Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives

Article abstract of DOI:10.1016/j.bmc.2016.01.047

Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC₅₀ values in the 80–250 nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.

Full text of DOI:10.1016/j.bmc.2016.01.047

Accepted Manuscript
Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cyclo-
alkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives
Euphemia Leung, Lisa I. Pilkington, Michelle van Rensburg, Chae Yeon Jeon,
Mirae Song, Homayon J. Arabshahi, Gayan Heruka De Zoysa, Vijayalekshmi
Sarojini, William A. Denny, Jóhannes Reynisson, David Barker
PII:
S0968-0896(16)30062-1
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.01.047
BMC 12790
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 November 2015
19 January 2016
26 January 2016
Please cite this article as: Leung, E., Pilkington, L.I., Rensburg, M.v., Jeon, C.Y., Song, M., Arabshahi, H.J., Zoysa,
G.H.D., Sarojini, V., Denny, W.A., Reynisson, J., Barker, D., Synthesis and cytotoxicity of thieno[2,3-
b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives, Bioorganic &
Medicinal Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bmc.2016.01.047
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Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and
cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives
Euphemia Leunga,b*, Lisa I. Pilkingtona,c, Michelle van Rensburgc, Chae Yeon Jeonc, Mirae
Songc, Homayon J. Arabshahic, Gayan Heruka De Zoysac, Vijayalekshmi Sarojinic, William A.
Dennya, Jóhannes Reynissonc* and David Barkerc*
aAuckland Cancer Society Research Centre, The University of Auckland, New Zealand
bDepartment of Molecular Medicine and Pathology, The University of Auckland, New
Zealand
cSchool of Chemical Sciences, The University of Auckland, New Zealand
Corresponding authors. Tel.: +64-9-373-7599; e-mail: e.leung@auckland.ac.nz;
j.reynisson@auckland.ac.nz; d.barker@auckland.ac.nz.
Abstract: Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-
b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine
and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained
commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468
and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active
against all cell lines with IC50 values in the 80-250 nM range. In general
hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity
observed as larger cycloalkyl rings were fused to the pyridine ring.
Keywords:
thieno[2,3-b]pyridines;
thieno[3,2-e]pyridines;
thieno[2,3-b]quinolones;
antiproliferative
1. Introduction
Thienopyridine derivatives have been reported to have significant antiproliferative activity
against a range of human cancer cell lines [1-8]. In tests against the National Cancer
Institute’s human tumour cell line panel (NCI60) [2,4,5], and later verified using thymidine
uptake assays, thienopyridines have been shown to be growth inhibitory to triple negative
breast cancer cell lines (those lacking the oestrogen and progesterone receptors and HER2)
such as MDA-MB-231/468, with GI50 values in the nanomolar range [3]. Thienopyridine
1

derivatives have been reported to have numerous effects on cell growth and development;
these include severe growth restriction, rounding with accompanying blebbing of the plasma
membrane, cell cycle arrest in G2/M-phase and slowed proliferation in scratch assays. Many
of the cellular effects induced by thienopyridines resemble behaviour seen in phospholipase
C – δ1 (PLC-δ1) and δ3 isoforms knockdown cells for MDA-MB-231 [9], indicating that
these compounds may bind with PLC. Additionally, inhibition of copper trafficking of Atox1
and CCS proteins has also been reported with this class of compound [10].
We have previously shown that thieno[2,3-b]pyridines, such as 1, which lack an additional
ring fused to the pyridine ring, have lower anti-proliferative activity than the
tetrahydrothieno[2,3-b]quinolones 2 (Fig. 1) [5]. However, compounds with a large
substituent at C-5 (e.g. 1b) or C-6 (e.g. 3) have greater activity than those without (e.g. 1a)
showing that substituents attached to the pyridine ring can increase activity. Compounds
where the 2-carboxamide and 3-amino groups were modified to form a cyclic structure (e.g.
4) were generally less active than those without modification. Whilst these effects have been
investigated, less was known about the effect of changing the ring(s) fused to the pyridine at
positions C-5 and C-6.
Figure 1. Previously prepared anti-proliferative thieno[2,3-b]pyridines
To investigate the effect of changing the ring fused to the pyridine ring, a range of
compounds were prepared. Firstly,
a
series of cycloalkyl-fused derivatives,
5, tetrahydrothieno[2,3-b]quinolines 6,
dihydrocyclopenta[b]thieno[3,2-e]pyridines
cyclohepta[b]thieno[3,2-e]pyridines 7 and hexahydrocycloocta[b]thieno[3,2-e]pyridines 8
2

investigate the change of ring size on activity, whilst thieno[2,3-b]quinolones explore the
effect of adding a further fused aromatic ring (Fig. 2)
Figure 2. Compounds prepared and evaluated.
2. Results and Discussion
2.1
Chemistry
Thieno[2,3-b]quinolines 6 and cycloalkyl[b]thieno[3,2-e]pyridines 5 and 7 were prepared in
an efficient three step process from the corresponding cyclic ketones 9a-c. The first step
involved the formation of the corresponding hydroxymethylene salts, which were obtained by
the reaction of ketones 9a-c with freshly-prepared sodium methoxide and methyl formate
[11]. These salts were then immediately heated at reflux with cyanothioacetamide and
piperidinium acetate, followed by acidification with acetic acid, which provided bicyclic
thiocarbonitriles 10a-c [12].
Anilines 11a-v were converted to 2-bromo-N-phenylacetamides 12a-v using 1 equivalent of
bromoacetyl bromide in the presence of Et3N and were not optimised if sufficient material for
further reactions was obtained [13]. The reactions These bromoacetamides 12a-v were then
coupled with the required bicyclic thiocarbonitrile 10a-c by heating at reflux with sodium
3

carbonate, which also effected concomitant cyclisation to give cycloalkyl[b]thieno[3,2-
e]pyridines, 5a-j and 7a-q and thieno[2,3-b]quinolines, 6a-t [5]. Again reactions were not
optimised if sufficient material for biological tesing was obtained.
Scheme 1. Reagents and conditions: (i) Na, MeOH, methyl formate, 52-67 %; (ii) cyanothioacetamide (1.1
equiv.), piperidinium acetate, water, reflux, 4 h, AcOH, r.t., 12 h, 10a-c 30-59 %; (iii) bromoacetyl bromide (1
equiv.), Et3N (1.1 equiv.), 0 ºC, 1 h, 12a-v 16-100 %; (iv) Na2CO3 (1.06 equiv.), EtOH, 100 ºC, 18 h, 5a-j, 6a-t,
7a-q 6-100 %.
2.2 Anti-proliferative activity of synthesised and commercially obtained compounds
The anti-proliferative activity of the synthesised cycloalkyl[b]thieno[3,2-e]pyridines 5a-j and
7a-q, and thieno[2,3-b]quinolines 6a-t, along with a series of related commercially-obtained
compounds (Fig. 3), was measured against three cancer cell-lines, HCT116, MDA-MB-468
and MDA-MB-231 with all compounds being initially tested at 1 μM concentration (Table 1).
These cell lines were chosen based on favourable results in previous studies against the entire
National Cancer Institute 60 human cell line panel [1-5]. The testing concentration of 1 μM
was chosen as previous studies, on structurally similar compounds, have shown this
concentration, and higher, to be non-toxic in whole animal murine studies [14]. Furthermore,
4

testing of thieno[2,3-b]pyridine analogues for in vitro antibacterial activity against E. coli, P.
aeruginosa and S. aureus pathogens showed no, or marginal, activity against these three
bacterial strains. This indicate that the ligands are not generally toxic, e.g., forming DNA
adducts via the aryl amine moiety [15].
Figure 3. Structures of commercially-obtained compounds.
5

Table 1. Anti-proliferative activity of cycloalkyl[b]thieno[2,3-e]pyridines and thieno[2,3-b]quinolines.
Relative growth (%) at 1 μM
Compound
n
R
HCT116a MDA-MB-468a MDA-MB-231a
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Ph
3-ClC6H4
3-BrC6H4
94
87
93
90
92
79
3
76
53
53
58
63
46
4
90
92
94
100
95
79
11
16
80
81
22
92
119
70
89
128
30
98
101
108
71
98
15
5
5a
5b
5c
5d
5e
5f
5g
5h
5i
3-CF3C6H4
3-OMeC6H4
3-NO2C6H4
2-Me-3-ClC6H3
2-Me-3-BrC6H3
1-naphthalene
2-naphthalene
Ph
2-FC6H4
2-ClC6H4
2-MeC6H4
2-EtC6H4
5
5
92
94
5
67
64
8
5j
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
84
94
84
86
104
11
80
85
82
75
99
3
48
95
53
63
93
11
58
45
41
44
84
6
2-CF3C6H4
3-FC6H4
3-ClC6H4
3-BrC6H4
3-CF3C6H4
3-NO2C6H4
4-OMeC6H4
2-Me-3-ClC6H3
2-Me-3-BrC6H3
2,3-di-MeC6H3
2,6-di-EtC6H3
2-Et-6-MeC6H3
2,6-di-ClC6H3
2,4,6-tri-MeC6H2
1-naphthalene
2-naphthalene
Ph
5
5
3
3
4
108
96
100
101
37
100
6
15
92
66
112
29
86
83
108
6
116
67
82
93
8
115
84
93
97
60
120
26
46
89
43
124
28
95
92
94
19
67
13
12
6
6t
6ub
7a
7b
7c
7d
7e
7f
76
5
2-FC6H4
2-ClC6H4
2-MeC6H4
2-CF3C6H4
3-FC6H4
11
73
25
100
10
39
45
92
3
18
3
3
4
89
3-ClC6H4
3-BrC6H4
7g
7h
7i
7j
7k
7l
7m
7n
7o
3-CF3C6H4
3-OMeC6H4
3-NO2C6H4
2-Me-3-ClC6H3
2-Me-3-BrC6H3
2,3-di-MeC6H3
2,4,6-tri-MeC6H2
51
10
8
6
99
98
6

2
2
1-naphthalene
2-naphthalene
see figure 3
2-Cl-5-CF3C6H3
3,4-di-OMeC6H3
2,5-di-OMeC6H3
3,4-di-ClC6H3
3-OnBuC6H4
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
see figure 3
93
103
65
98
98
98
103
97
112
5
85
91
97
71
106
77
94
77
53
100
5
72
65
82
84
107
110
94
4
12
77
84
91
89
81
68
70
87
104
93
101
101
87
101
106
118
89
105
114
117
115
100
116
24
117
100
117
107
102
119
131
3
7p
7q
7rb
7sb
2
2
2
2
2
7tb
7ub
7vb
7wb
8ab
8bb
8cb
8db
8eb
82
94
8fb
106
106
109
107
6
73
98
100
98
99
95
97
93
96
100
100
102
102
99
8gb
8hb
8ib
8jb
13b
14ab
14bb
14cb
14db
14eb
14fb
14gb
14hb
14ib
14jb
14kb
15b
16b
17b
73
103
105
103
104
92
101
95
97
86
97
90
81
97
107
96
a Values represent relative growth (%) versus control. All compounds were tested at 1μM against the specified
cell lines. Experiments were performed in duplicate; stated values are the averages of two independent
determinations. b Compound was obtained commercially, see Figure 3 for structures.
From the results from the bioactivity tests against the three cancer cell line, general trends can
be made. Firstly, the triple negative MDA-MB-468 cell line was the most susceptible to the
tested compounds with an average relative growth of 60% over the 79 compounds tested
versus 76% and 82% for HCT116 and MDA-MB-231, respectively. This result is in line with
previous observations of the susceptibility of triple negative breast cancer cell lines to
thienopyridines [3].
7

