[ CAS No. 1227382-01-5 ] {[proInfo.proName]}

Name: 1227382-01-5|tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate|95%
Brand: Ambeed
SKU: A280524
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Quality Control of [ 1227382-01-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1227382-01-5 ]

SDS Specification

Alternatived Products of [ 1227382-01-5 ]

Product Details of [ 1227382-01-5 ]

CAS No. :	1227382-01-5	MDL No. :	MFCD11976177
Formula :	C₁₂H₂₀N₂O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UMRJVCJJEKXMNB-UHFFFAOYSA-N
M.W :	288.30	Pubchem ID :	53350400
Synonyms :

Calculated chemistry of [ 1227382-01-5 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	4
Num. H-bond acceptors :	7.0
Num. H-bond donors :	3.0
Molar Refractivity :	76.21
TPSA :	116.17 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-9.61 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.78
Log Po/w (XLOGP3) :	-2.19
Log Po/w (WLOGP) :	-0.78
Log Po/w (MLOGP) :	-0.37
Log Po/w (SILICOS-IT) :	0.78
Consensus Log Po/w :	-0.16

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	0.02
Solubility :	299.0 mg/ml ; 1.04 mol/l
Class :	Highly soluble
Log S (Ali) :	0.28
Solubility :	552.0 mg/ml ; 1.91 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-1.54
Solubility :	8.28 mg/ml ; 0.0287 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.94

Safety of [ 1227382-01-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1227382-01-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1227382-01-5 ]

[ 1227382-01-5 ] Synthesis Path-Downstream 1~78

1
[ 1150618-17-9 ]
[ 144-62-7 ]
[ 1227382-01-5 ]

Yield	Reaction Conditions	Operation in experiment
		fer/-Butyl 2.6-diazaspiro[3 31heptane-2-carboxylate oxalate; Into a 5 L, 3 -neck, round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of acetyl chloride (25 3 g, 322 3 mmol) in methanol (2 7 L) To this was added di-tert-buty 2,6-diazaspiro[3 3]heptane-2,6-dicarboxylate (96 g, 321 mmol) The resulting solution was stirred for 20 h while the temperature was20 maintained at 20 0C Solid KOH (18 1 g, 323 2 mmol) was added in small portions in order to maintain the temperature below 30 0C The resulting mixture was concentrated under reduced pressure The residue was transferred to a separatory funnel using water (200 mL) and EtOAc (1 L) The aqueous layer was extracted with EtOAc (2 x 500 mL) The combined organic layers were dried over Na2Stheta4 and concentrated under reduced pressure To the residue was added 1 L25 of ether and oxalic acid (28 9 g, 321 mmol) The resulting solution was stirred for 1 h at room temperature The resulting solid was collected by vacuum filtration, washed once with EtOAc (500 mL) and once with ether (1 L) to give the title compound as a white solid 1H NMR (400 MHz, D2O) 5 4 20 (4H, s), 4 07 (4H, s), 1 31 (9H, s) MS (ESI, Q+) m/z 199 (M + 1)

Reference： [1]Patent: WO2010/108268,2010,A1 .Location in patent: Page/Page column 69

2
[ 202982-68-1 ]
[ 1227382-01-5 ]
[ 1246749-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃; for 16h;Sealed tube; Inert atmosphere;	Step 5 tert-Butyl 6-f2-chloro-5-fluorophenyl)-2,6-diazaspiro[3 3]heptane-2-carboxylate; Into a sealed tube, a mixture of tert-buty 2,6-diazaspiro[3 3]heptane-2- carboxylate oxalate (250 mg, 0 87 mmol), 1 -chloro-4-fluoro-2-iodobenzene (347 mg, 1 35 mmol), palladium(II) acetate (19 mg, 0 085 mmol), racem/c-BINAP (108 mg, 0 17 mmol) and sodium terf-butoxide (275 mg, 2 86 mmol) in toluene (1 8 mL) was degassed by bubbling N2 for 5 mm The vial was sealed with a cap and the mixture was heated to 120 0C for 16 h The reaction was diluted with EtOAc, poured into saturated aqueous NaHCO3, extracted with EtOAc, and the organic layer was washed with saturated aqueous NaHCtheta3 and brine, dried over Na2SO4, filtered and concentrated The resulting crude material was purified twice by column 0 chromatography through silica gel, eluting with 0% EtOAc in hexanes to 40% EtOAc in hexanes as a gradient The title product was obtained as a colorless oil MS (ESI, Q+) m/z 327 (M + 1)

Reference： [1]Patent: WO2010/108268,2010,A1 .Location in patent: Page/Page column 69-70

3
[ 1227382-01-5 ]
[ 1431868-57-3 ]

Reference： [1]Patent: US2013/109668,2013,A1

4
[ 1227382-01-5 ]
[ 1431868-35-7 ]

