Name: 194157-10-3|7-Oxa-2-azaspiro[3.5]nonane|98%
Brand: Ambeed
SKU: A158076
Price: 33.0 USD
Availability: InStock
Rating: 90 (32 reviews)

1
[ 194157-10-3 ]
[ 1450723-73-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 25 °C 2: ammonia; hydrogen / methanol / 1 h / 25 °C
	Multi-step reaction with 2 steps 1: dichloromethane / 2 h / 25 °C 2: hydrogen; ammonia / methanol / 1 h / 25 °C

Reference： [1]Dragovich, Peter S.; Bair, Kenneth W.; Baumeister, Timm; Ho, Yen-Ching; Liederer, Bianca M.; Liu, Xiongcai; Liu, Yongbo; O'Brien, Thomas; Oeh, Jason; Sampath, Deepak; Skelton, Nicholas; Wang, Leslie; Wang, Weiru; Wu, Hongxing; Xiao, Yang; Yuen, Po-Wai; Zak, Mark; Zhang, Lei; Zheng, Xiaozhang [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4875 - 4885]
[2]Zheng, Xiaozhang; Bair, Kenneth W.; Bauer, Paul; Baumeister, Timm; Bowman, Krista K.; Buckmelter, Alexandre J.; Caligiuri, Maureen; Clodfelter, Karl H.; Feng, Yezhen; Han, Bingsong; Ho, Yen-Ching; Kley, Nikolai; Li, Hong; Liang, Xiaorong; Liederer, Bianca M.; Lin, Jian; Ly, Justin; O'Brien, Thomas; Oeh, Jason; Oh, Angela; Reynolds, Dominic J.; Sampath, Deepak; Sharma, Geeta; Skelton, Nicholas; Smith, Chase C.; Tremayne, Jarrod; Wang, Leslie; Wang, Weiru; Wang, Zhongguo; Wu, Hongxing; Wu, Jiansheng; Xiao, Yang; Yang, Guangxing; Yuen, Po-Wai; Zak, Mark; Dragovich, Peter S. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 20, p. 5488 - 5497]

2
[ 194157-10-3 ]
[ 1450724-31-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 2 h / 25 °C 2: ammonia; hydrogen / methanol / 1 h / 25 °C 3: toluene / 2 h / 110 °C

Reference： [1]Dragovich, Peter S.; Bair, Kenneth W.; Baumeister, Timm; Ho, Yen-Ching; Liederer, Bianca M.; Liu, Xiongcai; Liu, Yongbo; O'Brien, Thomas; Oeh, Jason; Sampath, Deepak; Skelton, Nicholas; Wang, Leslie; Wang, Weiru; Wu, Hongxing; Xiao, Yang; Yuen, Po-Wai; Zak, Mark; Zhang, Lei; Zheng, Xiaozhang [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4875 - 4885]

3
[ 194157-10-3 ]
[ 1450723-51-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 2 h / 25 °C 2: ammonia; hydrogen / methanol / 1 h / 25 °C 3: toluene / 2 h / 110 °C 4: ethanol / 2 h / Reflux

Reference： [1]Dragovich, Peter S.; Bair, Kenneth W.; Baumeister, Timm; Ho, Yen-Ching; Liederer, Bianca M.; Liu, Xiongcai; Liu, Yongbo; O'Brien, Thomas; Oeh, Jason; Sampath, Deepak; Skelton, Nicholas; Wang, Leslie; Wang, Weiru; Wu, Hongxing; Xiao, Yang; Yuen, Po-Wai; Zak, Mark; Zhang, Lei; Zheng, Xiaozhang [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4875 - 4885]

4
[ 194157-10-3 ]
[ 49584-26-1 ]
[ 1450723-79-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 25℃; for 2h;
	In dichloromethane at 25℃; for 2h;

Reference： [1]Dragovich, Peter S.; Bair, Kenneth W.; Baumeister, Timm; Ho, Yen-Ching; Liederer, Bianca M.; Liu, Xiongcai; Liu, Yongbo; O'Brien, Thomas; Oeh, Jason; Sampath, Deepak; Skelton, Nicholas; Wang, Leslie; Wang, Weiru; Wu, Hongxing; Xiao, Yang; Yuen, Po-Wai; Zak, Mark; Zhang, Lei; Zheng, Xiaozhang [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4875 - 4885]
[2]Zheng, Xiaozhang; Bair, Kenneth W.; Bauer, Paul; Baumeister, Timm; Bowman, Krista K.; Buckmelter, Alexandre J.; Caligiuri, Maureen; Clodfelter, Karl H.; Feng, Yezhen; Han, Bingsong; Ho, Yen-Ching; Kley, Nikolai; Li, Hong; Liang, Xiaorong; Liederer, Bianca M.; Lin, Jian; Ly, Justin; O'Brien, Thomas; Oeh, Jason; Oh, Angela; Reynolds, Dominic J.; Sampath, Deepak; Sharma, Geeta; Skelton, Nicholas; Smith, Chase C.; Tremayne, Jarrod; Wang, Leslie; Wang, Weiru; Wang, Zhongguo; Wu, Hongxing; Wu, Jiansheng; Xiao, Yang; Yang, Guangxing; Yuen, Po-Wai; Zak, Mark; Dragovich, Peter S. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 20, p. 5488 - 5497]

