Flow Chemistry Synthesis of Zolpidem, Alpidem and Other GABAA Agonists and Their Biological Evaluation Through the Use of In-Line

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Supporting information

Flow Chemistry Synthesis of Zolpidem, Alpidem and other GABAA Agonists and their Biological Evaluation through the use of In-line

Frontal Affinity Chromatography

Synthesis S2 General S2 Synthesis of unsaturated ketone intermediates 3-5 S2 Synthesis of imidazo[1,2-a]pyridine intermediates 6-14 S3 Synthesis of amides 1, 2, 15-25 S7 Synthesis of carboxylic acids 26-34 S12

References S14

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Synthesis

General All solvents were distilled prior to use and stored under argon. Commercially available starting materials were bought from Sigma-Aldrich and Alfa Aesar; IRA-743 resin was purchased from Sigma- Aldrich, and QP-SA and QP-BZA resins from Johnson Matthey. All flow reactions were performed on a FlowsynTM (Uniqsis) equipped with Automatic Loop Filling (ALFTM, Uniqsis) and a FC203B fraction collector (Gilson). 1H and 13C NMR spectra were recorded either on a Bruker Avance DPX-400 or a DRX-500

spectrometer with residual solvent as the internal reference (CHCl3 in CDCl3 or CH3OH in CD3OD). LC/MS analysis was performed on an Agilent HP 1100 chromatograph (Luna Max RP column) attached to an HPLC/MSD mass spectrometer. Elution was carried out using a reverse-phase gradient of MeCN/water with the water containing 0.1% formic acid. For HRMS an LCT Premier Micromass spectrometer was used.

Synthesis of unsaturated ketone intermediates 3-5 In this first step the acid catalysed condensation between ethyl glyoxylate and acetophenone derivatives leads to unsaturated ketone intermediates (3-5) which need to be produced on large scale and repetitively, it is therefore important that a scalable and automated route can be used for this synthetic step.

EtO O Toluene 1.5 equiv. O O 0.1 mL/min QP-SA QP-BZA 1 EtO R = H, 3 1 O R = CH3, 4 100 psi O 1 120 °C R1 R = Cl, 5 R1 A mixture of 10 mmol of acetophenone derivative, 15 mmol of ethyl glyoxylate (50% in toluene) in toluene (total volume 10 mL) was injected through a reactor packed with 2 g of polymer supported sulfonic acid resin (QP-SA, 6 mmol) and heated at 120 °C, with a residence time of 25 minutes (0.1 mL/min). The exiting stream was passed through a column of QP-BZA (3 g, around 10 mmol), a supported benzyl amine that scavenges the excess of glyoxylate in the reaction stream. The combination of these two heterogeneous reagents affords a process that is free of downstream purification. The product is collected and transferred to the next step.

E oxo O ( )-Ethyl 4-phenyl-4- -2-butenoate 3: Yellow oil, isolated yield = 76%. In EtO agreement with the structural data reported in literature.[1] O 3 + Rt = 4.44 min. HRMS (ESI): m/z: calcd for C12H13O3 [M+H ]: 205.0865; found

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1 3 3 205.0872. H NMR (CDCl3, 400 MHz): δ (ppm) 8.00 (d, J H-H = 7.5 Hz, 2×CH), 7.90 (d, J H-H = 15.5 Hz, 3 3 3 3 CH), 7.60 (d, J H-H = 7.5 Hz, CH), 7.49 (app. t, J H-H = 7.5 Hz, J H-H = 7.5 Hz, 2×CH), 6.87 (d, J H-H = 15.5

3 3 13 Hz, CH), 4.29 (q, J H-H = 7.1 Hz, CH2), 1.35 (t, J H-H = 7.1 Hz, CH3). C NMR (CDCl3, 100 MHz): δ (ppm)

189.5 (Cketone), 165.5 (Cester), 136.6 (C), 136.4 (CH), 133.8 (C), 132.6 (CH), 128.9 (4 CH), 61.4 (CH2),

14.2 (CH3).

(E)-Ethyl 4-(4-methyl-phenyl)-4-oxo-2-butenoate 4: Yellow oil, isolated yield = O EtO 85%. In agreement with the structural data as reported in literature.[1,2] O 4 + 4 Rt = 4.60 min. HRMS (ESI): m/z: calcd for C13H15O3 [M+H ]: 219.1021; found

1 3 3 219.1014. H NMR (CDCl3, 400 MHz): δ (ppm) 7.88 (d, J H-H = 8.2 Hz, CH), 7.87 (d, J H-H = 15.3 Hz, 3 3 3 CH), 7.24 (d, J H-H = 8.2 Hz, 2×CH), 6.83 (d, J H-H = 15.3 Hz, CH), 4.27 (q, J H-H = 7.3 Hz, CH2), 2.40 (s,

3 13 CH3), 1.32 (t, J H-H = 7.3 Hz, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 189.0 (Cketone), 172.2 (Cester),

144.9 (C), 136.6 (C), 134.4 (2×CH), 132.2 (2×CH), 129.4 (CH), 129.2 (CH), 61.3 (CH2), 21.7 (CH3), 15.2

(CH3).

E oxo O ( )-Ethyl 4-(4-chloro-phenyl)-4- -2-butenoate 5: Yellow oil, isolated yield = EtO EtO 82%. In agreement with the structural data as reported in literature.[2] O 5 Cll + Rt = 4.96 min. HRMS (ESI): m/z: calcd for C13H15O3 [M+H ]: 239.0475; found 1 3 4 3 219.0479. H NMR (CDCl3, 400 MHz): 7.92 (dd, J H-H = 6.8 Hz, J H-H = 2 Hz, 2×CH), 7.84 (d, J H-H = 15.6 3 4 3 3 Hz, CH), 7.48 (dd, J H-H = 6.8 Hz, J H-H = 2 Hz, 2×CH), 6.87 (d, J H-H = 15.6 Hz, CH), 4.29 (q, J H-H = 7.2 3 13 Hz, CH2), 1.32 (t, J H-H = 7.2 Hz, CH3). C NMR (CDCl3, 100 MHz): 188.2 (Cketone), 165.4 (Cester), 140.5

(C), 135.8 (CH), 135.0 (C), 133.0 (CH), 130.2 (2×CH), 129.2 (2×CH), 61.5 (CH2), 14.1 (CH3).

