[ CAS No. 24016-03-3 ] {[proInfo.proName]}

Name: 24016-03-3|2-Amino-3-benzyloxypyridine|98%
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CAS No. :	24016-03-3	MDL No. :	MFCD00006316
Formula :	C₁₂H₁₂N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NMCBWICNRJLKKM-UHFFFAOYSA-N
M.W :	200.24	Pubchem ID :	90334
Synonyms :

Safety of [ 24016-03-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 24016-03-3 ]

* 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.

Upstream synthesis route of [ 24016-03-3 ]
Downstream synthetic route of [ 24016-03-3 ]

[ 24016-03-3 ] Synthesis Path-Upstream 1~15

1
[ 24016-03-3 ]
[ 16867-03-1 ]

Reference： [1] European Journal of Organic Chemistry, 2003, # 9, p. 1681 - 1686

2
[ 16867-03-1 ]
[ 100-44-7 ]
[ 24016-03-3 ]

Yield	Reaction Conditions	Operation in experiment
77.3%	With tetrabutylammomium bromide; sodium hydroxide In water at 40 - 75℃; for 6 h; Large scale	temperature below 40 ° C, to the 300L stainless steel reactor 48L of purified water was added slowly stirring 48kg sodium hydroxide, stirring until dissolved.To sodium hydroxide solution followed by adding 16kg 2-amino-3-hydroxypyridine, 1.6kg tetrabutylammonium bromide, 17.92L benzyl chloride, plus warming to 70 ~ 75 ° C reaction 6 hours, stirring was stopped,Let stand, liquid separation; aqueous phase extraction with toluene (20Lx3);Purified water washing (30Lx2), the organic phase was collected, concentrated to a large amount of solid precipitation, temperature 0 ~ 5 ° C, crystallization was stirred for 2 hours, centrifuged,The filter cake was rinsed with 3.2 L of pre-cooled toluene and dried under vacuum at 50~55 ° C. for 3 hours to afford Intermediate II as a bright yellow solid, 22.5 kg of 2-amino-3-benzyloxypyridine, with a molar yield of 77.3percent , Purity 99.53percent.
60%	With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 20℃; for 19 h;	2-Amino-3-hydroxypyridine (11 g, 100 mmol), chlorobenzyl (12.66 mL, 110 mmol) and tetrabutylammonium bromide (3 g, 10 mmol) were dissolved in 50 mL of 40percent sodium hydroxide solution and 50 mL of dichloromethane The mixture was stirred at room temperature for 19 h. After the reaction is completed, liquid is dispensed, The aqueous phase is diluted with water and extracted three times with dichloromethane. Combine the organic phase, Drying with anhydrous sodium sulfate, Filter and concentrate, Column chromatography of the residue gave the title compound as a brown solid (12 g, 60percent yield).

Reference： [1] Chemistry Letters, 2006, vol. 35, # 3, p. 270 - 271
[2] Synthesis, 1981, # 12, p. 971 - 973
[3] Patent: CN107311998, 2017, A, . Location in patent: Paragraph 0035-0036
[4] Journal of Chemical Research, Miniprint, 1986, # 11, p. 3368 - 3390
[5] Patent: CN103570683, 2018, B, . Location in patent: Paragraph 0927; 0928; 0930; 0931
[6] Heterocycles, 2008, vol. 75, # 6, p. 1355 - 1370
[7] Patent: US4450164, 1984, A,
[8] Patent: WO2004/4720, 2004, A1, . Location in patent: Page/Page column 63-64
[9] Archiv der Pharmazie, 2011, vol. 344, # 3, p. 158 - 164

3
[ 16867-03-1 ]
[ 100-39-0 ]
[ 24016-03-3 ]

Reference： [1] Journal of the American Chemical Society, 2015, vol. 137, # 27, p. 8851 - 8857
[2] European Journal of Medicinal Chemistry, 2017, vol. 128, p. 56 - 69
[3] Patent: WO2017/87905, 2017, A1, . Location in patent: Page/Page column 243
[4] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 322 - 334

4
[ 16867-03-1 ]
[ 24016-03-3 ]

Reference： [1] Tetrahedron Letters, 1985, vol. 26, # 21, p. 2571 - 2574

5
[ 24016-03-3 ]
[ 39903-01-0 ]

Reference： [1] Archiv der Pharmazie, 2011, vol. 344, # 3, p. 158 - 164

6
[ 24016-03-3 ]
[ 69214-22-8 ]

Reference： [1] Journal of Chemical Research, Miniprint, 1986, # 11, p. 3368 - 3390

7
[ 24016-03-3 ]
[ 609-15-4 ]
[ 96428-50-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	at 100℃; for 48 h; Molecular sieve	Example 1A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two tablespoons of 4 A molecular sieve were added, and the reaction mixture was then heated at reflux (bath temperature 100° C.) for 2 days. The mixture was concentrated, and excess ethyl 2-chloroacetoacetate was removed on a rotary evaporator with dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate gradient 9:1, 4:1). This gave 20.81 g of the target compound (54percent of theory, purity 99percent). LC-MS (Method 2): R_t=1.12 min MS (ESpos): m/z=311 (M+H)⁺ ¹H NMR (400 MHz, DMSO-d₆): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).
54%	at 100℃; for 48 h; Molecular sieve	Example 29A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, and 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 Å molecular sieve were added. The mixture was heated at reflux for 2 d (bath temperature 100° C.). The mixture was then concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator with dry ice-cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate 9:1, 4:1). This gave 20.81 g of the title compound (54percent of theory). LC-MS (Method 1): R_t=1.12 min MS (ESpos): m/z=311 (M+H)⁺ ¹H NMR (400 MHz, DMSO-d₆): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).
54%	at 100℃; for 48 h; Molecular sieve	Example 23A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two table spoons of 4 A molecular sieve were added and the reaction mixture was then heated at reflux (bath temperature 100° C.) for 2 days. The mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling. The residue was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient-9/1, 4/1). This gave 20.81 g of the target compound (54percent of theory, purity 99percent). LC-MS (Method 2): R_t=1.12 min MS (ESpos): m/z=311 (M+H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).

