4532-25-6|7-Chloroimidazo[1,2-a]pyridine| Ambeed

Structure of 4532-25-6

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Quality Control of [ 4532-25-6 ] Purity: 97% SDS Specification

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Product Details of [ 4532-25-6 ]

CAS No. :	4532-25-6
Formula :	C₇H₅ClN₂
M.W :	152.58
SMILES Code :	ClC1=CC2=NC=CN2C=C1
MDL No. :	MFCD08275126
InChI Key :	NGHRUBVFDAKWBC-UHFFFAOYSA-N
Pubchem ID :	19695901

Safety of [ 4532-25-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 4532-25-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	40.2
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	17.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.87
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.39
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.99
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.32
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.63
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.84

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.96
Solubility	0.168 mg/ml ; 0.0011 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.39
Solubility	0.615 mg/ml ; 0.00403 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.68
Solubility	0.316 mg/ml ; 0.00207 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.53 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.44

Application In Synthesis of [ 4532-25-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 4532-25-6 ]

[ 4532-25-6 ] Synthesis Path-Downstream 1~35

1
[ 4532-25-6 ]
[ 563-47-3 ]
[ 136117-81-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

3
[ 4532-25-6 ]
[ 136117-77-6 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

4
[ 4532-25-6 ]
[ 136117-86-7 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

5
[ 4532-25-6 ]
[ 136117-90-3 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

6
[ 700871-79-0 ]
[ 4532-25-6 ]
[ 705263-27-0 ]

Yield	Reaction Conditions	Operation in experiment
15%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; benzene; at 100℃; for 67h;	Combine 7-chloro-imidazo [1, 2-a] pyridine (PCT Appl. WO 01/38326 A2; 134 mg, 0.88 mmol) with 2- (pyridin-2-yl)-5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazole-3-boronic acid (Preparation 5; 369 mg, 0.97 mmol) in the presence of tetrakis (triphenylphosphine) palladium (0) (30 mg, 0.03 mmol) and 2M aqueous sodium bicarbonate (1.0 mL) in benzene (2.1 mL) and ethanol (0.3 mL). Heat the mixture for 67 h at 100 C. Dilute the reaction with methylene chloride (10 mL) and water (10 mL). Separate the layers and extract the aqueous layer with methylene chloride (2 x 10 mL). Combine the organic layers and dry over sodium sulfate. Filter the solution and evaporate the solvent. Purify the crude product by flash chromatography using the appropriate ammonia in methanol/methylene chloride mixture to give the title compound as a tan solid (41 mg, 15%). MS m/e (302.0, M+1). 1H NMR (CDC13) 8 8.57 (m, 1 H), 7.96 (dd, J = 1, 7 Hz, 1 H), 7.6 (m, 5 H), 7.19 (m, 1 H), 6.69 (dd, J = 1, 7 Hz, 1 H), 4.27 (t, J=8HZ, 2H), 3.08 (t, J=7HZ, 2H), 2.71 (q, J=7HZ, 2H).

References: [1]Patent: WO2004/50659,2004,A1 .Location in patent: Page 80.

7
[ 4532-25-6 ]
[ 73183-34-3 ]
[ 908268-52-0 ]

