[ CAS No. 475-11-6 ] {[proInfo.proName]}

Name: 475-11-6|H-N-Me-Pro-OH|97%
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Quality Control of [ 475-11-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 475-11-6 ]

Product Details of [ 475-11-6 ]

CAS No. :	475-11-6	MDL No. :	MFCD00011565
Formula :	C₆H₁₁NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	129.16	Pubchem ID :	-
Synonyms :	N-Methyl-L-proline	Chemical Name :	H-N-Me-Pro-OH

Calculated chemistry of [ 475-11-6 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.42
TPSA :	40.54 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) :	-9.22 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.31
Log Po/w (XLOGP3) :	-3.0
Log Po/w (WLOGP) :	-0.22
Log Po/w (MLOGP) :	0.0
Log Po/w (SILICOS-IT) :	0.04
Consensus Log Po/w :	-0.37

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	1.32
Solubility :	2670.0 mg/ml ; 20.7 mol/l
Class :	Highly soluble
Log S (Ali) :	2.71
Solubility :	66300.0 mg/ml ; 514.0 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	0.18
Solubility :	196.0 mg/ml ; 1.52 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.63

Safety of [ 475-11-6 ]

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 [ 475-11-6 ]

* 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 [ 475-11-6 ]
Downstream synthetic route of [ 475-11-6 ]

[ 475-11-6 ] Synthesis Path-Upstream 1~10

1
[ 475-11-6 ]
[ 34381-71-0 ]

Reference： [1] Journal of Organic Chemistry, 1983, vol. 48, # 13, p. 2195 - 2202

2
[ 50-00-0 ]
[ 147-85-3 ]
[ 475-11-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With palladium 10% on activated carbon; hydrogen In methanol; water	General procedure: L-Proline(2.0 g, 17.4 mmol) was dissolved in methanol (20 mL) and40 percent aqueous formaldehyde (1.4 mL, 19.1 mmol) wasadded to this solution. Next, 10 percent Pd/C catalyst (500 mg)was added to the reaction mixture and the resulting slurrywas stirred in hydrogen overnight. The slurry was then filtered through a Celite pad to remove the catalyst. Thepad was washed with methanol and the combined filtrateswere concentrated under reduced pressure. The residue wasdissolved in ethanol/benzene (1:1, 100 mL) and concentratedsecond time to provide a solid that was re-crystallizedin methanol/diethyl ether. In this way Nmethylproline7a was isolated as fine needles (2.1 g, 92 percentyield); mp 109–111°C; 1H NMR (D2O, 300 MHz):δ = 3.95–3.90 (1H, m, CH2 (CH2)2CHNCH3), 3.24–3.15(2H, m, CH2 (CH2)2CHNCH3), 2.97 (3H, s, CH2 (CH2)2CHNCH3), 2.22–2.01 (4H, m, CH2 (CH2)2CHNCH3); ESI–MS (m/z):130.2 [M + H] +(100).
89%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 24 h;	L-proline (4.0 g, 34.8 mmol)Soluble in methanol (40mL),40percent aqueous formaldehyde solution (2.8 mL, 38.2 mmol) was added in orderAnd 10percent Pd on carbon (1g), addition, hydrogenation,Reaction at room temperature for 24 hours,After the reaction is complete, filterThe mother liquor was concentrated and dried to give 4g of a white solid with a yield of 89percent.That is, N-methyl-L-proline (compound b).
88%	With sodium dihydrogenphosphate; zinc In water at 30℃; for 48 h;	The vigorously stirred suspension of zinc dust(6.50 g; 100 mmol), L-proline (5.57 g; 50 mmol) and NaH2PO4 (11.90 g; 100 mmol) in water (22 mL) was treated with 35percent aq. formaldehyde (2.10 mL).Stirring was continued for 48 h at 30°C. The suspension was discarded, the filtrate was neutralized with2 M aq. ammonia to pH 8, concentrated under vacuum,the solid residue was dissolved in small amount of water and lyophilized. Dry residue was extracted with hot mixture of benzene-ethanol (1 : 1, v/v).Collected extracts were evaporated to dryness and then recrystallized from the mixture methanol/ether affording L-N-methylproline (1) (5.68 g; yield 88percent)as white crystals m.p. 115-120°C, lit. (12) m.p.115-116°C.

Reference： [1] Journal of Organic Chemistry, 2003, vol. 68, # 7, p. 2652 - 2667
[2] Green Chemistry, 2016, vol. 18, # 16, p. 4374 - 4392
[3] European Journal of Organic Chemistry, 2005, # 5, p. 934 - 938
[4] Tetrahedron Letters, 2007, vol. 48, # 43, p. 7680 - 7682
[5] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[6] Journal of the American Chemical Society, 2012, vol. 134, # 5, p. 2823 - 2834
[7] Patent: CN107963987, 2018, A, . Location in patent: Paragraph 0046-0048
[8] Acta Poloniae Pharmaceutica - Drug Research, 2014, vol. 71, # 6, p. 994 - 1003
[9] Synthesis, 2011, # 3, p. 490 - 496
[10] Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 3592 - 3615
[11] Archiv der Pharmazie (Weinheim, Germany), 1976, vol. 309, p. 380,382
[12] Journal of Biological Chemistry, 1953, vol. 202, p. 193,194
[13] Angewandte Chemie, 1995, vol. 107, # 9, p. 1095 - 1098
[14] Analytical Chemistry, 2007, vol. 79, # 22, p. 8631 - 8638
[15] European Journal of Organic Chemistry, 2009, # 22, p. 3790 - 3794

3
[ 147-85-3 ]
[ 475-11-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With formaldehyd In methanol	3a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt percent of aqueous formaldehyde (24 mL) was added 10percent Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Arm of H₂. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90percent). MS (DCl/NH3) m/e 130 (M+H)⁺, 147 (M+NH₄)⁺; ¹ H-NMR (D₂ O) d 1.94-2.23 (m, 4 H); 2.45-2.57 (m, 1H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
90%	With formaldehyd In methanol	3a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt percent of aqueous formaldehyde (24 mL) was added 10percent Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Atm of H₂. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90percent). MS (DCl/NH₃) m/e 130 (M+H)⁺, 147 (M+NH₄)⁺; ¹ H-NMR (D₂ O) d 1.94-2.23 (m, 4 H); 2.45-2.57 (m, 1 H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
90%	With formaldehyd In methanol	3 a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt percent of aqueous formaldehyde (24 mL) was added 10percent Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Atm of H₂. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90percent). MS (DCl/NH3) m/e 130 (M+H)⁺, 147 (M+NH₄)⁺; 1H-NMR (D₂ O) d 1.94-2.23 (m, 4H); 2.45-2.57 (m, 1H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).

Reference： [1] Patent: US5424444, 1995, A,
[2] Patent: US5508418, 1996, A,
[3] Patent: US5516912, 1996, A,

4
[ 67-56-1 ]
[ 147-85-3 ]
[ 475-11-6 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 10, p. 2530 - 2533

5
[ 124-38-9 ]
[ 265660-44-4 ]
[ 475-11-6 ]
[ 475-11-6 ]

Reference： [1] Journal of the American Chemical Society, 1993, vol. 115, # 16, p. 7515 - 7516

6
[ 471-87-4 ]
[ 475-11-6 ]

Reference： [1] Journal of the American Chemical Society, 2012, vol. 134, # 5, p. 2823 - 2834

7
[ 50-00-0 ]
[ 7776-34-3 ]
[ 475-11-6 ]

Reference： [1] Croatica Chemica Acta, 1959, vol. 31, p. 157

8
[ 475-11-6 ]
[ 74-88-4 ]
[ 471-87-4 ]

Reference： [1] Helvetica Chimica Acta, 1925, vol. 8, p. 366

9
[ 475-11-6 ]
[ 27957-91-1 ]

Reference： [1] Patent: US5424444, 1995, A,
[2] Patent: US5516912, 1996, A,
[3] Patent: US5508418, 1996, A,

10
[ 67-56-1 ]
[ 475-11-6 ]
[ 27957-91-1 ]

Reference： [1] Angewandte Chemie, 1995, vol. 107, # 9, p. 1095 - 1098

[ 475-11-6 ] Synthesis Path-Downstream 1~88

1
[ 124-38-9 ]
[ 265660-44-4 ]
[ 475-11-6 ]
[ 475-11-6 ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 7515 - 7516