With the aryl carboxamide moiety of both the thieno[2,3-b]quinolines and
cycloalkyl[b]thieno[3,2-e]pyridines, it can be seen that 2,3-disubstitution on the aryl ring is
more favoured over others (as can be seen in compounds 5g, 5h, 6m, 6n, 6o, 7l, 7m, 7n and
8j).
It was noted that a decrease in cell growth was observed as the size of the ring fused to the
pyridine ring increased, regardless of substitution on the aryl carboxamide. This can be seen
when comparing the data for most susceptible cell line (MDA-MB-468); for example
compounds 5f (46% relative growth), 6k (44%), and 7k (18%); compounds 5a (76%), 6a
(8%) and 7a (5%); and compounds 6b (48%), 7b (11%) and 8b (5%).
The presence of a benzene ring fused to the pyridine ring (as in 14a-k, 15, 16) results in
inactive compounds. All compounds lacking the 2-aryl carboxamide and 3-amino moieties
were found to be inactive (e.g. 14a-e, 15, 16 and 17), a trend previously observed on smaller
thienopyridines [5].
From this screen of 79 compounds, 17 of the most active compounds were further tested to
obtain IC50 values. The previously used cancer cell lines along with leukaemia cell line K562,
which has been shown to be susceptible to this class of compounds[2] (Table 2). The IC50
results further validate the trends seen initially in terms of increased activity as the size of the
ring fused to the pyridine increase, as well as the importance of 2,3-disubstitution in the aryl
carboxamide for activity. The most active eight compounds were generally active against all
four cell lines with IC50 values in the 80-250 nM range.
Table 2. IC50 values of cycloalkyl[b]thieno[2,3-e]pyridines and thieno[2,3-b]quinolines.
IC50 (nM)a
Compound
HCT116
218 ± 22
161 ± 4
594 ± 2
563 ± 14
191 ± 9
207 ± 1
199 ± 4
720 ± 4
606 ± 29
798 ± 202
543 ± 47
601 ± 64
266 ± 62
MDA-MB-468
546 ± 16
79 ± 24
MDA-MB-231
593 ±1
K562
197 ± 2
83 ± 9
5g
5h
6a
6g
6m
6n
6o
6t
7a
7b
7f
7j
7l
84 ± 14
617 ± 8
407 ± 50
398 ± 23
134 ± 31
185 ± 9
148 ± 46
447 ± 76
383 ± 21
528 ± 15
351 ± 56
391 ± 16
160 ± 25
526 ± 33
554 ± 13
153 ± 6
185 ± 3
152 ± 6
576 ± 24
570 ± 71
575 ± 90
558 ± 63
580 ± 60
210 ± 19
632 ± 28
221 ± 8
233 ± 16
204 ± 9
854 ± 104
508 ± 56
672 ± 67
448 ± 47
524 ± 46
190 ± 5
8

442 ± 74
204 ± 9
599 ± 6
183 ± 1
199 ± 22
121 ± 26
372 ± 61
83 ± 16
198 ± 33
198 ± 1
587 ± 8
170 ± 10
223 ± 20
167 ± 1
562 ± 17
83 ± 6
7m
7n
8b
8j
aExperiments were performed in triplicate; stated values are the averages of three independent determinations.
3. Conclusions
In summary seventy nine synthetic or commercially obtained compounds all containing a
thienopyridine motif were tested for their antiproliferative activity against a range of human
cancer cell lines. The most susceptible cell line tested was MDA-MB-468 and the most active
compounds having IC50 values ~80 nM. In general hexahydrocycloocta[b]thieno[3,2-
e]pyridines were most active series of compounds with increasing activity observed as larger
cycloalkyl rings were fused to the pyridine ring. These results show that further modifications
to thienopyridine scaffolds, in particular changing the pyridine-fused ring, led to improved
cytotoxicity and shows that along with substitution of the aryl carboxamide are sites for
further investigations in this class of compound. The low IC50 values in selected cell lines
along with tolerance in animal toxicity studies show thienopyridines as a promising class of
novel antiproliferative agents.
4. Experimental Details and Methodology
4.1 Synthesis of Compounds
4.1.1 General Details: All reactions were carried out under a nitrogen atmosphere in dry,
freshly distilled solvents unless otherwise noted. All NMR spectra were recorded on either
Bruker Avance DRX 300 MHz or 400 MHz spectrometers at ambient temperatures.
1
Chemical shifts are reported relative to the solvent peak of chloroform (δ 7.26 for H and δ
13
1
13
1
77.0 for C), DMSO (δ 2.50 for H and δ 39.5 for C) or acetone (δ 2.05 for H and δ 29.8
13
for C). 1H NMR data is reported as position (δ), relative integral, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; dd, doublet of triplets; dd, doublet of doublets; tt, triplet of
triplets; m, multiplet; br, broad peak; qd, quartet of doublets), coupling constant (J, Hz), and
13
the assignment of the atom. C NMR data are reported as position (δ) and assignment of the
atom. All NMR assignments were performed using HSQC and HMBC experiments. High-
resolution mass spectroscopy (HRMS) was carried out by either chemical ionization (CI) or
9

electrospray ionization (ESI) on a MicroTOF-Q mass spectrometer. Unless noted, chemical
reagents were used as purchased.
4.1.2 General Procedure for the synthesis of thieno[2,3-b]pyridine-2-carboxamides 5-7
A mixture of 2-bromoacetamides 12a-v (1 equiv), carbonitrile 10a-c (1 equiv) and anhydrous
sodium carbonate (1.06 equiv) in absolute ethanol or methanol was stirred at reflux for 18 h.
The mixture was cooled to room temperature and the solvent removed in vacuo to give the
crude product which was washed with small amounts of ice water before being recrystallized
from methanol to give the thieno[2,3-b]pyridine-2-carboxamides 5-7.
4.1.2.1
3-Amino-N-phenyl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-
carboxamide 5a. The reaction was carried out according to general procedure C using 2-
bromo-N-phenylacetamide 12a (0.06 g, 0.28 mmol), carbonitrile 10a (0.05 g, 0.26 mmol) and
sodium carbonate (0.03 g, 0.28 mmol) in ethanol (2 mL) to give the title product 5a (0.04 g,
1
55%) as a black solid. m.p. 213-216 °C. H NMR (400 MHz; d6-DMSO) 2.19-2.27 (2H, m,
H-6), 3.07-3.14 (4H, m, H-5 and H-7), 7.13-7.18 (1H, m, H-4'), 7.38-7.42 (4H, m, NH2 and
H-3' and H-5'), 7.77-7.79 (2H, m, H-2' and H-6'), 8.37 (1H, s, H-4), 9.43 (1H, br s, NH); 13C
NMR (100 MHz; d6-DMSO) 23.2 (C-6), 29.6 (C-5), 33.6 (C-7), 95.7 (C-2), 121.0 (C-2' and
C-6'), 123.3 (C-4'), 124.1 (C-3a), 128.4 (C-3' and 5'), 128.7 (C-4), 133.3 (C-3), 139.0 (C-4a),
147.0 (C-1'), 159.3 (C-8a), 164.0 (C=O), 167.8 (C-7a); IR: υmax (film)/cm-1: 3410, 3288,
3042, 2954, 1677, 1590, 1509, 1430, 1226; m/z (ESI+): 377 (MNa+, 100%), 355 (MH+, 52%);
HRMS (ESI+) found (MNa+): 332.0815, C17H15N3NaOS requires 377.0679. The
spectroscopic data was consistent with literature values [16].
4.1.2.2 3-Amino-N-(3'-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-
carboxamide 5b. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-chlorophenyl)acetamide 12c (0.08 g, 0.31 mmol), carbonitrile 10a (0.05 g, 0.28
mmol) and sodium carbonate (0.03 g, 0.31 mmol) in methanol (2 mL) to give the title
1
product 5b (0.10 g, 100%) as a black solid. m.p. > 230 °C. H NMR (400 MHz; d6-DMSO)
2.14-2.20 (2H, m, H-6), 2.99-3.05 (4H, m, H-5 and H-7), 7.11-7.14 (1H, m, H-4'), 7.33-7.37
(1H, m, H-5'), 7.39 (2H, br s, NH2), 7.65-7.68 (1H, m, H-6'), 7.94 (1H, s, H-2'), 8.31 (1H, s,
13
H-4), 9.52 (1H, br s, NH); C NMR (100 MHz; d6-DMSO) 23.2 (C-6), 29.6 (C-5), 33.6 (C-
7), 95.2 (C-2), 119.1(C-6'), 120.1 (C-2'), 122.8 (C-4'), 124.0 (C-4a), 126.2 (C-4), 130.0 (C-
10

5'), 132.7 (C-3a), 133.1 (C-3), 140.7 (C-3'), 147.6 (C-1'), 157.3 (C-8a), 164.1 (C=O), 168.1
(C-7a); IR: υmax (film)/cm-1: 3426, 3323, 2952, 1673, 1586, 1522, 1497, 1474, 1253, 770,
675; m/z (ESI+): 368 (37ClMNa+, 8%), 366 (35ClMNa+, 22%), 253 (MNa+-Cl, 100%); HRMS
(ESI+) found (37ClMNa+): 368.0431, C17H1437ClN3NaOS requires 368.0412. Found
(35ClMNa+): 366.0447, C17H1435ClN3NaOS requires 366.0438.
4.1.2.3 3-Amino-N-(3'-bromophenyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-
carboxamide 5c. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-bromophenyl)acetamide 12i (0.09 g, 0.37 mmol), carbonitrile 10a (0.05 g, 0.34
mmol) and sodium carbonate (0.04 g, 0.37 mmol) in ethanol (2 mL) to give the title product
1
5c (0.09 g, 87%) as a black solid. m.p. 214-216 °C. H NMR (400 MHz; d6-DMSO) 2.12-
2.20 (2H, m, H-6), 2.99-3.01 (4H, m, H-5 and H-7), 7.24-7.31 (2H, m, H-4' and H-5'), 7.39
(2H, br s, NH2), 7.70-7.72 (1H, m, H-6'), 8.08 (1H, s, H-2'), 8.31 (1H, s, H-4), 9.51 (1H, br s,
13
NH); C NMR (100 MHz; d6-DMSO) 23.2 (C-6), 29.6 (C-5), 33.6 (C-7), 95.7 (C-2), 119.4
(C-2' and C-6'), 121.2 (C-3a), 123.0 (C-3'), 126.1 (C-4), 130.3 (C-5'), 130.7 (C-3), 133.4 (C-
4'), 140.3 (C-4a), 140.8 (C-1'), 147.6 (C-3'), 157.3 (C-8a), 164.1 (C=O), 168.1 (C-7a); IR:
υmax (film)/cm-1: 3430, 3329, 2929, 1677, 1585, 1451, 1395, 1259, 1078; m/z (ESI+): 412
(81BrMNa+, 28%), 410 (79BrMNa+, 26%), 393 (MNa+-Br, 100%); HRMS (ESI+) found
(81BrMNa+): 411.9920, C17H1481BrN3NaOS requires 411.9913. Found (79BrMNa+): 409.9939,
C17H1479BrN3NaOS requires 409.9933.
4.1.2.4
3-Amino-N-(3'-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-
e]pyridine-2-carboxamide 5d. The reaction was carried out according to general procedure C
using 2-bromo-N-(3'-(trifluoromethyl)phenyl)acetamide 12j (0.09 g, 0.31 mmol), carbonitrile
10a (0.05 g, 0.28 mmol) and sodium carbonate (0.03 g, 0.31 mmol) in methanol (2 mL) to
1
give the title product 5d (1.0 g, 100%) as a black solid. m.p. 215-216 °C. H NMR (400
MHz; d6-DMSO) 2.12-2.20 (2H, m, H-6), 2.99-3.06 (4H, m, H-5 and H-7), 7.40-7.42 (3H, m,
H-4' and NH2), 7.55-7.59 (2H, m, H-5' and H-6'), 8.23 (1H, s, H-4), 8.32 (1H, s, H-2'), 9.67
(1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 23.2 (C-6), 29.6 (C-5), 33.6 (C-7), 95.0 (C-
3
3
1
2), 116.8 (q, JF/C 3.6 Hz, C-2'), 119.4 (q, JF/C 3.8 Hz, C-4'), 124.0 (C-3a), 124.1 (q, JF/C
2
274.6 Hz, CF3), 124.2 (C-6'), 126.2 (C-5'), 129.6 (q, JF/C 39.0 Hz, C-3'), 129.9 (C-3), 133.4
(C-4), 140.0 (C-4a), 147.8 (C-1'), 157.3 (C-8a), 164.3 (C=O), 168.1 (C-7a); IR: υmax
(film)/cm-1: 3433, 3332, 2953, 1686, 1595, 1556, 1496, 1260, 1164, 1115; m/z (ESI+): 400
11

