Two-directional approach for the rapid synthesis of 2,4-bis-aminoaryl pyridine derivatives

Article abstract of DOI:10.1080/00397911.2010.520403

We have developed two different approaches in parallel to rapidly access 2,4-bis aminoaryl pyridine compounds from a common starting material. The C-4/C-2 approach uses palladium-mediated coupling reactions to sequentially functionalize C-4 and then C-2. An alternative C-2/C-4 route uses a regioselective SNAr reaction to first substitute at C-2 then subsequently at C-4 by a palladium-mediated reaction. Both approaches have been used successfully to provide a range of 2,4-bis-aminoaryl pyridine compounds.

Full text of DOI:10.1080/00397911.2010.520403

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Two-Directional Approach for the Rapid
Synthesis of 2,4-Bis-Aminoaryl Pyridine
Derivatives
Rémy Morgentin a , Bernard Barlaam a , Kevin Foote b , Lorraine
Hassall b , Janet Hawkins b , Clifford D. Jones b , Antoine Le Griffon a
, Aurelien Peru a & Patrick Plé a
a AstraZeneca, Centre de Recherches , Reims , France
b AstraZeneca Pharmaceuticals , Macclesfield , Cheshire , United
Kingdom
Accepted author version posted online: 30 Jun 2011.Published
online: 14 Sep 2011.
To cite this article: Rémy Morgentin , Bernard Barlaam , Kevin Foote , Lorraine Hassall , Janet
Hawkins , Clifford D. Jones , Antoine Le Griffon , Aurelien Peru & Patrick Plé (2012) Two-
Directional Approach for the Rapid Synthesis of 2,4-Bis-Aminoaryl Pyridine Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:1, 8-24, DOI: 10.1080/00397911.2010.520403
To link to this article: http://dx.doi.org/10.1080/00397911.2010.520403
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Synthetic Communications1, 42: 8–24, 2012
Copyright # AstraZeneca
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.520403
TWO-DIRECTIONAL APPROACH FOR THE RAPID
SYNTHESIS OF 2,4-BIS-AMINOARYL PYRIDINE
DERIVATIVES
1
Remy Morgentin, Bernard Barlaam, Kevin Foote,
1
2
´
Lorraine Hassall,2 Janet Hawkins,2 Clifford D. Jones,2
1
Antoine Le Griffon, Aurelien Peru, and Patrick Ple
1
1
´
1AstraZeneca, Centre de Recherches, Reims, France
2AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom
GRAPHICAL ABSTRACT
Abstract We have developed two different approaches in parallel to rapidly access 2,4-bis
aminoaryl pyridine compounds from a common starting material. The C-4/C-2 approach
uses palladium-mediated coupling reactions to sequentially functionalize C-4 and then
C-2. An alternative C-2/C-4 route uses a regioselective SNAr reaction to first substitute
at C-2 then subsequently at C-4 by a palladium-mediated reaction. Both approaches have
been used successfully to provide a range of 2,4-bis-aminoaryl pyridine compounds.
Keywords Nucleophilic substitution; palladium; pyridine; regioselectivity; strategy
INTRODUCTION
As part of our continuing interest in promising new scaffolds as inhibitors of
kinases, we focused our research on 5-substituted 2,4-bis-aminoaryl pyridines
(BAPyds). Very few synthetic methods have been reported in the literature,[1,2]
and the most straightforward synthesis of such compounds involves the successive
displacements of halogens by amino derivatives at the C-2 and C-4 positions of
the pyridine ring.[2] The main drawback of this approach is control of the mixture
of regioisomers; this can be achieved by using two different halogens (e.g., iodo
vs. chloro) to exploit their difference in reactivity. Iodo arenes are prone to react
Received August 10, 2010.
Address correspondence to Remy Morgentin, AstraZeneca, Centre de Recherches, Parc industrial
´
Pompelle B.P. 1050, 51689 Reims, Cedex 2, France. E-mail: remy.morgentin@astrazeneca.com
8

2,4-BIS-AMINOARYL PYRIDINE
9
Scheme 1. Retrosynthetic analysis showing the C-2=C-4 and C-4=C-2 approaches from common reagents.
(Figure is provided in color online.)
via a Buchwald–Hartwig coupling reaction, whereas chloro arenes can react via
either palladium-catalyzed reaction or aromatic nucleophilic substitution (SNAr).
Iodo arenes undergo palladium-mediated amination quicker than chloro arenes
under standard conditions and similar electronic effects.[3] Because we wanted to
shorten the time spent to identify the best druglike compounds, we faced an
additional challenge to control the order of functionalization (C-2=C-4 vs. C-4=
C-2). Although synthetic routes to 5-substituted 2-chloro,4-iodo pyridines are
known,[4] access to the 2-iodo,4-chloro pyridine analogs is more limited.[5] Thus,
we fixed the pyridine substitution pattern to 2-chloro,4-iodo pyridine to have a com-
mon key intermediate for the two approaches and developed several conditions that
allow control of regioselectivity (C-2=C-4 and C-4=C-2 in parallel) to rapidly
increase diversity and then make the best combinations. We describe this strategy
applied to the synthesis of a representative number of compounds in one of our
series: 2-(pyrazolylamino)-4-(anilino)-5-(trifluoromethyl)pyridine derivatives
(Scheme 1).
1
RESULTS AND DISCUSSION
Access to the Precursors
The retrosynthetic analysis shows the three required parts to be assembled
(Scheme 1). 2-Chloro-4-iodo-5-(trifluoromethyl) pyridine (4) and the aminopyra-
zoles 5 described here are readily available from commercial sources. The required
anilines 6 were synthesized from the corresponding commercially available anthra-
nilic acids. In the first method, anthranilic acids were treated with carbodiimidazole
(CDI) to give the corresponding 1H-benzo[d][1,3]oxazine-2,4-dione, which was
ring-opened in situ with 1 N methylamine in tetrahydrofuran (THF) to give the
desired anilines 6 in good yield (Table 1). This one-pot method gave lower yields
(ꢀ15%) when the corresponding 1H-benzo[d][1,3]oxazine-2,4-dione was treated with

10
R. MORGENTIN ET AL.
Table 1. Synthesis of starting 2-amino-N-methylbenzamides 6
Entry
Anthranilic acid
Yield (%)
Product
1
2
6-OMe
4-F
4-Cl
75a
62
74
33
77
89
61
69
51
87
6d
6e
6f
3
4
4-OMe
3-F
5-Cl
6g
6h
6i
5
6
7
5-OMe
4-SO2Me
5-SMe
—
6j
8
6k
6l
6mb
9
10
aRing opening of 7b by methylamine gave 76% yield.
bSynthesized from ring opening of commercially available 7a.
methoxyamine hydrochloride and base. A solution of methoxyamine in an organic
solvent would have been the best option to get good yields, but there are no commer-
cial sources. Instead, a two-step synthesis was developed where anthranilic acids
were treated with phosgene to give the corresponding cyclized intermediates 7, which
were isolated in good yields. Caution: Phosgene is a very toxic substance. A com-
merically available solution in toluene was used. It could be efficiently replaced by
di- or triphosgen, which are easier to handle. The ring opening was then performed
using an aqueous solution of methoxyamine hydrochloride and sodium hydroxide to
give the desired N-alkoxyamide anilines 6a–c in good yields (Table 2). The ring
opening of 1H-benzo[d][1,3]oxazine-2,4-dione (respectively 7b and 7a) was also
Table 2. Synthesis of starting 2-amino-N-methoxybenzamide 6
Entry
Anthranilic acid
Yield (%) (7 = 6)
Product
1
2
3
—
6-OMe
5-F
—=63a
88=90
88=97
7a/6a
7b/6b
7c/6c
aCompound 7a is commercially available.

