[ CAS No. 54221-37-3 ] {[proInfo.proName]}

Name: 54221-37-3|(2R,5S)-rel-Diethyl 2,5-dibromohexanedioate|98%
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SKU: A855502
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Quality Control of [ 54221-37-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 54221-37-3 ]

Product Details of [ 54221-37-3 ]

CAS No. :	54221-37-3	MDL No. :	MFCD00075379
Formula :	C₁₀H₁₆Br₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UBCNJHBDCUBIPB-OCAPTIKFSA-N
M.W :	360.04	Pubchem ID :	6994100
Synonyms :

Calculated chemistry of [ 54221-37-3 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	9
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	68.49
TPSA :	52.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.3 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.74
Log Po/w (XLOGP3) :	3.1
Log Po/w (WLOGP) :	2.42
Log Po/w (MLOGP) :	2.4
Log Po/w (SILICOS-IT) :	2.9
Consensus Log Po/w :	2.71

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.43
Solubility :	0.133 mg/ml ; 0.00037 mol/l
Class :	Soluble
Log S (Ali) :	-3.87
Solubility :	0.0483 mg/ml ; 0.000134 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.41
Solubility :	0.141 mg/ml ; 0.000392 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.49

Safety of [ 54221-37-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P233-P260-P261-P264-P271-P280-P302+P352-P304-P304+P340-P305+P351+P338-P312-P321-P332+P313-P337+P313-P340-P362-P403-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 54221-37-3 ]

* 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 [ 54221-37-3 ]
Downstream synthetic route of [ 54221-37-3 ]

[ 54221-37-3 ] Synthesis Path-Upstream 1~2

1
[ 54221-37-3 ]
[ 149771-44-8 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902
[2] Patent: US9404081, 2016, B2,

2
[ 54221-37-3 ]
[ 149771-43-7 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902
[2] Chinese Chemical Letters, 2011, vol. 22, # 5, p. 523 - 526
[3] Patent: US9404081, 2016, B2,

[ 54221-37-3 ] Synthesis Path-Downstream 1~53

1
[ 54221-37-3 ]
[ 1001-53-2 ]
1-(2-acetylamino-ethyl)-pyrrolidine-2r,5c-dicarboxylic acid diethyl ester [ No CAS ]

Reference： [1]Patent: US2596099,1946,

2
[ 54221-37-3 ]
[ 143-33-9 ]
[ 412346-70-4 ]

Yield	Reaction Conditions	Operation in experiment
	With ethanol

Reference： [1]Fuson; Kao [Journal of the American Chemical Society, 1929, vol. 51, p. 1538]
[2]Schuikina [Zhurnal Obshchei Khimii, 1943, vol. 13, p. 373,376][Chem.Abstr., 1944, p. 3258]

3
[ 54221-37-3 ]
[ 75-04-7 ]
1-ethyl-pyrrolidine-2r,5c-dicarboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzene at 100℃;

Reference： [1]Fuson; Lundquist [Journal of the American Chemical Society, 1938, vol. 60, p. 1889,1891]

4
[ 54221-37-3 ]
[ 109-89-7 ]
1-ethyl-pyrrolidine-2r,5c-dicarboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ethanol Erhitzen des hierbei erhaltenen Reaktionsprodukts unter vermindertem Druck;
	With acetone Erhitzen des hierbei erhaltenen Reaktionsprodukts unter vermindertem Druck;

Reference： [1]Fuson; Lundquist [Journal of the American Chemical Society, 1938, vol. 60, p. 1889,1891]
[2]Fuson; Lundquist [Journal of the American Chemical Society, 1938, vol. 60, p. 1889,1891]

5
[ 54221-37-3 ]
[ 74-89-5 ]
[ 52321-02-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran at 0 - 20℃; for 18h;
91%	In tetrahydrofuran at 0 - 20℃;	Diethyl mezo-2,5-dibromoadipate (101.7 g; 0.283 mol) was dissolved by heating under argon in THF (400 ml) and then cooled to 0°C. To the obtained so- lution a pre-cooled solution of methylamine (27.3 g; 0.88 mol) in THF (150 ml) was added and the mixture was stirred at room temperature for 18 hours. The separated crystalline material was filtered off, the filtrate concentrated and the residue chromatographed on a silica gel column (10 cm long) with hexane-ethyl acetate 4:1 as eluent to afford 58.9 g (91 %).1H NMR (300 MHz, CDCI3): 1.15 (t, 6H); 1.9-2.0 (m, 4H); 2.38 (s, 3H); 2.99 (m, 2H); 4.07 (q, 4H). 13C NMR (75 MHz, CDCI3): 13.98; 27.68; 40.82; 60.39; 67.93; 68.06; 172.32.
	With potassium iodide; benzene

Reference： [1]Paliulis, Osvaldas; Peters, Dan; Miknius, Linas; Sackus, Algirdas [Organic Preparations and Procedures International, 2007, vol. 39, # 1, p. 86 - 90]
[2]Current Patent Assignee: NEUROSEARCH A/S - WO2009/109517, 2009, A1 Location in patent: Page/Page column 17-18
[3]Current Patent Assignee: PFIZER INC - US2596099, 1946, A

