Name: 1207839-86-8|4-Bromo-6-methoxypyrazolo[1,5-a]pyridine|98%
Brand: Ambeed
SKU: A100727
Price: 107.0 USD
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1
[ 1207839-86-8 ]
[ 2068065-04-1 ]
[ 2068066-02-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trichlorophosphate / 0 - 20 °C 2: hydroxylamine hydrochloride / ethanol / 20 °C
	Multi-step reaction with 2 steps 1: trichlorophosphate / 0 - 20 °C 2: hydroxylamine hydrochloride / ethanol; water / 50 °C
	Multi-step reaction with 2 steps 1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2: hydroxylamine hydrochloride / ethanol; water / 50 °C

	Multi-step reaction with 2 steps 1: trichlorophosphate / 0 - 20 °C 2: hydroxylamine hydrochloride / ethanol; water / 20 - 50 °C
	Multi-step reaction with 2 steps 1: trichlorophosphate / 0 - 20 °C 2: hydroxylamine hydrochloride / ethanol; water / 50 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/11776, 2017, A1
[2]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1
[3]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1
[4]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - US2019/106438, 2019, A1
[5]Current Patent Assignee: PFIZER INC - WO2019/75108, 2019, A1 Current Patent Assignee: ELI LILLY & CO - WO2019/75114, 2019, A1

2
[ 1207839-86-8 ]
[ 68-12-2 ]
[ 2068065-03-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With trichlorophosphate at 0 - 25℃; for 3h;	3 Example 3 Synthesis of compound 4a Weigh 10.3g (45.4mmol) of 3a and 154.5mL of DMF, add them to a 250mL double-necked flask, cool to 0, add 20.9g (136.1mmol) of phosphorus oxychloride dropwise, transfer to a water bath at 25 after addition React for 3 hours; pour the reaction solution into 500 mL ice water, add sodium hydroxide to the solution pH=8.0-9.0, filter, wash with water, and dry to obtain 11.3 g of off-white solid 4a, with a yield of 98.0%.
86%	With trichlorophosphate at 0 - 20℃;	4-Bromo-6-methoxypyrazolo[ 1,5 -a]pyridine-3 -carbaldehyde A solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate P2; 5.0 g, 22mmol) in DMF (220 mL) was cooled to 0 °C and then slowly treated with POC13 (6.2 mL, 66 mmol). The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was cooled to 0 °C, quenched with water (220 mL), and basified with 6 M NaOH(aq) to pH 9-10. The reaction mixture was stirred for 1 h and then vacuum filtered. The solids were rinsed sequentially with water (3 x 50 mL) and MTBE (3 x 50 mL). The collected solid was suspended in DCM (500 mL) and stirred in a sonicating bath for 30 mm and then vacuum filtered. The filtratewas retained, while the filter cake was taken up in water (300 mL) and extracted with DCM (2300 mL). The organic extracts, along with the retained DCM filtrate, were combined and driedover anhydrous Na2SO4, then filtered and concentrated in vacuo to provide the title compound(4.84 g, 86% yield). MS (apci), m/z = 256.9 (M+H).
86%	With trichlorophosphate at 0 - 20℃;	B.4 Step 4: Preparation of 4-bromo-6-methoxypyrazolo[ 1.5 -alpyridine-3 - carbaldehyde A solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (5.0 g, 22 mmol) in DMF (220 mL) was cooled to 0 °C and then slowly treated with POC13 (6.2 mL, 66 mmol). The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was cooled to 0 °C, quenched with water (220 mL), and basified with 6 M NaOH(aq) to pH 9-10. The reaction mixture was stirred for 1 h and then vacuum filtered. The solids were rinsed sequentially with water (3 x 50 mL) and MTBE (3 x 50 mL). The collected solid was suspended in DCM (500 mL) and stirred in a sonicating bath for 30 mm and then vacuum filtered. The filtrate was retained, while the filter cake was taken up in water (300 mL) and extracted with DCM . The organic extracts, along with the retained DCM filtrate, were combined and dried over anhydrous Na2504, then filtered and concentrated in vacuo to provide the title compound (4.84 g, 86% yield). MS (apci), m/z = 256.9 (M+H).