2,4-BIS-AMINOARYL PYRIDINE
11
successfully carried out to make the methylamide substituted anilines 6d and 6m
when methylamine was used instead of methoxyamine.
C-4/C-2 Approach
Starting from 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (4), the C-4=C-2
approach[6,7] required that the 4-iodo of starting material 4 would react first in
palladium-mediated amination, compared to the 2-chloro.[3] As expected, the reac-
tion displayed excellent regioselectivity for C-4 amination with moderate to good
yields (Table 3). No product arising from a possible competing reaction with the ani-
line 6 at the 2-chloro position of the starting material 4 was observed, and the slow
overreaction (double arylation) at the 2-chloro position of the intermediate 2 was
minimized by using a stoichiometric amount of the required anilines 6. Any attempts
to use SNAr conditions with the pyridine 4 led to a loss of regioselectivity (see the
C-2=C-4 approach section).
The final C-2 functionalization of 2-chloro-4-anilino pyridines has been
reported but was limited to anilines.[6] For the first time, we have successfully
coupled aminopyrazoles using palladium-mediated conditions by treating the inter-
mediates 2 and aminopyrazoles 5 with palladium acetate, xantphos, and Cs2CO3 in
dioxane at 90 ꢁC (Table 4). The reaction of aminoheteroarenes on intermediates 2
worked moderately well for both substituted 3- and 4-aminopyrazoles 5, with little
difference in reactivity or obtained yields (Table 4, entries 1 and 12; entries 4, 6,
and 8; entries 13 and 14). Some traces of a by-product were also observed, formed
by reaction of the final products 1 with the pyridine C2 position of the starting mate-
rials 2. We successfully used Josiphos SL-J009-1[8] as an alternative ligand with
NaOtBu and Pd(OAc)2 in dimethoxyethane (DME), to suppress the formation of
this by-product because of its chemoselectivity for primary amines over secondary
amines.[9] For parallel synthesis, however, we preferred to use xantphos and Cs2CO3
because of the drawbacks of weighing out hygroscopic NaOtBu and the ease of
removal of the trace by-products in the examples presented in Table 4.
Table 3. Buchwald–Hartwig functionalization at C-4 with anilines
Entry
Aniline
Yield (%)
Product
1
2
3
4
6m
6d
6e
67
69
69
40
2a
2b
2c
2d
6c

12
R. MORGENTIN ET AL.
Table 4. Buchwald–Hartwig functionalization at C-2 with various amino-pyrazoles
Entry
Pyrazole
Starting material
Yield (%)a
Product
1
2
2,5-Dimethylpyrazol-3-amine (5b)
1,5-Dimethylpyrazol-4-amine
1-Ethyl-3-methyl-pyrazol-4-amine
1-Ethylpyrazol-4-amine
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2d
2d
40
20
34
32
52
28
26
51
23
59
55
34
38
40
1a
1b
1c
1d
1e
1f
3
4
5
2-Methylpyrazol-3-amine
1-Ethylpyrazol-3-amine
6
7
5-Cyclopropyl-2-methyl-pyrazol-3-amine
2-Ethylpyrazol-3-amine
1-Isobutylpyrazol-4-amine
1g
1h
1i
8
9
10
11
12
13
14
2,5-Dimethylpyrazol-3-amine (5b)
2,5-Dimethylpyrazol-3-amine (5b)
1,3-Dimethylpyrazol-4-amine (5a)
2,5-Dimethylpyrazol-3-amine (5b)
1,3-Dimethylpyrazol-4-amine (5a)
1j
1k
1l
1m
1n
aYields are unoptimized.
C-2/C-4 Approach
In addition to the C-4=C-2 approach, we looked for reaction conditions that
would allow substitution of the C-2 position of the 2,4-dihalopyridine derivative
by an aminoheteroarene. Very few examples have been reported in the literature
and were not applicable to our 2-chloro-4-iodo-5-(trifluoromethyl)pyridine substrate
(4).[2b,6b,10] The C-4=C-2 approach showed that the 4-iodo of starting material 4
reacted first in palladium-mediated amination compared to the 2-chloro (see the
C-4=C-2 approach section). This was confirmed when 4 was reacted with 3-amino
pyrazole 5b under palladium-mediated amination conditions. As the only product
formed came from the C-4 coupling reaction, we turned our attention to the SNAr
reaction. Free-palladium conditions were screened: NaH=dimethylformamide
(DMF), NaH=THF, NaH=toluene (solvent effect), K2CO3=DMF (base effect), cat.
HCl=ACN. None of them led to either consumption of 4 or clean reaction except
for the NaH=DMF condition, which was not regioselective and led to a 4:1 mixture
in favor of 4-iodo-displacement by 5b. Based on precedent from in-house work, the
pyridine 4 was reacted with the anion of acetylamino pyrazoles 8, and surprisingly an
efficient and highly regioselective substitution at the C-2 position occurred
(Scheme 2). The electron-withdrawing inductive effect of the C-5 trifluoromethyl
group would be expected to have a greater activating effect on C-4 compared to