6
[ 54221-37-3 ]
[ 100-46-9 ]
[ 17740-40-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	In toluene for 4h; Reflux;
	With potassium <i>tert</i>-butylate In tert-butyl methyl ether at 55℃; for 24h;

Reference： [1]Location in patent: body text Huang, Long Jiang; Teng, Da Wei [Chinese Chemical Letters, 2011, vol. 22, # 5, p. 523 - 526]
[2]v. Braun; Seemann [Chemische Berichte, 1923, vol. 56, p. 1841]
[3]Brown, Maria S.; Caporello, Michaella A.; Goetz, Adam E.; Johnson, Amber M.; Jones, Kris N.; Knopf, Kevin M.; Kulkarni, Samir A.; Lee, Taegyo; Li, Bryan; Lu, Cuong V.; Magano, Javier; Puchlopek-Dermenci, Angela L. A.; Reyes, Giselle P.; Ruggeri, Sally Gut; Wei, Lulin; Weisenburger, Gerald A.; Wisdom, Richard A.; Zhang, Mengtan [Organic Process Research and Development, 2021, vol. 25, # 6, p. 1419 - 1430]

7
[ 54221-37-3 ]
[ 100-46-9 ]
[ 52321-06-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	In benzene	3.A A. A. Diethyl meso-1-Benzyl-2,5-pyrrolidinedicarboxylate A solution of Diethyl meso-2,5-dibromoadipate (50 g, 139 mmol) in benzene (150 mL) was heated to reflux. Then heating was discontinued and benzylamine (50 mL) was added under stirring in 1 h. At the end of the addition, the mixture was refluxed for 20h. After cooling down, the hydrobromide salt was filtered off and washed with benzene, and the benzene solution was evaporated. The residue was distilled under reduced pressure (180-190° C./0.3 mmHg) to give a product (39.9 g, 94%) as a yellow oil. 1H NMR (CDCl3, 270 MHz) δ: 7.35-7.24 (m, 5H), 4.15-3.97 (m, 4H), 3.93 (s, 2H), 2.10-2,05 (m, 4H), 1.24 (t, J =7.1 Hz, 3H), 1.19 (t, J =7.3 Hz, 3H)
82%	In toluene for 72h; Heating / reflux;	2.iv iv) iv) (+-)-diethyl (2R,5S)-1-benzylpyrrolidine-2,5-dicarboxylate Benzyl amine (6 mL, 54 mmol) was added a solution of diethyl meso-2,5-dibromoadipate (6.5 g, 18 mmol) in toluene (100 mL) at 68° C. and the mixture was heated for 3 days. After cooling to room temperature, the product was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was dried and concentrated in vacuo. Flash chromatography (silica) afforded the title compound (4.5 g, 82%).
75%	With potassium carbonate In water; toluene at 110℃;	12.1 Step 1: Preparation of (2S,5R)-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (2): The mixture of (2R,5S)-diethyl 2,5-dibromohexanedioate (1) (100 g, 278 mmol), BnNH2 (44.6 g, 416 mmol) and K2C03 (76.84 g, 556 mmol) in toluene/H20 was stirred at 110°C for overnight, monitored by TLC. The mixture was extracted with EtOAc, washed with water and brine and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S,5R)-diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (2) (63.75 g, 75%) as a white oil.LC-MS (ESI) m/z = 306 [M+H].

74%	In benzene Heating;
72%	In toluene at 85℃; for 16h;	11 To a stirred solution of Diethyl meso-2,5-dibromoadipate (LXIV, 0.00069 mol, 250 mg) in toluene (5 mL) was added benzylamine (0.0021 mol, 0.234 mL) and the reaction mixture was heated at 85° C. for 16 h. After completion of the reaction (checked by TLC), the reaction mixture was cooled and the formed solid was filtered. The filtrate was concentrated under reduced pressure to leave the product as pale yellow liquid. The residue was purified by column chromatography (silica gel, 60-120 mesh; EA-Hexane, 2:8) to afford Diethyl pyrrolidine-2,5-carboxylate in 72% yield.
65%	In toluene for 24h; Heating;
46.9%	With potassium carbonate In toluene at 100℃; for 16h;	1.2 Step 2: To a stirred solution of compound 2 (400g, 11 17.6mmol, 1 eq) in toluene (800ml_) was added benzyl amine (239g, 2235.0mmol, 2eq) followed by K2CO3 (465g, 3351 mmol, 3eq) at RT and resulted reaction mixture was heated at 100 °C for 16h. The reaction was monitored by TLC. TLC analysis indicated formation of a non-polar spot. The reaction mixture was diluted with ice water and extracted with ethyl acetate (2x800mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 100-200) using 10% ethyl acetate in petroleum ether as an eluent to give compound 3 (160g, 46.9% yield) as a colorless liquid. LCMS: m/z 305.93 (M):
	With potassium iodide; benzene
	In toluene at 85℃;
	In toluene at 80℃; for 16h;
		120 Example 120. (2R,55)-l-(Phenylmethyl)-2,5-pyrrolidinedicarboxylic Acid, Diethyl Ester (120); [0506] In accordance with Stephen W. Wright et al, (J. Med. Chem., 2006, 49, 3068), diethyl /nesø-2,5-dibromoadipate (2.38 g, 6.60 mmol) was treated with benzylamine (2.24 mL, 20.5 mmol, d 0.981) to afford the title product as a clear oil: 1H NMR δH (250 MHz, CDCl3) 7.09-7.32 (5H, m), 3.95 (4H, q), 3.87 (2H, s), 3.35 (2H, m), 2.00 (4H, m), 1.12 (6H, t).
	With sodium phosphate In water; toluene at 75℃; for 48h;

