Name: 161330-30-9|2-((tert-Butoxycarbonyl)amino)-2-(2-fluorophenyl)acetic acid|96%
Brand: Ambeed
SKU: A190107
Price: 12.0 USD
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1
[ 4530-20-5 ]
[ 13139-15-6 ]
[ 2130-96-3 ]
[ 161330-30-9 ]
H-Tyr-Gly-Gly-Phg(o-F)-Leu-OH [ No CAS ]
H-Tyr-Gly-Gly-D-Phg(o-F)-Leu-OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Yield given. Multistep reaction. Yields of byproduct given;

Reference： [1]Maeda; Kawasaki; Taguchi; Kobayashi; Yamamoto; Shimokawa; Takahashi; Nakao; Kaneto [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 8, p. 1658 - 1662]

2
[ 24424-99-5 ]
[ 84145-28-8 ]
[ 161330-30-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃;	A solution of <strong>[84145-28-8]2-amino-2-(2-fluorophenyl)acetic acid</strong> (300 mg, 1.77 mmol) in THF (1.8 mL) was treated sequentially with 1 M NaOH(aq) (2.66 mL, 5.32 mmol) and di-tert-butyl dicarbonate (387 mg, 1.77 mmol). The resulting mixture was stirred overnight at ambient temperature before introducing additional di-tert-butyl dicarbonate (387 mg, 1.77 mmol). The reaction mixture was concentrated in vacuo. The residue was suspended in DCM, and washed sequentially with saturated NaHC03(aq), water and brine (2 x 2 mL each). The combined organic extracts were dried over anhydrous Na2S04(S), filtered, and concentrated in vacuo. The residue was triturated with DCM/Hexanes (1 : 10) and dried under high vacuum to afford the title compound (486 mg, quantitative yield). MS (apci) m/z = 268.1 (M+H)
70%		To a suspension of <strong>[84145-28-8]2-amino-2-(2-fluorophenyl)acetic acid</strong> (1.00 g, 5.91 mmol) in THF (30 ml) and water (30 ml), 2N sodium hydroxide (29.6 ml, 59.1 mmol) and di-tert-butyl dicarbonate (2.58 g, 11.8 mmol) were added. The reaction was stirred at RT for 15h. THF was evaporated, the aqueous phase was cooled to 0C and acidified with 37% HC1 until pH 1. The desired compound was extracted with EtOAc and the organic phase was washed with brine, dried over Na2SO4 and evaporated to obtain 2-(tert- butoxycarbonylamino)-2-(2-fluorophenyl)acetic acid (1.11 g; 70% yield).
70%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 15h;	To a suspension of <strong>[84145-28-8]2-amino-2-(2-fluorophenyl)acetic acid</strong> (1.00 g, 5.91 mmol) in THF (30 ml) and water (30 ml), were added 2N sodium hydroxide (29.6 ml, 59.1 mmol) and di-tert-butyl dicarbonate (2.58 g, 11.8 mmol). The reaction was stirred at RT for 15 hours. THF was evaporated, and the aqueous phase was cooled to 0 C. and acidified with 37% HCl until pH 1. The desired compound was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4 and evaporated to obtain 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetic acid (1.11 g; 70% yield).

Reference： [1]Tetrahedron,2003,vol. 59,p. 3719 - 3727
[2]Patent: WO2018/136661,2018,A1 .Location in patent: Paragraph 00841-00844
[3]Patent: WO2012/69275,2012,A1 .Location in patent: Page/Page column 66-67
[4]Patent: US2012/134934,2012,A1 .Location in patent: Page/Page column 31

3
[ 161330-30-9 ]
Merrifield resin-bound [(tert-butoxycarbonyl)amino](2-fluorophenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane for 96h; Heating;

Reference： [1]Le Roy, Isabelle; Mouysset, Dominique; Mignani, Serge; Vuilhorgne, Marc; Stella, Lucien [Tetrahedron, 2003, vol. 59, # 21, p. 3719 - 3727]

4
[ 161330-30-9 ]
[ 75-08-1 ]
[ 1021948-13-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;