2,4-BIS-AMINOARYL PYRIDINE
13
Scheme 2. SNAr at C-2 with N-(1,3-dimethyl-1H-pyrazol-4-yl)acetamide (8a) and N-(1,4-dimethyl-1H-
pyrazol-3-yl)acetamide (8b). Conditions: Ba, NaH, THF, 25 ꢁC, 1 h, 69%, or 8b, NaH, DMF=THF (1=
9), 75ꢁC, o=n, 72%.
C-2. Nevertheless, recent work[11] has shown that CF3 favors para-direct SNAr
nucleophile substitution in polar solvent on 2,4-dihaloaromatic compounds as this
activating group affords little stabilization of the ortho transition state. In our case,
even though chloride is a better leaving group than iodide, the 4-iodo displacement
of our substrate 4 is favored by aminopyrazole 5b compared to the 2-Cl displacement
under basic conditions in polar solvent. When acetyl pyrazoles 8 are used, we postu-
lated that a cyclic six-membered transition state could be envisaged, with chelation
of the sodium cation to the pyridine N-1 of 4 resulting in activation of the C-2 pos-
ition and overcoming the activating effect of CF3 at C-4 (Scheme 3). To help under-
stand whether the sodium cation was playing a role, the anion of acetyl pyrazole 8b
formed with NaH in THF was treated with 15-crown-5 before the addition of the
pyridine 4; the reaction gave the product 3b in 60% yield and no product arising from
4-iodo substitution was observed, countering our hypothesis. So we assumed that
steric hindrance of the C-4 position is the predominant factor affecting the regios-
electivity and the use of a bulkier anion favors C-2 attack. Some acetyl deprotection
occurred during the reaction, and deacylation was completed in situ by addition of
lithium hydroxide and water. N-Acetylated intermediates of 3 were also isolated and
reacted further successfully in palladium-mediated amination.
The final C-4 functionalization was achieved by treating the intermediate 3
with different anilines in parallel syntheses using the standard palladium-mediated
amination conditions. The desired compounds 1 were obtained in good to excellent
yields after purification. Few by-products resulting from overreaction with a second
molecule of 3 were observed. The results are summarized in Table 5. The reaction
does not seem to be strongly dependant on the nature of the aniline and the position
of the electron-donating group does not affect the yield (Table 5, entries 4, 8, and
11). Anilines substituted with electron-withdrawing groups also gave good results
(Table 5, entries 5, 9, and 12), and similar yields were obtained when the amide por-
tion was modified (Table 5, entries 3 vs. 4, 1 vs. 7). Not surprisingly, the anilines 6f
Scheme 3. Postulated cyclic six-membered transition state between 4 and 8.

14
R. MORGENTIN ET AL.
Table 5. Buchwald–Hartwig functionalization at C-4 with anilines 6
Entry
Starting material
Aniline
Yield (%)
Product
1
2
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
6m
6c
6b
6d
6e
6f
87
59
74
75
78
88
75
79
64
88
85
78
46
66
46
33
1l
1n
1o
1p
1q
1r
1s
1t
3
4
5
6
7
6a
6g
6h
6i
8
9
1u
1v
1w
1x
1y
1z
1j
10
11
12
13
14
15
16
6j
6k
6l
6b
6d
6e
1k
and 6i bearing a chlorine atom did not undergo any palladium-mediated amination
side reaction (Table 5, entries 6 and 10). Only the aniline bearing a thiomethyl group
6l (Table 5, entry 13) showed a lower conversion rate to give 1y in 46% yield. On the
other hand, the reaction seems to slightly depend on the nature of 3 as the yields
drop when the 3-aminopyrazole derivative 3b is used in place of the 4-aminopyrazole
derivative 3a (Table 5, entries 3 vs. 14, 4 vs. 15, 5 vs. 16).
Carrying Out Both Approaches
Using a two-directional approach allowed us to quickly increase diversity but
more importantly allowed us to have the flexibility of using either route (C-2=C-4 vs.
C-4=C-2), depending on the desired substitution pattern, costs of starting materials=
reagents, and speed of access to the required amount of compound. Both approaches
have advantages and drawbacks: the C-4=C-2 approach required only two
palladium-mediated coupling reactions, but large-scale purification can be problem-
atic. The C-2=C-4 approach required three steps (pyrazole acetylation and 2-chloro
and 4-iodo displacements) and excess reagents (2 eq. of acetylated pyrazole 8 for 2-Cl
displacement and 1.5 eq. of aniline 6 for 4-I displacement). Compounds 1l, 1j, 1n,

2,4-BIS-AMINOARYL PYRIDINE
15
Table 6. Comparison of the two approaches
Entry
Product
Overall (yield)% (C-4=C-2)
Overall (yield)% (C-2=C-4)
1
2
3
4
1j
1k
1l
40
36
23
16
26
18
50
32
1n
and 1k illustrate both approaches (Table 6). The 4-aminopyrazole compounds 1l and
1n were synthesized in greater overall yields using the C-2=C-4 approach, whereas
the best overall yields were obtained for 3-amino pyrazole compounds 1j and 1k
using the C-4=C-2 route.
In conclusion, we have developed approaches for the rapid synthesis of
2,4-bis-aminoaryl pyridine compounds starting from a common 2-chloro, 4-iodo,
5-CF3 pyridine derivative. The desired products could be obtained either via a dou-
ble Pd-mediated coupling reaction (C-4=C-2) or a SNAr=Pd-mediated reaction
sequence (C-2=C-4) from the 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (4)
substrate. Based exclusively on the overall yields, the C-2=C-4 approach seemed
preferable to access 4-aminopyrazole compounds (e.g., 1l and 1n), whereas the
C-4=C-2 approach gave the best results for the 3-aminopyrazole derivatives (e.g.,
1j and 1k).
EXPERIMENTAL
All compounds are known in the literature.[11] All reagents were purchased
from commercial sources and used without further purification. Flash chromato-
graphy was carried out on Merck Kieselgel 50 (Art. 9385). Preparative high-
performance liquid chromatography=mass specrometry (HPLC=MS) was carried
out on a Waters auto-purification system (injector=collector 2767, pump 2525 MS
detector ZQ) using a Waters ꢂ Bridge 5 microns, reverse-phase column (19 ꢂ 100 mm
mm or 30 ꢂ 150 mm) and decreasingly polar mixtures of water (containing 0.2%
ammonium carbonate) and acetonitrile as eluent. NMR spectra were recorded on
either a Bruker Avance 500 (500 MHz) spectrometer or a NMR spectrometer Jeol
Eclipse 270 (269.72 MHz). Chemical shifts are expressed in d (ppm) units, and peak
multiplicities are expressed as follows: s, singlet; d, doublet; dd, doublet of doublets;
t, triplet; q, quadruplet; br s, broad singlet; and m, multiplet. Mass spectrometry and
purity assessment at two wavelengths (254 nm and 310 nm) were carried out on an
analytical Waters HPLC=MS system with positive and negative ion data collected
automatically. Purity of isolated compounds was more than 95%. NMR and mass
spectra were run on isolated products and were consistent with the proposed struc-
tures. The following abbreviations have been used: Ac, acetyl; ACN, acetonitrile;
BAPyds, bis-aminoaryl pyridines; CDI, carbodiimidazole; DCM, dichloromethane;
DMSO, dimethyl sulfoxide; DME, 1,2-dimethoxyethane; DMF, N,N-dimethylfor-
mamide; Josiphos SLJ002-1, (R)-(ꢃ)-1-[(S)-2-(diphenylphosphino) ferrocenyl]
ethyldi-t-butylphosphine; PE, petroleum ether; SNAr, aromatic nucleophilic substi-
tution; TBME, ter-butyl methyl ether; tBu, ter-butyl; TFA, trifluoracetic acid;

