Name: 177948-02-6|tert-Butyl N-[(4-hydroxypiperidin-4-yl)methyl]carbamate|95%
Brand: Ambeed
SKU: A705740
Rating: 92 (27 reviews)

1
[ 174609-75-7 ]
[ 177948-02-6 ]
[ 177948-03-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate In isopropyl alcohol Heating;

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

2
[ 177948-01-5 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; ammsnium formate In methanol for 1h; Reflux;	28 Preparation 28: ieri-butyl N-[(4-hydroxypiperidin-4-yl)methyl]carbamate (P28) To a solution of ieri-butyl N-[(l-benzyl-4-hydroxypiperidin-4-yl)methyl]carbamate (P27, 2.9 g, 9.06 mmol) in MeOH (50 mL) ammonium formate (3.42 g, 54.3 mmol) and 10% Pd/C (0.3 g) were added at RT then the mixture was stirred under reflux for 1 h. The mixture was cooled down to RT and filtered through a pad of celite washing with MeOH. Solvent was eliminated under reduced pressure affording ieri-butyl N-[(4-hydroxypiperidin-4-yl)methyl]carbamate (P28, 2.2 g, y= quant. 90% weight), as clear oil. MS (ES) (m/z): 231.0 [M+H]+.
99%	With palladium on activated charcoal; ammsnium formate In methanol for 2h; Heating;
97%	With hydrazine hydrate monohydrate In ethanol for 3h; Heating;

78%	With anhydrous ammonium formate In methanol at 20℃;
70%	With palladium on activated charcoal; hydrazine hydrate monohydrate In ethanol for 3h; Reflux;	23.3 Step 3: tert-Butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate To a solution of tert-butyl ((1-benzyl-4- thyl)carbamate (800 mg, 2.5 mmol) in ethanol (25 mL) were added hydrazine hydrate (0.25 mL, 5 mmol) and Pd/C (280 mg). The mixture was refluxed for 3 hours. The mixture was filtered through Celite and the filtrate was concentrated under vacuum and purified by silica gel column chromatography (CH2Cl2:MeOH 20:1) to give to give tert-butyl ((4-hydroxypiperidin-4- yl)methyl)carbamate (400 mg, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 5.08 (br s, 1H), 3.17- 3.08 (m, 2H), 3.01- 2.92 (m, 2H), 2.90- 2.82 (m, 2H), 2.45 (br s, 2H), 1.61- 1.50 (m, 4H), 1.45 (s, 9H).
70%	With palladium on carbon; hydrogen In methanol at 60℃; for 16h;
	With hydrogen In methanol	3.3e.4 According to a hydrogenolysis reaction, using 5.1 g of amino alcohol obtained in stage 2, in the presence of 510 mg of 10% Pd/C in 200 ml of methanol, 2.8 g of expected piperidine are obtained after the usual treatment
	With hydrazine hydrate monohydrate In ethanol for 18h; Reflux;	251 A solution the compound prepared in Example 250 (0.68 g) in ethanol (11 mL) was treated with hydrazine monohydrate (0.208 mL), followed by 10% palladium-carbon (0.238 g). The mixture was refluxed for 18 hours. After allowing mixture to cool to room temperature, the catalyst was filtered off and washed with methanol. The filtrate was evaporated in vacuo to obtain the title compound (0.510 g) having the following physical data. 1H NMR (DMSOd6): δ 6.52 (br, IH), 4.17 (br, IH), 2.75-2.69 (m, 2H), 2.62-2.59 (m, 2H), 1.38 (s, 9H), 1.34-1.25 (m, 4H);Mass data (APCI, Pos.): m/z 231 (M + H)+.
	With palladium 10% on activated carbon; ammsnium formate In methanol for 2.5h; Reflux;	4 Step 4 : tert-butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate. Ammonium formate (276 mg, 4.78 mmol) and Pd/C (10% wt, 24 mg) were added to a solution of tert- butyl N-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]carbamate (235 mg, 0.73 mmol) in MeOH (4 mL) and the resulting mixture was refluxed for 1.5 h. Additional Pd/C was added and stirring at reflux was prolonged for 1 h. The cooled mixture was filtered through a pad of Celite and the solution was concentrated under reduced pressure to afford the crude amine (163 mg), which was directly progressed to the next step. LCMS [M+H] 231.4.
35.2 g	With hydrogen; Pearlman’s catalyst In ethanol for 18h;	1-3 Compound 2.4 (69.0 g, 215.3 mmol) was dissolved in EtOH (510 mL), Pd(OH)2 (21.0 g, 10%) was added under N2, the resulting mixture was exchanged with H2, the mixture was stirred for 18 hours, the mixture was filtered through CELITE pad, washed with DCM (100 mL), concentrated and stirred in MTBE (100 mL), filtered to afford compound 35.2 g of Compound 2a as a solid. 1H NMR (400 MHz, CDCl3): δ ppm 4.95 (brs, 1H), 3.13-3.21 (d, J=6.0 Hz, 2H), 2.91-2.97 (m, 2H), 2.82-2.87 (m, 2H), 2.08 (brs, 2H), 1.47-1.54 (m, 4H), 1.43 (s, 9H). LC-MS=231.1 [M+H]+.

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1 Location in patent: Page/Page column 73
[2]Nishida, Hidemitsu; Miyazaki, Yutaka; Mukaihira, Takafumi; Saitoh, Fumihiko; Fukui, Miyuki; Harada, Kousuke; Itoh, Manabu; Muraoka, Aki; Matsusue, Tomokazu; Okamoto, Atsushi; Hosaka, Yoshitaka; Matsumoto, Miwa; Ohnishi, Shuhei; Mochizuki, Hidenori [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 9, p. 1187 - 1194]
[3]Sonda, Shuji; Kawahara, Toshio; Katayama, Kenichi; Sato, Noriko; Asano, Kiyoshi [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 9, p. 3295 - 3308]
[4]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]
[5]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1 Location in patent: Page/Page column 563
[6]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]
[7]Current Patent Assignee: SANOFI - US2010/93668, 2010, A1 Location in patent: Page/Page column 16
[8]Current Patent Assignee: PFIZER INC - WO2010/80864, 2010, A1 Location in patent: Page/Page column 225
[9]Current Patent Assignee: CURZA GLOBAL LLC; UNIVERSITY OF UTAH - WO2020/150385, 2020, A1 Location in patent: Paragraph 00323; 00326
[10]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1 Location in patent: Paragraph 0315; 0325

3
[ 1121-76-2 ]
[ 177948-02-6 ]
[ 318986-82-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium hydrogencarbonate In i-Amyl alcohol for 6h; Heating;

Reference： [1]Nishida, Hidemitsu; Miyazaki, Yutaka; Mukaihira, Takafumi; Saitoh, Fumihiko; Fukui, Miyuki; Harada, Kousuke; Itoh, Manabu; Muraoka, Aki; Matsusue, Tomokazu; Okamoto, Atsushi; Hosaka, Yoshitaka; Matsumoto, Miwa; Ohnishi, Shuhei; Mochizuki, Hidenori [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 9, p. 1187 - 1194]

4
[ 82777-11-5 ]
[ 177948-02-6 ]
[ 188973-81-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2h;
	With potassium carbonate In <i>N</i>-methyl-acetamide; water	P.55.1 Preparation Example 55 (1) 6-Bromo-1-phenyl-1-hexanone (2.9 g) and potassium carbonate (3 g) were added to a solution of 4-hydroxy-4-tert-butoxycarbonylaminomethylpiperidine (2.5 g) in dimethylformamide (40 ml), and the mixture was stirred at 60°C for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 3.74 g of 4-hydroxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine. 1H-NMR (CDCl3,ppm)δ:1.36-1.82(20H,m), 2.36-2.88(4H,m), 2.60-2.67(2H,m), 2.97(2H,t,J=7.3Hz), 3.14(2H,d,J=6.6Hz), 5.01(1H,br), 7.42-7.59(3H,m), 7.93-7.97(2H,m)

Reference： [1]Sonda, Shuji; Kawahara, Toshio; Katayama, Kenichi; Sato, Noriko; Asano, Kiyoshi [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 9, p. 3295 - 3308]
[2]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP873990, 1998, A1