2
[ 475-11-6 ]
[ 34381-71-0 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 2195 - 2202

3
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride [ No CAS ]
[ 475-11-6 ]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylcarbonyl]piperidin-3-yloxy}quinazoline [ No CAS ]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylcarbonyl]piperidin-3-yloxy}quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2.5h;	Example 61; 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2- ylcarbonyl] piperidin-3-yloxy} quinazoline; HATU (0.26g) was added to a solution of 4- (3-Chloro-2-fluoroanilino)-7-methoxy-6- (piperidin-3-yloxy) quinazoline dihydrochloride (250mg; prepared as described in Example 45), diisopropylethylamine (2101) and <strong>[475-11-6]N-methyl-L-proline</strong> (0.120g) in DMF (7. 5ml) and the mixture was stirred at room temperature for 2.5 hours. The DMF was removed under reduced pressure and the residue dissolved in methylene chloride (50ml) and washed with sodium bicarbonate (50ml) then water (50ml). Purification by flash column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the expected product were evaporated to give a foam. This foam was dissolved in methylene chloride (5ml) and crystallised by the addition of isohexane (50ml) to give the title product as a mixture of two diastereoisomers (0. 130g). 1H NMR Spectrum: (DMSO d6) 1.43-1. 62 (m, 2H), 1.66-1. 95 (m, 4H), 1.96-2. 18 (m, 4H), 2.20-2. 29 (m, 2H), 2.67-2. 80 (m, 1H), 2.96 (m, 1H), 3.03-3. 20 (m, 1H), 3.51-3. 80 (m, 2H), 3.80-4. 05 (m, 4H), 4.51-4. 68 (m, 1H), 7. 22-7. 31 (m, 2H), 7.47-7. 59 (m, 2H), 7.89 (m, 1H), 8. 39 (s, 1H), 9.55 (m, 1H) ; Mass Spectrum : (M+H)+ 514.

Reference： [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 154-155

4
(2S,4R)-N-{1-[4-(3-amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide [ No CAS ]
[ 475-11-6 ]
(2S,4R)-1-Methyl-pyrrolidine-2-carboxylic acid [3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; 1,2-dichloro-ethane; In dichloromethane;	(2S,4R)-1-Methyl-pyrrolidine-2-carboxylic acid [3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-amide (H-59) (2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (100 mg, 0.204 mmol) was dissolved in methylene chloride (2 mL) and pyridine (2 mL). N-methyl proline (33 mg, 0.255 mmol) and EDC (63 mg, 0.255 mmol) were added and the reaction was stirred for 1 hour. The mixture was partitioned between methylene chloride and water; the methylene chloride layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate) to afford the product. 1H-NMR (CDCl3) delta: 1.1 (s, 3H), 1.2 (m, 1H), 1.8 (m, 2H), 2.0 (m, 2H), 2.0 (s, 3H), 2.2 (m, 2H), 2.3 (m, 1H), 2.4 (s, 3H), 2.6 (m, 1H), 3.2 (m, 2H), 3.4 (q, 2H), 4.0 (t, 2H), 4.1 (m, 1H), 4.8 (m 1H), 5.6 (bs, 1H), 6.5 (d, 1H), 6.6 (d, 2H), 6.9 (t, 1H), 7.2 (m, 6H), 7.4 (d, 2H). MS m/z: 603 (M+1).

Reference： [1]Patent: US2005/256158,2005,A1

5
[ 1001017-53-3 ]
[ 475-11-6 ]
[2S]-(4-[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(1-methyl-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With HATU; In dichloromethane; at 20℃; for 168h;	Example 25; <n="54"/>(4-{ [ [3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yI)-propyl] [2S] -(1-methyl- pyrroIidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester; The product of example 1, step (ix) (0.43 g), l-methyl-pyrrolidine-2-carboxylic acid (0.13g) and HATU (0.37g) were stirred in DCM (5ml) at rt for 7 days. The reaction mixture was purified by SCX and RPHPLC, to give the title compound. Yield 24mg. 1H NMR delta (DMSO- d6) 9.92 (IH, d), 9.61 (IH, s), 7.30 - 7.03 (5H, m), 6.44 (2H, s), 4.67 - 4.56 (2H, m), 4.54 - 4.42 (2H, m), 4.15 - 4.05 (4H, m), 3.69 - 3.58 (4H, m), 2.84 - 2.73 (4H, m), 2.05 (3H, s), 2.10 - 1.97 (2H, m), 1.97 - 1.84 (2H, m), 1.86 - 1.73 (2H, m), 1.66 - 1.53 (2H, m), 1.37 - 1.24 (2H, m), 0.96 - 0.83 (3H, m). MS: APCI (+ve): 554 (M+ 1).

Reference： [1]Patent: WO2008/4948,2008,A1 .Location in patent: Page/Page column 52-53

6
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 76-05-1 ]
[ 475-11-6 ]
Me-Pro-Pro-Asp-NH₂ trifluoroacetic acid salt [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 8420 - 8424

7
[ 67605-64-5 ]
[ 475-11-6 ]
N-[5-(4-aminophenyl)-10,15,20-triphenylporphyrinyl]-L-prolin(N-methyl)amide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2007,vol. 129,p. 6688 - 6689

8
[ 124-22-1 ]
[ 475-11-6 ]
(2S)-N-dodecyl-1-methylpyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Tetrahedron Asymmetry,2007,vol. 18,p. 1868 - 1876

9
[ 7311-30-0 ]
[ 475-11-6 ]
(2S)-N-dodecyl-N,1-dimethylpyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Tetrahedron Asymmetry,2007,vol. 18,p. 1868 - 1876

10
[ 475-11-6 ]
N-[5-(4-aminophenyl)-10,15,20-triphenylporphyrinyl]-L-(N,N-dimethyl)prolinium amide iodide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2007,vol. 129,p. 6688 - 6689

11
[ 475-11-6 ]
(1S,2S)-(1-oxido)-(1-methyl)-(N-(R)-1-phenylethyl)-2-pyrrolidinecarboxamide [ No CAS ]

Reference： [1]Organic Letters,2005,vol. 7,p. 3151 - 3154

12
C₆H₉NO₂ [ No CAS ]
[ 475-11-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogen;palladium 10% on activated carbon; In methanol; water;	L-Proline (86) (2.0 g, 17.4 mmol) was dissolved in methanol (20 ml) and to this solution was added 40% aqueous formaldehyde solution (1.4 ml, 19.1 mmol). This was followed by the addition of 10% palladium-on-charcoal catalyst (500 mg) and the resulting slurry was stirred in a hydrogen atmosphere overnight. The slurry was then filtered through a Celite pad to remove the catalyst. The pad was washed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was taken up in ethanol-benzene (1: 1, [100ML)] and concentrated a second time to provide a solid, which was recrystallised from methanol-diethyl ether. In this way N-methyl proline (87) was isolated as fine needles (2.2 g, 98%). Mp 142- 145 C [[?]23D -78.0 ] (c 2.0, MeOH). 1H NMR (300 MHz, D2O) 3.71-3. 65 and 3.55-3. 51 (2m, [1H),] 3.00-2. 91 (m, [1H),] 2.74 (s, 3H), 2. [34-2. 28] (m, [1H),] 1. [99-1. 78] (m, [3H). 13C] NMR [(75] MHz, [CDC13)] [5] 173.06, 70.18, 55.83, 40.26, 28.34, 22.37. IR (KBr disk) v 3000-2800 (CH, saturated), 2675 and 2605 (ammonium ion), 1669 [(CO2H),] 1612 [(C02-),] 1468, [1401,,] 1354, 1327,1234, 1183,1112, 1056,1025, 808,775 [CM~1.] HRMS calcd for [C6H1LNO2] (M+) 129.0790 found 129.0784.