(MNa+, 27%), 378 (MH+, 100%); HRMS (ESI+) found (MH+): 378.0895, C18H15F3N3OS
requires 378.0882.
4.1.2.5 3-Amino-N-(3'-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-
2-carboxamide 5e. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-methoxyphenyl)acetamide 12k (0.09 g, 0.37 mmol), carbonitrile 10a (0.06 g,
0.34 mmol) and sodium carbonate (0.04 g, 0.37 mmol) in methanol (2 mL) to give the title
1
product 5e (0.11 g, 91%) as a black solid. m.p. 215-218 °C. H NMR (400 MHz; d6-DMSO)
2.11-2.19 (2H, m, H-6), 2.99-3.06 (4H, m, H-5 and H-7), 3.76 (3H, s, OCH3), 6.64-6.67 (1H,
dd, J = 8.6, 2.4 Hz, H-4'), 7.22 (1H, t, J = 8.1 Hz, H-5'), 7.32-7.35 (3H, m, NH2 and H-6'),
13
7.40 (1H, s, H-2'), 8.30 (1H, s, H-4), 9.31 (1H, br s, NH); C NMR (100 MHz; d6-DMSO)
23.2 (C-6), 29.6 (C-5), 33.6 (C-7), 54.9 (OCH3), 95.7 (C-2), 106.5 (C-2'), 108.9 (C-4'), 113.1
(C-5'), 124.1 (C-3), 126.1 (C-4), 129.1 (C-6'), 133.3 (C-4a), 140.3 (C-1'), 147.1 (C-3a), 157.2
(C-8a), 159.3 (C-3'), 164.0 (C=O), 167.8 (C-7a); IR: υmax (film)/cm-1: 3435, 3327, 3000,
2951, 2827, 1671, 1590, 1527, 1448, 1255, 1160; m/z (ESI+): 362 (MNa+, 100%), 340 (MH+,
46%); HRMS (ESI+) found (MNa+): 362.0934, C18H17N3NaO2S requires 362.0934.
4.1.2.6 3-Amino-N-(3'-nitrophenyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-
carboxamide 5f. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-nitrophenyl)acetamide 12l (0.10 g, 0.37 mmol), carbonitrile 10a (0.06 g, 0.34
mmol) and sodium carbonate (0.04 g, 0.37 mmol) in methanol (2 mL) to give the title
1
product 5f (0.09 g, 75%) as a black solid. m.p. > 230 °C. H NMR (400 MHz; d6-DMSO)
2.12-2.20 (2H, m, H-6), 2.99-3.06 (4H, m , H-5 and H-7), 7.47 (2H, br s, NH2), 7.62 (1H, t, J
= 8.2 Hz, H-5'), 7.91-7.94 (1H, dd, J = 8.1, 1.9 Hz, H-6'), 8.16 (1H, d, J = 7.8 Hz, H-4'), 8.34
13
(1H, s, H-4), 8.80 (1H, s, H-2'), 9.84 (1H, br s, NH); C NMR (100 MHz; d6-DMSO) 23.2
(C-6), 29.6 (C-5), 33.6 (C-7), 94.8 (C-2), 114.7 (C-2'), 117.5 (C-6'), 123.2 (C-3a), 126.2 (C-
4), 126.5 (C-4'), 129.7 (C-5'), 133.4 (C-3), 138.5 (C-4a), 140.5 (C-1'), 148.1 (C-3'), 157.4 (C-
8a), 164.3 (C=O), 168.3 (C-7a); IR: υmax (film)/cm-1: 3424, 3328, 2951, 1683, 1582, 1498,
1349, 1290; m/z (ESI+): 377 (MNa+, 30%), 355 (MNa+-NO2, 100%); HRMS (ESI+) found
(MNa+): 377.0683, C17H14N4NaO3S requires 377.0679.
4.1.2.7
3-Amino-N-(3'-chloro-2'-methylphenyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-
e]pyridine-2-carboxamide 5g. The reaction was carried out according to general procedure C
using 2-bromo-N-(3'-chloro-2'-methylphenyl)acetamide 12n (0.1 g, 0.37 mmol), carbonitrile
12

10a (0.06 g, 0.34 mmol) and sodium carbonate (0.04 g, 0.37 mmol) in methanol (2 mL) to
1
give the title product 5g (0.03 g, 30%) as a black solid. m.p. 216-217 °C. H NMR (400
MHz; d6-DMSO) 2.14-2.20 (2H, m, H-6), 2.25 (3H, s, CH3), 2.99-3.05 (4H, m, H-5 and H-7),
7.18-7.26 (3H, m, NH2 and H-5'), 7.29-7.31 (1H, m, H-6'), 7.34-7.38 (1H, m, H-4'), 8.29 (1H,
13
s, H-4), 9.32 (1H, br s, NH); C NMR (100 MHz; d6-DMSO) 15.4 (CH3), 23.2 (C-6), 29.6
(C-5), 33.6 (C-7), 95.6 (C-2), 109.7(C-6'), 124.2 (3a), 126.1 (C-4), 126.2 (C-4'), 126.5 (C-6'),
126.7 (C-5'), 132.5 (C-3), 133.2 (C-4a), 133.6 (C-2'), 137.6 (C-3'), 146.8 (C-1'), 164.2 (C-8a),
167.8 (C=O), 174.9 (C-7a); IR: υmax (film)/cm-1: 3380, 3291, 2970, 1708, 1639, 1607, 1459,
1426, 1254; m/z (ESI+): 382 (37ClMNa+, 38%), 380 (35ClMNa+, 100%); HRMS (ESI+) found
(37ClMNa+): 382.0547, C18H1637ClN3NaOS requires 382.0569. Found (35ClMNa+): 380.0580,
C18H1635ClN3NaOS requires 380.0595.
4.1.2.8
3-Amino-N-(3'-bromo-2'-methylphenyl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-
e]pyridine-2-carboxamide 5h. The reaction was carried out according to general procedure C
using 2-bromo-N-(3'-bromo-2'-methylphenyl)acetamide 12o (0.1 g, 0.31 mmol), carbonitrile
10a (0.05 g, 0.28 mmol) and sodium carbonate (0.03 g, 0.31 mmol) in methanol (2 mL) to
1
give the title product 5h (0.84 g, 74%) as a black solid. m.p. > 230 °C. H NMR (400 MHz;
d6-DMSO) 2.10-2.20 (2H, m, H-6), 2.28 (3H, s, CH3), 2.99-3.05 (4H, m, H-5 and H-7), 7.11-
7.19 (1H, m, H-5'), 7.23 (2H, s, NH2), 7.31-7.33 (1H, m, H-4'), 7.51-7.53 (1H, m, H-6'), 8.29
13
(1H, s, H-4), 9.34 (1H, br s, NH); C NMR (100 MHz; d6-DMSO) 18.5 (CH3), 23.2 (C-6),
29.6 (C-5), 33.6 (C-7), 95.5 (C-2), 124.2(C-2'), 124.5 (C-3a), 126.1 (C-4), 126.9 (C-4'), 127.2
(C-5'), 129.8 (C-6'), 133.3 (C-3), 134.2 (C-3'), 138.0 (C-4a), 146.9 (C-1'), 157.2 (C-8a), 164.2
(C=O), 167.8 (C-7a); IR: υmax (film)/cm-1: 3402, 3294, 2945, 1695, 1605, 1545, 1432, 1254;
m/z (ESI+): 426 (81BrMNa+, 64%), 424 (79BrMNa+, 63%), 313 (MNa+-Br, 100%); HRMS
(ESI+) found (81BrMNa+): 426.0076, C18H1681BrN3NaOS requires 426.0070. Found
(79BrMNa+): 424.0091, C18H1679BrN3NaOS requires 426.0090.
4.1.2.9 3-Amino-N-(naphthalen-1'-yl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-
carboxamide 5i. The reaction was carried out according to general procedure C using 2-
bromo-N-(naphthalene-1'-yl)acetamide 12u (0.1 g, 0.31 mmol), carbonitrile 10a (0.05 g, 0.28
mmol) and sodium carbonate (0.03 g, 0.31 mmol) in methanol (2 mL) to give the title
1
product 5i (0.84 g, 74%) as a black solid. m.p. 213-215 °C. H NMR (400 MHz; d6-DMSO)
2.14-2.21 (2H, m, H-6), 3.01-3.07 (4H, m, H-5 and H-7), 7.23 (2H, s, NH2), 7.54-7.57 (4H,
m, H-3', H-4', H-7' and H-8'), 7.93-7.99 (3H, m, H-2', H-5' and H-6'), 8.30 (1H, s, H-4), 9.65
13

(1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 23.2 (C-6), 29.6 (C-5), 33.6 (C-7), 96.0 (C-
2), 123.5 (C-2'), 124.3 (C-3a), 125.5, 125.8, 125.9, 126.2 (C-3', C-4', C-7' and C-8'), 126.1
(C-4), 128.0 and 128.1 (C-1a' and C-5a'), 133.2 (C-3), 133.7 and 134.0 (C-5' and C-6'), 136.8
(C-4a), 146.7 (C-1'), 157.3 (C-8a), 164.9 (C=O), 167.7 (C-7a); IR: υmax (film)/cm-1: 3295,
2936, 1713, 1605, 1525, 1501; m/z (ESI+): 382 (MNa+, 100%), 360 (MH+, 31%); HRMS
(ESI+) found (MNa+): 382.0991, C21H17N3NaOS requires 382.0985.
4.1.2.10 3-Amino-N-(naphthalen-2'-yl)-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-
2-carboxamide 5j. The reaction was carried out according to general procedure C using 2-
bromo-N-(naphthalene-2'-yl)acetamide 12v (0.1 g, 0.31 mmol), carbonitrile 10a (0.05 g, 0.28
mmol) and sodium carbonate (0.03 g, 0.31 mmol) in methanol (2 mL) to give the title
1
product 5j (0.84 g, 74%) as a black solid. m.p. > 230 °C. H NMR (400 MHz; d6-DMSO)
2.15-2.20 (2H, m, H-6), 3.00-3.06 (4H, m, H-5 and H-7), 7.43-7.51 (4H, m, H-5', H-8' and
NH2), 7.83-7.94 (4H, m, H-3', H-4', H-6' and H-7'), 8.32 (1H, s, H-4), 8.35 (1H, s, H-2'), 9.57
(1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 23.2 (C-6), 29.6 (C-5), 33.6 (C-7), 95.7 (C-
2), 117.0 (C-2'), 121.6 (C-8'), 124.1 (C-5'), 124.6 (C-3a), 126.1 (C-4), 126.2 (C-3'), 127.3 (C-
4'), 127.4 (C-6'), 127.8 (C-6a'), 129.8 (C-7'), 133.2 (C-2a'), 133.3 (C-3), 136.8 (C-4a), 147.2
(C-1'), 157.3 (C-8a), 164.2 (C=O), 167.9 (C-7a); IR: υmax (film)/cm-1: 3424, 3358, 3306,
1713, 1603, 1542, 1499; m/z (ESI+): 382 (MNa+, 45%), 360 (MH+, 100%); HRMS (ESI+)
found (MH+): 360.1165, C21H18N3OS requires 360.1165. The spectroscopic data was
consistent with literature values [10].
4.1.2.11 3-Amino-N-phenyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide 6a. The
reaction was carried out according to general procedure C using 2-bromo-N-phenylacetamide
12a (105 mg, 0.49 mmol), carbonitrile 10b (93 mg, 0.49 mmol) and anhydrous sodium
carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml) to give the title compound 6a (136
1
mg, 86%) as a green solid. m.p. > 230 ºC. lit. m.p. 267 ºC [16]. H NMR (300 MHz, d6-
DMSO) 1.76-1.89 (4H, m, H-6 and H-7), 2.88 (2H, t, J = 6.3 Hz, H-5), 2.95 (2H, t, J = 6.2
Hz, H-8), 7.06 (1H, tt, J = 7.2, 1.2 Hz, H-4'), 7.28-7.34 (4H, m, NH2, H-3' and H-5'), 7.66-
13
7.70 (2H, m, H-2' and H-6'), 8.18 (1H, s, H-4), 9.33 (1H, s, NH); C NMR (75 MHz, d6-
DMSO) 22.3 and 22.4 (C-6 and C-7), 28.3 (C-5), 32.5 (C-8), 95.8 (C-2), 121.1 (C-2' and C-
6'), 123.3 (C-4'), 124.4 (C-3a), 128.3 (C-8a), 128.3 (C-3' and C-5'), 130.8 (C-4), 139.0 (C-1'),
146.8 (C-3), 155.9 (C-9a), 159.1 (C-4a), 164.1 (C=O); IR: υmax(ATR)/cm-1: 3448, 3333,
3180, 2943, 1607, 1590, 1522, 1495, 1318, 1166. m/z (ESI+): 346 (MNa+, 37%), 324 (MH+,
14