Reference： [1]Arosio, Dario; Caligiuri, Antonio; D'Arrigo, Paola; Pedrocchi-Fantoni, Giuseppe; Rossi, Cristina; Saraceno, Caterina; Servi, Stefano; Tessaro, Davide [Advanced Synthesis and Catalysis, 2007, vol. 349, # 8-9, p. 1345 - 1348]

5
[ 124-38-9 ]
[ 1174761-19-3 ]
[ 153903-21-0 ]
[ 161330-30-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-(tert-butoxycarbonyl)-α-(phenylsulfonyl)-2-fluorobenzylamine With trimethylsilyltributyltin; cesium fluoride In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: carbon dioxide In N,N-dimethyl-formamide at 100℃; for 3h; Autoclave; Stage #3: With hydrogenchloride In diethyl ether; water; N,N-dimethyl-formamide Inert atmosphere;

Reference： [1]Mita, Tsuyoshi; Chen, Jianyang; Sugawara, Masumi; Sato, Yoshihiro [Angewandte Chemie - International Edition, 2011, vol. 50, # 6, p. 1393 - 1396]

6
[ 4248-19-5 ]
[ 153903-21-0 ]
[ 161330-30-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: formic acid / methanol; water / 60 h / 20 °C / Inert atmosphere 2.1: trimethylsilyltributyltin; cesium fluoride / N,N-dimethyl-formamide / 0.08 h / 20 °C / Inert atmosphere 2.2: 3 h / 100 °C / 7500.75 Torr / Autoclave 2.3: pH 2 / Inert atmosphere

Reference： [1]Mita, Tsuyoshi; Chen, Jianyang; Sugawara, Masumi; Sato, Yoshihiro [Angewandte Chemie - International Edition, 2011, vol. 50, # 6, p. 1393 - 1396]

7
[ 446-52-6 ]
[ 153903-21-0 ]
[ 161330-30-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: formic acid / methanol; water / 60 h / 20 °C / Inert atmosphere 2.1: trimethylsilyltributyltin; cesium fluoride / N,N-dimethyl-formamide / 0.08 h / 20 °C / Inert atmosphere 2.2: 3 h / 100 °C / 7500.75 Torr / Autoclave 2.3: pH 2 / Inert atmosphere

Reference： [1]Mita, Tsuyoshi; Chen, Jianyang; Sugawara, Masumi; Sato, Yoshihiro [Angewandte Chemie - International Edition, 2011, vol. 50, # 6, p. 1393 - 1396]

8
[ 124-38-9 ]
[ 1358791-63-5 ]
[ 161330-30-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: carbon dioxide; N-(tert-butoxycarbonyl)-α-(tributylstannyl)-2-fluorobenzylamine With cesium fluoride In N,N-dimethyl-formamide at 100℃; for 3h; Autoclave; Stage #2: With hydrogenchloride In diethyl ether; water; N,N-dimethyl-formamide at 0℃; Inert atmosphere;

Reference： [1]Location in patent: experimental part Mita, Tsuyoshi; Sugawara, Masumi; Hasegawa, Hiroyuki; Sato, Yoshihiro [Journal of Organic Chemistry, 2012, vol. 77, # 5, p. 2159 - 2168]

9
[ 161330-30-9 ]
[ 18107-18-1 ]
[ 709665-72-5 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; diethyl ether for 1h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Mita, Tsuyoshi; Sugawara, Masumi; Hasegawa, Hiroyuki; Sato, Yoshihiro [Journal of Organic Chemistry, 2012, vol. 77, # 5, p. 2159 - 2168]

10
[ 161330-30-9 ]
[ 25333-42-0 ]
[ 1379513-72-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 15h;	20 To a solution of 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetic acid (155) (1.11 g, 4.12 mmol) in THF (50 ml), Ν,Ν'- methanediylidenedicyclohexanamine (1.02 g, 4.95 mmol), 1H- benzo[d][l,2,3]triazol-l-ol (0.67 g, 4.95 mmol) and (R)-quinuclidin-3-ol (0.63 g, 4.95 mmol) were added. The reaction was stirred at RT for 15h and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetate (1.56 g; quantitative yield).
100%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃;	20 To a solution of 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetic acid (I55) (1.11 g, 4.12 mmol) in THF (50 ml), were added N,N'-methanediylidene-dicyclohexanamine (1.02 g, 4.95 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.67 g, 4.95 mmol), and (R)-quinuclidin-3-ol (0.63 g, 4.95 mmol). The reaction was stirred at RT for hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetate (1.56 g; quantitative yield).
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 18h;

