Name: 215790-29-7|tert-Butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate|98%
Brand: Ambeed
SKU: A201451
Rating: 99 (28 reviews)

1
[ 166398-34-1 ]
[ 215790-29-7 ]
[ 215790-38-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 16h;

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

2
[ 149355-52-2 ]
[ 215790-29-7 ]
[ 215790-43-5 ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;
	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 16h;
	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; Inert atmosphere;

Reference： [1]Shonberg, Jeremy; Herenbrink, Carmen Klein; López, Laura; Christopoulos, Arthur; Scammells, Peter J.; Capuano, Ben; Lane, J. Robert [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221]
[2]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]
[3]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]

3
[ 215789-45-0 ]
[ 215790-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	With diisobutylaluminium hydride In toluene at -78℃; for 0.3h;

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

4
[ 215790-29-7 ]
[ 149354-01-8 ]
[ 264264-24-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 0℃; for 18h;

Reference： [1]Austin, Nigel E.; Avenell, Kim Y.; Boyfield, Izzy; Branch, Clive L.; Hadley, Michael S.; Jeffrey, Phillip; Johnson, Christopher N.; Macdonald, Gregor J.; Nash, David J.; Riley, Graham J.; Smith, Alexander B.; Stemp, Geoffrey; Thewlis, Kevin M.; Vong, Antonio K. K.; Wood, Martyn [Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 22, p. 2553 - 2555]

5
[ 215790-29-7 ]
[ 127168-88-1 ]
[ 437650-81-2 ]

Yield	Reaction Conditions	Operation in experiment
	With NaBH(OAc)2 In 1,2-dichloro-ethane at 20℃; for 16h;

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]

6
[ 215790-29-7 ]
[ 127168-84-7 ]
[ 437651-72-4 ]

Yield	Reaction Conditions	Operation in experiment
	With NaBH(OAc)2 In 1,2-dichloro-ethane at 20℃; for 16h;

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]

7
[ 215790-29-7 ]
[ 263888-58-0 ]
[ 437651-10-0 ]

Yield	Reaction Conditions	Operation in experiment
	With NaBH(OAc)2 In 1,2-dichloro-ethane at 20℃; for 16h;

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]

8
[ 215790-29-7 ]
[ 263888-60-4 ]
[ 437650-82-3 ]

Yield	Reaction Conditions	Operation in experiment
	With NaBH(OAc)2 In 1,2-dichloro-ethane at 20℃; for 16h;

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]

9
[ 215790-29-7 ]
[ 342638-03-3 ]
[ 437651-92-8 ]

Yield	Reaction Conditions	Operation in experiment
	With NaBH(OAc)2 In 1,2-dichloro-ethane at 20℃; for 16h;

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]

10
[ 215790-29-7 ]
[ 123018-23-5 ]
[ 264264-44-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 48h;

Reference： [1]Macdonald, Gregor J.; Branch, Clive L.; Hadley, Michael S.; Johnson, Christopher N.; Nash, David J.; Smith, Alexander B.; Stemp, Geoffrey; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Winborn, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Watson, Jeannette M.; Wood, Martyn; Parker, Steve G.; Ashby Jr., Charles R. [Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4952 - 4964]

11
[ 215790-29-7 ]
[ 264264-51-9 ]
[ 264264-52-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 48h;

Reference： [1]Macdonald, Gregor J.; Branch, Clive L.; Hadley, Michael S.; Johnson, Christopher N.; Nash, David J.; Smith, Alexander B.; Stemp, Geoffrey; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Winborn, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Watson, Jeannette M.; Wood, Martyn; Parker, Steve G.; Ashby Jr., Charles R. [Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4952 - 4964]

12
[ 61502-37-2 ]
[ 215790-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: H₂SO₄ / 5 h / Heating 2: Et₃N / CH₂Cl₂ / 18 h / 20 °C 3: diisobutylaluminum hydride / toluene / 0.3 h / -78 °C

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

13
[ 76308-27-5 ]
[ 215790-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / CH₂Cl₂ / 18 h / 20 °C 2: diisobutylaluminum hydride / toluene / 0.3 h / -78 °C

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

14
[ 215790-29-7 ]
trans-2-(2-(1-(4-amino)cyclohexyl)ethyl)-6-cyano-1,2,3,4-tetrahydroisoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 87 percent / NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 81 percent / TFA / CH₂Cl₂ / 2 h / 20 °C

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

15
[ 215790-29-7 ]
2-(2-((trans)-4-aminocyclohexyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: TFA / CH₂Cl₂ / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / 1,2-dichloro-ethane / 20 °C / Inert atmosphere 2: trifluoroacetic acid / 1,2-dichloro-ethane / 16 h / 20 °C
	Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / 1,2-dichloro-ethane / 20 °C 2: trifluoroacetic acid / dichloromethane

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]
[2]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]
[3]Kopinathan, Anitha; Draper-Joyce, Christopher; Szabo, Monika; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2019, vol. 62, # 1, p. 371 - 377]

16
[ 215790-29-7 ]
trans-(E)-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-3-phenyl-2-propenamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 87 percent / NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride / CH₂Cl₂ / 16 h

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

17
[ 215790-29-7 ]
trans-(E)-N-[4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-3-phenyl-2-propenamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / CH₂Cl₂ / 16 h

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

18
[ 215790-29-7 ]
trans-N-[4-[2-(6-cyano-1,2,3,4-tetyrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-2-2naphthalenecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 87 percent / NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride / CH₂Cl₂ / 16 h

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

19
[ 215790-29-7 ]
trans-(E)-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-3-(4-fluorophenyl)-2-propenamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 87 percent / NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride / CH₂Cl₂ / 16 h

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

20
[ 215790-29-7 ]
trans-N-[4-[2-(6-cyano-1,2,3,4-tetyrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1-naphthalenecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 87 percent / NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride / CH₂Cl₂ / 16 h

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

21
[ 215790-29-7 ]
trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 87 percent / NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 49.4 percent / 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride / CH₂Cl₂ / 20 h / 20 °C

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

22
[ 215790-29-7 ]
SB 269652 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / CH₂Cl₂ / 16 h
	Multi-step reaction with 3 steps 1: sodium tris(acetoxy)borohydride / 1,2-dichloro-ethane / 20 °C / Inert atmosphere 2: trifluoroacetic acid / 1,2-dichloro-ethane / 16 h / 20 °C 3: 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C / Inert atmosphere

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]
[2]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]

23
[ 215790-29-7 ]
trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 87 percent / NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride / CH₂Cl₂ / 16 h

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

24
[ 215790-29-7 ]
trans-(E)-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-3-[3-(methylsulfonyl)phenyl]-2-propenamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 87 percent / NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 38 percent / 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride / CH₂Cl₂ / 16 h

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

25
[ 215790-29-7 ]
trans-(E)-N-[4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-3-(3-1H-indole)-2-propenamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaBH(OAc)3 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 1-hydroxybenzotriazole; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / CH₂Cl₂ / 16 h

Reference： [1]Stemp, Geoffrey; Ashmeade, Tracey; Branch, Clive L.; Hadley, Michael S.; Hunter, A. Jacqueline; Johnson, Christopher N.; Nash, David J.; Thewlis, Kevin M.; Vong, Antonio K. K.; Austin, Nigel E.; Jeffrey, Phillip; Avenell, Kim Y.; Boyfield, Izzy; Hagan, Jim J.; Middlemiss, Derek N.; Reavill, Charlie; Riley, Graham J.; Routledge, Carole; Wood, Martyn [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1878 - 1885]