100%); HRMS (ESI+) found (MH+): 324.1161, C18H18N3OS requires 324.1165. Found
1
(MNa+): 346.0977, C18H17N3NaOS requires 346.0985. The H NMR data was in agreement
with the literature values [16].
4.1.2.12
3-Amino-N-(2'-fluorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6b. The reaction was carried out according to general procedure C using 2-
bromo-N-(2'-fluorophenyl)acetamide 12b (114 mg, 0.49 mmol), carbonitrile 10b (93 mg,
0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml)
to give the title compound 6b (85 mg, 51%) as a green solid. m.p. > 230 ºC. lit. m.p. 280-285
ºC [16]. 1H NMR (400 MHz, d6-DMSO) 1.80-1.91 (4H, m, H-6 and H-7), 2.88 (2H, t, J = 6.4
Hz, H-5), 2.95 (2H, t, J = 6.4 Hz, H-8), 7.17-7.28 (5H, m, H-3', H-4', H-5' and NH2), 7.51
(1H, t, J = 7.8 Hz, H-6'), 8.18 (1H, s, H-4), 9.22 (1H, s, NH); 13C NMR (100 MHz, d6-
DMSO) 22.3 and 22.4 (C-6 and C-7), 28.3 (C-5), 32.5 (C-8), 95.5 (C-2), 115.6 (d, 2JF/C 19.9
Hz, C-3'), 124.1 (d, 4JF/C 3.1 Hz, C-5'), 124.4 (C-3a), 125.8 (d, 2JF/C 12.3 Hz, C-1'), 126.7 (d,
3JF/C 7.7 Hz, C-4'), 127.5 (C-6'), 128.3 (C-4a), 130.9 (C-4), 146.8 (C-3), 156.2 (d, 1JF/C 245.4
Hz, C-2'), 156.0 (C-9a), 159.1 (C-8a), 163.9 (C=O); IR: υmax(ATR)/cm-1: 3411, 3275, 2938,
1645, 1606, 1507, 1447, 1319, 1244, 1186; m/z (ESI+): 342 (MH+, 100%); HRMS (ESI+)
1
found (MH+): 342.1081, C18H17FN3OS requires 342.1071. The H NMR data was in
agreement with the literature values [16].
4.1.2.13
3-Amino-N-(2'-chlorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6c. The reaction was carried out according to general procedure C using 2-
bromo-N-(2'-chlorophenyl)acetamide 12c (261 mg, 1.10 mmol), carbonitrile 10b (200 mg,
1.10 mmol) and anhydrous sodium carbonate (0.12 g, 1.1 mmol) in absolute ethanol (4 ml) to
1
give the title compound 6c (292 mg, 78%) as a brown solid, m.p. 228-229 ºC. H NMR (400
MHz, d6-DMSO) 1.77-1.91 (4H, m, H-6 and H-7), 2.88 (2H, t, J = 6.2 Hz, H-5), 2.95 (2H, t,
J = 6.2 Hz, H-8), 7.22-7.27 (3H, m, H-4' and NH2), 7.36 (1H, dt, J = 7.8, 1.2 Hz, H-5'), 7.53
(1H, dd, J = 8.0, 1.2 Hz, H-3'), 7.66 (1H, dd, J = 7.9, 1.1 Hz, H-6'), 8.18 (1H, s, H-4), 9.05
(1H, s, NH); 13C NMR (100 MHz, d6-DMSO) 22.3 and 22.4 (C-6 and C-7), 28.3 (C-5), 32.5
(C-8), 95.7 (C-2), 124.5 (C-3a), 126.7 (C-4'), 127.4 and 127.5 (C-5' and C-6'), 128.4 (C-2'),
128.7 (C-4a), 129.4 (C-3'), 130.9 (C-4), 135.2 (C-1'), 146.8 (C-3), 155.9 (C-9a), 159.2 (C-8a),
163.8 (C=O); IR: υmax(ATR)/cm-1: 3404, 3283, 2928, 1645, 1585, 1504, 1432, 1303, 1187,
746, 691; m/z (ESI+): 360(37ClMH+, 38%), 358 (35ClMH+, 100%); HRMS (ESI+) found
15

(37ClMH+): 360.0759, C18H1737ClN3OS requires 360.0750. Found (35ClMH+): 358.0788,
C18H1735ClN3OS requires 358.0775.
4.1.2.14
3-Amino-N-(2'-methylphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6d. The reaction was carried out according to general procedure C using 2-
bromo-N-(o-tolyl)acetamide 12d (112 mg, 0.49 mmol), carbonitrile 10b (93 mg, 0.49 mmol)
and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml) to give the
1
title compound 6d (130 mg, 79%) as a brown solid. m.p. > 250 ºC. H NMR (400 MHz, d6-
DMSO) 1.79-1.89 (4H, m, H-6 and H-7), 2.22 (3H, s, CH3), 2.88 (2H, t, J = 6.4 Hz, H-5),
2.95 (2H, t, J = 6.4 Hz, H-8), 7.12-7.21 (4H, m, H-5', H-4' and NH2), 7.25 (1H, d, J = 7.2 Hz,
13
H-3'), 7.31 (1H, dd, J = 7.6, 1.2 Hz, H-6'), 8.16 (1H, s, H-4), 9.03 (1H, s, NH); C NMR
(100 MHz, d6-DMSO) 17.9 (CH3), 22.3 and 22.5 (C-6 and C-7), 28.3 (C-5), 32.5 (C-8), 96.2
(C-2), 124.5 (C-3a), 125.7 (C-5'), 125.9 (C-4'), 126.8 (C-6'), 128.2 (C-4a), 130.1 (C-3'), 130.7
(C-4), 133.9 (C-2'), 136.5 (C-1'), 146.2 (C-3), 155.9 (C-9a), 158.8 (C-8a), 164.0 (C=O); IR:
υmax(ATR)/cm-1: 3412, 3281, 2928, 1642, 1583, 1506, 1446, 1241, 1188; m/z (ESI+): 338
(MH+, 100%); HRMS (ESI+) found (MH+): 338.1332, C19H20N3OS requires 338.1322.
4.1.2.15
3-Amino-N-(2'-ethylphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6e. The reaction was carried out according to general procedure C using 2-
bromo-N-(2'-ethylphenyl)acetamide 12e (135 mg, 0.56 mmol), carbonitrile 10b (100 mg,
0.56 mmol) and anhydrous sodium carbonate (63 mg, 0.59 mmol) in absolute ethanol (2 ml)
1
to give the title compound 6e (159 mg, 81%) as a brown solid. m.p. 177-180 ºC. H
NMR (400 MHz, d6-DMSO) 1.14 (3H, dt, J = 7.6, 2.4 Hz, CH2CH3), 1.80-1.88 (4H, m, H-6
and H-7), 2.61 (2H, dq, J = 7.6, 2.0 Hz, CH2CH3), 2.88-2.89 (2H, m, H-5), 2.94-2.95 (2H, m,
H-8), 7.16 (2H, br s, NH2), 7.19-7.28 (4H, m, H-3', H-4', H-5' and H-6'), 8.15 (1H, s, H-4),
9.02 (1H, br s, NH); 13C NMR (100 MHz, d6-DMSO) 14.0 (CH2CH3), 22.3 and 22.5 (C-6 and
C-7), 24.0 (CH2CH3), 28.3 (C-5), 32.5 (C-8), 96.1 (C-2), 124.6 (C-3a), 125.9 (C-6'), 126.2
and 127.7 (C-4' and C-5'), 128.2 (C-4a), 128.3 (C-3'), 130.7 (C-4), 135.8 (C-1'), 139.9 (C-2'),
146.2 (C-3), 155.9 (C-9a), 158.8 (C-8a), 164.4 (C=O); IR: υmax(ATR)/cm-1: 3419, 3354,
2957, 1677, 1583, 1528, 1436, 1262, 1145; m/z (ESI+): 352 (MH+, 100%), 374 (MNa+, 76%);
HRMS (ESI+) found (MH+): 352.1470, C20H22N3OS requires 352.1478. Found (MNa+):
374.1288, C20H21N3NaOS requires 374.1298.
16

4.1.2.16 3-Amino-N-(2'-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6f. The reaction was carried out according to general procedure C using 2-
bromo-N-(2'-(trifluoromethyl)phenyl)acetamide 12f (138 mg, 0.49 mmol), carbonitrile 10b
(93 mg, 0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol
1
(2 ml) to give the title compound 6f (124 mg, 65%) as a brown solid. m.p. 188-190 ºC. H
NMR (400 MHz, d6-DMSO) 1.78-1.91 (4H, m, H-6 and H-7), 2.88 (2H, t, J = 6.4 Hz, H-5),
2.95 (2H, t, J = 6.4 Hz, H-8), 7.21 (2H, s, NH2), 7.49 (1H, t, J = 7.6 Hz, H-4'), 7.58 (1H, d, J
= 7.6 Hz, H-6'), 7.71 (1H, t, J = 8.0 Hz, H-5'), 7.76 (1H, d, J = 8.0 Hz, H-3'), 8.18 (1H, s, H-
4), 9.12 (1H, s, NH); 13C NMR (100 MHz, d6-DMSO) 22.2 and 22.4 (C-6 and C-7), 28.3 (C-
1
2
5), 32.5 (C-8), 95.4 (C-2), 123.7 (q, JF/C 271.9 Hz, CF3), 124.4 (C-3a), 125.7 (q, JF/C 28.9
Hz, C-2'), 126.4 (q, 3JF/C 4.8 Hz, C-3'), 126.8 (C-4'), 128.3 (C-4a), 130.6 (C-6'), 130.9 (C-4),
132.9 (C-5'), 135.9 (C-1'), 146.8 (C-3), 155.9 (C-9a), 159.1 (C-8a), 164.6 (C=O); IR:
υmax(ATR)/cm-1: 3435, 3305, 2931, 1653, 1588, 1525, 1453, 1290, 1167, 1106; m/z (ESI+):
392 (MH+, 100%); HRMS (ESI+) found (MH+): 392.1052, C19H17F3N3OS requires 392.1039.
4.1.2.17
3-Amino-N-(3'-fluorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6g. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-fluorophenyl)acetamide 12g (114 mg, 0.49 mmol), carbonitrile 10b (93 mg,
0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml)
1
to give the title compound 6g (110 mg, 66%) as a green solid. m.p. 244-247 ºC. H
NMR (400 MHz, d6-DMSO) 1.78-1.90 (4H, m, H-6 and H-7), 2.87 (2H, t, J = 6.4 Hz, H-5),
2.95 (2H, t, J = 6.4 Hz, H-8), 6.87 (1H, dt, J = 8.4, 2.4 Hz, H-4'), 7.30-7.36 (3H, m, H-5' and
NH2), 7.52 (1H, d, J = 8.8 Hz, H-6'), 7.68 (1H, dt, J = 12.0, 2.0 Hz, H-2'), 8.19 (1H, s, H-4),
9.51 (1H, s, NH); 13C NMR (100 MHz, d6-DMSO) 22.3 and 22.4 (C-6 and C-7), 28.3 (C-5),
2
2
32.5 (C-8), 95.2 (C-2), 107.4 (d, JF/C 26.0 Hz C-2'), 109.6 (d, JF/C 20.9 Hz C-4'), 116.4 (d,
4JF/C 1.9 Hz C-6'), 124.3 (C-3a), 128.4 (C-4a), 129.9 (d, 3JF/C 9.4 Hz C-5'), 130.9 (C-4), 141.0
3
1
(d, JF/C 11.0 Hz C-1'), 147.4 (C-3), 156.0 (C-9a), 160.1 (d, JF/C 143.1 Hz C-3'), 163.2
(C=O); IR: υmax(ATR)/cm-1: 3442, 3331, 2957, 1599, 1525, 1484, 1433, 1312, 1246, 1166;
m/z (ESI+): 342 (MH+, 100%); HRMS (ESI+) found (MH+): 342.1073, C18H17FN3OS requires
342.1071.
4.1.2.18
3-Amino-N-(3'-chlorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6h. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-chlorophenyl)acetamide 12h (122 mg, 0.49 mmol), carbonitrile 10b (93 mg,
17