5
[ 19867-34-6 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: aq. ammonia / ethanol / 9 h / 20 °C 2: 36.5 g / CH₂Cl₂ / 3 h / 20 °C 3: 97 percent / hydrazine hydrate / Pd/C / ethanol / 3 h / Heating
	Multi-step reaction with 3 steps 1: ammonium hydroxide / methanol; water monomer / 20 °C 2: dichloromethane / 14 h / 20 °C 3: ammsnium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 3 steps 1: ammonium hydroxide / methanol / 16 h / 20 °C 2: dichloromethane / 1 h / 20 °C 3: palladium 10% on activated carbon; ammsnium formate / methanol / 2.5 h / Reflux

	Multi-step reaction with 3 steps 1: ammonium hydroxide / methanol / 16 h / 0 - 20 °C 2: dichloromethane / 3 h / 20 °C 3: Pearlman’s catalyst; hydrogen / ethanol / 18 h
	Multi-step reaction with 3 steps 1: ammonia / methanol; water monomer / 16.25 h / 5 - 20 °C 2: triethylamine / 2-methyltetrahydrofuran / 16.33 h / 0 °C 3: palladium on carbon; hydrogen / methanol / 16 h / 60 °C / 11251.1 Torr

Reference： [1]Sonda, Shuji; Kawahara, Toshio; Katayama, Kenichi; Sato, Noriko; Asano, Kiyoshi [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 9, p. 3295 - 3308]
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1
[3]Current Patent Assignee: CURZA GLOBAL LLC; UNIVERSITY OF UTAH - WO2020/150385, 2020, A1
[4]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1
[5]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

6
[ 24424-99-5 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 36.5 g / CH₂Cl₂ / 3 h / 20 °C 2: 97 percent / hydrazine hydrate / Pd/C / ethanol / 3 h / Heating

Reference： [1]Sonda, Shuji; Kawahara, Toshio; Katayama, Kenichi; Sato, Noriko; Asano, Kiyoshi [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 9, p. 3295 - 3308]

7
[ 23804-68-4 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 36.5 g / CH₂Cl₂ / 3 h / 20 °C 2: 97 percent / hydrazine hydrate / Pd/C / ethanol / 3 h / Heating
	Multi-step reaction with 2 steps 1: 75 percent / aq. NaOH / dioxane / 4 h / 60 °C 2: 99 percent / HCO₂NH₄; 10 percent Pd/C / methanol / 2 h / Heating
	Multi-step reaction with 2 steps 1: 70 percent / CH₂Cl₂ / 20 °C 2: 78 percent / ammonium formate / 10 percent Pd/C / methanol / 20 °C

	Multi-step reaction with 2 steps 1: dichloromethane / 14 h / 20 °C 2: ammsnium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 2 steps 1: dichloromethane / 20 °C 2: palladium on activated charcoal; hydrazine hydrate monohydrate / ethanol / 3 h / Reflux
	Multi-step reaction with 2 steps 1: dichloromethane / 1 h / 20 °C 2: palladium 10% on activated carbon; ammsnium formate / methanol / 2.5 h / Reflux
	Multi-step reaction with 2 steps 1: dichloromethane / 3 h / 20 °C 2: Pearlman’s catalyst; hydrogen / ethanol / 18 h
	Multi-step reaction with 2 steps 1: triethylamine / 2-methyltetrahydrofuran / 16.33 h / 0 °C 2: palladium on carbon; hydrogen / methanol / 16 h / 60 °C / 11251.1 Torr

Reference： [1]Sonda, Shuji; Kawahara, Toshio; Katayama, Kenichi; Sato, Noriko; Asano, Kiyoshi [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 9, p. 3295 - 3308]
[2]Nishida, Hidemitsu; Miyazaki, Yutaka; Mukaihira, Takafumi; Saitoh, Fumihiko; Fukui, Miyuki; Harada, Kousuke; Itoh, Manabu; Muraoka, Aki; Matsusue, Tomokazu; Okamoto, Atsushi; Hosaka, Yoshitaka; Matsumoto, Miwa; Ohnishi, Shuhei; Mochizuki, Hidenori [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 9, p. 1187 - 1194]
[3]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]
[4]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1
[5]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1
[6]Current Patent Assignee: CURZA GLOBAL LLC; UNIVERSITY OF UTAH - WO2020/150385, 2020, A1
[7]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1
[8]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

8
[ 177948-02-6 ]
6-(4-aminomethyl-4-hydroxypiperidin-4-yl)-1-phenylhexan-1-one dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: K₂CO₃ / dimethylformamide / 2 h / 60 °C 2: 2.92 g / hydrochloric acid / propan-2-ol / 3 h / 60 °C

Reference： [1]Sonda, Shuji; Kawahara, Toshio; Katayama, Kenichi; Sato, Noriko; Asano, Kiyoshi [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 9, p. 3295 - 3308]

9
[ 177948-02-6 ]
4-amino-5-chloro-N-((4-hydroxy-1-(6-oxo-6-phenylhexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: K₂CO₃ / dimethylformamide / 2 h / 60 °C 2: 2.92 g / hydrochloric acid / propan-2-ol / 3 h / 60 °C 3: 63 percent / Et₃N; 1-hydroxybenzotriazole; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / dimethylformamide / 6 h / 20 °C

Reference： [1]Sonda, Shuji; Kawahara, Toshio; Katayama, Kenichi; Sato, Noriko; Asano, Kiyoshi [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 9, p. 3295 - 3308]

10
[ 24424-99-5 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 75 percent / aq. NaOH / dioxane / 4 h / 60 °C 2: 99 percent / HCO₂NH₄; 10 percent Pd/C / methanol / 2 h / Heating

Reference： [1]Nishida, Hidemitsu; Miyazaki, Yutaka; Mukaihira, Takafumi; Saitoh, Fumihiko; Fukui, Miyuki; Harada, Kousuke; Itoh, Manabu; Muraoka, Aki; Matsusue, Tomokazu; Okamoto, Atsushi; Hosaka, Yoshitaka; Matsumoto, Miwa; Ohnishi, Shuhei; Mochizuki, Hidenori [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 9, p. 1187 - 1194]

11
[ 177948-02-6 ]
[ 318986-85-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 37 percent / NaHCO₃ / 3-methyl-butan-1-ol / 6 h / Heating 2: 71 percent / H₂ / Raney Ni / methanol / 3.5 h / 20 °C

Reference： [1]Nishida, Hidemitsu; Miyazaki, Yutaka; Mukaihira, Takafumi; Saitoh, Fumihiko; Fukui, Miyuki; Harada, Kousuke; Itoh, Manabu; Muraoka, Aki; Matsusue, Tomokazu; Okamoto, Atsushi; Hosaka, Yoshitaka; Matsumoto, Miwa; Ohnishi, Shuhei; Mochizuki, Hidenori [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 9, p. 1187 - 1194]

12
[ 177948-02-6 ]
4-(aminomethyl)-1-(4-pyridinyl)-4-piperidinol dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 37 percent / NaHCO₃ / 3-methyl-butan-1-ol / 6 h / Heating 2: 71 percent / H₂ / Raney Ni / methanol / 3.5 h / 20 °C 3: 89 percent / aq. HCl / methanol / 2 h / 20 °C

Reference： [1]Nishida, Hidemitsu; Miyazaki, Yutaka; Mukaihira, Takafumi; Saitoh, Fumihiko; Fukui, Miyuki; Harada, Kousuke; Itoh, Manabu; Muraoka, Aki; Matsusue, Tomokazu; Okamoto, Atsushi; Hosaka, Yoshitaka; Matsumoto, Miwa; Ohnishi, Shuhei; Mochizuki, Hidenori [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 9, p. 1187 - 1194]

13
[ 177948-02-6 ]
4-[(6-chloro-2-naphthalenyl)sulfonyl]-1-[[4-hydroxy-1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 37 percent / NaHCO₃ / 3-methyl-butan-1-ol / 6 h / Heating 2.1: 71 percent / H₂ / Raney Ni / methanol / 3.5 h / 20 °C 3.1: 89 percent / aq. HCl / methanol / 2 h / 20 °C 4.1: AcOH / CH₂Cl₂ / 1 h / 20 °C 4.2: 29 percent / NaBH(OAc)3 / CH₂Cl₂ / 20 °C