54%

at 100℃; for 48 h; Molecular sieve

25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 A molecular sieve were added and the mixture was heated at reflux (bath temperature 100° C.) for 2 d. Then, the mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate=9:1, 4:1). This gave 20.81 g of the title compound (54percent of theory).10693] LC-MS (Method 2): R=1.12 mm10694] MS (ESpos): mlz=311 (M+H)10695] ‘H-NMR (400 MHz, DMSO-d5): ö=1.35 (t, 3H),2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H),7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).

Reference： [1] Patent: US2014/128386, 2014, A1, . Location in patent: Paragraph 0984; 0985; 0986; 0987; 0988
[2] Patent: US2014/128372, 2014, A1, . Location in patent: Paragraph 0489; 0490; 0491; 0492; 0493
[3] Patent: US2017/57954, 2017, A1, . Location in patent: Paragraph 0620; 0621; 0622; 0623; 0624
[4] Patent: US2016/347770, 2016, A1, . Location in patent: Paragraph 0691; 0692; 0693; 0694; 0695
[5] Journal of Medicinal Chemistry, 1985, vol. 28, # 7, p. 876 - 892

8
[ 537-46-2 ]
[ 24016-03-3 ]
[ 609-15-4 ]
[ 96428-50-1 ]

Reference： [1] Patent: US2017/217954, 2017, A1,

9
[ 24016-03-3 ]
[ 173530-73-9 ]

Reference： [1] Patent: US2014/128386, 2014, A1,
[2] Patent: US2017/217954, 2017, A1,

10
[ 24016-03-3 ]
[ 609-15-4 ]
[ 173530-73-9 ]

Reference： [1] Patent: US2017/57954, 2017, A1,

11
[ 24016-03-3 ]
[ 891785-18-5 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 45, p. 8757 - 8762

12
[ 24016-03-3 ]
[ 754230-78-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sulfuric acid; bromine; acetic acid In water at 0 - 4℃; for 4.5 h;	2-Amino-3-benzyloxypyridine (85.0 g, 0.42 mol) was dissolved in a 10 percent aqueous solution of sulphuric acid (1000 ml). The yellow solution was cooled to 0 to 4 °C and a solution of bromine (80.5 g, 0.50 mol) in acetic acid (276 g, 4.6 mol) was added dropwise over a period of 2 hours. A red suspension was obtained which was stirred for 2.5 hours at 0 °C and was then poured onto a mixture of ice water (500 ml) and dichloromethane (1000 ml). A pH-value of 8 was adjusted by addition of 25 percent aqueous ammonia solution (approx. 600 ml) to the well-stirred biphasic mixture. The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 500 ml). The combined organic phases were washed with water (400 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography [1 kg of silica gel, eluant : petrol ether/ethyl acetate = 7: 3 (v/v) ]. Thus, 96.0 g of the title compound were isolated in form of a brown solid (81 percent yield). Melting point: 109-110 °C 'H-NMR (CDCI3, 200 MHz): 8= 4.73 (bs, 2 H), 5.04 (s, 2 H), 7.08 (d, 1 H), 7.40 (me, 5 H), 7.73 (d, 1 H).
81%	Stage #1: With sulfuric acid; bromine; acetic acid In water at 0 - 4℃; for 4.5 h; Stage #2: With ammonia In water	IV. Starting Compounds and Intermediates; Synthesis ofintermediates for racemic 7H-8, 9-dihydro-pvranof2, 3-cl-imidazo ( ?, 2- alpvridines via cross metathesis; i. 2-Amino-3-benzyloxy-5-bromo-pyridine; 2-Amino-3-benzyloxypyridine (85. 0 g, 0.42 mol) was dissolved in a 10 percent aqueous solution of sulphuric acid (1000 ml). The yellow solution was cooled to 0 to 4 °C and a solution of bromine (80.5 g, 0.50 mol) in acetic acid (276 g, 4.6 mol) was added dropwise over a period of 2 h. A red suspension was ob- tained which was stirred for 2.5 h at 0 °C and was then poured onto a mixture of ice water (500 mi) and dichloromethane (1000 ml). A pH-value of 8 was adjusted by addition of 25 percent aqueous ammonia solu- tion (approx. 600 ml) to the well-stirred biphasic mixture. The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 500 ml). The combined organic phases were washed with water (400 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography [1 kg of silica gel, eluant : petrol ether/ethyl acetate = 7: 3 (v/v) ]. Thus, 96.0 g of the tide compound were isolated in form of a brown solid (81 percent yield).
77%	With bromine In dichloromethane at 0℃; for 1.5 h;	Example 84A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0° C. over a period of 30 min. After the addition had ended, the reaction solution was stirred at 0° C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was separated off and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:4), and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound. LC-MS (Method 1): R_t=0.92 min MS (ESpos): m/z=279 (M+H)⁺ ¹H NMR (400 MHz, DMSO-d₆): δ=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).