Reference： [1]Current Patent Assignee: Valline SRL - WO2012/69275, 2012, A1 Location in patent: Page/Page column 66-67
[2]Current Patent Assignee: Valline SRL - US2012/134934, 2012, A1 Location in patent: Page/Page column 31-32
[3]Armani, Elisabetta; Rizzi, Andrea; Capaldi, Carmelida; De Fanti, Renato; Delcanale, Maurizio; Villetti, Gino; Marchini, Gessica; Pisano, Anna Rita; Pitozzi, Vanessa; Pittelli, Maria Gloria; Trevisani, Marcello; Salvadori, Michela; Cenacchi, Valentina; Puccini, Paola; Amadei, Francesco; Pappani, Alice; Civelli, Maurizio; Patacchini, Riccardo; Baker-Glenn, Charles A.G.; Van De Poël, Hervé; Blackaby, Wesley P.; Nash, Kevin; Amari, Gabriele [Journal of Medicinal Chemistry, 2021, vol. 64, # 13, p. 9100 - 9119]

11
[ 161330-30-9 ]
[ 1379513-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 15 h / 20 °C 2: ethyl acetate; acetonitrile / 15 h / 20 °C
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 20 °C 2: ethyl acetate; acetonitrile / 15 h / 20 °C

Reference： [1]Current Patent Assignee: Valline SRL - WO2012/69275, 2012, A1
[2]Current Patent Assignee: Valline SRL - US2012/134934, 2012, A1

12
[ 161330-30-9 ]
C₂₉H₃₄FN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / acetonitrile / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C 3: triethylamine / methanol / 2 h / 120 °C / Molecular sieve; Microwave irradiation 4: N-Bromosuccinimide / dichloromethane / 2 h / 20 °C 5: sodium hydroxide; water / methanol; 1,4-dioxane / 65 °C 6: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / acetonitrile / 20 °C 7: trifluoroacetic acid / dichloromethane / 2 h / 20 °C

Reference： [1]Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He [Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2601 - 2610]

13
[ 161330-30-9 ]
C₁₇H₁₇FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / acetonitrile / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C

Reference： [1]Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He [Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2601 - 2610]

14
[ 161330-30-9 ]
C₂₇H₃₃FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / acetonitrile / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C 3: triethylamine / methanol / 2 h / 120 °C / Molecular sieve; Microwave irradiation

Reference： [1]Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He [Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2601 - 2610]

15
[ 161330-30-9 ]
C₂₇H₃₁FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / acetonitrile / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C 3: triethylamine / methanol / 2 h / 120 °C / Molecular sieve; Microwave irradiation 4: N-Bromosuccinimide / dichloromethane / 2 h / 20 °C

Reference： [1]Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He [Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2601 - 2610]

16
[ 161330-30-9 ]
C₂₆H₂₉FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / acetonitrile / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C 3: triethylamine / methanol / 2 h / 120 °C / Molecular sieve; Microwave irradiation 4: N-Bromosuccinimide / dichloromethane / 2 h / 20 °C 5: sodium hydroxide; water / methanol; 1,4-dioxane / 65 °C

Reference： [1]Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He [Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2601 - 2610]

17
[ 161330-30-9 ]
C₃₃H₄₂FN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / acetonitrile / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C 3: triethylamine / methanol / 2 h / 120 °C / Molecular sieve; Microwave irradiation 4: N-Bromosuccinimide / dichloromethane / 2 h / 20 °C 5: sodium hydroxide; water / methanol; 1,4-dioxane / 65 °C 6: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / acetonitrile / 20 °C

Reference： [1]Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He [Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2601 - 2610]

18
[ 6232-11-7 ]
[ 161330-30-9 ]
C₂₂H₂₅FN₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃;