0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml)
1
to give the title compound 6h (90 mg, 51%) as a dark brown solid. m.p. > 250 ºC. H
NMR (300 MHz, d6-DMSO) 1.80-1.88 (4H, m, H-6 and H-7), 2.87 (2H, t, J = 6.3 Hz, H-5),
2.95 (2H, t, J = 6.0 Hz, H-8), 7.10 (1H, d, J = 7.8 Hz, H-4'), 7.30-7.37 (3H, m, H-5' and
NH2), 7.64 (1H, d, J = 8.4 Hz, H-6'), 7.91 (1H, t, J = 2.1 Hz, H-2'), 8.20 (1H, s, H-4), 9.49
(1H, br s, NH); 13C NMR (75 MHz, d6-DMSO) 22.2 and 22.4 (C-6 and C-7), 28.3 (C-5), 32.5
(C-8), 95.1 (C-2), 119.1 (C-6'), 120.2 (C-2'), 122.8 (C-4'), 124.3 (C-3a), 128.3 (C-8a), 130.0
(C-5'), 130.9 (C-4), 132.7 (C-3'), 140.7 (C-1'), 147.4 (C-3), 156.0 (C-9a), 159.3 (C-4a), 164.2
(C=O); IR: υmax(ATR)/cm-1: 3432, 3328, 2957, 1607, 1584, 1518, 1417, 1251, 1166; m/z
(ESI+): 360 (37ClMH+, 39%), 358 (35ClMH+, 100%); HRMS (ESI+) found (37ClMH+):
360.0756, C18H1737ClN3OS requires 360.0750. Found (35ClMH+): 358.0786, C18H1735ClN3OS
requires 358.0775.
4.1.2.19
3-Amino-N-(3'-bromophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6i. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-bromophenyl)acetamide 12i (143 mg, 0.49 mmol), carbonitrile 10b (93 mg, 0.49
mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml) to
1
give the title compound 6i (0.114 mg, 58%) as an orange solid. m.p. 244-245 ºC. H
NMR (400 MHz, d6-DMSO) 1.79-1.89 (4H, m, H-6 and H-7), 2.87 (2H, t, J = 6.4 Hz, H-5),
2.95 (2H, t, J = 6.0 Hz, H-8), 7.24 (1H, dt, J = 8.0, 1.6 Hz, H-4'), 7.28 (1H, t, J = 8.0 Hz, H-
5'), 7.38 (2H, br s, NH2), 7.69 (1H, dt, J = 8.0, 1.6 Hz, H-6'), 8.05 (1H, t, J = 1.6 Hz, H-2'),
8.20 (1H, s, H-4), 9.48 (1H, s, NH); 13C NMR (100 MHz, d6-DMSO) 22.3 and 22.4 (C-6 and
C-7), 28.3 (C-5), 32.5 (C-8), 95.1 (C-2), 119.5 (C-6'), 121.2 (C-3'), 123.0 (C-2'), 124.3 (C-
3a), 125.7 (C-4'), 128.4 (C-4a), 130.3 (C-5'), 130.9 (C-4), 140.8 (C-1'), 147.5 (C-3), 156.0 (C-
9a), 159.4 (C-8a), 164.2 (C=O); IR: υmax(ATR)/cm-1: 3432, 3328, 2923, 1606, 1581, 1515,
1471, 1291, 1163; m/z (ESI+): 404 (81BrMH+, 100%), 402 (79BrMH+, 96%); HRMS (ESI+)
found (81BrMH+): 404.0244, C18H1781BrN3OS requires 404.0251. Found (79BrMH+):
402.0264, C18H1779BrN3OS requires 402.0270.
4.1.2.20 3-Amino-N-(3'-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6j. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-(trifluoromethyl)phenyl)acetamide 12j (138 mg, 0.49 mmol), carbonitrile 10b
(93 mg, 0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol
1
(2 ml) to give the title compound 6j (43 mg, 22%) as a yellow solid. m.p. 193-194 ºC. H
18

NMR (300 MHz, (CD3)2CO) 1.79-1.95 (4H, m, H-6 and H-7), 2.87-2.98 (4H, m, H-5 and H-
8), 7.09 (2H, br s, NH2), 7.40 (1H, dt, J = 7.7, 0.7 Hz, H-4'), 7.54 (1H, t, J = 7.9 Hz, H-5'),
7.99 (1H, dt, J = 8.8, 0.6 Hz, H-2'), 8.04 (1H, s, H-4), 8.27 (1H, s, H-6'), 8.87 (1H, br s, NH);
13C NMR (75 MHz, (CD3)2CO) 23.5 and 23.6 (C-6 and C-7), 29.5 (C-5), 33.7 (C-8), 97.3 (C-
3
3
5
2), 117.8 (q, JF/C 4.0 Hz, C-2'), 120.5 (q, JF/C 3.9 Hz, C-4'), 124.7 (q, JF/C 1.0 Hz, C-6'),
1
125.3 (q, JF/C 270.0 Hz, CF3), 125.4 (C-3a), 129.6 (C-4a), 130.3 (C-5'), 131.1 (C-4), 131.2
2
(q, JF/C 31.6 Hz, C-3'), 141.0 (C-1'), 148.5 (C-3), 157.4 (C-9a), 160.6 (C-8a), 165.4 (C=O);
IR: υmax(ATR)/cm-1: 3441, 3326, 2940, 1591, 1541, 1482, 1439, 1331, 1250, 1165; m/z
(ESI+): 392 (MH+, 100%), 381 (22%); HRMS (ESI+) found (MH+): 392.1033, C19H17F3N3OS
requires 392.1039.
4.1.2.21
3-Amino-N-(3'-nitrophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6k. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-nitrophenyl)acetamide 12l (127 mg, 0.49 mmol), carbonitrile 10b (93 mg, 0.49
mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml) to
1
give the title compound 6k (157 mg, 87%) as a brown solid. m.p. > 250 ºC. H NMR (400
MHz, d6-DMSO) 1.81-1.91 (4H, m, H-6 and H-7), 2.90 (2H, t, J = 6.4 Hz, H-5), 2.98 (2H, t,
J = 6.4 Hz, H-8), 7.48 (2H, br s, NH2), 7.63 (1H, t, J = 8.4 Hz, H-5'), 7.93 (1H, dd, J = 7.6,
1.6 Hz, H-4'), 8.16 (1H, dd, J = 8.0, 1.2 Hz, H-6'), 8.25 (1H, s, H-4), 8.80 (1H, t, J = 2.0 Hz,
13
H-2'), 9.83 (1H, br s, NH); C NMR (100 MHz, d6-DMSO) 22.2 and 22.4 (C-6 and C-7),
28.3 (C-5), 32.5 (C-8), 94.7 (C-2), 114.7 (C-2'), 117.5 (C-4'), 124.2 (C-3a), 126.6 (C-6'),
128.4 (C-4a), 129.7 (C-5'), 131.0 (C-4), 140.5 (C-1'), 147.8 and 147.9 (C-3 and C-3'), 156.1
(C-9a), 159.5 (C-8a), 164.4 (C=O); IR: υmax(ATR)/cm-1: 3388, 2948, 1649, 1584, 1496, 1427,
1523, 1344, 1250, 1062; m/z (ESI+): 391 (MNa+, 64%), 381 (58%), 369 (MH+, 100%);
HRMS (ESI+) found (MNa+): 391.0825, C18H16N4NaO3S requires 391.0835. Found (MH+):
369.1007, C18H17N4O3S requires 369.1016.
4.1.2.22
3-Amino-N-(4'-methoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6l. The reaction was carried out according to general procedure C using 2-
bromo-N-(4'-methoxyphenyl)acetamide 12m (120 mg, 0.49 mmol), carbonitrile 10b (93 mg,
0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml)
1
to give the title compound 6l (10 mg, 6%) as a yellow solid. m.p. > 250 ºC. H NMR (400
MHz, d6-DMSO) 1.79-1.91 (4H, H-6 and H-7), 2.87 (2H, t, J = 6.3 Hz, H-5), 2.95 (2H, t, J =
6.3 Hz, H-8), 3.74 (3H, s, CH3), 6.89 (2H, d, J = 9.0 Hz, H-3' and H-5'), 7.23 (2H, br s, NH2),
19

7.56 (2H, d, J = 9.0 Hz, H-2' and H-6'), 8.16 (1H, s, H-4), 9.23 (1H, s, NH); 13C NMR (100
MHz, d6-DMSO) 22.3 and 22.5 (C-6 and C-7), 28.3 (C-5), 32.5 (C-8), 55.1 (CH3), 95.6 (C-
2), 113.5 (C-3' and C-5'), 122.9 (C-2' and C-6'), 124.5 (C-3a), 128.2 (C-4a), 130.7 (C-4),
131.9 (C-1'), 146.4 (C-3), 155.4 (C-4'), 155.9 (C-9a), 159.0 (C-8a), 163.9 (C=O); IR:
υmax(ATR)/cm-1: 3421, 3316, 2945, 1597, 1509, 1497, 1390, 1315, 1235, 1041; m/z (ESI+):
376 (MNa+, 100%), 354 (MH+, 21%); HRMS (ESI+) found (MNa+): 376.1083,
C19H19N3NaO2S requires 376.1090. Found (MH+): 354.1258, C19H20N3O2S requires
354.1271.
4.1.2.23 3-Amino-N-(3'-chloro-2'-methylphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6m. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-chloro-2'-methylphenyl)acetamide 12n (129 mg, 0.49 mmol), carbonitrile 10b
(93 mg, 0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol
1
(2 ml) to give the title compound 6m (34 mg, 19%) as a yellow solid. m.p. > 250 ºC. H
NMR (400 MHz, d6-DMSO) 1.79-1.89 (4H, m, H-6 and H-7), 2.23 (3H, s, CH3), 2.88 (2H, t,
J = 6.4 Hz, H-5), 2.95 (2H, t, J = 6.4 Hz, H-8), 7.20-7.28 (4H, m, H-4' or H-6', H-5' and
13
NH2), 7.34 (1H, d, J = 8.0 Hz, H-4' or H-6'), 8.17 (1H, s, H-4), 9.30 (1H, s, NH); C NMR
(100 MHz, d6-DMSO) 15.5 (CH3), 22.3 and 22.4 (C-6 and C-7), 28.3 (C-5), 32.5 (C-8), 95.5
(C-2), 124.4 (C-3a), 126.2 and 126.7 (C-4' and C-6'), 126.5 (C-5'), 128.3 (C-4a), 130.8 (C-4),
132.5 (C-2'), 133.6 (C-3'), 138.2 (C-1'), 146.7 (C-3), 156.0 (C-9a), 159.1 (C-8a), 164.2
(C=O); IR: υmax(ATR)/cm-1: 3421, 3315, 2931, 1590, 1427, 1294, 1012; m/z (ESI+): 374
(37ClMH+, 37%), 372 (35ClMH+, 100%); HRMS (ESI+) found (37ClMH+): 374.0893,
C19H1937ClN3OS requires 374.0907. Found (35ClMH+): 372.0923, C19H1935ClN3OS requires
372.0932.
4.1.2.24 3-Amino-N-(3'-bromo-2'-methylphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6n. The reaction was carried out according to general procedure C using 2-
bromo-N-(3'-bromo-2'-methylphenyl)acetamide 12o (171 mg, 0.56 mmol), carbonitrile 10b
(100 mg, 0.56 mmol) and anhydrous sodium carbonate (63 mg, 0.59 mmol) in absolute
ethanol (2 ml) to give the title compound 6n (176 mg, 76%) as a brown solid. m.p. > 230 ºC.
1H NMR (400 MHz, d6-DMSO) 1.79-1.89 (4H, m, H-6 and H-7), 2.26 (3H, s, CH3), 2.87
(2H, t, J = 6.4 Hz, H-5), 2.95 (2H, t, J = 6.4 Hz, H-8), 7.15 (1H, t, J = 8.0 Hz, H-5'), 7.21
(2H, br s, NH2), 7.30 (1H, d, J = 8.0 Hz, H-4'), 7.50 (1H, d, J = 8.0 Hz, H-6'), 8.17 (1H, s, H-
4), 9.33 (1H, br s, NH); 13C NMR (100 MHz, d6-DMSO) 18.5 (CH3), 22.3 and 22.4 (C-6 and
20