26
[ 846036-10-0 ]
[ 215790-29-7 ]
trans-4-{2-[4-(indan-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.8%	Stage #1: 1-(indan-4-yl)-piperazine hydrochloride; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With sodium tris(acetoxy)borohydride; triethylamine In 1,1-dichloroethane at 20℃; for 20h; Stage #2: With potassium carbonate In 1,1-dichloroethane; water	1 Example 1 trans-4-{2-[4-(indan-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl-carbamic acid tert- butylester (intermediate)3.58 g (15 mmol) of 1-(indan-4-yl)-piperazine hydrochloride and 3.62 g (15 mmol) of ifraϖs-4-(2-oxoethyl)cyclohexyl-carbamic acid tert-butyl ester were dissolved in dichloroethane (120 ml), 2.1 ml (15 mmol) triethylamine was added, then 4.6 g (22 mmol) sodium triacetoxyborohydride was added portionswise and the reaction mixture was stirred for 20 hours at ambient temperature, then 20 % potassium carbonate solution in water (40 ml) was added. The organic layer was separated, dried and evaporated to dryness in vacuo. The precipitate was recrystallized from acetonitrile to give the title compound 5.5 g (yield: 85.8 %), m.p.: 115-8 0C.

Reference： [1]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2006/82456, 2006, A1 Location in patent: Page/Page column 23

27
[ 215790-29-7 ]
[ 56346-57-7 ]
trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.2%		Intermediate E Trans-(4-{2-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester A mixture of <strong>[56346-57-7]4-(4-fluorobenzoyl)piperidine</strong> (0.850 g, 3.4 mmol), Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.926 g, 4 mmol), in 1, 2 dichloroethane (10 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 1.4 g (3.25 mmol, 93.2% yield) of a light yellow solid. MS (m/e): 433.4 (M+H+).

Reference： [1]Patent: US2007/197531,2007,A1 .Location in patent: Page/Page column 25

28
[ 215790-29-7 ]
[ 55695-51-7 ]
(trans-4-{2-[4-(4-chloro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		Step 1 (trans-4-{2-[4-(4-Chloro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester From (4-chlorophenyl)(4-piperidyl)methanone hydrochloride (100 mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate C, 102 mg) by procedure A.1. Yield: 128 mg (74%). Light yellow solid. MS (m/z): 449.3 ([M+H]+). ; General Procedure A.1 for the Reductive Amination A mixture of amine hydrochloride (1.0 eq.) and aldehyde (1.1 eq.) in 1,2-dichloroethane (ca. 0.2 M) was stirred over night at room temperature. Na(AcO)3BH (1.5 eq.) was added and the reaction was monitored by TLC and MS. After completion sat. aq. NHCO3 sol. was added and the product was extracted with CH2Cl2. After drying (Na2SO4 or MgSO4) the solvent was evaporated and the product purified by flash chromatography.

Reference： [1]Patent: US2007/197531,2007,A1 .Location in patent: Page/Page column 54-55

29
[ 215790-29-7 ]
[ 3413-28-3 ]
trans-(4-{2-[4-(4-fluorophenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.5%		trans-(4-{2-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester A mixture of <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.150 g, 0.485 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.117 g, 0.48 mmol), in 1, 2 dichloroethane (3 mL) and methanol (0.500 mL) was stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (0.175 g, 0.829 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/CH3OH (1-9:1). The product fractions were concentrated to give 0.176 g (0.45 mmol, 92.5% yield) of a light yellow solid. MS (m/e): 393.4 (M+H+).

Reference： [1]Patent: US2008/103174,2008,A1 .Location in patent: Page/Page column 14

30
[ 25519-78-2 ]
[ 215790-29-7 ]
[ 946598-35-2 ]

Yield	Reaction Conditions	Operation in experiment
93.2%		Step 5: Trans-(4-{2-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester A mixture of <strong>[25519-78-2]4-(4-fluorobenzoyl)piperidine hydrochloride</strong> (0.850 g, 3.4 mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.926 g, 4 mmol), in dichloromethane (10 mL) was stirred for 2 hours at room temperature and sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 1.4 g (3.25 mmol, 93.2% yield) of a light yellow solid. MS (m/e): 433.4 (M+H+).

Reference： [1]Patent: US2009/42943,2009,A1 .Location in patent: Page/Page column 10

31
[ 946598-34-1 ]
[ 215790-29-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With diisobutylaluminium hydride In toluene at -78℃; for 4.5h; Inert atmosphere;
100%	With diisobutylaluminium hydride In toluene at -78℃; for 1h;
99%	With diisobutylaluminium hydride In toluene at -78℃; for 0.5h;

89%	With diisobutylaluminium hydride In toluene at -78℃; Inert atmosphere;
	With diisobutylaluminium hydride In toluene at -78℃; for 0.5h;	4 Step 4: Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester To a solution of trans-(4-tert-Butoxycarbonylamino-cyclohexyl)-acetic acid ethyl ester (1.04 g, 4 mmol), in toluene (10 mL) at -78° C. a 1.2M solution of DIBAL-H (5.1 mL, 6 mmol) in toluene was added. The mixture was stirred at -78° C. until TLC after 0.5 h indicated completion of the reaction. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was used without purification on the next step. MS (m/e): 242.3 (M+H+).
	With diisobutylaluminium hydride In methanol; toluene at -40℃; Flow reactor;	Synthesis of trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde (2) bycontinuous-flow reduction system is constructed, consisting of two Asia Syringe Pumps (Syrris,Royston, United Kingdom, Pump 1) both having two separate flow channels, two of which are connected to two Asia Reagent Injectors (Syrris, Royston, United Kingdom, 5 ml (loop 1), 1 ml (loop 2)respectively), the third channel (Pump 2) was used directly. The two channels of the injectors areconnected to a T-adaptor (Diba Omnifit PTFE T-adaptor, 1.5 mm i.d), preceded by pre-cooling loops(0.5 ml), which is followed by an alternating diameter reactor (3 units of 10 cm long, 397.3 l net volume).The output of the reactor and pump 2 are connected to a T-adaptor, followed by a second reactor (PTFEtubing, 0.8 mm i.d., 1.6 mm o.d., 0.9 ml), after which the reaction mixture is collected. The system waswashed with methanol, followed by toluene and finally anhydrous toluene. The reactors, pre-coolingloops and T-adaptors were cooled down to -40°C using a thermostated isopropanol bath. Washing withanhydrous toluene was upheld until steady temperature was reached. Other parts were kept at ambienttemperature.Anhydrous toluene was transferred on both channels of the pumps with a flow rate of 1.25ml/min and 187.5 l/min, respectively. Loop 1 was filled with the solution of the ester (0.05 M inanhydrous toluene), while loop 2 was filled with the solution of DIBAL-H (1M in anhydrous toluene).The flow rate of pump 2 was set at 1.25 ml/min, and the 2:1 mixture of toluene:MeOH was streamed onit. The reaction was controlled using the Asia Manager computer program, which was responsible forswitching the injector valves at appropriate times. The dead volume was discarded to the waste, untilthe reaction mixture appeared at the output. Then, the reaction mixture was collected in a flaskcontaining saturated potassium sodium tartrate solution (10 ml). After collection, the program was shutdownand the system was washed with toluene, followed by methanol.