Reference： [1]Demong, Duane; Dai, Xing; Hwa, Joyce; Miller, Michael; Lin, Sue-Ing; Kang, Ling; Stamford, Andrew; Greenlee, William; Yu, Wensheng; Wong, Michael; Lavey, Brian; Kozlowski, Joseph; Zhou, Guowei; Yang, De-Yi; Patel, Bhuneshwari; Soriano, Aileen; Zhai, Ying; Sondey, Christopher; Zhang, Hongtao; Lachowicz, Jean; Grotz, Diane; Cox, Kathleen; Morrison, Richard; Andreani, Teresa; Cao, Yang; Liang, Mark; Meng, Tao; McNamara, Paul; Wong, Jesse; Bradley, Prudence; Feng, Kung-I; Belani, Jitendra; Chen, Ping; Dai, Peng; Gauuan, Jolicia; Lin, Peishan; Zhao, He [Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2601 - 2610]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24h;	Intermediate 4(R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (14) General procedure: Phenylglycine (1.51 g, 10 mmol) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooledto 0°C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0°C for 10 minutes. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 24 hours. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0N aqueous potassium hydrogen sulphate solution (pH 2.5) and subsequently washed with ethyl acetate (2 x 40 mL). The combined organic fractions were dried over magnesium sulfate and the solvent was removed in vacuo to yield the title compound (1.8 g, 72%) as a clear oil, which solidified on standing.
	With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24.17h; Cooling with ice;	Intermediate 4. (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (I4) General procedure: Intermediate 4. (R)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (I4) Phenylglycine (1.51 g, 10 mmol) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooled to 0° C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0° C. for 10 minutes. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 24 hours. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0 N aqueous potassium hydrogen sulphate solution (pH 2.5) and subsequently washed with ethyl acetate (240 mL). The combined organic fractions were dried over magnesium sulfate and the solvent was removed in vacuo to yield the title compound (1.8 g, 72%) as a clear oil, which solidified on standing. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.47-7.27 (m, 5H), 5.48or + (dd, J=72.0 Hz, 6.5 Hz, 1H), 5.13or + (d, J=5.6 Hz, 1H), 3.71 (s, 1H), 1.43 (s, 3H), 1.21 (s, 6H). and † refer to different isomers.
	With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24.1667h;	General procedure: Intermediate 41. 2-((tert-Butoxycarbonyl)amino)-2-phenylacetic acid (I-41) Phenylglycine (1.51 g, 10 mmol) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooled to 0° C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0° C. for 10 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 h. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0 N aqueous potassium hydrogen sulfate solution (pH 2.5) and washed with ethyl acetate (2*40 mL). The combined organic fractions were dried over magnesium sulfate and the solvent was removed in vacuo to yield the title compound (1.8 g, 72%) as a clear oil, which solidified on standing.

With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24.1667h;

2-((tert-Butoxycarbonyl)amino)-2-phenylacetic acid (1-41) General procedure: Phenyiglycine (1.51 g, 10 mmo 1) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooled to 0°C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0°C for 10 minutes.The ice bath was removed and the reaction mixture was stirred at room temperature for 24h. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0 N aqueous potassium hydrogen sulfate solution (pH 2.5) and washed with ethyl acetate (2 x 40 mL). The combined organic fractions were dried over magnesium sulfate and thesolvent was removed in vacuo to yield the title compound (1.8 g, 72%) as a clear oil,which solidified on standing.