Reference： [1]Current Patent Assignee: PFIZER INC - US2002/128271, 2002, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - US2007/37816, 2007, A1 Location in patent: Page/Page column 25
[3]Current Patent Assignee: TB ALLIANCE INC - WO2017/15106, 2017, A1 Location in patent: Page/Page column 118; 119
[4]Fraenkel, Gideon; Duncan, Joseph H.; Wang, Jinhai [Journal of the American Chemical Society, 1999, vol. 121, # 2, p. 432 - 443]
[5]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9404081, 2016, B2 Location in patent: Page/Page column 177-178
[6]Liu, Hong; Cheng, Tie-Ming; Zhang, Hong-Mei; Li, Run-Tao [Archiv der Pharmazie, 2003, vol. 336, # 11, p. 510 - 513]
[7]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/153080, 2019, A1 Location in patent: Paragraph 00478
[8]Current Patent Assignee: PFIZER INC - US2596099, 1946, A
[9]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]
[10]Wright, Stephen W.; Ammirati, Mark J.; Andrews, Kim M.; Brodeur, Anne M.; Danley, Dennis E.; Doran, Shawn D.; Lillquist, Jay S.; McClure, Lester D.; McPherson, R. Kirk; Orena, Stephen J.; Parker, Janice C.; Polivkova, Jana; Qiu, Xiayang; Soeller, Walter C.; Soglia, Carolyn B.; Treadway, Judith L.; VanVolkenburg, Maria A.; Wang, Hong; Wilder, Donald C.; Olson, Thanh V. [Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3068 - 3076]
[11]Current Patent Assignee: EVOTEC AG - WO2008/134035, 2008, A1 Location in patent: Page/Page column 191-192
[12]Brown, Maria S.; Caporello, Michaella A.; Goetz, Adam E.; Johnson, Amber M.; Jones, Kris N.; Knopf, Kevin M.; Kulkarni, Samir A.; Lee, Taegyo; Li, Bryan; Lu, Cuong V.; Magano, Javier; Puchlopek-Dermenci, Angela L. A.; Reyes, Giselle P.; Ruggeri, Sally Gut; Wei, Lulin; Weisenburger, Gerald A.; Wisdom, Richard A.; Zhang, Mengtan [Organic Process Research and Development, 2021, vol. 25, # 6, p. 1419 - 1430]

8
[ 627-37-2 ]
[ 54221-37-3 ]
(2S,5S)-2-Allyl-1-methyl-pyrrolidine-2,5-dicarboxylic acid diethyl ester [ No CAS ]
(2S,5R)-2-Allyl-1-methyl-pyrrolidine-2,5-dicarboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]

9
[ 54221-37-3 ]
2,5-bis-(4-butoxybenzoyloxy)benzoic acid 4-acryloyloxybutyl ester [ No CAS ]
polymer, M_w 1.59 kDa, M_w/M_n 1.04; monomer(s): diethyl meso-2,5-dibromoadipate; 4-(acryloyloxy)butyl 2,5-bis[(4-butoxybenzoyl)oxy]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With 4,4'-dinonyl-2,2'-bipyridine; copper(I) bromide; copper(ll) bromide In toluene at 80℃; for 49h;

Reference： [1]Li, Min-Hui; Keller, Patrick; Albouy, Pierre-Antoine [Macromolecules, 2003, vol. 36, # 7, p. 2284 - 2292]

10
[ 54221-37-3 ]
8-methyl-3,8-diazabicyclo[3.2.1]-octane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 91 percent / tetrahydrofuran / 18 h / 0 - 20 °C 2: 0.24 g / xylene / 16 h / Heating 3: 30.9 g / 18 h / Heating 4: 65 percent / LiAlH₄ / dioxane / 18 h / Heating 5: 93 percent / hydrogene / Pd/C / methanol / 3 h / 40 °C

Reference： [1]Paliulis, Osvaldas; Peters, Dan; Miknius, Linas; Sackus, Algirdas [Organic Preparations and Procedures International, 2007, vol. 39, # 1, p. 86 - 90]