Reference： [1]Mistry, Shailesh N.; Shonberg, Jeremy; Draper-Joyce, Christopher J.; Klein Herenbrink, Carmen; Michino, Mayako; Shi, Lei; Christopoulos, Arthur; Capuano, Ben; Scammells, Peter J.; Lane, J. Robert [Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6819 - 6843]
[2]Kopinathan, Anitha; Draper-Joyce, Christopher; Szabo, Monika; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2019, vol. 62, # 1, p. 371 - 377]
[3]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]
[4]Shonberg, Jeremy; Herenbrink, Carmen Klein; López, Laura; Christopoulos, Arthur; Scammells, Peter J.; Capuano, Ben; Lane, J. Robert [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221]
[5]Current Patent Assignee: ROCHE HOLDING AG - US2009/42943, 2009, A1 Location in patent: Page/Page column 10
[6]Éles, János; Bana, Péter; Fülöp, Zsolt; Greiner, István [Molecules, 2021, vol. 26, # 7]

32
[ 215790-29-7 ]
[ 84163-77-9 ]
trans-(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		Trans (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4 g, 18.1 mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.4 g, 22.7 mmol), in 1, 2 dichloroethane (55 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (6.9 g, 32.7 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 9.4 g (21 mmol, 100% yield) of a light brown solid. MS (m/e): 446.3 (M+H+).

Reference： [1]Patent: US2009/29977,2009,A1 .Location in patent: Page/Page column 37

33
[ 1312577-43-7 ]
[ 215790-29-7 ]
[trans-4-(2,4-dihydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	In water; dimethyl sulfoxide at 20℃; for 14h; Inert atmosphere;	15 A solution of [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.80 g, 8.86 mmol, 1.0 eq), 3-hydroxy-6-methoxy-quinoline-4-carbaldehyde (2.14 g, 8.86 mmol, 1.0 eq) and Z-proline (408 mg, 3.54 mmol, 0.04 eq) in dimethyl sulfoxide (23 mL) and water (2.3 mL) is stirred at room temperature for 14 hours. The reaction mixture is then extracted with dichloromethane (230 mL) and water (230 mL). The organic layer is washed with brine (230 mL), dried over magnesium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 25: 1, v/v) to afford [tra/75-4-(2,4-dihydro-6-methoxy-3,4-dihydro-2H-l-oxa-9-aza-phenanthren-3-yl)- cyclohexyl]-carbamic acid tert-butyl ester as a light yellow solid (2.80 g, 71% yield). MS m/z (+ESI): 445.2 [M+H]+.

Reference： [1]Current Patent Assignee: BASILEA PHARMACEUTICA - WO2011/73378, 2011, A1 Location in patent: Page/Page column 74-75

34
[ 1312578-18-9 ]
[ 215790-29-7 ]
{trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-2-hydroxy-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	In water; dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere;	76 A solution of [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (3.1 g, 25.1 mmol, 1.0 eq), 3-chloro-6-methoxy-[l,5]naphthyridine-4-carbaldehyde (5.6 g, 25.1 mmol, 1.0 eq) and Z-proline (1.16 mg, 10.1 mmol, 0.4 eq) in dimethyl sulfoxide (100 mL) and water (15 mL) is stirred at room temperature for 16 hours. The reaction mixture is then extracted with ethyl acetate (500 mL) and water (500 mL). The organic layer is washed with brine (300 mL), dried over magnesium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate :petroleum ether, 1 : 1, v/v) to afford {tra/75-4-[2-(3-chloro-6-methoxy-[l,5]naphthyridin-4-yl)-l-formyl-2-hydroxy-ethyl]- cyclohexyl}-carbamic acid tert-butyl ester as a light yellow solid (4.5 g, 39% yield).1H-NMR (400 MHz, CDC13) δ ppm: 9.85 (d, J = 4.0 Hz, 1H), 8.72 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.15 (m, 2H), 5.86 (dd, J= 4.8, 10.0 Hz, 1H), 4.37 (br, 1H), 4.01 (s, 3H), 3.38 (m, 1H), 2.62 (m, 1H), 1.10-2.07 (m, 9H), 1.43 (s, 9H).MS m/z (+ESI): 464.2 [M+H]+.

Reference： [1]Current Patent Assignee: BASILEA PHARMACEUTICA - WO2011/73378, 2011, A1 Location in patent: Page/Page column 105-106

35
[ 215790-29-7 ]
[ 81078-84-4 ]
trans-{4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%		Intermediate A trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochlorideStep A trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-Nr. 215790-29-7] (4.1 g, 17 mmol) was added to a solution under N2 of commercially available <strong>[81078-84-4]4-piperazine-1-yl-furo[3,2-c]pyridine</strong> [CAS-Nr. 81078-84-4] (3.1 g, 15 mmol) in 1,2-dichloroethane (40 ml) and MeOH (0.5 ml). The resulting yellow solution was stirred 8 h at room temperature before addition of Na(AcO)3BH (4.9 g, 23 mmol). Stirring was continued at room temperature for 18 h. The reaction mixture was poured on sat. aq. NaHCO3 sol. (130 ml) and the product was extracted with EtOAc (3×100 ml). The combined organic layers were washed with H2O (130 ml) and brine (100 ml). After drying (MgSO4) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 95:5) to yield trans-{4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as white crystals (3.4 g, 52%), MS (ISP) m/z=429.4 [(M+H)+]

Reference： [1]Patent: US2011/313151,2011,A1 .Location in patent: Page/Page column 16-17

36
[ 106261-27-2 ]
[ 215790-29-7 ]
[ 1352737-07-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 4-(1-piperazinyl)thieno<3,2-c>pyridine; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With acetic acid In 1,2-dichloro-ethane at 20℃; for 8h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; Stage #3: With sodium hydrogencarbonate In water; 1,2-dichloro-ethane	A Step Atrans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-Nr. 215790-29-7] (1.0 g, 4 mmol) was added to a solution under N2 of commercially available 4-piperazine-l-yl- thieno[3,2-c]pyridine [CAS-Nr. 106261-27-2] (0.85 g, 4 mmol) in 1,2-dichloroethane (45 ml) and AcOH (0.22 ml, 4 mmol). The resulting reaction mixture was stirred 8 h at room temperature before addition of Na(AcO)3BH (1.2 g, 6 mmol). Stirring was continued over night at room temperature. Sat. aq. NaHC03 sol. was added and the product was extracted with EtOAc (2 x). The combined organic layers were washed with H20 and brine. After drying (MgS04) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 90: 10) to yield trans-{4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-l- yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a light yellow solid (1.2 g, 72%), MS (ISP) m/z = 445.3 [(M+H)+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2011/161009, 2011, A1 Location in patent: Page/Page column 38

37
[ 81078-84-4 ]
[ 215790-29-7 ]
[ 1352737-05-3 ]

Yield	Reaction Conditions	Operation in experiment
52%		Step Atrans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-Nr. 215790-29-7] (4.1 g, 17 mmol) was added to a solution under N2 of commercially available 4-piperazine-l-yl- furo[3,2-c]pyridine [CAS-Nr. 81078-84-4] (3.1 g, 15 mmol) in 1,2-dichloroethane (40 ml) and MeOH (0.5 ml). The resulting yellow solution was stirred 8 h at room temperature before addition of Na(AcO)3BH (4.9 g, 23 mmol). Stirring was continued at room temperature for 18 h. The reaction mixture was poured on sat. aq. NaHC03 sol. (130 ml) and the product was extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with H20 (130 ml) and brine (100 ml). After drying (MgS04) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 95:5) to yield trans- {4-[2-(4- furo[3,2-c]pyridin-4-yl-piperazin-l-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as white crystals (3.4 g, 52%), MS (ISP) m/z = 429.4 [(M+H)+].

