Name: 1023595-11-0|4-Boc-1-Oxa-4,9-diazaspiro[5.5]undecane|95%
Brand: Ambeed
SKU: A738020
Price: 31.0 USD
Availability: InStock
Rating: 91 (35 reviews)

1
[ 1023595-11-0 ]
[ 104-88-1 ]
C₂₀H₂₉ClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride In 1-methyl-pyrrolidin-2-one

Reference： [1]Location in patent: scheme or table Stocks, Michael J.; Alcaraz, Lilian; Bailey, Andrew; Bowers, Keith; Donald, David; Edwards, Helen; Hunt, Fraser; Kindon, Nicholas; Pairaudeau, Garry; Theaker, Jill; Warner, Daniel J. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7458 - 7461]

2
[ 1023595-11-0 ]
[ 89-98-5 ]
C₂₀H₂₉ClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride In 1-methyl-pyrrolidin-2-one

Reference： [1]Location in patent: scheme or table Stocks, Michael J.; Alcaraz, Lilian; Bailey, Andrew; Bowers, Keith; Donald, David; Edwards, Helen; Hunt, Fraser; Kindon, Nicholas; Pairaudeau, Garry; Theaker, Jill; Warner, Daniel J. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7458 - 7461]

3
[ 1023595-11-0 ]
[ 100-52-7 ]
tert-butyl 9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride In 1-methyl-pyrrolidin-2-one

Reference： [1]Location in patent: scheme or table Stocks, Michael J.; Alcaraz, Lilian; Bailey, Andrew; Bowers, Keith; Donald, David; Edwards, Helen; Hunt, Fraser; Kindon, Nicholas; Pairaudeau, Garry; Theaker, Jill; Warner, Daniel J. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7458 - 7461]

4
[ 1023595-11-0 ]
[ 75-07-0 ]
C₁₅H₂₈N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride In 1-methyl-pyrrolidin-2-one

Reference： [1]Location in patent: scheme or table Stocks, Michael J.; Alcaraz, Lilian; Bailey, Andrew; Bowers, Keith; Donald, David; Edwards, Helen; Hunt, Fraser; Kindon, Nicholas; Pairaudeau, Garry; Theaker, Jill; Warner, Daniel J. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7458 - 7461]

5
[ 1023595-11-0 ]
[ 587-04-2 ]
C₂₀H₂₉ClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride In 1-methyl-pyrrolidin-2-one

Reference： [1]Location in patent: scheme or table Stocks, Michael J.; Alcaraz, Lilian; Bailey, Andrew; Bowers, Keith; Donald, David; Edwards, Helen; Hunt, Fraser; Kindon, Nicholas; Pairaudeau, Garry; Theaker, Jill; Warner, Daniel J. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7458 - 7461]

6
[ 923595-50-0 ]
[ 1023595-11-0 ]
[ 1208069-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In pentan-1-ol at 150℃; for 24h;	7.2 Step 7.2. tert-Butyl 9-(2-methyl-3-pyridin-4-ylimidazo[1,2-b]pyridazin-6-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate In a reactor a solution of 0.50 g (2.0 mmol) of 6-chloro-3-(pyridin-4-yl)imidazo[1,2-b]-pyridazine, obtained in step 7.1., 0.90 g (3.1 mmol) of tert-butyl 1-oxa-4,9-diazaspiro[5.5]-undecane-4-carboxylate and 0.84 ml (5.1 mmol) of diisopropylethylamine in 5 ml of pentanol is heated at 150° C. for 24 hours. After cooling, the pentanol is removed by evaporation under reduced pressure and the residue is taken up with aqueous sodium bicarbonate solution. The product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated under reduced pressure and the residue is chromatographed, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (97/3/0.3), to give 0.17 g of orange oil, which is used as it is in the remainder of the synthesis.