Reference： [1]Patent: WO2004/7427,2004,A1 .Location in patent: Page 79-80

13
[ 187345-38-6 ]
[ 475-11-6 ]
C₂₃H₄₁N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃;	[0356] To a solution of <strong>[475-11-6]N-methyl-L-proline</strong> monohydrate (0.26 g, 1.79 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (1.4 g, 2.69 mmol) in anhydrous dichloromethane (3.0 ml) at 25 C. is added diisopropylethylamine (0.63 ml, 3.62 mmol) under an inert atmosphere. To this solution is added a solution of ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate (0.39 g, 1.27 mmol, WO 99/32509) in anhydrous dichloromethane (2.0 ml). The resulting reaction mixture is stirred at room temperature overnight. The reaction mixture is evaporated in vacuo. The residue (300 mg, 0.78 mmol) is dissolved in methanol (6.85 ml), water (1.8 ml) and tetrahydrofuran (3.25 ml). To this reaction mixture is added aqueous lithium hydroxide solution (3.54 ml, 3.54 mol) The resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane/water. The organic layer is washed with citric acid, brine, dried over sodium sulfate and filtered. The solvent is removed in vacuo, and the residue is chromatographed by HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the product as a yellow oil, 0.08 g (28% yield). MS: m/z 396.28 (M+1)

Reference： [1]Patent: US2005/37977,2005,A1 .Location in patent: Page 39

14
[ 345582-96-9 ]
[ 125700-67-6 ]
[ 475-11-6 ]
[ 345583-03-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	EXAMPLE 125 (2S)-N-{3-Chloro-4-[4-(2-oxo-2H-3,1-benzoxazin-1(4H)-yl)piperidin-1-yl]phenyl}-1-methylpyrrolidine-2-carboxamide A mixture of the product from example 120 step (ii) (0.1 g), <strong>[475-11-6]N-methyl-L-proline</strong> (0.044 g), N,N-diisopropylethylamine (0.17 ml), 1-hydroxybenzotriazole (0.043 g), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.103 g) in N,N-dimethylformamide (3 ml) were stirred at room temperature overnight then partitioned between ethyl acetate and water. The organic layer was washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluding with 4% methanol/dichloromethane. Yield 0.038 g. MS: APCI(+ve) 469(M+1) 1H NMR: delta(DMSO-d6) 9.73(1H, s), 7.88(1H, d), 7.59(1H, dd), 7.38(1H, t), 7.30(2H, d), 7.14-7.10(2H, m), 5.15(2H, s), 4.04-3.98(1H, m), 3.30(2H, d), 3.12-3.08(1H, m), 2.90-2.67(5H, m), 2.35-2.29(1H, m), 2.33(3H, s), 2.18-2.09(1H, m) 1.87(2H, br d), 1.82-1.75(3H, m)

Reference： [1]Patent: US2003/40513,2003,A1

15
[ 23602-98-4 ]
[ 475-11-6 ]
[ 190660-12-9 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 257 Preparation of 1-N-(N-(N-methyl prolyl)-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except substituting "N-methyl proline" for "4-pyridyl acetic acid" and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+H+ =543.

Reference： [1]Patent: US5998470,1999,A

Yield	Reaction Conditions	Operation in experiment
37%; 95%		EXAMPLE 1 Benzeneacetamide. 3,4-dichloro-N-methyl-N-1-(1-methyl-2-pyrrolidinyl) -1-phenylmethyl]-hydrochloride STR4 N-methyl-L-proline was prepared following a procedure given in Helv. Chim. Acta 1967, 50, 8, p. 2527. Collected 7.1 g white crystals (95% yield). 2-benzoyl-N-methylpyrrolidine was also prepared according to a method given in Helv. Chim. Acta 1967, 50, 8, p. 2527. Collected 5.5 g (37% yield) yellow crystals after recrystallization from hexane.

17
[ 147-85-3 ]
[ 475-11-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With formaldehyd;palladium-carbon; In methanol;	3a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt % of aqueous formaldehyde (24 mL) was added 10% Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Arm of H2. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90%). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1 H-NMR (D2 O) d 1.94-2.23 (m, 4 H); 2.45-2.57 (m, 1H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
90%	With formaldehyd;palladium-carbon; In methanol;	3a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt % of aqueous formaldehyde (24 mL) was added 10% Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Atm of H2. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90%). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1 H-NMR (D2 O) d 1.94-2.23 (m, 4 H); 2.45-2.57 (m, 1 H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
90%	With formaldehyd;palladium-carbon; In methanol;	3 a. N-Methyl (L)-proline To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt % of aqueous formaldehyde (24 mL) was added 10% Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Atm of H2. After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum. The crude product was obtained as a white powder (33.44 g, 90%). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1H-NMR (D2 O) d 1.94-2.23 (m, 4H); 2.45-2.57 (m, 1H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).

Reference： [1]Patent: US5424444,1995,A
[2]Patent: US5508418,1996,A
[3]Patent: US5516912,1996,A

18
[ 475-11-6 ]
[ 933-94-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sulfuryl dichloride; trimethyl orthoformate; In methanol; ethyl acetate;	10a N-Methyl-proline Methyl Ester A 2-L three neck round-bottom flask equipped with an overhead stirrer, internal temperature monitor, and addition funnel was charged with N-methyl proline (155.3 g, 1.20 mole) and methanol (800 mL). The vessel was chilled to 0 C. and sulfuryl chloride (110 mL, 1.33 mole) was added dropwise via the addition funnel at a rate such that the internal temperature remained ?+15 C. The cold bath was replaced with a heating mantle and trimethyl orthoformate (150 mL, 1.37 mole) was added quickly over 5 min. The reaction was heated to gentle reflux for 5 hours, then cooled to room temperature. The bulk of the solvent was evaporated in vacuo. The remainder was basified with saturated Na2 CO3 solution (ca. 1 L, pH 9-10) and partitioned with ethyl acetate (1 L). The aqueous phase was extracted with ethyl acetate (4500 mL), and the combined organics were washed with brine (11 L) and then dried (Na2 SO 4). After filtration and solvent evaporation the residue was distilled at reduced pressure (13 mm Hg, bp 56 C.) to give 125.7 g (73% yield, ?99% ee).
73%	With sulfuryl dichloride; trimethyl orthoformate; In methanol; ethyl acetate;	10a N-Methyl-proline methyl ester A 2-L three neck round-bottom flask equipped with an overhead stirrer, internal temperature monitor, and addition funnel was charged with N-methyl proline (155.3 g, 1.20 mole) and methanol (800 mL). The vessel was chilled to 0 C. and sulfuryl chloride (110 mL, 1.33 mole) was added dropwise via the addition funnel at a rate such that the internal temperature remained ?+15 C. The cold bath was replaced with a heating mantle and trimethyl orthoformate (150 mL, 1.37 mole) was added quickly over 5 min. The reaction was heated to gentle reflux for 5 hours, then cooled to room temperature. The bulk of the solvent was evaporated in vacuo. The remainder was basified with saturated Na2 CO3 solution (ca. 1 L, pH 9-10) and partitioned with ethyl acetate (1 L). The aqueous phase was extracted with ethyl acetate (4500 mL), and the combined organics were washed with brine (11 L) and then dried (Na2 SO 4). After filtration and solvent evaporation the residue was distilled at reduced pressure (13 mm Hg, bp 56 C.) to give 125.7 g (73% yield, ?99% ee).

Reference： [1]Patent: US5424444,1995,A
[2]Patent: US5516912,1996,A

19
[ 475-11-6 ]
[ 27957-91-1 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In hydrogenchloride; methanol;	3b. N-Methyl (L)-Proline Methyl Ester To a solution of N-methyl (L)-proline, from step 3a, in methanol at 0 C. is added thionyl chloride (1.1 eq) dropwise, and the reaction mixture is slowly allowed to warm to room temperature. Upon completion of the reaction the solvent is removed in vacuo, and the crude product is dissolved in 10% aq. HCl and washed with ether. The aqueous layer is adjusted to pH--12 with K2 CO3 (solid) and extracted with CH2 Cl2. The combined CH2 Cl2 layers are dried (MgSO4) and concentrated to afford the crude product as a clear oil.
	With thionyl chloride; In hydrogenchloride; methanol;	3b. N-Methyl (L)-Proline Methyl Ester To a solution of N-methyl (L)-proline, from step 3a, in methanol at 0 C. is added thionyl chloride (1.1 eq) dropwise, and the reaction mixture is slowly allowed to warm to room temperature. Upon completion of the reaction the solvent is removed in vacuo, and the crude product is dissolved in 10% aq. HCl and washed with ether. The aqueous layer is adjusted to pH ~12 with K2 CO3 (solid) and extracted with CH2 Cl2. The combined CH2 Cl2 layers are dried (MgSO4) and concentrated to afford the crude product as a clear oil.

