purification. Rf = 0.09 (EtOAc/cyclohexane 3:7).
4.1.37. 6-(Benzyloxy)-5-(2,4-difluorophenyl)-N-phenylpyridin-3-amine (62).
Compound 62 was prepared according to general procedure A, starting from 4 (115 mg, 0.324
mmol) and the corresponding boronic acid. The mixture was refluxed for 22 h. Due to the
presence of residual starting material 4, catalyst PdCl2(PPh3)2 was added (5.1 mg, 0.0073
mmol, 0.02 eq.) and the mixture was refluxed for additional 17 h. The crude was
chromatographed (SiO2, pentane to EtOAc/pentane 6:94) but some impurities remained in the
obtained pink-brown oil (97.6 mg). Compound 62 was used for the next step without further
purification. Rf = 0.21 (EtOAc/pentane 5:95).
4.1.38. 6-(Benzyloxy)-5-(1H-indol-7-yl)-N-phenylpyridin-3-amine (63).
Indole-7-boronic acid was prepared from 7-bromoindole according to literature procedure
[28]. To a solution under argon cooled to 0 °C of 7-bromoindole (171 mg, 0.87 mmol, 1 eq.)
in anhydrous THF (1.4 mL) was added a suspension of KH (30% dispersion in mineral oil,
121.6 mg, 0.91 mmol, 1 eq.) in anhydrous THF (0.33 mL) cooled to 0 °C. The mixture was
stirred at 0 °C for 20 min then was cooled to –78 °C and a 1.08 M t-butyllithium solution in
pentane (1.65 mL, 1.78 mmol, 2 eq.) cooled to –78 °C was added dropwise. The mixture was
then stirred at room temperature for 15 min in the dark. The mixture was cooled to –78 °C
and trimethyl borate was added (0.19 mL, 1.7 mmol, 2 eq.). The mixture was stirred at room
temperature for 3 h. Water was added and the mixture was washed with EtOAc. Aqueous
phase was acidified with a 10% HCl solution (pH 1) and was extracted with EtOAc. The
organic phase was dried over MgSO4, filtered and evaporated giving a 46:54 mixture of
1
indole-7-boronic acid and indole (213 mg, ratio evaluated by H-NMR). The obtained crude
was used without purification.
Compound 63 was prepared according to general procedure A, starting from 4 (105.1 mg,
0.296 mmol) and the mixture of indole-7-boronic acid and indole obtained in the preceding
step. The reaction mixture was refluxed for 15.5 h. The crude oil was purified by column
24

chromatography (SiO2, cyclohexane to EtOAc/cyclohexane 2:8) to give 63 (57 mg, 0.146
mmol, 49%) as a beige powder. Rf = 0.32 (EtOAc/cyclohexane 2:8); Mp 135 °C; IR (ATR)
3389, 3316, 1596, 1497, 1420, 1230, 1023, 798, 722, 692 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ 10.91 (s, 1H), 8.09 (s, 1H), 8.08 (d, J = 2.8, 1H), 7.57–7.53 (m, 1H), 7.55 (d, J = 2.8,
1H), 7.30 (t, J = 2.9, 1H), 7.24–7.17 (m, 7H), 7.08–6.99 (m, 4H), 6.76 (tt, J = 7.3, 1.1, 1H),
13
6.47 (dd, J = 3.1, 1.9, 1H), 5.34 (s, 2H); C NMR (101 MHz, DMSO-d6) δ 154.9 (C), 144.5
(C), 137.5 (C), 135.7 (CH), 134.3 (C), 133.6 (C), 131.2 (CH), 129.3 (2CH), 128.0 (2CH),
127.9 (C), 127.5 (2CH), 127.3 (CH), 125.5 (CH), 122.2 (CH), 122.0 (C), 120.6 (C), 119.9
(CH), 119.0 (CH), 118.8 (CH), 115.1 (2CH), 101.1 (CH), 67.1 (CH2); HRMS (ESI+) calcd for
C26H22N3O (M+H)+ 392.1757, found 392.1754.
4.1.39. 5-(3-Aminophenyl)-6-(benzyloxy)-N-phenylpyridin-3-amine (64).
Compound 64 was prepared according to general procedure A, starting from 4 (121.6 mg,
0.342 mmol) and the corresponding boronic acid. The mixture was refluxed for 15 h 30 min.