Reference： [1]Current Patent Assignee: SANOFI - US2011/312934, 2011, A1 Location in patent: Page/Page column 16

7
[ 1023595-11-0 ]
5-fluoro-3-(3-fluorophenoxy)-2-methylbenzonitrile [ No CAS ]
tert-butyl 9-[3-cyano-5-(3-fluorophenoxy)-4-methylphenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate In dimethyl sulfoxide at 110 - 115℃; Sealed tube;	25.b Preparation 25: tert-butyl 9-[3-cyano-5-(3-fluorophenoxy)-4-methylphenyl]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P25) A mixture of 5-fluoro-3-(3-fluorophenoxy)-2-methylbenzonitrile (from step a, 27 mg, 0.11 mmol), tertbutyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (prepared according to p6, 56 mg, 0.22 mmol) and K2C03 (30 mg, 0.22 mmol) in DMSO (0.7 mL) in a sealed vial was heated at 110°C and shakenovernight. An additional amount of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (28 mg) was added; the reaction temperature was brought to 115 °C and the mixture was shaken for further 48 hrs. Ether and water were added, the organic phase was washed with water, dried and solvent removed under reduced pressure. The crude material was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 90/10) to give tert-butyl 9-[3-cyano-5-(3-fluorophenoxy)-4-methyl phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p25, 11 mg, y= 21%).MS (ES) (m/z): 482.3 [M÷H]

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 106

8
[ 1023595-11-0 ]
5-fluoro-3-(3-fluorophenoxy)-2-methylbenzonitrile [ No CAS ]
3-(3-fluorophenoxy)-2-methyl-5-{1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 110 - 115 °C / Sealed tube 2: trifluoroacetic acid / dichloromethane / 2 h

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1

9
[ 1023595-11-0 ]
2-chloro-6-(3-fluorophenoxy)pyridine [ No CAS ]
tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With potassium carbonate In dimethyl sulfoxide at 90 - 100℃; for 50.5h; Sealed tube;	57 Preparation 57: tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yI]-1-oxa-4,9-diazaspiro[5.5] undecane-4- carboxylate (P57) A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).MS (ES) (m/z): 444.2 [M÷H]

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120

10
[ 1023595-11-0 ]
2-chloro-6-(3-fluorophenoxy)pyridine [ No CAS ]
9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 50.5 h / 90 - 100 °C / Sealed tube 2: trifluoroacetic acid / dichloromethane / 2 h

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1

11
[ 1023595-11-0 ]
2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine [ No CAS ]
tert-butyl 9-[6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate In dimethyl sulfoxide at 90℃; for 2h; Sealed tube;	58 Preparation 58: tert-butyl 9-[6-(3-fI uorophenoxy)-4-(trifluoromethyl)pyridin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P58) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6,60 mg, 0.23 mmol) and 1-benzyl-3-bromobenzene (p27, 68 mg, 0.23 mmol) in analogous manner asdescribed in Preparation 57 (T= 90 °C, t= 2 hrs). tert-butyl 9-[6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p58, 75 mg, y= 64%).MS (ES) (m/z): 512.2 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120

12
[ 1023595-11-0 ]
2-chloro-6-(3-fluorophenoxy)pyridine-4-carbonitrile [ No CAS ]
tert-butyl 9-[4-cyano-6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate In dimethyl sulfoxide at 80℃; for 18h; Sealed tube;	59 Preparation 59: tert-butyl 9-[4-cyano-6-(3-fluorophenoxy)pyridin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P59) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6,65 mg, 0.26 mmol) and 2-chloro-6-(3-fluorophenoxy)pyridine-4-carbonitrile (p28, 128 mg, 0.51 mmol) inanalogous manner as described in Preparation 57 (T= 80 °C, t= 18 hrs). tert-butyl 9-[4-cyano-6-(3- fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p59, 82 mg, y= 67%). MS (ES) (m/z): 469.1 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120; 121

13
[ 1023595-11-0 ]
6-chloro-2-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile [ No CAS ]
tert-butyl 9-[5-cyano-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 2h; Sealed tube;	60 Preparation 60: tert-butyl 9-[5-cyano-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yI]-1-oxa-4,9-diazaspiro[5.5] undecane-4-carboxylate (P60) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 36 mg, 0.139 mmol) and a mixture of 2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3- carbonitrile and 6-chloro-2-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile (p29, 53 mg,0.167 mmol) in analogous manner as described in Preparation 57 (T= 100 °C, t= 2 hrs). tert-butyl 9-[5- cyano-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p60, 27 mg, y= 36%). MS (ES) (m/z): 537.3 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120; 121