Reference： [1]Patent: WO2011/161009,2011,A1 .Location in patent: Page/Page column 37

38
[ 1352737-09-7 ]
[ 215790-29-7 ]
[ 1352737-10-0 ]

Yield	Reaction Conditions	Operation in experiment
61.5%	Stage #1: 4-(piperazin-1-yl)-2,3-dihydrofuro[3,2-c]pyridine; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In methanol; dichloromethane at 20℃; for 0.5h; Stage #2: With methanol; sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 16h;	B Step BTo a solution of 4-(piperazin-l-yl)-2,3-dihydrofuro[3,2-c]pyridine (0.38 g, 1.85 mmol) in dichloromethane (11 ml) and MeOH (0.3 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (596 mg, 2.22 mmol) and triethylamine (375 mg, 516 μ, 3.7 mmol) and the solution was allowed to stir for 30 min.Sodium triacetoxyboron hydride (706 mg, 3.33 mmol) was added step wise and the mixture was allowed to stir for 16 h at room temperature. The solution was added to ice/ 2N sodium carbonate solution (50 ml), extracted with dichloromethane (2 x 30 ml). The combined organic layers were dried (MgS04) and evaporated. The crude material (0.95 g) was purified by flash chromatography on silica gel (20% to 100% dichloromethane/ dichloromethane-MeOH 9: 1) to yield trans-tert-butyl-(4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-l-yl]-ethyl}- cyclohexylcarbamate as a white solid (0.49 g, 61.5%), MS (ISP) m/z = 431.5 [(M+H)+], mp 89.5°C.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2011/161009, 2011, A1 Location in patent: Page/Page column 39

39
[ 1354934-84-1 ]
[ 215790-29-7 ]
[ 1354934-85-2 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 7-(piperazin-1-yl)-2,3-dihydro-furo[2,3-c]pyridine; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In methanol; dichloromethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In methanol; dichloromethane at 20℃; for 4h; Stage #3: With sodium carbonate In methanol; dichloromethane; water Cooling with ice;	B.B Step B; To a solution of 7-(piperazin-1-yl)-2,3-dihydro-furo[2,3-c]pyridine (0.96 g, 4.68 mmol) in dichloromethane (30 ml) and MeOH (0.8 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.71 mg, 6.02 mmol) and triethylamine (1.02 g, 1.4 ml, 10 mmol) and the solution was allowed to stir for 30 min. Sodium triacetoxyboron hydride (1.91 g, 9.03 mmol) was added step wise and the mixture was allowed to stir for 4 h at room temperature. The solution was added to ice/2N sodium carbonate solution (50 ml), extracted with dichloromethane (2×30 ml). The combined organic layers were dried (MgSO4) and evaporated. The crude material (2.53 g) was purified by flash chromatography on silica gel (20% to 100% dichloromethane/dichloromethane-MeOH 9:1) to yield trans-(4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester as off-white solid (1.3 g, 65%), MS (ISP) m/z=431.5 [(M+H)+], mp 141° C.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/10201, 2012, A1 Location in patent: Page/Page column 15

40
[ 850734-85-9 ]
[ 215790-29-7 ]
[ 1354934-82-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 7-piperazine-1-yl-thieno[2,3-c]pyridine hydrochloride; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With sodium tris(acetoxy)borohydride; acetic acid In methanol; 1,2-dichloro-ethane at 20℃; for 6h; Stage #2: With sodium tris(acetoxy)borohydride In methanol; 1,2-dichloro-ethane at 20℃; for 16h; Stage #3: With sodium hydrogencarbonate; sodium chloride In methanol; water; ethyl acetate; 1,2-dichloro-ethane	A.A Step ATrans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-No. 215790-29-7]; (352 mg, 1.46 mmol), commercially available 7-piperazine-1-yl-thieno[2,3-c]pyridine hydrochloride [CAS-No. 850734-85-9] (339 mg, 1.33 mmol) and AcOH (0.15 ml, 2.65 mmol) were dissolved in a mixture of 1,2-dichloroethane (7.5 ml) and MeOH (1.5 ml). The reaction mixture was stirred 6 h at room temperature before addition of Na(AcO)3BH (421 mg, 1.99 mmol). After 16 h more stirring at room temperature the reaction mixture was diluted with EtOAc (100 ml) and washed with sat. aq. NaHCO3 sol. (100 ml), water (100 ml) and brine (100 ml). The aqueous layers were extracted with one more portion of EtOAc (100 ml) and the combined organic layers were dried (MgSO4). After evaporation of the solvent trans-{4-[2-(4-thieno[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester was obtained as an off-white solid (590 mg, 100%), MS (ISP) m/z=445.3 [(M+H)+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/10201, 2012, A1 Location in patent: Page/Page column 14-15

41
4-(1-benzofuran-4-yl)piperidine [ No CAS ]
[ 215790-29-7 ]
[ 1382986-06-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 4-(1-benzofuran-4-yl)piperidine; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: With sodium triacetoxyboron hydride In dichloromethane at 20℃; for 16h;	B To a stirred solution of 4-(4-benzofuranyl)-piperidine (0.3 g, 1.49 mmol) in dichloromethane (8 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.71 mg, 6.02 mmol) and triethylamine (0.3 g, 0.42 ml, 2.98 mmol) and the solution was allowed to stir for 30 min. Sodium triacetoxyboron hydride (0.57 g, 2.68 mmol) was added step wise and the mixture was allowed to stir for 16 h at room temperature. The solution was poured into saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (20 ml), dried (MgSO4) and evaporated. The crude material (0.77 g) was purified by flash chromatography on silica gel (dichloromethane/MeOH 5-10%) to yield trans-{4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (0.63 g, 99%), MS (ISP) m/z=427.4 [(M+H)+], mp 133° C.
99%	Stage #1: 4-(1-benzofuran-4-yl)piperidine; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 16h; Stage #3: With sodium hydrogencarbonate In dichloromethane	B Step BTo a stirred solution of 4-(4-benzofuranyl)-piperidine (0.3 g, 1.49 mmol) in dichloromethane (8 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)- cyclohexylcarbamate (1.71 mg, 6.02 mmol) and triethylamnie (0.3 g, 0.42 ml, 2.98 mmol) and the solution was allowed to stir for 30 min. Sodium triacetoxyboron hydride (0.57 g, 2.68 mmol) was added step wise and the mixture was allowed to stir for 16 h at room temperature. The solution was poured into saturated sodium bicarbonate solution (20 ml) and extracted with dichloromethane (2 x 40 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (20 ml), dried (MgS04) and evaporated. The crude material (0.77 g) was purified by flash chromatography on silica gel (dichloromethane/MeOH 5-10%) to yield trans- {4-[2-(4-benzofuran-4-yl-piperidin-l-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (0.63 g, 99%), MS (ISP) m/z = 427.4 [(M+H)+], mp 133°C.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/157449, 2012, A1 Location in patent: Page/Page column 13
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2012/80149, 2012, A1 Location in patent: Page/Page column 28-29