The crude oil was purified by column chromatography (SiO2, EtOAc/cyclohexane 2:8 to
25:75) to give 64 (120.2 mg, 0.327 mmol, 96%) a light yellow oil. Rf = 0.07
(EtOAc/cyclohexane 1:9); Mp 106 °C; IR (ATR) 3380, 1586, 1426, 1360, 1020, 754, 735,
1
693 cm-1; H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.93 (d, J = 2.8, 1H), 7.45 (d, J =
2.8, 1H), 7.43–7.39 (m, 2H), 7.37–7.32 (m, 2H), 7.30–7.25 (m, 1H), 7.20 (dd, J = 8.6, 7.4,
2H), 7.05 (t, J = 7.8, 1H), 6.96 (dd, J = 8.6, 1.1, 2H), 6.79–6.72 (m, 3H), 6.54 (ddd, J = 8.0,
2.3, 1.0, 1H), 5.36 (s, 2H), 5.11 (br s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 154.3 (C),
148.5 (C), 144.4 (C), 137.8 (C), 136.7 (C), 135.2 (CH), 134.3 (C), 130.2 (CH), 129.3 (2CH),
128.6 (CH), 128.3 (2CH), 127.4 (CH), 127.3 (2CH), 124.7 (C), 119.0 (CH), 116.6 (CH),
115.2 (2CH), 114.4 (CH), 113.2 (CH), 66.9 (CH2); HRMS (ESI+) calcd for C24H22N3O
(M+H)+ 368.1757, found 368.1743.
4.1.40. 6-(Benzyloxy)-5-(3-methoxyphenyl)-N-phenylpyridin-3-amine (65).
Compound 65 was prepared according to general procedure A, starting from 4 (114 mg, 0.321
mmol) and the corresponding boronic acid. The mixture was refluxed for 15 h 30 min. The
crude oil was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane
8:92) to give a mixture of 65 and 3-methoxyphenol. Ethyl acetate was added and the organic
phase was washed with an 0.5 M NaOH aqueous solution of and then with water. The organic
phase was dried over MgSO4, filtered and then evaporated to give 65 (106 mg, 0.277 mmol,
86%) a brown oil. Rf = 0.57 (EtOAc/cyclohexane 2:8); IR (ATR) 3375, 1587, 1418, 1360,
1
1262, 1014, 864, 754, 693 cm-1; H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 8.00 (d, J =
2.7, 1H), 7.55 (d, J = 2.7, 1H), 7.44–7.41 (m, 2H), 7.38–7.27 (m, 4H), 7.23–7.18 (m, 3H),
7.14 (ddd, J = 7.7, 1.5, 1.0, 1H), 6.98 (dd, J = 8.6, 1.0, 2H), 6.91 (ddd, J = 8.3, 2.6, 0.9, 1H),
6.77 (tt, J = 7.3, 1.1, 1H), 5.36 (s, 2H), 3.72 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 158.9
(C), 154.3 (C), 144.4 (C), 137.6 (C), 137.4 (C), 135.7 (CH), 134.5 (C), 130.5 (CH), 129.31
(2CH), 129.30 (CH), 128.3 (2CH), 127.61 (2CH), 127.56 (CH), 123.6 (C), 121.2 (CH), 119.1
(CH), 115.1 (2CH), 114.3 (CH), 113.6 (CH), 67.1 (CH2), 55.0 (CH3); HRMS (ESI+) calcd for
C25H23N2O2 (M+H)+ 383.1751, found 383.1754.
4.1.41. 5-(Phenylamino)-3-(quinolin-4-yl)pyridin-2(1H)-one (66).