5
[ 194157-10-3 ]
[ 1453175-77-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dichloromethane / 2 h / 25 °C 2: hydrogen; ammonia / methanol / 1 h / 25 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 25 °C

Reference： [1]Zheng, Xiaozhang; Bair, Kenneth W.; Bauer, Paul; Baumeister, Timm; Bowman, Krista K.; Buckmelter, Alexandre J.; Caligiuri, Maureen; Clodfelter, Karl H.; Feng, Yezhen; Han, Bingsong; Ho, Yen-Ching; Kley, Nikolai; Li, Hong; Liang, Xiaorong; Liederer, Bianca M.; Lin, Jian; Ly, Justin; O'Brien, Thomas; Oeh, Jason; Oh, Angela; Reynolds, Dominic J.; Sampath, Deepak; Sharma, Geeta; Skelton, Nicholas; Smith, Chase C.; Tremayne, Jarrod; Wang, Leslie; Wang, Weiru; Wang, Zhongguo; Wu, Hongxing; Wu, Jiansheng; Xiao, Yang; Yang, Guangxing; Yuen, Po-Wai; Zak, Mark; Dragovich, Peter S. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 20, p. 5488 - 5497]

6
[ 1261276-98-5 ]
[ 194157-10-3 ]
C₃₆H₃₅N₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₂₃H₂₁N₃O₂S; 2-halo-pyridine-3-carbonyl chloride With N-ethyl-N,N-diisopropylamine In pyridine Stage #2: 7-oxa-2-azaspiro[3.5]nonane With N-ethyl-N,N-diisopropylamine Reflux;

Reference： [1]Xiong, Hui; Foulk, Melinda; Aschenbrenner, Lisa; Fan, Jun; Tiong-Yip, Choi-Lai; Johnson, Kenneth D.; Moustakas, Demetri; Fleming, Paul R.; Brown, Dean G.; Zhang, Minli; Ferguson, Douglas; Wu, Dedong; Yu, Qin [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6789 - 6793]

7
[ 13991-36-1 ]
[ 194157-10-3 ]
[ 1595286-21-7 ]
[ 1595286-03-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 4-bromocrotonic acid With thionyl chloride In dichloromethane at 20℃; Stage #2: N⁴-(3-chloro-4-fluorophenyl)thieno[2,3-d]pyrimidine-4,6-diamine With pyridine In tetrahydrofuran at 0 - 20℃; Stage #3: 7-oxa-2-azaspiro[3.5]nonane With sodium iodide In N,N-dimethyl-formamide at 0 - 20℃;	General method to synthesize compounds 9a-z General procedure: To a solution of compound 20 (0.10mol) in DMF (0.5mL) was added different amines (0.15mol) and NaI (0.15mol) at 0°C. Then the mixture was stirred at room temperature overnight. After the start material was completed, water was added to quench the reaction and extracted with EA, washed by water, NaHCO3 solution, NaCl solution and dried by Na2SO4, concentrated and purified by flash silica gel column to obtain desired compounds 9a-z.

Reference： [1]Ji, Xun; Peng, Ting; Zhang, Xu; Li, Jian; Yang, Wei; Tong, Linjiang; Qu, Rong; Jiang, Hualiang; Ding, Jian; Xie, Hua; Liu, Hong [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2366 - 2378]

8
[ 194157-10-3 ]
7-chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine [ No CAS ]
[ 76-05-1 ]
5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.8%	Stage #1: 7-oxa-2-azaspiro[3.5]nonane; 7-chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine With triethylamine In acetonitrile at 60℃; Inert atmosphere; Stage #2: trifluoroacetic acid In water; acetonitrile	II.8-4 Example 8-4 5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine Example 8-4 5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine 7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine (60 mg, 0.177 mmol, INTERMEDIATE a8) was added to a solution of 7-oxa-2-azaspiro[3.5]nonane (57.8 mg, 0.353 mmol) and triethylamine (0.098 mL, 0.706 mmol) in acetonitrile (3 mL). The mixture was stirred at 60° C. overnight under nitrogen. The residue was purified by preparative-HPLC (column: Waters SunFire C18 19*150 mm, 5 μm; mobile phase A: water/0.05% trifluoroacetic acid, mobile phase B: acetonitrile; flow rate: 20 mL/minute; gradient: 15% B to 50% B in 9 minutes; 254 nm) the titled compound as a trifluoroacetic acid salt (70 mg, 72.8%). MS(ESI+) m/z 431.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 1.75 (d, 3H), 1.94 (t, 4H), 2.51 (s, 3H), 3.32 (s, 2H), 3.70 (t, 4H), 4.25 (s, 2H), 4.44 (q, 1H), 5.95 (s, 1H), 6.18 (s, 1H), 7.54 (d, 2H), 7.63 (d, 2H).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2016/304527, 2016, A1 Location in patent: Paragraph 0418