42
[ 215790-29-7 ]
[ 104632-26-0 ]
tert-butyl trans-N-(4-(2-(((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Trans-N-(4-2-(((s)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)cyclohexyl)carbamate (13)Tert-butyl trans-4-(2-oxoethyl)cyclohexylcarbamate (114 mg, 0.47 mmol), acetic acid (HAc) (57 mg, 0.95 mmol) and sodium triacetoxyborohydride (NaBH(OAc)3 (200 mg, 0.95 mmol) were added to a solution of <strong>[104632-26-0]pramipexole</strong> (100 mg, 0.47 mmol) in dichloroethane (20 mL) and the reaction mixture was stirred at room temperature (RT) for 6 hr. The reaction was quenched with water and the pH was adjusted to 9-10 by addition of aqueous sodium carbonate solution. Then, the mixture was extracted with dichloromethane (DCM) for 3 times. The organic lawyer was separated, combined, and evaporated. The residue was chromatographed (SiO2, ethyl acetate:methanol=95:5) to give compound 13 as a colorless oil (155 mg, 75%).1H NMR (CDCl3, 300 MHz) delta 4.70 (s, 2H), 4.50-4.30 (m, 1H), 3.50-3.25 (m, 1H), 3.10-2.90 (m, 1H), 2.75-2.25 (m, 8H), 2.00-1.55 (m, 7H), 1.44 (s, 9H), 1.42-0.98 (m, 8H), 0.87 (t, J=7.3 Hz, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5612 - 5617
[2]Patent: US2012/232118,2012,A1 .Location in patent: Page/Page column 9-10

43
[ 1260769-18-3 ]
[ 215790-29-7 ]
[ 1395922-25-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: 4-benzo[1,3]dioxol-4-yl-piperidine; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde In methanol; dichloromethane at 20℃; for 2h; Stage #2: With methanol; sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 16h;	D Step D : Trans- { 4- [2-(4-Benzo [1,3] dioxol-4-yl-piperidin- 1 -yl)-ethyl] -cyclohexyl } -carbamic acid tert-butyl esterTo a stirred solution of 4-Benzo[l,3]dioxol-4-yl-piperidine (0.680 g, 3.31 mmol,) indichloromethane (35 ml) and methanol (1 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.04 g, 4.31 mmol) and the solution was allowed to stir for 120 min. Sodium triacetoxyboron hydride (1.26 g, 5.96 mmol) was added portion wise and the mixture was allowed to stir for 16 h at room temperature. The solution was poured into saturated sodium bicarbonate solution (15 ml) and extracted with dichloromethane (2 x 20 ml). The combined organic layers were dried (MgS04) and evaporated. The crude material was purified by flash chromatography on silica gel The crude material was purified by flash chromatography (methanol in dichloromethane 0-10%) to yield trans-{4-[2-(4- Benzo[l,3]dioxol-4-yl-piperidin-l-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.43 g, 74%), MS (ISP) m/z = 431.5 [(M+H)+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2012/117001, 2012, A1 Location in patent: Page/Page column 30

44
[ 1416224-42-4 ]
[ 215790-29-7 ]
[ 1416224-44-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	Stage #1: (3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-ylmethyl)-phosphonic acid diethyl ester With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde In tetrahydrofuran at 18 - 25℃; for 15h;	13 Preparation of (tra/? -4-[3-(3-benzyloxy-6-methoxy-[l,51naphthyridin-4-yl)-allyll- cyclohexyll-carbamic acid tert-butyl ester:Sodium hydride (86 mg, 1.91 mmol, 2.3 eq) is added at 0 °C to a stirred solution of (3- benzyloxy-6-methoxy-[l,5]naphthyridin-4-ylmethyl)-phosphonic acid diethyl ester (350 mg, 0.83 mmol, 1.0 eq) in tetrahydrofuran (30 mL) and the resulting mixture is stirred at 0 °C for 1 hour before the addition of a solution of [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (200 mg, 0.83 mmol, 1.0 eq) in tetrahydrofuran (5 mL). After 15 hours stirring at room temperature, the reaction mixture is quenched with ammonium chloride aqueous solution (20 mL), tetrahydrofuran is removed and the resulting residue is extracted with ethyl acetate (3 x 50 mL) and brine (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ethenethyl acetate, 10:1 to 6: 1, v/v) to afford {trans-4-[3-(3- benzyloxy-6-methoxy-[ 1 ,5]naphthyridin-4-yl)-allyl]-cyclohexyl} -carbamic acid tert-butyl ester as a white solid (548 mg, 55% yield). - -1H-NMR (400 MHz, CDC13) δ ppm: 8.62 (s, 1H), 8.17 (m, 1H), 7.00-7.47 (m, 8H), 5.32 (s, 2H), 4.37 (s, 1H), 4.08 (s, 3H), 3.37 (m, 1H), 1.81-2.25 (m, 6H), 1.25-1.44 (m, 10H), 1.03 (m, 4H). MS m/z (+ESI): 504.2 [M+H]+.

Reference： [1]Current Patent Assignee: BASILEA PHARMACEUTICA - WO2012/171860, 2012, A1 Location in patent: Page/Page column 54-55

45
[ 91-21-4 ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;
85%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; Inert atmosphere;
49%	With sodium tris(acetoxy)borohydride In dichloromethane

Reference： [1]Shonberg, Jeremy; Herenbrink, Carmen Klein; López, Laura; Christopoulos, Arthur; Scammells, Peter J.; Capuano, Ben; Lane, J. Robert [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221]
[2]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]
[3]Shen, Yudao; McCorvy, John D.; Martini, Michael L.; Rodriguiz, Ramona M.; Pogorelov, Vladimir M.; Ward, Karen M.; Wetsel, William C.; Liu, Jing; Roth, Bryan L.; Jin, Jian [Journal of Medicinal Chemistry, 2019, vol. 62, # 9, p. 4755 - 4771]

46
[ 99365-69-2 ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9199 - 9221

47
1-(2,3-dichlorophenyl)-1,4-diazepane [ No CAS ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;

Reference： [1]Shonberg, Jeremy; Herenbrink, Carmen Klein; López, Laura; Christopoulos, Arthur; Scammells, Peter J.; Capuano, Ben; Lane, J. Robert [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221]

48
[ 41202-77-1 ]
[ 215790-29-7 ]
trans N-tert-butoxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]ethyl}-cyclohexylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; Inert atmosphere;
75%	With sodium tris(acetoxy)borohydride In dichloromethane
69%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;

With platinum on carbon; hydrogen In methanol; toluene at 80℃;

Synthesis of the tert-butyl (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (3) by continuous-flow reductive amination A 5% Pt/C CatCart (30mm) was loaded into the H-Cube (ThalesNano, Budapest, Hungary) continuous-flow hydrogenationreactor, and the system was washed with methanol, followed by a 5:1 mixture of toluene:MeOH.Reaction parameters were set to 80°C temperature, 0.5 ml/min flow rate and full H2 mode at ambientpressure. Washing with this mixture was upheld until steady state was reached.The solution of 23.1 mg (0.1 mmol) of 2 and 24.1 mg (0.1 mmol) of 5 in 2 ml of the mixture of 5:1toluene:MeOH was transferred by an AZURA P4.1S (KNAUER, Berlin, Germany) HPLC pump at 0.5ml/min flow rate into the reactor. The dead volume was discarded to the waste, until the reactionmixture appeared at the output. Then, the product mixture was collected, until the starting solution isconsumed. The system was shut-down and washed with methanol.