Synthesis of imidazo[1,2-a]pyridine intermediates 6-14

O MeCN loop A EtO 0.1 mL/min R2 O 1 R 100 psi Biota e 3-5 MgSO4 QP-SA g N R1 R2 N R3 NH2 50 °C 1.5 equiv. 120 °C O N 2 6-14 5-30 % 3 14 mL R R MeCN OEt NH2 cat. HBF4.Et2O 0.1 mL/min Uniqsis ALF loop B NH in MeOH 3 N R3 The dispensing of different unsaturated ketones and aminopyridines into the reactors is done automatically to prepare a diverse collection of compounds. The use of flow process also accommodates safely superheating the solvent under pressure. Indeed, using conventional heating conditions the reaction typically takes 24 hours to progress whereas in the superheated equivalent

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only 4 hours are required. Similar results can be achieved by using microwave reactors, although scaling up these microwave reactions is not always easy.

Using an autosampler with Automatic Loop Filling (ALF™, Uniqsis), 1 equivalent of unsaturated ketone (3-5) and a solution of 1.5 equivalents of a commercially available aminopyridine with a

catalytic amount of HBF4.Et2O in acetonitrile were used to fill sample loop A and B (1 mL loop each). Both delivery pumps were operated at a flow rate of 0.1 mL/min and the mixture was injected then mixed at a standard T-connector and passed through a column packed with magnesium sulfate to promote ketimine formation. The reaction stream was then progressed into a 14 mL CFC (Continuous Flow Coil) reactor at 120 °C leading to 5-exo cyclization. For the preparation of analogues 6-9 and 11-13, this process was best catalysed by acid. The reaction mixture was then eluted through a column packed with 1 g of QP-SA to capture the excess aminopyridine. The aminopyridine reagent can be easily recovered later by injecting ammonia in methanol to displace it from the column.

N Ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate 6: N.B. The solution of 2- N aminopyridine was prepared in DMF instead of acetonitrile. Yellow solid, isolated O 6 OEt 6 yield = 18% after chromatography (Biotage SP1, 12g cartridge, eluent: hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). In agreement with the structural data reported in literature.[3] + 1 Rt = 4.42 min. HRMS (ESI): m/z: calcd for C17H17N2O2 [M+H ]: 281.1285; found 281.1281. H NMR

3 3 3 (CDCl3, 400 MHz): δ (ppm) 8.12 (d, J H-H = 8.0 Hz, CH), 7.84 (d, J H-H = 8.0 Hz, 2×CH), 7.66 (d, J H-H = 3 3 8.0 Hz, CH), 7.48 (t, J H-H = 8.0 Hz, 2×CH), 7.39 (m, CH), 7.23 (m, 2×CH), 6.87 (t, J H-H = 8.0 Hz, CH),

3 3 13 4.22 (q, J H-H = 7.2 Hz, CH2), 4.05 (s, CH2), 1.28 (t, J H-H = 7.2 Hz, CH3). C NMR (CDCl3, 100 MHz): δ

(ppm) 169.4 (Cester), 145.0 (C), 144.7 (C), 134.1 (C), 128.6 (2×2×CH), 128.0 (CH), 124.5 (CH), 127.8

(CH), 117.7 (CH), 113.0 (C), 112.4 (CH), 61.7 (CH2), 30.9 (CH2), 14.2 (CH3).

N Ethyl 2-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate 7: N.B. The solution N of 5-methyl-2-aminopyridine was prepared in DMF instead of acetonitrile. Yellow O 7 OEtt solid, isolated yield = 12% after chromatography (Biotage SP1, 12g cartridge, eluent: hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). In agreement with the structural data reported in literature.[4] + 1 Rt = 4.66 min. HRMS (ESI): m/z: calcd for C18H19N2O2 [M+H ]: 295.1441; found 295.1427. H NMR

4 3 3 (CDCl3, 400 MHz): δ (ppm) 7.88 (d, J H-H = 1.2 Hz, CH), 7.82 (d, J H-H = 8.5 Hz, 2×CH), 7.56 (d, J H-H =

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3 4 3 9.2 Hz, CH), 7.46 (m, 2×CH), 7.37 (m, CH), 7.06 (dd, J H-H = 9.2 Hz, J H-H = 1.2 Hz, CH), 4.22 (q, J H-H =

3 13 7.2 Hz, CH2), 4.01 (s, CH2), 2.35 (s, CH3), 1.28 (t, J H-H = 7.2 Hz, CH3). C NMR (CDCl3, 100 MHz): δ

(ppm) 169.6 (Cester), 144.4 (C), 144.1 (C), 134.3 (C), 128.6 (2×2×CH), 127.8 (CH), 127.7 (CH), 122.1 (C),

121.4 (CH), 116.9 (CH), 112.7 (C), 61.6 (CH2), 30.9 (CH2), 18.5 (CH3), 14.2 (CH3).

N Ethyl 2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate 8: Yellow solid, N Cl isolated yield = 8% after chromatography (Biotage SP1, 12g cartridge, eluent: O 8 OEt hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). In agreement with the structural data reported in literature.[4] + 1 Rt = 4.38 min. HRMS (ESI): m/z: calcd for C17H16ClN2O2 [M+H ]: 315.0895; found 315.0890. H NMR

4 3 3 (CDCl3, 400 MHz): δ (ppm) 8.18 (d, J H-H = 2.1 Hz, CH), 7.79 (d, J H-H = 8.0 Hz, 2×CH), 7.60 (d, J H-H = 3 4 3 9.5 Hz, CH), 7.47 (m, 2×CH), 7.40 (m, CH), 7.18 (dd, J H-H = 9.5 Hz, J H-H = 2.1 Hz, CH), 4.23 (q, J H-H =

3 13 7.2 Hz, CH2), 4.01 (s, CH2), 1.28 (t, J H-H = 7.2 Hz, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 169.1

(Cester), 145.6 (C), 144.3 (C), 133.6 (C), 128.7 (2×CH), 128.6 (2×CH), 128.2 (CH), 125.9 (CH), 123.4 (CH),

121.8 (C), 117.9 (CH), 113.7 (C), 108.4 (C), 61.9 (CH2), 14.2 (CH3).