Yield	Reaction Conditions	Operation in experiment
90%		Combine <strong>[4532-25-6]7-chloro-imidazo[1,2-a]pyridine</strong> (500.4 g, 3.28 mol), bis(pinacolato)diboron (999 g; 3.93 mol), tricyclohexylphosphine (92 g; 328.06 mmoles), and potassium acetate (483 g; 4.92 mol), in diglyme (4 L) and water (4.83 mL) and stir for 5 min. Add palladium (II) acetate (36.81 g; 163.96 mmoles) and more diglyme (1 L) and heat to 100 C. for 17 hours. Cool the reaction and add potassium carbonate (340 g; 2.46 moles) and stir 18 hr. Filter reaction slurry and wash solids with diglyme (21 L). Slurry the solids in water (5 L) and then filter and wash with water (21 L) and heptane (1 L). Dry the solid in a vacuum oven at 60 C. to afford 695.1 g (90%) of the titled product. MS (m/z): 245 (M+1).
	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 80℃;	Preparation 27; 3-Iodo-7-pyridin-2-yl-imidazo[l,2-a]pyridine A. 7-Pyridin-2-yl-imidazo[l,2-a]pyridineTo a round bottomed flask add 7-chloro-imidazo[l,2-a]pyridine (0.25 g, 1.6 mmol), tricyclohexylphosphine (55 mg, 0.12 equiv.), potassium acetate (0.24 g, 1.5 equiv.), bis(pinacolato)diboron (0.46 g, 1.1 equiv.) and dioxane (10 mL). Deoxygenate this mixture thoroughly with N2 then add tris(dibenzylideneacetone)dipalladium (0) (75 mg, 0.05 equiv.) and heat the reaction to 80 C overnight under N2. Filter the reaction thru Celite and wash with DCM then concentrate to dryness. To this residue, add 2- bromopyridine (0.14 mL, 1.5 mmol), S-Phos (75 mg, 0.125 equiv.), potassium phosphate (0.62 g, 2 equiv.), dioxane (10 mL), and water (5 mL). Deoxygenate this mixture thoroughly with N2, add palladium (II) acetate (16 mg, 0.05 equiv.), and reflux the reaction overnight. Concentrate the reaction to dryness and slurry in DCM. Filter this slurry thru Celite and wash with DCM. Concentrate the filtrate then purify by silica column (EtOAc to 5% MeOH : DCM) to give a residue (0.325 g, >100 %). MS (ES), m/z 196 (M+l).
	With potassium carbonate; tricyclohexylphosphine;palladium diacetate; In water; diethylene glycol; at 100℃; for 15h;Inert atmosphere;	7-Chloro-imidazo[1,2-a]pyridine (10 g; 65.54 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (19.93 g; 78.65 mmol), K2CO3 (13.59 g; 98.31 mmol), tricyclohexylphosphine (1.84 g; 6.55 mmol), Palladium acetate (47% Pd) (0.74 g; 3.28 mmol) in 2-methoxyethylether (100 ml) and water (0.13 ml) were heated to 100 C. for 15 hours under N2. The reaction mixture was cooled to room temperature. The mixture was cooled to 5 C., filtered, washed the cake with 2×10 ml of water and poured into in 50 ml of water then filtered and the insoluble was washed with 2×20 ml of water, dried to give 11.25 g (70.396) of intermediate shown.

With potassium carbonate; tricyclohexylphosphine;palladium diacetate; In water; at 100℃;

To a solution of 7-chloroimidazo-[1 ,2,a]pyridine (10 g, 65.5 mmol) and bis(pinocolato)diboron (20 g, 78.7 mmol) in diglyme (100 ml) were added K2CO3 (13.5 g, 97.7 mmol), palladium (II) acetate (730 mg, 3.25 mmol), tricyclohexylphosphine (1.8 g, 6.42 mmol) and water (0.14 ml). The resulting mixture was heated at 100 0C overnight under an inert atmosphere, diluted with water (50 ml) and stirred for 1 h at room temperature. The precipitate was separated by filtration, washed with diglyme/water (2/1 , 30 ml) and water (20 ml) then dried to generate the product (7.58 g) as a grey powder. MS: [M+H]+ = 246.

References: [1]Patent: US2009/111800,2009,A1 .Location in patent: Page/Page column 45.
[2]Patent: WO2006/91671,2006,A1 .Location in patent: Page/Page column 27.
[3]Patent: US2012/41000,2012,A1 .Location in patent: Page/Page column 36.
[4]Patent: WO2009/150240,2009,A1 .Location in patent: Page/Page column 110.