86%	With trichlorophosphate In N,N-dimethyl-formamide at 0℃;	B.4 Step 4 Preparation of 4-bromo-6-methoxypyrazolorL5-a1pyridine-3- carbaldehyde: A solution of 4-bromo-6-methoxypyrazolo[l,5-a]pyridine (5.0 g, 22 mmol) in DMF (220 mL) was cooled to 0 °C and then slowly treated with POCh (6.2 mL, 66 mmol). The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was cooled to 0 °C, quenched with water (220 mL), and basified with 6 M NaOH(aq) to pH 9- 10. The reaction mixture was stirred for 1 h and then vacuum filtered. The solids were rinsed sequentially with water and MTBE. The collected solid was suspended in DCM (500 mL) and stirred in a sonicating bath for 30 min and then vacuum filtered. The filtrate was retained, while the filter cake was taken up in water (300 mL) and extracted with DCM . The organic extracts, along with the retained DCM filtrate, were combined and dried over anhydrous Na2S04, then filtered and concentrated in vacuo to provide the title compound (4.84 g, 86% yield). MS (apci), m/z = 256.9 (M+H).
86%	With trichlorophosphate at 0 - 20℃;	3 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (6C) A solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (5C) (5.0 g, 22 mmol) in DMF (220 mL) was cooled to 0° C. and then slowly treated with POCl3 (6.2 mL, 66 mmol). The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was cooled to 0° C., quenched with water (220 mL), and basified with 6 M NaOH(aq) to pH 9-10. The reaction mixture was stirred for 1 h and then vacuum filtered. The solids were rinsed sequentially with water (350 mL) and MTBE (350 mL). The collected solid was suspended in DCM (500 mL) and stirred in a sonicating bath for 30 min and then vacuum filtered. The filtrate was retained, while the filter cake was taken up in water (300 mL) and extracted with DCM. The organic extracts, along with the retained DCM filtrate, were combined and dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to provide the title compound (4.84 g, 86% yield). MS (apci), m/z=256.9 (M+H).
86%	With trichlorophosphate at 0 - 20℃;	1.B.4; 4.1 Step 4: 4-bromo-6-methoxypyrazolo[1.5-alpyridine-3-carbaldehyde: A solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (5.0 g, 22 mmol) in DMF (220 mL) was cooled to 0°Cand then slowly treated with POC13 (6.2 mL, 66 mmol). The reaction was warmed to ambienttemperature and stirred overnight. The reaction mixture was cooled to 0°C, quenched with water(220 mL), and basified with 6 M NaOH(aq) to pH 9-10. The reaction mixture was stirred for 1 hand then vacuum filtered. The solids were rinsed sequentially with water (3 x 50 mL) and MTBE(3 x 50 mL). The collected solid was suspended in DCM (500 mL) and stirred in a sonicating bathfor 30 mm and then vacuum filtered. The filtrate was retained, while the filter cake was taken upin water (300 mL) and extracted with DCM. The organic extracts, along with the retained DCM filtrate, were combined and dried over anhydrous Na2504, then filtered and concentrated in vacuo to provide the title compound (4.84 g, 86% yield). MS (apci), m/z = 256.9 (M+H).
86%	With trichlorophosphate at 0 - 20℃;	2.4 Step 4: Preparation of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde A solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (5.0 g, 22 mmol) in DMF (220 mL) was cooled to 0°C and then slowly treated with POCl3 (6.2 mL, 66 mmol). The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was cooled to 0°C, quenched with water (220 mL), and basified with 6 M NaOH(aq) to pH 9-10. The reaction mixture was stirred for 1 h and then vacuum filtered. The solids were rinsed sequentially with water (3 × 50 mL) and MTBE (3 × 50 mL). The collected solid was suspended in DCM (500 mL) and stirred in a sonicating bath for 30 min and then vacuum filtered. The filtrate was retained, while the filter cake was taken up in water (300 mL) and extracted with DCM. The organic extracts, along with the retained DCM filtrate, were combined and dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to provide the title compound (4.84 g, 86% yield). MS (apci), m/z = 256.9 (M+H).