16
R. MORGENTIN ET AL.
TLC, thin-layer chromatography; TMSCl, chlorotrimethylsilane; and xantphos,
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
Synthesis of Compounds 1 from Intermediate 2 (C-4/C-2 Approach)
Argon was passed through a suspension of the appropriate intermediate 2 (1
eq.), the appropriate aminopyrazole 5 (1.2 eq.), Pd(OAc)2 (0.08 eq.), xantphos
(0.16 eq.), and cesium carbonate (1.2 eq.) in dioxane (0.25 M) for 10 min at room
temperature. The reaction mixture was heated at 90 ꢁC for 5 h, allowed to cool to
room temperature, and concentrated in vacuo. The crude product was purified by
either flash chromatography on silica gel (0–5% MeOH=EtOAc) or preparative
HPLC=MS, depending on the reaction scale and synthesis method (parallel synthesis
or large-scale reaction). The solvent was evaporated in vacuo. The residue was tritu-
rated in either TBME or DCM, collected by filtration, and dried to afford the
expected product 1 as a white solid.
2-[[2-[(2,5-Dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N-methyl-benzamide (1a). Yield 40%; dH (500 MHz, DMSO-d6) 2.08 (s,
3H), 2.76 (d, 3H), 3.54 (s, 3H), 6.01 (s, 1H), 6.70 (s, 1H), 7.13 (dd, 1H), 7.50 (dd, 1H),
7.56 (d, 1H), 7.71 (d, 1H), 8.24 (s, 1H), 8.68 (q, 1H), 8.99 (s, 1H), 10.19 (s, 1H); MS
(ESI) m=z 405 (MHþ).
2-[[2-[(1,5-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N-methyl-benzamide (1b). Yield 20%; dH (500 MHz, DMSO-d6) 2.11 (s,
3H), 2.76 (d, 3H), 3.69 (s, 3H), 6.46 (bs, 1H), 7.08 (dd, 1H), 7.43 (s, 1H), 7.46 (d, 1H),
7.50 (d, 1H), 7.69 (d, 1H), 8.16 (s, 1H), 8.35 (s, 1H), 8.65 (q, 1H), 10.08 (s, 1H); MS
(ESI) m=z 405 (MHþ).
2-[[2-[(1-Ethyl-3-methyl-pyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N-methyl-benzamide (1c). Yield 34%; dH (500 MHz, DMSO-d6) 1.31 (t,
3H), 2.07 (s, 3H), 2.76 (d, 3H), 3.99 (q, 2H), 6.62 (bs, 1H), 7.09 (dd, 1H), 7.47 (dd,
1H), 7.52 (d, 1H), 7.70 (d, 1H), 7.88 (s, 1H), 8.20 (s, 1H), 8.41 (s, 1H), 8.66 (q, 1H),
10.11 (s, 1H); MS (ESI) m=z 419 (MHþ).
2-[[2-[(1-Ethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-
N-methyl-benzamide (1d). Yield 32%; dH (500 MHz, DMSO-d6) 1.34 (t, 3H), 2.77
(d, 3H), 4.07 (q, 2H), 6.61 (s, 1H), 7.10 (dd, 1H), 7.39 (s, 1H), 7.48 (dd, 1H), 7.56 (d,
1H), 7.71 (d, 1H), 7.90 (s, 1H), 8.24 (s, 1H), 8.67 (q, 1H), 9.03 (bs, 1H), 10.13 (s, 1H);
MS (ESI) m=z 405 (MHþ).
N-Methyl-2-[[2-[(2-methylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-
pyridyl]amino]benzamide (1e). Yield 52%; dH (500 MHz, DMSO-d6) 2.77 (d,
3H), 3.63 (s, 3H), 6.21 (d, 1H), 6.70 (s, 1H), 7.13 (ddd, 1H), 7.32 (d, 1H), 7.49
(ddd, 1H), 7.55 (d, 1H), 7.71 (dd, 1H), 8.25 (s, 1H), 8.68 (q, 1H), 9.03 (s, 1H),
10.20 (s, 1H); MS (ESI) m=z 391 (MHþ).
2-[[2-[(1-Ethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-
N-methyl-benzamide (1f). Yield 28%; dH (500 MHz, DMSO-d6) 1.27 (t, 3H), 2.77
(d, 3H), 3.95 (q, 2H), 6.09 (s, 1H), 7.11 (ddd, 1H), 7.49 (ddd, 1H), 7.54 (d, 1H), 7.62