Reference： [1]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]
[2]Shen, Yudao; McCorvy, John D.; Martini, Michael L.; Rodriguiz, Ramona M.; Pogorelov, Vladimir M.; Ward, Karen M.; Wetsel, William C.; Liu, Jing; Roth, Bryan L.; Jin, Jian [Journal of Medicinal Chemistry, 2019, vol. 62, # 9, p. 4755 - 4771]
[3]Shonberg, Jeremy; Herenbrink, Carmen Klein; López, Laura; Christopoulos, Arthur; Scammells, Peter J.; Capuano, Ben; Lane, J. Robert [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221]
[4]Éles, János; Bana, Péter; Fülöp, Zsolt; Greiner, István [Molecules, 2021, vol. 26, # 7]

49
[ 76308-28-6 ]
[ 215790-29-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9199 - 9221
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 5287 - 5307

50
[ 1607474-23-6 ]
[ 215790-29-7 ]
[ 1607474-28-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 2-tert-butyl-4-(2-methoxyethyl)-6-piperazin-1-ylpyrimidine; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With acetic acid In dichloromethane at 20℃; for 0.166667h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane for 4h;	1.1 Trans-[4-(2-{4-[2-tert-Butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl} ethyl)-cyclohexyl]carbamic acid tert-butyl ester A mixture of 2-tert-butyl-4-(2-methoxy-ethyl)-6-piperazin-l-yl-pyrimidine (500 mg, 1.796 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (433 mg, 1.796 mmol) and AcOH (108 mg, 1.796 mmol) in DCE (30 ml) was stirred at room temperature for 10 min. Sodium triacetoxyhydroborate (571 mg, 2.69 mmol) was added. After 4 h, water was added. The aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the yellow title compound (900 mg, 1.680 mmol, 94 % yield) which was used next step without purification. LC-MS: m/z = 504 (M+H).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2014/64038, 2014, A1 Location in patent: Page/Page column 48; 49

51
[ 7216-22-0 ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; Inert atmosphere;

Reference： [1]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]

52
[ 799274-06-9 ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; Inert atmosphere;

Reference： [1]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]

53
[ 82771-60-6 ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5287 - 5307
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 4755 - 4771

54
[ 17680-55-6 ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5287 - 5307

55
7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride [ No CAS ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; Inert atmosphere;

Reference： [1]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]

56
[ 28783-41-7 ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; Inert atmosphere;

Reference： [1]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]

57
[ 5464-78-8 ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(4-(2-methoxyphenyl)piperazin-1-yl)-ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; Inert atmosphere;

Reference： [1]Shonberg, Jeremy; Draper-Joyce, Christopher; Mistry, Shailesh N.; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307]

58
2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid [ No CAS ]
[ 215790-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / Reflux 2: diisobutylaluminium hydride / toluene / 4.5 h / -78 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 50 °C 2: diisobutylaluminium hydride / toluene / 1 h / -78 °C
	Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine 2: Petroleum ether

	Multi-step reaction with 2 steps 1: O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 20 °C 2: sodium bis(2-methoxyethoxy)aluminium dihydride / dichloromethane; toluene / 2 h / 0 °C
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C 2: dichloromethane; toluene / 2 h / 0 °C

Reference： [1]Mistry, Shailesh N.; Shonberg, Jeremy; Draper-Joyce, Christopher J.; Klein Herenbrink, Carmen; Michino, Mayako; Shi, Lei; Christopoulos, Arthur; Capuano, Ben; Scammells, Peter J.; Lane, J. Robert [Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6819 - 6843]
[2]Kopinathan, Anitha; Draper-Joyce, Christopher; Szabo, Monika; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2019, vol. 62, # 1, p. 371 - 377]
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2022/2273, 2022, A1
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2022/2273, 2022, A1
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2021/403454, 2021, A1

59
[ 506-59-2 ]
[ 215790-29-7 ]
[ 1356953-51-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 16h; Inert atmosphere;

Reference： [1]Mistry, Shailesh N.; Shonberg, Jeremy; Draper-Joyce, Christopher J.; Klein Herenbrink, Carmen; Michino, Mayako; Shi, Lei; Christopoulos, Arthur; Capuano, Ben; Scammells, Peter J.; Lane, J. Robert [Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6819 - 6843]

60
[ 142-84-7 ]
[ 215790-29-7 ]
tert-butyl ((trans)-4-(2-(dipropylamino)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 16h; Inert atmosphere;

Reference： [1]Mistry, Shailesh N.; Shonberg, Jeremy; Draper-Joyce, Christopher J.; Klein Herenbrink, Carmen; Michino, Mayako; Shi, Lei; Christopoulos, Arthur; Capuano, Ben; Scammells, Peter J.; Lane, J. Robert [Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6819 - 6843]

61
5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide hydrochloride [ No CAS ]
[ 215790-29-7 ]
tert-butyl (trans-4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100 mg	With sodium cyanoborohydride; triethylamine In methanol at 70℃; for 18h;	18-18A.1 Step 1: tert-butyl (trans-4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H- pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)carbamate (Example 18A) A mixture of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 120 mg, 0.24 mmol, HCl salt), Intermediate 23 (87 mg, 0.36 mmol), Et3N (121 mg, 0.17 mL, 1.2 mmol) and NaBH3CN (75 mg, 1.2 mmol) in anhydrous MeOH (6 mL) was stirred at 70oC for 18 h. The mixture was then concentrated under reduced pressure. The residue was added to H2O (20 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatograph on silica gel (eluting with CH2Cl2/MeOH = 9/1) to give tert-butyl (trans-4-(2-(4-(1-(4-fluoro-2- (isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1- yl)ethyl)cyclohexyl)carbamate (100 mg, 68% yield) as white solid. LCMS method E: Rt= 0.836 min; (M+H)+= 620.5.1H NMR (CD3OD): δ ppm 8.52-8.61 (m, 1H), 8.14-8.18 (m, 1H), 7.74-7.75 (m, 1H), 7.60-7.7 (m, 1H), 7.30-7.45 (m, 3H), 4.40-4.49 (m, 1H), 3.50-3.60 (m, 1H), 2.85-3.25 (m, 5H), 2.40-2.66 (m, 5H), 2.15-2.25 (m, 2H), 2.00-2.10 (m, 2H), 1.75-1.95 (m, 6H), 1.40-1.60 (m, 10H), 0.95-1.35 (m, 7H), 0.20-0.55 (m, 3H).19F NMR (CD3OD δ ppm -117.52 ~ -113.25.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2018/53267, 2018, A1 Location in patent: Page/Page column 106; 107