N Ethyl 2-(2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetate 9: Yellow solid, isolated yield = N 14% after chromatography (Biotage SP1, 12g cartridge, eluent: hexane:ethyl O 9 OEt 9 acetate 1:9 gradually changed to 4:6 over 8 column volumes). + 1 Rt = 4.23 min. HRMS (ESI): m/z: calcd for C18H19N2O2 [M+H ]: 295.1441; found 295.1427. H NMR

3 3 (CDCl3, 400 MHz): δ (ppm) 8.13 (d, J H-H = 6.4 Hz, CH), 7.71 (m, 3×CH), 7.26 (m, 3×CH), 6.89 (t, J H-H = 3 3 13 6.2 Hz, CH), 4.21 (q, J H-H = 7.2 Hz, CH2), 4.03 (s, CH2), 2.40 (s, CH3), 1.27 (t, J H-H = 7.2 Hz, CH3). C

NMR (CDCl3, 100 MHz): δ (ppm) 169.4 (Cester), 144.7 (C), 144.1 (C), 138.0 (C), 130.6 (C), 129.4 (2×CH),

128.6 (2×CH), 125.0 (CH), 123.8 (CH), 117.3 (CH), 112.8 (C), 112.7 (CH), 61.7 (CH2), 30.8 (CH2), 21.3

(CH3), 14.2 (CH3).

N Ethyl 2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetate 10: Yellow solid, N

O isolated yield = 30% after chromatography (Biotage SP1, 12g cartridge, eluent: OEt 10 OEt hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). In agreement with the structural data reported in literature.[3-5] + 1 Rt = 4.78 min. HRMS (ESI): m/z: calcd for C19H21N2O2 [M+H ]: 308.1525; found 308.1536. H NMR

3 3 (CDCl3, 400 MHz): δ (ppm) 7.88 (s, m, CH), 7.70 (d, J H-H = 7.9 Hz, 2×CH), 7.58 (d, J H-H = 8.8 Hz, CH), 3 3 3 7.27 (d, J H-H = 7.9 Hz, 2×CH), 7.06 (d, J H-H = 8.8 Hz, CH), 4.22 (q, J H-H = 7.2 Hz, CH2), 4.00 (s , CH2), 3 13 2.40 (s, CH3), 2.36 (s, CH3), 1.28 (t, J H-H = 7.2 Hz, CH3). C NMR (CDCl3, 100 MHz): 169.6 (Cester),

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144.0 (C), 137.7 (C), 131.1 (C), 129.3 (2×CH), 128.4 (2×CH), 127.8 (CH), 122.1 (C), 121.4 (CH), 120.6

(C), 116.8 (C), 112.4 (C), 61.6 (CH2), 30.9 (CH2), 21.3 (CH3), 18.5 (CH3), 14.2 (CH3).

N Ethyl 2-(6-chloro-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetate 11: Yellow solid, N Cll isolated yield = 10% after chromatography (Biotage SP1, 12g cartridge, eluent: O 11 OEt 11 hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). + 1 Rt = 4.50 min. HRMS (ESI): m/z: calcd for C18H18ClN2O2 [M+H ]: 329.1074; found 329.1057. H NMR

4 3 4 (CDCl3, 400 MHz): δ (ppm) 8.18 (d, J H-H = 2 Hz, CH), 7.70 (dd, J H-H = 6.8 Hz, J H-H = 2 Hz, 2×CH), 7.59 3 3 4 3 4 (d, J H-H = 9.6 Hz, CH), 7.28 (dd, J H-H = 6.8 Hz, J H-H = 2 Hz, 2×CH), 7.18 (dd, J H-H = 9.6 Hz, J H-H = 2 3 3 13 Hz, CH), 4.25 (q, J H-H = 7.2 Hz, CH2), 4.01 (s , CH2), 2.42 (s, CH3), 1.28 (t, J H-H = 7.2 Hz, CH3). C NMR

(CDCl3, 100 MHz): 169.2 (Cester), 145.7 (C), 143.4 (C), 138.2 (C), 130.6 (C), 129.4 (2×CH), 128.4 (2×CH),

126.8 (CH), 121.7 (CH), 120.6 (C), 117.8 (CH), 113.4 (C), 61.8 (CH2), 30.8 (CH2), 21.4 (CH3), 14.2 (CH3).

Ethyl 2-(8-bromo-6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetate 12: Br N Orange solid, isolated yield = 5% after chromatography (Biotage SP1, 12g N cartridge, eluent: hexane:ethyl acetate 5:95 gradually changed to 30:70 over 15 O 12 OEt 12 column volumes). + 1 Rt = 4.55 min. HRMS (ESI): m/z: calcd for C19H20BrN2O2 [M+H ]: 387.0708; found 387.0708. H NMR

4 3 4 (CDCl3, 400 MHz): δ (ppm) 7.86 (d, J H-H = 1.2 Hz, CH), 7.71 (d, J H-H = 8.0 Hz, 2×CH), 7.36 (d, J H-H = 3 3 1.2 Hz, CH), 7.27 (d, J H-H = 8.0 Hz, 2×CH), 4.21 (q, J H-H = 7.1 Hz, CH2), 3.98 (s, CH2), 2.40 (s, CH3),

3 13 2.36 (s, CH3), 2.40 (t, J H-H = 7.1 Hz, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 169.3 (Cester), 145.2 (C), 137.9 (C), 130.8 (C), 129.9 (CH), 129.3 (2×CH), 128.8 (2×CH), 122.3 (C), 121.8 (C), 120.9 (CH), 114.3

(C), 111.0 (C), 61.7 (CH2), 31.1 (CH2), 21.3 (CH3), 18.3 (CH3), 14.2 (CH3).

N Ethyl 2-(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)acetate 13: Cl N Yellow solid, isolated yield = 15% after chromatography (Biotage SP1, 12g O 13 OEtt 13 cartridge, eluent: hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). + 1 Rt = 4.27 min. HRMS (ESI): m/z: calcd for C18H18ClN2O2 [M+H ]: 329.1043; found 329.1057. H NMR

3 3 (CDCl3, 400 MHz): δ (ppm) 7.88 (s, CH), 7.75 (d, J H-H = 7.1 Hz, 2×CH), 7.51 (d, J H-H = 9.1 Hz, CH), 3 3 3 7.40 (d, J H-H = 8.3 Hz, 2×CH), 7.05 (d, J H-H = 9.1 Hz, CH), 4.20 (q, J H-H = 7.1 Hz, CH2), 3.95 (s , CH2),

3 13 2.34 (s, CH3), 1.26 (t, J H-H = 7.1 Hz, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 169.3 (Cester), 144.2 (C), 143.2 (C), 133.8 (C), 132.8 (C), 129.7× (2 CH), 128.8 (2×CH), 128.0 (CH), 122.3 (C), 121.4 (CH), 116.9

(CH), 112.8 (C), 61.7 (CH2), 30.8 (CH2), 18.4 (CH3), 14.2 (CH3).