Reference： [1]Patent: US2013/109668,2013,A1

5
[ 1227382-01-5 ]
[ 19654-32-1 ]
[ 1431868-56-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; In dichloromethane; at 20℃; for 1h;	To a stirred solution of <strong>[1227382-01-5]6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate</strong> (200 mg, 1.01 mmol) in dichloromethane (10 mL) was added triethylamine (141 mu?, 1.01 mmol) followed by 2,4-dichloro-l-(isocyanatomethyl)benzene (204 mg, 1.01 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (Si02; methanol: dichloromethane 0: 1 to 1 :9) to give the title compound (344 mg, 85%) as a white solid. MS (EI) m/e: 400.0 (M+H)+.
85%	With triethylamine; In dichloromethane; at 20℃; for 1h;	To a stirred solution of <strong>[1227382-01-5]6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate</strong> (200 mg, 1.01 mmol) in dichloromethane (10 mL) was added triethylamine (141 mul, 1.01 mmol) followed by 2,4-dichloro-1-(isocyanatomethyl)benzene (204 mg, 1.01 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; methanol:dichloromethane 0:1 to 1:9) to give the title compound (344 mg, 85%) as a white solid. MS (EI) m/e: 400.0 (M+H)+.

Reference： [1]Patent: WO2013/64467,2013,A1 .Location in patent: Page/Page column 40
[2]Patent: US2013/109668,2013,A1 .Location in patent: Paragraph 0212-0213

6
[ 1227382-01-5 ]
[ 1451260-29-9 ]
[ 1453832-77-3 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In acetonitrile; for 120h;Reflux;	To a solution of <strong>[1227382-01-5]tert-butyl 6-aza-2-azoniaspiro[3.3]heptane-6-carboxylate oxalate</strong> (0.956 mmol) in acetonitrile (20 mL) were added dipotassium carbonic acid (0.670 g, 4.78 mmol) then 3-(2-bromothiazol-4-yl)-5-(2,6-difluorophenyl)-4,5-dihydroisoxazole (0.330 g, 0.956mmol). After heating at reflux for 5days, solvent was evaporated and the residue was suspended in ethylacetate, washed with water 2x and brine, dried and solvent evaporated under pressure. The crude mixture was purified by column chromatography (ethylacetate/cyclohexane,0-50%) to give tert-butyl 2-[4-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl]thiazol-2-yl]-2,6-diazaspiro[3.3]heptane-6-carboxylate(371 mg,84%).1H-NMR (400 MHz, CDCl3): delta=1.48 (s, 9H), 3.50-3.60 (m, 1H), 3.65-3.75 (m, 1H),4.11 (s, 4H), 4.25 (s, 4H), 6.00-6.10 (m, 1H), 6.85-6.98 (m, 2H), 7-00 (s, 1H), 7.25-7.4 (m, 1H), 7.7 (s, 1H). MS: m/z = 463 (M+1).

Reference： [1]Patent: WO2013/127789,2013,A1 .Location in patent: Page/Page column 24

7
[ 1227382-01-5 ]
[ 460-00-4 ]
[ 1333215-19-2 ]

Reference： [1]Patent: US2014/221340,2014,A1

8
[ 1227382-01-5 ]
[ 460-00-4 ]
[ 1333215-20-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; In toluene; at 110℃; for 24h;	6-(tert-Butoxycarbonyl)-6-aza-2-azospiro[3,3]heptane oxalate (Organic Letters, vol. 10, page 3525, 2008; 0.050 g, 0.103 mmol) was dissolved in toluene (2.5 mL), 1-bromo-4-fluorobenzene (0.036 g, 0.206 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.009 g, 0.010 mmol), (+-)-BINAP (0.019 g, 0.031 mmol), potassium tert-butoxide (0.069 g, 0.617 mmol) and triethylamine (0.005 g, 0.051 mmol) were added, and the mixture was stirred at 110 C. for 24 hr. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the title compound (0.029 g, 48%).

Reference： [1]Patent: US2014/221340,2014,A1 .Location in patent: Paragraph 0526

9
[ 1227382-01-5 ]
2-morpholinoacetaldehyde [ No CAS ]
6-(2-morpholin-4-yl-ethyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		a2.1) 6-(2-Morpholin-4-yl-ethyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert- butyl ester 2-Morpholinoacetaldehyde as NaHS03-salt (6.9 mmol, 1.6 g) and concentrated acetic acid (0.8 mL) were added to a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2- carboxylate oxalate (6.9 mmol, 2.0 g) in EtOH (100 mL). The mixture was stirred for lh, NaCNBH3 (8.3 mmol, 0.5 g) was added portionswise, and further stirred over night at rt. The mixture was poured onto cold 5% aq. K2C03 (100 mL) and extracted three- times with ethyl acetate (100 mL); the organic phases were combined, washed with water three-times (100 mL), dried on Na2S04, filtered and evaporated in vacuo. The crude product was passed through a silicagel column (eluent: CH2Cl2:MeOH 9: 1). Yield: 1.19 g (55%).