9
[ 194157-10-3 ]
C₃₂H₂₄ClFN₄O₄S₂ [ No CAS ]
C₃₉H₃₆FN₅O₅S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; for 2h;	132.b An oven-dried vial was charged with compound from Example 132 step a (12 mg, 0.019 mmol), 7-oxa-2-azaspiro[3.5]nonane (4 mg, 0.019 mmol), DIPEA (0.010 mL, 0.056 mmol), and DMSO (1 mL). The reaction mixture was stirred for 2 h at 90 °C, then purified by RPHPLC to provide the titled product (3 mg, 22%). ESI MS m/z = 738.5 [M+H].

Reference： [1]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2017/123884, 2017, A1 Location in patent: Page/Page column 179-180

10
[ 194157-10-3 ]
C₁₃H₁₉N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 1 h / 50 °C 2: palladium 10% on activated carbon; hydrogen / ethyl acetate / 5 h / 50 °C

Reference： [1]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2017/123884, 2017, A1

11
[ 194157-10-3 ]
C₂₁H₂₅N₃O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 1 h / 50 °C 2: palladium 10% on activated carbon; hydrogen / ethyl acetate / 5 h / 50 °C 3: dichloromethane

Reference： [1]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2017/123884, 2017, A1

12
[ 23056-40-8 ]
[ 194157-10-3 ]
C₁₃H₁₇N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 50℃; for 1h;	133.a An oven-dried vial was charged with 2-chloro-5-methyl-3-nitropyridine (254 mg,1.472 mmol), 7-oxa-2-azaspiro[3.5]nonane (319 mg, 1.472 mmol), DMSO (10 mL), and DIPEA (0.771 mL, 4.42 mmol).The reaction mixture was stirred for 1 h at 50 °C, then purified by RPHPLC to provide the titled product (350 mg, 90%). ESI MS m/z = 264.2 [M+H].

Reference： [1]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2017/123884, 2017, A1 Location in patent: Page/Page column 180

13
[ 36178-05-9 ]
[ 194157-10-3 ]
C₃₉H₃₆FN₅O₃S [ No CAS ]

Reference： [1]Patent: WO2017/123884,2017,A1

14
[ 36178-05-9 ]
[ 194157-10-3 ]
C₁₂H₁₅BrN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 50℃; for 2h;	An oven-dried vial was charged with 7-oxa-2-azaspiro[3.5]nonane (90 mg, 0.551 mmol), 3- bromo-2-fluoropyridine (97 mg, 0.551 mmol), DIPEA (0.289 mL, 1.654 mmol), and DMSO (5 mL). The reaction mixture was stirred for 2 h at 50 °C, then purified by RPHPLC to provide the titled product (50 mg, 32percent). ESI MS m/z = 284.2 [M+H].

Reference： [1]Patent: WO2017/123884,2017,A1 .Location in patent: Page/Page column 182

15
[ 194157-10-3 ]
[ 545348-98-9 ]
C₂₂H₂₅N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 24h;	135.b An oven-dried vial was charged with compound from Example 135 step a (1.524 g, 5.000 mmol), 7-oxa-2-azaspiro[3.Sjnonane (1.085 g, 5.000 mmol), DIPEA (2.62 mL, 15.000mmol), and NMP (20 mL). The reaction mixture was stirred for 24 h at 100 °C. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The product was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and concentrated. The residue was purified on silica gel with 1:1 EtOAc:hexanes to provide the titled product (1.58 g, 80%). ESI MS m/z = 396.3 [M+Hj.

Reference： [1]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2017/123884, 2017, A1 Location in patent: Page/Page column 184

16
[ 194157-10-3 ]
ethyl 4-(4-(2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamido)benzoyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxylate [ No CAS ]
ethyl 4-(4-(2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamido)benzoyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 20 - 140℃;	Ethyl 4-(4-(2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-6,7-dihydro-5H-cyclopenta[i)]pyridine- 3-carboxamido)benzoyl)-5,6-dihydro-4A -dithieno[3,2-i3:2',3'-c/lazepine-8-carboxylate. To a solution of ethyl 4-(4-(2-chloro-6,7-dihydro-5/-/-cyclopenta[0]pyridine-3-carboxamido) benzoyl)-5,6-dihydro-4/-/-dithieno[3,2-0:2',3'-c]azepine-8-carboxylate (723 mg, 1.25 mmol) and 7-oxa-2-azaspiro[3.5]nonane (477 mg, 3.75 mmol) in NMP (40 ml.) was added K2CO3 (1.04 g, 7.50 mmol). The reaction mixture was heated at 120°C for 3 hr, and at 140°C for an additional 4 hr and then cooled to RT overnight. The mixture was partitioned between water (50 ml_) and EtOAc (50 mL) and the organic phase was separated, washed with brine (2 x 30 ml_) and then passed through a phase separator and evaporated in vacuo. The brown oil thus obtained was purified by flash column chromatography (S1O2, 40 g, 0-100% EtOAc in isohexane, gradient elution) to afford the title compound as a pale yellow solid (798 mg, 95% yield, 66% pure by 1 H NMR); R'2.17 min (Method 1 a); m/z 669 (M+H)+ (ES+). The main impurity was identified as NMP by 1H NMR and the material was used in the subsequent step without additional purification.