Reference： [1]Nishida, Hidemitsu; Miyazaki, Yutaka; Mukaihira, Takafumi; Saitoh, Fumihiko; Fukui, Miyuki; Harada, Kousuke; Itoh, Manabu; Muraoka, Aki; Matsusue, Tomokazu; Okamoto, Atsushi; Hosaka, Yoshitaka; Matsumoto, Miwa; Ohnishi, Shuhei; Mochizuki, Hidenori [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 9, p. 1187 - 1194]

14
[ 24424-99-5 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 70 percent / CH₂Cl₂ / 20 °C 2: 78 percent / ammonium formate / 10 percent Pd/C / methanol / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

15
[ 177948-02-6 ]
[ 177948-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 60 percent / K₂CO₃ / propan-2-ol / Heating 2: TFA / CH₂Cl₂ / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

16
[ 177948-02-6 ]
[ 177946-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 60 percent / K₂CO₃ / propan-2-ol / Heating 2: TFA / CH₂Cl₂ / 20 °C 3: NaCNBH₃; AcOH / methanol / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

17
[ 177948-02-6 ]
4-[(benzyl-methyl-amino)-methyl]-1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 60 percent / K₂CO₃ / propan-2-ol / Heating 2: TFA / CH₂Cl₂ / 20 °C 3: NaCNBH₃; AcOH / methanol / 20 °C 4: 83 percent / NaCNBH₃; AcOH; MeOH / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

18
[ 177948-02-6 ]
4-[(methyl-pyridin-2-ylmethyl-amino)-methyl]-1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 60 percent / K₂CO₃ / propan-2-ol / Heating 2: TFA / CH₂Cl₂ / 20 °C 3: NaCNBH₃; AcOH / methanol / 20 °C 4: NaCNBH₃; AcOH / methanol / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

19
[ 177948-02-6 ]
[ 177946-90-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 60 percent / K₂CO₃ / propan-2-ol / Heating 2: TFA / CH₂Cl₂ / 20 °C 3: NaCNBH₃; AcOH / methanol / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

20
[ 177948-02-6 ]
4-hydroxy-4-[N-(2-methylphenylmethyl)-N-methylamino]-methyl-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 60 percent / K₂CO₃ / propan-2-ol / Heating 2: TFA / CH₂Cl₂ / 20 °C 3: NaCNBH₃; AcOH / methanol / 20 °C 4: NaCNBH₃; AcOH / methanol / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

21
[ 177948-02-6 ]
[ 177946-91-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 60 percent / K₂CO₃ / propan-2-ol / Heating 2: TFA / CH₂Cl₂ / 20 °C 3: NaCNBH₃; AcOH / methanol / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

22
[ 177948-02-6 ]
N-{4-[({4-hydroxy-1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-phenyl}-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 60 percent / K₂CO₃ / propan-2-ol / Heating 2: TFA / CH₂Cl₂ / 20 °C 3: NaCNBH₃; AcOH / methanol / 20 °C

Reference： [1]Bourrain, Sylvie; Neduvelil, Joseph G.; Beer, Margaret S.; Stanton, Josephine A.; Showell, Graham A.; Macleod, Angus M. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 23, p. 3369 - 3374]

23
[ 177948-02-6 ]
[ 318986-82-2 ]

Yield	Reaction Conditions	Operation in experiment
1.03 g	With 4-chloropyridine N-oxide In i-Amyl alcohol for 4h; Heating / reflux;

Reference： [1]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - EP1191028, 2002, A1 Location in patent: Example 7

24
[ 1121-76-2 ]
[ 177948-02-6 ]
6-(acetoxymethyl)-1,4-diaza-4-(6-chloronaphthalen-2-ylsulfonyl)-7-oxa-1'-(4-pyridyl)spiro[bicyclo[4.3.0]nonane-8,4'-piperidin]-2-one [ No CAS ]
[ 318986-82-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In i-Amyl alcohol; water	7 <Step A-1> Example 7 Synthesis of 6-(acetoxymethyl)-1,4-diaza-4-(6-chloronaphthalen-2-ylsulfonyl)-7-oxa-1'-(4-pyridyl)spiro[bicyclo[4.3.0]nonane-8,4'-piperidin]-2-one Synthesis of 4-[4-(t-butoxycarbonylamino)methyl-4-hydroxypiperidin-1-yl]pyridine 1-oxide To a suspension in isoamyl alcohol (35 ml) of conventionally known compounds: 4-[(t-butoxycarbonylamino)methyl]-4-hydroxypiperidine (2.00 g) and 4-chloropyridine 1-oxide (1.12 g), was added sodium hydrogencarbonate (1.75 g) and the mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool and water was added thereto. The reaction mixture was extracted with methylene chloride and the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: methylene chloride:methanol 9:1-4:1) to obtain the title compound (1.03 g). NMR spectrum (*DMSo-d 6) δppm: 7.90-7.83(2H,m),6.92-6.84(2H,m),6.78-6.70(1H,m),4.58(1H,brs),3.64-3.50(2H,m),3.17-3.04(2H,m),2.92(2H,d,J=6 Hz),1.60-1.30(4H,m),1.35(9H,s)

Reference： [1]Current Patent Assignee: MOCHIDA PHARMACEUTICAL CO LTD - US2003/45520, 2003, A1

25
[ 82777-11-5 ]
[ 177948-02-6 ]
[ 188973-81-1 ]
6-(4-aminomethyl-4-hydroxypiperidin-4-yl)-1-phenylhexan-1-one dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In <i>N</i>-methyl-acetamide; water	P.138.1 PREPARATION EXAMPLE 138 (1) 6-Bromo-1-phenyl-1-hexanone (2.9 g) and potassium carbonate (3 g) were added to a solution of 4-hydroxy-4-tert-butoxycarbonylaminomethylpiperidine (2.5 g) in dimethylformamide (40 ml), and the mixture was stirred at 60° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 3.74 g of 4-hydroxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine. 1 H-NMR (CDCl3,ppm) δ: 1.36-1.82(20 H,m), 2.36-2.88(4 H,m), 2.60-2.67(2 H,m), 2.97(2 H,t,J=7.3 Hz), 3.14(2 H,d,J=6.6 Hz), 5.01(1 H,br), 7.42-7.59(3 H,m), 7.93-7.97(2 H,m) (2) 4-Hydroxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine (3.6 g) was dissolved in isopropyl alcohol (30 ml) and 15% hydrochloric acid-isopropyl alcohol (10 ml) was added under ice-cooling, which was followed by stirring at 60° C. for 3 hr. The solvent was evaporated under reduced pressure to give 2.92 g of 4-aminomethyl-4-hydroxy-1-(6-oxo-6-phenylhexyl)piperidine dihydrochloride. 1 H-NMR (DMSO-d6,ppm) δ: 1.33-1.41(2 H,m), 1.59-1.97(8 H,m), 2.80-2.83(2 H,m), 3.01-3.09(8 H,m), 5.54(1 H,br), 7.50-7.67(3 H,m), 7.96-7.99(2 H,m), 8.13(3 H,br), 10.61(1 H,br)

Reference： [1]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US5864039, 1999, A

Yield	Reaction Conditions	Operation in experiment
78%		38.b b b 4-Hydroxy-4-(tert-butyloxycarbonylamino)methyl piperidine To a solution of the foregoing amine (12.5 g, 39 mmol) in methanol (300 ml) was added 10% palladium on carbon (2.5 g) in methanol (20 ml), and ammonium formate (7 g, 11 mmol). The suspension was stirred at ambient temperature for 3 h, then the catalyst filtered off and washed with methanol. The solvent was evaporated in vacuo and the residue triturated with dichloromethane. The resulting solid was dissolved in saturated aqueous potassium carbonate and extracted with dichloromethane (12*). The combined organics were dried (sodium sulphate) and evaporated to give the required product as a solid (7 g, 78%) mp 136°-138° C. δ (360 MHz, d6 -DMSO) 1.22-1.48 (4H, m, 2 of CH2), 1.38 (9H, s, OC(Me)3), 2.52-2.62 (2H, m, CH2), 2.62-2.76 (2H, m, CH2), 2.88 (2H, d, J=6 Hz, CH2), 4.12 (1H, s, OH), 6.49 (1H, t, J=6 Hz, NH). MS, m/e=231 for (M+H)+.