14
[ 894416-95-6 ]
[ 1023595-11-0 ]
tert-butyl 9-[6-(3-fluorophenoxy)pyrazin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 1h; Sealed tube;	62 Preparation 62: tert-butyl 9-[6-(3-fluorophenoxy)pyrazin-2-yI]-1-oxa-4,9-diazaspiro[5.5] undecane-4- carboxylate (P62) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4,50 mg, 0.195 mmol) and 2-chloro-6-(3-fluorophenoxy)pyrazine (p30, 44 mg, 0.195 mmol) in analogousmanner as described in Preparation 57 (T= 100 °C, t= 1 h). tert-butyl 9-[6-(3-fluorophenoxy)pyrazin-2-yl]- 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p62, 37 mg, y= 42%).MS (ES) (m/z): 445.3 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120; 122

15
[ 1023595-11-0 ]
2-chloro-4-(3-fluorophenoxy)pyrimidine [ No CAS ]
tert-butyl 9-[4-(3-fluorophenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 18h; Sealed tube;	63 Preparation 63: tert-butyl 9-[4-(3-fluorophenoxy)pyrimidin-2-yI]-1-oxa-4,9-diazaspiro[5.5]undecane-4- carboxylate (P63) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4,50 mg, 0.195 mmol) and 2-chloro-4-(3-fluorophenoxy)pyrimidine (p31, 44 mg, 0.195 mmol) in analogousmanner as described in Preparation 57 (T= 100 °C, t= 18 hrs). tert-butyl 9-[4-(3-fluorophenoxy)pyrimidin- 2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p63, 38 mg, y= 42%).MS (ES) (m/z): 445.2 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).MS (ES) (m/z): 444.2 [M÷H]

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120; 123

16
[ 1023595-11-0 ]
2-chloro-4-methyl-6-(3-methylphenoxy)pyrimidine [ No CAS ]
tert-butyl 9-[4-methyl-6-(3-methylphenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium carbonate In dimethyl sulfoxide at 90℃; for 18h; Sealed tube;	66 Preparation 66: tert-butyl 9-[4-methyl-6-(3-methyl phenoxy)pyrimidin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P66) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 53 mg, 0.21 mmol) and 2-chloro-4-methyl-6-(3-methylphenoxy)pyrimidine (p34, 54 mg, 0.23 mmol) inanalogous manner as described in Preparation 57 (T= 90 °C, t= 18 hrs). tert-butyl 9-[4-methyl-6-(3- methylphenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p66, 51 mg, y= 54%). MS (ES) (m/z): 455.3 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120; 124

17
[ 1023595-11-0 ]
3-[(2-chloro-6-methylpyrimidin-4-yl)oxy]benzonitrile [ No CAS ]
tert-butyl 9-[4-(3-cyanophenoxy)-6-methylpyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h; Sealed tube;	67 Preparation 67: tert-butyl 9-[4-(3-cyanophenoxy)-6-methylpyrimidin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P67) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4,55 mg, 0.21 mmol) and 3-[(2-chloro-6-methylpyrimidin-4-yl)oxy]benzonitrile (p35, 57 mg, 0.23 mmol) inanalogous manner as described in Preparation 57 (T= 100 °C, t= 3 hrs). tert-butyl 9-[4-(3-cyanophenoxy)- 6-methylpyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p67, 47 mg, y= 48%). MS (ES) (m/z): 466.1 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120; 125

18
[ 1023595-11-0 ]
2-chloro-4-methyl-6-(2-methylphenoxy)pyrimidine [ No CAS ]
tert-butyl 9-[4-methyl-6-(2-methylphenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 1.5h; Sealed tube;	72 Preparation 72: tert-butyl 9-[4-methyl-6-(2-methyl phenoxy)pyrimidin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P72) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 50 mg, 0.195 mmol) and 2-chloro-4-methyl-6-(2-methylphenoxy)pyrimidine (p40, 55 mg, 0.234 mmol) inanalogous manner as described in Preparation 57 (T= 100 °C, t= 1.5 h). tert-butyl 9-[4-methyl-6-(2- methylphenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p72, 33 mg, y= 37%). MS (ES) (m/z): 455.3 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 120; 127