Reference： [1]Current Patent Assignee: XIAMEN YUNFAN PHARMACEUTICAL - CN111548349, 2020, A Location in patent: Paragraph 0033; 0039; 0040
[2]Current Patent Assignee: PFIZER INC - WO2017/11776, 2017, A1 Location in patent: Paragraph 00665; 00666; 00667
[3]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1 Location in patent: Paragraph 00805; 00809
[4]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1 Location in patent: Paragraph 00934; 00938
[5]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - US2019/106438, 2019, A1 Location in patent: Paragraph 0298
[6]Current Patent Assignee: ELI LILLY & CO - WO2019/75114, 2019, A1 Location in patent: Page/Page column 303; 305; 325; 326
[7]Current Patent Assignee: PFIZER INC - WO2019/75108, 2019, A1 Location in patent: Paragraph 00621

3
1-amino-3-bromo-5-methoxypyridin-1-ium 2.4.6-trimethylbenzenesulfonate [ No CAS ]
[ 623-47-2 ]
[ 1207557-36-5 ]
4-bromo-6- methoxypyrazolo[1,5-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a magnetically stirred white suspension of 1 -amino-3 -bromo-5 -methoxypyridin- 1 -ium 2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and airdried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer).Independently the original aqueous reaction mixture filtrate was extracted with EtOAc(2 x 500 mL). The combined organic extracts were dried (Na2504), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[ 1,5 -a]pyridine (Intermediate P1) as white solid (upperRf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate P2) also as white solid (lower Rf spot,1.32 g). MS (apci) mlz = 226.9, 228.9 (M+H). ?HNIVIR (CDC13) 8.02 (m, 1H), 7.85 (d, 1H),7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
		To a magnetically stirred white suspension of 1 -amino-3 -bromo-5 -methoxypyridin- 1 -ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by dropwise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and air- dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer; The i someric mixture of ethyl 6-bromo-4- methoxypyrazolo[ 1,5 -a]pyridine-3 -carboxyl ate and ethyl 4-bromo-4-methoxypyrazolo[ 1,5 - a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80 C for 90 mm followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2504, filtered and concentrated in vacuo to yield 6-bromo-4-methoxypyrazolo[1,5-a]pyridine as a beige solid (about 98:2 6-/4- Br; 5.08 g). MS (apci) m/z = 226.9, 228.9 (M+H). ?H NMR (CDC13) 8.26 (m, 1H),7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently the original aqueous reactionmixture filtrate was extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo- 4-methoxypyrazolo[1,5-a]pyridine (Intermediate P1) as white solid (upperRf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[ 1, 5-a]pyridine (Intermediate P2) also as white solid (lower Rf spot, 1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H). ?H NMR (CDC13) 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
		Preparation of 6-bromo-4-methoxypyrazolorL5-a1pyridine (PI) and 4- bromo-6-methoxypyrazolo[L5-alpyridine. The isomeric mixture of ethyl 6-bromo-4- methoxypyrazolo[l,5-a]pyridine-3-carboxylate and ethyl 4-bromo-4-methoxypyrazolo[l,5- a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80 C for 90 min followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2S04, filtered and concentrated in vacuo to yield 6-bromo-4- methoxypyrazolo[l,5-a]pyridine as a beige solid (about 98:2 6-/4- Br; 5.08 g). MS (apci) m/z = 226.9, 228.9 (M+H). NMR (CDCh) delta 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently the original aqueous reaction mixture filtrate was extracted with EtOAc. The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50%) EtOAc/hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[l,5- a]pyridine (Intermediate PI) as white solid (upper Ri spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[l,5-a]pyridine (Intermediate P2) also as white solid (lower Rf spot, 1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H). NMR (CDCh) delta 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).