20
6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile dihydrochloride [ No CAS ]
[ 161330-30-9 ]
tert-butyl (2-(4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)piperazin-1-yl)-1-(2-fluorophenyl)-2-oxoethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 1h;	63.1 Step 1 : Preparation of teit-butyl (2-(4-(5-(3-cvano-6-(l-methyl-lH-pyrazol-4- yl)pyrazolo[ 1 ,5 -alpyrazin-4-yl)pyridin-2-yl)piperazin- 1 -yl)- 1 -(2-fluorophenyl)-2- oxoethyDcarbamate. A mixture of 6-(l-methyl-lH-pyrazol-4-yl)-4-(6-(piperazin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyrazine-3-carbonitrile (Example 8; 100 mg, 0.259 mmol), 2-((tert- butoxycarbonyl)amino)-2-(2-fluorophenyl)acetic acid (Intermediate R2; 69.9 mg, 0.259 mmol) and HATU (296 mg, 0.778 mmol) in anhydrous DCM (1.3 mL) was treated with DIEA (181 μ, 1.04 mmol). The resulting mixture was stirred for 1 h at ambient temperature. The resulting suspension was filtered, and the filtrate was purified by CI 8 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as the gradient eluent). Fractions containing the desired product were combined, diluted with 4: 1 DCM:iPrOH and washed with brine. The organic extracts were dried over anhydrous Na2S04(S), filtered, and concentrated in vacuo to afford the title compound in sufficient purity for subsequent use (165 mg, quantitative yield). MS (apci) m/z = 637.3 (M+H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/136661, 2018, A1 Location in patent: Paragraph 001089

21
6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile dihydrochloride [ No CAS ]
[ 161330-30-9 ]
4-(6-(4-(2-amino-2-(2-fluorophenyl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: HATU; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2018/136661, 2018, A1

22
[ 161330-30-9 ]
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[[[1-(2-fluorophenyl)-2-oxo-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate [ No CAS ]
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[[[1-(2-fluorophenyl)-2-oxo-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 18 h / 20 °C 2.1: hydrogenchloride / 1,4-dioxane; diethyl ether / 20 h / 20 °C 3.1: triethylamine / ethyl acetate / 2 h / 20 °C 3.2: 20 h / 20 °C 3.3: 20 °C

Reference： [1]Armani, Elisabetta; Rizzi, Andrea; Capaldi, Carmelida; De Fanti, Renato; Delcanale, Maurizio; Villetti, Gino; Marchini, Gessica; Pisano, Anna Rita; Pitozzi, Vanessa; Pittelli, Maria Gloria; Trevisani, Marcello; Salvadori, Michela; Cenacchi, Valentina; Puccini, Paola; Amadei, Francesco; Pappani, Alice; Civelli, Maurizio; Patacchini, Riccardo; Baker-Glenn, Charles A.G.; Van De Poël, Hervé; Blackaby, Wesley P.; Nash, Kevin; Amari, Gabriele [Journal of Medicinal Chemistry, 2021, vol. 64, # 13, p. 9100 - 9119]

23
[ 161330-30-9 ]
(3R)-quinuclidin-3-yl 2-amino-2-(2-fluorophenyl)acetate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 18 h / 20 °C 2: hydrogenchloride / 1,4-dioxane; diethyl ether / 20 h / 20 °C

Reference： [1]Armani, Elisabetta; Rizzi, Andrea; Capaldi, Carmelida; De Fanti, Renato; Delcanale, Maurizio; Villetti, Gino; Marchini, Gessica; Pisano, Anna Rita; Pitozzi, Vanessa; Pittelli, Maria Gloria; Trevisani, Marcello; Salvadori, Michela; Cenacchi, Valentina; Puccini, Paola; Amadei, Francesco; Pappani, Alice; Civelli, Maurizio; Patacchini, Riccardo; Baker-Glenn, Charles A.G.; Van De Poël, Hervé; Blackaby, Wesley P.; Nash, Kevin; Amari, Gabriele [Journal of Medicinal Chemistry, 2021, vol. 64, # 13, p. 9100 - 9119]

24
[ 124-38-9 ]
[ 1174761-19-3 ]
[ 161330-30-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With tetrabutyl ammonium fluoride In N,N-dimethyl-formamide at 0℃; Electrochemical reaction;

Reference： [1]Senboku, Hisanori; Minemura, Yoshihito; Suzuki, Yuto; Matsuno, Hidetoshi; Takakuwa, Mayu [Journal of Organic Chemistry, 2021, vol. 86, # 22, p. 16077 - 16083]

25
[ 161330-30-9 ]
1-(tert-butyl) 3-methyl 5-(2-fluorophenyl)-4-hydroxy-1H-pyrrole-1,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / acetonitrile / 1 h / 20 °C 1.2: 2 h / 20 - 80 °C 2.1: toluene / 4 h / 40 °C