Reference： [1]Current Patent Assignee: PULMOCIDE LTD - WO2017/175000, 2017, A1 Location in patent: Page/Page column 40-41

17
[ 194157-10-3 ]
4-(4-(2-chloro-5,6-dimethylnicotinamido)benzoyl)-N-(2,6-difluorophenyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxamide [ No CAS ]
N-(2,6-difluorophenyl)-4-(4-(5,6-dimethyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinamido)benzoyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 140℃; for 2h;	4 Example 4: N-(2,6-difluorophenyl)-4-(4-(5,6-dimethyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinamido)benzoyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxamide. A suspension of 4-(4-(2-chloro-5,6-dimethylnicotinamido)benzoyl)-/V-(2,6-difluorophenyl)-5,6- dihydro-4 -/-dithieno[3, 2-b:2', 3'-c]azepine-8-carboxamide (140 mg, 0.216 mmol), 7-oxa-2-aza spiro[3.5]nonane (82.0 mg, 0.647 mmol) and K2CO3 (179 mg, 1.29 mmol) in NMP (10.0 mL) was heated at 140°C for 2 hr. After cooling to RT the reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) and was passed through a phase separator. The organics were evaporated in vacuo and the resulting yellow oil purified by flash column chromatography (S1O2, 12 g, 0-10% MeOH in DCM, gradient elution) to afford the title compound, Example 4, as a pale yellow solid (82 mg, 51 % yield); Rl 1.86 min (Method 1a); m/z 740 (M+H)+ (ES+); 1 H NMR δ: 1.63 (4H, br t), 2.15 (3H, s), 2.31 (3H, s), 3.24 (2H, apparent t), 3.48 (4H, br t), 3.63 (4H, s), 3.78-4.18 (2H, br), 6.40 (1 H, d), 7.19-7.29 (5H, over-lapping m), 7.38-7.47 (2H, overlapping m), 7.64 (2H, d), 7.90 (1 H, s), 10.24 (1 H, s), 10.36 (1 H, s).

Reference： [1]Current Patent Assignee: PULMOCIDE LTD - WO2017/175000, 2017, A1 Location in patent: Page/Page column 51

18
[ 194157-10-3 ]
4-(4-(2-chloro-6-methylnicotinamido)-2-fluorobenzoyl)-N-(2,6-difluorophenyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxamide [ No CAS ]
N-(2,6-difluorophenyl)-4-(2-fluoro-4-(6-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinamido)benzoyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium carbonate In 1,4-dioxane at 80℃; for 3h;	5 Example 5: N-(2,6-difluorophenyl)-4-(2-fluoro-4-(6-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinamido)benzoyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxamide. A suspension of 4-(4-(2-chloro-6-methylnicotinamido)-2-fluorobenzoyl)-//-(2,6-difluorophenyl) -5,6-dihydro-4 - -dithieno[3,2-0:2',3'-cf]azepine-8-carboxamide (87 mg, 0.13 mmol), 7-oxa-2- azaspiro[3.5]nonane (32 mg, 0.25 mmol) and K2CO3 (53 mg, 0.38 mmol) in 1 ,4-dioxane (2.0 mL) was heated at 80°C for 3 hr. After cooling to RT the solvent was evaporated in vacuo and the residue was triturated with water (10.0 mL). The resulting precipitate was collected by filtration and was purified by flash column chromatography (S1O2, 4 g, 0-50% THF in DCM, gradient elution) and then by preparative HPLC (Method 4) to afford the title compound, Example 5, as an off-white solid (28 mg, 30% yield); R1 1.91 min (Method 1a); m/z 744 (M+H)+ (ES+); 1 H NMR δ: 1.65 (4H, br t), 2.34 (3H, s), 3.18-3.30 (2H, br), 3.49 (4H, br t), 3.66 (4H, s), 3.66-4.23 (2H, br), 6.33-6.48 (1 H, br), 6.60 (1 H, d), 7.19-7.29 (3H, over-lapping m), 7.33-7.60 (4H, over-lapping m), 7.59 (1 H, d), 7.89 (1 H, s), 10.25 (1 H, s), 10.54 (1 H, s).