C-7), 28.3 (C-5), 32.5 (C-8), 95.5 (C-2), 124.4 (C-3'), 124.5 (C-3a), 126.9 (C-4'), 127.2 (C-
5'), 128.2 (C-4a), 129.8 (C-6'), 130.8 (C-4), 134.2 (C-2'), 138.1 (C-1'), 146.7 (C-3), 156.0 (C-
9a), 159.0 (C-8a), 164.2 (C=O); IR: υmax(ATR)/cm-1: 3314, 3207, 2933, 1614, 1588, 1504,
1428, 1296, 1162; m/z (ESI+): 440 (81BrMNa+, 38%), 438 (79BrMNa+, 38%), 418 (81BrMH+,
26%), 416 (79BrMH+, 26%); HRMS (ESI+) found (81BrMNa+): 440.0208, C19H1881BrN3NaOS
requires 440.0227. Found (79BrMNa+): 438.0232, C19H1879BrN3NaOS requires 438.0246.
Found (81BrMH+): 418.0391, C19H1981BrN3OS requires 418.0407. Found (79BrMH+):
416.0413, C19H1979BrN3OS requires 416.0427.
4.1.2.25
3-Amino-N-(2',3'-dimethylphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6o. The reaction was carried out according to general procedure C using 2-
bromo-N-(2',3'-dimethylphenyl)acetamide 12p (119 mg, 0.49 mmol), carbonitrile 10b (93
mg, 0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2
1
ml) to give the title compound 6o (132 mg, 77%) as a green solid. m.p. 249-250 ºC. H
NMR (400 MHz, d6-DMSO) 1.79-1.89 (4H, m, H-6 and H-7), 2.09 (3H, s, CH3), 2.27 (3H, s,
CH3), 2.88 (2H, t, J = 6.0 Hz, H-5), 2.95 (2H, t, J = 6.0 Hz, H-8), 7.05-7.11 (3H, m, H-4', H-
5' and H-6'), 7.15 (2H, s, NH2), 8.15 (1H, s, H-4), 9.09 (1H, s, NH); 13C NMR (100 MHz, d6-
DMSO) 14.3 (CH3), 20.1 (CH3), 22.3 and 22.5 (C-6 and C-7), 28.3 (C-5), 32.5 (C-8), 96.1
(C-2), 124.5 (C-3a), 125.0 and 125.1 (C-4' and C-5'), 127.3 (C-6'), 128.1 (C-4a), 130.7 (C-4),
133.0 (C-2'), 136.3 (C-1'), 136.8 (C-3'), 146.2 (C-3), 156.0 (C-9a), 158.8 (C-8a), 164.2
(C=O); IR: υmax(ATR)/cm-1: 3429, 3322, 2945, 1601, 1519, 1493, 1471, 1267, 1165; m/z
(ESI+): 352 (MH+, 100%); HRMS (ESI+) found (MH+): 352.1492, C20H22N3OS requires
352.1478.
4.1.2.26
3-Amino-N-(2',6'-diethylphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6p. The reaction was carried out according to general procedure C using 2-
bromo-N-(2'-ethylphenyl)acetamide 12q (135 mg, 0.56 mmol), carbonitrile 10b (100 mg,
0.56 mmol) and anhydrous sodium carbonate (63 mg, 0.59 mmol) in absolute ethanol (2 ml)
1
to give the title compound 6p (159 mg, 81%) as a brown solid. m.p. 111-114 ºC. H
NMR (400 MHz, d6-DMSO) 1.13 (6H, t, J = 7.6 Hz, CH2CH3), 1.82-1.90 (4H, m, H-6 and
H-7), 2.57 (4H, q, J = 7.6 Hz, CH2CH3), 2.90-2.91 (2H, m, H-5), 2.95-2.97 (2H, m, H-8),
7.13-7.15 (4H, m, H-3', H-5' and NH2), 7.21-7.24 (1H, m, H-4'), 8.16 (1H, s, H-4), 8.90 (1H,
13
br s, NH); C NMR (125 MHz, d6-DMSO) 14.4 (CH2CH3), 22.3 and 22.5 (C-6 and C-7),
24.5 (CH2CH3), 28.4 (C-5), 32.5 (C-8), 96.0 (C-2), 124.7 (C-3a), 125.8 (C-3' and C-5'), 127.2
21

(C-4'), 128.2 (C-4a), 130.7 (C-4), 134.4 (C-1'), 142.0 (C-2' and C-6'), 146.0 (C-3), 155.9 (C-
9a), 158.8 (C-8a), 164.6 (C=O); IR: υmax(ATR)/cm-1: 3411, 3298, 2936, 1682, 1598, 1504,
1448, 1253, 1185; m/z (ESI+): 402 (MNa+, 100%), 380 (MH+, 11%); HRMS (ESI+) found
(MNa+): 402.1598, C22H25N3NaOS requires 402.1611. Found (MH+): 380.1772, C22H26N3OS
requires 380.1791.
4.1.2.27 3-Amino-N-(2'-ethyl-6'-methylphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6q. The reaction was carried out according to general procedure C using 2-
bromo-N-(2'-ethyl-6'-methylphenyl)acetamide 12r (125 mg, 0.49 mmol), carbonitrile 10b (93
mg, 0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2
1
ml) to give the title compound 6q (118 mg, 66%) as a tan solid. m.p. 150-152 ºC. H
NMR (400 MHz, d6-DMSO) 1.11 (3H, t, J = 7.6 Hz, CH2CH3), 1.80-1.88 (4H, m, H-6 and
H-7), 2.18 (3H, s, CH3), 2.55 (2H, q, J = 7.6 Hz, CH2CH3), 2.88-2.95 (4H, m, H-5 and H-8),
7.07-7.14 (5H, m, H-3', H-4', H-5' and NH2), 8.14 (1H, s, H-4), 8.89 (1H, br s, NH); 13C
NMR (100 MHz, d6-DMSO) 14.4 (CH2CH3), 18.2 (CH3), 22.3 and 22.5 (C-6 and C-7), 24.4
(CH2CH3), 28.3 (C-5), 32.5 (C-8), 95.9 (C-2), 124.6 (C-3a), 125.8 (C-3'), 126.8 (C-4'), 127.5
(C-5'), 128.1 (C-4a), 130.6 (C-4), 134.9 (C-1'), 136.3 (C-6'), 141.8 (C-2'), 146.0 (C-3), 155.9
(C-9a), 158.7 (C-8a), 164.3 (C=O); IR: υmax(ATR)/cm-1: 3372, 3292, 2936, 1598, 1489, 1394,
1266, 1077; m/z (ESI+): 388 (MNa+, 69%), 366 (MH+, 100%); HRMS (ESI+) found (MNa+):
388.1446, C21H23N3NaOS requires 388.1454. Found (MH+): 366.1628, C21H24N3OS requires
366.1635.
4.1.2.28
3-Amino-N-(2',6'-dichlorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6r. The reaction was carried out according to general procedure C using 2-
bromo-N-(2',6'-dichlorophenyl)acetamide 12s (139 mg, 0.49 mmol), carbonitrile 10b (93 mg,
0.49 mmol) and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml)
to give the title compound 6r (161 mg, 84%) as a brown solid. m.p. > 250 ºC. 1H NMR (400
MHz, d6-DMSO) 1.78-1.91 (4H, m, H-6 and H-7), 2.88 (1H, t, J = 6.0 Hz, H-5), 2.96 (1H, t,
J = 6.4 Hz, H-8), 7.23 (2H, br s, NH2), 7.37 (1H, t, J = 8.0 Hz, H-4'), 7.56 (2H, d, J = 8.0 Hz,
13
H-3' and H-5'), 8.17 (1H, s, H-4), 9.40 (1H, s, NH); C NMR (100 MHz, d6-DMSO) 22.3
and 22.4 (C-6 and C-7), 28.3 (C-5), 32.5 (C-8), 94.8 (C-2), 124.3 (C-3a), 128.3 (C-4a), 128.4
(C-3' and C-5'), 129.2 (C-4'), 130.9 (C-4), 133.5 (C-1'), 134.7 (C-2' and C-6'), 147.0 (C-3),
156.1 (C-9a), 159.2 (C-8a), 163.90 (C=O); IR: υmax(ATR)/cm-1: 3398, 3308, 2940, 1600,
1499, 1473, 1243, 1197; m/z (ESI+): 396 (37,37Cl2MH+, 13%), 394 (35,37Cl2MH+, 71%), 392
22

(
35,35Cl2MH+, 100%); HRMS (ESI+) found (37,37Cl2MH+): 396.0322, C18H1637,37Cl2N3OS
requires 396.0333. Found (35,37Cl2MH+) 394.0356, C18H1635,37Cl2N3OS requires 394.0358.
Found (35,35Cl2MH+): 392.0383, C18H1635,35Cl2N3OS requires 392.0386.
4.1.2.29
3-Amino-N-(2',4',6'-trimethylphenyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6s. The reaction was carried out according to general procedure C using 2-
bromo-N-mesitylacetamide 12t (125 mg, 0.49 mmol), carbonitrile 10b (93 mg, 0.49 mmol)
and anhydrous sodium carbonate (55 mg, 0.52 mmol) in absolute ethanol (2 ml) to give the
title compound 6s (108 mg, 60%) as a light tan solid. m.p. > 250 ºC. 1H NMR (400 MHz, d6-
DMSO) 1.79-1.88 (4H, m, H-6 and H-7), 2.13 (6H, s, 2'-CH3 and 6'-CH3), 2.25 (3H, s, 4'-
CH3), 2.88 (2H, t, J = 6.0 Hz, H-5), 2.95 (2H, t, J = 5.6 Hz, H-8), 6.90 (2H, s, H-3' and H-5'),
7.11 (2H, s, NH2), 8.13 (1H, s, H-4), 8.81 (1H, s, NH); 13C NMR (100 MHz, d6-DMSO) 18.1
(2'-CH3 and 6'-CH3), 20.5 (4'-CH3), 22.3 and 22.5 (C-6 and C-7), 28.3 (C-5), 32.5 (C-8), 96.0
(C-2), 124.8 (C-3a), 128.2 (C-3', C-5' and C-4a), 130.6 (C-4), 132.8 (C-1'), 135.4 (C-4'),
135.6 (C-2' and C-6'), 145.9 (C-3), 155.9 (C-9a), 158.7 (C-8a), 164.0 (C=O); IR:
υmax(ATR)/cm-1: 3371, 3314, 2937, 1599, 1505, 1489, 1247, 1162; m/z (ESI+): 388 (MNa+,
62%), 366 (MH+, 100%); HRMS (ESI+) found (MNa+): 388.1441, C21H23N3NaOS requires
388.1454. Found (MH+): 366.1623, C21H24N3OS requires 366.1635.
4.1.2.30
3-Amino-N-(naphthalen-1'-yl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-
carboxamide 6t. The reaction was carried out according to general procedure C using 2-
bromo-N-(naphthalen-1'-yl)acetamide 12u (139 mg, 0.56 mmol), carbonitrile 10b (100 mg,
0.56 mmol) and anhydrous sodium carbonate (63 mg, 0.59 mmol) in absolute ethanol (2 ml)
1
to give the title compound 6t (162 mg, 81%) as a dark green solid. m.p. 206-207 ºC. H
NMR (400 MHz, d6-DMSO) 1.83-1.92 (4H, m, H-6 and H-7), 2.89 (2H, t, J = 6.0 Hz, H-5),
2.97 (2H, t, J = 6.4 Hz, H-8), 7.21 (2H, br s, NH2), 7.52-7.55 (4H, m, H-5', H-6', H-8' and H-
9'), 7.83-7.85 (1H, m, H-10'), 7.91-7.97 (2H, m, H-3' and H-4'), 8.18 (1H, s, H-4), 9.62 (1H,
br s, NH); 13C NMR (100 MHz, d6-DMSO) 22.3 and 22.5 (C-6 and C-7), 28.3 (C-5), 32.5 (C-
8), 95.9 (C-2), 124.3 (C-3a), 124.5 (C-8'), 123.5, 125.5, 125.8, 125.9, 126.2 and 128.0 (C-3',
C-4', C-5', C-6', C-9' and C-10'), 128.2 (C-1'), 129.7 (C-4a), 130.8 (C-4), 133.7 (C-7'), 134.0
(C-2'), 146.6 (C-3), 156.0 (C-9a), 158.9 (C-8a), 164.9 (C=O); IR: υmax(ATR)/cm-1: 3437,
3323, 2947, 1668, 1603, 1501, 1433, 1254, 1098; m/z (ESI+): 374 (MH+, 25%), 144 (100%);
HRMS (ESI+) found (MH+): 374.1334, C22H20N3OS requires 374.1322.
23