19
[ 43212-41-5 ]
[ 372-20-3 ]
[ 1023595-11-0 ]
tert-butyl 9-[4-(3-fluorophenoxy)-6-methoxypyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%		3-fluorophenol (0.023 mL, 0.251 mmol), <strong>[43212-41-5]2,4-dichloro-6-methoxypyrimidine</strong> (50 mg, 0.279 mmol) and K2C03 (50.13 mg, 0.363 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 2 hrs at RT. The mixture was diluted with EtOAC and water. The organic phase was washed several times with brine, dried, filtered and evaporated. Crude material was purified by FC on silica gel (eluent: Cy to Cy/EtOAc 90/10) affording a mixture of 2 regioisomers and starting material (65 mg); Mixture from step a (62 mg), tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 50 mg, 0.195 mmol) and K2C03 (35 mg, 0.254 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 2 hrs at RT. The mixture was diluted with EtOAc and water. The organic phase was washed several times with brine, dried, filtered and evaporated. Crude was purified by FC on silica gel (eluent: Cy to 10% EtOAc) togive a mixture of desired compound and chlorinated analogue (30 mg); 3-fluorophenol (7 ilL, 0.075 mmol), mixture from step b (30 mg) and K2C03 (13.54 mg, 0.098 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 12 hrs at RT. Then further 2 eq of K2C03 were added and the reaction mixture was stirred at 100 C for 48 hrs. The mixture was diluted with EtOAc and water and theorganic phase was washed several times with brine, dried, filtered and evaporated. Crude was purified by FC on silica gel (eluent: Cy to Cy/EtOAc 90/10) affording tert-butyl 9-[4-(3-fluorophenoxy)-6- methoxypyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p87, 20 mg, y= 17%) as colourless oil.MS (ES) (m/z): 475.3 [M÷H]

Reference： [1]Patent: WO2016/42452,2016,A1 .Location in patent: Page/Page column 150

20
[ 1018608-18-8 ]
[ 1023595-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 2: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 2 steps 1: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 2: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1

21
[ 3612-20-2 ]
[ 1023595-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / mineral oil; dimethyl sulfoxide / 1.17 h / 10 - 20 °C / Cooling with ice 1.2: 1.5 h / 20 °C 2.1: triethylamine / methanol; water / 36 h / 50 °C 3.1: sodium hydroxide / tetrahydrofuran; ethanol / 5 h / Reflux 4.1: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 5.1: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 7 steps 1.1: sodium hydride / mineral oil; dimethyl sulfoxide / 1.17 h / 10 - 20 °C / Cooling with ice 1.2: 1.5 h / 20 °C 2.1: ammonium hydroxide / methanol; water / 0 - 20 °C 3.1: triethylamine / dichloromethane / 0.92 h / 0 °C / Inert atmosphere 4.1: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 6.1: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 7.1: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 7 steps 1.1: sodium hydride / mineral oil; dimethyl sulfoxide / 1.16 h / 10 - 20 °C / Inert atmosphere 1.2: 1.5 h / 20 °C / Inert atmosphere 2.1: ammonium hydroxide / water; methanol / 0 - 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 1.17 h / 0 - 20 °C / Inert atmosphere 4.1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 - 20 °C / Inert atmosphere 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 6.1: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 7.1: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1
[3]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1

22
[ 23804-68-4 ]
[ 1023595-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 0.92 h / 0 °C / Inert atmosphere 2: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 3: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 4: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 5: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 1.17 h / 0 - 20 °C / Inert atmosphere 2: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 - 20 °C / Inert atmosphere 3: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 4: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 5: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1

23
[ 19867-34-6 ]
[ 1023595-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / methanol; water / 36 h / 50 °C 2: sodium hydroxide / tetrahydrofuran; ethanol / 5 h / Reflux 3: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 4: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 6 steps 1: ammonium hydroxide / methanol; water / 0 - 20 °C 2: triethylamine / dichloromethane / 0.92 h / 0 °C / Inert atmosphere 3: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 4: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 5: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 6: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 6 steps 1: ammonium hydroxide / water; methanol / 0 - 20 °C / Inert atmosphere 2: triethylamine / dichloromethane / 1.17 h / 0 - 20 °C / Inert atmosphere 3: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 - 20 °C / Inert atmosphere 4: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 5: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 6: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1
[3]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1

24
9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
[ 1023595-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 2: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 3: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 2: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 3: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1

25
N-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]-2-chloroacetamide [ No CAS ]
[ 1023595-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 3: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 4: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
	Multi-step reaction with 4 steps 1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 - 20 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 3: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 4: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1

26
(2-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]amino}ethoxy)sulfonic acid [ No CAS ]
[ 1023595-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydroxide / tetrahydrofuran; ethanol / 5 h / Reflux 2: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 3: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1