Reference： [1]Patent: WO2015/173393,2015,A1 .Location in patent: Page/Page column 66

10
[ 3612-20-2 ]
[ 1227382-01-5 ]
6-(1-benzyl-piperidin-4-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%		al .1) 6-(l-Benzyl-piperidin-4-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert- butyl ester l-Benzylpiperidin-4-one (20.8 mmol, 3.9 g) and concentrated acetic acid (1.2 mL) were added to a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (10.4 mmol, 3 g) in MeOH (100 mL). The solution was stirred for lh and NaCNBH3 (12.5 mmol, 0.8 g) was added portionswise. The mixture was stirred over night at rt and poured onto cold 5% aq. K2CO3 (100 mL) and extracted three-times with ethyl acetate (lOOmL), the organic phases were combined and washed with water three-times (100 mL) and dried on Na2S04. It was filtered off, evaporated in vacuo and passed through a silicagel column (eluent: EtOAc:MeOH 1 : 1). Yield: 3.77 g (98%). ESI-MS: [M+H+] = 372.2

Reference： [1]Patent: WO2015/173393,2015,A1 .Location in patent: Page/Page column 65

11
[ 1227382-01-5 ]
(±)-3-(2-ethoxy-5-methoxy-phenyl)-3-[6-(2-morpholin-4-yl-ethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2015/173393,2015,A1

12
[ 1227382-01-5 ]
6-(1-oxetan-3-yl-piperidin-4-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2015/173393,2015,A1

13
[ 1227382-01-5 ]
2-(1-oxetan-3-yl-piperidin-4-yl)-2,6-diaza-spiro[3.3]heptane [ No CAS ]

Reference： [1]Patent: WO2015/173393,2015,A1

14
[ 1227382-01-5 ]
4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)morpholine [ No CAS ]

Reference： [1]Patent: WO2015/173393,2015,A1

15
[ 1227382-01-5 ]
tert-butyl 6-(1-(2-methoxyethyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2 carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/173393,2015,A1

16
[ 1227382-01-5 ]
6-piperidin-4-yl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2015/173393,2015,A1

17
[ 1227382-01-5 ]
N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-6-carboxamide [ No CAS ]

Reference： [1]Patent: US2015/344489,2015,A1

18
[ 1227382-01-5 ]
4-(2-bromoethyl)morpholine hydrogen chloride [ No CAS ]
6-(2-morpholin-4-yl-ethyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%		14.1 tert-Butyl 6-(2-morpholinoethyl)-2,6-diazaspiro[3 .3]heptane-2-carboxylate10679] K2C03 (52.0 mmol, 7.2 g) was added to a suspension of tert-butyl 2,6-diazaspiro[3 .3]heptane-2-carboxylate oxalate (10.4 mmol, 3.0 g) in DMF (90 ml). After 1 h stirring at it, 4-(2-bromoethyl)morpholine hydrochloride (11.5 mmol, 2.6 g) was added portionwise and the mixture was stirred at it for 12 h. The precipitate was filtered off, and the filtrate evaporated in vacuo. The residue was passed through a silicagel column (eluent: CH2C12:MeOH 9:1).Yield: 1.9 g (59%).

Reference： [1]Patent: US2015/344489,2015,A1 .Location in patent: Paragraph 0679

19
[ 1227382-01-5 ]
(S)-phenyl (5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamate [ No CAS ]
(S)-tert-butyl 6-((5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 12h;	1.2 (S)-tert-Butyl 6-((5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate DIPEA (2.05 mmol, 0.36 ml) was added to a suspension of <strong>[1227382-01-5]tert-butyl 2,6-diazaspiro[3.3]-heptane-2-carboxylate oxalate</strong> (0.41 mmol, 118 mg) in CH2Cl2 (10 ml). Once in solution, (S)-phenyl (5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)carbamate (0.41 mmol, 240 mg) was added and the mixture was stirred for 12 h. The mixture was poured into cold 5% aq. K2CO3 (10 ml) and extracted with CH2Cl2 (310 ml); and the organic phases were combined, washed with water (310 ml), dried on Na2SO4, filtered, evaporated, and finally passed through a silicagel column (eluent: EtOAc). Yield: 205.5 mg (73%). ESI-MS: [M+-55 (isobutene)]=633.2; [M+H+]=689.2

Reference： [1]Patent: US2015/344489,2015,A1 .Location in patent: Paragraph 0617; 0618

20
[ 1227382-01-5 ]
N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-2-(2-morpholinoethyl)-2,6-diazaspiro[3.3] heptane-6-carboxamide 2,2,2-trifluoroacetic acid [ No CAS ]

Reference： [1]Patent: US2015/344489,2015,A1

21
[ 1227382-01-5 ]
(S)-N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-6-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide [ No CAS ]