77%	With bromine In dichloromethane at 0℃; for 1.5 h;	Example 14A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0° C. over a period of 30 min. After the addition had ended, the reaction solution was stirred at 0° C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was separated off and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound. LC-MS (Method 2): R_t=0.92 min MS (ESpos): m/z=279 (M+H)⁺ ¹H NMR (400 MHz, DMSO-d₆): δ=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine In dichloromethane at 0℃; for 1.5 h;	Example 236A 3-(Benzyloxy)-5-bromopyridine-2-amine [1076] 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0° C. over a period of 30 min. After the addition had ended, the reaction solution was stirred at 0° C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was separated off and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound. [1078] LC-MS (Method 2): R_t=0.92 min [1079] MS (ESpos): m/z=279 (M+H)⁺ [1080] ¹H NMR (400 MHz, DMSO-d₆): δ=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H)
77%	With bromine In dichloromethane at 0℃; for 1.5 h;	10600] 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 1 of dichloromethane, and at 00 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 mi Afier the addition had ended, the reaction solution was stirred at 00 C. for 60 mm. About 4 1 of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave214 g (77percent of theory) of the title compound.10601] LC-MS (Method 1): R=0.92 mm10602] MS (ESpos): mlz=279 (M+H)10603] ‘H-NMR (400 MHz, DMSO-d5): ö=5.16 (s, 2H),5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine In dichloromethane at 0℃; for 1.5 h;	Example 19A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and at 0° C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 min. After the addition had ended, the reaction solution was stirred at 0° C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound. LC-MS (Method D): R_t=0.92 min MS (ESpos): m/z=279 (M+H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ=5.16 (s, 2H), 5.94-6.00 (min, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine; sodium hydrogencarbonate In dichloromethane at 0℃; for 1.5 h;	Example 17A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and at 0° C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 min After the addition had ended, the reaction solution was stirred at 0° C. for 60 min About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound. LC-MS (Method 1): R_t=0.92 min MS (ESpos): m/z=279 (M+H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine In dichloromethane at 0℃; for 1.5 h;	Further Preparation Method:10589] 200 g (1 mol) of 2-amino-3-benzyloxypyridinewere initially charged in 4 1 of dichloromethane, and at 00 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichioromethane was added over 30 mm. After the addition had ended, the reaction solution was stirred at 00 C. for 60 mm. About 4 1 of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound.10590] LC-MS (Method 1): R=0.92 mm MS (ESpos): mlz=279 (M+H)j0592] ‘H-NMR (400 MHz, DMSO-d5): ö=5.16 (s, 2H),5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine In dichloromethane at 0℃; for 1.5 h;	200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 1 of dichloromethane, and at 0° C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichioromethane was added over 30 mm. After the addition had ended, the reaction solution was stirred at 0° C. for 60 mm. About 4 1 of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound. LC-MS (Method 1): R=0.92 mm, MS (ESpos): mlz=279 (M+H); ‘H-NMR (400 MHz, DMSO-d5): ö=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine In dichloromethane at 0℃; for 1.5 h;	200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 1 of dichioromethane, and at 00 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 mm. After the addition had ended, the reaction solution was stirred at 00 C. for 60 mm. About 4 1 of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound. LC-MS (Method 1): R=0.92 min. MS (ESpos): mlz=279 (M+H). 1H-NMR (400 Mhz, DMSO-d5): ö=5.16 (s, 2H),5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine In dichloromethane at 0℃; for 1.5 h;	200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 1 of dichloromethane, and at 00 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichioromethane was added over 30 mm Afier the addition had ended, the reaction solution was stirred at 00 C. for 60 mm. The mixture was then quenched with about 4 1 of saturated sodium bicarbonate solution. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether/ethyl acetate=6:4) and the product fractions were concentrated. This gave 214 g (77percent of theory) of the title compound.10534] LC-MS (Method 2): R=0.92 mm10535] MS (ESpos): mlz=279 (M+H)10536] ‘H-NMR (400 MHz, DMSO-d5): ö=5.16 (s, 2H),5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
70%	Stage #1: at 20℃; Stage #2: at 0℃; for 3.58333 h; Stage #3: With ammonia In water	Sulfuric acid (10percent, 160 mL) was introduced in a three necked flask equipped with mechanical stirrer. 3-Benzyloxypyridi-2-ylamine 12 (8 g, 40 mmol) was added at room temperature under efficient stirring. The reaction mixture was cooled at 0 °C, where a mixture of Br₂ (7.68 g, 48.1 mmol) in acetic acid (25 mL) was added dropwise over a period of 35 min. The resulting mixture was stirred for 3 h at 0 °C. Then, ice water (160 mL) was added and the solution was basified by addition of 30percent aqueous ammonia solution. The aqueous phase was extracted with CH₂Cl₂ (thrice). Combined organic layers were washed with water, dried over MgSO₄, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (cyclohexane/EtOAc 8/2, v/v) afforded 13 (8 g, 70percent) as a yellow/orange solid. ¹H NMR (300 MHz, CDCl₃) δ 4.71 (br s, 2H), 5.05 (s, 2H), 7.08 (d, J=1.87 Hz, 1H), 7.37-7.42 (m, 5H), 7.73 (d, J=1.87 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 70.7, 107.0, 119.6, 127.8, 128.7, 128.9, 135.6, 135.6, 139.3, 141.9, 149.1. MS (ESI⁺) m/z (percent): 281 (98), 279 (100).
57%	Stage #1: With bromine In N,N-dimethyl-formamide at 0 - 20℃; for 2 h; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide	To a solution of 3-benzyloxy-pyridin-2-ylamine (2.00 g, 10.0 mmol) in DMF (15 mL) was slowly added bromine (0.56 mL, 11 mmol) at 0 ⁰C, and the mixture was stirred at room <n="100"/>temperature for 2 h. The mixture was diluted with ice-water (25 mL) and neutralized with 3 N NaOH to pH 5-6. The resulting precipitate was collected by filtration to give the title compound (1.6 g, 57percent) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J= 1.8 Hz, IH), 7.42-7.37 (m, 5H), 7.08 (d, J= 2.1 Hz, IH), 5.05 (s, 2H), 4.74 (br s, 2H); ESI MS m/e 219 (M + H)⁺.
53%	With N-Bromosuccinimide In acetonitrile at 0℃; for 1 h;	1. To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH₃CN (600 mL) at 0° C. was added N-bromosuccinimide (37.1 g, 0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with EtOAc (900 mL) and partitioned with H₂O (900 mL). The organic layer was washed with brine and dried (Na₂SO₄), filtered and concentrated to dryness under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53percent). ¹H NMR (CDCl₃, 300 MHz) 64.63-4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).
53%	With N-Bromosuccinimide In acetonitrile at 0℃; for 1 h;	To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH₃CN (600 mL) at 0°C was added N-bromosuccinimide (37.1 g, 0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with EtOAc (900 mL) and partitioned with H₂0 (900 mL). The organic layer was washed with brine and dried (Na₂S0₄), filtered and concentrated to dryness under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53percent). ¹H NMR (CDCI₃, 300 MHz) 6 4.63-4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).
34.3%	With N-Bromosuccinimide In acetonitrile at 0℃; for 0.25 h;	Step A: Preparation of 3-(benzyloxy)-5-bromopyridin-2-arnine:; 3-(Benzyloxy)pyridin-2-amine (25.0 g, 124.9 mmol) was added to acetonitrile (300 mL) and cooled to 0 ⁰C. l-Bromopyrrolidine-2,5-dione (22.22 g, 124.9 mmol) was added portionwise and the reaction mixture was stirred for 15 minutes, then concentrated to dryness. The residue was dissolved in EtOAc and partitioned with water. The organic layer was washed twice with saturated sodium bicarbonate and once with brine. Activated charcoal was added to the organic layer, and the organic layer was warmed to reflux, then cooled, filtered through a plug of celite, and concentrated to give 9.4 g of the title compound. The celite and charcoal were resupended in EtOAc and filtered through a celite plug to give an additional 3.6 g of the title compound, to provide a total of 12.0 g (34.3percent yield). ¹H NMR (CDCl₃) δ 7.74 (d, IH), 7.41 (m, 5H), 7.08 (d, IH), 5.04 (s, 2H), 4.74 (bs, 2H). Mass spectrum (apci) m/z = 279.1 (M+H).