Compound 66 was prepared according to general procedure C, starting from 46 (100 mg,
0.248 mmol). The mixture was stirred for 3 h and was quenched with NEt3 (12 eq.) and
MeOH (4 eq.). After evaporation, EtOAc was added. The mixture was washed with brine,
25

then the organic phase was dried over MgSO4, and filtered. After evaporation, the crude was
purified by column chromatography (SiO2, CH2Cl2/MeOH 98:2). EtOAc was added to the
obtained product which was then washed with water to remove residual NEt3 salts. The
organic phase was dried over MgSO4, filtered and concentrated to give 66 (54 mg, 0.172
mmol, 69%) as a light brown solid. Rf = 0.17 (CH2Cl2/MeOH 95:5); Mp > 275 °C
-1
1
(decomposition); IR (ATR) 1627, 1592, 1561, 1479, 1337, 1255, 836, 742, 689 cm ; H
NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H), 8.91 (d, J = 4.4, 1H), 8.06 (d, J = 8.3, 1H),
7.80–7.74 (m, 2H), 7.60–7.55 (m, 2H), 7.49 (d, J = 3.0, 1H), 7.46 (d, J = 4.4, 1H), 7.38 (br s,
13
1H), 7.15 (dd, J = 8.6, 7.3, 2H), 6.80 (dd, J = 8.6, 1.0, 2H), 6.68 (tt, J = 7.3, 1.1, 1H); C
NMR (101 MHz, DMSO-d6) δ 159.0 (C), 150.1 (CH), 147.8 (C), 146.2 (C), 143.5 (C), 139.9
(CH), 129.30 (CH), 129.27 (CH), 129.25 (2CH), 128.7 (CH), 128.1 (C), 126.4 (CH), 126.3
(C), 126.0 (CH), 122.9 (C), 122.1 (CH), 118.1 (CH), 114.0 (2CH); HRMS (ESI+) calcd for
C20H16N3O (M+H)+ 314.1288, found 314.1291; HPLC purity ≥ 96%, tR = 6.83 min, λ = 280
nm.
4.1.42. 3-(1H-Indol-4-yl)-5-(phenylamino)pyridin-2(1H)-one (67).
Compound 67 was prepared according to general procedure C, starting from 47 (96.6 mg,
0.247 mmol). The mixture was stirred for 6 h and was quenched with NEt3 (15 eq.) and
MeOH (5 eq.). After evaporation, EtOAc was added. The mixture was washed with H2O,
dried over MgSO4, and filtered. After evaporation, the crude was purified by column
chromatography (SiO2, EtOAc/cyclohexane 6:4 to 9:1) to give 67 (49.9 mg, 0.166 mmol,
67%) as a yellow solid. Rf = 0.13 (EtOAc/cyclohexane 6:4); Mp > 143 °C (decomposition);
1
IR (ATR) 3500–3000, 1595, 1495, 1333, 1250, 746, 691 cm-1; H NMR (400 MHz, DMSO-
d6) δ 11.56 (br s, 1H), 11.14 (s, 1H), 7.52 (d, J = 3.0, 1H), 7.51 (s, 1H), 7.37–7.33 (m, 2H),
7.27 (dd, J = 7.3, 0.9, 1H), 7.20 (br s, 1H), 7.15 (dd, J = 8.5, 7.3, 2H), 7.09 (t, J = 7.7, 1H),
6.77 (dd, J = 8.6, 1.0, 2H), 6.68 (tt, J = 7.3, 1.1, 1H), 6.37–6.35 (m, 1H); 13C NMR (101 MHz,
DMSO-d6) δ 159.6 (C), 146.6 (C), 138.3 (CH), 136.1 (C), 130.6 (C), 129.2 (2CH), 128.3 (C),
126.7 (CH), 126.1 (C), 125.4 (CH), 122.5 (C), 120.5 (CH), 119.9 (CH), 117.9 (CH), 113.9
(2CH), 110.9 (CH), 100.5 (CH); HRMS (ESI+) calcd for C19H16N3O (M+H)+ 302.1288,
found 302.1282. HPLC purity ≥ 95%, tR = 7.82 min, λ = 278 nm.
4.1.43. 3-(2-Chlorophenyl)-5-(phenylamino)pyridin-2(1H)-one (68).
Compound 68 was prepared according to general procedure C, starting from 48 (82.1 mg,
0.212 mmol). The mixture was stirred for 2 h 40 min and was quenched with NEt3 (12 eq.)