11
[ 54221-37-3 ]
[ 866396-72-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: toluene / 16 h / 80 °C 2: 95 percent / H₂; aq. NH₃ / CH₂Cl₂ / 18 h / 20 °C / 2585.74 Torr 3: 93 percent / NH₃ / methanol / 168 h / 20 °C

12
[ 54221-37-3 ]
[ 90514-00-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: toluene / 16 h / 80 °C 2: 95 percent / H₂; aq. NH₃ / CH₂Cl₂ / 18 h / 20 °C / 2585.74 Torr
	Multi-step reaction with 2 steps 1: 74 percent / benzene / Heating 2: 95 percent / H₂ / 10 percent Pd/C / ethanol / 40 °C / 20685.9 - 62057.8 Torr
	Multi-step reaction with 2 steps 1: potassium carbonate / water; toluene / 110 °C 2: hydrogen; acetic acid; palladium on activated charcoal / methanol / 5 h / 50 °C / 3040.2 Torr

Reference： [1]Wright, Stephen W.; Ammirati, Mark J.; Andrews, Kim M.; Brodeur, Anne M.; Danley, Dennis E.; Doran, Shawn D.; Lillquist, Jay S.; McClure, Lester D.; McPherson, R. Kirk; Orena, Stephen J.; Parker, Janice C.; Polivkova, Jana; Qiu, Xiayang; Soeller, Walter C.; Soglia, Carolyn B.; Treadway, Judith L.; VanVolkenburg, Maria A.; Wang, Hong; Wilder, Donald C.; Olson, Thanh V. [Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3068 - 3076]
[2]Fraenkel, Gideon; Duncan, Joseph H.; Wang, Jinhai [Journal of the American Chemical Society, 1999, vol. 121, # 2, p. 432 - 443]
[3]Current Patent Assignee: TB ALLIANCE INC - WO2017/15106, 2017, A1

13
[ 54221-37-3 ]
[ 866396-75-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: toluene / 16 h / 80 °C 2: 95 percent / H₂; aq. NH₃ / CH₂Cl₂ / 18 h / 20 °C / 2585.74 Torr 3: 93 percent / NH₃ / methanol / 168 h / 20 °C 4: 100 percent / dioxane; H₂O / 18 h / 20 °C

14
[ 54221-37-3 ]
[ 52321-07-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 65 percent / toluene / 24 h / Heating 2: 74 percent / conc. HCl / 2 h / Heating

Reference： [1]Liu, Hong; Cheng, Tie-Ming; Zhang, Hong-Mei; Li, Run-Tao [Archiv der Pharmazie, 2003, vol. 336, # 11, p. 510 - 513]

15
[ 54221-37-3 ]
[ 67571-90-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: toluene / 85 °C 2: xylene / Heating 3: 230 °C 4: H₂; HCl / Pd/C / H₂O / 85 h / 760 Torr 5: LiAlH₄ / diethyl ether / Heating
	Multi-step reaction with 5 steps 1: toluene / 16 h / 85 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Inert atmosphere; Reflux 3: 3 h / 210 - 220 °C / 760.05 Torr 4: hydrogenchloride; palladium 10% on activated carbon; hydrogen / methanol; water / 4 h / 20 °C 5: lithium aluminium tetrahydride / diethyl ether / 30 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]
[2]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9404081, 2016, B2

16
[ 54221-37-3 ]
[ 149771-44-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: toluene / 85 °C 2: xylene / Heating 3: 230 °C 4: H₂; HCl / Pd/C / H₂O / 85 h / 760 Torr 5: LiAlH₄ / diethyl ether / Heating 6: CH₂Cl₂ / 20 °C 7: 72 percent / H₂ / Pd/C / methanol / 760 Torr
	Multi-step reaction with 7 steps 1: toluene / 16 h / 85 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Inert atmosphere; Reflux 3: 3 h / 210 - 220 °C / 760.05 Torr 4: hydrogenchloride; palladium 10% on activated carbon; hydrogen / methanol; water / 4 h / 20 °C 5: lithium aluminium tetrahydride / diethyl ether / 30 h / 0 - 20 °C / Inert atmosphere 6: dichloromethane / 16 h / 20 °C 7: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]
[2]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9404081, 2016, B2

17
[ 54221-37-3 ]
[ 149771-43-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: toluene / 85 °C 2: xylene / Heating 3: 230 °C 4: H₂; HCl / Pd/C / H₂O / 85 h / 760 Torr 5: LiAlH₄ / diethyl ether / Heating 6: CH₂Cl₂ / 20 °C
	Multi-step reaction with 5 steps 1: toluene / 4 h / Reflux 2: lithium aluminium tetrahydride / tetrahydrofuran / 0.08 h / 0 - 20 °C 3: palladium on activated charcoal; hydrogen / methanol / 4 h / 40 °C / 3102.97 Torr 4: triethylamine / dichloromethane / 20 °C 5: acetonitrile / Reflux
	Multi-step reaction with 6 steps 1: toluene / 16 h / 85 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Inert atmosphere; Reflux 3: 3 h / 210 - 220 °C / 760.05 Torr 4: hydrogenchloride; palladium 10% on activated carbon; hydrogen / methanol; water / 4 h / 20 °C 5: lithium aluminium tetrahydride / diethyl ether / 30 h / 0 - 20 °C / Inert atmosphere 6: dichloromethane / 16 h / 20 °C