		To a magnetically stirred white suspension of 1-amino-3-bromo-5-methoxypyridin-1-ium-2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by dropwise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by 1H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H NMR (CDCl3) delta 3.98 (6-Br isomer) vs.3.83 (4-Br isomer). The isomeric mixture of ethyl-6-bromo-4- methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl-4-bromo-6-methoxypyrazolo[1,5- a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80C for 90 min, followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 6-bromo-4-methoxypyrazolo[1,5-a]pyridine as a beige solid (about 98:2 6-/4- Br; 5.08 g). MS (apci) m/z = 226.9, 228.9 (M+H). 1H NMR (CDCl3): delta 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently, the original aqueous reaction mixture filtrate was extracted with EtOAc (2 × 500 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo- 4-methoxypyrazolo[1,5-a]pyridine (Intermediate 1) as a white solid (upper Rf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine also as a white solid (lower Rf spot, 1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H).1H NMR (CDCl3): delta 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
1.32 g		To a magnetically stirred white suspension of 1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air- dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by 1H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H NMR (CDCl3) delta 3.98 (6-Br isomer) vs.3.83 (4-Br isomer).; The isomeric mixture of ethyl 6-bromo-4- methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl 4-bromo-4-methoxypyrazolo[1,5- a]pyridine-3-carboxylate from Step 2 (15 g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heated at 80C for 90 min followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTBE and vacuum filtered to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (Intermediate A1) as a beige solid (about 98:26-/4- Br; 5.08 g). MS (apci) m/z = 226.9, 228.9 (M+H).1H NMR (CDCl3) delta 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). (1120) [00593] Independently the original aqueous reaction mixture filtrate was extracted with EtOAc (2 × 500 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was taken up in DCM (50 mL) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (Intermediate A1) as white solid (upper Rf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate A2) also as white solid (lower Rf spot, 1.32 g). MS (apci) m/z = 226.9, 228.9 (M+H). 1H NMR (CDCl3) delta 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).
2.06 g; 1.32 g		To a magnetically stirred white suspension of1 -amino-3-bromo-5-methoxypyridin-1 -ium 2,4,6-trimethyl- benzenesulfonate (2a) (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). Afier vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with compound 3a as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in the next step without further purification. MS (apci) mlz=298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) oe 3.98 (3a) vs. 3.83 (4a).The isomeric mixture of ethyl-6-bromo-4- methoxypyrazolo[1 ,S-a]pyridine-3-carboxylate (3a) and ethyl-4-bromo-4-methoxypyrazolo[1 ,5-a]pyridine-3-car- boxylate (4a) described above (15 g, 50.1 mmol) was added to 48% HEr (114 mE) while stirring, tben beated at 80 C. for 90 mm, followed by stirring at ambient temperature overnight. The resulting suspension was vacuum filtered and rinsed with water. The aqueous filtrate and the filter cake were treated independently. The filter cake was taken up in MTEE and vacuum filtered to remove insoluble impurities. The MTEE filtrate was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield 6-bromo-4- methoxypyrazolo[1 ,5-a]pyridine (5A) as a beige solid (about 98:2 6-14-Br; 5.08 g). MS (apci) mlz=226.9, 228.9 (M+H). ?H NMR (CDC13): oe 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H). Independently, the original aqueous reaction mixture filtrate was extracted with EtOAc (2x500 mE). The combined organic extracts were dried (Na2504), filtered, and concentrated in vacuo. The crude residue was taken up in DCM (50 mE) and then filtered to remove insoluble solids. Concentration of the DCM filtrate under vacuum followed by silica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of 6-bromo-4-methoxypyrazolo[ 1 ,5-a]pyridine (5A) as white solid (upper Rf spot, 2.06 g), as well as the minor isomer title compound 4-bromo-6-methoxypyrazolo[1 ,5-a]pyridine (SC), also as white solid (lower Rf spot, 1.32 g). MS (apci) mlz=226.9, 228.9 (M+H). ?H NMR (CDC13) oe 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H).

Reference： [1]Patent: WO2017/11776,2017,A1 .Location in patent: Paragraph 00633; 00634; 00635
[2]Patent: WO2018/71447,2018,A1 .Location in patent: Paragraph 00805; 00807; 00808
[3]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 00934; 00936; 00937
[4]Patent: WO2019/75114,2019,A1 .Location in patent: Page/Page column 303-305
[5]Patent: WO2019/75108,2019,A1 .Location in patent: Paragraph 00591-00593; 00619; 00620
[6]Patent: US2019/106438,2019,A1 .Location in patent: Paragraph 0280; 0281