27
6-chloro-3-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-amine [ No CAS ]
[ 177948-02-6 ]
C₂₁H₂₇F₃N₆O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h;	72.a A solution of 6-chloro-3-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin- 2-amine (70 mg, 0.304 mmol), fer?-butyl ((4-hydroxypiperidine-4-yl)methyl)carbamate (103 mg, 0.336 mmol), and DIPEA (2.0 mL, 11.45 mmol) in NMP (1 mL) was stirred for 3 h at 120 °C. After cooling to RT, the reaction was diluted with EtOAc, the organic phase was washed with water, brine, dried over Na2S04, and the volatiles were removed under reduced pressure to give a brown oily residue. This residue was taken up in DCM (5 mL) and HC1 (4 M in dioxane; 760 μ^, 3.04 mmol) was added in two portions (half at the beginning of the reaction and the other half 3 h later). The reaction was stirred a total of 4 h. The volatiles were removed under reduced pressure and the resulting residue was triturated witih MeCN to give a brown solid. The resulting crude was freebased suspending in 5% MeOH/DCM and adding sat. aq NaHC03. The resulting layers were separated and the aqueous was extracted again with 5% MeOH DCM. The combine organic phases were concentrated under reduced pressure to give l-(6-amino-5-((2- (trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-4-(aminomethyl)piperidin-4-ol (65 mg, 0.149 mmol) as an off-white-tan solid. NMR (400 MHz, DMSO-<4) δ ppm 8.47 (dd, J=4.6, 1.4 Hz, 1 H), 7.68 (s, 1 H), 7.55 (dd, J=8.3, 4.5 Hz, 1H) 7.32 (dd, J=8.3, 1.4 Hz, 1 H), 4.04 (dt, J=13.8, 4.2 Hz, 2 H), 3.38-3.28 (m, 2 H), 2.83 (s, 2 H), 1.70-1.48 (m, 4 H). MS m/z 401.2 (M+H)+.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2015/107495, 2015, A1 Location in patent: Paragraph 00428

28
N-[3-(1H-imidazol-1-yl)propyl]-2-(4-oxopiperidin-1-yl)-3-phenylquinoxaline-6-carboxamide [ No CAS ]
[ 177948-02-6 ]
C₃₇H₄₈N₈O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	With borane-2-picoline complex; acetic acid In methanol at 20℃; for 16h;	21 tert-Butyl {14-hydroxy-1’-(6- [3-(1H-imidazol-1-yl)propyllcarbamoyl}-3- phenylquiuoxalin-2-yI)-1,4’-bipiperidin-4-yl]methyl}carbamate 1-231 To a solution of N-(3-(lH-imidazol-l-yl)propyl)-2-(4-oxopiperidin-l-yl)-3- phenylquinoxaline-6-carboxamide (140 mg, 0.31 mmol) (prepared according to Example 20, step 1) in MeOH (2.7 mL) and AcOH (0.27 mL) were added teri-butyl((4-hydroxypiperidin-4-yl)methyl)carbamate (116 mg, 0.50 mmol) and 2-picoline borane complex (32.9 mg, 0.31 mmol) at rt. The resulting mixture was stirred at rt for 16 h.The reaction mixture was diluted with H20 (4 mL) at rt. To the mixture was added 2 M HCl (0.5 mL) at rt. The reaction mixture was stirred at rt for 5 min. The reaction mixture was diluted with EtOAc and saturated NaHCOs aq. The aqueous layer was extracted with EtOAc. The separated organic layers were combined, washed with brine, dried over Na2S04and concentrated in vacuo. The residue was purified by NH silica gel chromatography to give tert-butyl [4-hydroxy-l'-(6- { [3-( lH-imidazol- 1 -yl)propyl]carbamoyl} -3-phenylquinoxalin-2-yl)- 1 ,4'-bipiperidin-4- yl]methyl} carbamate (11.0 mg, 5%) as a yellow amorphous solid. LCMS (ESI+): m/z = 669.5 (Μ+Η).1H NMR (300 MHz, CDCL) δ 1.44 (s, 9 H), 1.58-1.65 (m, 6 H), 1.80-1.85 (m, 2 H), 2.09-2.21 (m, 2 H), 2.27 (s, 1 H), 2.32-2.83 (m, 7 H), 3.13 (d, J= 6.3 Hz, 2 H), 3.53 (q, J= 6.5 Hz, 2 H), 3.88-3.98 (m, 2 H), 4.08 (t, J= 6.9 Hz, 2 H), 4.86 (br s, 1 H), 6.28 (t, J= 6.1 Hz, 1 H), 6.99 (t, J= 1.2 Hz, 1 H), 7.09 (s, 1 H), 7.42-7.55 (m, 4 H), 7.82 (d, J= 8.8 Hz, 1 H), 7.95 (dd, J= 7.8, 1.6 Hz, 2 H), 8.03 (dd, J= 8.7, 2.1 Hz, 1 H), 8.24 (d, J= 2.0 Hz, 1 H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/161142, 2015, A1 Location in patent: Paragraph 00315

29
1-bromo-3-fluoro-5-(3-fluorophenoxy)benzene [ No CAS ]
[ 177948-02-6 ]
tert-butyl N-({1-[3-fluoro-5-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin-4-yl}methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; DavePhos In 1,2-dimethoxyethane at 110℃; Inert atmosphere;	31 Preparation 31: tert-butyl N-({l-[3-fluoro-5-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin-4- yl}methyl)carbamate (P31) To a stirred solution of ieri-butyl N-[(4-hydroxypiperidin-4-yl)methyl]carbamate (P28, 50 mg, 0.217 mmol) and l-bromo-3-fluoro-5-(3-fluorophenoxy)benzene (P3, 62 mg, 0.21 mmol) in DM E (2 mL) at RT, DavePhos (8.5 mg, 0.0217 mmol), Pd2(dba)3 (6 mg, 0.007 mmol) and K3P04 (92 mg, 0.434 mmol) were added and nitrogen was purged for 10 min. Then the reaction was shaken at 110 °C overnight. The reaction mixture was partitioned between water and EtOAc, organic phase was separated, dried and concentrated under reduced pressure. Crude material was purified by FC on silica gel (eluent: Cy to Cy/AcOEt 70/30) affording ieri-butyl N-({l-[3-fluoro-5-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin-4- yl}methyl)carbamate (P31, 37 mg, y= 39 %), as yellow oil. MS (ES) (m/z): 435.3 [M+H]+.

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1 Location in patent: Page/Page column 76

30
1-bromo-3-fluoro-5-(3-fluorophenoxy)benzene [ No CAS ]
[ 177948-02-6 ]
4-(aminomethyl)-1-[3-fluoro-5-(3-fluorophenoxy)phenyl]piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: DavePhos; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium phosphate / 1,2-dimethoxyethane / 110 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

31
1-bromo-2,5-difluoro-3-(3-fluorophenoxy)benzene [ No CAS ]
[ 177948-02-6 ]
tert-butyl N-({1-[2,5-difluoro-3-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin-4-yl}methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; DavePhos In 1,2-dimethoxyethane at 110℃; Inert atmosphere;	32 Preparation 32: tert-butyl N-({l-[2,5-difluoro-3-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin-4- yl}methyl)carbamate (P32) To a stirred solution of ieri-butyl N-[(4-hydroxypiperidin-4-yl)methyl]carbamate (P28, 50 mg, 0.217 mmol) and l-bromo-2,5-difluoro-3-(3-fluorophenoxy)benzene (P5, 66 mg, 0.217 mmol) in DM E (2 mL) at T, DavePhos (8.5 mg, 0.0217 mmol), Pd2(dba)3 (6 mg, 0.007 mmol) and K3P04 (92 mg, 0.434 mmol) were added and nitrogen was purged for 10 min. The reaction mixture was shaken at 110 °C overnight. The reaction mixture was partitioned between water and EtOAc, organic phase was separated, dried and concentrated under reduced pressure. Crude material was purified by FC on silica gel (eluent: Cy to Cy 70/AcOEt 30) affording ieri-butyl N-({l-[2,5-difluoro-3-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin- 4-yl}methyl)carbamate (P32, 10 mg, y= 10%), as yellow oil. MS (ES) (m/z): 453.3 [M+H]+.