and MeOH (6 eq.). The crude was purified by column chromatography (SiO2,
EtOAc/cyclohexane 6:4 to 75:25). The product was washed with CH2Cl2 to give 68 (31.4 mg,
0.106 mmol, 50%) as a light yellow-green powder. Rf = 0.12 (EtOAc/cyclohexane 7:3); Mp >
231 °C; IR (ATR) 3267, 1654, 1593, 1563, 745, 696 cm-1; 1H NMR (400 MHz, DMSO-d6) δ
11.64 (br s, 1H), 7.53–7.48 (m, 2H), 7.41–7.34 (m, 3H), 7.32 (d, J = 2.9, 1H), 7.27–7.23 (br s,
13
1H), 7.14 (dd, J = 8.5, 7.4, 2H), 6.75 (dd, J = 8.6, 1.0, 2H), 6.68 (tt, J = 7.3, 1.0, 1H); C
NMR (101 MHz, DMSO-d6) δ 158.9 (C), 146.4 (C), 139.4 (CH), 135.8 (C), 132.6 (C), 131.9
(CH), 129.5 (C), 129.3 (CH), 129.23 (CH), 129.22 (2CH), 128.0 (CH), 126.9 (CH), 122.3 (C),
118.0 (CH), 113.9 (2CH); HRMS (ESI+) calcd for C17H14ClN2O (M+H)+ 297.0789, found
297.0781; HPLC purity ≥ 98%, tR = 8.19 min, λ = 280 nm.
4.1.44. 3-(2-Bromophenyl)-5-(phenylamino)pyridin-2(1H)-one (69).
26

Compound 69 was prepared according to general procedure C, starting from impure
compound 49 (65 mg). The mixture was stirred for 3 h and was quenched with NEt3 (13 eq.)
and MeOH (7 eq.). After work-up, the crude was purified by column chromatography (SiO2,
EtOAc/cyclohexane 7:3 to EtOAc). The product was washed with CH2Cl2 to give 69 (18.6
mg, 0.055 mmol, 18% over 2 steps from 29) as a white solid. Rf = 0.32 (EtOAc); Mp > 236
1
°C (decomposition); IR (ATR) 3272, 1596, 744 cm-1 ; H NMR (400 MHz, DMSO-d6) δ
11.63 (br s, 1H), 7.67 (d, J = 7.9, 1H), 7.52 (s, 1H), 7.44–7.34 (m, 2H), 7.32–7.22 (m, 3H),
7.14 (t, J = 7.6, 2H), 6.75 (d, J = 7.9, 2H), 6.67 (t, J = 7.1, 1H); 13C NMR (101 MHz, DMSO-
d6) δ 158.8 (C), 146.4 (C), 139.3 (CH), 137.8 (C), 132.4 (CH), 131.8 (CH), 131.3 (C), 129.5
(CH), 129.2 (2CH), 127.9 (CH), 127.4 (CH), 123.2 (C), 122.3 (C), 118.0 (CH), 113.9 (2CH);
HRMS (ESI+) calcd for C17H14BrN2O (M+H)+ 341.0284, found 341.0281; HPLC purity ≥
95%, tR = 8.24 min, λ = 280 nm.
4.1.45. Ethyl 2-(2-oxo-5-(phenylamino)-1,2-dihydropyridin-3-yl)benzoate (70).
Compound 70 was prepared according to general procedure C, starting from 50 (83.2 mg,
0.196 mmol). The mixture was stirred for 3 h and was quenched with NEt3 (15 eq.) and
MeOH (6 eq.). The crude was purified by column chromatography (SiO2, EtOAc/cyclohexane
5:5 to AcOEt) to give 70 (51.4 mg, 0.154 mmol, 78%) as a brown powder. Rf = 0.28 (EtOAc);
Mp > 83 °C (decomposition); IR (ATR) 3450–3150, 1705, 1595, 1495, 1283, 1250, 748, 693
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 11.54 (br s, 1H), 7.75 (dd, J = 7.5, 1.5, 1H), 7.59 (td,
J = 7.5, 1.4, 1H), 7.51 (s, 1H), 7.45 (td, J = 7.6, 1.3, 1H), 7.35–7.32 (m, 2H), 7.19–7.5 (br s,
1H), 7.14 (dd, J = 8.6, 7.3, 2H), 6.74 (dd, J = 8.6, 1.1, 2H), 6.67 (tt, J = 7.3, 1.0, 1H), 4.10 (q,
13
J = 7.1, 2H), 1.13 (t, J = 7.1, 3H); C NMR (101 MHz, DMSO-d6) δ 167.1 (C), 159.7 (C),
146.6 (C), 136.9 (CH), 136.8 (C), 133.0 (C), 131.8 (CH), 131.7 (C), 130.5 (CH), 129.2
(2CH), 128.9 (CH), 127.7 (CH), 126.7 (CH), 122.5 (C), 117.9 (CH), 113.7 (2CH), 60.3
(CH2), 13.8 (CH3); HRMS (ESI+) calcd for C20H19N2O3 (M+H)+ 335.1390, found 335.1397;
HPLC purity ≥ 95 %, tR = 8.13 min, λ = 272 nm.