Reference： [1]Patent: US5424444,1995,A
[2]Patent: US5516912,1996,A

20
[ 771-61-9 ]
[ 475-11-6 ]
C₁₂H₁₀F₅NO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1530 - 1533

21
[ 911417-28-2 ]
[ 475-11-6 ]
[ 1024582-70-4 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of (S)-l-methylpyrrolidine-2-carboxylic acid monohydrate (14 mg, 0.11 mmol), PyBOP (57 mg, 0.11 mmol), DffiA (49 muL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH-indazole-l- carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3x). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-((S)-l-methylpyrrolidine-2- carboxamido)phenyl)-quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate.
		A suspension of (S)- l -methylpyrroliotadine-2-carboxylic acid monohydrate ( 14 mg. 0 1 1 mmol). PyBOP* (57 mg. 0.1 1 mmol). DIEA (49 muL. 0.28 mmol) in CH2Cl2 (0 5 ml_) was stirred at RT for 10- 15 minutes This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)- l H-indazole- l - carboxylate ( 100 mg, 0 22 mmol) and CH2CI2 ( 1 mL) The reaction mixture was stirred at RT for 1 5 h Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2CI2 and extracted with H2O (3x). Organic layer was dried under NajSCXj and concentrated /// vacuo to give the desired oil product tert-butyl 5-(2-(3-((S)- l-methylpyrrolidine-2- carboxamido)phenyl)-quinazolin-4-yIamino)-1H-indazole- l -carboxylate.
		[0203] A suspension of (S)-l-methylpyrrolidine-2-carboxylic acid monohydrate(14 mg, 0.11 mmol), PyBOP (57 mg, 0.11 mmol), DIEA (49 muh, 0.28 mmol) in CH2Cl2 (0.5 niL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)qumazolin-4-ylamino)-lH-indazole-l- carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3x). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-((S)-l-methylpyrrolidine-2- carboxamido)phenyl)-quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate.

Reference： [1]Patent: WO2008/54599,2008,A2 .Location in patent: Page/Page column 118
[2]Patent: WO2010/104851,2010,A1 .Location in patent: Page/Page column 113; 1142
[3]Patent: WO2006/105081,2006,A2 .Location in patent: Page/Page column 102

22
C₃₄H₄₄N₄O₅S [ No CAS ]
[ 475-11-6 ]
C₄₀H₅₃N₅O₆S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2996 - 2999

23
[ 475-11-6 ]
[ 147539-41-1 ]
tert-butyl 4-[methyl(1-methyl-L-prolyl)amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;	Reference Example 5 By allowing benzyl 4-(methylamino)piperidine-1-carboxylate to react with EDCI hydrochloride, HOBt and 1-methyl-L-proline, tert-butyl 4-[methyl(1-methyl-L-prolyl)amino]piperidine-1-carboxylate was obtained. Then, trifluoroacetic acid was added thereto to obtain N,1-dimethyl-N-piperidin-4-yl-L-prolinamide. ES: 226.

Reference： [1]Patent: EP2000469,2008,A2 .Location in patent: Page/Page column 14

24
[ 913541-69-2 ]
[ 475-11-6 ]
[ 1013941-81-5 ]

Reference： [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 567 - 576

25
[ 1105044-16-3 ]
[ 475-11-6 ]
[ 1105044-40-3 ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 5553 - 5562

26
[ 2325-10-2 ]
[ 475-11-6 ]
[ 1105044-36-7 ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 5553 - 5562

27
[ 29841-69-8 ]
[ 475-11-6 ]
[ 1022161-75-6 ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 5553 - 5562

28
[ 35132-20-8 ]
[ 475-11-6 ]
[ 1105044-55-0 ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 5553 - 5562

29
[ 122798-27-0 ]
[ 475-11-6 ]
[ 1105044-39-0 ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 5553 - 5562

30
[ 475-11-6 ]
[ 1003010-61-4 ]
[ 1105044-38-9 ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 5553 - 5562

31
5-(phenylsulfonyl)-N-piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide hydrochloride [ No CAS ]
[ 475-11-6 ]
[ 1095322-95-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 105 - 116

32
[ 67-56-1 ]
[ 475-11-6 ]
[ 27871-48-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With thionyl chloride; at -50℃; for 25h;Reflux;	General procedure: Stirred suspension of L-N-methylproline (6.45g; 50 mmol) in n-propanol (100 mL) was cooled to50C and thionyl chloride (6 mL; 78 mmol) was added dropwise in such a rate to maintain the temperature below 45C. Then, the solution was allowed to warm up and stirring was continued fo r20 h at room temperature followed by boiling under reflux for additional 5 h. Clear solution was concentrated under vacuum and the solid residue was twice dissolved in dichloromethane (50 mL), and concentratedto oily residue. The residue was dissolved in dioxane and lyophilized yielding L-N-methylprolinen-propyl ester hydrochloride (3b) as white plates(8.3 g; yield 86%)

Reference： [1]Acta poloniae pharmaceutica,2014,vol. 71,p. 994 - 1003
[2]European Journal of Organic Chemistry,2009,p. 3790 - 3794

33
(4-hydroxy-piperidin-1-yl)-(4-{4-[4-(3-methane-sulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone [ No CAS ]
[ 475-11-6 ]
[ 1195972-48-5 ]

Yield	Reaction Conditions	Operation in experiment
86.8%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	A mixture of 18.6mMol I (10.33g), 38.7mMol II (5.Og), 37.2mMol DCC (7.67g), and 27.9mMol DMAP (3.4Ig) were stirred in 15OmL dry DCM under N2 at r.t. overnight. Et3N (5.4mL) was then added as well as 7.5 g DCC and 3.4g DMAP and stirred at r.t. overnight. Ig DCC and 1.5g DMAP then added and stirred for 2 days at r.t. The mixture was filtered and the filtrate washed with H2O (x4) and brine, dried with Na2SO4, filtered, and the solvent removed in vacuo. The product was purified on a silica gel column (2- 8%MeOH-DCM). The white solid obtained was then heated in boiling EtOAc and filtered hot, to yield 10.769g III (86.8%) (MP: 128-1300C).

Reference： [1]Patent: WO2009/138340,2009,A1 .Location in patent: Page/Page column 56

34
[ 1205603-47-9 ]
[ 475-11-6 ]
[ 1205601-86-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In dichloromethane; at 2℃; for 5h;	B. (S)-1-Methyl-pyrrolidine-2-carboxylic acid {1-[1-benzyl-5-(4-fluoro-phenyl)-1H-[1,2,4]-triazol-3-ylcarbamoyl]-1-methyl-ethyl}-amideA 100 mL rbf was charged DCM (14.29 ml) followed by addition of 2-amino-N-(1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-2-methylpropanamide (1.000 g, 2.83 mmol) and <strong>[475-11-6](S)-1-methylpyrrolidine-2-carboxylic acid</strong> (0.402 g, 3.11 mmol). And it was stirred at room temperature for 10 min, the clear solution save for a couple of particles, was placed in an ice bath at 2 C. Then HATU (2.152 g, 5.66 mmol) and triethylamine (0.789 ml, 5.66 mmol) were added. The yellow semi-solution was allowed to stir at 2 C. for 5 h. It was allowed to warm to room temperarture over night. It was diluted with DCM (25 mL) and H2O (30 mL). The white precipitates were collected by filtration and washed with 1:1 water/sat. NaHCO3 solution. (2×60 mL), brine (2×40 mL). This afforded the title compound 1H NMR (400 MHz, DMSO-d6) d ppm 1.53 (d, J=1.52 Hz, 6H) 1.66-1.78 (m, 3H) 1.96-2.13 (m, 1H) 2.21-2.29 (m, 1H) 2.30 (s, 3H) 2.61-2.70 (m, 1H) 2.99-3.09 (m, 1H) 5.43 (s, 2H) 7.13 (d, J=6.95 Hz, 2H) 7.26-7.43 (m, 5H) 7.68-7.75 (m, 2H) 7.97 (s, 1H) 10.21 (s, 1H). Theoretical mass 464.23, found 464.23. MS (m/z) 465.00 M (+1), tR=1.23, Meth A. ee: 95%, using 30% EtOH Heptane.