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1 Location in patent: Page/Page column 77

32
1-bromo-2,5-difluoro-3-(3-fluorophenoxy)benzene [ No CAS ]
[ 177948-02-6 ]
4-(aminomethyl)-1-[2,5-difluoro-3-(3-fluorophenoxy)phenyl]piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: DavePhos; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium phosphate / 1,2-dimethoxyethane / 110 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

33
1-bromo-2-fluoro-3-phenoxybenzene [ No CAS ]
[ 177948-02-6 ]
tert-butyl N-[1-(2-fluoro-3-phenoxyphenyl)-4-hydroxypiperidin-4-yl]methyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; DavePhos In 1,2-dimethoxyethane at 110℃; Inert atmosphere;	33 Preparation 33: tert-butyl N-[l-(2-fluoro-3-phenoxyphenyl)-4-hydroxypiperidin-4- yl]methyl}carbamate (P33) To a stirred solution of ferf-butyl N-[(4-hydroxypiperidin-4-yl)methyl]carbamate (P28, 50mg, 0.217mmol) and l-bromo-2-fluoro-3-phenoxybenzene (P6, 58 mg, 0.217 mmol) in DM E (2 mL) at RT, DavePhos (8.5 mg, 0.0217 mmol), Pd2(dba)3 (6 mg, 0.007 mmol) and K3P04 (92 mg, 0.434 mmol) were added and nitrogen was purged for 10 min. The reaction was then shaken at 110 °C overnight. The mixture was partitioned between water and EtOAc, organic phase was separated, dried and concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluent: Cy to Cy70/AcOEt 30) affording ferf-butyl N-[l-(2-fluoro-3-phenoxyphenyl)-4-hydroxypiperidin-4- yl]methyl}carbamate (P33, 30 mg, y= 33%), as yellow oil. MS (ES) (m/z): 417.3 [M+H]+

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1 Location in patent: Page/Page column 78

34
1-bromo-2-fluoro-3-phenoxybenzene [ No CAS ]
[ 177948-02-6 ]
4-(aminomethyl)-1-(2-fluoro-3-phenoxyphenyl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: DavePhos; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium phosphate / 1,2-dimethoxyethane / 110 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

35
1-bromo-2-fluoro-3-(3-fluorophenoxy)benzene [ No CAS ]
[ 177948-02-6 ]
tert-butyl N-({1-[2-fluoro-3-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin-4-yl}methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; DavePhos In dichloromethane at 110℃; Inert atmosphere;	34 Preparation 34: tert-butyl N-({l-[2-fluoro-3-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin-4- yl}methyl)carbamate (P34) To a stirred solution of ieri-butyl N-[(4-hydroxypiperidin-4-yl)methyl]carbamate (P28, 50 mg, 0.217 mmol) and l-bromo-2-fluoro-3-(3-fluorophenoxy)benzene (P7, 62 mg, 0.217 mmol) in DM E (2 mL) at RT, DavePhos (8.5 mg, 0.0217 mmol), Pd2(dba)3 (6 mg, 0.007 mmol) and K3P04 (92 mg, 0.434 mmol) were added and nitrogen was purged for 10 min. The reaction was then shaken at 110 °C overnight. The mixture was partitioned between water and EtOAc, organic phase was separated, dried and concentrated under reduced pressure. Crude material was purified by FC on silica gel (eluent: Cy to Cy 65/AcOEt 35) affording ieri-butyl N-({l-[2-fluoro-3-(3-fluorophenoxy)phenyl]-4-hydroxypiperidin-4- yl}methyl)carbamate (P34, 30 mg, y= 32%), as yellow oil. MS (ES) (m/z): 435.3 [M+H]+.

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1 Location in patent: Page/Page column 79

36
1-bromo-2-fluoro-3-(3-fluorophenoxy)benzene [ No CAS ]
[ 177948-02-6 ]
4-(aminomethyl)-1-[2-fluoro-3-(3-fluorophenoxy)phenyl]piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: DavePhos; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium phosphate / dichloromethane / 110 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

37
[ 3612-20-2 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / dimethyl sulfoxide; mineral oil / 1 h / 10 - 20 °C 1.2: 1.5 h / 20 °C 2.1: ammonium hydroxide / methanol; water monomer / 20 °C 3.1: dichloromethane / 14 h / 20 °C 4.1: ammsnium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 3 steps 1.1: triethylamine / 3 h / 20 °C 1.2: 1.5 h / Reflux 2.1: dichloromethane / 20 °C 3.1: palladium on activated charcoal; hydrazine hydrate monohydrate / ethanol / 3 h / Reflux
	Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; dimethyl sulfoxide / 1.17 h / 0 - 20 °C 1.2: 1.5 h / 20 °C 2.1: ammonium hydroxide / methanol / 16 h / 20 °C 3.1: dichloromethane / 1 h / 20 °C 4.1: palladium 10% on activated carbon; ammsnium formate / methanol / 2.5 h / Reflux

	Multi-step reaction with 4 steps 1.1: sodium hydride / dimethyl sulfoxide / 2 h / 18 - 20 °C / Inert atmosphere 1.2: 2 h / 18 - 20 °C / Inert atmosphere 2.1: ammonium hydroxide / methanol / 16 h / 0 - 20 °C 3.1: dichloromethane / 3 h / 20 °C 4.1: Pearlman’s catalyst; hydrogen / ethanol / 18 h
	Multi-step reaction with 4 steps 1.1: potassium-t-butoxide / dimethyl sulfoxide / 1.25 h / 20 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: ammonia / methanol; water monomer / 16.25 h / 5 - 20 °C 3.1: triethylamine / 2-methyltetrahydrofuran / 16.33 h / 0 °C 4.1: palladium on carbon; hydrogen / methanol / 16 h / 60 °C / 11251.1 Torr

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1
[2]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1
[3]Current Patent Assignee: CURZA GLOBAL LLC; UNIVERSITY OF UTAH - WO2020/150385, 2020, A1
[4]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1
[5]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

38
2-chloro-4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidine [ No CAS ]
[ 177948-02-6 ]
tert-butyl N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium carbonate In dimethyl sulfoxide at 50℃; for 2h;	29 Preparation 29: tert-butyl N-({l-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4- hydroxypiperidin-4-yl}methyl)carbamate (P29) To a solution of ieri-butyl N-[(4-hydroxypiperidin-4-yl)methyl]carbamate (P28, 0.34 g, 1.36 mmol (90% weight) in DMSO (6 mL) 2-chloro-4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidine (P2, 0.4 g, 1.36 mmol) and K2C03 (0.37 g, 2.72 mmol) were added at RT then the mixture was shaken at 50 °C for 2 hrs. The mixture was cooled down, diluted with DCM and washed with water. Organic phase was dried and concentrated and the crude material purified by FC on silica gel (eluent: Cy to Cy/AcOEt 1:1) affording ferf-butyl N-({l-[4-(3-fluorophenoxy)-6-(trifluoro yl}methyl)carbamate (P29, 350 mg, y= 53%) as a white solid. MS (ES) (m/z): 487.0 [M+H]+.