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N Ethyl 2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate 14, in Cl N Cl agreement with the structural data reported in literature:[3,4] Yellow solid, O 14 OEt 14 isolated yield = 18% after chromatography (Biotage SP1, 12g cartridge, eluent: hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). + 1 Rt = 4.82 min. HRMS (ESI): m/z: calcd for C17H15Cl2N2O2 [M+H ]: 349.0496; found 349.0511. H NMR

3 3 4 (CDCl3, 400 MHz): δ (ppm) 8.20 (d, J H-H = 2 Hz, CH), 7.76 (dd, J H-H = 6.8 Hz, J H-H = 2 Hz, 2×CH), 7.58 3 3 4 3 4 (d, J H-H = 9.6 Hz, CH), 7.45 (dd, J H-H = 6.8 Hz, J H-H = 2 Hz, 2×CH), 7.20 (dd, J H-H = 9.6 Hz, J H-H = 2 3 3 13 Hz, CH), 4.24 (q, J H-H = 7.2 Hz, CH2), 3.99 (s , CH2), 1.28 (t, J H-H = 7.2 Hz, CH3). C NMR (CDCl3, 100

MHz) δ (ppm) 168.9 (Cester), 144.6 (C), 143.5 (C), 134.3 (C), 132.1 (C), 129.8 (2×CH), 129.0 (2×CH),

126.1 (CH), 121.8 (CH), 120.9 (C), 118.0 (CH), 113.7 (C), 61.9 (CH2), 30.8 (CH3), 14.1 (CH3).

Synthesis of amides 1, 2, 15-25

oo R3 DCM l p A 0.05 mL/min N R3 R1 N 2 N IRA-743 40 psi R R1 N O R2 6-14 OEt O 1, 2, 15-25 4 40 °C n s s rac on o ec or 4 HN(R )2 (5 equiv.) U iq i F ti C ll t R DCM 14 mL DIPEA 10 e uiv. ( q ) 0.05 mL/min 4 R = NMe2, 1, 15-22 26-99% Me2AlCl (4 equiv.) Uniqsis ALF loop B 4 = r - - R NP 2, 2, 23 25 33 93% Reaction to convert the esters directly to the corresponding amides using aluminium chloride salts has already been achieved in flow using microfluidic devices.[6] The authors mentioned that the reaction can be accelerated upon heating whereas in batch sub-zero temperatures are typically utilized. However, in our hands, degradation was observed at high temperatures; consequently the reaction was carried out at 40 °C with a residence time of 280 min. Finally, as long as anhydrous conditions are maintained, a library of corresponding amides can be prepared in an automated fashion. Using an autosampler with Automatic Loop Filling (ALF™, Uniqsis), 1 equivalent of ester intermediate (6-14, 0.3 mmol) and a solution containing 10 equivalents of DIPEA, 4 equivalents of dimethyl aluminium chloride (1 M in hexane) and 5 equivalents of amine were respectively filled in sample loop A (1 mL) and sample loop B (1 mL); when the amine was dimethylamine (2 M in THF), the mixture was cooled at 0 °C prior to injection. Both delivery pumps were running at 0.05 mL/min and the mixture was injected then mixed at a standard T-connector and passed through a 14 mL CFC reactor heated at 40 °C. The exiting mixture was passed through a column packed with 0.5 g of IRA- 743 (polyol resin) and a plug of silica gel to conveniently remove the aluminium salts and the excess of base. Final compounds 1, 2, 15-25 were collected using a Uniqsis fraction collector, evaporated S7

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and analyzed. For each reaction, a 10 µL aliquot of the reaction mixture was also automatically collected and transferred into a 2 mL LC-MS vial containing PBS. These samples were then used to run automated FAC experiments.

N N,N- dimethyl-2- (6-methyl-2-p-tolylimidazo [1,2-a] pyridin-3-yl) acetamide N (zolpidem) 1: White solid, isolated yield = 90%. In agreement with the O 1 [3, 5, 7] NMe2 structural data as reported in literature. + 1 Rt = 3.94 min. HRMS (ESI): m/z: calcd for C19H22N3O [M+H ]: 308.1752; found 308.1763. H NMR 4 3 3 (CDCl3, 400 MHz): 7.99 (d, J H-H = 1.7 Hz, CH),.7.53 (d, J H-H = 7.4 Hz, 2×CH), 7.51 (d, J H-H = 9.2 Hz, 3 3 4 CH), 7.25 (d, J H-H = 7.4 Hz, 2×CH), 7.03 (dd, J H-H = 9.2 Hz, J H-H = 1.7 Hz, CH), 4.07 (s, CH2), 2.94 (s, 13 CH3), 2.87 (s, CH3), 2.39 (s, CH3), 2.33 (s, CH3). C NMR (CDCl3, 100 MHz): 168.3 (Camide), 144.1 (C), 143.7 (C), 137.5 (C), 131.8 (C), 129.4 (2×CH), 128.5 (2×CH), 127.6 (CH), 122.3 (CH), 121.8 (C), 116.6

(CH), 113.7 (C), 37.6 (CH3), 35.9 (CH3), 30.3 (CH2), 21.3 (CH3), 18.5 (CH3).

N 2-(6-chloro-2- (4-chlorophenyl) imidazo[1,2-a] pyridin-3-yl) -N,N-dipropyl Cl N Cll acetamide (alpidem) 2: White solid, isolated yield = 36 %. In agreement with O 2 [4] NPr2 the structural data reported in literature. + 1 Rt = 4.84 min. HRMS (ESI): m/z: calcd for C21H24Cl2N3O [M+H ]: 404.1298; found 404.1296. H NMR 3 3 3 (CDCl3, 400 MHz): 8.26 (s, CH), 7.58 (d, JH-H = 8.4 Hz, 2×CH), 7.56 (d, JH-H = 9.6 Hz, CH), 7.43 (d, JH-H 3 3 3 = 8.4 Hz, 2×CH), 7.17 (d, JH-H = 9.6 Hz, CH), 4.06 (s, CH2), 3.31 (t, JH-H = 7.4 Hz, CH2), 3.14 (t, JH-H = 3 3 13 7.4 Hz, CH2), 1.54 (m, 2×CH2), 0.87 (t, JH-H = 7.4 Hz, CH3), 0.78 (q, JH-H = 7.4 Hz, CH3). C NMR

(CDCl3, 100 MHz): 167.2 (Camide), 143.6 (C), 140.1 (C), 134.2 (C), 132.7 (C), 129.9 (2×CH), 129.0

(2×CH), 126.1 (CH), 122.7 (CH), 120.7 (C), 117.8 (CH), 115.6 (C), 50.1 (CH2), 37.6 (CH2), 30.1 (CH2),

22.2 (CH2), 20.1 (CH2), 11.3 (CH3), 11.0 (CH3).

