[ CAS No. 250275-15-1 ] {[proInfo.proName]}

Name: 250275-15-1|cis-2-Boc-Hexahydropyrrol[3,4-c]pyrrole|97%
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Quality Control of [ 250275-15-1 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 250275-15-1 ]

CAS No. :	250275-15-1	MDL No. :	MFCD04116224
Formula :	C₁₁H₂₀N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FYUVLZRRIRGSTE-DTORHVGOSA-N
M.W :	212.29	Pubchem ID :	1514452
Synonyms :

Calculated chemistry of [ 250275-15-1 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	66.0
TPSA :	41.57 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.07 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.59
Log Po/w (XLOGP3) :	0.74
Log Po/w (WLOGP) :	0.31
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	0.65
Consensus Log Po/w :	1.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.42
Solubility :	7.99 mg/ml ; 0.0376 mol/l
Class :	Very soluble
Log S (Ali) :	-1.19
Solubility :	13.6 mg/ml ; 0.0643 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.37
Solubility :	8.97 mg/ml ; 0.0423 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.99

Safety of [ 250275-15-1 ]

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

Application In Synthesis of [ 250275-15-1 ]

* 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.

Upstream synthesis route of [ 250275-15-1 ]
Downstream synthetic route of [ 250275-15-1 ]

[ 250275-15-1 ] Synthesis Path-Upstream 1~4

1
[ 370879-56-4 ]
[ 250275-15-1 ]

Yield	Reaction Conditions	Operation in experiment
66%	With 10 wt% Pd(OH)2 on carbon; hydrogen In methanol at 60℃;	To a solution of (3 aR,6a5)-tert-butyl 5 -benzylhexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)carboxylate (5 g, 16.5 mmol) in MeOH (50 mL) was added Pd(OH)2/C (10 percent) (0.5 g). The reaction mixture was stirred at 60 °C overnight under an H2 atmosphere at 60 psi and then cooled to ambient temperature. The reaction mixture was filtered through Celite and the filtrate was evaporated to provide (3 aR,6aS)-tert-butyl hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate get as a colorless oil (2.3 g, 66 percent).
66%	With 10% palladium hydroxide on charcoal; hydrogen In methanol at 60℃;	Step 4 To a solution of (3aR,6aS)-tert-butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (5 g, 16.5 mmol) in methanol (50 mL) was added Pd(OH)₂/C (10 percent) (0.5 g). The mixture was stirred at 60 °C overnight under hydrogen atmosphere at 60 psi before cooling to ambient temperature. The reaction mixture was filtered by celite. The filtrated solution was evaporated under vacuum to obtain (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate as a colorless oil (2.3 g, 66 percent).

Reference： [1] Patent: US2002/19388, 2002, A1,
[2] Patent: WO2015/120049, 2015, A1, . Location in patent: Page/Page column 139; 140
[3] Patent: WO2016/191172, 2016, A1, . Location in patent: Page/Page column 86
[4] Patent: US2009/281118, 2009, A1, . Location in patent: Page/Page column 10
[5] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4126 - 4141
[6] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5620 - 5636

2
[ 172739-04-7 ]
[ 250275-15-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5620 - 5636
[2] Patent: WO2015/120049, 2015, A1,
[3] Patent: WO2016/191172, 2016, A1,

3
[ 370879-53-1 ]
[ 250275-15-1 ]

Reference： [1] Patent: WO2015/120049, 2015, A1,
[2] Patent: WO2016/191172, 2016, A1,

4
[ 24424-99-5 ]
[ 250275-15-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5620 - 5636

[ 250275-15-1 ] Synthesis Path-Downstream 1~88

1
[ 250275-15-1 ]
8-(5-tert-butoxycarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4202 - 4213

2
[ 250275-15-1 ]
1-cyclopropyl-8-(cis-3,7-diaza-3-bicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4(H)-4-oxoquinolizine-3-carboxylic acid hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4202 - 4213