8
[ 4532-25-6 ]
[ 908267-60-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With N-iodo-succinimide; In acetonitrile; for 0.5h;	Preparation 22; 3-Iodo-7-chloro-imidazo[l,2,a]pyridineTo a solution of 7-chloro-imidazo[l,2,a]pyridine (6.10 g, 40 mmol) (Yamanaka, Motosuke et al., Chemical & Pharmaceutical Bulletin (1991), 39(6), 1556-67) in dry acetonitrile (100 mL), add N-iodosuccinamide. Stir for 30 minutes. Filter off the precipitate and then wash with acetonitrile. Recrystallize the precipitate from acetonitrile to give a white solid. Concentrate the filtrate, dilute with ethyl acetate, wash with 10% sodium hydrogensulfite (NaHSO3), saturated aqueous sodium bicarbonate, saturated aqueous NaCl, dry over MgSO4, filter and evaporate. Use the combined solid without further purification (8.0 g, 73%). 1H NMR (DMSO) delta 8.33 (d, IH, J = 7.3 Hz), 7.79 (d, IH, J = 2.0 Hz), 7.72 (s, IH), 7.07 (dd, IH, J = 7.3 and 2.0 Hz).
50%	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 6h;	Synthesis of 7-Chloro-3-iodoimidazo [1 ,2-a]pyridine (compound 65-4)[0000230] To a solution of compound 65-3 (450 mg, 2.9 mmol, 1 equiv) in dimethyl formamide (4.5 mL) was added Niodosuccinimide (700 mg, 3.1 mmol, 1.05 equiv) . The reaction was stirred at room temperature for 6 hours followed by the addition of water (20 ml) and ethyl acetate (20 ml) . The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 5 ml) . The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to a black residue. The residue from 2 runs was chromatographed on an AnaLogix 8g column using a gradient of 0-70% ethyl acetate in heptanes. The product containing fractions were combined and washed with saturated sodium thiosulfate solution (2 x 20 ml) to remove the remaining iodine color. The fractions were concentrated to give compound 65-4 as a white solid (829 mg, 50% yield)
38%	With N-iodo-succinimide; In acetonitrile; at 20℃; for 3h;	(2b) 7-Chloro-3-iodoimidazo[1,2-a]pyridine Into acetonitrile (40 mL), <strong>[4532-25-6]7-chloroimidazo[1,2-a]pyridine</strong> (635 mg, 4.16 mmol) produced in Example 2 (2a) was dissolved, to which N-iodosuccinimide (936 mg, 4.16 mmol) was added, followed by stirring at room temperature for three hours. A solid precipitated, which was collected by filtration and purified by basic silica gel column chromatography (dichloromethane : ethyl acetate = 4 : 1, V/V) to give the desired title compound (436 mg, yield 38%). 1H-NMR (CDCl3) 5: 6.92 (1H, dd, J = 7.3, 1.8 Hz), 7.63 (1H, d, J = 1.8 Hz), 7.69 (1H, s), 8.06 (1H, d, J = 7.3 Hz).

	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃;	Procedure A2 - General iodination; To a solution of 7-Chloro-imidazo[1 ,2-a]pyridine (30.9 g, 186 mmol, 1.0 equiv) in DMF (280ml) was added N-iodosuccinimide (43.6 g, 194 mmol, 1.05 equiv) and the resulting mixture was stirred overnight at RT. The thin brown slurry was diluted with water (840ml), brine (280ml) and extracted with EtOAc (560 ml). The aqueous layer was further extracted with EtOAc (3 x 280ml). The combined organic phases were washed with water (2 x 280ml), 10%w/v sodium thiosulfate (280 ml), brine (280 ml), dried (MgSO4), filtered and concentrated in vacuo to give a brown residue. The residue was triturated with ether (200ml), filtered and the solid was washed with ether (2 x 50ml) and dried on the filter to give 39 g of product.
	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃;	To a solution of 7-Chloro-imidazo[1 ,2-a]pyridine (30.9 g, 186 mmol, 1.0 equiv) in DMF (280ml) was added N-iodosuccinimide (43.6 g, 194 mmol, 1.05 equiv) and the resulting mixture was stirred overnight at RT. The thin brown slurry was diluted with water (840ml), brine (280ml) and extracted with EtOAc (560 ml). The aqueous was further extracted with EtOAc (3 x 280ml). The combined organic phases were washed with water (2 x 280ml), 10%w/v sodium thiosulfate (280 ml), brine (280 ml), dried (MgSO4) and concentrated in vacuo to give a brown residue. The residue was triturated with ether (200ml), filtered and the solid was washed ether (2 x 50ml) and dried on the filter to give 39 g of product. MS: [M+H]+ 279
1.58 g	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of 7-chloroimidazo[l,2-a]pyridine (7.78 mmol, 1.0 eq) in DMF (12 mL) at rt was added N-iodosuccinimide (1.84 g, 8.17 mmol, 1.05 eq). After 16 h, the brown slurry was diluted with H2O (100 mL) and Brine (15 mL). The mixture was extracted with EtOAc (100 mL). The aqueous layer was re-extracted with EtOAc (100 mL) and the collected organic layers were washed with H2O (2 x 20 mL), 10% sodium thiosulfate (20 mL), Brine (20 mL) and dried (MgSC ). After filtration, the solution was concentrated. The residue was triturated with diethyl ether (15 mL) and filtered to afford an off-white solid (1.58 g, 73% yield over 2 steps). (0246) LCMS: RT = 0.265 min, >98% 215 and 254 nM, m/z = 279.0 [M + H]+.
	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃;	To a solution of 7-Chloro-imidazo[1 ,2-a]pyridine (30.9 g, 186 mmol, 1.0 equiv) in DMF (280ml) was added N-iodosuccinimide (43.6 g, 194 mmol, 1.05 equiv) and the resulting mixture was stirred overnight at RT. The thin brown slurry was diluted with water (840ml), brine (280ml) and extracted with EtOAc (560 ml). The aqueous layer was further extracted with EtOAc (3 x 280ml). The combined organic phases were washed with water (2 x 280ml), 10%w/v sodium thiosulfate (280 ml), brine (280 ml), dried (MgSO4), filtered and concentrated in vacuo to give a brown residue. The residue was triturated with ether (200ml), filtered and the solid was washed with ether (2 x 50ml) and dried on the filter to give 39 g of product. MS: [M+H]+ = 279.