Reference： [1]Patent: US2010/22513,2010,A1 .Location in patent: Page/Page column 57

35
6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-amine dihydrochloride [ No CAS ]
[ 475-11-6 ]
[ 1207602-77-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 18h;	21. (S)-N-[6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 1 -yl]-1 -methylprolinamide 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydro- chloride (example 2) (69 mg) is suspended in dichloromethane (2 ml) and (2S)-1-methyl-pyrroli- dine-2-carboxylic acid (47 mg), diisopropylethylamine (108 mul) and 1-ethyl-3-(3-dimethylamino- propyl)-carbodiimide hydrochloride (69 mg) are added. The mixture is stirred for 18 h at room temperature. After that, saturated sodium hydrogencarbonate solution (2 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 3 ml), the combined organic extracts are dried(MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC to yield 41 mg (55%) of the title compound.1H-NMR (400 MHz, d6-DMSO); delta = 1.01 (s, 3H), 1.09 (s, 3H), 1.39-1.50 (m, 1 H), 1.53-1.68 (m, 1 H), 1.85 (s, 1 H), 1.90-2.18 (m, 3H), 2.20 (s, 2H), 2.63-2.94 (m, 4H), 3.68 (s, 3H), 4.24-4.41 (m, 2H), 5.50-5.62 (m, 1 H), 6.83 (d, J = 8.7 Hz, 2H), 7.11 (dd, J = 7.2 Hz, 7.7 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 2H), 7.45-7.53 (m, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.78 (dd, J = 7.9 Hz, 7.9 Hz, 1 H), 8.16 (s, 1 H), 1 1.62 (s, 1 H). MS (MH+ found) = 497.4

Reference： [1]Patent: WO2010/15585,2010,A1 .Location in patent: Page/Page column 100

36
1-amino-4-ethylamino-2-nitrobenzene [ No CAS ]
[ 475-11-6 ]
[ 1219483-79-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In acetonitrile; at 20℃;	A solution of 2-nitro-1,4-phenylenediamine (10.0 g, 65.3 mmol), di-tert-butyl dicarbonate (15.7 g, 71.8 mmol) and DIPEA (13.5 mL, 71.8 mmol) in dioxane (150 mL) was heated at gentle reflux for 1 hr and then allowed to cool to room temperature. The solvent was evaporated and the residue partitioned between DCM (500 mL) and water (200 mL) and the phases separated. The aqueous phase was extracted with DCM (2×200 mL) and the combined DCM layers washed with brine, dried over magnesium sulfate, and concentrated to give tert-butyl 4-amino-3-nitrophenylcarbamate as a brown solid (16.6 g).Sodium hydride (5.24 g of a 60% dispersion in mineral oil, 131 mmol) was added in portions over 25 min to a stirred solution of tert-butyl 4-amino-3-nitrophenylcarbamate (16.6 g, 65.6 mmol) in anhydrous THF (200 mL). The mixture was stirred for a further 10 min and iodoethane (5.2 mL, 65.0 mmol) was added. The mixture was stirred at room temperature for 22 hr and was then quenched by the addition of a little water. The solvent was evaporated and the residue partitioned between EA and brine (300 mL each). The phases were separated and the aqueous phase extracted with EA (2×150 mL). The combined EA layers were washed with brine, dried over magnesium sulfate, and concentrated to give a brown gum (16.0 g), which was purified by column chromatography eluting with 30% EA, 70% hexanes to give tert-butyl 4-amino-3-nitrophenyl(ethyl)carbamate as a brown foam (3.59 g).The tert-butyl 4-amino-3-nitrophenyl(ethyl)carbamate from the previous step was dissolved in dioxane (35 mL) and hydrogen chloride (35 mL of a 4M solution in dioxane) was added. The mixture was stirred at room temperature for 18 hr and then the solvent was evaporated. The residue was dissolved in water (200 mL) and the solution adjusted to pH10 with 5M sodium hydroxide solution. The solution was extracted with EA (3×100 mL), and the combined EA extracts were washed with brine, dried over magnesium sulfate, and concentrated to give N1-ethyl-3-nitrobenzene-1,4-diamine as a purple solid (1.68 g).Triethylamine (1.0 mL, 7.33 mmol) was added to a stirred solution of N1-ethyl-3-nitrobenzene-1,4-diamine (440 mg, 2.43 mmol), <strong>[475-11-6]N-methyl-L-proline</strong> (314 mg, 2.43 mmol) and DEPBT (727 mg, 2.43 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature and further aliquots of <strong>[475-11-6]N-methyl-L-proline</strong> (314 mg, 2.43 mmol), DEPBT (727 mg, 2.43 mmol), and triethylamine (1.0 mL, 7.33 mmol) were added after 1, 2, and 3 days. After stirring for a further 1 day, the mixture was concentrated and the residue taken up in EA (75 mL). The EA solution was extracted with water, and with 1M sodium carbonate solution (2×). The combined water and 1M sodium carbonate solution extracts were back-extracted with EA (4×) and the combined EA extracts washed with brine, dried over magnesium sulfate, and concentrated to give (S)-N-(4-amino-3-nitrophenyl)-N-ethyl-1-methyl-pyrrolidine-2-carboxamide (388 mg) as an orange/brown oil. This was hydrogenated in ethanol, using 10% palladium on carbon (153 mg) as the catalyst. After stirring overnight under a hydrogen atmosphere (balloon), the mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated to give (S)-N-(3,4-diaminophenyl)-N-ethyl-1-methylpyrrolidine-2-carboxamide (335 mg).

Reference： [1]Patent: US2010/81653,2010,A1 .Location in patent: Page/Page column 14

37
[ 1219483-97-2 ]
[ 475-11-6 ]
[ 1219483-98-3 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 5h;	A solution of 1,1,1-trifluoro-2,4-pentanedione (5.00 g; 32.4 mmol) and S-methylisothiourea hemisulfate (4.06 g; 29.2 mmol) in pyridine (3.75 mL) and water (62 mL) was heated at reflux for 1 day. The mixture was cooled to room temperature, extracted with chloroform, and the chloroform extract washed with water to give 4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine as an off-white solid (4.60 g, 22.1 mmol). This was dissolved in MeOH (60 mL), and a solution of OXONE (27.1 g, 44.2 mmol) in water (100 mL) was added over 10 min. The mixture was stirred at room temperature for 4 hr and then extracted with EA. The EA was washed with water, dried, and concentrated to give 4-methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (4.8 g) as a white solid. Sodium hydride (0.16 g of a 60% dispersion in mineral oil; 4.0 mmol) was added to a stirred solution of ethyl cyanoacetate (0.21 mL; 2.0 mmol) in THF (8 mL), and the resulting suspension stirred at room temperature for 15 min. 4-Methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (0.48 g; 2.0 mmol) was then added, and the mixture stirred overnight. Water was added, followed by 1M hydrochloric acid to adjust to pH 3-4. The solid that formed solid was filtered, washed with water, and dried under high vacuum to give ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (0.43 g) as a pale yellow solid.4-Nitro-1,2-phenylenediamine (50 mg; 0.32 mmol) and ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (101 mg; 0.32 mmol) were heated at 198 C. in a microwave for 3 min. Acetic acid (1.5 mL) was added to the crude material and the mixture heated at 100 C. for 6 hr. The solid was collected by filtration, washed with acetonitrile, and dried under high vacuum to give 2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2-(5-nitro-1H-benzimidazol-2(3H)-ylidene)acetonitrile (59 mg) as a yellow solid. 2-[4-Methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2-(5-nitro-1H-benzimidazol-2(3H)-ylidene)acetonitrile (55 mg; 0.15 mmol) in DMF (3 mL) was hydrogenated over 10% palladium on carbon (11 mg). The mixture was filtered through diatomaceous earth, washing with methanol, and the filtrate was concentrated to give 2-(5-amino-1H-benzimidazol-2(3H)-ylidene)-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile, which was dissolved in DMF (1 mL) and added to a solution of <strong>[475-11-6]N-methyl-L-proline</strong> (19.3 mg; 0.16 mmol), HBTU (56.8 mg; 0.15 mmol), and DIPEA (104.5 muL; 0.60 mmol) in DMF (1 mL). The mixture was stirred for 5 hr and then partitioned between EA and water. The EA phase was dried and concentrated to give 2-{5-[(S)-(1-methylpyrrolidin-2-yl)carbonylamino]-1H-benzimidazol-2 (3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile (65 mg) as a brown oil. 2-{5-[(S)-(1-Methylpyrrolidin-2-yl)-carbonylamino]-1H-benzimidazol-2(3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-acetonitrile (65 mg) was dissolved in concentrated sulfuric acid and stirred at room temperature overnight. The mixture was diluted with ice-water and acetonitrile and, after coming to room temperature, was purified by reverse phase preparative HPLC using a Peeke Ultro 120, 7 mum, C18Q, 250×30 mm column at a flow rate of 42 mL/min and mobile phases of 95% water, 5% acetonitrile (with 0.01% hydrochloric acid) and 5% water, 95% acetonitrile (with 0.01% hydrochloric acid) to give 2-{5-[(S)-(1-methylpyrrolidin-2-yl)carbonylamino]-1H-benzimidazol-2 (3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetamide hydrochloride salt (18 mg) as a yellow solid.