27
tert-butyl 9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
[ 1023595-11-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With palladium 10% on activated carbon; ammonium formate In methanol for 1h; Reflux;	4; 6 Preparation 4: tert-butyl 1-oxa-4,9-diazaspiro[5.5] undecane-4-carboxylate (P4) To a solution of tert-butyl 9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (2.26 g, 6.52 mmol, p3) in MeOH (45 mL) ammonium formate (2.47 g, 39.14 mmol) and 10% Pd/c (650 mg) were added atRT 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 tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 1.6 g, y= 96%) as white wax.MS (ES) (m/z): 257.2 [M÷H]
	With palladium 10% on activated carbon; ammonium formate In methanol at 20℃; for 1h; Reflux; Inert atmosphere;	P69 Preparation 69: tert-butyl 1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate (P69) Preparation 69: tert-butyl 1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate (P69) To a solution of ieri-butyl 9-benzyl-l-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p68, 186 mg, 0.537 mmol) in MeOH (4 mL) ammonium formate (133 mg, 2.11 mmol) and 10% Pd/C (57 mg) 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 l-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p69, 159 mg, crude material) as white wax.MS (ES) (m/z): 257.2 [M+H]+.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 78; 79
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1 Location in patent: Page/Page column 103

28
[ 1023595-11-0 ]
1-bromo-4,5-difluoro-2-(3-fluorophenoxy)benzene [ No CAS ]
tert-butyl 9-[4,5-difluoro-2-(3-fluorophenoxy)phenyl]-1-oxa-4,9diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 100℃; Inert atmosphere;	1.a To a stirred solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 150 mg, 0.585mmol) in Toluene (5 mL) at RT, BINAP (36 mg, 0.0585 mmol), sodium tert-butoxide (112 mg, 1.17 mmol)and 1-bromo-4,5-difluoro-2-(3-fluorophenoxy)benzene (p7, 178 mg, 0.585 mmol) were added and argon was purged for 10 mm. Eventually, Pd2(dba)3 (16 mg, 0.017 mmol) was added and the reaction mixture was shaken at 100 °C overnight. The reaction mixture was concentrated, water was added and then the mixture was extracted with EtOAc. The organic phase was dried, filtered and the solvent was eliminatedunder reduced pressure. The crude material was purified by FC on silica gel (eluent: Cy to 15% EtOAc) affording tert-butyl 9-[4,5-difluoro-2-(3-fluorophenoxy)phenyl]-1-oxa-4,9diazaspiro[5.5]undecane-4- carboxylate (77 mg) as yellow oil.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1 Location in patent: Page/Page column 89

29
[ 1023595-11-0 ]
1-bromo-4,5-difluoro-2-(3-fluorophenoxy)benzene [ No CAS ]
9-[4,5-difluoro-2-(3-fluorophenoxy)phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 100 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2016/42452, 2016, A1

30
[ 1023595-11-0 ]
9-[bis(4-fluorophenyl)methyl]-1-oxa-4,9-diazaspiro[5,5]undecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 20 °C / Reflux; Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1

31
[ 27064-94-4 ]
[ 1023595-11-0 ]
tert-butyl 9-[bis(4-fluorophenyl)methyl]-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 20℃; Reflux; Inert atmosphere;	E31.a Step a Step a To a solution of tert-butyl 9-benzyl-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate (p69, 30 mg, 0.117 mmol) in Acetonitrile (1 mL), l-[chloro(4-fluorophenyl)methyl]-4-fluorobenzene (27 μ, 0.14 mmol) was added followed by K2C03(41 mg, 0.29 mmol). The mixture was heated to reflux for 7 hrs, then 0.2 eq of l-[chloro(4-fluorophenyl)methyl]-4-fluorobenzene were further added, the mixture refluxed for further 1 h, and then left stirring at T overnight. The day after, solid was filtered off washing with AcOEt and solvent was eliminated under reduced pressure affording ieri-butyl 9-[bis(4-fluorophenyl)methyl]-l-oxa- 4,9-diazaspiro[5.5]undecane-4-carboxylate (60 mg) used as such in next step.