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 19, p. 7669 - 7678
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 24, p. 6240 - 6264
[3] Patent: WO2005/58325, 2005, A1, . Location in patent: Page/Page column 39
[4] Patent: WO2005/90358, 2005, A2, . Location in patent: Page/Page column 74
[5] Journal of the American Chemical Society, 2015, vol. 137, # 27, p. 8851 - 8857
[6] Patent: US2014/128386, 2014, A1, . Location in patent: Paragraph 1273; 1274; 1275; 1276; 1277
[7] Patent: US2014/128425, 2014, A1, . Location in patent: Paragraph 0426-0430
[8] Patent: US2014/128372, 2014, A1, . Location in patent: Paragraph 1076; 1077; 1078; 1079; 1080
[9] Patent: US2016/122341, 2016, A1, . Location in patent: Paragraph 0594; 0600; 0601; 0602; 0603
[10] Patent: US2017/50961, 2017, A1, . Location in patent: Paragraph 0890; 0891; 0892; 0893; 0894
[11] Patent: US2017/57954, 2017, A1, . Location in patent: Paragraph 0591; 0592; 0593; 0594; 0595
[12] Patent: US2016/347770, 2016, A1, . Location in patent: Paragraph 0582; 0588; 0589; 0590; 0591; 0592
[13] Patent: US2017/50962, 2017, A1, . Location in patent: Paragraph 0588; 0591-0595
[14] Patent: US2017/304278, 2017, A1, . Location in patent: Paragraph 0567; 0573; 0574; 0575; 0576
[15] Patent: US2016/362408, 2016, A1, . Location in patent: Paragraph 0532; 0533; 0534; 0535; 0536
[16] Tetrahedron, 2011, vol. 67, # 45, p. 8757 - 8762
[17] Patent: WO2007/67416, 2007, A2, . Location in patent: Page/Page column 58; 98-99
[18] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 31-32
[19] Patent: WO2006/21886, 2006, A1, . Location in patent: Page/Page column 62
[20] Patent: WO2007/53345, 2007, A1, . Location in patent: Page/Page column 77
[21] Patent: WO2003/91253, 2003, A1, . Location in patent: Page/Page column 27
[22] Archiv der Pharmazie, 2011, vol. 344, # 3, p. 158 - 164

13
[ 24016-03-3 ]
[ 144-55-8 ]
[ 754230-78-9 ]

Reference： [1] Patent: US2017/217954, 2017, A1,

14
[ 517-23-7 ]
[ 24016-03-3 ]
[ 130049-82-0 ]

Reference： [1] Patent: US2011/293889, 2011, A1,

15
[ 24016-03-3 ]
[ 130049-82-0 ]

Reference： [1] Patent: WO2012/134445, 2012, A1,
[2] Patent: US8481729, 2013, B2,
[3] Patent: CN107311998, 2017, A,

[ 24016-03-3 ] Synthesis Path-Downstream 1~32

1
[ 2379-60-4 ]
[ 24016-03-3 ]
[ 143702-66-3 ]
[ 143702-80-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1992,vol. 29,p. 771 - 777

2
[ 34329-73-2 ]
[ 24016-03-3 ]
[ 110270-90-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	In 1,2-dimethoxyethane for 48h; Ambient temperature;

Reference： [1]Kaminski, James J.; Perkins, D. G.; Frantz, J. D.; Solomon, Daniel M.; Elliott, Arthur J.; et al. [Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2047 - 2051]

3
[ 24016-03-3 ]
[ 78-95-5 ]
[ 79707-53-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	In ethanol for 20h; Heating;

Reference： [1]Kaminski, James J.; Bristol, James A.; Puchalski, Chester; Lovey, Raymond G.; Elliott, Arthur J.; et al. [Journal of Medicinal Chemistry, 1985, vol. 28, # 7, p. 876 - 892]

4
[ 24016-03-3 ]
[ 609-15-4 ]
[ 96428-50-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	In ethanol; at 100℃; for 48.0h;Molecular sieve;	Example 1A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two tablespoons of 4 A molecular sieve were added, and the reaction mixture was then heated at reflux (bath temperature 100 C.) for 2 days. The mixture was concentrated, and excess ethyl 2-chloroacetoacetate was removed on a rotary evaporator with dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate gradient 9:1, 4:1). This gave 20.81 g of the target compound (54% of theory, purity 99%). LC-MS (Method 2): Rt=1.12 min MS (ESpos): m/z=311 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).
54%	In ethanol; at 100℃; for 48.0h;Molecular sieve;	Example 29A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, and 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 A molecular sieve were added. The mixture was heated at reflux for 2 d (bath temperature 100 C.). The mixture was then concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator with dry ice-cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate 9:1, 4:1). This gave 20.81 g of the title compound (54% of theory). LC-MS (Method 1): Rt=1.12 min MS (ESpos): m/z=311 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).
54%	In ethanol; at 100℃; for 48.0h;Molecular sieve;	Example 23A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two table spoons of 4 A molecular sieve were added and the reaction mixture was then heated at reflux (bath temperature 100 C.) for 2 days. The mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling. The residue was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient-9/1, 4/1). This gave 20.81 g of the target compound (54% of theory, purity 99%). LC-MS (Method 2): Rt=1.12 min MS (ESpos): m/z=311 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).