3
[ 10517-21-2 ]
[ 250275-15-1 ]
C₂₀H₂₄ClN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl acetamide; at 20℃; for 16h;	A solution of 5-chloro-1H-indole-2-carboxylic acid (100 mg, 0.51 mmol) in N,N-dimethylacetamide (5 ml) was treated with <strong>[250275-15-1]tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate</strong> (108 mg, 0.51 mmol) and O-benzotriazo-1-yl-N,N,N'N'-tetramethyluronium hexafluorophosphate (256 mg, 0.67 mmol) and the resulting solution left to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and water (20 ml) and the organic phase separated, dried (sodium sulphate) and the solvent reduced in vacuo. The residue was treated with a 1M solution of HCl in methanol (15 ml) and left to stir at room temperature for 16 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluding with dichloromethane:methanol:880 ammonia (99:1:0.1 changing to 90:10:1, by volume) to give the title compound as a pale yellow solid (42 mg). 1H NMR (400 MHz, DMSOd6): delta 11.77 (1H, bs), 7.69 (1H, bs), 7.45 (1H, d), 7.20 (1H, d), 6.93 (1H, s), 4.13-3.45 (4H, m), 2.99-2.63 (6H, m), 2.52 (3H, s) ppm (poorly resolved spectrum). MS (APCI) m/z 290/292 [M+H]+, 288/290 [M-H]-

Reference： [1]Patent: US2006/111416,2006,A1 .Location in patent: Page/Page column 16

4
[ 39811-14-8 ]
[ 250275-15-1 ]
C₁₉H₂₃ClN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl acetamide; at 20℃; for 16h;	A solution of 5-chloro-1H-benzimidazole-2-carboxylic acid (preparation 8) (100 mg, 0.50 mmol) in N,N-dimethylacetamide (5 ml) was treated with <strong>[250275-15-1]tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate</strong> (108 mg, 0.51 mmol) and O-benzotriazo-1-yl-N,N,N'N'-tetramethyluronium hexafluorophosphate (256 mg, 0.67 mmol) and the resulting solution left to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and water (20 ml) and the organic phase separated, dried (sodium sulphate) and the solvent reduced in vacuo. The residue was treated with a 1M solution of HCl in methanol (15 ml) and left to stir at room temperature for 16 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluding with dichloromethane:methanol:880 ammonia (99:1:0.1 changing to 90:10:1, by volume) to give the title compound as a colourless solid (50 mg). 1H NMR (400 MHz, CD3OD): delta 7.69-7.65 (2H, m), 7.34(1H, d), 4.45-4.40 (1H, m), 4.24-4.20 (1H, m), 3.99-3.94 (1H, m), 3.71-3.66 (1H, m), 3.19-3.11 (2H, m), 3.09-2.92 (2H, m), 2.83-2.79 (2H, m) ppm. MS (APCI) m/z 291/293 [M+H]+, 289/291 [M-H]-

Reference： [1]Patent: US2006/111416,2006,A1 .Location in patent: Page/Page column 15

5
[ 370879-56-4 ]
[ 250275-15-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	palladium-carbon; In ethanol;	EXAMPLE 1D tert-butyl cis-hexahydropyrrolo [3,4-c]pyrrole-2(1H)-carboxylate The product from Example 1C (4.89 g, 16.2 mmol) in ethanol (150 mL) was treated with 10% Pd/C (0.45 g) at ambient temperature under a hydrogen (1 atm) overnight. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was passed through a small plug of silica gel with ether to provide the title compound as a white solid (3.01 g, 88% yield). 1H NMR (CDCl3, 300 MHz) delta 1.46 (s, 9H), 2.75 (m, 4H), 3.09 (m, 2H), 3.20 (br d, J=11 Hz, 2H), 3.54 (m, 2H); MS (DCI/NH3) m/z 213 (M+H)+.
66%	With 10 wt% Pd(OH)2 on carbon; hydrogen; In methanol; at 60℃; under 3102.97 Torr;	To a solution of (3 aR,6a5)-tert-butyl 5 -benzylhexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)carboxylate (5 g, 16.5 mmol) in MeOH (50 mL) was added Pd(OH)2/C (10 %) (0.5 g). The reaction mixture was stirred at 60 C overnight under an H2 atmosphere at 60 psi and then cooled to ambient temperature. The reaction mixture was filtered through Celite and the filtrate was evaporated to provide (3 aR,6aS)-tert-butyl hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate get as a colorless oil (2.3 g, 66 %).
66%	With 10% palladium hydroxide on charcoal; hydrogen; In methanol; at 60℃; under 3102.97 Torr;	Step 4 To a solution of (3aR,6aS)-tert-butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (5 g, 16.5 mmol) in methanol (50 mL) was added Pd(OH)2/C (10 %) (0.5 g). The mixture was stirred at 60 C overnight under hydrogen atmosphere at 60 psi before cooling to ambient temperature. The reaction mixture was filtered by celite. The filtrated solution was evaporated under vacuum to obtain (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate as a colorless oil (2.3 g, 66 %).