N N,N-dimethyl-2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetamide 15: Yellow solid, N isolated yield = 60% O 15 + NMe2 Rt = 3.48 min. HRMS (ESI): m/z: calcd for C17H18N3O [M+H ]: 280.1450; found 1 3 3 280.1440. H NMR (CDCl3, 400 MHz): δ (ppm) 8.26 (d, J H-H = 6.8 Hz, CH), 7.67 (d, J H-H = 7.4 Hz, 3 3 3 3 2×CH), 7.63 (d, J H-H = 7.4 Hz, CH), 7.45 (t, J H-H = 7.4 Hz, 2×CH), 7.38 (d, J H-H = 7.4 Hz, CH), 7.21 (d, J 3 13 H-H = 6.8 Hz, CH), 6.83 (d, J H-H = 6.8 Hz, CH), 4.14 (s, CH2), 2.93 (s, CH3), 2.86 (s, CH3). C NMR

(CDCl3, 100 MHz): δ (ppm) 168.2 (Camide), 145.2 (C), 144.1 (C), 134.7 (C), 128.7 (2×2×CH), 127.9 (CH),

124.8 (CH), 124.4 (CH), 117.4 (CH), 114.1 (C), 112.2 (CH), 37.5 (CH3), 35.9 (CH3), 30.3 (CH2).

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N N,N-dimethyl-2-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetamide 16: N Yellow solid, isolated yield = 42%. O O 16 + 16 Rt = 3.82 min. HRMS (ESI): m/z: calcd for C18H20N3O [M+H ]: 294.1606; found NMe2 1 3 3 294.1605. H NMR (CDCl3, 400 MHz): δ (ppm) 8.00 (s, CH), 7.65 (d, J H-H = 7.0 Hz, 2×CH), 7.53 (d, J H-H 3 3 = 9.1 Hz, CH), 7.44 (m, 2×CH), 7.36 (d, J H-H = 7.0 Hz, CH), 7.04 (d, J H-H = 9.1 Hz, CH), 4.09 (s, CH2),

13 2.94 (s, CH3), 2.87 (s, CH3), 2.34 (s, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 168.3 (Camide), 144.3 (C), 143.9 (C), 134.9 (C), 128.7 (2×CH), 128.6 (2×CH), 127.7 (CH), 127.6 (CH), 122.3 (CH), 121.8 (C), 116.8

(CH), 113.8 (C), 37.5 (CH3), 35.9 (CH3), 30.3 (CH2), 18.5 (CH3).

N 2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylacetamide 17: N Cll Yellow solid, isolated yield = 99% O 17 + NMe2 Rt = 3.77 min. HRMS (ESI): m/z: calcd for C17H17ClN3O [M+H ]: 314.1055; found

1 3 3 314.1045. H NMR (CDCl3, 400 MHz): δ (ppm) 8.25 (s, CH), 7.63 (d, J H-H = 7.0 Hz, 2×CH), 7.55 (d, J H-H 3 3 = 9.5 Hz, CH), 7.45 (m, 2×CH), 7.38 (d, J H-H = 7.0 Hz, CH), 7.15 (d, J H-H = 9.5 Hz, CH), 4.08 (s, CH2),

13 2.96 (s, CH3), 2.93 (s, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 167.8 (Camide), 145.1 (C), 134.3 (C), 128.7 (2×CH), 128.6 (2×CH), 128.1 (CH), 125.8 (CH), 122.6 (CH), 120.4 (C), 118.7 (C), 117.7 (CH), 115.1

(C), 37.5 (CH3), 35.9 (CH3), 29.9 (CH2).

N N,N-dimethyl-2-(2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide 18: Yellow solid, N isolated yield = 62%. O 18 + NMe2 Rt = 3.91 min. HRMS (ESI): m/z: calcd for C18H20N3O [M+H ]: 294.1601; found

1 3 3 294.1587. H NMR (CDCl3, 400 MHz): δ (ppm) 8.21 (d, J H-H = 7.0 Hz, CH), 7.60 (d, J H-H = 7.0 Hz, CH), 3 3 3 3 7.54 (d, J H-H = 8.0 Hz, 2×CH), 7.24 (d, J H-H = 8.0 Hz, 2×CH), 7.16 (t, J H-H = 7.0 Hz, CH), 6.78 (t, J H-H =

13 7.0 Hz, CH), 4.09 (s, CH2), 2.90 (s, CH3), 2.84 (s, CH3), 2.34 (s, CH3). C NMR (CDCl3, 100 MHz): δ

(ppm) 168.3 (Camide), 145.1 (C), 144.1 (C), 137.6 (C), 131.7 (C), 129.4 (2×CH), 128.5 (2×CH), 124.7 (CH),

124.3 (CH), 117.3 (CH), 113.8 (C), 112.1 (CH), 37.5 (CH3), 35.8 (CH3), 30.3 (CH2), 21.3 (CH3).

N 2-(6-chloro-2-p-tolylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylacetamide 19: N Cll White solid, isolated yield = 87%. O 19 + Rt = 4.01 min. HRMS (ESI): m/z: calcd for C18H19ClN3O [M+H ]: 328.1211; NMe2 1 4 3 found 328.1196. H NMR (CDCl3, 400 MHz): δ (ppm) 8.25 (d, J H-H = 1.9 Hz, CH), 7.55 (d, J H-H = 9.5 3 3 3 4 Hz, CH), 7.53 (d, J H-H = 8.3 Hz, 2×CH), 7.26 (d, J H-H = 8.3 Hz, 2×CH), 7.13 (dd, J H-H = 9.5 Hz, J H-H =

13 1.9 Hz, CH), 4.10 (s, CH2), 2.96 (s, CH3), 2.92 (s, CH3), 2.40 (s, CH3). C NMR (CDCl3, 100 MHz): δ

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(ppm) 167.9 (Camide), 145.2 (C), 143.5 (C), 137.9 (C), 131.3 (C), 129.4 (2×CH), 128.5 (2×CH), 127.6 (CH),

122.6 (CH), 122.3 (C), 117.6 (CH), 114.8 (C), 37.6 (CH3), 35.9 (CH3), 30.3 (CH2), 14.2 (CH3).