4
[ 1207839-86-8 ]
[ 2222658-89-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: aluminum (III) chloride / 1,2-dichloro-ethane / 76 °C / Inert atmosphere 3: potassium carbonate / 55 - 85 °C
	Multi-step reaction with 3 steps 1: N-chloro-succinimide / dichloromethane / 24.08 h / 20 °C / Sonication 2: aluminum (III) chloride / trans-1,2-dichloroethylene / 16.08 h / 76 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl acetamide / 2 h / 85 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1
[2]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

5
[ 1207839-86-8 ]
[ 2222756-22-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-chloro-succinimide In dichloromethane at 20℃; Sonication;	1 Step 1: Preparation of 4-bromo-3 -chloro-6-methoxypyrazolo[ 1.5 -alpyridine. A suspension of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate P1, Part B, step 3; 15 g, 66 mmol) in DCM (100 mL) was treated with NCS (8.821 g, 66.06 mmol), and the mixture was sonicated for 5 mm. After stirring the resulting mixture overnight at ambient temperature, additional NCS (1.25 g) was introduced. The reaction mixture was stirred for an additional 6 h, then diluted with Et20 (100 mL), stirred for 10 mm and sonicated for 2 mm at ambient temperature. The resultant suspension was vacuum filtered, rinsing the solids with Et20 (2 x 100 mL). The filtrate was diluted with additional Et20 (100 mL), then sonicated and vacuum filtered. The solids from both filtrations were combined to afford the title compound (18.69 g, quantitative yield). MS (apci) m/z = 260.9, 263.0 (M+H).
	With N-chloro-succinimide In dichloromethane at 20℃; for 24.0833h; Sonication;	1 Step 1 Preparation of 4-bromo-3-chloro-6-methoxypyrazolorL5-a1pyridine. To a solution of 4-bromo-6-methoxypyrazolo[l,5-a]pyridine (15 g, 66.06 mmol) in DCM (100 mL) was added NCS (8.821 g, 66.06 mmol). The reaction mixture was sonicated for 5 min then stirred at rt for 24 h. The reaction mixture was diluted with Et20, in which it was stirred for 10 min then sonicated for 2 min. The solid precipitate was isolated by vacuum filtration to afford the title compound (18.69 g, 71.47 mmol, 108.2% yield) in sufficient purity for step 2. MS (apci) m/z = 263.1 (M+H).

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1 Location in patent: Paragraph 001009
[2]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1 Location in patent: Paragraph 001104; 001106

6
[ 1207839-86-8 ]
[ 2222654-39-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: aluminum (III) chloride / 1,2-dichloro-ethane / 76 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: N-chloro-succinimide / dichloromethane / 24.08 h / 20 °C / Sonication 2: aluminum (III) chloride / trans-1,2-dichloroethylene / 16.08 h / 76 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1
[2]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

7
[ 1207839-86-8 ]
[ 2222756-35-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: aluminum (III) chloride / 1,2-dichloro-ethane / 76 °C / Inert atmosphere 3: potassium carbonate / 55 - 85 °C 4: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; 1,4-dioxane / 90 °C / Inert atmosphere; Sealed tube
	Multi-step reaction with 4 steps 1: N-chloro-succinimide / dichloromethane / 24.08 h / 20 °C / Sonication 2: aluminum (III) chloride / trans-1,2-dichloroethylene / 16.08 h / 76 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl acetamide / 2 h / 85 °C 4: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 16 h / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1
[2]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

8
[ 1207839-86-8 ]
[ 2222756-86-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: aluminum (III) chloride / 1,2-dichloro-ethane / 76 °C / Inert atmosphere 3: potassium carbonate / 55 - 85 °C 4: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; 1,4-dioxane / 90 °C / Inert atmosphere; Sealed tube 5: potassium carbonate / dimethyl sulfoxide / 90 - 105 °C / Sealed tube 6: dichloromethane

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

9
[ 1207839-86-8 ]
[ 2222756-87-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: aluminum (III) chloride / 1,2-dichloro-ethane / 76 °C / Inert atmosphere 3: potassium carbonate / 55 - 85 °C 4: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; 1,4-dioxane / 90 °C / Inert atmosphere; Sealed tube 5: potassium carbonate / dimethyl sulfoxide / 90 - 105 °C / Sealed tube