With hydrogen;Pd(OH)2/C; In methanol; at 50℃; under 3102.97 Torr; for 4h;

Example 1C; (3aR,6as)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; The crude product from Example 1B (64.70 g, 0.212 mol) from Example 1B was dissolved in methanol (250 mL). Pearlman's catalyst (Pd(OH)2, 20% on C, 6.5 g) was added, and the mixture was agitated at 50 C. under hydrogen (60 psi) for 4 h. The mixture was cooled to room temperature, filtered under nitrogen to remove the catalyst, and the filtrate was concentrated under vacuum to a pale oil (46.55 g). This was dissolved in ether (150 mL), applied to a column of silica gel (300 g), and eluted with ether (1 L). The silica was then eluted with methanol (2 L) and the methanol fraction was concentrated under vacuum. The residue was taken up in EtOAc (500 mL), filtered to remove insoluble material, and concentrated under vacuum to provide the titled compound as an off-white solid (33.84 g, 75% for steps B and C), of sufficient purity for use in subsequent operations. 1H NMR (300 MHz, CD3OD) delta ppm 1.45 (s, 9H), 2.65 (dd, J=11.5, 4.4 Hz, 2H), 2.75-2.89 (m, 2H), 3.01-3.11 (m, 2H), 3.20 (dd, J=11.5, 3.7 Hz, 2H), 3.47-3.58 (m, 2H).

Reference： [1]Patent: US2002/19388,2002,A1
[2]Patent: WO2015/120049,2015,A1 .Location in patent: Page/Page column 139; 140
[3]Patent: WO2016/191172,2016,A1 .Location in patent: Page/Page column 86
[4]Patent: US2009/281118,2009,A1 .Location in patent: Page/Page column 10
[5]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141
[6]Journal of Medicinal Chemistry,2015,vol. 58,p. 5620 - 5636

6
[ 24186-78-5 ]
[ 250275-15-1 ]
[ 946488-67-1 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃;	EXAMPLE 31; 3,3-Difluoro-cyclobutanecarboxylic Acid ((S)-3-{5-[2,4-dimethyl-6-oxo-1-(2,2,2-trifluoro-ethyl)-1,6-dihydro-pyridine-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl-propyl)-amide (III-23); step 1-; A solution of 68b (4.44 g), 2, (4.7 g), TEA (5.6 g), TBTU (9.25 g) in DCM and was stirred at RT overnight. The reaction mixture was poured into water and extracted with DCM, dried (Na2SO4), filtered and volatiles removed in vacuo. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0-6% MeOH containing 0.5% NH4OH) to afford 5.73 g of 139.

Reference： [1]Patent: US2007/191335,2007,A1 .Location in patent: Page/Page column 46

7
[ 1241977-17-2 ]
[ 250275-15-1 ]
[ 946488-53-5 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; for 3h;	step 4-; To a mixture of 59 (5.01 mmol) and TEA (3 mL) in DCM (25 mL) was added 11b (1.15 g) followed by TBTU (1.9 g). The reaction was stirred for 3 h and partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified via SiO2 chromatography eluting with DCM/MeOH/NH4OH to afford 2.04 g of 60a.

Reference： [1]Patent: US2007/191335,2007,A1 .Location in patent: Page/Page column 30-31

8
[ 4774-14-5 ]
[ 250275-15-1 ]
[ 1194687-82-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 23h;	Example 19; (3aR,6aS)-2-(6-(3,5-difluorobenzyloxy)pyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole; Example 19A; (3aR,6aS)-tert-butyl 5-(6-chloropyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; 2,6-dichloropyrazine (1.02 g, 6.85 mmol) was dissolved in DMSO (7 mL). The product from Example 1C (1.61 g, 7.58 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.61 mmol) were added to the reaction mixture. The reaction was stirred at ambient temperature for 23 h. The reaction was diluted with water (200 mL) and extracted with CH2Cl2 (4×100 mL). The organic extracts were combined and washed with and brine (150 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc, Rf=0.38) to afford the title compound as a white solid (1.99 g, 89%). MS (DCI/NH3) m/z 325 (M+H)+.