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1 Location in patent: Page/Page column 73; 74

39
[ 177948-02-6 ]
tert-butyl N-({4-fluoro-1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2: diethylamino-sulfur trifluoride / dichloromethane / 1 h / 0 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

40
[ 177948-02-6 ]
4-fluoro-1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl methanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2: diethylamino-sulfur trifluoride / dichloromethane / 1 h / 0 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

41
[ 177948-02-6 ]
N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)-2-(propan-2-yloxy)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.17 h 3.2: 4 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

42
[ 177948-02-6 ]
N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.17 h 3.2: 4 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

43
[ 177948-02-6 ]
tert-butyl 3-[({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)carbamoyl]azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.17 h 3.2: 12 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

44
[ 177948-02-6 ]
N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)azetidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.17 h 3.2: 12 h / 20 °C 4.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

45
[ 177948-02-6 ]
N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.33 h / 20 °C 3.2: 8 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

46
[ 177948-02-6 ]
N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.33 h / 20 °C 3.2: 3 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

47
[ 177948-02-6 ]
N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)pyrazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.33 h / 20 °C 3.2: 3 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

48
[ 177948-02-6 ]
tert-butyl N-[({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)carbamoyl]methyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.33 h / 20 °C 3.2: 3 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

49
[ 177948-02-6 ]
2-amino-N-({1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / dichloromethane / 0.33 h / 20 °C 3.2: 3 h / 20 °C 4.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

50
[ 177948-02-6 ]
4-(aminomethyl)-1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 2 h / 50 °C 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED; TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42453, 2016, A1

51
6-chloro-3-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-amine [ No CAS ]
[ 177948-02-6 ]
1-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-4-(aminomethyl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65 mg	Stage #1: 6-chloro-3-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-amine; 4-[(t-butoxycarbonylamino)methyl]-4-hydroxypiperidine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 120℃; for 3h; Stage #2: With hydrogenchloride In 1,4-dioxane; dichloromethane for 4h;	72.a A solution of 6-chloro-3-((2-(trifluorom- ethyl)pyridin-3-yl)thio)pyrazin-2-amine (70 mg, 0.304 mmol), tert-butyl ((4-hydroxypiperidine-4-yl)methyl)car-bamate (103 mg, 0.336 mmol), and DIPEA (2.0 mE, 11.45 mmol) in NMP (1 mE) was stirred for 3 h at 120° C. After cooling to RT, the reaction was diluted with EtOAc, the organic phase was washed with water, brine, dried over Na2504, and the volatiles were removed under reduced pressure to give a brown oily residue. This residue was taken up in DCM (5 mE) and HC1 (4 M in dioxane; 760 IL, 3.04 mmol) was added in two portions (half at the begiiming of the reaction and the other half 3 h later). The reaction was stirred a total of 4 h. The volatiles were removed under reduced pressure and the resulting residue was triturated with MeCN to give a brown solid. The resulting crude was freebased suspending in 5% MeOH/DCM and adding sat. aq NaHCO3. The resulting layers were separated and the aqueous was extracted again with 5% MeOH/DCM. The combine organic phases were concentrated under reduced pressure to give 1 -(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl) thio)pyrazin-2-yl)-4-(aminomethyl)piperidin-4-ol (65 mg, 0.149 mmol) as an off-white-tan solid. ‘H NMR (400 MHz, DMSO-d5) ö ppm 8.47 (dd, J=4.6, 1.4 Hz, 1H), 7.68 (s, 1H), 7.55 (dd, J=8.3, 4.5 Hz, 1H) 7.32 (dd, J=8.3, 1.4 Hz, 1H),4.04 (dt, J=13.8, 4.2 Hz, 2H), 3.38-3.28 (m, 2H), 2.83 (s, 2H), 1.70-1.48 (m, 4H). MS mlz 401.2 (M+H).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2017/15680, 2017, A1 Location in patent: Paragraph 0514; 0515

52
(S)-4-(6-(4-amino-2-oxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-ol [ No CAS ]
[ 177948-02-6 ]
tert-butyl (1-(6-chloro-5-(3-chloro-2-methoxyisonicotinoyl) pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	120 tert-Butyl (1-(6-chloro-5-(3-chloro-2-methoxyisonicotinoyl) pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methyl carbamate tert-Butyl (1-(6-chloro-5-(3-chloro-2-methoxyisonicotinoyl) pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methyl carbamate To a solution of Intermediate 109 (63.7 mg, 0.2 mmol) in DMF (2 mL) under N2 was added tert-butyl (4-hydroxypiperidin-4-yl)methyl carbamate (46 mg, 0.2 mmol) and K2CO3 (55.3 mg, 0.4 mmol). The resulting mixture was stirred overnight at RT and poured into H2O (20 mL). The solid that formed was removed by filtration and dried to give the crude title compound as a yellow solid (120 mg) which was used directly without further purification. MS (ES+) C22H27Cl2N5O5 requires: 511, found: 512 [M+H]+.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TEXAS SYSTEM - US2017/342078, 2017, A1 Location in patent: Paragraph 0745; 0746

53
(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone [ No CAS ]
[ 177948-02-6 ]
tert-butyl (1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)-pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	114 tert-Butyl (1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)-pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methyl carbamate tert-Butyl (1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)-pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methyl carbamate To a solution of Intermediate 108 (84.4 mg, 0.2 mmol) in DMF (2 mL) under N2 was added tert-butyl (4-hydroxypiperidin-4-yl)methyl carbamate (46 mg, 0.2 mmol) and K2CO3 (55.3 mg, 0.4 mmol). The result mixture was stirred overnight at RT then poured into H2O (20 mL). The solid that formed was removed via filtration and dried to give the crude title compound as a yellow solid (120 mg) which was used directly without further purification. MS (ES+) C29H34Cl2N6O5 requires: 616, found: 617 [M+H]+.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TEXAS SYSTEM - US2017/342078, 2017, A1 Location in patent: Paragraph 0706; 0707

54
(2-chloro-3-fluorophenyl)(3,5-dichloropyrazin-2-yl)methanone [ No CAS ]
[ 177948-02-6 ]
tert-butyl (1-(6-chloro-5-(2-chloro-3-fluorobenzoyl)pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	37 tert-Butyl (1-(6-chloro-5-(2-chloro-3-fluorobenzoyl)pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methyl carbamate tert-Butyl (1-(6-chloro-5-(2-chloro-3-fluorobenzoyl)pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methyl carbamate To a solution of the product from the previous step in DMF (2 mL), under N2, was added tert-butyl (4-hydroxypiperidin-4-yl)methyl carbamate (57.5 mg, 0.25 mmol) and K2CO3 (69 mg, 0.5 mmol). The resulting mixture was stirred overnight at RT and then poured into H2O (20 mL). The solid was collected and dried to give the crude title compound as a yellow solid (120 mg), which was used directly without further purification. MS (ES+) C22H25Cl2FN4O4 requires: 498, found: 499 [M+H]+.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TEXAS SYSTEM - US2017/342078, 2017, A1 Location in patent: Paragraph 0531; 0532

55
[ 177948-02-6 ]
tert-butyl (1-(3-(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-4-hydroxypiperidin-4-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TEXAS SYSTEM - US2017/342078, 2017, A1

56
[ 177948-02-6 ]
1-((3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-aminomethyl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux; Inert atmosphere 3: trifluoroacetic acid / 0.33 h / 120 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TEXAS SYSTEM - US2017/342078, 2017, A1

57
[ 177948-02-6 ]
tert-butyl ((1-(2-((6-chloro-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl)-4-hydroxypiperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium tris(acetoxy)borohydride / dichloromethane / 20 °C 1.2: 20 °C 2.1: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1

58
[ 177948-02-6 ]
tert-butyl ((1-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl)-4-hydroxypiperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium tris(acetoxy)borohydride / dichloromethane / 20 °C 1.2: 20 °C 2.1: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.1: potassium thioacetate / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.2: 25 °C

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1

59
[ 177948-02-6 ]
2-((6-((2-(4-(aminomethyl)-4-hydroxypiperidin-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium tris(acetoxy)borohydride / dichloromethane / 20 °C 1.2: 20 °C 2.1: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.1: potassium thioacetate / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.2: 25 °C 4.1: trifluoroacetic acid / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1

60
[ 177948-02-6 ]
tert-butyl ((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 15 h / 25 °C 2.1: potassium thioacetate / N,N-dimethyl-formamide / 2 h / 25 °C 2.2: 15 h / 25 °C

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1

61
[ 177948-02-6 ]
2-((6-(4-(aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 15 h / 25 °C 2.1: potassium thioacetate / N,N-dimethyl-formamide / 2 h / 25 °C 2.2: 15 h / 25 °C 3.1: dichloromethane / 15 h / 25 °C