Br N 2-(8-bromo -6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl) N N -N,N-dimethylacetamide 20: Yellow solid, isolated yield = 26%. O 20 + e Rt = 4.09 min. HRMS (ESI): m/z: calcd for C19H21BrN3O [M+H ]: 386.0868; found NMe2 1 4 3 386.0858. H NMR (CDCl3, 400 MHz): δ (ppm) 8.03 (d, J H-H = 1.4 Hz, CH), 7.54 (d, J H-H = 8.0 Hz, 4 3 2×CH), 7.33 (d, J H-H = 1.4 Hz, CH), 7.24 (d, J H-H = 8.0 Hz, 2×CH), 4.07 (s, CH2), 2.94 (s, CH3), 2.86 (s,

13 CH3), 2.40 (s, CH3), 2.34 (s, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 168.1 (Camide), 137.8 (2×C), 133.7 (C), 131.4 (C), 129.8 (CH), 129.3 (2×CH), 128.8 (2×CH), 122.0 (CH), 121.9 (C), 115.6 (C), 110.7

(C), 37.6 (CH3), 35.9 (CH3), 30.6 (CH2), 21.3 (CH3), 18.2 (CH3). N 2-(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethyl Cl N acetamide 21: Yellow solid, isolated yield = 59%. O 21 e + NMe2 Rt = 4.03 min. HRMS (ESI): m/z: calcd for C18H19ClN3O [M+H ]: 328.1211;

1 3 found 328.1209. H NMR (CDCl3, 400 MHz): δ (ppm) 7.90 (s, CH), 7.58 (d, J H-H = 6.6 Hz, 2×CH), 7.49 3 3 3 (d, J H-H = 9.2 Hz, CH), 7.40 (d, J H-H = 6.6 Hz, 2×CH), 7.02 (d, J H-H = 9.2 Hz, CH), 4.01 (s, CH2), 2.94 (s,

13 CH3), 2.91 (s, CH3), 2.31 (s, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 168.1 (Camide), 144.3 (C), 142.7 (C), 133.6 (C), 133.4 (C), 129.8 (2×CH), 128.7 (2×CH), 127.8 (CH), 122.1 (CH), 122.0 (C), 116.7 (CH),

114.1 (C), 37.5 (CH3), 35.9 (CH3), 30.1 (CH2), 18.5 (CH3).

N 2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dimethyl Cl N Cll acetamide 22: White solid, isolated yield = 60%. O 22 + e NMe2 Rt = 4.14 min. HRMS (ESI): m/z: calcd for C17H16Cl2N3O [M+H ]: 348.0687;

1 4 3 found 348.0670. H NMR (CDCl3, 400 MHz): δ (ppm) 8.20 (d, J H-H = 2 Hz, CH), 7.58 (d, J H-H = 6.8 Hz, 3 3 3 4 2×CH), 7.56 (d, J H-H = 9.6 Hz, CH), 7.43 (d, J H-H = 6.8 Hz, 2×CH), 7.17 (dd, J H-H = 9.6 Hz, J H-H = 2 Hz,

13 CH), 4.05 (s, CH2), 2.99 (s, 2 CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 167.6 (Camide), 144.0 (C), 143.6 (C), 134.2 (C), 132.7 (C), 129.9 (2×CH), 129.0 (2×CH), 126.1 (CH), 122.5 (CH), 120.6 (C), 117.8 (CH),

115.2 (C), 37.6 (CH3), 36.0 (CH3), 29.8 (CH2).

N 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide 23: Yellow solid, N isolated yield = 93 %. In agreement with the structural data as reported in O 23 NPr NPr2 literature.[5] + 1 Rt = 4.30 min. HRMS (ESI): m/z: calcd for C21H26N3O [M+H ]: 336.2076; found 336.2087. H NMR 3 4 3 4 (CDCl3, 400 MHz): 8.30 (dt, JH-H = 7.0 Hz, JH-H = 1.1 Hz, CH), 7.65 (dt, JH-H = 7.0 Hz, JH-H = 1.1 Hz,

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3 4 3 2×CH), 7.59 (dt, JH-H = 9.0 Hz, JH-H = 1.1 Hz, CH), 7.44 (m, 2×CH), 7.35 (m, CH), 7.16 (ddd, JH-H = 7.0 3 4 3 4 Hz, JH-H = 9.0 Hz, JH-H = 1.1 Hz, CH), 6.78 (td, JH-H = 7.0 Hz, JH-H = 1.1 Hz, CH), 4.11 (s , CH2), 3.22 (t, 3 3 3 J H-H = 7.8 Hz, CH2), 3.00 (t, J H-H = 7.8 Hz, CH2), 1.47 (m, CH2), 1.36 (m, CH2), 0.79 (t, J H-H = 7.4 Hz,

3 13 CH3), 0.60 (q, J H-H = 7.4 Hz, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 167.7 (Camide), 145.1 (C), 143.8 (C), 134.6 (C), 128.7 (2×2×CH), 127.9 (CH), 125.0 (CH), 124.4 (CH), 117.3 (CH), 114.6 (C), 112.1 (CH),

49.8 (CH2), 47.9 (CH2), 30.6 (CH2), 22.1 (CH2), 20.9 (CH2), 11.3 (CH3), 10.8 (CH3).

N N,N-dipropyl-2-(2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide 24: Yellow solid, N isolated yield = 33 %.

O + 24 Rt = 4.40 min. HRMS (ESI): m/z: calcd for C22H28N3O [M+H ]: 350.2227; found NPr2 1 3 3 350.2221. H NMR (CDCl3, 400 MHz): 8.26 (d, JH-H = 7.0 Hz, CH), 7.58 (d, JH-H = 3 3 3 7.0 Hz, CH), 7.54 (d, JH-H = 6.4 Hz, 2×CH), 7.25 (d, JH-H = 6.4 Hz, 2×CH), 7.35 (m, CH), 7.15 (t, JH-H = 3 3 3 7.0 Hz, CH), 6.78 (t, JH-H = 7.0 Hz, CH), 4.10 (s, CH2), 3.22 (t, J H-H = 7.8 Hz, CH2), 3.00 (t, J H-H = 7.8 3 3 Hz, CH2), 2.37 (s, CH3), 1.47 (m, CH2), 1.35 (m, CH2), 0.79 (t, J H-H = 7.4 Hz, CH3), 0.60 (q, J H-H = 7.4

13 Hz, CH3). C NMR (CDCl3, 100 MHz): δ (ppm) 167.8 (Camide), 145.1 (C), 143.8 (C), 134.7 (C), 131.7 (C),

129.4 (2×CH), 128.6 (2×CH), 124.9 (CH), 124.3 (CH), 117.2 (CH), 114.3 (C), 113.1 (CH), 49.8 (CH2),

47.9 (CH2), 30.6 (CH2), 22.1 (CH2), 21.2 (CH3), 20.9 (CH2), 11.3 (CH3), 10.8 (CH3).