54%

In ethanol; at 100℃; for 48.0h;Molecular sieve;

25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 A molecular sieve were added and the mixture was heated at reflux (bath temperature 100 C.) for 2 d. Then, the mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate=9:1, 4:1). This gave 20.81 g of the title compound (54% of theory).10693] LC-MS (Method 2): R=1.12 mm10694] MS (ESpos): mlz=311 (M+H)10695] ?H-NMR (400 MHz, DMSO-d5): oe=1.35 (t, 3H),2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H),7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).

Reference： [1]Patent: US2014/128386,2014,A1 .Location in patent: Paragraph 0984; 0985; 0986; 0987; 0988
[2]Patent: US2014/128372,2014,A1 .Location in patent: Paragraph 0489; 0490; 0491; 0492; 0493
[3]Patent: US2017/57954,2017,A1 .Location in patent: Paragraph 0620; 0621; 0622; 0623; 0624
[4]Patent: US2016/347770,2016,A1 .Location in patent: Paragraph 0691; 0692; 0693; 0694; 0695
[5]Journal of Medicinal Chemistry,1985,vol. 28,p. 876 - 892

5
[ 5391-39-9 ]
[ 24016-03-3 ]
1-acetyl-2-[2-(3-benzyloxypyridinyl)]iminoimidazolidine [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 729 - 733

6
1-(4-isocyanophenyl)-N-Boc-methanamine [ No CAS ]
[ 24016-03-3 ]
[ 563-96-2 ]
[4-(8-benzyloxy-imidazo[1,2-a]pyridin-3-ylamino)-benzyl]-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Organic Letters,2004,vol. 6,p. 4989 - 4992

7
[ 14542-93-9 ]
[ 24016-03-3 ]
[ 563-96-2 ]
(8-benzyloxy-imidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine [ No CAS ]

Reference： [1]Organic Letters,2004,vol. 6,p. 4989 - 4992

8
[ 76393-16-3 ]
[ 24016-03-3 ]
2-[3-(3-benzyloxy-pyridin-2-yl)-ureido]-benzoic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 900 - 910

9
[ 56309-56-9 ]
[ 24016-03-3 ]
1-(3-benzyloxy-pyridin-2-yl)-3-(2-isopropyl-phenyl)-urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	In tetrahydrofuran Heating;

Reference： [1]Guichou, Jean-François; Viaud, Julien; Mettling, Clȩment; Subra, Guy; Lin, Yea-Lih; Chavanieu, Alain [Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 900 - 910]

10
[ 24016-03-3 ]
[ 754230-78-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sulfuric acid; bromine; acetic acid; In water; at 0 - 4℃; for 4.5h;	2-Amino-3-benzyloxypyridine (85.0 g, 0.42 mol) was dissolved in a 10 % aqueous solution of sulphuric acid (1000 ml). The yellow solution was cooled to 0 to 4 C and a solution of bromine (80.5 g, 0.50 mol) in acetic acid (276 g, 4.6 mol) was added dropwise over a period of 2 hours. A red suspension was obtained which was stirred for 2.5 hours at 0 C and was then poured onto a mixture of ice water (500 ml) and dichloromethane (1000 ml). A pH-value of 8 was adjusted by addition of 25 % aqueous ammonia solution (approx. 600 ml) to the well-stirred biphasic mixture. The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 500 ml). The combined organic phases were washed with water (400 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography [1 kg of silica gel, eluant : petrol ether/ethyl acetate = 7: 3 (v/v) ]. Thus, 96.0 g of the title compound were isolated in form of a brown solid (81 % yield). Melting point: 109-110 C 'H-NMR (CDCI3, 200 MHz): 8= 4.73 (bs, 2 H), 5.04 (s, 2 H), 7.08 (d, 1 H), 7.40 (me, 5 H), 7.73 (d, 1 H).
81%		IV. Starting Compounds and Intermediates; Synthesis ofintermediates for racemic 7H-8, 9-dihydro-pvranof2, 3-cl-imidazo ( ?, 2- alpvridines via cross metathesis; i. 2-Amino-3-benzyloxy-5-bromo-pyridine; 2-Amino-3-benzyloxypyridine (85. 0 g, 0.42 mol) was dissolved in a 10 % aqueous solution of sulphuric acid (1000 ml). The yellow solution was cooled to 0 to 4 C and a solution of bromine (80.5 g, 0.50 mol) in acetic acid (276 g, 4.6 mol) was added dropwise over a period of 2 h. A red suspension was ob- tained which was stirred for 2.5 h at 0 C and was then poured onto a mixture of ice water (500 mi) and dichloromethane (1000 ml). A pH-value of 8 was adjusted by addition of 25 % aqueous ammonia solu- tion (approx. 600 ml) to the well-stirred biphasic mixture. The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 500 ml). The combined organic phases were washed with water (400 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography [1 kg of silica gel, eluant : petrol ether/ethyl acetate = 7: 3 (v/v) ]. Thus, 96.0 g of the tide compound were isolated in form of a brown solid (81 % yield).
77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	Example 84A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0 C. over a period of 30 min. After the addition had ended, the reaction solution was stirred at 0 C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was separated off and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:4), and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound. LC-MS (Method 1): Rt=0.92 min MS (ESpos): m/z=279 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).