4.1.2.31
3-Amino-N-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-e]pyridine-2-
carboxamide 7a. The reaction was carried out according to general procedure C using 2-
bromo-N-phenylacetamide 12a (0.07 g, 0.34 mmol), carbonitrile 10c (0.07 g, 0.34 mmol) and
anhydrous sodium carbonate (0.04 g, 0.38 mmol) in absolute ethanol (1.8 mL) to give the
1
title product 7a (0.11 g, 91%) as a brown solid. m.p. > 230 °C. H NMR (400 MHz; d6-
DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.88-2.91 (2H, m, H-5),
3.08-3.11 (2H, m, H-9), 7.08 (1H, tt, J = 7.3, 1.0 Hz, H-4'), 7.29 (2H, s, NH2), 7.34 (2H, td, J
= 8.0, 2.0 Hz, H-3' and H-5'), 7.71 (2H, dd, J = 8.5, 1.0 Hz, H-2' and H-6'), 8.21 (1H, s, H-4),
13
9.36 (1H, s, NH); C NMR (100 MHz; d6-DMSO) 26.2 (C-8), 27.9 (C-6), 31.6 (C-7), 34.5
(C-5), 38.8 (C-9), 96.1 (C-2), 121.1 (C-2' and C-6'), 123.3 (C-4'), 124.3 (C-3), 128.4 (C-3'
and C-5'), 130.4 (C-4), 134.1 (C-4a), 139.0 (C-1'), 147.0 (C-3a), 155.45 (C-9a), 164.04
(C=O), 164.76 (C-10a); IR: υmax (film)/cm-1: 3382, 3287, 3033, 2916, 2848, 1647, 1596,
1531, 1494, 1435, 1320; m/z (ESI+): 360 (MNa+, 36%), 338 (MH+, 100%); HRMS (ESI+)
found (MH+): 338.1311, C19H20N3OS requires 338.1322. The spectroscopic data was
consistent with literature values [17].
4.1.2.32
3-Amino-N-(2'-fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-
e]pyridine-2-carboxamide 7b. The reaction was carried out according to general procedure C
using 2-bromo-N-(2'-fluorophenyl)acetamide 12b (0.11 g, 0.49 mmol), carbonitrile 10c (0.10
g, 0.49 mmol) and anhydrous sodium carbonate (0.06 g, 0.54 mmol) in absolute ethanol (2.5
1
mL) to give the title product 7b (0.14 g, 82%) as a brown solid. m.p. 228-230 °C. H NMR
(400 MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.88-2.91
(2H, m, H-5), 3.09-3.11 (2H, m, H-9), 7.18-7.30 (5H, m, NH2, H-3', H-5’ and H-4'), 7.54
13
(1H, t, J = 7.7 Hz, H-6'), 8.21 (1H, s, H-4), 9.24 (1H, br s, NH); C NMR (100 MHz; d6-
DMSO) 26.2 (C-8), 27.9 (C-6), 31.6 (C-7), 34.4 (C-5), 38.8 (C-9), 95.9 (C-2), 115.6 (d, 2JF/C
4
2
20.1 Hz, C-3'), 124.1 (d, JF/C 3.4 Hz, C-5'), 124.3 (C-3a), 125.8 (d, JF/C 12.0 Hz, C-1'),
3
126.7 (d, JF/C 7.2 Hz, C-4'), 127.5 (C-6'), 130.5 (C-4), 134.1 (C-4a), 146.9 (C-3), 155.5
1
(C-10a), 158.5 (d, JF/C 210.1 Hz, C-2'), 163.9 (C=O), 164.8 (C-9a); IR: υmax (film)/cm-1:
3423, 3286, 2930, 2853, 1644, 1518, 1445, 1322, 1245; m/z (ESI+): 378 (MNa+, 30%), 356
(MH+, 100%); HRMS (ESI+) found (MH+): 356.1224, C19H19FN3OS requires 356.1227.
4.1.2.33
3-Amino-N-(2'-chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-
e]pyridine-2-carboxamide 7c. The reaction was carried out according to general procedure C
using 2-bromo-N-(2'-chlorophenyl)acetamide 12c (0.08 g, 0.34 mmol), carbonitrile 10c (0.07
24

g, 0.34 mmol) and anhydrous sodium carbonate (0.04 g, 0.38 mmol) in absolute ethanol (2
1
mL) to give the title product 7c (0.09 g, 86%) as a dark brown solid. m.p. 228-230 °C. H
NMR (400 MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.88-
2.91 (2H, m, H-5), 3.09-3.11 (2H, m, H-9), 7.23-7.29 (3H, m, NH2 and H-4'), 7.38 (1H, td, J
= 7.7, 1.5 Hz, H-5'), 7.55 (1H, dd, J = 8.0, 2.5 Hz, H-3'), 7.68 (1H, dd, J = 8.0, 2.0 Hz, H-6'),
8.22 (1H, s, H-4), 9.09 (1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 26.2 (C-8), 27.9 (C-
6), 31.6 (C-7), 34.4 (C-5), 38.7 (C-9), 96.1 (C-2), 124.4 (C-3a), 126.8 (C-5'), 127.4 (C-4'),
127.5 (C-3'), 128.7 (C-6'), 129.4 (C-2'), 130.5 (C-4), 134.2 (C-4a), 135.2 (C-1'), 146.9 (C-3),
155.4 (C-10a), 163.8 (C=O), 164.9 (C-9a); IR: υmax (film)/cm-1: 3423, 3392, 3302, 2921,
1651, 1589, 1522, 1434, 1307; m/z (ESI+): 396 (37ClMNa+, 12%), 394 (35ClMNa+, 33%), 374
(37ClMH+, 37%), 372 (35ClMH+, 100%); HRMS (ESI+) found (37ClMNa+): 374.0896,
C19H1937ClN3OS requires 374.0907. Found (35ClMH+): 372.0924, C19H1935ClN3OS requires
372.0932.
4.1.2.34
3-Amino-N-(2'-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-
e]pyridine-2-carboxamide 7d. The reaction was carried out according to general procedure C
using 2-bromo-N-(2'-methylphenyl)acetamide 12d (0.08 g, 0.34 mmol), carbonitrile 10c
(0.07 g, 0.34 mmol) and anhydrous sodium carbonate (0.04 g, 0.38 mmol) in absolute ethanol
(2 mL) to give the title product 7d (0.09 g, 84%) as a brown solid. m.p. 195-197 °C. 1H NMR
(400 MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.24 (3H, s,
CH3), 2.88-2.91 (2H, m, H-5), 3.08-3.11 (2H, m, H-9), 7.14-7.23 (4H, m, NH2, H-4' and H-
5'), 7.27 (1H, dd, J = 7.5, 1.5 Hz, H-6'), 7.33 (1H, dd, J = 7.5, 1.5 Hz, H-3'), 8.19 (1H, s, H-
13
4), 9.05 (1H, s, NH); C NMR (100 MHz; d6-DMSO) 17.9 (CH3), 26.2 (C-8), 27.9 (C-6),
31.6 (C-7), 34.4 (C-5), 38.5 (C-9), 96.6 (C-2), 124.4 (C-3a), 125.87 (C-4'), 125.93 (C-5'),
126.8 (C-3'), 130.2 (C-4), 130.3 (C-6'), 133.9 (C-2'), 134.2 (C-4a), 136.3 (C-1'), 146.3 (C-3),
155.3 (C-10a), 164.1 (C=O), 164.7 (C-9a); IR: υmax (film)/cm-1: 3423, 3392, 3306, 2922,
2851, 1650, 1587, 1521, 1434, 1307, 1195; m/z (ESI+): 374 (MNa+, 70%), 352 (MH+, 100%);
HRMS (ESI+) found (MH+): 352.1473, C20H22N3OS requires 352.1478.
4.1.2.35
3-Amino-N-(2'-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide 7e. The reaction was carried out
according to general procedure C using 2-bromo-N-(2'-(fluoromethyl)phenyl)acetamide 12f
(0.10 g, 0.34 mmol), carbonitrile 10c (0.07 g, 0.34 mmol) and anhydrous sodium carbonate
(0.04 g, 0.38 mmol) in absolute ethanol (2 mL) to give the title product 7e (0.12 g, 86%) as a
25

1
dark yellow solid. m.p. 210-212 °C. H NMR (400 MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8
and H-6), 1.84-1.90 (2H, m, H-7), 2.88-2.91 (2H, m, H-5), 3.09-3.11 (2H, m, H-9), 7.20 (2H,
s, NH2), 7.51 (1H, t, J = 7.7 Hz, H-4'), 7.60 (1H, d, J = 7.7 Hz, H-6'), 7.72 (1H, t, J = 7.7 Hz,
13
H-5'), 7.78 (1H, d, J = 7.7 Hz, H-3'), 8.20 (1H, s, H-4), 9.09 (1H, br s, NH); C NMR (100
MHz; d6-DMSO) 26.3 (C-8), 28.0 (C-6), 31.6 (C-7), 34.4 (C-5), 38.7 (C-9), 95.8 (C-2), 124.3
(C-3a), 125.8 (q, 2JF/C 27.0 Hz, C-2'), 126.1 (q, 1JF/C 284.8 Hz, CF3), 126.4 (q, 3JF/C 4.2 Hz, C-
3'), 126.8 (C-4'), 130.5 (C-4), 130.6 (C-6'), 132.9 (C-5'), 134.1 (C-4a), 135.9 (C-1'), 146.9 (C-
3), 155.5 (C-10a), 164.6 (C=O), 164.8 (C-9a); IR: υmax (film)/cm-1: 3432, 3316, 2930, 2847,
1603, 1320, 1290, 1165, 1121; m/z (ESI+): 428 (MNa+, 42%), 406 (MH+, 100%); HRMS
(ESI+) found (MNa+): 428.1001, C20H18F3N3NaOS requires 428.1015.
4.1.2.36
3-Amino-N-(3'-fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-
e]pyridine-2-carboxamide 7f. The reaction was carried out according to general procedure C
using 2-bromo-N-(3'-fluorophenyl)acetamide 12g (0.08 g, 0.34 mmol), carbonitrile 10c (0.07
g, 0.34 mmol) and anhydrous sodium carbonate (0.04 g, 0.38 mmol) in absolute ethanol (2
1
mL) to give the title product 7f (0.10 g, 85%) as a brown solid. m.p. > 230 °C. H NMR (400
MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.88-2.91 (2H, m,
H-5), 3.09-3.11 (2H, m, H-9), 6.89 (1H, td, J = 8.5, 2.0 Hz, H-4'), 7.32-7.38 (3H, m, NH2 and
H-5'), 7.55 (1H, dd, J = 8.0, 2.0 Hz, H-6'), 7.70 (1H, dt, J = 12.0, 2.3 Hz, H-2'), 8.23 (1H, s,
13
H-4), 9.54 (1H, br s, NH); C NMR (100 MHz; d6-DMSO) 26.2 (C-8), 27.9 (C-6), 31.6 (C-
2
2
7), 34.5 (C-5), 38.5 (C-9), 96.6 (C-2), 107.3 (d, JF/C 26.1 Hz, C-2'), 109.4 (d, JF/C 20.9 Hz,
3
C-4'), 116.4 (C-6'), 124.2 (C-3a), 129.9 (d, JF/C 9.6 Hz, C-5'), 130.5 (C-4), 134.2 (C-4a),
3
1
141.0 (d, JF/C 11.5 Hz, C-1'), 147.5 (C-3), 155.5 (C-10a), 163.8 (d, JF/C 140.2 Hz, C-3'),
164.2 (C=O), 165.0 (C-9a); IR: υmax (film)/cm-1: 3385, 3292, 2914, 2848, 1650, 1597, 1531,
1435, 1280; m/z (ESI+): 378 (MNa+, 41%), 356 (MH+, 100%); HRMS (ESI+) found (MH+):
356.1221, C19H19FN3OS requires 356.1227.
4.1.2.37
3-Amino-N-(3'-chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-
e]pyridine-2-carboxamide 7g. The reaction was carried out according to general procedure C
using 2-bromo-N-(3'-chlorophenyl)acetamide 12h (0.05 g, 0.20 mmol), carbonitrile 10c (0.04
g, 0.20 mmol) and anhydrous sodium carbonate (0.02 g, 0.22 mmol) in absolute ethanol (1.3
1
mL) to give the title product 7g (0.10 g, 100%) as a brown solid. m.p. > 230 °C. H NMR
(400 MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.88-2.91
(2H, m, H-5), 3.08-3.11 (2H, m, H-9), 7.13 (1H, dt, J = 8.0, 1.3 Hz, H-4'), 7.35 (3H, m, H-5'
26