2,4-BIS-AMINOARYL PYRIDINE
17
(d, 1H), 7.63 (bs, 1H), 7.70 (dd, 1H), 8.23 (s, 1H), 8.68 (q, 1H), 9.52 (s, 1H), 10.28
(s, 1H); MS (ESI) m=z 405 (MHþ).
2-[[2-[(5-Cyclopropyl-2-methyl-pyrazol-3-yl)amino]-5-(trifluoromethyl)-
4-pyridyl]amino]-N-methyl-benzamide (1g). Yield 26%; dH (500 MHz, DMSO-
d6) 0.54–0.60 (m, 2H), 0.76–0.84 (m, 2H), 1.72–1.80 (m, 1H), 2.75 (d, 3H), 3.52 (s,
3H), 5.91 (s, 1H), 6.66 (s, 1H), 7.13 (ddd, 1H), 7.48 (ddd, 1H), 7.55 (d, 1H), 7.70
(dd, 1H), 8.23 (s, 1H), 8.67 (q, 1H), 8.97 (s, 1H), 10.17 (s, 1H); MS (ESI) m=z 431
(MHþ).
2-[[2-[(2-Ethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-N-
methyl-benzamide (1h). Yield 51%; dH (500 MHz, DMSO-d6) 1.24 (t, 3H), 2.76
(d, 3H), 3.96 (q, 2H), 6.19 (s, 1H), 6.66 (s, 1H), 7.11 (dd, 1H), 7.35 (d, 1H), 7.47
(dd, 1H), 7.53 (d, 1H), 7.70 (d, 1H), 8.23 (s, 1H), 8.68 (q, 1H), 8.96 (s, 1H), 10.20
(s, 1H); MS (ESI) m=z 405 (MHþ).
2-[[2-[(1-Isobutylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-
N-methyl-benzamide (1i). Yield 23%; dH (500 MHz, DMSO-d6) 0.81 (d, 6H),
2.01–2.12 (m, 1H), 2.76 (d, 3H), 3.84 (d, 2H), 6.59 (s, 1H), 7.09 (ddd, 1H), 7.39 (s,
1H), 7.46 (ddd, 1H), 7.54 (d, 1H), 7.70 (dd, 1H), 7.87 (s, 1H), 8.24 (s, 1H), 8.66
(q, 1H), 9.02 (bs, 1H), 10.14 (s, 1H); MS (ESI) m=z 433 (MHþ).
2-[[2-[(2,5-Dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-6-methoxy-N-methyl-benzamide (1j). Yield 59%; dH (500 MHz,
DMSO-d6) 2.08 (s, 3H), 2.73 (d, 3H), 3.54 (s, 1H), 3.82 (s, 1H), 5.97 (s, 1H), 6.48
(s, 1H), 6.88 (d, 1H), 7.08 (d, 1H), 7.41 (dd, 1H), 8.19 (s, 1H), 8.28 (q, 1H), 8.83
(s, 1H), 8.95 (s, 1H); MS (ESI) m=z 435 (MHþ).
2-[[2-[(2,5-Dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-4-fluoro-N-methyl-benzamide (1k). Yield 55%; dH (500 MHz, DMSO-
d6) 2.08 (s, 3H), 2.76 (d, 3H), 3.55 (s, 3H), 6.04 (s, 1H), 6.76 (s, 1H), 6.95 (ddd,
1H), 7.39 (dd, 1H), 7.79 (dd, 1H), 8.27 (s, 1H), 8.69 (q, 1H), 10.65 (s, 1H); MS
(ESI) m=z 423 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N-methyl-benzamide (1l). Yield 34%; dH (500 MHz, DMSO-d6) 2.05 (s,
3H), 2.69–2.77 (m, 3H), 3.70 (s, 3H), 6.62 (s, 1H), 7.06–7.11 (m, 1H), 7.48–7.50
(m, 2H), 7.69 (dd, 1H), 7.82 (s, 1H), 8.19 (s, 1H), 8.38 (s, 1H), 8.63 (q, 1H), 10.09
(s, 1H); MS (ESI) m=z 405 (MHþ).
2-[[2-[(2,5-Dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-5-fluoro-N-methoxy-benzamide (1m). Yield 38%; dH (500 MHz,
DMSO-d6) 2.07 (s, 3H), 3.53 (s, 3H), 3.58 (s, 3H), 5.98 (s, 1H), 5.49 (s, 1H), 7.42
(dd. 1H), 7.46 (dd, 1H), 7.60 (dd, 1H), 8.22 (s, 1H), 8.96 (s, 1H), 9.20 (bs, 1H),
11.94 (bs, 1H); MS (ESI) m=z 439 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-5-fluoro-N-methoxy-benzamide (1n). Yield 40%; dH (500 MHz, DMSO-
d6) 2.05 (s, 3H), 32.69 (s, 3H), 3.70 (s, 3H), 6.45 (bs, 1H), 7.42 (dd, 1H), 7.45 (d, 1H),
7.56 (dd, 1H), 7.83 (s, 1H), 8.18 (s, 1H), 8.40 (s, 1H), 9.15 (s, 1H), 11.95 (bs, 1H); MS
(ESI) m=z 439 (MHþ).

18
R. MORGENTIN ET AL.
Synthesis of Compounds 1 from Intermediate 3 (C-2/C-4 Approach)
Argon was passed through a suspension of the appropriate intermediate 3 (1
eq.), the appropriate aniline 6 (1.7 eq.), Pd(OAc)2 (0.05 eq.), xantphos (0.1 eq.),
and cesium carbonate (1.2 eq.) in dioxane (0.3 M) for 10 min at room temperature.
The reaction mixture was heated at 90 ꢁC overnight and then allowed to cool to
room temperature. The reaction mixture was diluted with DCM and filtered through
celite, and the solvent evaporated in vacuo to give the crude product, which was pur-
ified by either flash chromatography on silica gel (0–5% MeOH=EtOAc) or prepara-
tive HPLC=MS, depending on the reaction scale, and synthesis method (parallel
synthesis or large scale reaction). The solvent was evaporated in vacuo. The residue
was triturated in either TBME or DCM, collected by filtration, and dried to afford
the expected product 1 as a white solid.
2-[[2-[(2,5-Dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-6-methoxy-N-methyl-benzamide (1j). Yield 46%.
2-[[2-[(2,5-Dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-4-fluoro-N-methyl-benzamide (1k). Yield 33%.
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N-methyl-benzamide (1l). Yield 87%.
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-5-fluoro-N-methoxy-benzamide (1n). Yield 59%.
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N,6-dimethoxy-benzamide (1o). Yield 74%; dH (500 MHz, DMSO-d6)
2.04 (s, 3H), 3.62 (s, 3H), 3.69 (s, 3H), 3.81 (s, 3H), 6.31 (bs, 1H), 6.89 (d, 1H),
7.06 (d, 1H), 7.43 (dd, 1H), 7.79 (s, 1H), 7.86 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H),
11.38 (s, 1H); MS (ESI) m=z 451 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-6-methoxy-N-methyl-benzamide (1p). Yield 75%; dH (500 MHz,
CDCl3) 2.14 (s, 3H), 2.95 (d, 3H), 3.72 (s, 3H), 3.90 (s, 3H), 5.94 (s, 1H), 6.31 (s,
1H), 6.54 (d, 1H), 7.03 (d, 1H), 7.19 (dd, 1H), 7.34 (s, 1H), 7.44 (q, 1H), 8.22 (s,
1H), 10.57 (s, 1H); MS (ESI) m=z 451 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-4-fluoro-N-methyl-benzamide (1q). Yield 78%; dH (500 MHz, CDCl3)
2.15 (s, 3H), 2.96 (d, 3H), 3.81 (s, 3H), 5.97 (s, 1H), 6.02 (bs, 1H), 6.34 (bs, 1H),
6.65 (ddd, 1H), 7.10 (dd, 1H), 7.39 (s, 1H), 7.44 (dd, 1H), 8.26 (s, 1H), 10.11 (bs,
1H); MS (ESI) m=z 423 (MHþ).
4-Chloro-2-[[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-
pyridyl]amino]-N-methyl-benzamide (1r). Yield 88%; dH (500 MHz, DMSO-d6)
2.06 (s, 3H), 2.74 (d, 3H), 3.70 (s, 3H), 7.12 (dd, 1H), 7.51 (d, 1H), 7.70 (d, 1H), 7.83
(s, 1H), 8.22 (s, 1H), 8.51 (s, 1H), 8.75 (q, 1H), 10.39 (s, 1H); MS (ESI) m=z 439 and
441 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N-methoxy-benzamide (1s). Yield 75%; dH (500 MHz, DMSO-d6) 2.05