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]
[2]Huang, Long Jiang; Teng, Da Wei [Chinese Chemical Letters, 2011, vol. 22, # 5, p. 523 - 526]
[3]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9404081, 2016, B2

18
[ 54221-37-3 ]
[ 96483-83-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: toluene / 85 °C 2: xylene / Heating 3: 230 °C 4: H₂; HCl / Pd/C / H₂O / 85 h / 760 Torr
	Multi-step reaction with 4 steps 1: toluene / 16 h / 85 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 18 h / Inert atmosphere; Reflux 3: 3 h / 210 - 220 °C / 760.05 Torr 4: hydrogenchloride; palladium 10% on activated carbon; hydrogen / methanol; water / 4 h / 20 °C

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]
[2]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9404081, 2016, B2

19
[ 54221-37-3 ]
[ 429685-67-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: K₂CO₃ / dimethylformamide / 0 - 20 °C 2: 55 percent / xylene / 48 h / Heating 3: 100 percent / H₂ / Pd/C / ethanol / 760 Torr 4: 70 percent / 230 °C 5: LiAlH₄ / diethyl ether / 0 °C / Heating 6: H₂ / Pd/C / ethanol / 35 h / 35 °C / 4875.39 Torr

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]

20
[ 54221-37-3 ]
[ 627101-65-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: K₂CO₃ / dimethylformamide / 0 - 20 °C 2: 55 percent / xylene / 48 h / Heating 3: 100 percent / H₂ / Pd/C / ethanol / 760 Torr 4: 70 percent / 230 °C 5: LiAlH₄ / diethyl ether / 0 °C / Heating

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]

21
[ 54221-37-3 ]
[ 429685-66-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: K₂CO₃ / dimethylformamide / 0 - 20 °C 2: 55 percent / xylene / 48 h / Heating 3: 100 percent / H₂ / Pd/C / ethanol / 760 Torr 4: 70 percent / 230 °C

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]

22
[ 54221-37-3 ]
(2R,5S)-5-Benzylcarbamoyl-1-methyl-2-propyl-pyrrolidine-2-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: K₂CO₃ / dimethylformamide / 0 - 20 °C 2: 55 percent / xylene / 48 h / Heating 3: 100 percent / H₂ / Pd/C / ethanol / 760 Torr

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]

23
[ 54221-37-3 ]
stemofoline mimic [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: K₂CO₃ / dimethylformamide / 0 - 20 °C 2: 55 percent / xylene / 48 h / Heating 3: 100 percent / H₂ / Pd/C / ethanol / 760 Torr 4: 70 percent / 230 °C 5: LiAlH₄ / diethyl ether / 0 °C / Heating 6: H₂ / Pd/C / ethanol / 35 h / 35 °C / 4875.39 Torr 7: Et₃N / 4 h / 20 °C

Reference： [1]Smith, Stephen C; Bentley, Philip D [Tetrahedron Letters, 2002, vol. 43, # 5, p. 899 - 902]

24
[ 124-04-9 ]
[ 54221-37-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: SO₂Cl₂ / 2.5 h / 65 - 70 °C 2: Br₂ / 85 - 90 °C / Irradiation

Reference： [1]Fraenkel, Gideon; Duncan, Joseph H.; Wang, Jinhai [Journal of the American Chemical Society, 1999, vol. 121, # 2, p. 432 - 443]

25
[ 54221-37-3 ]
[ 81919-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 74 percent / benzene / Heating 2: 95 percent / H₂ / 10 percent Pd/C / ethanol / 40 °C / 20685.9 - 62057.8 Torr 3: LiAlH₄ / diethyl ether / 1 h / Ambient temperature

Reference： [1]Fraenkel, Gideon; Duncan, Joseph H.; Wang, Jinhai [Journal of the American Chemical Society, 1999, vol. 121, # 2, p. 432 - 443]

26
[ 54221-37-3 ]
[ 220264-29-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 74 percent / benzene / Heating 2: 95 percent / H₂ / 10 percent Pd/C / ethanol / 40 °C / 20685.9 - 62057.8 Torr 3: LiAlH₄ / diethyl ether / 1 h / Ambient temperature

Reference： [1]Fraenkel, Gideon; Duncan, Joseph H.; Wang, Jinhai [Journal of the American Chemical Society, 1999, vol. 121, # 2, p. 432 - 443]

27
[ 111-50-2 ]
[ 54221-37-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Br₂ / 85 - 90 °C / Irradiation

Reference： [1]Fraenkel, Gideon; Duncan, Joseph H.; Wang, Jinhai [Journal of the American Chemical Society, 1999, vol. 121, # 2, p. 432 - 443]