Reference： [1]Patent: US2015/344489,2015,A1

22
[ 1227382-01-5 ]
3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-3-[2-[2-(2-morpholinoethyl)-2,6-diazaspiro[3.3]heptan-6-yl]-2-oxo-ethyl]-2-oxo-indoline-5-carbonitrile [ No CAS ]

Reference： [1]Patent: US2015/344489,2015,A1

23
[ 1227382-01-5 ]
4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)morpholine tris(2,2,2-trifluoroacetate) [ No CAS ]

Reference： [1]Patent: US2015/344489,2015,A1

24
[ 1227382-01-5 ]
6-chloro-2-(5-iodo-3-pyridyl)-3,4-dihydroisoquinolin-1-one [ No CAS ]
tert-butyl 6-[5-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium t-butanolate; In toluene; at 85℃; for 2h;Inert atmosphere;	GammaBeta1 fer?-Butyl6-r5-(6-chloro- l-oxo-3,4-dihvdroisoquinolin-2-yl)-3-pyridyll-2,6-diazaspiro r3.31heptane-2-carboxylate To a solution of 6-chloro-2-(5-iodo-3-pyridyl)-3,4-dihydroisoquinolin- l-one (480 mg, 1.25 mmol), ie/t-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (500 mg, 1.74 mmol), Pd2dba3 (100 mg, 0.11 mmol), BINAP (120 mg, 0.19 mmol) and tBuONa (400 mg, 4.8 mmol) in toluene (10 mL) was added 10 drops of triethylamine. The resulting reaction mixture was then heated to 85 C for 2 hours. After it was cooled to the room temperature, the mixture was poured into brine and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over anhy. Na2S04, filtered and concentrated in vacuo to give a crude product, which was then purified by silica gel flash chromatography to afford the title compound (283 mg, 50%) as a brown solid. MS: 455.1 (M+H+).

Reference： [1]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 49; 50

25
[ 1227382-01-5 ]
2-(5-bromo-3-pyridyl)-5-chloro-3-methyl-isoindolin-1-one [ No CAS ]
tert-butyl 6-[5-(5-chloro-3-methyl-1-oxo-isoindolin-2-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium t-butanolate; In toluene; at 110℃; for 12h;Inert atmosphere;	GammaBeta1 fe/t-Butyl 6-r5-(5-chloro-3-methyl-l-oxo-isoindolin-2-yl)-3-pyridyll-2,6- diazaspiror3.31heptane-2-carboxylate A mixture of 2-(5-bromo-3-pyridyl)-5-chloro-3-methyl-isoindolin-l-one (674 mg, 2 mmol), ie/t-butyl 2,6-diazasprio[3.3]heptane-2-carboxylateoxalate (870 mg, 3 mmol), Pd2(dba)3 (137 mg), BINAP (165 mg), t-BuONa (580 mg, 6 mmol) and TEA (1 mL, 7.2 mmol) in toluene (20 mL) were stirred at 110 C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhy. Na2S04, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to afford the title compound (800 mg, 88.9%) as a light yellow foam. MS: 455.2 (M+H+).

Reference： [1]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 51

26
[ 1227382-01-5 ]
5-chloro-2-(5-iodopyridin-3-yl)-3,3-dimethyl-2,3-dihydroisoindol-1-one [ No CAS ]
tert-butyl 6-[5-(6-chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium t-butanolate; In toluene; at 85℃; for 2h;Inert atmosphere;	GammaBeta1 fe/t-Butyl 6-r5-(6-chloro-lJ-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyll-2,6- diazaspiror3.31heptane-2-carboxylate To a solution of 5-chloro-2-(5-iodo-3-pyridyl)-3,3-dimethyl-isoindolin-l-one (300 mg, 1.25 mmol), ie/t-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (500 mg, 1.74 mmol), Pd2dba3 (100 mg, 0.11 mmol), BINAP (120 mg, 0.19 mmol) and tBuONa (400 mg, 4.8 mmol) in toluene (10 mL) was added 10 drops of triethylamine. The reaction mixture was the heated to 85 C for 2 hours. After cooling to room temperature, the mixture was poured into brine and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over anhy. Na2S04, filtered and concentrated in vacuo to give a crude product, which was then purified by silica gel flash chromatography to afford the title compound (460 mg, 52%) as a brown solid. MS: 469.1 (M+H+).

Reference： [1]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 53

27
[ 1227382-01-5 ]
2-(5-iodo-3-pyridyl)-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile [ No CAS ]
tert-butyl 6-[5-(6-cyano-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium t-butanolate; In toluene; at 100℃; for 3h;Inert atmosphere;	GammaBeta1 fe/t-Butyl 6-r5-(6-cvano-lJ-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyll-2,6- diazaspiror3.31heptane-2-carboxylate To a solution of 2-(5-iodo-3-pyridyl)-3,3-dimethyl-l-oxo-isoindoline-5-carbonitrile (561 mg, 1.44 mmol), ie/t-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (500 mg, 1.74 mmol), Pd2dba3 (100 mg, 0.11 mmol), BINAP (120 mg, 0.19 mmol) and tBuONa (400 mg, 4.8 mmol) in toluene (10 mL) was added 10 drops of triethylamine. The reaction mixture was the heated to 100 C for 3 hours. After cooling to room temperature, the mixture was poured into brine and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhy. Na2S04, filtered and concentrated in vacuo to give a crude product, which was then purified by silica gel flash chromatography to afford the title compound (300 mg, 45%) as a brown solid. MS: 460.1 (M+H+).