N 2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide 25: N Orange solid, isolated yield = 45 %. O 25 + r NPr2 Rt = 4.40 min. HRMS (ESI): m/z: calcd for C23H30N3O [M+H ]: 364.2383; found 1 3 3 364.2365. H NMR (CDCl3, 400 MHz): 8.04 (s, CH), 7.53 (d, JH-H = 8.0 Hz, 2×CH), 7.49 (d, JH-H = 9.2 3 3 3 Hz, CH), 7.24 (d, JH-H = 8.0 Hz, 2×CH), 7.01 (d, JH-H = 9.2 Hz, CH), 4.08 (s, CH2), 3.17 (t, J H-H = 7.8 Hz, 3 13 CH2), 3.03 (t, J H-H = 7.8 Hz, CH2), 2.38 (s, CH3), 2.34 (s, CH3), 1.56 (m, 2×CH2), 0.87 (m, 2×CH3). C

NMR (CDCl3, 100 MHz): δ (ppm) 168.0 (Camide), 144.2 (C), 143.7 (C), 137.5 (C), 131.9 (C), 129.3 (2 CH),

128.5 (2 CH), 124.4 (CH), 122.4 (CH), 121.6 (C), 116.6 (CH), 114.1 (C), 49.8 (CH2), 47.9 (CH2), 30.7

(CH2), 22.5 (CH2), 21.6 (CH3), 21.2 (CH2), 11.6 (CH3), 11.2 (CH3).

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Synthesis of carboxylic acids 26-34

oo R2 l p A N R2 R1 N 3 N R combined 100 psi R1 N O flow rate R3 6-14 of 0.5 mL/min OEt O 26-34 10-70 % 90 °C NaOH 2M Uniqsis Fraction Collector OH EtOH 14 mL (4 equiv.) Uniqsis ALF loop B Using an autosampler with Automatic Loop Filling (ALF™, Uniqsis), 1 equivalent of ester intermediate (6-14) (0.3 mmol) and a solution of 2 M sodium hydroxide in ethanol were respectively filled in sample loops A and B (1 mL loop each). Both delivery pumps were running at a combined flow rate of 0.5 mL/min using 4 equivalents of base relative to the ester intermediate (residence time of 30 min) The mixture was injected then mixed at a standard T-connector and passed through a 14 mL CFC reactor heated at 90 °C. Final compounds 26-34 were collected using a Uniqsis fraction collector, precipitated with a solution of 1 M HCl and analyzed. For each reaction, a 10 µL aliquot of the reaction mixture was also automatically collected and transferred into a 2 mL LC-MS vial containing PBS. Moderate yields obtained through this process are due to the solubility of the final products in aqueous media, even at low pH.

N 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid 26: Yellow solid, isolated yield = N 60 %. O O 26 26 + OH Rt = 3.38 min. HRMS (ESI): m/z: calcd for C15H13N2O2 [M+H ]: 253.0977; found

1 3 3 253.0986. H NMR (CD3OD, 400 MHz): δ (ppm) 8.84 (d, J H-H = 7.0 Hz, CH), 8.05 (m, CH), 7.96 (d, J H-H

13 = 9.0 Hz, CH), 7.73 (m, 2×CH), 7.68-7.56 (m, 4×CH), 4.27 (s, CH2). C NMR (CD3OD, 100 MHz): δ

(ppm) 171.4 (Cacid), 141.1 (C), 135.5 (C), 135.1 (CH), 132.0 (CH), 130.8 (2×CH), 129.8 (2×CH), 128.4

(CH), 127.6 (C), 118.9 (C), 118.6 (CH), 113.0 (CH), 29.8 (CH2).

N 2-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid 27: Yellow solid, N

O isolated yield = 20%. 27 OH + Rt = 3.48 min. HRMS (ESI): m/z: calcd for C16H15N2O2 [M+H ]: 267.1134; found

1 267.1136. H NMR (CD3OD, 500 MHz): δ (ppm) 8.64 (s, CH), 7.87 (m, 2×CH), 7.67 (m, 2×CH), 7.62 (m,

13 3×CH), 4.23 (s, CH2), 2.54 (s, CH3). C NMR (CD3OD, 120 MHz): δ (ppm) 171.5 (Cacid), 139.8 (C), 137.7 (CH), 135.4 (C), 131.9 (CH), 130.7 (2×CH), 129.7 (2×CH), 129.6 (CH), 127.5 (C), 126.1 (CH), 118.6 (C),

112.2 (C), 29.8 (CH2), 18.1 (CH3).

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N 2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid 28: Yellow solid, N Cll isolated yield = 57 %. O 28 + OH Rt = 3.41 min. HRMS (ESI): m/z: calcd for C15H12ClN2O2 [M+H ]: 287.0587; found

1 287.0577. H NMR (CD3OD, 500 MHz): δ (ppm) 8.61 (s, CH), 7.84 (m, CH), 7.72-7.60 (m, 2×CH), 7.51-

13 7.33 (m, 3×CH), 6.63 (m, CH), 4.12 (s, CH2). C NMR (CD3OD, 120 MHz): δ (ppm) 171.2 (Cacid), 157.2 (C), 142.3 (C), 138.9 (CH), 131.9 (C), 128.5 (2×CH), 128.2 (2×CH), 127.8 (C), 123.2 (CH), 121.4 (C),

115.6 (CH), 110.8 (CH), 29.3 (CH2).

N 2-(2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid 29: Yellow solid, isolated yield = N 35 %. O 29 OH + Rt = 4.32 min. HRMS (ESI): m/z: calcd for C16H15N2O2 [M+H ]: 267.1134; found

1 3 3 267.1134. H NMR (CD3OD, 400 MHz): δ (ppm) 8.65 (d, J H-H = 7.0 Hz, CH), 7.84 (m, 2×CH), 7.59 (d, J 13 H-H = 6.9 Hz, 2×CH), 7.40 (m, 2×CH), 7.27 (m, CH), 4.15 (s, CH2), 2.38 (s, CH3). C NMR (CD3OD, 100

MHz): δ (ppm) 172.4 (Cacid), 142.2 (C), 141.7 (C), 137.6 (C), 132.7 (CH), 131.1 (2×CH), 129.6 (2×CH),

127.7 (CH), 126.6 (C), 118.3 (C), 117.2 (CH), 113.9 (CH), 30.6 (CH2), 21.5 (CH3).