2,4-BIS-AMINOARYL PYRIDINE
19
(s, 3H), 3.68 (s, 3H), 3.69 (s, 3H), 6.60 (bs, 1H), 7.07 (ddd, 1H), 7.45–7.60 (m, 3H),
7.83 (s, 1H), 8.19 (s, 1H), 8.45 (s, 1H), 9.52 (bs, 1H), 11.93 (bs, 1H); MS (ESI) m=z
421 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-4-methoxy-N-methyl-benzamide (1t). Yield 79%; dH (500 MHz,
CDCl3) 2.13 (s, 3H), 2.94 (d, 3H), 3.72 (s, 3H), 3.79 (s, 3H), 5.93 (s, 1H), 6.03 (q,
1H), 6.39 (s, 1H), 6.49 (dd, 1H), 6.89 (d, 1H), 7.37 (s, 1H), 7.39 (d, 1H), 8.24 (s,
1H), 10.09 (bs, 1H); MS (ESI) m=z 435 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-3-fluoro-N-methyl-benzamide (1u). Yield 64%; dH (500 MHz, DMSO-
d6) 2.01 (s, 3H), 2.74 (d, 3H), 3.68 (s, 3H), 5.87 (bs, 1H), 7.24–7.40 (m, 1H),
7.43–7.62 (m, 2H), 7.78 (bs, 1H), 8.14 (s, 1H), 8.39 (s, 1H), 8.73 (q, 1H), 9.19 (s,
1H); MS (ESI) m=z 423 (MHþ).
5-Chloro-2-[[2-[(1,3-dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-
pyridyl]amino]-N-methyl-benzamide (1v). Yield 88%; dH (500 MHz, DMSO-d6)
2.05 (s, 3H), 2.74 (d, 3H), 3.69 (s, 3H), 6.61 (bs, 1H), 7.23 (s, 2H), 7.77 (s, 1H), 7.84
(s, 1H), 8.20 (s, 1H), 8.45 (s, 1H), 8.80 (q, 1H), 10.07 (s, 1H); MS (ESI) m=z 439 and
441 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-5-methoxy-N-methyl-benzamide (1w). Yield 85%; dH (500 MHz,
CDCl3) 2.11 (s, 3H), 2.92 (d, 3H), 3.77 (s, 3H), 3.81 (s, 3H), 5.86 (s, 1H), 5.99 (s,
1H), 6.30 (q, 1H), 6.93 (dd, 1H), 7.09 (d, 1H), 7.26 (d, 1H), 7.37 (s, 1H), 8.18 (s,
1H), 8.34 (bs, 1H); MS (ESI) m=z 435 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N-methyl-4-methylsulfonyl-benzamide (1x). Yield 78%; dH (500 MHz,
DMSO-d6) 2.01 (s, 3H), 2.77 (s, 3H), 3.26 (s, 3H), 3.68 (s, 3H), 6.49 (bs, 1H), 7.57 (d,
1H), 7.74 (bs, 1H), 7.85–8.01 (m, 2H), 8.24 (s, 1H), 8.51 (s, 1H), 8.92 (q, 1H), 10.24
(s, 1H); MS (ESI) m=z 483 (MHþ).
2-[[2-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N-methyl-5-methylsulfanyl-benzamide (1y). Yield 46%; dH (500 MHz,
CDCl3) 2.14 (s, 3H), 2.48 (s, 3H), 2.96 (d, 3H), 3.79 (s, 3H), 6.14 (q, 1H), 6.18 (s,
1H), 6.50 (bs, 1H), 7.31 (s, 1H), 7.33–7.37 (m, 2H), 7.40 (d, 1H), 8.18 (s, 1H), 9.48
(bs, 1H); MS (ESI) m=z 451 (MHþ).
2-[[2-[(2,5-Dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]
amino]-N,6-dimethoxy-benzamide (1z). Yield 66%; dH (500 MHz, DMSO-d6)
2.06 (s, 3H), 3.52 (s, 3H), 3.62 (s, 3H), 3.81 (s, 3H), 5.96 (s, 1H), 6.34 (s, 1H), 6.93
(d, 1H), 7.08 (d, 1H), 7.45 (dd, 1H), 7.95 (s, 1H), 8.17 (s, 1H), 8.94 (s, 1H), 11.36
(s, 1H); MS (ESI) m=z 451 (MHþ).
Synthesis of Intermediate 2
Argon was passed through a suspension of 2-chloro-4-iodo-5-(trifluoromethyl)
pyridine (4) (1 eq.), the appropriate aniline 6 (1.05 eq.), Pd(OAc)2 (0.08 eq.),

20
R. MORGENTIN ET AL.
xantphos (0.16 eq.), and cesium carbonate (1.2 eq.) in dioxane (0.3 M) for 10 min at
room temperature. The reaction mixture was heated at 90 ꢁC for 5 h and then
allowed to cool to room temperature. The reaction mixture was diluted with
DCM and filtered through celite, and the solvent evaporated in vacuo to give the
crude product, which was purified by flash chromatography on silica gel (10–60%
EtOAc=PE) to give the expected product 2.
2-(2-Chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide
(2a). Yield 67%; dH (500 MHz, DMSO-d6) 2.75 (d, 3H), 7.21 (dt, 1H), 7.51 (dt, 1H),
7.59 (dd, 1H), 7.73 (dd, 1H), 8.48 (s, 1H), 8.72 (q, 1H), 10.52 (s, 1H); MS (ESI) m=z
330 and 332 (MHþ).
2-(2-Chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methyl-
benzamide (2b). Yield 69%; dH (500 MHz, DMSO-d6) 2.68 (d, 3H), 3.82 (s, 3H),
6.81 (s, 1H), 7.06 (d, 1H), 7.08 (d, 1H), 7.55 (t, 1H), 8.18 (q, 1H), 8.51 (s, 1H),
9.13 (s, 1H); MS (ESI) m=z 360 and 362 (MHþ).
2-(2-Chloro-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methyl-
benzamide (2c). Yield 69%; dH (500 MHz, DMSO-d6) 2.77 (d, 3H), 7.06 (dt, 1H),
7.45 (s, 1H), 7.52 (dd, 1H), 7.82 (dd, 1H), 8.54 (s, 1H), 8.77 (q, 1H), 11.00 (s, 1H);
MS (ESI) m=z 348 and 350 (MHþ).
2-(2-Chloro-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxy-
benzamide (2d). Yield 40%; dH (500 MHz, DMSO-d6) 3.61 (s, 3H), 6.85 (s, 1H),
7.47 (m, 1H), 7.62 (m, 1H), 8.52 (s, 1H), 9.35 (bs, 1H), 11.85 (s, 1H); MS (ESI)
m=z 364 and 366 (MHþ).
N-(1,3-Dimethyl-1h-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-
amine (3a). Sodium hydride 60% oil dispersion (3.9 g, 97.34 mmol) was added por-
tionwise to aminopyrazole acetamide 8a (14.2 g, 92.7 mmol) dissolved in THF
(200 mL) at 35 ꢁC under nitrogen. The resulting beige suspension was stirred for
15 min at 35 ꢁC and then cooled to 5 ꢁC. 2-Chloro-4-iodo-5-(trifluoromethyl)pyridine
(4) (14.25 g, 46.35 mmol) was added, and the suspension was warmed to 50 ꢁC and
stirred for 2 h. The dark suspension was cooled to 5 ꢁC, and water (200 mL) was
added, followed by lithium hydroxide hydrate (7.78 g, 185.40 mmol). The resulting
purple solution was stirred at room temperature for 2.5 h. The solution was diluted
with water and extracted twice with ethyl acetate. The combined organic phases were
washed with water and brine, dried over magnesium sulfate, and concentrated in
vacuo. The crude product was purified by flash chromatography on silica gel (0–
60% EtOAc=DCM). The solvent was evaporated to dryness to afford the title com-
pound 3a (12.2 g, 69%) as an off-white solid; dH (500 MHz, DMSO-d6) 2.08 (s, 3H),
3.75 (s, 3H), 7.40 (bs, 1H), 7.78 (bs, 1H), 8.27 (s, 1H), 8.85 (s, 1H); MS (ESI) m=z 382
(MHþ).
N-(1,3-Dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-
amine (3b). A solution of aminopyrazole acetamide 8b (31.9 g, 208.2 mmol)
in THF (100 mL) was added dropwise to a stirred suspension of sodium
hydride 60% in oil dispersion (8.74 g, 218.6 mmol) in a mixture of THF (299 mL)
and DMF (40 mL) over a period of 20 min under a nitrogen atmosphere at
room temperature. The resulting suspension was stirred at 30 ꢁC for 15 min,