Reference： [1]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 55

28
[ 1227382-01-5 ]
6-(5-iodo-3-pyridyl)-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one [ No CAS ]
tert-butyl 6-[5-(2-methoxy-7,7-dimethyl-5-oxo-pyrrolo[3,4-b]pyridin-6-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.2%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium t-butanolate; In toluene; at 110℃; for 12h;Inert atmosphere;	GammaBeta1 fe/t-Butyl 6-r5-(2-methoxy-7,7-dimethyl-5-oxo-pyrrolor3,4-blpyridin-6-yl)-3-pyridyll- 2,6-diazaspiror3.31heptane-2-carboxylate A mixture of 6-(5-iodo-3-pyridyl)-2-methoxy-7,7-dimethyl-pyrrolo[3,4-b]pyridin-5-one (395 mg, 1 mmol), ie/t-butyl 2,6-diazasprio[3.3]heptane-2-carboxylate oxalate (435 mg, 1.5 mmol), Pd2(dba)3 (70 mg), BINAP (85 mg), t-BuONa (290 mg, 3 mmol) and TEA (1 mL, 7.2 mmol) in toluene (20 mL) was stirred at 110 C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhy. Na2S04, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to afford the title compound (350 mg, 75.2%) as a light yellow foam. MS: 466.1 (M+H+).

Reference： [1]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 57

29
[ 1227382-01-5 ]
5'-chloro-2'-(5-iodo-3-pyridyl)spiro[cyclopropane-1,3'-isoindoline]-1'-one [ No CAS ]
tert-butyl 6-[5-(6'-chloro-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.9%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium t-butanolate; In toluene; at 110℃; for 12h;Inert atmosphere;	GammaBeta1 fe/t-Butyl 6-r5-(6,-chloro-3,-oxo-spirorcvclopropane-lJ,-isoindolinel-2,-yl)-3- pyridyll-2,6-diazaspiror3.31heptane-2-carboxylate A solution of 5'-chloro-2'-(5-iodo-3-pyridyl)spiro[cyclopropane-l,3'-isoindoline]-l'-one (396 mg, 1 mmol), ie/t-butyl 2,6-diazasprio[3.3]heptane-2-carboxylate oxalate (435 mg, 1.5 mmol), Pd2(dba)3 (70 mg), BINAP (85 mg), t-BuONa (290 mg, 3 mmol) and TEA(1 mL, 7.2 mmol) in toluene ( 20 mL) was stirred at 110 C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhy. Na2S04, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to afford the title compound (414 mg, 88.9%) as a light yellow foam. MS: 467.1 (M+H+).

Reference： [1]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 58; 59

30
[ 1227382-01-5 ]
5-chloro-2-(5-iodo-4-methyl-3-pyridyl)-3-methyl-isoindolin-1-one [ No CAS ]
tert-butyl 6-[5-(5-chloro-3-methyl-1-oxo-isoindolin-2-yl)-4-methyl-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium t-butanolate; In toluene; at 100℃; for 10h;Inert atmosphere;	TCI fe/t-Butyl 6-r5-(5-chloro-3-methyl-l-oxo-isoindolin-2-yl)-4-methyl-3-pyridyll-2,6- diazaspiror3.31heptane-2-carboxylate A mixture of 5-chloro-2-(5-iodo-4-methyl-3-pyridyl)-3-methyl-isoindolin-l-one (300 mg, 0.75 mmol), ie/t-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (300 mg, 1.04 mmol), Pd2(dba)3 (80 mg), BINAP (80 mg), tBuONa (240 mg, 2.5 mmol) and triethylamine (0.5 mL) in toluene (5 mL) was heated at 100 C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with satd. aq. NaCl solution (5 ml), extracted with EtOAc (4 x 10 mL), dried over anhy. Na2S04, filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel flash chromatography (PE:EtOAc=2: 1 ) to afford the title compound (160 mg, 45% ) as a yellow solid. MS: 369.1 (M+H+).