77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	Example 14A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0 C. over a period of 30 min. After the addition had ended, the reaction solution was stirred at 0 C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was separated off and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound. LC-MS (Method 2): Rt=0.92 min MS (ESpos): m/z=279 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	Example 236A 3-(Benzyloxy)-5-bromopyridine-2-amine [1076] 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0 C. over a period of 30 min. After the addition had ended, the reaction solution was stirred at 0 C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was separated off and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound. [1078] LC-MS (Method 2): Rt=0.92 min [1079] MS (ESpos): m/z=279 (M+H)+ [1080] 1H NMR (400 MHz, DMSO-d6): delta=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H)
77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	10600] 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 1 of dichloromethane, and at 00 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 mi Afier the addition had ended, the reaction solution was stirred at 00 C. for 60 mm. About 4 1 of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave214 g (77% of theory) of the title compound.10601] LC-MS (Method 1): R=0.92 mm10602] MS (ESpos): mlz=279 (M+H)10603] ?H-NMR (400 MHz, DMSO-d5): oe=5.16 (s, 2H),5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	Example 19A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and at 0 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 min. After the addition had ended, the reaction solution was stirred at 0 C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound. LC-MS (Method D): Rt=0.92 min MS (ESpos): m/z=279 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=5.16 (s, 2H), 5.94-6.00 (min, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine; sodium hydrogencarbonate; In dichloromethane; at 0℃; for 1.5h;	Example 17A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and at 0 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 min After the addition had ended, the reaction solution was stirred at 0 C. for 60 min About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound. LC-MS (Method 1): Rt=0.92 min MS (ESpos): m/z=279 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	Further Preparation Method:10589] 200 g (1 mol) of 2-amino-3-benzyloxypyridinewere initially charged in 4 1 of dichloromethane, and at 00 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichioromethane was added over 30 mm. After the addition had ended, the reaction solution was stirred at 00 C. for 60 mm. About 4 1 of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound.10590] LC-MS (Method 1): R=0.92 mm MS (ESpos): mlz=279 (M+H)j0592] ?H-NMR (400 MHz, DMSO-d5): oe=5.16 (s, 2H),5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 1 of dichloromethane, and at 0 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichioromethane was added over 30 mm. After the addition had ended, the reaction solution was stirred at 0 C. for 60 mm. About 4 1 of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound. LC-MS (Method 1): R=0.92 mm, MS (ESpos): mlz=279 (M+H); ?H-NMR (400 MHz, DMSO-d5): oe=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 1 of dichioromethane, and at 00 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 mm. After the addition had ended, the reaction solution was stirred at 00 C. for 60 mm. About 4 1 of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether:ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound. LC-MS (Method 1): R=0.92 min. MS (ESpos): mlz=279 (M+H). 1H-NMR (400 Mhz, DMSO-d5): oe=5.16 (s, 2H),5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
77%	With bromine; In dichloromethane; at 0℃; for 1.5h;	200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 1 of dichloromethane, and at 00 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichioromethane was added over 30 mm Afier the addition had ended, the reaction solution was stirred at 00 C. for 60 mm. The mixture was then quenched with about 4 1 of saturated sodium bicarbonate solution. The organic phase was removed and concentrated. The residue was purified by silica gel colunm chromatography (petroleum ether/ethyl acetate=6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound.10534] LC-MS (Method 2): R=0.92 mm10535] MS (ESpos): mlz=279 (M+H)10536] ?H-NMR (400 MHz, DMSO-d5): oe=5.16 (s, 2H),5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H),7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).
70%		Sulfuric acid (10%, 160 mL) was introduced in a three necked flask equipped with mechanical stirrer. 3-Benzyloxypyridi-2-ylamine 12 (8 g, 40 mmol) was added at room temperature under efficient stirring. The reaction mixture was cooled at 0 C, where a mixture of Br2 (7.68 g, 48.1 mmol) in acetic acid (25 mL) was added dropwise over a period of 35 min. The resulting mixture was stirred for 3 h at 0 C. Then, ice water (160 mL) was added and the solution was basified by addition of 30% aqueous ammonia solution. The aqueous phase was extracted with CH2Cl2 (thrice). Combined organic layers were washed with water, dried over MgSO4, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (cyclohexane/EtOAc 8/2, v/v) afforded 13 (8 g, 70%) as a yellow/orange solid. 1H NMR (300 MHz, CDCl3) delta 4.71 (br s, 2H), 5.05 (s, 2H), 7.08 (d, J=1.87 Hz, 1H), 7.37-7.42 (m, 5H), 7.73 (d, J=1.87 Hz, 1H). 13C NMR (75 MHz, CDCl3) delta 70.7, 107.0, 119.6, 127.8, 128.7, 128.9, 135.6, 135.6, 139.3, 141.9, 149.1. MS (ESI+) m/z (%): 281 (98), 279 (100).
57%		To a solution of 3-benzyloxy-pyridin-2-ylamine (2.00 g, 10.0 mmol) in DMF (15 mL) was slowly added bromine (0.56 mL, 11 mmol) at 0 0C, and the mixture was stirred at room <n="100"/>temperature for 2 h. The mixture was diluted with ice-water (25 mL) and neutralized with 3 N NaOH to pH 5-6. The resulting precipitate was collected by filtration to give the title compound (1.6 g, 57%) as a brown solid: 1H NMR (300 MHz, CDCl3) delta 7.73 (d, J= 1.8 Hz, IH), 7.42-7.37 (m, 5H), 7.08 (d, J= 2.1 Hz, IH), 5.05 (s, 2H), 4.74 (br s, 2H); ESI MS m/e 219 (M + H)+.
53%	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 1.0h;	1. To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH3CN (600 mL) at 0 C. was added N-bromosuccinimide (37.1 g, 0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with EtOAc (900 mL) and partitioned with H2O (900 mL). The organic layer was washed with brine and dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53%). 1H NMR (CDCl3, 300 MHz) 64.63-4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).
53%	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 1.0h;	To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH3CN (600 mL) at 0C was added N-bromosuccinimide (37.1 g, 0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with EtOAc (900 mL) and partitioned with H20 (900 mL). The organic layer was washed with brine and dried (Na2S04), filtered and concentrated to dryness under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53%). 1H NMR (CDCI3, 300 MHz) 6 4.63-4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).
34.3%	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 0.25h;	Step A: Preparation of 3-(benzyloxy)-5-bromopyridin-2-arnine:; 3-(Benzyloxy)pyridin-2-amine (25.0 g, 124.9 mmol) was added to acetonitrile (300 mL) and cooled to 0 0C. l-Bromopyrrolidine-2,5-dione (22.22 g, 124.9 mmol) was added portionwise and the reaction mixture was stirred for 15 minutes, then concentrated to dryness. The residue was dissolved in EtOAc and partitioned with water. The organic layer was washed twice with saturated sodium bicarbonate and once with brine. Activated charcoal was added to the organic layer, and the organic layer was warmed to reflux, then cooled, filtered through a plug of celite, and concentrated to give 9.4 g of the title compound. The celite and charcoal were resupended in EtOAc and filtered through a celite plug to give an additional 3.6 g of the title compound, to provide a total of 12.0 g (34.3% yield). 1H NMR (CDCl3) delta 7.74 (d, IH), 7.41 (m, 5H), 7.08 (d, IH), 5.04 (s, 2H), 4.74 (bs, 2H). Mass spectrum (apci) m/z = 279.1 (M+H).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7669 - 7678
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 6240 - 6264
[3]Patent: WO2005/58325,2005,A1 .Location in patent: Page/Page column 39
[4]Patent: WO2005/90358,2005,A2 .Location in patent: Page/Page column 74
[5]Journal of the American Chemical Society,2015,vol. 137,p. 8851 - 8857
[6]Patent: US2014/128386,2014,A1 .Location in patent: Paragraph 1273; 1274; 1275; 1276; 1277
[7]Patent: US2014/128425,2014,A1 .Location in patent: Paragraph 0426-0430
[8]Patent: US2014/128372,2014,A1 .Location in patent: Paragraph 1076; 1077; 1078; 1079; 1080
[9]Patent: US2016/122341,2016,A1 .Location in patent: Paragraph 0594; 0600; 0601; 0602; 0603
[10]Patent: US2017/50961,2017,A1 .Location in patent: Paragraph 0890; 0891; 0892; 0893; 0894
[11]Patent: US2017/57954,2017,A1 .Location in patent: Paragraph 0591; 0592; 0593; 0594; 0595
[12]Patent: US2016/347770,2016,A1 .Location in patent: Paragraph 0582; 0588; 0589; 0590; 0591; 0592
[13]Patent: US2017/50962,2017,A1 .Location in patent: Paragraph 0588; 0591-0595
[14]Patent: US2017/304278,2017,A1 .Location in patent: Paragraph 0567; 0573; 0574; 0575; 0576
[15]Patent: US2016/362408,2016,A1 .Location in patent: Paragraph 0532; 0533; 0534; 0535; 0536
[16]Tetrahedron,2011,vol. 67,p. 8757 - 8762
[17]Patent: WO2007/67416,2007,A2 .Location in patent: Page/Page column 58; 98-99
[18]Patent: US2006/46991,2006,A1 .Location in patent: Page/Page column 31-32
[19]Patent: WO2006/21886,2006,A1 .Location in patent: Page/Page column 62
[20]Patent: WO2007/53345,2007,A1 .Location in patent: Page/Page column 77
[21]Patent: WO2003/91253,2003,A1 .Location in patent: Page/Page column 27
[22]Archiv der Pharmazie,2011,vol. 344,p. 158 - 164