28
[ 54221-37-3 ]
[ 106-47-8 ]
1-(4-chlorophenyl)-pyrrolidine-2,5-dicarboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium iodide	5.A A. A. 1-(4-Chlorophenyl)-pyrrolidine-2,5-dicarboxylic acid diethyl ester Diethyl meso-2,5-dibromo adipate (5.0 g, 13.89 mmol), 4-chloro-aniline (6.2 g, 48.60 mmol), potassium iodide (0.032 g, 0.193 mmol) were combined and heated at 80° C. for 3 h then 90° C. for 1/2 h. Mix was cooled, diluted with 6N hydrochloric acid (400 mL) and extracted with ethyl acetate (3400 mL). The combined organic layers were washed with water (5200 mL), brine (200 mL), dried with magnesium sulfate and concentrated to yield a mixture of cis and trans 1-(4-Chloro-phenyl)-pyrrolidine-2,5-dicarboxylic acid diethyl ester (4.53 g, 100%) as a brown oil. Oil was used without further purification.
100%	With potassium iodide In methanol at 80 - 90℃; for 4.5h;

Reference： [1]Current Patent Assignee: PFIZER INC - US2002/68748, 2002, A1
[2]Current Patent Assignee: PFIZER INC - EP1178047, 2002, A1 Location in patent: Page 20

29
[ 54221-37-3 ]
[ 74-89-5 ]
diethyl cis-1-methylpyrrolidine-2,5-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran at 0 - 20℃; for 18h;	1 Diethyl mezo-2,5-dibromoadipate (101 .7 g, 0.283 mol) was dissolved by heating under argon in THF (400 ml) and then cooled to O0C. To the obtained solution a precooled solution of methylamine (27.3 g; 0.88 mol) in THF (150 ml) was added and the mixture was stirred at room temperature for 18 hours. The separated crystalline30 material was filtered off, the filtrate concentrated and the residue chromatographed on a silica gel column (10 cm long) with hexane-ethyl acetate 4:1 as eluent to afford 58.9 g (91 %).1 H NMR (300 MHz, CDCI3): δ 1 .15 (t, 6H); 1 .9-2.0 (m, 4H); 2.38 (s, 3H); 2.99 (m, 2H); 4.07 (q, 4H). 13C NMR (75 MHz, CDCI3): δ 13.98; 27.68; 40.82; 60.39;35 67.93; 68.06; 172.32.
91%	In tetrahydrofuran at 0 - 20℃; for 18h;	1 Diethyl c/s-1-methylpyrrolidine-2.5-dicarboxylate (Intermediate compound)Diethyl /77ezo-2,5-dibromoadipate (101.7 g; 0.283 mol) was dissolved by heating under argon in THF (400 ml) and then cooled to 0°C. To the obtained solution a pre-cooled solution of methylamine (27.3 g; 0.88 mol) in THF (150 ml) was added and the mixture was stirred at room temperature for 18 hours. The separated crystalline material was filtered off, the filtrate concentrated and the residue chromatographed on a silica gel column (10 cm long) with hexane-ethyl acetate 4:1 as eluent to afford 58.9 g (91%).1H NMR (300 MHz, CDCI3): δ 1.15 (t, 6H); 1.9-2.0 (m, 4H); 2.38 (s, 3H); 2.99 (m, 2H); 4.07 (q, 4H). 13C NMR (75 MHz, CDCI3): δ 13.98; 27.68; 40.82; 60.39; 67.93; 68.06; 172.32.
91%	In tetrahydrofuran at 0 - 20℃; for 18h;	1 Diethyl c/s-1-methylpyrrolidine-2.5-dicarboxylate (Intermediate compound); Diethyl /77ezo-2,5-dibromoadipate (101.7 g, 0.283 mol) was dissolved by heating under argon in THF (400 ml) and then cooled to 0°C. To the obtained solution a pre-cooled solution of methylamine (27.3 g, 0.88 mol) in THF (150 ml) was added and the mixture was stirred at room temperature for 18 hours. The separated crystalline material was filtered off, the filtrate concentrated and the residue EPO chromatographied on a silica gel column (10 cm long) with hexane-ethyl acetate 4:1 as eluent to afford 58.9 g (91 %).1H NMR (300 MHz, CDCI3): δ 1.15 (t, 6H); 1.9-2.0 (m, 4H); 2.38 (s, 3H); 2.99 (m, 2H); 4.07 (q, 4H). 13C NMR (75 MHz, CDCI3): δ 13.98; 27.68; 40.82; 60.39; 67.93; 68.06; 172.32.