Reference： [1]Current Patent Assignee: PULMOCIDE LTD - WO2017/175000, 2017, A1 Location in patent: Page/Page column 52

19
[ 194157-10-3 ]
ethyl 2-[2-(pyrazin-2-yl)propan-2-yl]amino}pyrimidine-5-carboxylate [ No CAS ]
7-oxa-2-azaspiro[3.5]non-2-yl(2-[2-(pyrazin-2-yl)propan-2-yl]amino}pyrimidin-5-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In N,N-dimethyl-formamide at 50℃; for 16h;	131 Example 131 7-oxa-2-azaspiro[3.51non-2-yl(2-[2-(pyrazin-2-yl)propan-2-yl1amino)pyrimidin-5- vQmethanone Ethyl 2-[2-(pyrazin-2-yl)propan-2-yl]amino}pyrimidine-5-carboxylate (Preparation 15, 2.15 g, 7.48 mmol), 7-oxa-2-azaspiro[3.5]nonane (1 .43 g, 1 1 .2 mmol) and TBD (2.08 g, 15.0 mmol) were dissolved in DMF (40 mL) and the resulting mixture was stirred at 50 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue which was partially purified by column chromatography on silica gel eluting with petroleum ether:EtOAc (100:0 to 0: 100) then EtOAC:MeOH(100:0 to 85: 15) to give a yellow oil. The product was isolated using preparative HPLC using a Phenomenex Gemini C18 250*50 10μ column, eluting with water (0.05% ammonium hydroxide): MeCN (10 to 31 %) over 20 mins at a flow rate of 120 mL/min, to afford the title compound as a white solid (1.74 g, 63%). 1H NMR (400 MHz, CDCI3): δ 1 .79 (dd, 4H), 1 .84 (s, 6H), 3.62 (dd, 4H), 3.85-4.09 (m, 4H), 6.42 (br s, 1 H), 8.43 (d, 1 H), 8.45- 8.59 (m, 3H), 8.73 (s, 1 H). LCMS m/z = 369 [M+H]+

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/11681, 2018, A1 Location in patent: Page/Page column 147

20
[ 194157-10-3 ]
2-bromopyrimidine-5-carboxylic acid [ No CAS ]
(2-chloropyrimidin-5-yl)(7-oxa-2-azaspiro[3.5]nonan-2-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In tetrahydrofuran; ethyl acetate at 60℃; for 16h;	23 Preparation 23 (2-Chloropyrimidin-5-yl)(7-oxa-2-azaspiro[3.51non-2-yl)methanone A yellow suspension of 2-chloropyrimidine-5-carboxylic acid (3.0 g, 18.92 mmol), 7-oxa-2-azaspiro[3.5]nonane (2.89 g, 22.72 mmol), propylphosphonic anhydride solution (12.0 g, 37.8 mmol, 50% in EtOAc) and Et3N (9.57 g, 94.6 mmol) in THF (50 mL) was stirred at 60 °C for 16 hrs. The cooled mixture was diluted wth EtOAc (300 mL) washed with sat. aqueous NH4CI (150 mL), brine (150 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with Pet. EtherEtOAc (100:0 to 50:50) to afford the title compound as a pale yellow solid, 3.07 g, 61 %. 1H NMR (400 MHz, DMSO-d6): δ 1 .64-1 .79 (m, 4H), 3.43-3.48 (m, 2H), 3.52-3.56 (m, 2H), 3.81 (s, 2H), 4.16 (s, 2H), 9.00 (s, 2H). LCMS m/z = 268 [M+H]+
61%	With propylphosphonic anhydride; triethylamine In tetrahydrofuran; ethyl acetate at 60℃; for 16h;

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/11681, 2018, A1 Location in patent: Page/Page column 89-90
[2]Casimiro-Garcia, Agustin; Allais, Christophe; Brennan, Agnes; Choi, Chulho; Dower, Gabriela; Farley, Kathleen A.; Fleming, Margaret; Flick, Andrew; Frisbie, Richard K.; Hall, Justin; Hepworth, David; Jones, Hannah; Knafels, John D.; Kortum, Steve; Lovering, Frank E.; Mathias, John P.; Mohan, Sashi; Morgan, Paul M.; Parng, Chuenlei; Parris, Kevin; Pullen, Nick; Schlerman, Franklin; Stansfield, John; Strohbach, Joseph W.; Vajdos, Felix F.; Vincent, Fabien; Wang, Hong; Wang, Xiaolun; Webster, Robert; Wright, Stephen W. [Journal of Medicinal Chemistry, 2022, vol. 65, # 1, p. 757 - 784]

21
[ 194157-10-3 ]
[ 1578246-23-7 ]
2-(6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-7-oxa-2-azaspiro[3.5]nonane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With triethylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 36h;

Reference： [1]Woodward, Hannah L.; Innocenti, Paolo; Cheung, Kwai-Ming J.; Hayes, Angela; Roberts, Jennie; Henley, Alan T.; Faisal, Amir; Mak, Grace Wing-Yan; Box, Gary; Westwood, Isaac M.; Cronin, Nora; Carter, Michael; Valenti, Melanie; De Haven Brandon, Alexis; O'Fee, Lisa; Saville, Harry; Schmitt, Jessica; Burke, Rosemary; Broccatelli, Fabio; Van Montfort, Rob L. M.; Raynaud, Florence I.; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Hoelder, Swen [Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8226 - 8240]