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

10
[ 1207839-86-8 ]
[ 2222655-40-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 2.25 h / 90 °C / Inert atmosphere; Sealed tube
	Multi-step reaction with 3 steps 1: N-chloro-succinimide / dichloromethane / 24.08 h / 20 °C / Sonication 2: aluminum (III) chloride / trans-1,2-dichloroethylene / 16.08 h / 76 °C / Inert atmosphere 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 2.5 h / 90 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1
[2]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

11
[ 1207839-86-8 ]
[ 2222757-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trichlorophosphate / 0 - 20 °C 2: tetrahydrofuran / 1 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

12
[ 1207839-86-8 ]
[ 2222757-08-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trichlorophosphate / 0 - 20 °C 2: tetrahydrofuran / 1 h / 0 - 20 °C 3: boron trifluoride diethyl etherate / dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

13
[ 1207839-86-8 ]
[ 2168435-97-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trichlorophosphate / 0 - 20 °C 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 22 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

14
[ 1207839-86-8 ]
[ 2168465-26-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trichlorophosphate / 0 - 20 °C 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 22 h / 20 °C 3: boron trifluoride diethyl etherate / dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

15
[ 1207839-86-8 ]
[ 2222754-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: aluminum (III) chloride / 1,2-dichloro-ethane / 76 °C / Inert atmosphere 3: potassium carbonate / 55 - 85 °C 4: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; 1,4-dioxane / 90 °C / Inert atmosphere; Sealed tube 5: potassium carbonate / dimethyl sulfoxide / 90 - 105 °C / Sealed tube 6: dichloromethane 7: triethylamine; sodium tris(acetoxy)borohydride / N,N-dimethyl acetamide / 3 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

16
[ 1207839-86-8 ]
[ 2222754-59-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: aluminum (III) chloride / 1,2-dichloro-ethane / 76 °C / Inert atmosphere 3: potassium carbonate / 55 - 85 °C 4: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; 1,4-dioxane / 90 °C / Inert atmosphere; Sealed tube 5: potassium carbonate / dimethyl sulfoxide / 90 - 105 °C / Sealed tube 6: dichloromethane 7: triethylamine; sodium tris(acetoxy)borohydride / N,N-dimethyl acetamide / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

17
[ 1207839-86-8 ]
[ 2222754-63-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 76 °C / Inert atmosphere 3.1: potassium carbonate / 55 - 85 °C 4.1: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; 1,4-dioxane / 90 °C / Inert atmosphere; Sealed tube 5.1: potassium carbonate / dimethyl sulfoxide / 90 - 105 °C / Sealed tube 6.1: dichloromethane 7.1: bis(trichloromethyl) carbonate; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 7.2: 0 - 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

18
[ 1207839-86-8 ]
[ 2222755-18-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-chloro-succinimide / dichloromethane / 20 °C / Sonication 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 2.25 h / 90 °C / Inert atmosphere; Sealed tube 3: XPhos; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium phosphate / 1,4-dioxane / 80 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

19
[ 1207839-86-8 ]
[ 2222755-19-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: trichlorophosphate / 0 - 20 °C 2: tetrahydrofuran / 1 h / 0 - 20 °C 3: boron trifluoride diethyl etherate / dichloromethane / 2 h / 0 - 20 °C 4: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 15 h / 80 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

20
[ 1207839-86-8 ]
[ 2222755-20-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: trichlorophosphate / 0 - 20 °C 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 22 h / 20 °C 3: boron trifluoride diethyl etherate / dichloromethane / 2 h / 0 - 20 °C 4: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 15 h / 80 °C

Reference： [1]Current Patent Assignee: PFIZER INC; ELI LILLY & CO - WO2018/71447, 2018, A1