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1

62
2-amino-2-oxo-1-phenylethyl methanesulfonate [ No CAS ]
2,6-dichloro-4-cyclopropylpyridine-3,5-dicarbonitrile [ No CAS ]
[ 177948-02-6 ]
tert-butyl ((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
233 mg	Stage #1: 2,6-dichloro-4-cyclopropylpyridine-3,5-dicarbonitrile; 4-[(t-butoxycarbonylamino)methyl]-4-hydroxypiperidine With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: With potassium thioacetate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #3: 2-amino-2-oxo-1-phenylethyl methanesulfonate With triethylamine In N,N-dimethyl-formamide at 20℃;	23.4 Step 4: tert-Butyl ((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4- cyclopropylpyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)carbamate To a solution of 2,6-dichloro-4-cyclopropylpyridine-3,5-dicarbonitrile (synthesis described in example 4 step 2, 237 mg, 1 mmol) in N,N-dimethylformamide (10 mL) was added tert- butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate (230 mg, 1 mmol), followed by Et3N (0.14 mL 1 mmol). The mixture was stirred at room temperature for 5 minutes, then diluted with water . The precipitated solid was collected by filtration and purified by silica gel column chromatography (DCM:ethyl acetate 1:1) to afford 300 mg of a residue. A solution the residue and KSAc (96 mg, 0.84 mmol) in N,N-dimethylformamide (7 mL) was stirred at room temperature for 30 minutes then 2-amino-2-oxo-1-phenylethyl methanesulfonate (synthesis described in example 3 step 5, 191 mg, 0.84 mmol) and Et3N (0.19 mL, 1.4 mmol) were added to the solution. The mixture was stirred at room temperature overnight then diluted with water. The precipitated solid was collected by filtration and purified by silica gel column chromatography (CH2Cl2:MeOH 20:1) to give tert-butyl ((1-(6-((2-amino- 2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)-4-hydroxypiperidin-4- yl)methyl)carbamate (233 mg) as a yellow solid. LCMS m/z = 562.8 [M+H]+.

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1 Location in patent: Page/Page column 563-564

63
2-amino-2-oxo-1-phenylethyl methanesulfonate [ No CAS ]
2,6-dichloro-4-cyclopropylpyridine-3,5-dicarbonitrile [ No CAS ]
[ 177948-02-6 ]
2-((6-(4-(aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine / N,N-dimethyl-formamide / 0.08 h / 20 °C 1.2: 0.5 h / 20 °C 1.3: 20 °C 2.1: trifluoroacetic acid / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1

64
[ 107201-33-2 ]
[ 177948-02-6 ]
tert-butyl ((4-hydroxy-1-(2-(methylamino)ethyl)piperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: N-<(benzyloxy)carbonyl>-N-methylaminoacetaldehyde; 4-[(t-butoxycarbonylamino)methyl]-4-hydroxypiperidine With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; Stage #2: With palladium 10% on activated carbon; hydrogen In methanol at 20℃;	170.1 Step 1: tert-Butyl ((4-hydroxy-1-(2-(methylamino)ethyl)piperidin-4-yl)methyl) carbamate To a solution of tert-butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate (320 mg, 1.39 mmol) and benzyl methyl(2-oxoethyl)carbamate (288 mg, 1.39 mmol) in dichloromethane (14 mL) was added sodium triacetoxyborohydride (589 mg, 2.78 mmol). The reaction mixture was stirred at room temperature overnight then diluted with DCM and washed with sat. NaHCO3 solution. The organic layer was dried, concentrated and purified by Flash column chromatography (eluted by petroleum ether/EtOAc, 3:1) to give 400 mg of a residue. The residue was dissolved in methanol (10 mL), and palladium on carbon (10%, 10 mg, 0.1 mmol) was added. The reaction mixture was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered and the filtrate was concentrated to give tert-butyl ((4-hydroxy-1-(2-(methylamino)ethyl)piperidin-4-yl)methyl)carbamate (270 mg, 0.939 mmol, 68% yield).1H NMR (400 MHz, CDCl3) δ ppm 5.07 (br. s, 1H), 3.19- 3.10 (m, 2H), 2.71 (t, J = 6.1 Hz, 2H), 2.66- 2.58 (m, 2H), 2.56- 2.50 (m, 2H), 2.46 (s, 3H), 2.44- 2.36 (m, 2H), 1.69- 1.57 (m, 4H), 1.45 (s, 9H). One proton not observed.

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1 Location in patent: Page/Page column 741-742

65
[ 18520-07-5 ]
[ 177948-02-6 ]
tert-butyl ((1-(6-chloro-3,5-dicyano-4-ethylpyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With triethylamine In dichloromethane at 25℃; for 15h;	243.1 Step 1: tert-Butyl ((1-(6-chloro-3,5-dicyano-4-ethylpyridin-2-yl)-4-hydroxypiperidin-4- yl) methyl)carbamate To a solution of 2,6-dichloro-4-ethylpyridine-3,5-dicarbonitrile (synthesis described in example 3 step 2, 1 g, 4.42 mmol) in dichloromethane (50 mL) were added tert-butyl ((4- hydroxypiperidin-4-yl)methyl)carbamate (1.019 g, 4.42 mmol) and triethylamine (0.448 g, 4.42 mmol). The reaction mixture was stirred at 25 °C for 15 hours. The solvent was removed and water (50 mL) and DCM (50 mL) were added to the residue. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 1:2) to give the product tert-butyl ((1-(6-chloro-3,5- dicyano-4-ethylpyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)carbamate (1.1 g, 2.62 mmol, 59% yield). LCMS m/z = 441.8 [M+Na]+.

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; GLAXOSMITHKLINE PLC - WO2017/216726, 2017, A1 Location in patent: Page/Page column 837

66
[ 1175526-48-3 ]
[ 177948-02-6 ]
C₁₉H₂₆Cl₂N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In dichloromethane; water at 20℃; for 1h;

Reference： [1]Thomson, Christopher G.; Le Grand, Darren; Dowling, Mark; Brocklehurst, Cara E.; Chinn, Colin; Elphick, Lucy; Faller, Michael; Freeman, Mark; Furminger, Vikki; Gasser, Cornelia; Hamadi, Ahmed; Hardaker, Elizabeth; Head, Victoria; Hill, Johan C.; Janus, Diana I.; Pearce, David; Poulaud, Anne-Sophie; Stanley, Emily; Sviridenko, Lilya [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 13, p. 2279 - 2284]

67
[ 177948-02-6 ]
C₂₃H₂₄ClN₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / dichloromethane; water / 1 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1 h / 0 - 20 °C 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 20 °C

Reference： [1]Thomson, Christopher G.; Le Grand, Darren; Dowling, Mark; Brocklehurst, Cara E.; Chinn, Colin; Elphick, Lucy; Faller, Michael; Freeman, Mark; Furminger, Vikki; Gasser, Cornelia; Hamadi, Ahmed; Hardaker, Elizabeth; Head, Victoria; Hill, Johan C.; Janus, Diana I.; Pearce, David; Poulaud, Anne-Sophie; Stanley, Emily; Sviridenko, Lilya [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 13, p. 2279 - 2284]

68
[ 177948-02-6 ]
C₁₅H₂₁ClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane; water / 1 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 1 h / 0 - 20 °C

Reference： [1]Thomson, Christopher G.; Le Grand, Darren; Dowling, Mark; Brocklehurst, Cara E.; Chinn, Colin; Elphick, Lucy; Faller, Michael; Freeman, Mark; Furminger, Vikki; Gasser, Cornelia; Hamadi, Ahmed; Hardaker, Elizabeth; Head, Victoria; Hill, Johan C.; Janus, Diana I.; Pearce, David; Poulaud, Anne-Sophie; Stanley, Emily; Sviridenko, Lilya [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 13, p. 2279 - 2284]

69
tert-butyl (2-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)ethyl)carbamate [ No CAS ]
[ 177948-02-6 ]
tert-butyl ((1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)-4-hydroxypiperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 120℃; Inert atmosphere;	17.A Step A: tert-butyl ((1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(N-(2-((tert- butoxycarbonyl)amino)ethyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)-4- hydroxypiperidin-4-yl)methyl)carbamate. To a solution of tert-butyl (2-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3- (2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenylsulfonamido)ethyl)carbamate (REFERENCE EXAMPLE 41) (200 mg, 0.214 mmol) in DMF (10 ml) was added tert-butyl ((4- hydroxypiperidin-4-yl)methyl)carbamate (99 mg, 0.428 mmol) and 1,4- diazabicyclo[2.2.2]octane (0.035 ml, 0.321 mmol). The reaction mixture was heated at 120 °C under nitrogen overnight. The reation mixture was cooled to RT, diluted with 10 mL of EtOAc, filtered through a CELITE pad. The filtrate was dried (MgSO4), concentrated and chromatographed over silica gel with 0-10% MeOH in DCM as eluent to give the title compound. LC-MS 1036.7.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 99