2,4-BIS-AMINOARYL PYRIDINE
21
2-chloro-4-iodo-5-(trifluoromethyl)pyridine (4) (32 g, 104.1 mmol) was added, and
the reaction mixture was stirred at 70 ꢁC overnight. The reaction mixture was
allowed to cool to room temperature, and water (300 mL) was added, followed by
lithium hydroxide hydrate (13.1 g, 312.26 mmol). The mixture was stirred at room
temperature for 2.5 h and then extracted with EtOAc. The organic phases were com-
bined, washed with water and brine, dried over magnesium sulfate, and concentrated
in vacuo. The crude product was purified by flash chromatography on silica gel (0–
100% EtOAc=DCM). The solvent was evaporated to dryness. The residue was tritu-
rated with PE (100 mL), collected by filtration, washed with PE (100 mL), and dried
to give 3b (28 g, 72%) as a pale purple solid; dH (500 MHz, DMSO-d6) 2.12 (s, 3H),
3.56 (s, 3H), 6.07 (s, 1H), 7.42 (s, 1H), 8.33 (s, 1H), 9.37 (s, 1H); MS (ESI) m=z 382
(MHþ).
Using CDI for the Synthesis of 6d–m
A suspension of CDI (1.2 eq.) and the appropriate 2-amino-benzoic acid (1 eq.)
in THF (1 M) was stirred under a hydrogen atmosphere at room temperature over-
night. A 1 N solution of methylamine in THF (2 eq.) was added dropwise. The
resulting solution was stirred for 3 h. The reaction mixture was concentrated in
vacuo, and the residue was dissolved in EtOAc and washed with a saturated aqueous
sodium bicarbonate solution, water, and brine. The organic phase was dried over
magnesium sulfate and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (30% EtOAc=DCM) to give the expected
product 6.
2-Amino-6-methoxy-N-methylbenzamide (6d). Yield 75%; dH (500 MHz,
DMSO-d6) 2.71 (d, 3H), 3.72 (s, 3H), 5.94 (bs, 2H), 6.17 (d, 1H), 6.28 (d, 1H),
6.98 (dd, 1H), 7.99 (q, 1H); MS (ESI) m=z 181 (MHþ).
2-Amino-4-fluoro-N-methylbenzamide (6e). Yield 62%; dH (500 MHz,
DMSO-d6) 2.69 (d, 3H), 6.28 (ddd, 1H), 6.42 (dd, 1H), 6.74 (bs, 2H), 7.48 (dd,
1H), 8.16 (q, 1H); MS (ESI) m=z 169 (MHþ).
2-Amino-4-chloro-N-methylbenzamide (6f). Yield 74%; dH (500 MHz,
CDCl3) 2.95 (d, 3H), 5.63 (bs, 2H), 5.98 (bs, 1H), 6.59 (dd, 1H), 6.67 (d, 1H), 7.20
(d, 1H); MS (ESI) m=z 183 and 185 [(M-H)-].
2-Amino-4-methoxy-N-methylbenzamide (6g). Yield 33%; dH (500 MHz,
DMSO-d6) 2.67 (d, 3H), 3.67 (s, 3H), 6.07 (dd, 1H), 6.19 (d, 1H), 6.60 (bs, 2H),
7.39 (d, 1H), 7.97 (q, 1H); MS (ESI) m=z 181 (MHþ).
2-Amino-3-fluoro-N-methylbenzamide (6h). Yield 77%; dH (500 MHz,
CDCl3) 2.97 (d, 3H), 5.59 (bs, 2H), 6.07 (bs, 1H), 6.56 (dt, 1H), 7.04 (dd, 1H),
7.08 (d, 1H); MS (ESI) m=z 169 (MHþ).
2-Amino-5-chloro-N-methylbenzamide (6i). Yield 89%; dH (500 MHz,
CDCl3) 2.96 (d, 3H), 5.49 (bs, 2H), 6.03 (bs, 1H), 6.62 (d, 1H), 7.26 (d, 1H); MS
(ESI) m=z 185 and 187 (MHþ).