and NH2), 7.67 (1H, dq, J = 8.5, 1.0 Hz, H-6'), 7.93-7.94 (1H, m, H-2'), 8.23 (1H, s, H-4),
9.52 (1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 26.2 (C-8), 27.9 (C-6), 31.6 (C-7), 34.5
(C-5), 38.6 (C-9), 95.5 (C-2), 119.1 (C-6'), 120.2 (C-2'), 122.8 (C-4'), 124.2 (C-3a), 130.0 (C-
5'), 130.5 (C-4), 132.7 (C-1'), 134.2 (C-4a), 140.7 (C-3'), 147.6 (C-3), 155.6 (C-10a), 164.1
(C=O), 165.0 (C-9a); IR: υmax (film)/cm-1: 3429, 3320, 3197, 2924, 2852, 1668, 1584, 1497,
1479, 1300; m/z (ESI+): 396 (37ClMNa+, 11%), 394 (35ClMNa+, 30%), 374 (37ClMH+, 38%),
372 (35ClMH+, 100%); HRMS (ESI+) found (37ClMH+): 374.0890, C19H1937ClN3OS requires
374.0907. Found (35ClMH+): 372.0920, C19H1935ClN3OS requires 372.0932.
4.1.2.38
3-Amino-N-(3'-bromophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-
e]pyridine-2-carboxamide 7h. The reaction was carried out according to general procedure C
using 2-bromo-N-(3'-bromophenyl)acetamide 12i (0.06 g, 0.20 mmol), carbonitrile 10c (0.04
g, 0.20 mmol) and anhydrous sodium carbonate (0.02 g, 0.22 mmol) in absolute ethanol (1.5
1
mL) to give the title product 7h (0.06 g, 79%) as a tan solid. m.p. > 230 °C. H NMR (400
MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.88-2.90 (2H, m,
H-5), 3.08-3.11 (2H, m, H-9), 7.24-7.31 (2H, m, H-4' and H-5'), 7.37 (2H, s, NH2), 7.71 (1H,
dt, J = 8.0, 1.5 Hz, H-6'), 8.08 (1H, t, J = 1.8 Hz, H-2'), 8.23 (1H, s, H-4), 9.51 (1H, br s,
13
NH); C NMR (100 MHz; d6-DMSO) 26.2 (C-8), 27.9 (C-6), 31.6 (C-7), 34.5 (C-5), 38.6
(C-9), 95.5 (C-2), 119.5 (C-6'), 121.2 (C-3'), 123.0 (C-2'), 124.2 (C-3a), 125.7 (C-4'), 130.3
(C-4), 130.5 (C-5'), 134.2 (C-4a), 140.8 (C-1'), 147.6 (C-3), 155.6 (C-10a), 164.1 (C=O),
165.0 (C-9a); IR: υmax (film)/cm-1: 3435, 3323, 3198, 2919, 2851, 1674, 1579, 1515, 1497,
1474, 1396, 1301; m/z (ESI+): 467 (100%), 440 (81BrMNa+, 13%), 438 (79BrMNa+, 11%);
HRMS (ESI+) found (81BrMNa+): 440.0224, C19H1881BrN3NaOS requires 440.0227. Found
(79BrMNa+): 438.0243, C19H1879BrN3NaOS requires 438.0246.
4.1.2.39
3-Amino-N-(3'-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide 7i. The reaction was carried out
according to general procedure C using 2-bromo-N-(3'-(trifluoromethyl)phenyl)acetamide 12j
(0.06 g, 0.20 mmol), carbonitrile 10c (0.04 g, 0.20 mmol) and anhydrous sodium carbonate
(0.02 g, 0.22 mmol) in absolute ethanol (1.3 mL) to give the title product 7i (0.07 g, 90%) as
1
a tan solid. m.p. 220-222 °C. H NMR (400 MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-
6), 1.84-1.90 (2H, m, H-7), 2.88-2.90 (2H, m, H-5), 3.09-3.11 (2H, m, H-9), 7.40-7.43 (3H,
m, NH2 and H-4'), 7.57 (1H, t, J = 8.0 Hz, H-5'), 8.01 (1H, d, J = 8.0 Hz, H-6'), 8.24 (2H, br
13
s, H-2' and H-4), 9.68 (1H, br s, NH); C NMR (100 MHz; d6-DMSO) 26.2 (C-8), 27.9 (C-
27

6), 31.6 (C-7), 34.5 (C-5), 38.8 (C-9), 95.3 (C-2), 116.8 (q, 3JF/C 3.7 Hz, C-2'), 119.4 (q, 3JF/C
1
5
3.9 Hz, C-4'), 124.1 (C-3a), 124.2 (d, JF/C 273.6 Hz, CF3), 124.2 (q, JF/C 4.46 Hz, C-6'),
129.2 (d, 2JF/C 31.2 Hz, C-3'), 129.6 (C-5'), 130.6 (C-4), 134.2 (C-4a), 140.0 (C-1'), 147.8 (C-
3), 155.6 (C-10a), 164.3 (C=O), 165.1 (C-9a); IR: υmax (film)/cm-1: 3396, 3309, 2922, 2854,
1649, 1597, 1541, 1439, 1165, 1114; m/z (ESI+): 428 (MNa+, 20%), 406 (MH+, 100%);
HRMS (ESI+) found (MH+): 406.1190, C20H19F3N3OS requires 406.1195.
4.1.2.40
3-Amino-N-(3'-methoxyphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-
e]pyridine-2-carboxamide 7j. The reaction was carried out according to general procedure C
using 2-bromo-N-(3'-methoxyphenyl)acetamide 12k (0.04 g, 0.15 mmol), carbonitrile 10c
(0.03 g, 0.15 mmol) and anhydrous sodium carbonate (0.02 g, 0.16 mmol) in absolute ethanol
1
(1 mL) to give the title product 7j (0.04g, 78%) as a dark brown solid. m.p. 220-222 °C. H
NMR (400 MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.88-
2.90 (2H, m, H-5), 3.08-3.11 (2H, m, H-9), 3.76 (3H, s, OCH3), 6.66 (1H, ddd, J = 8.0, 2.5,
1.0 Hz, H-4'), 7.22 (1H, t, J = 8.0 Hz, H-5'), 7.30-7.35 (3H, m, NH2 and H-6'), 7.41 (1H, t, J
= 2.0 Hz, H-2'), 8.21 (1H, s, H-4), 9.32 (1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 26.2
(C-8), 27.9 (C-6), 31.6 (C-7), 34.5 (C-5), 38.4 (C-9), 55.0 (OCH3), 96.0 (C-2), 106.5 (C-2'),
108.9 (C-4'), 113.1 (C-6'), 124.3 (C-3a), 129.1 (C-5'), 130.4 (C-4), 134.1 (C-4a), 140.3 (C-1'),
147.1 (C-3), 155.4 (C-10a), 159.3 (C-3'), 164.0 (C=O), 164.8 (C-9a); IR: υmax (film)/cm-1:
3441, 3330, 3185, 3031, 2926, 1668, 1590, 1490, 1301, 1278; m/z (ESI+): 390 (MNa+, 63%),
368 (MH+, 100%); HRMS (ESI+) found (MH+): 368.1420, C20H22N3O2S requires 368.1427.
4.1.2.41
3-Amino-N-(3'-nitrophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]thieno[3,2-
e]pyridine-2-carboxamide 7k. The reaction was carried out according to general procedure C
using 2-bromo-N-(3'-nitrophenyl)acetamide 12l (0.05 g, 0.20 mmol), carbonitrile 10c (0.04 g,
0.20 mmol) and anhydrous sodium carbonate (0.02 g, 0.22 mmol) in absolute ethanol (1.3
mL) to give the title product 7k (0.06 g, 75%) as a light brown solid. m.p. > 230 °C. 1H NMR
(400 MHz; d6-DMSO) 1.65-1.70 (4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.88-2.90
(2H, m, H-5), 3.09-3.11 (2H, m, H-9), 7.45 (2H, s, NH2), 7.62 (1H, t, J = 7.9 Hz, H-5'), 7.92
(1H, d, J = 7.9 Hz, H-4'), 8.16 (1H, d, J = 7.9 Hz, H-6'), 8.25 (1H, s, H-4), 8.80 (1H, s, H-2'),
9.85 (1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 26.2 (C-8), 27.9 (C-6), 31.6 (C-7), 34.5
(C-5), 38.8 (C-9), 95.1 (C-2), 114.7 (C-2'), 117.5 (C-4'), 124.1 (C-3a), 126.6 (C-6'), 129.7 (C-
5'), 130.6 (C-4), 134.2 (C-4a), 140.5 (C-1'), 147.8 and 148.0 (C-3 and C-3'), 155.7 (C-10a),
164.3 (C=O), 165.2 (C-9a); IR: υmax (film)/cm-1: 3431, 3384, 3328, 3144, 2925, 2848, 1652,
28

1594, 1519, 1344, 1328; m/z (ESI+): 405 (MNa+, 70%), 383 (MH+, 86%), 381 ([M-H]+,
100%); HRMS (ESI+) found (MH+): 383.1161, C19H19N4O3S requires 383.1172.
4.1.2.42
3-Amino-N-(3'-chloro-2'-methylphenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide 7l. The reaction was carried out
according to general procedure C using 2-bromo-N-(3'-chloro-2'-methylphenyl)acetamide
12n (0.09 g, 0.34 mmol), carbonitrile 10c (0.07 g, 0.34 mmol) and anhydrous sodium
carbonate (0.04 g, 0.38 mmol) in absolute ethanol (1.8 mL) to give the title product 7l (0.09
1
g, 86%) as a dark beige solid. m.p. 228-230 °C. H NMR (400 MHz; d6-DMSO) 1.65-1.70
(4H, m, H-8 and H-6), 1.84-1.90 (2H, m, H-7), 2.28 (3H, s, CH3), 2.88-2.91 (2H, m, H-5),
3.09-3.11 (2H, m, H-9), 7.21-7.30 (3H, m, NH2, H-5' and H-4'), 7.36 (1H, d, J = 7.6 Hz, H-
6'), 8.20 (1H, s, H-4), 9.33 (1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 15.4 (CH3), 26.3
(C-8), 28.0 (C-6), 31.6 (C-7), 34.5 (C-5), 38.8 (C-9), 95.9 (C-2), 124.3 (C-3a), 126.2 (C-5'),
126.5 and 126.7 (C-4' and C-6'), 130.4 (C-4), 132.5 (C-2'), 133.6 (C-3'), 134.1 (C-4a), 138.2
(C-1'), 146.8 (C-3), 155.5 (C-10a), 164.2 (C=O), 164.7 (C-9a); IR: υmax (film)/cm-1: 3448,
3332, 3139, 2927, 2849, 1673, 1501, 1464, 1432, 1289; m/z (ESI+): 410 (37ClMNa+, 30%),
408 (35ClMNa+, 80%), 388 (37ClMH+, 38%), 386 (35ClMH+, 100%); HRMS (ESI+) found
(37ClMH+): 388.1054, C20H2137ClN3OS requires 388.1064. Found (35ClMH+): 386.1081,
C20H2135ClN3OS requires 386.1088.
4.1.2.43
3-Amino-N-(3'-bromo-2'-methylphenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]thieno[3,2-e]pyridine-2-carboxamide 7m. The reaction was carried out
according to general procedure C using 2-bromo-N-(3'-bromo-2'-methylphenyl)acetamide
12o (0.07 g, 0.25 mmol), carbonitrile 10c (0.05 g, 0.25 mmol) and anhydrous sodium
carbonate (0.03 g, 0.27 mmol) in absolute ethanol (1.5 mL) to give the title product 7m (0.03
1
g, 46%) as a brown solid. m.p. > 230 °C. H NMR (400 MHz; d6-DMSO) 1.65-1.70 (4H, m,
H-8 and H-6), 1.84-1.89 (2H, m, H-7), 2.28 (3H, s, CH3), 2.88-2.90 (2H, m, H-5), 3.08-3.11
(2H, m, H-9), 7.14-7.20 (3H, m, H-5' and NH2), 7.33 (1H, d, J = 7.4 Hz, H-6'), 7.51 (1H, d, J
= 7.4 Hz, H-4'), 8.19 (1H, s, H-4), 9.35 (1H, br s, NH); 13C NMR (100 MHz; d6-DMSO) 18.5
(CH3), 26.3 (C-8), 28.0 (C-6), 31.6 (C-7), 34.4 (C-5), 38.5 (C-9), 95.9 (C-2), 124.3 (C-3a),
124.5 (C-3'), 126.9 (C-6'), 127.2 (C-5'), 129.9 (C-4'), 130.4 (C-4), 134.1 (C-4a), 134.2 (C-2'),
138.0 (C-1'), 146.8 (C-3), 155.5 (C-10a), 164.2 (C=O), 164.7 (C-9a); IR: υmax (film)/cm-1:
3446, 3333, 3137, 2926, 2849, 1682, 1500, 1462, 1432, 1288; m/z (ESI+) : 454 (81BrMNa+,
75%), 452 (79BrMNa+, 73%), 432 (81BrMH+, 100%), 430 (79BrMH+, 99%); HRMS (ESI+)
29