4.1.46. 2-(2-Oxo-5-(phenylamino)-1,2-dihydropyridin-3-yl)benzamide (71).
Compound 71 was prepared according to general procedure C, starting from impure
compound 51 (76.6 mg). The mixture was stirred for 5 h 30 min and was quenched with NEt3
(10 eq.) and MeOH (6 eq.). After work-up, the crude was purified by column chromatography
(SiO2, EtOAc/MeOH 95:5 to 85:15) to give 71 (24.6 mg, 0.081 mmol, 32% over 2 steps from
31) as a yellow powder. Rf = 0.29 (EtOAc/MeOH 85:15); Mp > 226 °C (decomposition); IR
(ATR) 3500–3000, 1657, 1596, 1494, 746, 691 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 11.41
(br s, 1H), 7.65 (br s, 1H), 7.50–7.47 (m, 2H), 7.43 (td, J = 7.5, 1.5, 1H), 7.36 (td, J = 7.5, 1.4,
1H), 7.36–7.33 (m, 1H), 7.26 (d, J = 2.9, 1H), 7.15 (dd, J = 8.5, 7.3, 2H), 7.11 (br s, 2H), 6.75
(dd, J = 8.6, 1.0, 2H), 6.66 (tt, J = 7.3, 1.1, 1H); 13C NMR (101 MHz, DMSO-d6) δ 170.4 (C),
159.5 (C), 146.4 (C), 137.4 (CH), 137.2 (C), 135.3 (C), 132.0 (C), 130.6 (CH), 129.2 (2CH),
129.1 (CH), 127.4 (CH), 127.2 (CH), 126.2 (CH), 122.4 (C), 117.8 (CH), 113.8 (2CH);
HRMS (ESI+) calcd for C18H16N3O2 (M+H)+ 306.1237, found 306.1233; HPLC purity ≥
94%, tR = 6.88 min, λ = 294 nm.
4.1.47. 3-(2-Nitrophenyl)-5-(phenylamino)pyridin-2(1H)-one (72).
Compound 72 was prepared according to general procedure C, starting from 52 (80.5 mg,
0.203 mmol). The mixture was stirred for 4 h and was quenched with NEt3 (18 eq.) and
MeOH (6 eq.). After work-up, the crude was purified by column chromatography (SiO2,
27

EtOAc/cyclohexane 3:7 to 5:5) to give 72 (55.6 mg, 0.181 mmol, 89%) as a red powder. Rf =
0.58 (Acetone/cyclohexane 5:5); Mp > 224 °C (decomposition); IR (ATR) 3375, 1658, 1597,
1
1519, 1488, 1465, 1336, 741, 695 cm-1; H NMR (400 MHz, DMSO-d6) δ 11.63 (br s, 1H),
7.98 (dd, J = 8.1, 1.3, 1H), 7.75 (td, J = 7.6, 1.3, 1H), 7.60 (ddd, J = 8.1, 7.5, 1.4, 1H), 7.56
(br s, 1H), 7.55 (d, J = 2.9, 1H), 7.51 (dd, J = 7.6, 1.5, 1H), 7.23 (br s, 1H), 7.16 (dd, J = 8.5,
7.3, 2H), 6.77 (dd, J = 8.6, 1.0, 2H), 6.69 (tt, J = 7.3, 1.1, 1H); 13C NMR (101 MHz, DMSO-
d6) δ 158.6 (C), 148.9 (C), 146.3 (C), 137.7 (CH), 133.5 (CH), 132.1 (CH), 131.0 (C), 129.7
(C), 129.3 (2CH), 129.1 (CH), 127.4 (CH), 123.9 (CH), 122.6 (C), 118.0 (CH), 133.9 (2CH);
HRMS (ESI+) calcd for C17H14N3O3 (M+H)+ 308.1030, found 308.1030; HPLC purity ≥
97%, tR = 8.07 min, λ = 276 nm.
4.1.48. 3-([1,1'-biphenyl]-4-yl)-5-(phenylamino)pyridin-2(1H)-one (73).