11
[ 24016-03-3 ]
[ 109388-59-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 70 percent / NaHCO₃ / ethanol; H₂O / 8 h / Heating 2: 68 percent / Br₂ / H₂O; ethanol / 8 h / Ambient temperature

Reference： [1]Rydzkowski, Richard; Blondeau, Dominique; Sliwa, Henri [Journal of Chemical Research, Miniprint, 1986, # 11, p. 3368 - 3390]

12
[ 24016-03-3 ]
[ 69214-22-8 ]

Reference： [1]Journal of Chemical Research, Miniprint,1986,p. 3368 - 3390

13
[ 24016-03-3 ]
[ 50876-74-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 97 percent / CH₂Cl₂ / 3 h / Heating 2: 85 percent / various solvent(s) / 0.75 h / 250 °C 3: 78 percent / cyclohexene / 10percent Pd(OH)2 / ethanol / 2 h / Heating
	Multi-step reaction with 3 steps 1: 97 percent 2: 85 percent 3: 25 percent / hydrogenolysis

Reference： [1]Dennin, F.; Blondeau, D.; Sliwa, H. [Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1287 - 1291]
[2]Dennin, F.; Blondeau, D.; Sliwa, H. [Tetrahedron Letters, 1989, vol. 30, # 12, p. 1529 - 1530]

14
[ 24016-03-3 ]
[ 123458-49-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 68 percent / Heating 2: 47 percent / 250 °C 3: 30 percent / H₂ / Pd/C

Reference： [1]Dennin, F.; Blondeau, D.; Sliwa, H. [Tetrahedron Letters, 1989, vol. 30, # 12, p. 1529 - 1530]

15
[ 24016-03-3 ]
[ 86467-41-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ethanol / 20 h / Heating 2: 60 percent / hydroxylamine-O-sulfonic acid, pyridine / methanol / 18 h / Heating 3: 86 percent / H₂ / 5percent Pd/C / tetrahydrofuran; ethanol

Reference： [1]Moormann, Alan E.; Pitzele, Barnett S.; Jones, P. H.; Gullikson, Gary W.; Albin, David; et al. [Journal of Medicinal Chemistry, 1990, vol. 33, # 2, p. 614 - 626]

16
[ 70-23-5 ]
[ 24016-03-3 ]
[ 79707-07-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	In ethanol for 2h; Reflux;

Reference： [1]Location in patent: experimental part Groselj, Uros; Bezensek, Jure; Meden, Anton; Svete, Jurij; Stanovnik, Branko; Oblak, Marko; Stefanic Anderluh, Petra; Urleb, Uros [Heterocycles, 2008, vol. 75, # 6, p. 1355 - 1370]