62
2-(3-(azetidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide [ No CAS ]
[ 76-05-1 ]
[ 215790-29-7 ]
tert-butyl ((1r,4r)-4-(2-(3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)azetidin-1-yl)ethyl)cyclohexyl)carbamate trifluoroacetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.3 mg	Stage #1: 2-(3-(azetidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With sodium acetate In methanol at 20℃; for 0.25h; Stage #2: With methanol; sodium cyanoborohydride at 20℃; for 1h; Stage #3: trifluoroacetic acid In water; acetonitrile	136.3 Step 3: tert-butyl ((1r,4r)-4-(2-(3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H- pyrrolo[2,3-c]pyridin-3-yl)azetidin-1-yl)ethyl)cyclohexyl)carbamate To the solution of the above crude product (~0.10 mmol) in MeOH (1 mL), there was added NaOAc (24 mg), tert-butyl ((1r,4r)-4-(2-oxoethyl)cyclohexyl)carbamate (36 mg, 0.15 mmol), and the resulting mixture was stirred at RT for 15 min, at which point NaCNBH3 (15 mg) was added into the solution. The resulting mixture was stirred at RT for 1 h to give a clear solution, which was purified directly by preparative RP-HPLC method E to give tert-butyl ((1r,4r)-4-(2-(3-(1-(2-(diisopropylcarbamoyl)-4- fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)azetidin-1-yl)ethyl)cyclohexyl)carbamate as a TFA salt (26.3 mg); LCMS method B: Rt = 0.87 min; (M+H)+ = 620.7.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2018/53267, 2018, A1 Location in patent: Page/Page column 228; 230

63
5-fluoro-N-isopropyl-N-methyl-2-(2-oxo-1-(piperidin-4-yl)-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)benzamide hydrochloride [ No CAS ]
[ 215790-29-7 ]
tert-butyl ((1r,4r)-4-(2-(4-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)ethyl)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 mg	With sodium cyanoborohydride; triethylamine In methanol at 20℃; for 24h;	78.5 Step 5: tert-butyl ((1r,4r)-4-(2-(4-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-2- oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1- yl)ethyl)cyclohexyl)carbamate To a solution of 5-fluoro-N-isopropyl-N-methyl-2-(2-oxo-1-(piperidin-4-yl)-1,2- dihydro-3H-imidazo[4,5-c]pyridin-3-yl)benzamide HCl salt (20 mg, 0.044 mmol), Et3N (0.02 mL, 0.13 mmol) and tert-butyl (trans)-4-(2-oxoethyl)(cyclohexyl)carbamate (21 mg, 0.088 mmol) in MeOH was added NaBH3CN (6 mg, 0.088 mmol) at RT and the reaction mixture was stirred at RT for 24 h. Evaporation of the solvent and purification using ISCO flash column chromatography (eluting with 15% MeOH in DCM) gave tert- butyl ((trans)-4-(2-(4-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)ethyl)cyclohexyl)carbamate (30 mg, >95%). LCMS Method C: tR = 4.842 min; [M + H]+ = 637.70

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2018/53267, 2018, A1 Location in patent: Page/Page column 170; 174

64
[ 917342-29-1 ]
[ 215790-29-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With pyridinium chlorochromate; In dichloromethane; at 5 - 17℃;	A mixture of <strong>[917342-29-1]tert-butyl (trans-4-(2-hydroxyethyl)cyclohexyl)carbamate</strong> (250 mg, 1.03 mmol) and PCC (444 mg, 2.06 mmol) in anhydrous DCM (10 mL) was stirred at 5- 17oC for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatograph on silica gel (eluting with petroleum ether/ethyl acetate = 3/1) to give tert-butyl (trans-4-(2- oxoethyl)cyclohexyl)carbamate as white solid. Yield: 190 mg (76%);1H NMR (CDCl3): delta ppm 9.69 (s, 1H), 4.30-4.34 (m, 1H), 3.32-3.35 (m, 1H), 2.26 (d, J = 6.4 Hz, 2H), 1.93- 1.98 (m, 2H), 1.70-1.77 (m, 3H), 1.37 (s, 9H), 1.01-1.09 (m, 4H). Intermediates 24-24A.2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)ethyl formate

Reference： [1]Patent: WO2018/53267,2018,A1 .Location in patent: Page/Page column 95; 96

65
[ 215790-29-7 ]
[ 215790-43-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;

Reference： [1]Kopinathan, Anitha; Draper-Joyce, Christopher; Szabo, Monika; Christopoulos, Arthur; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben [Journal of Medicinal Chemistry, 2019, vol. 62, # 1, p. 371 - 377]

66
C₁₃H₁₅N₃*C₂HF₃O₂ [ No CAS ]
[ 215790-29-7 ]
C₂₆H₃₈N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
851 mg	Stage #1: C₁₃H₁₅N₃*C₂HF₃O₂; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In 1,4-dioxane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,4-dioxane at 20℃; for 3h;	19.5 Step 4 Synthesis of I-144 General procedure: To the compound 4 (610 mg) obtained as a crude product in Step 3 were added dioxane (30 mL), triethylamine (1.44 mL, 10.4 mmol), a compound 5 (600 mg, 2.49 mmol, synthetic method for the compound 5 is described in J. Med. Chem.2015, 58, 6819-6843). The mixture was stirred at room temperature for 30 minutes. To the mixture was added sodium triacetoxyborohydride (879 mg, 4.15 mmol). The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with chloroform. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (hexane-ethyl acetate) to give a compound I-144 (851 mg, yield 92%).1H-NMR (CDCl3) δ: 0.27-0.31 (m, 1H), 0.72-0.78 (m, 1H), 0.97-1.11 (m, 4H), 1.22-1.30 (m, 1H), 1.44-1.48 (m, 11H), 1.60-1.63 (m, 2H), 1.75-1.78 (m, 2H), 1.96-2.00 (m, 2H), 2.50-2.54 (m, 2H), 2.66-2.74 (m, 4H), 3.36 (br, 1H), 3.45-3.47 (m, 4H), 3.54-3.57 (m, 2H), 4.35 (br, 1H).

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - US2019/161501, 2019, A1 Location in patent: Paragraph 0770; 0777; 0778; 0933; 0938; 0939

67
C₁₁H₁₄F₂N₂O*C₂HF₃O₂ [ No CAS ]
[ 215790-29-7 ]
C₂₄H₃₇F₂N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
299 mg	Stage #1: C₁₁H₁₄F₂N₂O*C₂HF₃O₂; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In dichloromethane at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 0.666667h;	1'.3 Step 3 Synthesis of Compound II-109 The crude compound 3a was dissolved in dichloromethane (5 mL). To the solution were added triethylamine (0.475 mL, 3.43 mmol) and, the compound 4a (182 mg, 0.754 mmol). The mixture was stirred at room temperature for 1 hour. To the mixture was added sodium triacetoxyborohydride (436 mg, 2.06 mmol). The mixture was stirred at room temperature for 40 minutes. To the reaction solution was added saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed by brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (hexane-ethyl acetate) to give a compound II-109 (299 mg, 2 steps yield 96%).1H-NMR (CDCl3) δ: 1.05 (m, 4H), 1.21 (m, 1H), 1.41 (m, 2H), 1.44 (s, 9H), 1.77 (m, 2H), 1.99 (m, 2H), 2.48 (m, 2H), 2.58-2.64 (m, 4H), 2.81 (m, 2H), 3.02 (m, 2H), 3.37 (m, 1H), 4.36 (m, 1H), 4.51 (td, J=13.7, 4.3 Hz, 2H), 6.13 (tt, J=56.0, 4.3 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H).
299 mg	Stage #1: C₁₁H₁₄F₂N₂O*C₂HF₃O₂; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In dichloromethane at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 0.666667h;	1'.3 Step 3 Synthesis of Compound II-109 The crude product of compound 3a was dissolved in dichloromethane (5 mL), triethylamine (0.475 mL, 3.43 mmol) and compound 4a (182 mg, 0.754 mmol) were added, and the mixture was stirred at room temperature for 1 hour. To this was added sodium triacetoxyborohydride (436 mg, 2.06 mmol), and the mixture was stirred at room temperature for 40 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound II-109 (299 mg, yield of 96% in two steps).