Reference： [1]Patent: US2009/281118,2009,A1 .Location in patent: Page/Page column 15-16

9
[ 20986-40-7 ]
[ 250275-15-1 ]
[ 1194688-52-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 72h;	Example 33; 5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-(trifluoromethyl)benzyl)nicotinamide; Example 33A; (3aR,6aS)-tert-butyl 5-(5-(ethoxycarbonyl)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; A suspension of the product from Example 1C (2.00 g, 9.42 mmol), ethyl 5-bromonicotinate (2.80 g, 12.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (259 mg, 0.283 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (491 mg, 0.848 mmol) and cesium carbonate (4.91 g, 15.1 mmol) in anhydrous dioxane (50 mL) were heated at 90 C. for 72 hours. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated and the residue was purified by silica gel chromatography (eluted with 50% EtOAc in hexane) to afford the title compound (3.2 g, 94%). MS (APCI) m/z 362 (M+H)+.

Reference： [1]Patent: US2009/281118,2009,A1 .Location in patent: Page/Page column 20
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 7678 - 7692

10
[ 625-92-3 ]
[ 250275-15-1 ]
[ 1173179-62-8 ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 22h;Product distribution / selectivity;	Example 26; (3aR,6aS)-2-(5-styrylpyridin-3-yl)octahydropyrrolo[3,4-c]pyrrole; Example 26A; (3aR,6aS)-tert-butyl 5-(5-bromopyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; The product from Example 1C (1.01 g, 4.76 mmol) and 3,5-dibromopyridine (1.22 g, 5.15 mmol) were dissolved in toluene (20 mL). Pd2(dba)3 (86.8 mg, 0.095 mmol), BINAP (175.0 mg, 0.28 mmol) and sodium tert-butoxide (665.4 mg, 1.460 mmol) were added to the reaction mixture. The reaction was heated to 80 C. for 22 h, then allowed to cool to ambient temperature, diluted with water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic extracts were combined and washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc, Rr=0.33) to afford the title compound as a white solid (1.17 g, 67%). MS (DCI/NH3) m/z 370 (M+H)+.

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141
[2]Patent: US2009/281118,2009,A1 .Location in patent: Page/Page column 18

11
[ 250275-15-1 ]
[ 23611-75-8 ]
[ 1194686-95-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;	Example 1F; (3aR,6aS)-tert-butyl 5-(6-(methoxycarbonyl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; The product from Example 1E (1.74 g, 10.08 mmol) was dissolved in DMSO (10 mL). The product from Example 1C (2.29 g, 10.79 mmol) and sodium carbonate (1.61 g, 15.19 mmol) were added to the reaction mixture. The reaction was stirred at 120 C. for 16 h. The reaction was then allowed to cool to ambient temperature, diluted with water (100 mL) and extracted with CH2Cl2 (4×100 mL). The organic extracts were combined and washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc, Rf=0.36) to afford the title compound as a thick oil that slowly solidified (2.78 g, 78%). MS (DCI/NH3) m/z 349 (M+H)+.

Reference： [1]Patent: US2009/281118,2009,A1 .Location in patent: Page/Page column 11
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 7678 - 7692

12
[ 1194688-12-4 ]
[ 250275-15-1 ]
[ 1194688-13-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 18h;	Example 25B; (3aR,6aS)-tert-butyl 5-(5-(benzylamino)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; The product from Example 25A (201.7 mg, 0.77 mmol) was dissolved in tolulene (7.7 mL). To the reaction mixture was added the product from Example 1C (204.6 mg, 0.96 mmol), Pd2(dba)3 (27.0 mg, 0.029 mmol), BINAP (60.7 mg, 0.097 mg) and sodium tert-butoxide (105.3 mg, 1.10 mmol). The reaction was heated to 90 C. overnight (18 h), then allowed to cool to ambient temperature, diluted with water (100 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts were combined and washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC on a Waters Nova-PakHR C18 6 mum 60 Prep-Pak cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 min at a flow rate of 70 mL/min to provide the title compound MS (DCI/NH3) m/z 395 (M+H)+.