22
[ 194157-10-3 ]
2-(6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-7-oxa-2-azaspiro[3.5]nonane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / 1-methyl-pyrrolidin-2-one / 36 h / 100 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 18 h / 0 - 20 °C

Reference： [1]Woodward, Hannah L.; Innocenti, Paolo; Cheung, Kwai-Ming J.; Hayes, Angela; Roberts, Jennie; Henley, Alan T.; Faisal, Amir; Mak, Grace Wing-Yan; Box, Gary; Westwood, Isaac M.; Cronin, Nora; Carter, Michael; Valenti, Melanie; De Haven Brandon, Alexis; O'Fee, Lisa; Saville, Harry; Schmitt, Jessica; Burke, Rosemary; Broccatelli, Fabio; Van Montfort, Rob L. M.; Raynaud, Florence I.; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Hoelder, Swen [Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8226 - 8240]

23
[ 194157-10-3 ]
N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / 1-methyl-pyrrolidin-2-one / 36 h / 100 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 18 h / 0 - 20 °C 3: caesium carbonate / dimethyl sulfoxide / 18 h / 120 °C

Reference： [1]Woodward, Hannah L.; Innocenti, Paolo; Cheung, Kwai-Ming J.; Hayes, Angela; Roberts, Jennie; Henley, Alan T.; Faisal, Amir; Mak, Grace Wing-Yan; Box, Gary; Westwood, Isaac M.; Cronin, Nora; Carter, Michael; Valenti, Melanie; De Haven Brandon, Alexis; O'Fee, Lisa; Saville, Harry; Schmitt, Jessica; Burke, Rosemary; Broccatelli, Fabio; Van Montfort, Rob L. M.; Raynaud, Florence I.; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Hoelder, Swen [Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8226 - 8240]

24
[ 194157-10-3 ]
t-butyl 4-(3-bromo-4-chlorobenzyl)piperazine-1-carboxylate [ No CAS ]
t-butyl 4-(4-chloro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; ruphos In toluene at 90℃;	8.2 Step 2: Preparation of t-butyl 4-(4-chloro-3-(7-oxa-2-azaspiro j3.5J nonan-2-yl)benzyl)piperazine- 1-carboxylate j00254J A flask was charged with t-butyl 4-(3 -bromo-4-chlorobenzyl)piperazine- 1 -carboxylate (200 mg, 0.5 13 mmol, 1.00 equiv), 7-oxa-2-azaspiro[3.5]nonane (78.2 mg, 0.616 mmol, 1.20 equiv), tris(dibenzylideneacetone)dipalladium (23.5 mg, 0.0256 mmol, 0.05 equiv), dicyclohexyl(2’,6’-diisopropoxybiphenyl-2-yl)phosphine (47.9 mg, 0.102 mmol, 0.20 equiv), cesium carbonate (502 mg, 1.54 mmol, 3.00 equiv), and toluene (5 mL). The resulting solution was stirred overnight at 90 °C and quenched with water (5 mL). The resulting solution was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 105 mg (47% yield) of t-butyl 4-(4-chloro-3 -(7- oxa-2-azaspiro[3 .5 ]nonan-2-yl)benzyl)piperazine- 1 -carboxylate as a yellow oil. LCMS (ESI, m/z):436 [M+H].

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S - WO2018/217809, 2018, A1 Location in patent: Paragraph 00254

25
[ 766-11-0 ]
[ 194157-10-3 ]
2-(5-bromopyridin-2-yl)-7-oxa-2-azaspiro[3.5]nonane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h;	39.A Step A To a solution of commercially available 5-bromo-2-fluoro-pyridine (0.5 g, 2.84 mmol) and 7-oxa- 2-azaspiro[3.5]nonane (0.36 g, 2.84 mol) in DMF(5 mL) potassium carbonate (1.17 g, 8.52 mmol) and the mixture was heated to 90° C for 12 h. The reaction mixture was diluted with ethyl acetate (30 mL) and water (30 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate two more times. The combined organic phase was dried over Na2S04, filtered and the solvents were evaporated under reduced pressure to afford title compound (0.44 g, 55%).1H-NMR (400 MHz, DMSO -d6) d 8.12 (d, J = 2.40 Hz, 1 H), 7.64-7.65 (m, 1 H), 6.36 (d, J = 1 1.60 Hz, 1 H), 3.66-3.69 (m, 4H), 3.52-3.54 (m, 4H), 1.71-1.73 (m, 4H).MS: 285.0 (M +H)+.