Reference： [1]Patent: US2010/81653,2010,A1 .Location in patent: Page/Page column 17-18

38
[ 1235842-15-5 ]
[ 475-11-6 ]
[ 1235841-51-6 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 60h;	To a solution of <strong>[475-11-6](S)-1-methylpyrrolidine-2-carboxylic acid</strong> (16 mg), DIPEA (6OuI) and HBTU (51.7 mg) in dichloromethane (2ml) was added 1-methyl-6-(4-(2- (methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1 H-imidazo[4,5-c]pyridine-4- carbonitrile (51.1 mg).The reaction was left stirring at room temperature for 60hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)-N-(2-(4-(4-cyano-1-methyl-1H- imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N,1-dimethylpyrrolidine- 2-carboxamide (30.2mg).1H NMR (CDCI3) delta: 8.25 (m, 2H), 8.09 (s, 1 H), 7.88 (s, 1 H), 7.10 (d, 1 H), 4.32 (t, 2H), 4.00 (s, 3H), 3.85 (m, 2H),3.27 (s, 3H), 3.16 (m, 2H), 2.39 (s, 3H), 2.32-1.73 (broad m, 6H).MS m/z 487.2 (M + H).
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine;	EXAMPLE 26a (S)-N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)-phenoxy)ethyl)-N,1-dimethylpyrrolidine-2-carboxamide To a solution of <strong>[475-11-6](S)-1-methylpyrrolidine-2-carboxylic acid</strong> (16 mg), DIPEA (60 ul) and HBTU (51.7 mg) in dichloromethane (2 ml) was added 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (51.1 mg). The reaction was left stirring at room temperature for 60 hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)-N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N,1-dimethylpyrrolidine-2-carboxamide (30.2 mg).1H NMR (CDCl3) delta: 8.25 (m, 2H), 8.09 (s, 1H), 7.88 (s, 1H), 7.10 (d, 1H), 4.32 (t, 2H), 4.00 (s, 3H), 3.85 (m, 2H), 3.27 (s, 3H), 3.16 (m, 2H), 2.39 (s, 3H), 2.32-1.73 (broad m, 6H). MS m/z 487.2 (M+H).

Reference： [1]Patent: WO2010/81859,2010,A1 .Location in patent: Page/Page column 67
[2]Patent: US2010/184761,2010,A1 .Location in patent: Page/Page column 36

39
[ 1235842-23-5 ]
[ 475-11-6 ]
[ 1235841-59-4 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 60h;	To a solution of <strong>[475-11-6](S)-1-methylpyrrolidine-2-carboxylic acid</strong> (16 mg), DIPEA (6OuI) and HBTU (51.7 mg) in dichloromethane (2ml) was added 1-methyl-6-(4-(2- (ethylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1 H-imidazo[4,5-c]pyridine-4- carbonitrile (55 mg).The reaction was left stirring at room temperature for 60hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)-N-(2-(4-(4-cyano-1-methyl-1H- imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-ethyl-1-methyl- pyrrolidine-2-carboxamide (40mg). 1H NMR (CDCI3) delta: 8.24 (m, 2H), 8.07 (s, 1 H), 7.85 (s, 1 H), 7.09 (d, 1 H), 4.33 (m, 2H), 3.99 (s, 3H), 3.76 (dm, 2H), 3.60 (m, 2H), 3.15 (m, 2H), 2.34 (s, 3H), 2.33-1.74 (broad m, 6H), 1.24 (t, 3H).MS m/z 501.2 (M + H).
		B: (S)-N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-ethyl-1-methylpyrrolidine-2-carboxamideTo a solution of <strong>[475-11-6](S)-1-methylpyrrolidine-2-carboxylic acid</strong> (16 mg), DIPEA (60 ul) and HBTU (51.7 mg) in dichloromethane (2 ml) was added 1-methyl-6-(4-(2-(ethylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (55 mg). The reaction was left stirring at room temperature for 60 hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)-N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-ethyl-1-methyl-pyrrolidine-2-carboxamide (40 mg).1H NMR (CDCl3) delta: 8.24 (m, 2H), 8.07 (s, 1H), 7.85 (s, 1H), 7.09 (d, 1H), 4.33 (m, 2H), 3.99 (s, 3H), 3.76 (dm, 2H), 3.60 (m, 2H), 3.15 (m, 2H), 2.34 (s, 3H), 2.33-1.74 (broad m, 6H), 1.24 (t, 3H). MS m/z 501.2 (M+H).

Reference： [1]Patent: WO2010/81859,2010,A1 .Location in patent: Page/Page column 69
[2]Patent: US2010/184761,2010,A1 .Location in patent: Page/Page column 37

40
[ 99-09-2 ]
[ 475-11-6 ]
[ 1254216-44-8 ]

Yield	Reaction Conditions	Operation in experiment
	With HATU; In N,N-dimethyl-formamide; for 20h;	To a solution of (S)-I -methylpyrrolidine-2-carboxylic acid (258 mg, 2 mmol) in DMF (4 mL) was added 3-nitroaniline (276 mg, 2 mmol) and HATU (760 mg).After stirring for 20 h, it was added with EtOAc, washed with Sat. NaHCO3, brine, dried and concentrated to give (S)-l-methyl-N-(3-nitrophenyl)pyrrolidine-2-carboxamide.

Reference： [1]Patent: WO2010/129802,2010,A1 .Location in patent: Page/Page column 193

41
[ 1257049-55-0 ]
[ 475-11-6 ]
N-[(3-chloro-4-[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 312 N-[(3-chloro-4-[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide To EXAMPLE 294B (0.065 g) was added hydrogen chloride (4.0M in dioxane, 0.339 mL) and a few drops of methanol. After 30 minutes, the reaction was concentrated, and <strong>[475-11-6](S)-1-methylpyrrolidine-2-carboxylic acid</strong> (0.013 g), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.026 g), suspended in dichloromethane (0.5 mL) were added followed by diisopropylethylamine (0.036 mL). The mixture stirred at room temperature. After stirring overnight, the reaction mixture was loaded onto silica gel (Reveleris 40 g) and eluted using a gradient of 1% to 10% methanol (containing 1N NH3)/dichloromethane over 30 minutes (flow=40 mL/minutes) to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) delta 11.51 (s, 1H), 10.00-9.22 (m, 1H), 7.92 (d, 1H), 7.68 (d, 1H), 7.57 (d, 1H), 7.47 (dd, 1H), 7.44-7.38 (m, 1H), 7.38-7.31 (m, 2H), 7.29 (d, 1H), 7.12-7.01 (m, 2H), 6.90 (d, 1H), 6.61 (dd, 1H), 6.31 (dd, 1H), 6.25 (d, 1H), 5.85 (d, 1H), 4.40 (s, 1H), 3.92 (s, 4H), 3.17-2.89 (m, 8H), 2.73 (s, 4H), 2.38 (s, 3H), 2.18 (m, 6H), 1.96 (s, 2H), 1.80 (m, 2H), 1.57 (s, 2H), 1.39 (s, 2H), 1.22 (m, 2H), 0.96 (m, 6H).
	With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; methanol; at 20℃;	(0949) To Compound 294B (0.065 g) was added hydrogen chloride (4.0M in dioxane, 0.339 ml) and a few drops of methanol. After 30 minutes, the reaction was concentrated, and <strong>[475-11-6](S)-1-methylpyrrolidine-2-carboxylic acid</strong> (0.013 g), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.026 g), suspended in dichloromethane (0.5 ml) were added followed by diisopropylethylamine (0.036 ml). The mixture stirred at room temperature. After stirring overnight, the reaction mixture was loaded onto silica gel (Reveleris 40 g) and eluted using a gradient of 1% to 10% methanol (containing 1N NH3)/dichloromethane over 30 minutes (flow=40 ml/minutes) to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) delta 11.51 (s, 1H), 10.00-9.22 (m, 1H), 7.92 (d, 1H), 7.68 (d, 1H), 7.57 (d, 1H), 7.47 (dd, 1H), 7.44-7.38 (m, 1H), 7.38-7.31 (m, 2H), 7.29 (d, 1H), 7.12-7.01 (m, 2H), 6.90 (d, 1H), 6.61 (dd, 1H), 6.31 (dd, 1H), 6.25 (d, 1H), 5.85 (d, 1H), 4.40 (s, 1H), 3.92 (s, 4H), 3.17-2.89 (m, 8H), 2.73 (s, 4H), 2.38 (s, 3H), 2.18 (m, 6H), 1.96 (s, 2H), 1.80 (m, 2H), 1.57 (s, 2H), 1.39 (s, 2H), 1.22 (m, 2H), 0.96 (m, 6H).