17
[ 26377-17-3 ]
[ 24016-03-3 ]
[ 1202398-75-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4 (Compound No. 6 of table 1) 9-(benzyloxy)-2-pyridin-4-yl-4H-pyrido[1,2-a]pyrimidin-4-one ; To a mixture of 5.02mmol) of 3-(benzyloxy)pyridin-2-amine and 1.16g (6.02 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate were added 0.774 ( 10.04 mmol) of ammonium acetate.The reaction mixture was heated at 150C for 12 hours. After cooling, water was added and the mixture was extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and evaporated. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 99/1 to 90/10 to give 0.32g (19%) of the desired compound which was transformed into the hydrochloride salt in the usual manner to give the pure product as a yellow solid. MP: 215-217C RMN 1H (DMSO-d6; 200 MHz) delta (ppm) : 9.00 (d, 2H), 8.65 (d, 1 H), 8.50 (d, 2H), 7.65 (m, 3H), 7.50-7.30 (m, 5H), 5.50 (s, 2H).

Reference： [1]Patent: EP2138493,2009,A1 .Location in patent: Page/Page column 8

18
[ 24016-03-3 ]
[ 39903-01-0 ]

Reference： [1]Archiv der Pharmazie,2011,vol. 344,p. 158 - 164

19
[ 24016-03-3 ]
[ 891785-18-5 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 8757 - 8762

20
[ 517-23-7 ]
[ 24016-03-3 ]
[ 130049-82-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydrogen; trichlorophosphate; In cyclohexane; acetic acid; toluene;	Example-1 Preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one. (formula-7) To a solution of 2-Amino-3-benzyloxypyridine (formula-2) (20 grams) in toluene (40 ml) added 2-acetyl gammabutyro lactone (formula-3) (16.6 grams), stirred for 15 min and added phosphorus oxychloride (0.27 ml). The reaction mixture was refluxed for 12 hours and water was removed azeotropically. Then the reaction mixture was cooled to 70-80 C., added phosphorus oxychloride (11.9 ml) and then heated to 90-95 C. and stirred for 8 hr. The solvent was distilled off under reduced pressure and concentrated hydrochloric acid (70 ml) was added to the reaction mixture followed by toluene (100 ml) and stirred at 65-70 C. for 9 hours. The reaction mixture was cooled to 0-5 C. and the solid formed was filtered, washed with toluene and acetic acid. The wet solid was taken in autoclave along with acetic acid (110 ml), added Pd/C and applied 3.0-3.5 kg/cm2 hydrogen pressure. The reaction mixture was heated to 50-60 C., stirred for 8 hrs, then cooled to 25 C. and quenched with water. The reaction mixture was filtered and the pH of the filtrate was adjusted to 11 using aqueous sodium hydroxide solution. Extracted the reaction mixture with ethyl acetate. The ethyl acetate layer was treated with basic carbon, filtered and distilled off under reduced pressure. The solid formed was taken in cyclohexane (45 ml) and stirred for 60 min at 25 C. The solid was filtered, washed with cyclohexane and dried to provide the title compound. Yield: 11.0 grams.

Reference： [1]Patent: US2011/293889,2011,A1

21
[ 24016-03-3 ]
[ 130049-82-0 ]

Reference： [1]Patent: WO2012/134445,2012,A1
[2]Patent: US8481729,2013,B2
[3]Patent: CN107311998,2017,A

22
[ 394-50-3 ]
[ 24016-03-3 ]
(E)-2-((3-(benzyloxy) pyridin-2-ylimino) methyl)-6-fluorophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With potassium hydroxide; 1-butyl-3-methylimidazolium trifluoromethanesulfonimide; In methanol; at 20 - 50℃;	General procedure: Equimolar quantities (0.5mmol) of <strong>[394-50-3]3-fluoro-salicylaldehyde</strong>, followed by the addition of various amines were dissolved in methanol (10mL) in the presence of ionic liquid (1molpercent) 1-Butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide and KOH (1molpercent). The reaction mixture stirred at room temperature for an hour and refluxed for 4?6h at 50°C. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, the solid product formed was filtered, washed three times with water and methanol (2:1) mixture and dried. The crude was further purified by column chromatography using hexane and ethyl acetate (9:2) mixture as eluent (Scheme 1).

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2013,vol. 116,p. 394 - 400

23
[ 24016-03-3 ]
[ 144-55-8 ]
[ 754230-78-9 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine;	Example 17A 3-(Benzyloxy)-5-bromopyridine-2-amine 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and at 0 C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 min. After the addition had ended, the reaction solution was stirred at 0 C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound. LC-MS (Method 1): Rt=0.92 min MS (ESpos): m/z=279 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).

Reference： [1]Patent: US2017/217954,2017,A1

24
[ 24016-03-3 ]
[ 173530-73-9 ]

Reference： [1]Patent: US2014/128386,2014,A1
[2]Patent: US2017/217954,2017,A1

25
[ 537-46-2 ]
[ 24016-03-3 ]
[ 609-15-4 ]
[ 96428-50-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 23A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two tablespoons of 4 A molecular sieve were added and the reaction mixture was then heated at reflux (bath temperature 100 C.) for 2 days. The mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling. The residue was purified by silica gel chromatography (mobile phase: cyclohexane:ethyl acetate-gradient 9:1, 4:1). This gave 20.81 g of the target compound (54% of theory). LC-MS (Method 2): Rt=1.12 min MS (ESpos): m/z=311 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).

Reference： [1]Patent: US2017/217954,2017,A1

26
[ 24016-03-3 ]
[ 609-15-4 ]
[ 173530-73-9 ]

Reference： [1]Patent: US2017/57954,2017,A1

27
[ 33985-71-6 ]
[ 119072-55-8 ]
[ 24016-03-3 ]
5-(benzyloxy)-N-(tert-butyl)-2-(2,3,6,7-tetrahydro-1H,5H-pyrido-[3,2,1-ij]quinolin-9-yl)imidazo[1,2-a]pyridin-3-amine [ No CAS ]