Reference： [1]Current Patent Assignee: AC IMMUNE SA - WO2019/233883, 2019, A1 Location in patent: Page/Page column 80-81

26
[ 1365060-89-4 ]
[ 194157-10-3 ]
C₁₆H₁₈ClN₃O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-((5-chloro-6-methylthieno[2,3-d]pyrimidin-4-yl)thio)acetic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 7-oxa-2-azaspiro[3.5]nonane In N,N-dimethyl-formamide

Reference： [1]Atkinson, Benjamin N.; Bayle, Elliott D.; Bictash, Magda; Fish, Paul V.; Frew, Sarah; Jeganathan, Fiona; Jones, E. Yvonne; Mahy, William; Monaghan, Amy; Papageorgiou, George; Sipthorp, James; Steadman, David; Svensson, Fredrik; Zhao, Yuguang [Bioorganic and medicinal chemistry letters, 2020, vol. 30, # 3]

27
[ 194157-10-3 ]
2-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-phenylpropanoic acid [ No CAS ]
2-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-phenyl-1-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.43%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 3h;	Compound B26: 2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4, 3-e] [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yl) -2-phenyl-1- (7-oxa-2-azaspiro [3.5] nonan-2-yl) propan-1-one A mixture of 2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4, 3-e] [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yl) -2-phenylpropanoic acid (100 mg, 0.2570 mmol) , 7-oxa-2-azaspiro [3.5] nonane (39 mg, 0.3085 mmol) , HATU (146 mg, 0.3856 mmol) , DIPEA (99 mg, 0.7712 mmol) in DMF (3 mL) was stirred at rt for 3 hours. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (15 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (DCM/MeOH = 40: 1 10: 1) to give the product (62 mg, 48.43%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H) , 8.07 (s, 2H) , 7.96 (s, 1H) , 7.32 -7.23 (m, 4H) , 7.04 (d, J = 6.5 Hz, 2H) , 6.75 (dd, J = 3.3, 1.7 Hz, 1H) , 3.72 (q, J = 9.6 Hz, 2H) , 3.47 -3.33 (m, 4H) , 2.33 (s, 3H) , 1.48 (dd, J = 12.5, 6.0 Hz, 2H) , 1.36 -1.20 (m, 4H) . MS: M/e 499 (M+1)+.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2020/20097, 2020, A1 Location in patent: Paragraph 0927-0928

28
[ 194157-10-3 ]
N-((4-chloro-3-nitrophenyl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-(hydroxymethyl)pyrazolo[4,3-b]pyrrolo [3,2-e]pyridin-1(5H)-yl)benzamide [ No CAS ]
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’- biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(7-oxa-2-azaspiro-[3.5]nonan-2-yl)phenyl)sulfonyl)-2-(pyrazolo [4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzamide HCl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.42%	Stage #1: 7-oxa-2-azaspiro[3.5]nonane; N-((4-chloro-3-nitrophenyl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-(hydroxymethyl)pyrazolo[4,3-b]pyrrolo [3,2-e]pyridin-1(5H)-yl)benzamide With oxalic acid; N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 3h; Inert atmosphere; Stage #2: With hydrogenchloride In water; acetonitrile Inert atmosphere;

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2020/41406, 2020, A1 Location in patent: Page/Page column 205-206

29
C₁₀H₁₇NO₃ [ No CAS ]
[ 194157-10-3 ]

Yield	Reaction Conditions	Operation in experiment
35.8 g	With lithium aluminium tetrahydride In tetrahydrofuran at -10 - 10℃; for 5h; Inert atmosphere;	1.2; 2.2; 3.2; 4.2; 5.2; 6.2 (2): Preparation of Compound I: Add 770ml of tetrahydrofuran to the reactor, add 76.8g (0.36mol) of crude compound 3, and replace with nitrogen. Cool down to -1010, add 15.2g (0.40mol) lithium aluminum tetrahydrogen in 10 equal parts within one hour, stir and react for 4 hours, Slowly add 15ml purified water, Then slowly add 15ml of 15% sodium hydroxide solution, Then add 45ml purified water, filter, The filtrate was concentrated to obtain the crude compound I, Purified by neutral alumina column, 35.8g of compound I refined product was obtained, and the total yield was 56.3%. The molar ratio of compound 3 and lithium tetrahydroaluminum in the structural formula is 1.0:1.1.

Reference： [1]Current Patent Assignee: HEFEI YUANZHI PHARMACEUTICAL R D - CN112321599, 2021, A Location in patent: Paragraph 0035-0036; 0042-0047; 0053-0058; 0064-0068; 0074

30
[ 194157-10-3 ]
2-methoxy-3-tert-butoxycarbonylamino-5-bromopyridine [ No CAS ]
C₁₈H₂₇N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; sodium t-butanolate In tetrahydrofuran at 70℃; for 16h; Inert atmosphere;	19.1 Step 1 Dissolve 16c (100 mg, 0.330 mmol), 3a (42.0 mg, 0.330 mmol) and sodium tert-butoxide (79.3 mg, 0.825 mmol) in tetrahydrofuran (2.0 mL). Add (2-di-tert-butylphosphino-2',4',6'-triisopropyl- 1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (13.1 mg ,0.0165 mmol) with the protection of nitrogen, and stir the reaction liquid for 16 hours at 70 °C. Add water (3.0 mL) to the reaction liquid and extract the reaction liquid with ethyl acetate (8.0 mL x 3). Dry up the organic phase with anhydrous sodium sulphate. Filter and spin the organic phase dry. Separate and purify the residues with preparative thin-layer chromatography to obtain 19a.