Reference： [1]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 61

31
[ 1227382-01-5 ]
6-(5-(ethoxycarbonyl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-ium 2,2,2-trifluoroacetate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3048 - 3051

32
[ 1227382-01-5 ]
ethyl 6-(6-(4-benzylphthalazin-1-yl)-2,6-diazaspiro[3.3]heptan-2-yl)nicotinate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3048 - 3051

33
[ 1227382-01-5 ]
[ 49608-01-7 ]
tert-butyl 6-(5-(ethoxycarbonyl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.5%	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere;	General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3048 - 3051

34
[ 1227382-01-5 ]
(±)-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide [ No CAS ]
tert-butyl 6-{4-[((4S)-7,8-dimethoxy-4-methyl-3-(methylcarbamoyl)-4,5-dihydro-3H-2,3-benzodiazepine-1-yl)]phenyl}-2,6-diazaspiro[3.3]heptane-2-cartoxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Under argon,(4S)-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide(Example 30.2A) 1.00 g (2.31 mmol) was added to fill to 35 ml of toluenedeaerated initially. 1,1-thiazol-6-oxo-1-azaspiro [3.3] heptane trifluoroacetate(free base CAS [1352546-75-8]) 2.41 g (9.25 mmol), sodium tert- butoxide, 445mg ( 4.62 mmol) and chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II)(CAS [1310584-14-5]) 91 mg (0.12 mmol) was added. The mixture was degassedagain, saturated with argon and stirred at 80for 7 hours. After cooling, the mixture was added to saturated sodiumbicarbonate solution, extracted with ethyl acetate. Wash the combined organicphase with saturated sodium chloride solution, dried over sodium sulfate. Thesolvent was removed by rotary evaporator, the residue (an orange foam 1.6 g)was purified by flash chromatography (SiO2, dichloromethane / methanol 0-3-5%).In this manner was obtained (49% of theory) of the desired product 570 mg as ayellow solid. Method IV: System: Agilent: FC refined for 1200, 2x purification pumps, DLA, MWD, for refining; Column: Chiralpak IC 5mum 250x30mm; Mobile phase: ethanol / methanol / diethylamine 70: 30: 0.1 (v / v / v); Flow rate: 30 ml / min; Temperature: RT; Detection: UV 280 nm

Reference： [1]Patent: KR2015/119926,2015,A .Location in patent: Paragraph 0870; 1008; 1021

35
[ 623-00-7 ]
[ 1227382-01-5 ]
C₁₇H₂₁N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere;	Preparation of intermediate CT A solution of 2-Boc-2,6-diazaspiro[3.3]heptane oxalate (CAS [1041026-71-4], 2.0 g, 6.73 mmol), 4-Bromobenzonitrile (CAS [623-00-7], 1.84 g, 10.1 mmol) and sodium ter-butoxide (2.59 g, 26.9 mmol) in 1,4-dioxane (70 mL) was degassed. Then, palladium acetate (0.151 g, 0.673 mmol) and Xantphos (0.389 g, 0.673 mmol) were added, the mixture was purged again with N2 and stirred at 100 C for 3 h. The mixture was cooled down to room temperature and filtered on a pad of Celite. The cake was washed with EtOAc and the filtrate was evaporated in vacuo. The crude product was purified by preparative LC (irregular silica, 15-40 muiotaeta, 120 g, dry loading (Celite), mobile phase gradient Heptane/EtOAc from 95/5 to 60/40) to give 0.919 g of intermediate CT as a white solid (48%).

Reference： [1]Patent: WO2017/1660,2017,A1 .Location in patent: Page/Page column 110

36
[ 1227382-01-5 ]
C₁₂H₁₃N₃ [ No CAS ]

Reference： [1]Patent: WO2017/1660,2017,A1

37
[ 1227382-01-5 ]
C₁₄H₁₅N₃O [ No CAS ]

Reference： [1]Patent: WO2017/1660,2017,A1

38
[ 1227382-01-5 ]
C₁₄H₁₉N₃O [ No CAS ]

Reference： [1]Patent: WO2017/1660,2017,A1

39
[ 1227382-01-5 ]
C₂₄H₂₆ClN₅O₂ [ No CAS ]

Reference： [1]Patent: WO2017/1660,2017,A1

40
[ 1227382-01-5 ]
C₁₉H₁₇N₃O [ No CAS ]

Reference： [1]Patent: WO2017/1660,2017,A1

41
[ 1227382-01-5 ]
C₁₉H₂₁N₃O [ No CAS ]

Reference： [1]Patent: WO2017/1660,2017,A1

42
[ 1227382-01-5 ]
C₂₉H₂₈ClN₅O₂ [ No CAS ]

Reference： [1]Patent: WO2017/1660,2017,A1

43
[ 70258-18-3 ]
[ 1227382-01-5 ]
tert-butyl 6-((6-chloropyridin-3-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In acetonitrile; at 70℃; for 16h;	A mixture of 2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester oxalate (400 mg, 1.39 mmol) And 2-chloro-5- (chloromethyl) analog (225 mg, 1.39 mmol) were dissolved in acetonitrile (50 mL), potassium carbonate (966 mg, 7.0 mmol) was added and reacted at 70 C for 16 hours.The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo To give the title compound as a pale yellow oil (400 mg, yield 89%).