References: [1]Patent: WO2006/91671,2006,A1 .Location in patent: Page/Page column 25.
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 750 - 756.
[3]Patent: WO2013/123215,2013,A2 .Location in patent: Paragraph 0000230.
[4]Patent: EP2565185,2013,A1 .Location in patent: Paragraph 0116.
[5]Patent: WO2008/78100,2008,A2 .Location in patent: Page/Page column 93-94.
[6]Patent: WO2009/47506,2009,A1 .Location in patent: Page/Page column 111.
[7]Patent: WO2018/136634,2018,A1 .Location in patent: Page/Page column 41.
[8]Patent: WO2009/150240,2009,A1 .Location in patent: Page/Page column 101.

9
[ 110-91-8 ]
[ 4532-25-6 ]
[ 1036761-88-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 80℃;	Procedure E; To a solution of 7-Chloro-imidazo[1 ,2-a]pyridine (1.0g, 6.58mmol) in anhydrous dioxane (60ml) was added morpholine (0.64ml, 6.58mmol), NaO'Bu (1.9g, 19.74mmol) [reaction degassed by bubbling N2 through] followed by BINAP (0.43g, 0.69mmol) and Pd2dba3 (tris- (dibenzylideneacetone)dipalladium(O)) (0.32g, 0.36mmol). The mixture was heated at 80 0C overnight, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude <n="102"/>residue was purified by silica chromatography to give the desired product (0.55g) MS: [M+H]+ 204.

References: [1]Patent: WO2008/78100,2008,A2 .Location in patent: Page/Page column 100-101.