Reference： [1]Patent: US2010/305122,2010,A1 .Location in patent: Page/Page column 219
[2]Patent: US10213433,2019,B2 .Location in patent: Page/Page column 229

42
(R)-2-amino-3,3-dicyclohexyl-N-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-propionamide dihydrochloride [ No CAS ]
[ 76-05-1 ]
[ 475-11-6 ]
(S)-1-methyl-pyrrolidine-2-carboxylic acid {(R)-2,2-dicyclohexyl-1-[(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-carbamoyl]-ethyl}-amide ditrifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		(R)-2-Amino-3,3-dicyclohexyl-N-(lH-pyrrolo[2,3-b]pyridin-5-ylmethyl)-propionarnide dihydrochloride (lOOmg, 0.22mmol) was dissolved in CH2C12 (20mls) and DMF (2mls). This solution was cooled to 0C. N-Me-Pro-OH (31mg, 0.24mmol) was added followed by HOBt (36mg, 0.26mmol) and triethylamine (67mg, 0.66mmol). Water soluble carbodiimide (46mg, 0.24mmol) was then added. After 18 hrs at room temperature the reaction mixture was diluted with CHCI3 (50mls), this solution was washed with sat. NaHC03 (lx20mls), water (lx20mls), brine (lx20mls), dried (Na2S04) and evaporated in vacuo. The residue was purified by Prep HPLC (19x250 mm Sunfire C-18 Column) 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H2O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.Yield = 62mg, 0.086mmol, 39%[M+H]+ = 494.33 NMR: (CD3OD) 0.98-1.29(12H, m), 1.50-1.78(1 lH,m), 2.09-2.10(3H, m), 2.26- 2.28(lH,m), 2.60-2.63(1 H,m), 2.92(3H,s), 3.25-3.31(1H, m), 3.76-3.78(lH, m), 4.16- 4.20(lH,m), 4.48-4.53(lH,m), 4.62-4.7 l(2H,m), 6.67(1H, d, J = 3.48 Hz) 7.58(lH,d,J=3.52Hz), 8.31-8.35(3H,m), 8.87-8.90 (1H, m).

Reference： [1]Patent: WO2011/51672,2011,A1 .Location in patent: Page/Page column 78

43
[ 475-11-6 ]
[ 100-51-6 ]
benzyl (2S)-1-methyltetrahydro-1H-pyrrole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h;Inert atmosphere;	General procedure: Benzyl alcohol (1.00 mmol), N,N-dimethylamino acid (1.20 mmol), 1,3-dicyclohexylocarbodiimide (1.20) mmol and DMAP (0.10 mmol) were stirred in dry DCM (5 mL) under an argon atmosphere for 24 h. The precipitate was removed by filtration, and the residue was washed with DCM (5 mL). The solvent was evaporated, and the residue was purified by flash column chromatography.

Reference： [1]Tetrahedron Asymmetry,2011,vol. 22,p. 464 - 467

44
(R)-2-amino-N-(2-amino-thiazol-5-ylmethyl)-3,3-dicyclohexyl-propionamide ditrifluoroacetate [ No CAS ]
[ 76-05-1 ]
[ 475-11-6 ]
(S)-1-methyl-pyrrolidine-2-carboxylic acid {(R)-1-[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide ditrifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		N-Me-Pro-OH (60mg, 0.46mmol) was dissolved in CH2C12 (30mls). Triethylamine (Hlrng, 1.392mmol) and HBTU (194mg, 0.51mmol) was added followed by (R)-2- amino-N-(2-amino-thiazol-5 -ylmethyl)-3 ,3 -dicyclohexyl-propionamideditrifluoroacetate (303mg, 0.51mmol). After 20mins at room temperature the reaction mixture was diluted with CHC13 (50mls), this solution was washed with sat. NaHC03 (lx20mls), water (lx20mls), brine (lx20mls), dried (Na2S04) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 7% methanol, 93% CHC13, fractions combined and evaporated in vacuo. The residue was further purified by Prep HPLC (19x250 mm Sunfire C-18 Column) 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H2O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.Yield = 32mg, 0.045mmol, 10%[M+H]+ = 476.27 NMR: (CD3OD) 1.04-1.38(12H, m), 1.50-1.82(1 lH,m), 2.05-2.15(2H, m), 2.25- 2.31(lH,m), 2.62-2.68(1 H,m), 2.98(3H,s), 3.25-3.32(l H, m), 3.76-3.81(lH, m), 4.20- 4.24(lH,m), 4.29-4.34(1 H,m), 4.44-4.49(1 H,m), 4.70(1H, d, J = 7.48 Hz), 4.91 (4H,s), 7.17(lH,s).

Reference： [1]Patent: WO2011/51673,2011,A1 .Location in patent: Page/Page column 76-77

45
[ 1215385-42-4 ]
[ 475-11-6 ]
[ 1215384-62-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 20℃; for 48h;Inert atmosphere;	EXAMPLE 8 1-methyl-7-[4-((2S)-1-methyl-pyrrolidine-2-carbonyl)-[1,4]diazepan-1-ylmethyl]-1H-indole-2-carboxylic acid-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide Under nitrogen, 90 mg of 7-[1,4]diazepan-1-ylmethyl-1-methyl-1H-indole-2-carboxylic acid-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide and 28 mg of (S)-1-methyl-pyrrolidine-2-carboxylic acid are dissolved in 2 ml of tetrahydrofuran. 140 mul triethylamine and 160 mul of a 50% solution of n-propylphosphonic anhydride in ethyl acetate are added one after the other and the mixture is stirred for 48 hours at ambient temperature. Then it is diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol/(ammonia in methanol (saturated)) 97:3:0 to 93:6:1). The product thus obtained is dissolved in a little diethyl ether and crystallised out by the addition of n-hexane. The solid is suction filtered and dried. Yield: 38 mg (35% of theory) Rf value: 0.76 (silica gel, dichloromethane/methanol/(ammonia in methanol (saturated)) 90:10:0.1) Mass spectrum (ESI+): m/z=653 [M+H]+

Reference： [1]Patent: US2011/269737,2011,A1 .Location in patent: Page/Page column 73

46
[ 471-87-4 ]
[ 475-11-6 ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 2823 - 2834

47
[ 2592-95-2 ]
[ 475-11-6 ]
C₁₂H₁₄N₄O₂ [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 2389 - 2397

48
[ 475-11-6 ]
[ 112515-27-2 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 2389 - 2397

49
[ 475-11-6 ]
Amathamide D [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 2389 - 2397
[2]Journal of Organic Chemistry,2012,vol. 77,p. 2389 - 2397

50
[ 39565-07-6 ]
[ 475-11-6 ]
[ 1373511-37-5 ]

Reference： [1]European Journal of Inorganic Chemistry,2012,p. 1680 - 1687

51
[osmium(II)dichloride(η6-p-cymene)]2 [ No CAS ]
[ 475-11-6 ]
[(η6-p-MeC6H4iPr)Os(N-methyl-L-prolinate)Cl] [ No CAS ]

Reference： [1]Organometallics,2012,vol. 31,p. 3333 - 3345

52
(8S,9S,10R,13S,14S,17S)-17-((E)-1-(hydroxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)one [ No CAS ]
[ 475-11-6 ]
C₂₇H₄₀N₂O₃ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 362 - 366