Reference： [1]Patent: CN104910137,2017,B .Location in patent: Paragraph 0275; 0277-0279

44
[ 1227382-01-5 ]
2-((6-chloropyridin-3-yl)methyl)-2,6-diazaspiro[3.3]heptane [ No CAS ]

Reference： [1]Patent: CN104910137,2017,B

45
[ 1227382-01-5 ]
2-((6-chloropyridin-3-yl)methyl)-6-methyl-2,6-diazaspiro[3.3]heptane [ No CAS ]

Reference： [1]Patent: CN104910137,2017,B

46
[ 1227382-01-5 ]
5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)-N-(5-((6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl)pyridine-2-yl)pyridine-2-amine [ No CAS ]

Reference： [1]Patent: CN104910137,2017,B

47
[ 835616-61-0 ]
[ 1227382-01-5 ]
tert-butyl 6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine;	Step 6: tert-butyl 6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (300 mg, 1.09 mmol, 1.00 eq) and <strong>[1227382-01-5]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate; oxalic acid</strong> (317 mg, 0.65 mmol, 0.60 eq) in (methylsulfinyl)methane (5 mL) was added N,N-diisopropylethylamine (561 mg, 4.34 mmol, 4.00 eq) in one portion under nitrogen. The mixture was heated to 120 C. and stirred for 16 hours. The mixture was poured into ice-water (w/w=1/1) (30 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phase was washed with brine (50 mL3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was triturated by Petroleum ether: Ethyl acetate (1:1, 50 mL) to afford tert-butyl 6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (420 mg, 0.92 mmol, 85% yield) as a yellow solid.

Reference： [1]Patent: US2018/125821,2018,A1

48
[ 1227382-01-5 ]
5-(2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione formate [ No CAS ]

Reference： [1]Patent: US2018/125821,2018,A1

49
[ 1227382-01-5 ]
5-[6-[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Patent: US2018/125821,2018,A1

50
[ 1227382-01-5 ]
5-[6-[2,2-difluoro-5-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [ No CAS ]

Reference： [1]Patent: US2018/125821,2018,A1

51
[ 1227382-01-5 ]
5-[6-[2,2-difluoro-5-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione formate [ No CAS ]

Reference： [1]Patent: US2018/125821,2018,A1

52
[ 1227382-01-5 ]
C₂₁H₁₉FN₆O [ No CAS ]

Reference： [1]Patent: WO2018/200855,2018,A1

53
[ 1227382-01-5 ]
C₂₂H₂₁FN₆O [ No CAS ]

Reference： [1]Patent: WO2018/200855,2018,A1

54
[ 1227382-01-5 ]
4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-7-fluoro-6-methoxyquinoline [ No CAS ]
C₂₆H₂₇FN₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (370.8 mg, 1.29 mmol, 1.2 eq, oxalic acid salt) and tert-BuONa (515.1 mg, 5.36 mmol, 5 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times, then stirred at 20C for lh under N2 atmosphere. Compound 283 (400 mg, 1.07 mmol, 1 eq), Pd2(dba (196.3 mg, 214.37 umol, 0.2 eq), and XPhos (204.4 mg, 428.8 umol, 0.4 eq) were added and the mixture was stirred at 110C for 1 h under N2 atmosphere until there was no more starting material as indicated by LC/MS analysis. The reaction mixture was then concentrated under vacuum to give a residue, which was purified by prep-TLC (S1O2, 20: 1 DCM/MeOH) to provide compound 284 (285 mg, 511 umol, 48% yield, 88% purity) as a yellow solid.