Compound 73 was prepared according to general procedure C, starting from 53 (77.6 mg,
0.181 mmol) and the corresponding boronic acid. The mixture was stirred for 3 h and was
quenched with NEt3 (14 eq.) and MeOH (7 eq.). After evaporation, EtOAc was added. A
precipitate appeared in the organic phase and was filtered and washed with EtOAc and
CH2Cl2 to give 73 (48.8 mg, 0.144 mmol, 80%) was obtained as a beige solid. Rf = 0.09
(EtOAc/cyclohexane 5:5); Mp > 245 °C (decomposition); IR (ATR) 3412, 1599, 749, 691 cm-
1
1; H NMR (400 MHz, DMSO-d6) δ 11.67 (br s, 1H), 7.85 (d, J = 7.8, 2H), 7.73–7.66 (m,
4H), 7.60 (s, 1H), 7.52 (s, 1H), 7.48 (t, J = 7.3, 2H), 7.37 (t, J = 6.8, 1H), 7.21 (s, 1H), 7.15 (t,
13
J = 7.5, 2H), 6.76 (d, J = 7.8, 2H), 6.68 (t, J = 7.2, 1H); C NMR (101 MHz, DMSO-d6) δ
159.5 (C), 146.5 (C), 139.8 (C), 139.1 (C), 137.4 (CH), 135.6 (C), 129.4 (C), 129.2 (2CH),
129.0 (2CH), 128.7 (2CH), 127.5 (CH), 127.1 (CH), 126.6 (2CH), 126.2 (2CH), 122.8 (C),
117.9 (CH), 113.8 (2CH); HRMS (ESI+) calcd for C23H19N2O (M+H)+ 339.1492, found
339.1487; HPLC purity ≥ 97%, tR = 9.16 min, λ = 284 nm.
4.1.49. 3-(3-Chlorophenyl)-5-(phenylamino)pyridin-2(1H)-one (74).
Compound 74 was prepared according to general procedure C, starting from 54 (78.8 mg,
0.204 mmol). The mixture was stirred for 2 h 40 min and was quenched with NEt3 (10 eq.)
and MeOH (6 eq.). The crude was purified by column chromatography (SiO2,
EtOAc/cyclohexane 5:5 to 7:3) to give 74 (55.4 mg, 0.187 mmol, 92%) as a yellow-brown
powder. Rf = 0.34 (EtOAc/cyclohexane 7:3); Mp > 187 °C (decomposition); IR (ATR) 3275,
1
1596, 1547, 1449, 1350, 1286, 746, 703, 683 cm-1; H NMR (400 MHz, DMSO-d6) δ 11.75
(br s, 1H), 7.89 (t, J = 1.7, 1H), 7.66 (dt, J = 7.4, 1.6, 1H), 7.62 (d, J = 2.9, 1H), 7.51 (s, 1H),
7.41 (t, J = 7.7, 1H), 7.37 (ddd, J = 8.0, 2.0, 1.5, 1H), 7.23 (d, J = 2.9, 1H), 7.15 (dd, J = 8.6,
7.3, 2H), 6.75 (dd, J = 8.6, 1.1, 2H), 6.68 (tt, J = 7.3, 1.1, 1H); 13C NMR (101 MHz, DMSO-
d6) δ 159.3 (C), 146.4 (C), 138.5 (C), 138.2 (CH), 132.6 (C), 129.9 (CH), 129.2 (2CH), 128.1
(C), 127.9 (CH), 127.8 (CH), 127.3 (CH), 126.6 (CH), 122.8 (C), 118.0 (CH), 113.8 (2CH);
HRMS (ESI+) calcd for C17H14ClN2O (M+H)+ 297.0789, found 297.0796; HPLC purity ≥
99%, tR = 8.59 min, λ = 284 nm.
4.1.50. 3-(3-Acetylphenyl)-5-(phenylamino)pyridin-2(1H)-one (75).
To a solution under argon of 55 (46 mg, 0.117 mg, 1 eq.) in anhydrous CH2Cl2 (0.75 mL) was
added dropwise iodotrimethylsilane (20 µL, 0.141 mmol, 1.2 eq.). The mixture was stirred at
room temperature overnight. Due to the presence of residual starting material 55, additional
iodotrimethylsilane (10 µL, 0.07 mmol, 0.6 eq.) was added and the mixture was stirred for 2
h. The reaction was quenched by addition of NEt3 (0.05 mL) and MeOH (0.75 mL) and the
28