Reference： [1]Patent: US2009/281118,2009,A1 .Location in patent: Page/Page column 17

13
[ 1194688-40-8 ]
[ 250275-15-1 ]
[ 1194688-41-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In toluene; at 95℃; for 4h;Inert atmosphere;	Example 31B; (3aR,6aS)-tert-butyl 5-(5-(2-methylbenzylcarbamoyl)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; The product from Example 1C (80 mg, 0.38 mmol), the product from Example 31A (155 mg, 0.51 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (34 mg, 0.034 mmol), tris(dibenzylideneacetone)dipalladium(0) (10.4 mg, 0.011 mmol), and sodium tert-butoxide (54.2 mg, 0.054 mmol) were combined with toluene (5 mL). The suspension was evacuated and purged with nitrogen. The mixture was heated at 95 C. under nitrogen for 4 h. The residue was partitioned between saturated sodium bicarbonate solution(aq) (100 mL) and EtOAc (2×50 mL). The combined organic extract was washed with brine (100 mL), dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography (eluted with EtOAc) on silica to provide the title compound (150 mg, 91%). MS (APCI) m/z 437 (M+H)+.

Reference： [1]Patent: US2009/281118,2009,A1 .Location in patent: Page/Page column 19
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 7678 - 7692

14
[ 1186515-28-5 ]
[ 250275-15-1 ]
C₃₃H₃₈N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 16h;	To a solution of 4'-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3- carboxylic acid (25 mg, 0.069 mmol) in NN-dimethylformamide (1 mL) were added (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (30 mg, 0.14 mmol), NNN',N'-tetramethyl-O-(7- azabenzotriazol-l-yl)uronium hexafluorophosphate (60 mg, 0.16 mmol) and N,N-diisopropylethylamine (100 muL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25 0C. The reaction mixture was purified by preparative HPLC to yield Boc protected product as a white solid, which was dissolved in methylene chloride (3.0 mL) and trifluoroacetic acid (0.20 mL, 2.6 mmol) was added. The reaction mixture was stirred at rt overnight. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (100 x 21.2 mm C18 column, 20-60% MeCN/water[10 mM Et2NH]) to afford the product as a white foam.LC-MS: 455.4 [M+l]+; 1H NMR (400 MHz, DMSO-d6): 9.26 (t, IH, J = 5.3 Hz), 8.44 (bs, IH), 8.21 (bs, IH), 7.95-7.80 (m, 2H), 7.70-7.60 (m, 3H), 7.31 (d, 2H, J = 7.9 Hz), 7.22 (d, IH, J = 7.9 Hz), 4.48 (d, IH, J = 5.5 Hz), 3.90-3.15 (m, 4H), 2.90 (m, IH), 2.85-2.60 (m, 4H), 2.50-2.30 (m, 2H), 2.44 (s, 3H), 2.36 (s, 3H).

Reference： [1]Patent: WO2009/110985,2009,A2 .Location in patent: Page/Page column 98-99

15
[ 1001065-84-4 ]
[ 250275-15-1 ]
C₂₀H₂₆ClN₅O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7855 - 7865

16
[ 1020254-18-5 ]
[ 250275-15-1 ]
[ 1192361-94-6 ]

Yield	Reaction Conditions	Operation in experiment
83%		A solution of sodium tert-butoxide (98 mg, 1 ,017 mmol) and (3aR,6aS)-tert-butyl hexa- hydropyrrolo[3,4-c]pyrrole-2(1 H)-carboxylate (95 mg, 0.436 mmol) in THF (3 ml.) was stirred under nitrogen. To this was added 1 ,1 '-bis(diphenylphosphino)ferrocene (25 mg, 0.05 mmol), Pd2(DBA)3 (12 mg, 0.02 mmol) and 1-(7-bromoquinolin-4-yl)-3- (pyrazin-2-yl)urea (100 mg, 0.291 mmol). The mixture was then heated at reflux for 12 h before partitioning between CH2CI2 and water. The mixture was filtered through Celite and the organic phase was separated. The water phase was extracted twice with CH2CI2 and the combined extracts dried (Na2SO4), filtered and concentrated in vacuo to provide the crude material, which was purified by flash chromatography to give the title compound (127 mg, 83%) as a white solid.1H-NMR (DMSO, 400 MHz) delta 1.40 (s, 9H), 3.05 (s, 2H), 3.23 (s, 2H), 3.32 (m, 2H), 3.65 (m, 4H), 6.86 (s, 1 H), 7.20 (d, 1 H), 7.92 (d, 1 H), 8.00 (d, 1 H), 8.33 (s, 1 H), 8.43 (s, 1 H), 8.56 (d, 1 H), 9.09 (s, 1 H), 10.20 (m, 2H). MS (APCI+) m/z 476.3 (M+H+, 100%).