70
[ 6094-60-6 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: tetrahydrofuran 2: ammonium hydroxide / methanol; dichloromethane 3: Pd(OH)2 / ethanol

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2002/165241, 2002, A1

71
[ 177948-01-5 ]
[ 177948-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol	54.3 4-BOC-aminomethyl-piperidin-4-ol Step 3 4-BOC-aminomethyl-piperidin-4-ol A mixture of 4-BOC-aminomethyl-1-benzyl-piperidin-4-ol (0.50 g, 1.56 mmol), Pd(OH)2 (20% on carbon, 0.05 g) in absolute ethanol (15 mL) was shaken under 60 psi H2 atmosphere for 3 h. Filtered and concentrated, the reaction gave 4-BOC-aminomethyl-piperidin-4-ol. M.S.(M+1):231.28.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2002/165241, 2002, A1

72
[ 1246372-52-0 ]
[ 177948-02-6 ]
tert-butyl ((4-hydroxy-1-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With N-ethyl-N,N-diisopropylamine In 2-methyltetrahydrofuran at 85℃; for 9h;
67.1 g	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 110℃; for 3h;	1-3 Compound 2a (83.8 g, 363.7 mmol) and Compound 1 (80 g, 242.5 mmol) was dissolved in DMSO (800 mL), DIPEA (62.6 g, 485 mmol) was added dropwise, the resulting mixture was heated to 110° C., the mixture was stirred for 3 hours, the mixture was cooled to room temperature and added H2O (800 mL), extracted with EtOAc (1 L4), the combined organic layers were washed with H2O (200 mL3), brine (200 mL*3), dried on Na2SO4, concentrated and the residue was stirred in MeCN:MeOH (10:1, 500 mL) to afford 67.1 g of Compound 3 as a solid. 1H NMR (400 MHz, MeOD-d4): δ ppm 7.06 (s, 1H), 2.69-3.72 (m, 2H), 3.45-3.52 (m, 2H), 3.11 (s, 2H), 1.63-1.76 (m, 4H), 1.44 (s, 9H). LC-MS=480.0 [M+H]+.

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1 Location in patent: Paragraph 0315; 0334-0335

73
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(2-(dimethylamino)-6-methylpyridin-3-yl)imidazolo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere 3: tetrahydrofuran / 8 h / 140 °C / Microwave irradiation 4: hydrogenchloride / methanol; tetrahydrofuran / 1 h / 20 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1

74
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(6-methyl-2-(methylthio)pyridin-3-yl)imidazolo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere 3: sodium hydrogencarbonate / tetrahydrofuran / 2 h / 120 °C 4: hydrogenchloride / methanol; tetrahydrofuran / 1 h / 20 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1

75
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(4-(1-hydroxycyclobutyl)-2-methoxyphenyl)imidazolo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; 1,4-dioxane / 6 h / 100 °C 3: hydrogenchloride / methanol; 1,4-dioxane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1

76
[ 177948-02-6 ]
tert-butyl ((4-hydroxy-1-(5-(6-isopropyl-2- methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Inert atmosphere; Sealed tube
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 16 h / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1
[2]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

77
[ 177948-02-6 ]
C₂₃H₃₃N₇O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere 3: tetrahydrofuran / 8 h / 140 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1

78
[ 177948-02-6 ]
C₂₁H₂₇FN₆O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1

79
[ 177948-02-6 ]
C₂₂H₃₀N₆O₃S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere 3: sodium hydrogencarbonate / tetrahydrofuran / 2 h / 120 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1

80
[ 177948-02-6 ]
C₃₂H₄₉N₅O₅SSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; 1,4-dioxane / 6 h / 100 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1

81
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3 h / 110 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Inert atmosphere; Sealed tube 3: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 3: 7 h / 0 - 20 °C / Inert atmosphere 4: sodium hydroxide / water monomer / 1 h / 20 °C / pH 13

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2021/115065, 2021, A1
[2]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

82
[ 177948-02-6 ]
C₂₂H₂₈FN₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

83
[ 177948-02-6 ]
C₂₃H₃₀FN₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

84
[ 177948-02-6 ]
C₂₃H₃₁N₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

85
[ 177948-02-6 ]
C₂₂H₃₀N₆O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

86
[ 177948-02-6 ]
C₂₅H₃₆N₆O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

87
[ 177948-02-6 ]
C₁₉H₂₆N₆O₂S*CH₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 16 h / 85 °C / Inert atmosphere 3: 7 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

88
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

89
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(2-ethoxy-4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

90
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

91
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

92
[ 177948-02-6 ]
4-(aminomethyl)-1-(5-(2-ethoxy-6-isopropylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 2-methyltetrahydrofuran / 9 h / 85 °C 2: tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / water monomer; 1,4-dioxane / 3 h / 80 °C / Sealed tube; Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C

Reference： [1]Abas, Siti Nurdiana; Aguiar, Anna Caroline Campos; Ang, Xiaoman; Blaquiere, Nicole; Bodenreider, Christophe; Campbell, Simon; Campo, Brice; Chan, Katherine; Chan, Wai Ling; Chen, Yen-Liang; Cooper, Roland A.; Crespo-Fernandez, Benigno; Diagana, Thierry T.; Ding, Mei; Fang, Eric; Gamo, Francisco Javier; Guiguemde, Armand; Huang, Richard; Jain, Jay Prakash; Kirrane, Tom; Lakshminarayana, Suresh B.; Lanshoeft, Christian; Lim, Jessie; Liu, Yugang; Mata, Anne-Catherine; Pei, Luying; Qumber, Jafri; Rosenthal, Philip J.; Sarko, Christopher; Schulz, Hanna; Shu, Wei; Sim, Sandra; Simon, Oliver; Straimer, Judith; Taft, Benjamin R.; Thompson, Christopher; Tumwebaze, Patrick; Vankadara, Subramanyam; Waldron, Grace; Yokokawa, Fumiaki; Zou, Bin; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wagner, Jürgen [Journal of Medicinal Chemistry, 2022, vol. 65, # 5, p. 3798 - 3813]

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	177948-02-6	MDL No. :	MFCD09753931
Formula :	C₁₁H₂₂N₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZVUCOORWSKRJII-UHFFFAOYSA-N
M.W :	230.30	Pubchem ID :	10868112
Synonyms :

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	3.0
Molar Refractivity :	65.31
TPSA :	70.59 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.57 cm/s

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	0.19
Log Po/w (WLOGP) :	0.24
Log Po/w (MLOGP) :	0.32
Log Po/w (SILICOS-IT) :	0.73
Consensus Log Po/w :	0.77

[ CAS No. 177948-02-6 ] {[proInfo.proName]}

Quality Control of [ 177948-02-6 ]

Related Doc. of [ 177948-02-6 ]

Product Details of [ 177948-02-6 ]

Calculated chemistry of [ 177948-02-6 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

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Medicinal Chemistry

Safety of [ 177948-02-6 ]

Application In Synthesis of [ 177948-02-6 ]

[ 177948-02-6 ] Synthesis Path-Downstream 1~92

Technical Information

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[ 177948-02-6 ]

Alcohols

Amides

Amines

Related Parent Nucleus of
[ 177948-02-6 ]

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-1.06
Solubility :	20.2 mg/ml ; 0.0876 mol/l
Class :	Very soluble
Log S (Ali) :	-1.23
Solubility :	13.5 mg/ml ; 0.0588 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.1
Solubility :	1.84 mg/ml ; 0.008 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.44

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 177948-02-6 ] {[proInfo.proName]}

Quality Control of [ 177948-02-6 ]

Related Doc. of [ 177948-02-6 ]

Product Details of [ 177948-02-6 ]

Calculated chemistry of [ 177948-02-6 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 177948-02-6 ]

Application In Synthesis of [ 177948-02-6 ]

[ 177948-02-6 ] Synthesis Path-Downstream 1~92

Technical Information

Related Functional Groups of [ 177948-02-6 ]

Alcohols

Amides

Amines

Related Parent Nucleus of [ 177948-02-6 ]

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 177948-02-6 ]

Related Parent Nucleus of
[ 177948-02-6 ]