21
4-bromo-6- methoxypyrazolo[1,5-a]pyridine [ No CAS ]
[ 444120-95-0 ]
4-(6-fluoropyridin-3-yl)-6-methoxypyrazolo[1,5-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.13%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 16.0h;	Preparation of 4-(6-fluoropyridin-3-yl)-6-methoxypyrazolorL5-a1pyridine. To a solution of 4-bromo-6-methoxypyrazolo[l,5-a]pyridine (5.122 g, 22.56 mmol) in 1,4- dioxane (45.12 mL) was added 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (6.038 g, 27.07 mmol), tetrakis(triphenylphosphine)palladium (0) (1.043 g, 0.9023 mmol), and aqueous sodium carbonate (2M, 23.69 mL, 47.37 mmol). The reaction mixture was stirred at 80C for 16 h. After cooling to ambient temperature, the reaction mixture was poured onto water and stirred for 4 h. The resultant precipitate was isolated by vacuum filtration then taken up in MTBE and stirred an additional 30 min. The precipitate was isolated by vacuum filtration to afford the title compound (4.616 g, 18.98 mmol, 84.13 % yield) in sufficient purity for step 2. MS (apci) m/z = 244.1 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 001093; 001095

22
[ 1207839-86-8 ]
[ 2222644-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: potassium carbonate; XPhos; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / water; 1,4-dioxane / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

23
[ 1207839-86-8 ]
[ 1822680-43-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C
	Multi-step reaction with 2 steps 1: trichlorophosphate / 3 h / 0 - 25 °C 2: hydroxylamine-O-sulfonic acid / N,N-dimethyl-formamide / 25 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1
[2]Current Patent Assignee: XIAMEN YUNFAN PHARMACEUTICAL - CN111548349, 2020, A

24
[ 1207839-86-8 ]
[ 2222653-69-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl acetamide / 3 h / 60 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

25
[ 1207839-86-8 ]
[ 2222653-70-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl acetamide / 3 h / 60 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 8 h / 90 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

26
[ 1207839-86-8 ]
[ 2222653-71-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 50 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

27
[ 1207839-86-8 ]
[ 2222653-72-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 50 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 8 h / 90 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

28
[ 1207839-86-8 ]
[ 2222653-73-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 60 - 85 °C / Sealed tube

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

29
[ 1207839-86-8 ]
[ 2222653-74-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 60 - 85 °C / Sealed tube 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 12 h / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

30
[ 1207839-86-8 ]
[ 2222653-75-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 60 - 85 °C / Sealed tube 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 12 h / 85 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 90 °C / Inert atmosphere 7.1: trifluoroacetic acid / dichloromethane / 1.5 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

31
[ 1207839-86-8 ]
[ 2222653-76-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 60 - 85 °C / Sealed tube 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 12 h / 85 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

32
[ 1207839-86-8 ]
[ 2222653-77-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 60 - 85 °C / Sealed tube 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 12 h / 85 °C / Inert atmosphere 6.1: triethylamine; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 90 - 100 °C / Inert atmosphere 7.1: sodium hydroxide; water / ethanol / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

33
[ 1207839-86-8 ]
[ 2222653-78-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 60 - 85 °C / Sealed tube 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 12 h / 85 °C / Inert atmosphere 6.1: triethylamine; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 90 - 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/71454, 2018, A1

34
[ 1207839-86-8 ]
[ 2222654-14-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl acetamide / 3 h / 60 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 8 h / 90 °C / Inert atmosphere; Sealed tube 6.1: potassium carbonate / dimethyl sulfoxide / 72 h / 110 °C 7.1: lithium borohydride / tetrahydrofuran / 24 h / 0 - 20 °C 8.1: lithium borohydride / tetrahydrofuran / 2 h / 20 °C 9.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide / dichloromethane / 24 h / 20 °C 10.1: Dess-Martin periodane / dichloromethane / 1.42 h / 0 - 20 °C
	Multi-step reaction with 10 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 0 °C 2.1: hydroxylamine hydrochloride / ethanol; water / 50 °C 2.2: 25 h / 140 °C 3.1: aluminum (III) chloride / trans-1,2-dichloroethylene / 19 h / 76 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl acetamide / 3 h / 60 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate / 1,4-dioxane / 8 h / 90 °C / Inert atmosphere; Sealed tube 6.1: potassium carbonate / dimethyl sulfoxide / 72 h / 110 °C 7.1: trifluoroacetic acid / dichloromethane / 24 h / 20 °C 8.1: N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide / dichloromethane / 1 h / 20 °C 8.2: 1 h / 50 °C 9.1: lithium borohydride / tetrahydrofuran / 1 h / 0 °C 10.1: Dess-Martin periodane / dichloromethane / 1.42 h / 0 - 20 °C