Reference： [1]Current Patent Assignee: NEUROSEARCH A/S - WO2006/58879, 2006, A1 Location in patent: Page/Page column 13
[2]Current Patent Assignee: NEUROSEARCH A/S - WO2006/87306, 2006, A2 Location in patent: Page/Page column 19
[3]Current Patent Assignee: NEUROSEARCH A/S - WO2006/45716, 2006, A1 Location in patent: Page/Page column 15-16

30
[ 54221-37-3 ]
[ 107-15-3 ]
(+/-)-ethyl (6R,8aS)-1-oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 20℃; for 36h;	1.1.i (i) (+-)-Ethyl (6R,8aS)-1-oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate (i) (+-)-Ethyl (6R,8aS)-1-oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a mixture of 1,2-ethylene diamine (20 mL, 0.28 mol), K2CO3 (40 g, 0.29 mol) and CH3CN (300 mL) was added slowly a solution of diethyl meso-2,5-dibromoadipate (50 g, 0.14 mol) in CH3CN (200 mL) over 36 h at room temperature. The solvent was removed and DCM (300 mL) was added. After filtration, the DCM was evaporated to afford the crude product (32 g, purity>90%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.30 (t, 3H), 1.96-2.18 (m, 4H), 2.52 (m, 1H), 2.94 (m, 1H), 3.15 (m, 1H), 3.35 (m, 2H), 3.60 (m, 1H), 4.23 (q, 2H), 6.12 broad, 1H).
	With potassium carbonate In acetonitrile at 20℃; for 36h;	1 (+-)-Ethyl(6R,8aS)-1-oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate EXAMPLE 1 (+-)-Ethyl(6R,8aS)-1-oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a mixture of 1,2-ethylene diamine (20 mL, 0.28 mol), K2CO3 (40 g, 0.29 mol) and acetonitrile (300 mL) was added slowly a solution of diethyl meso-2,5-dibromoadipate (50 g, 0.139 mol) in acetonitrile (200 mL) over 36 h at RT. The solvent was removed and DCM (300 mL) was added. After filtration, the DCM was evaporated to afford the crude product (32 g, purity >90%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.30 (t, 3H), 1.96-2.18 (m, 4H), 2.52 (m, 1H), 2.94 (m, 1H), 3.15 (m, 1H), 3.35 (m, 2H), 3.60 (m, 1H), 4.23(q, 2H), 6.12 broad, 1H).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2007/37816, 2007, A1 Location in patent: Page/Page column 22
[2]Current Patent Assignee: ASTRAZENECA PLC - US2007/37817, 2007, A1 Location in patent: Page/Page column 26

31
[ 54221-37-3 ]
[ 54221-38-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide	126 Example 126. (2R,5S)-2,5-Diazidohexanedioic Acid, Diethyl Ester (126); [0512] In accordance with the procedure of Howard Newman (J. Het. Chem., 1974, 11,449), diethyl mesO-2,5-dibromoadipate (10 g, 27.8 mmol) was treated with NaN3 (5.1 g, 77.8 mmol) to afford the title compound as a clear oil: 1H NMR δH (250 MHz, CDCl3) 4.27 (4H, q), 3.92 (2H, t), 1.92 (4H, m), 1.33 (6H, t).

Reference： [1]Current Patent Assignee: EVOTEC AG - WO2008/134035, 2008, A1 Location in patent: Page/Page column 194

32
[ 54221-37-3 ]
[ 107-11-9 ]
(2S,5R)-1-Allyl-pyrrolidine-2,5-dicarboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With triethylamine In toluene at 100℃;

Reference： [1]Pryde, David C.; Corless, Martin; Fenwick, David R.; Mason, Helen J.; Stammen, Blanda C.; Stephenson, Peter T.; Ellis, David; Bachelor, David; Gordon, David; Barber, Christopher G.; Wood, Anthony; Middleton, Donald S.; Blakemore, David C.; Parsons, Gemma C.; Eastwood, Rachel; Platts, Michelle Y.; Statham, Keith; Paradowski, Kerry A.; Burt, Catherine; Klute, Wolfgang [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 4, p. 1084 - 1088]

33
[ 54221-37-3 ]
[ 107-15-3 ]
[ 46399-02-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In acetonitrile at 20℃; for 18h;	XIV.A Step A: Preparation of 16; To a solution of 1,2-ethylene diamine (2.0 mL, 29.9 mmol, 2.1 eq.) and K2CO3 (4.0 g, 28.9 mmol, 2.0 eq.) in CH3CN (30 mL) at room temperature was added a solution of diethyl meso-2,5-dibromoadipate (5.1 g, 14.2 mmol, 1.0 eq.) in CH3CN (20 mL) over 2 hours. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was filtered, the precipitate washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with dichloromethane-methanol (100:0 to 90:10) to afford 16 (2.6 g, 86%) as a white solid.