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - US2019/161501, 2019, A1 Location in patent: Paragraph 0955; 0959; 0960
[2]Current Patent Assignee: SHIONOGI & CO., LTD. - TW2019/32461, 2019, A Location in patent: Paragraph 0042

68
C₈H₁₀F₂N₂OS*ClH [ No CAS ]
[ 215790-29-7 ]
C₂₁H₃₃F₂N₃O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: C₈H₁₀F₂N₂OS*ClH; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In dichloromethane at 20℃; for 0.166667h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 2h;	2.3 Step 3 Synthesis of Compound I-145 To compound 9 (950 mg, 3.70 mmol) of the crude product obtained in step 2 was added dichloromethane (20 mL), triethylamine (1.54 mL, 11.1 mmol), and compound 5 (938 mg, 3.89 mmol). At room temperature stir for 10 minutes. To this was added sodium triacetoxyborohydride (1.57 g, 7.40 mmol), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by amine silica gel column chromatography (hexane-ethyl acetate) to obtain compound I-145 (1.59 g, yield 96%).
1.59 g	Stage #1: C₈H₁₀F₂N₂OS*ClH; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In dichloromethane at 20℃; for 0.166667h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 2h;	2.3 Step 3 Synthesis of Compound I-145 To the compound 9 (950 mg, 3.70 mmol) obtained as a crude product in Step 2 were added dichloromethane (20 mL), triethylamine (1.54 mL, 11.1 mmol), a compound 5 (938 mg, 3.89 mmol). The mixture was stirred at room temperature for 10 minutes. To the mixture was added sodium triacetoxyborohydride (1.57 g, 7.40 mmol). The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed by saturated aqueous solution of sodium hydrogen carbonate, brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by amino silica-gel column chromatography (hexane-ethyl acetate) to give a compound I-145 (1.59 g, yield 96%).1H-NMR (CDCl3) δ: 0.99-1.12 (m, 4H), 1.26 (br, 1H), 1.42-1.49 (m, 11H), 1.75-1.80 (m, 2H), 1.97-2.02 (m, 2H), 2.52-2.56 (m, 2H), 2.71-2.75 (m, 2H), 3.37 (br, 1H), 3.44 (s, 2H), 4.35 (br, 1H), 4.53 (t, J=13.0 Hz, 2H), 6.11 (t, J=55.3 Hz, 1H).

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - TW2019/32461, 2019, A Location in patent: Paragraph 0040
[2]Current Patent Assignee: SHIONOGI & CO., LTD. - US2019/161501, 2019, A1 Location in patent: Paragraph 0782; 0786; 0787

69
C₁₁H₁₅N₃S*2ClH [ No CAS ]
[ 215790-29-7 ]
C₂₄H₃₈N₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: C₁₁H₁₅N₃S*2ClH; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In 1,4-dioxane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,4-dioxane at 20℃; for 3h;	1.4 Step 4 Synthesis of I-144 To compound 4 (610 mg) of the crude product obtained in step 3 was added dioxane (30 mL), triethylamine (1.44 mL, 10.4 mmol), and compound 5 (600 mg, 2.49 mmol. The synthesis method is described in J. Med. Chem. 2015, 58, 6819-6843), and stirred at room temperature for 30 minutes. To this was added sodium triacetoxyborohydride (879 mg, 4.15 mmol), and the mixture was stirred at room temperature for 3 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound I-144 (851 mg, yield 92%).
851 mg	Stage #1: C₁₁H₁₅N₃S*2ClH; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In 1,4-dioxane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,4-dioxane at 20℃; for 3h;	1.4 Step 4 Synthesis of I-144 To the compound 4 (610 mg) obtained as a crude product in Step 3 were added dioxane (30 mL), triethylamine (1.44 mL, 10.4 mmol), a compound 5 (600 mg, 2.49 mmol, synthetic method for the compound 5 is described in J. Med. Chem.2015, 58, 6819-6843). The mixture was stirred at room temperature for 30 minutes. To the mixture was added sodium triacetoxyborohydride (879 mg, 4.15 mmol). The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with chloroform. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (hexane-ethyl acetate) to give a compound I-144 (851 mg, yield 92%).1H-NMR (CDCl3) δ: 0.27-0.31 (m, 1H), 0.72-0.78 (m, 1H), 0.97-1.11 (m, 4H), 1.22-1.30 (m, 1H), 1.44-1.48 (m, 11H), 1.60-1.63 (m, 2H), 1.75-1.78 (m, 2H), 1.96-2.00 (m, 2H), 2.50-2.54 (m, 2H), 2.66-2.74 (m, 4H), 3.36 (br, 1H), 3.45-3.47 (m, 4H), 3.54-3.57 (m, 2H), 4.35 (br, 1H).

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - TW2019/32461, 2019, A Location in patent: Paragraph 0038
[2]Current Patent Assignee: SHIONOGI & CO., LTD. - US2019/161501, 2019, A1 Location in patent: Paragraph 0770; 0777; 0778

70
C₁₂H₁₉N₃*C₂HF₃O₂ [ No CAS ]
[ 215790-29-7 ]
C₂₅H₄₂N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
851 mg	Stage #1: C₁₂H₁₉N₃*C₂HF₃O₂; trans-2-(1-(4-(N-tert-butoxycarbonyl)amino)cyclohexyl)acetaldehyde With triethylamine In 1,4-dioxane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,4-dioxane at 20℃; for 3h;	18.4 Step 4 Synthesis of I-144 General procedure: To the compound 4 (610 mg) obtained as a crude product in Step 3 were added dioxane (30 mL), triethylamine (1.44 mL, 10.4 mmol), a compound 5 (600 mg, 2.49 mmol, synthetic method for the compound 5 is described in J. Med. Chem.2015, 58, 6819-6843). The mixture was stirred at room temperature for 30 minutes. To the mixture was added sodium triacetoxyborohydride (879 mg, 4.15 mmol). The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with chloroform. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (hexane-ethyl acetate) to give a compound I-144 (851 mg, yield 92%).1H-NMR (CDCl3) δ: 0.27-0.31 (m, 1H), 0.72-0.78 (m, 1H), 0.97-1.11 (m, 4H), 1.22-1.30 (m, 1H), 1.44-1.48 (m, 11H), 1.60-1.63 (m, 2H), 1.75-1.78 (m, 2H), 1.96-2.00 (m, 2H), 2.50-2.54 (m, 2H), 2.66-2.74 (m, 4H), 3.36 (br, 1H), 3.45-3.47 (m, 4H), 3.54-3.57 (m, 2H), 4.35 (br, 1H).

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - US2019/161501, 2019, A1 Location in patent: Paragraph 0770; 0777; 0778; 0910; 0915; 0916

71
[ 62456-15-9 ]
[ 215790-29-7 ]