Reference： [1]Current Patent Assignee: GUIZHOU INOCHINI TECHNOLOGY - EP3783005, 2021, A1 Location in patent: Paragraph 0139

31
[ 194157-10-3 ]
4-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid [ No CAS ]
N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-2-{3-[(2-methoxy-4-{7-oxa-2-azaspiro[3.5]nonane-2-carbonyl}phenyl)amino]prop-1-yn-1-yl}-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With triethylamine; HATU In N,N-dimethyl-formamide at 25 - 50℃;	D86 EXAMPLE D86: Synthesis of Compounds 924A, 933A, 949A, 956A, and 969A General procedure: To a solution of 4-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid (0.07 g, 127.50 mmol, 1 eq.) in DMF (2 mL) were added 2-morpholinoethanamine (33.20 mg, 255 mmol, 33.47 mL, 2 eq.), HATU (42.84 mg, 112.67 mmol, 1.2 eq.), and TEA (95.01 mg, 938.92 mmol, 130.69 mL, 10 eq.). The mixture was stirred at 25~50 °C for 2~3 h. TLC analysis (DCM:MeOH = 10:1, Rf = 0.30) indicated that the starting material was consumed completely, and one new spot was detected. The reaction mixture was quenched by adding water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the desired products as yellow solids. 2-[3-({4-[4-(dimethylamino)piperidine-1-carbonyl]-2-methoxyphenyl}amino)prop-1-yn-1-yl]- N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine, 38.0 mg 44.1% yield, MS (ES+, m/z): 643.3; 4-[3-(4-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-[2-(morpholin-4-yl)ethyl]benzamide, 25.0 mg 41.1% yield, MS (ES+, m/z): 645.4; 4-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)- 1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-N-(1-hydroxypropan-2-yl)-3- methoxybenzamide, 40.0 mg, MS (ES+, m/z): 590.3; methyl (2S)-4-carbamoyl-2-[(4-[3-(4-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl]amino}-3- methoxyphenyl)formamido]butanoate, 3.0 mg MS (ES+, m/z): 675.3; and 4-[3-(4-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl]amino}-N-(2- methanesulfonylethyl)-3-methoxybenzamide, 25.7% yield, MS (ES+, m/z): 638.1. [4-[3-[4-[[(3S,4R)-3- fluoro-1-methyl-4-piperidyl]amino]-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-ynylamino]-3-methoxy- phenyl]-(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone (0.02 g, 32.23 mmol, 79% yield), MS (ES+, m/z): 614.3. Compound [4-[3-[4-[[(3S,4R)-3-fluoro-1-methyl-4-piperidyl]amino]-1-(2,2,2-trifluoroethyl)indol- 2-yl]prop-2-ynylamino]-3-methoxy-phenyl]-(7-oxa-2-azaspiro[3.5]nonan-2-yl)methanone (0.025 g, 38.96 mmol, 42% yield) was obtained as a yellow solid. MS (ES+, m/z): 642.3.

Reference： [1]Current Patent Assignee: PMV PHARMACEUTICALS INC - WO2021/61643, 2021, A1 Location in patent: Paragraph 0774-0775

32
[ 194157-10-3 ]
4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)cyclohexan-1-one [ No CAS ]
N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With titanium(IV) tetraethanolate; diisopropylamine In ethanol at 50℃; for 3h; Inert atmosphere;	C9 General Procedure for the preparation of N-(4-(7-oxa-2-azaspiro[3.5]nonan-2- yl)cyclohexyl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine and N¹-(2-iodo-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)-N⁴,N⁴-dimethylcyclohexane-1,4-diamine General procedure: To a solution of 4-((2-iodo-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)cyclohexan-1-one (1 eq.) in EtOH were added 7-oxa-2- azaspiro[3.5]nonane or dimethylamine (5 eq.), Ti(OEt)4 (5 eq.), and i-Pr2NH (1 eq.). The reaction mixture was stirred at 50 °C for 3 h. Then, NaBH3CN (5 eq.) was added to the reaction mixture under N2 at 0 °C, and the mixture was stirred further for 5 min, warmed to 50 °C, and stirred for 1 h. TLC and LC- MS analysis showed that the starting material was consumed completely. The solution was concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography (SiO2) to afford the desired products.

Reference： [1]Current Patent Assignee: PMV PHARMACEUTICALS INC - WO2021/61643, 2021, A1 Location in patent: Paragraph 0347

33
[ 194157-10-3 ]
3-methoxy-4-[3-(4-[(1R,4R)-4-{7-oxa-2-azaspiro[3.5]nonan-2-yl}cyclohexyl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl]amino}benzamide [ No CAS ]
4-((3-(4-(((1S,4S)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: diisopropylamine; titanium(IV) tetraethanolate / ethanol / 3 h / 50 °C / Inert atmosphere 2: copper(l) iodide; diisopropylamine; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / dimethyl sulfoxide / 1 h / 25 °C / Inert atmosphere