53
[ 1315484-16-2 ]
[ 475-11-6 ]
[ 1315484-69-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5901 - 5921

54
[ 1383728-81-1 ]
[ 475-11-6 ]
[ 1383728-84-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 3h;Inert atmosphere;	HATU (1 16 mg, 0.30 mmol) was added to a mixture of 9-piperidin-4-yl-3,9-dihydro-3,4,6,9-tetraaza-cyclopenta[a]naphthalene-8-one (75.0 mg, 0.27 mmol), N-methyl-l-proline (36.0 mg, 0.28 mmol) and diisopropylethylamine (95.0 muL·, 0.55 mmol) in DMF (2 mL) and stirred under argon for 3 hours. Methanol was added and the resulting suspension was filtered and the isolated solid was air dried. Purification by HPLC (gradient: 5 to 60% acetonitrile in water with 0.1% ammonium hydroxide) gave 9-[l -((S)-l -methyl-pyrrolidine-2-carbonyl)-piperidin-4-yl]- 3,9-dihydro-3,4,6,9-tetraaza-cyclopenta[a]naphthalene-8-one as a white solid. LCMS (Method A, ESI): RT = 1.96 mm, m+H = 381.16; XH NMR (400MHz, OMSO-d6) delta: 12.34 (1 H, br s), 8.60 (1 H, s), 7.97 (1 H, s), 7.60 (1 H, d), 6.85 (1 H, d), 5.13 (1 H, m), 4.58 (1 H, d), 4.42 (1 H, m), 3.30-3.08 (2 H, m), 2.96 (1 H, t), 2.76 (2 H, m), 2.64 (1 H, m), 2.24 (3 H, s), 2.19 - 2.07 (2 H, m), 1.85 (2 H, m), 1.73 (3 H, m).

Reference： [1]Patent: WO2012/85176,2012,A1 .Location in patent: Page/Page column 100-101

55
C₁₅H₂₃ClO₂Rh [ No CAS ]
[ 475-11-6 ]
C₁₆H₂₅ClNO₂Rh [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In methanol; for 24h;	General procedure: To a solution of the corresponding acetylacetonate compound [(etan-ring)M(acac)Cl] (1.0 mmol) in methanol (20 mL) the appropriate amino acid (1.0 mmol) was added. The resulting solution was stirred for 24 h and then filtered through Kieselguhr to eliminate any solid residue. The solvent was then removed in vacuum until dryness. The d.e. of the residue was determined by 1H NMR spectroscopy. Then, it was redissolved in a minimum amount of methanol. Orange ( rhodium or ruthenium) or yellow (iridium) products were precipitated by addition of Et2O. The solids were filtered off, washed with Et2O and vacuum dried.

Reference： [1]Journal of Organometallic Chemistry,2012,vol. 717,p. 152 - 163

56
[ 1314960-42-3 ]
[ 475-11-6 ]
[ 1443245-52-0 ]

Yield	Reaction Conditions	Operation in experiment
56%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;Inert atmosphere;	c. (S)-l-Methyl-pyrrolidine-2-carboxylic acid N'-(5-fluoro-3-methyl- pyridin-2-yl)-hydrazide (Interme A solution of Intermediate 105b (76 mg, 0.537 mmol), (S)-l-methyl- pyrrolidine-2-carboxylic acid (55 mg, 0.72 mmol) and HOBT (8 mg, 0.72 mmol) in anhydrous DCM (5 mL) was treated with EDC (138 mg, 0.717 mmol) and stirred at RT under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM, to afford the title compound (76 mg, 56%). NM (400 MHz, CDC13): 1.74-2.05 (3H, m), 2.15-2.33 (4H, m), 2.34- 2.46 (1H, m), 2.52 (3H, s), 3.02-3.12 (1H, m), 3.15-3.25 (1H, m), 6.70 (1H, s), 7.08-7.18 (1H, m), 7.90 (1H, d, J = 2.8 Hz), 9.52 (1H, br s).

Reference： [1]Patent: WO2013/83604,2013,A1 .Location in patent: Page/Page column 352; 353

57
(5-fluoro-pyridin-2-yl)-hydrazine [ No CAS ]
[ 475-11-6 ]
[ 1443242-90-7 ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;	a. (S)-l-Methyl-pyrrolidine-2-carboxylic acid [N'-(5-fluoro-pyridin- 2-yl)-hydrazide (Intermediate 5a) EDC (271 mg, 1.41 mmol) was added portionwise to a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO2010022076; 0.15 g, 1.18 mmol), <strong>[475-11-6]N-methyl-L-proline</strong> monohydrate (0.20 g, 1.36 mmol) and HOBt (16 mg, 0.12 mmol) in dry DCM (5 mL) at RT and stirred for 16 h. The solution was diluted with DCM (15 mL), washed with water (150 mL), dried (Na2SO4) and evaporated to give the title compound as a pale yellow gum (189 mg, 67%). LCMS (Method 1): Rt 0.31 min, m/z 239 [MH+].
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;	a. (S)-1-Methyl-pyrrolidine-2-carboxylic acid[N'-(5-fluoro-pyridin-2-yl)-hydrazide (Intermediate 5a) EDC (271 mg, 1.41 mmol) was added portionwise to a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 0.15 g, 1.18 mmol), <strong>[475-11-6]N-methyl-L-proline</strong> monohydrate (0.20 g, 1.36 mmol) and HOBt (16 mg, 0.12 mmol) in dry DCM (5 mL) at RT and stirred for 16 h. The solution was diluted with DCM (15 mL), washed with water (150 mL), dried (Na2SO4) and evaporated to give the title compound as a pale yellow gum (189 mg, 67%). LCMS (Method 1): Rt 0.31 min, m/z 239 [MH+].
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;	a. (S)-1-Methyl-pyrrolidine-2-carboxylic acid [N'-(5-fluoro-pyridin-2-yl)-hydrazide (Intermediate Ea) EDC (271 mg, 1.41 mmol) was added portionwise to a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO2010/02207, which is incorporated herein by reference 6; 0.15 g, 1.18 mmol), <strong>[475-11-6]N-methyl-L-proline</strong> monohydrate (0.20 g, 1.36 mmol) and HOBt (16 mg, 0.12 mmol) in dry DCM (5 mL) at RT and stirred for 16 h. The solution was diluted with DCM (15 mL), washed with water (150 mL), dried (Na2SO4) and evaporated to give Intermediate Ea (189 mg, 67%). LCMS (Method 1): Rt 0.31 min, m/z 239 [MH+].

67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;	EDC (271 mg, 1.41 mmol) was added portionwise to a solution of 5- fluoro-2-hydrazinyl-pyridine (for reference procedure see WO2010022076; 0.15 g, 1.18 mmol), <strong>[475-11-6]N-methyl-L-proline</strong> monohydrate (0.20 g, 1.36 mmol) and HOBt (16 mg, 0.12 mmol) in dry DCM (5 mL) at RT and stirred for 16 h. The solution was diluted with DCM (15 mL), washed with water (150 mL), dried (Na2SO4) and evaporated to give the title compound as a pale yellow gum (189 mg, 67%). LCMS (Method 1): Rt 0.31 min, m/z 239 [MH+].
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;	EDC (271 mg, 1.41 mmol) was added portionwise to a solution of 5-fluoro-2- hydrazinyl-pyridine (for reference procedure see WO2010022076; 0.15 g, 1.18 mmol), N- methyl-L-proline monohydrate (0.20 g, 1.36 mmol) and HOBt (16 mg, 0.12 mmol) in dry DCM (5 mL) at RT and stirred for 16 h. The solution was diluted with DCM (15 mL), washed with water (150 mL), dried (Na2S04) and evaporated to give Intermediate Ea (189 mg, 67%). LCMS (Method 1): Rt 0.31 min, m/z 239 [MH+].

Reference： [1]Patent: WO2013/83604,2013,A1 .Location in patent: Page/Page column 134; 135
[2]Patent: US2013/150343,2013,A1 .Location in patent: Paragraph 0587; 0588
[3]Patent: US2014/364412,2014,A1 .Location in patent: Paragraph 0457; 0458
[4]Patent: WO2014/194956,2014,A1 .Location in patent: Page/Page column 99-100
[5]Patent: WO2014/195402,2014,A1 .Location in patent: Page/Page column 97

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[ 475-11-6 ]
[ 1443239-97-1 ]