Reference： [1]Patent: WO2018/200855,2018,A1 .Location in patent: Paragraph 00562

55
[ 1227382-01-5 ]
[ 202982-67-0 ]
tert-butyl 6-(4-chloro-3-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 98℃; for 18h;	Tris(dibenzylideneacetone)dipalladium(0) (47.6 mg, 0.05 mmol), 2- (dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (XPhos, 49.6 mg, 0.10 mmol), 4-chloro-3- fluoroiodobenzene (400 mg, 1.56 mmol, Aldrich), teri-butyl 2,6-diazaspiro[3.3]heptane-2- carboxylate, oxalic acid (300 mg, 1.04 mmol, ArkPharm), and cesium carbonate (1017 mg, 3.12 mmol) were suspended in dioxane (12 mL). The reaction mixture was stirred at 98 C for 18 hours and then cooled to ambient temperature. The crude reaction mixture was combined with 5 grams of Celite and concentrated under reduced pressure to a free flowing powder. The powder was directly purified by reversed-phase flash chromatography [Interchim PuriFlash C18XS 30 mupiiota 175 g column, flow rate 100 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.27 g, 0.83 mmol, 79 % yield).JH NMR (400 MHz, DMSO-de) delta ppm 7.29 (t, J = 8.6 Hz, 1H), 6.42 (dd, J = 11.7, 2.6 Hz, 1H), 6.25 (ddd, J = 8.8, 2.6, 0.8 Hz, 1H), 4.01 (s, 4H), 3.94 (s, 4H), 1.38 (s, 9H); MS (ESI+) m/z 327 (M+H)+.
79%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 98℃; for 18h;	Tris(dibenzylideneacetone)dipalladium(0) (47.6 mg, 0.05 mmol), 2-(dicyclohexylphosphino)-2?,4?,6?-triisopropylbiphenyl (XPhos, 49.6 mg, 0.10 mmol), 4-chloro-3- fluoroiodobenzene (400 mg, 1.56 mmol, Aldrich), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, oxalic acid,(300 mg, 1.04 mmol, ArkPharm) and cesium carbonate (1017 mg, 3.12 mmol) were suspended in dioxane (12 mL). The reaction mixture was stirred at 98 C for 18 hours and then cooled to ambient temperature. The crude reaction mixture was combined with 5 g of diatomaceous earth and concentrated under reduced pressure to a free flowing powder. The powder was directly purified by reversed-phase flash chromatography [Interchim PuriFlashC18XS 30 jim 175 g column, flow rate 100 mL/minute, 5-100% gradient of acetonitrile in buffer(0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] togive the title compound (0.27 g, 0.83 mmol, 79 % yield). 1H NMR (400 MHz, DMSO-d6) 5 ppm7.29 (t, J = 8.6 Hz, 1H), 6.42 (dd, J = 11.7, 2.6 Hz, 1H), 6.25 (ddd, J = 8.8, 2.6, 0.8 Hz, 1H), 4.01(s, 4H), 3.94 (s, 4H), 1.38 (s, 9H); MS (ESf?) m/z 327 (M+H).

Reference： [1]Patent: WO2019/90090,2019,A1 .Location in patent: Page/Page column 122; 123
[2]Patent: WO2019/90088,2019,A1 .Location in patent: Page/Page column 140-141

56
[ 1227382-01-5 ]
[ 202982-67-0 ]
2-(4-chloro-3-fluorophenoxy)-N-{3-[6-(4-chloro-3-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]bicyclo[1.1.1]pentan-1-yl}acetamide [ No CAS ]

Reference： [1]Patent: WO2019/90090,2019,A1

57
[ 779345-37-8 ]
[ 1227382-01-5 ]
[ 1360056-47-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; for 16h;	To a solution of 5-fluoro-2-nitropyridine (31, 14.2 g, 99.9 mmol, 2.7 equiv) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (18.0 g, 37.0 mmol, 1.0equiv) in DMSO (450 mL) was added DIPEA (31.6 mL, 182 mmol, 4.9 equiv). Themixture was stirred at 80 oC for 16 h. After cooling to roomtemperature, the reaction mixture was diluted with water (500 mL) and extractedwith EtOAc (300 mL x 3). The combined organic phases were washed with brine(150 mL), dried over anhydrous sodiumsulfate, filtered and concentrated underreduced pressure. Theresidue was purified by silica gel chromatography (MeOH / DCM =1 : 20) to afford titlecompound 32 (20.5 g, 86%) as ayellow solid. 1H NMR (400 MHz, CDCl3): delta 8.15 (d, J = 8.8 Hz, 1H), 7.66 (d, J= 2.8 Hz, 1H), 6.74 (dd, J = 8.8, 2.8 Hz, 1H), 4.24 (s, 4H), 4.17(s, 4H), 1.46 (s, 9H). LCMS M/Z [M+H]+ = 321.0.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2294 - 2301

58
[ 1227382-01-5 ]
N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2294 - 2301

59
[ 1227382-01-5 ]
(R)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyrimidin-2-amine [ No CAS ]
(S)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2294 - 2301

60
[ 1227382-01-5 ]
2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2294 - 2301

61
[ 1227382-01-5 ]
2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2294 - 2301

62
[ 1227382-01-5 ]
5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2294 - 2301

63
[ 1227382-01-5 ]
[ 202982-67-0 ]
2-(4-chloro-3-fluorophenyl)-2,6-diazaspiro[3.3]heptane [ No CAS ]

Reference： [1]Patent: WO2019/90088,2019,A1

64
[ 1227382-01-5 ]
dioxathion [ No CAS ]
tert-butyl 6-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-6-methylpyrazolo[1,5-a]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With tris-(dibenzylideneacetone)dipalladium(0);	Step 1: tert-butyl 6-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-6-methylpyrazolo[1,5-a]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (97a) To a solution of Intermediate 1 (0.40 g, 0.9 mmol) in toluene (10 mL) under air were successively added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (9a) (0.28 g, 1.4 mmol), sodium tert-butoxide (0.43 g, 4.5 mmol), RuPhos (90 mg, 0.2 mmol), and Pd2(dba)3 (91 mg, 0.1 mmol). The reaction mixture was heated at 100 C. for 1 h. After cooling to room temperature, the reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 97a (0.40 g, 80%) as a brown solid.