Reference： [1]Current Patent Assignee: SOPARFIN SCA - US2010/9980, 2010, A1 Location in patent: Page/Page column 15-16

34
[ 54221-37-3 ]
[ 885277-59-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: toluene / 4 h / Reflux 2: lithium aluminium tetrahydride / tetrahydrofuran / 0.08 h / 0 - 20 °C 3: palladium on activated charcoal; hydrogen / methanol / 4 h / 40 °C / 3102.97 Torr

Reference： [1]Huang, Long Jiang; Teng, Da Wei [Chinese Chemical Letters, 2011, vol. 22, # 5, p. 523 - 526]

35
[ 54221-37-3 ]
[ 100-46-9 ]
[ 1384448-78-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	In toluene at 85℃; for 16h;	11 Synthesis of (2R,5S)-ethyl 1-benzyl-5-(benzylcarbamoyl)pyrrolidine-2-carboxylate (LXV). To a stirred solution of Diethyl meso-2,5-dibromoadipate (LXIV, 0.00069 mol, 250 mg) in toluene (5 mL) was added benzylamine (0.0021 mol, 0.234 mL) and the reaction mixture was heated at 85° C. for 16 h. After completion of the reaction (checked by TLC), the reaction mixture was cooled and the formed solid was filtered. The filtrate was concentrated under reduced pressure to leave the product as pale yellow liquid. The residue was purified by column chromatography (silica gel, 60-120 mesh; EA-Hexane, 2:8) to afford Diethyl pyrrolidine-2,5-carboxylate in 72% yield.

Reference： [1]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US2012/172349, 2012, A1 Location in patent: Page/Page column 58

36
[ 54221-37-3 ]
(1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: toluene / 16 h / 85 °C 2: hydrogenchloride; hydrogen / palladium 10% on activated carbon / methanol / 4 h / 20 °C 3: lithium aluminium tetrahydride / diethyl ether / 30 h / 0 - 20 °C / Inert atmosphere 4: dichloromethane / 16 h / 20 °C 5: hydrogen / palladium 10% on activated carbon / methanol / 4 h / 20 °C
	Multi-step reaction with 8 steps 1: potassium carbonate / toluene / 16 h / 100 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 96 h / 140 °C 3: water; sodium hydroxide / methanol / 5 h / 20 °C 4: oxalyl dichloride / dichloromethane / 16 h / 0 - 20 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 20 °C 6: lithium aluminium tetrahydride / tetrahydrofuran / 36 h / 0 - 70 °C 7: triethylamine / dichloromethane / 16 h / 0 - 20 °C 8: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 20 °C

Reference： [1]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US2012/172349, 2012, A1
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/153080, 2019, A1

37
[ 54221-37-3 ]
(1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: toluene / 16 h / 85 °C 2: hydrogenchloride; hydrogen / palladium 10% on activated carbon / methanol / 4 h / 20 °C 3: lithium aluminium tetrahydride / diethyl ether / 30 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1: potassium carbonate / toluene / 16 h / 100 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 96 h / 140 °C 3: water; sodium hydroxide / methanol / 5 h / 20 °C 4: oxalyl dichloride / dichloromethane / 16 h / 0 - 20 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 20 °C 6: lithium aluminium tetrahydride / tetrahydrofuran / 36 h / 0 - 70 °C

Reference： [1]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US2012/172349, 2012, A1
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/153080, 2019, A1

38
[ 54221-37-3 ]
3-benzyl-3,8-diazabicyclo[3.2.1]octan-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: toluene / 16 h / 85 °C 2: hydrogenchloride; hydrogen / palladium 10% on activated carbon / methanol / 4 h / 20 °C
	Multi-step reaction with 5 steps 1: potassium carbonate / toluene / 16 h / 100 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 96 h / 140 °C 3: water; sodium hydroxide / methanol / 5 h / 20 °C 4: oxalyl dichloride / dichloromethane / 16 h / 0 - 20 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 20 °C

Reference： [1]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US2012/172349, 2012, A1
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/153080, 2019, A1

39
[ 54221-37-3 ]
tert-butyl (1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: toluene / 16 h / 85 °C 2: hydrogenchloride; hydrogen / palladium 10% on activated carbon / methanol / 4 h / 20 °C 3: lithium aluminium tetrahydride / diethyl ether / 30 h / 0 - 20 °C / Inert atmosphere 4: dichloromethane / 16 h / 20 °C
	Multi-step reaction with 7 steps 1: potassium carbonate / toluene / 16 h / 100 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 96 h / 140 °C 3: water; sodium hydroxide / methanol / 5 h / 20 °C 4: oxalyl dichloride / dichloromethane / 16 h / 0 - 20 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 20 °C 6: lithium aluminium tetrahydride / tetrahydrofuran / 36 h / 0 - 70 °C 7: triethylamine / dichloromethane / 16 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US2012/172349, 2012, A1
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/153080, 2019, A1

40
[ 54221-37-3 ]
C₁₈H₂₆N₂O₂*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: toluene / 16 h / 85 °C 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / methanol / 4 h / 20 °C 3.1: lithium aluminium tetrahydride / diethyl ether / 30 h / 0 - 20 °C / Inert atmosphere 4.1: dichloromethane / 16 h / 20 °C 5.1: hydrogen / palladium 10% on activated carbon / methanol / 4 h / 20 °C 6.1: acetic acid / dichloromethane / 0.5 h / 20 °C 6.2: 16 h / 20 °C