22
R. MORGENTIN ET AL.
2-Amino-5-methoxy-N-methylbenzamide (6j). Yield 61%; dH (500 MHz,
DMSO-d6) 2.71 (d, 3H), 3.66 (s, 3H), 5.95 (bs, 2H), 6.62 (d, 1H), 6.81 (dd, 1H),
7.01 (d, 1H), 8.18 (q, 1H); MS (ESI) m=z 181 (MHþ).
2-Amino-N-methyl-4-(methylsulfonyl)benzamide (6k). Yield 69%; dH
(269.72 MHz, CD3OH) 2.88 (s, 3H), 3.08 (s, 3H), 3.31 (s partially hidden by
CD2HOH, 3H), 7.06 (dd, 1H), 7.27 (d, 1H), 7.57 (d, 1H); MS (ESI) m=z 229 (MHþ).
2-Amino-N-methyl-5-(methylthio)benzamide (6 l). Yield 51%; dH
(500 MHz, CDCl3) 2.40 (s, 3H), 2.96 (d, 3H), 33H), 5.55 (bs, 2H), 6.12 (bs, 1H),
6.63 (d, 1H), 7.25 (dd, 1H), 7.36 (d, 1H); MS (ESI) m=z 197 (MHþ).
Synthesis of 6a–c from the Ring Opening of 7
A 2 N solution of NaOH in water (3.1 eq.) was added to a 25% solution of
O-methylhydroxylamine hydrochloride (3.2 eq.) at 5 ꢁC, and then the appropriate
1H-benzo[d][1,3]oxazine-2,4-dione 7 (1 eq.) was added in several portions. The
resulting suspension was stirred at 5 ꢁC for 30 min allowed to warm to room tem-
perature (bubbling occurred), and stirred for 3 h. The resulting solution was
extracted twice with EtOAc, and the combined organic phases were washed with
brine, dried over magnesium sulfate, and concentrated in vacuo to afford the crude
product 6 as an oil, which crystallized on standing.
2-Amino-N-methoxybenzamide (6a). Yield 63%; dH (500 MHz, DMSO-d6)
3.66 (s, 3H), 6.29 (bs, 2H), 6.47 (dd, 1H), 6.69 (d, 1H), 7.14 (ddd, 1H), 7.29 (dd, 1H),
11.40 (bs, 1H); MS (ESI) m=z 167 (MHþ).
2-Amino-N,6-dimethoxybenzamide (6b). Yield 90%; dH (500 MHz,
DMSO-d6) 3.67 (s, 3H), 3.71 (s, 3H), 5.57 (bs, 2H), 6.19 (d, 1H), 6.31 (d, 1H),
7.02 (dd, 1H); 11.02 (bs, 1H); MS (ESI) m=z 197 (MHþ).
2-Amino-5-fluoro-N-methoxybenzamide (6c). Yield 97%; dH (500 MHz,
DMSO-d6) 3.82 (s, 3H), 6.20 (bs, 2H), 6.72 (dd, 1H), 7.09 (ddd, 1H), 7.15 (dd,
1H), 11.49 (bs, 1H); MS (ESI) m=z 183 [(M-H)-].
Synthesis of 6d and 6m from the Ring Opening of 7
A 40% solution of methylamine in water (6 eq.) was added dropwise to a stirred
suspension of 7 (1 eq.) in water (0.6 M) at 5 ꢁC. The resulting suspension was stirred
at room temperature for 2 h and concentrated to half of volume. The precipitate was
collected by filtration, washed with water, and dried to give a first batch of the
expected compound 6. The aqueous filtrate was extracted twice with EtOAc, and
the organic phases were combined, washed with brine, dried over magnesium sulfate,
and concentrated in vacuo to give a second batch of the expected compound 6. The
two batches were combined.
2-Amino-6-methoxy-N-methylbenzamide (6d). Yield 76% from 7b.

2,4-BIS-AMINOARYL PYRIDINE
23
2-Amino-N-methylbenzamide (6m). Yield 87% from 7a; dH (500 MHz,
DMSO-d6) 2.72 (d, 3H), 6.39 (s, 2H), 6.49 (t, 1H), 6.66 (d, 1H), 7.11 (td, 1H),
7.44 (dd, 1H), 8.14 (bs, 1H); MS (ESI) m=z 151 (MHþ).
Synthesis of 7b and 7c
A 20% solution of phosgene in toluene (1.1 eq.) was dropwise added to a sol-
ution of the appropriate anthranilic acid (1 eq.) in a 1 N solution of NaOH in water
(2.1 eq.) at 10 ꢁC, and then the mixture was stirred for 30 min at room temperature.
The resulting solid was collected by filtration, washed with water and a solution of
20% of MeCN in Et2O, and dried to give the compound 7.
5-Methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (7b). Yield 88%; dH
(500 MHz, DMSO-d6) 3.88 (s, 3H), 6.69 (d, 1H), 6.83 (d, 1H), 7.64 (t, 1H), 11.59
(s, 1H); MS (ESI) m=z 192 [(M-H)-].
6-Fluoro-1H-benzo[d][1,3]oxazine-2,4-dione
(7c). Yield
88%;
dH
(500 MHz, DMSO-d6) 3.33 (s, 3H), 6.64–7.70 (m, 3H), 11.79 (s, 1H); MS (ESI)
m=z 180 [(M-H)-].
N-(1,3-Dimethyl-1N-pyrazol-4-yl)acetamide (8a). Acetyl chloride (4.2 mL,
59.6 mmol) was added dropwise to a suspension of 11,3-dimethyl-1H-pyrazol-
4-amine hydrochloride (5a) (8 g, 54.2 mmol) and triethylamine (18.9 mL,
135.5 mmol) in CH2Cl2 (120 mL) over a period of 15 min at 25 ꢁC. The resulting sus-
pension was stirred at 25 ꢁC for 3 h and then concentrated in vacuo. The residue was
taken into CH2Cl2 (10 mL), and the insolubles were removed by filtration. The fil-
trate was purified by flash chromatography on silica gel (2–7% MeOH=EtOAc).
The solvent was evaporated to dryness to afford 8a (6.8 g, 82%) as a pink oil, which
crystallized on standing; dH (500 MHz, DMSO-d6) 1.98 (s, 3H), 2.10 (s, 3H), 3.67 (s,
3H), 7.79 (s, 1H), 9.29 (s, 1H); MS (ESI) m=z 154 (MHþ).
N-(1,3-Dimethyl-1H-pyrazol-4-yl)acetamide (8b). A suspension of 1,3-
dimethyl-1H-pyrazol-5-amine (5b) (42 g, 377.9 mmol), potassium acetate (41 g,
415.7 mmol), and acetic anhydride (42 ml, 377.9 mmol) in ethyl acetate (714 ml)
was stirred at 25 ꢁC overnight. Basic aluminium oxide 90 (200 g) was added, and stir-
ring was carried on for 10 min. The solids were removed by filtration, and the filtrate
was passed through a pad of basic aluminium oxide 90 (150 g) (5% MeOH=EtOAc).
The filtrate was concentrated in vacuo to afford 8b (81 g, 88%) as a red oil, which
crystallized on standing; dH (500 MHz, DMSO-d6) 2.03 (s, 3H), 2.08 (s, 3H), 3.65
(s, 3H), 5.96 (s, 1H), 9.83 (s, 1H); MS (ESI) m=z 154 (MHþ).
ACKNOWLEDGMENTS
We acknowledge the excellent technical expertise and useful advice of the fol-
lowing scientists and organizations: Myriam Didelot, Ryan Greenwood, Nick Howe,
Franck Lach, Jean Jacques Lohmann, Nathalie Monk, Stuart Pearson, Fabrice
Renaud, Michel Vautier, and ONYX Ltd.

24
R. MORGENTIN ET AL.
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