10
[ 107-20-0 ]
[ 19798-80-2 ]
[ 4532-25-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium hydrogencarbonate; In ethanol; water; at 20℃; for 20h;Reflux;	Synthesis of 7-Chloroimidazo[1 , 2-a]pyridine (compound 65-3)[0000229] To a suspension of compound 65-2 (HC1) in ethanol (15 mL) was added sodium bicarbonate powder (3.3g, 38.4 mmol, 4 equiv) and a 50% solution of chloroacetaldehyde in water (2.26 g, 14.4 mmol, 1.5 equiv) . The reaction was heated at reflux for 4 hours and stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure and the residue was dissolved in water (10 mL) and ethyl acetate (10 mL) . The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 5 mL) . The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give compound 65-3 as a dark yellow oil (980 mg, 89% yield)
85%	In ethanol; water; for 2h;Reflux;	(2a) 7-Chloroimidazo[1,2-a]pyridine Into ethanol (50 mL), 2-amino-4-chloropyridine (643 mg, 5.00 mmol) was dissolved, to which a 40% aqueous solution of chloroacetaldehyde (8.25 mL, 50 mmol) was added, followed by heating under reflux for two hours. The resulting mixture was left to cool, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (dichloromethane) to give the desired title compound (645 mg, yield 85%). 1H-NMR (CDCl3) delta: 6.79 (1H, dd, J = 7.4, 2.3 Hz), 7.57 (1H, s), 7.63 (2H, br s), 8.05 (1H, d, J = 7.4 Hz).
79%	In water; butan-1-ol; at 130℃; for 12h;	General procedure: 2-aminopyridine (15 g, 0.159 M) was dissolved in 1-butanol (64 mL) in a 250 mL round bottom flask affixed with a magnetic stir bar. 2-chloroacetaldehyde 50% solution in water (24.3 mL, 0.191 M) was added hitherto and the reaction was heated to 130 C for 12 h.The reaction solvent was condensed in vacuo and the crude product was adsorbed onto silica. The product was purified via flash chromatography utilizing a DCM/MeOH gradient and isolated as a light, yellow oil (17 g, 90%).

	With sodium hydrogencarbonate; In ethanol; for 6h;Heating / reflux;	General Route A; Procedure A1 - General im idazopyridine ring formation; To a solution of 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (19.0 ml, 150 <n="95"/>mmol, 1.5 equiv). The mixture was refluxed for 6 h. Solvents removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAC-petrol) to afford 13.2 g of product.
	With sodium hydrogencarbonate; In ethanol; for 6h;Heating / reflux;	To a solution of 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 equiv). The mixture was refluxed <n="112"/>for 6 h. Solvents removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAC-petrol) to afford 13.2 g of product. MS: [M+H]+ 153
	With sodium hydrogencarbonate; In ethanol; for 17h;Heating / reflux;	4-Chloro-pyridin-2-ylamine (1 eq, 38.9 mmol, 5 g) is added to a solution of chloroacetic aldehyde (3 eq, 117 mmol, 15.1 ml) in EtOH (60 ml). NaHCO3 (2 eq, 77.8 mmol, 6.53 g) is added and the reaction mixture is heated at reflux for 17 h. The solvent is removed in vacuo and the product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 7-chloro-imidazo- [1,2-a]- pyridine as a red solid; [M+H]+ = 153
	With sodium hydrogencarbonate; In ethanol; water; for 10h;Reflux;	To a mixture of 4-chloropyridin-2-amine (1.0 g, 7.78 mmol, 1.0 eq) and NaHCCb (1.31 g, 15.56 mmol, 2.0 eq) in EtOH (18 mL) was added chloroacetaldehyde, 50% wt in water, (1.48 mL, 11.67 mmol, 1.5 eq). The reaction mixture was heated to reflux. After 10 h, the solvent was removed under reduced pressure and the residue was partitioned between EtOAc: H20 (1 : 1, 100 mL). The organic layer was washed with Brine (50 mL), dried (MgS04), filtered and concentrated. The material was taken through without further purification. (0243) LCMS: RT = 0.123 min, >98% 215 and 254 nM, m/z = 153.0 [M + H]+.
	With sodium hydrogencarbonate; In ethanol; for 6h;Reflux;	To a solution of 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 equiv). The mixture was refluxed for 6 h. Solvents removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAC-petrol) to afford 13.2 g of product. MS: [M+H]+ = 153.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 750 - 756.
[2]Patent: WO2013/123215,2013,A2 .Location in patent: Paragraph 0000229.
[3]Patent: EP2565185,2013,A1 .Location in patent: Paragraph 0114-0115.
[4]European Journal of Medicinal Chemistry,2015,vol. 94,p. 123 - 131.
[5]Patent: WO2008/78100,2008,A2 .Location in patent: Page/Page column 93-94.
[6]Patent: WO2009/47506,2009,A1 .Location in patent: Page/Page column 110; 111.
[7]Patent: WO2009/50183,2009,A2 .Location in patent: Page/Page column 114.
[8]Patent: WO2018/136634,2018,A1 .Location in patent: Page/Page column 40; 41.
[9]Patent: WO2009/150240,2009,A1 .Location in patent: Page/Page column 101.

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