N 2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid 30: Yellow solid, N isolated yield = 70%. In agreement with the structural data reported in O 30 [5, 7] OH literature. + 1 Rt = 3.87 min. HRMS (ESI): m/z: calcd for C17H17N2O2 [M+H ]: 281.1290; found 281.1294. H NMR

3 3 (CD3OD, 400 MHz): δ (ppm) 8.61 (s, CH), 7.88 (d, J H-H = 9.1 Hz, CH), 7.83 (d, J H-H = 9.1 Hz, CH), 7.58 3 3 13 (d, J H-H = 8.0 Hz, 2×CH), 7.45 (d, J H-H = 8.0 Hz, 2×CH), 4.22 (s, CH2), 2.53 (s, CH3), 2.45 (s, CH3). C

NMR (CD3OD, 100 MHz): δ (ppm) 170.2 (Cacid), 141.2 (C), 138.4 (C), 136.1 (CH), 134.2 (C), 130.0

(2×CH), 128.2 (2×CH), 128.1 (C), 124.6 (CH), 123.4 (C), 116.8 (C), 110.8 (CH), 28.5 (CH2), 20.0 (CH3),

16.7 (CH3).

N 2-(6-chloro-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid 31: Yellow solid, N Cll isolated yield = 15 %. O 31 + OH Rt = 3.88 min. HRMS (ESI): m/z: calcd for C16H14ClN2O2 [M+H ]: 301.0744;

1 3 found 301.0742. H NMR (CD3OD, 400 MHz): δ (ppm) 8.91 (s, CH), 7.82 (m, 2×CH), 7.57 (d, J H-H = 6.4 3 13 Hz, CH), 7.41 (d, J H-H = 6.4 Hz, 2×CH), 7.27 (m, CH), 4.19 (s, CH2), 2.43 (s, CH3). C NMR (CD3OD, 100

MHz): δ (ppm) 170.4 (Cacid), 140.5 (C), 139.6 (C), 137.8 (C), 131.8 (CH), 129.7 (2×CH), 128.2 (2×CH),

128.6 (CH), 124.6 (CH), 123.8 (C), 117.0 (C), 113.4 (C), 28.8 (CH2), 19.9 (CH3).

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Br 2-(8-bromo-6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid 32: Yellow N N solid, isolated yield = 10 %. + O Rt = 4.00 min. HRMS (ESI): m/z: calcd for C17H16BrN2O2 [M+H ]: 359.0395; 32 OH OH 1 found 359.0399. H NMR (CD3OD, 500 MHz): δ (ppm) 8.34 (s, CH), 7.80 (m, CH), 3 3 7.58 (d, J H-H = 8.0 Hz, 2×CH), 7.35 (d, J H-H = 8.0 Hz, 2×CH), 4.07 (s, CH2), 2.45 (s, CH3), 2.41 (s, CH3).

13 C NMR (CD3OD, 125 MHz): δ (ppm) 172.4 (Cacid), 140.7 (C), 135.1 (CH), 130.6 (2×CH), 130.1 (2×CH),

128.7 (C), 126.4 (C), 124.1 (CH), 118.8 (C), 108.3 (C), 30.8 (CH2), 21.4 (CH3), 17.9 (CH3).

N 2-(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)acetic acid 33: Cl N Yellow solid, isolated yield = 62 %. O 33 H + OH Rt = 4.01 min. HRMS (ESI): m/z: calcd for C16H14ClN2O2 [M+H ]: 301.0744;

1 3 found 301.0750. H NMR (CD3OD, 400 MHz): δ (ppm) 8.54 (s, CH), 7.98 (d, J H-H = 8.4 Hz, CH), 7.70 3 3 3 (d, J H-H = 8.4 Hz, 2×CH), 7.62 (d, J H-H = 8.4 Hz, 2×CH), 7.47 (d, J H-H = 8.4 Hz, CH), 4.18 (s, CH2), 2.51

13 (s, CH3). C NMR (CD3OD, 100 MHz): δ (ppm) 170.4 (Cacid), 139.3 (C), 136.2 (C), 135.6 (C), 131.0 (CH),

129.9 (2×CH), 129.3 (2×CH), 128.4 (CH), 127.4 (C), 124.2 (C), 117.3 (C), 111.5 (CH), 28.8 (CH2), 16.8

(CH3).

N 2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetic acid 34: Cl N Cl Yellow solid, isolated yield = 41 %. O O 4 34 + OH Rt = 4.00 min. HRMS (ESI): m/z: calcd for C15H11Cl2N2O2 [M+H ]: 321.0198;

1 found 321.0204. H NMR (CD3OD, 400 MHz): δ (ppm) 9.06 (s, CH), 7.99 (m, 2×CH), 7.73-7.45 (m,

13 4×CH), 4.26 (s, CH2). C NMR (CD3OD, 100 MHz): δ (ppm) 169.8 (Cacid), 138.7 (C), 136.8 (C), 134.5 (C), 134.0 (CH), 130.0 (2×CH), 129.6 (2×CH), 125.3 (CH), 125.2 (C), 125.1 (C), 118.3 (C), 112.8 (CH), 28.6

(CH2).

References [1] S.S. Bhella, M. Elango, M.P.S. Mohar, Tetrahedron 2009, 65, 240-246 [2] H.-H. Lu, X.-F. Wang, C.-J. Yao, J.-M. Zhang, H. Wu, W.-J Xiao, Chem. Commun. 2009, 4251- 4253 [3] N. Chernyak, V. Gevorgyan, Angew. Chem. Int. Ed. 2010, 49, 2743-2746 [4] G. Trapani, M. Franco, L. Ricciardi, A. Latrofa, G. Genchi, E. Sanna, F. Tuveri, E. Cagetti, G. Biggio, G. Liso, J. Med. Chem. 1997, 40, 3109-3118 [5] Y. Sumalatha, T.R. Reddy, P.P. Reddy, B. Satyanarayana, Arkivoc 2009, 315-320 [6] T. Gustafsson, F. Pontén, P. H. Seeberger, Chem. Commun. 2008, 1100-1102

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[7] J.-P. Kaplan, P. George, US 4,382,938 1983

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