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2016/42451, 2016, A1 Location in patent: Page/Page column 104

32
[ 1023595-11-0 ]
pentafluorophenyl (2R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl carbonate [ No CAS ]
4-tert-butyl 9-{(2R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl} 1-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.2 g	With triethylamine In acetonitrile at 0 - 25℃; for 15h;	7.1 Step 1. Synthesis of 4-tert-butyl 9-{(2R)-1 , 1 , 1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl} 1- oxa-4, 9-diazaspiro[5.5]undecane-4, 9-dicarboxylate ( C30). Triethylamine (9.28 g, 91.7 mmol) was added to a 0 °C solution of te/ -butyl 1-oxa-4,9- diazaspiro[5.5]undecane-4-carboxylate (4.70 g, 18.3 mmol) in acetonitrile (60 mL); C2 (reaction solution in acetonitrile, containing 27.5 mmol) was then added drop-wise, and the reaction mixture was stirred at 0 °C few minutes. It was then allowed to warm to 25 °C and stir for 15 hours, whereupon it was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 100% dichloromethane in petroleum ether). The product (11.2 g) was isolated as a yellow oil, which by LCMS analysis was impure; this material was used without additional purification. LCMS m/z 555.1 [M+Na+].

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/21805, 2017, A1 Location in patent: Page/Page column 89

33
[ 1023595-11-0 ]
2-fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)-4-(2-hydroxypropan-2-yl)benzamide [ No CAS ]
tert-butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.42 g	Stage #1: tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate; 2-fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)-4-(2-hydroxypropan-2-yl)benzamide In tetrahydrofuran at 60℃; Stage #2: With sodium cyanoborohydride In tetrahydrofuran at 60℃;	1 Step 1 : Tert-butvl 9-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2- methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)-1 -oxa-4,9-diazaspiro[5.5]undecane-4- carboxylate A mixture of tert-butyl 1 -oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (155 mg, 0.605 mmol) and 2-fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)- 4-(2-hydroxypropan-2-yl)benzamide (intermediate 3, 350 mg, 0.665 mmol) in THF (6 ml) was stirred overnight at 60°C. Solid NaBH(OAc)3(384 mg, 1 .814 mmol) was added and stirring was continued at 60°C for 9 h and at RT overnight. The RM was diluted with EtOAc, and washed with an aq. solution of NaHC03and brine. The organic phase was dried over Na2S04and concentrated to afford the title compound as a solid (0.42 g).Method A: Rt = 0.90 min; [M+H]+ = 767.5.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2019/186343, 2019, A1 Location in patent: Page/Page column 153

34
[ 1023595-11-0 ]
4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde [ No CAS ]
tert-butyl 9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate; 4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde In methanol at 20℃; for 0.5h; Stage #2: With methanol; sodium cyanoborohydride at 20℃; for 2h;	60.5 Step 5: Preparation of tert-butyl 9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6- dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (i60-6) A solution of 4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde(100 mg, 0.295 mmol, 1.00 equiv) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (83.1 mg, 0.324 mmol, 1.1 equiv) in MeOH (1.5 mL) was stirred for 30 minutes at room temperature. Then NaBH3CN (125 mg, 1.989 mmol, 6.75 equiv) was added. The resulting mixture was stirred for 2 hours at room temperature. The reaction solution was purified by Prep-TLC (DCM/ MeOH 20:1) to afford tert-butyl 9-[[4- (7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9- diazaspiro[5.5]undecane-4-carboxylate (134 mg, 78%) as a light brown foam. LCMS (ESI) m/z: [M+H]+ = 580.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2020/160198, 2020, A1 Location in patent: Page/Page column 319-321

35
[ 835616-61-0 ]
[ 1023595-11-0 ]
C₂₆H₃₂N₄O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With 1-methyl-pyrrolidin-2-one; diisopropylamine at 20 - 90℃; for 6h; Inert atmosphere;	78.1 Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3- dione (i78-2) To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.50 g, 5.430 mmol, 1.00 equiv) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (1.67 g, 6.516 mmol, 1.20 equiv) in NMP (10.00 mL) was added DIEA (1.40 g, 10.861 mmol, 2.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 6 hours at 90 °C under nitrogen atmosphere. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 20 minutes; detector, UV 254 nm). This resulted in tert-butyl 9-(2- (2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (2 g, 72%) as a green oil. LCMS (ESI) m/z: [M+H]+ = 513.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2020/160198, 2020, A1 Location in patent: Page/Page column 348-349

36
[ 1023595-11-0 ]
2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1-methyl-pyrrolidin-2-one; diisopropylamine / 6 h / 20 - 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C