Reference： [1]Patent: WO2009/130317,2009,A1 .Location in patent: Page/Page column 53

17
[ 109-09-1 ]
[ 250275-15-1 ]
[ 1173179-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

18
[ 626-55-1 ]
[ 250275-15-1 ]
t-butyl cis-5-(3-pyridinyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

19
[ 370879-78-0 ]
[ 250275-15-1 ]
[ 370879-79-1 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

20
[ 53939-30-3 ]
[ 250275-15-1 ]
[ 370879-64-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

21
[ 624-28-2 ]
[ 250275-15-1 ]
[ 1173179-66-2 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

22
[ 141-30-0 ]
[ 250275-15-1 ]
[ 1173179-68-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 2h;	To a solution of 3,6-dichloropyridazine (462 mg, 3.10 mmol) in n-butanol (8 ml) was addedDIPEA (1.354 ml, 7.75 mmol) and (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1 H)carboxylate(658 mg, 3.1 mmol). The reaction mixture was heated at 120oc for 2 hour, and then10 diluted with DCM and water. The organic layer was separated and concentrated to a brownish oil,which was purified by silica gel chromatography (0-25% EtOAc/DCM) to afford (3aR,6aS)-tert-butyl5-(6-chloropyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1 H)-carboxylate (730 mg, 2.180 mmol,70% yield), MS(M+1) = 325.2.

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 11021 - 11036
[2]Patent: WO2014/28459,2014,A1 .Location in patent: Page/Page column 179
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

23
[ 50720-12-2 ]
[ 250275-15-1 ]
tert-butyl cis-5-(5-methoxy-3-pyridinyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

24
[ 17117-17-8 ]
[ 250275-15-1 ]
tert-butyl cis-5-(5-ethoxy-3-pyridinyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

25
[ 20375-65-9 ]
[ 250275-15-1 ]
[ 1173179-74-2 ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 105℃; for 21h;	First Step Synthesis of Tert-butyl cis-5-(6-phenylpyridazine-3-yl)-hexahydro-pyrrolo[3,4-c]-pyrrole-2(1H)-carboxylate To a solution (5.0 mL) of 3-chloro-6-phenylpyridazine (0.90 g, 4.7 mmol) in dimethyl sulfoxide, tert-butyl cis-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.0 g, 4.7 mmol) and diisopropylethylamine (2.9 mL, 16 mmol) were added, and the resulting mixture was stirred at 105 C. Twenty one hours later, the reaction solution was cooled to 40 C., water was added thereto, and the resultant was stirred. One hour later, the obtained solid was filtered off, washed with water and diethyl ether, and dried to obtain the title compound (0.98 g; 57%) as a brown solid. 1H-NMR (400 MHz, CD3OD): 1.46 (9H, s), 3.07-3.16 (2H, m), 3.30-3.35 (2H, m), 3.46-3.52 (2H, m), 3.62-3.72 (2H, m), 3.77-3.84 (2H, m), 7.00-7.05 (1H, m), 7.37-7.43 (1H, m), 7.43-7.50 (2H, m), 7.81-7.86 (1H, m), 7.89-7.94 (2H, m).MS (ESI) [M+H]+367

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141
[2]Patent: US2014/128606,2014,A1 .Location in patent: Paragraph 0156; 0157; 0158; 0159; 0160; 0161

26
[ 1120-87-2 ]
[ 250275-15-1 ]
[ 1173179-86-6 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

27
[ 106-37-6 ]
[ 250275-15-1 ]
[ 1173179-67-3 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

28
[ 200064-13-7 ]
[ 250275-15-1 ]
[ 1173179-64-0 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

29
[ 212332-40-6 ]
[ 250275-15-1 ]
[ 1173179-63-9 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

30
[ 130722-95-1 ]
[ 250275-15-1 ]
t-butyl cis-5-[5-(benzyloxy)-3-pyridinyl]hexahydropyrrolo-[3,4-c]pyrrole-2(1H)-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4126 - 4141

31
[ 49608-01-7 ]
[ 250275-15-1 ]
C₁₉H₂₇N₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6657 - 6660

32
[ 148550-51-0 ]
[ 250275-15-1 ]
[ 1286279-99-9 ]