[ CAS No. 41365-75-7 ] {[proInfo.proName]}

Name: 41365-75-7|1-Amino-3,3-diethoxypropane|97%
Brand: Ambeed
SKU: A468946
Rating: 95 (28 reviews)

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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 41365-75-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 41365-75-7 ]

CAS No. :	41365-75-7	MDL No. :	MFCD00142581
Formula :	C₇H₁₇NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PXXMSHBZYAOHBD-UHFFFAOYSA-N
M.W :	147.22	Pubchem ID :	521029
Synonyms :

Calculated chemistry of [ 41365-75-7 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	6
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	40.64
TPSA :	44.48 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.03 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.09
Log Po/w (XLOGP3) :	0.24
Log Po/w (WLOGP) :	0.73
Log Po/w (MLOGP) :	0.48
Log Po/w (SILICOS-IT) :	0.57
Consensus Log Po/w :	0.82

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.51
Solubility :	45.7 mg/ml ; 0.311 mol/l
Class :	Very soluble
Log S (Ali) :	-0.73
Solubility :	27.1 mg/ml ; 0.184 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.42
Solubility :	5.56 mg/ml ; 0.0378 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.14

Safety of [ 41365-75-7 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3267
Hazard Statements:	H227-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 41365-75-7 ]

* 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 [ 41365-75-7 ]
Downstream synthetic route of [ 41365-75-7 ]

[ 41365-75-7 ] Synthesis Path-Upstream 1~7

1
[ 107833-73-8 ]
[ 41365-75-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 12 h;	To a solution of 5 (17.7 g, 0.1 mol) in MeOH (20 mL) was added Pd/C (10percent, 15 mg) and stirred at rt for 12 h under 10 atmospheres of H₂. The filtrate through Celite was concentrated under reduced pressure to give 6 (14.4 g, 98percent) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.14 (t, 6H, J = 6.8 Hz), 1.29 (br s, 2H), 1.71 (q, 2H, J = 6.4 Hz), 2.73 (t, 2H, J = 6.4 Hz), 3.45 (q, 2H, J = 7.2 Hz), 3.60 (q, 2H, J = 7.2 Hz), 4.53 (t, 1H, J = 5.2 Hz). IR (neat): 3385, 2953, 2831, 1621, 1389 cm⁻¹; MS (EI): m/z: 147 [M⁺]

Reference： [1] Tetrahedron Asymmetry, 2013, vol. 24, # 4, p. 207 - 211

2
[ 2453-90-9 ]
[ 41365-75-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With hydrazine In methanol; dichloromethane	2. Preparation of 3,3-diethoxypropylamine (Compound 2), A solution of N-(3,3-diethoxypropyl)phthalimide (1) (16.5 g, 59.5 mmol) and hydrazine (3.8 g, 120 mmol) in methanol (300 ml) was stirred at reflux for 4 hours (a mechanical stirrer was necessary as the mixture thickened considerably). The mixture was cooled with continued stirring, and filtered, washing the precipitate with methanol. The filtrate was evaporated to a semi-solid mass, which was taken up in methylene chloride (150 ml) and filtered again. The filtrate was concentrated and the residue was distilled in vacuo to provide Compound 2 as a colorless liquid (6.5 g, 70percent). (The reported boiling point is ca. 60° C. at 4 mm of Hg, ca. 70° C. at 20 mm of Hg.).

Reference： [1] Journal of Heterocyclic Chemistry, 1981, vol. 18, # 5, p. 941 - 946
[2] Patent: US5171754, 1992, A,

3
[ 688317-69-3 ]
[ 41365-75-7 ]

Reference： [1] Bioorganic Chemistry, 2005, vol. 33, # 2, p. 90 - 107

4
[ 35573-93-4 ]
[ 41365-75-7 ]

Reference： [1] Chemische Berichte, 1944, vol. 77/79, p. 617,626
[2] Journal of Organic Chemistry, 1988, vol. 53, # 18, p. 4175 - 4181
[3] Bioorganic Chemistry, 2005, vol. 33, # 2, p. 90 - 107
[4] Journal of Heterocyclic Chemistry, 1981, vol. 18, # 5, p. 941 - 946

5
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[ 41365-75-7 ]

Reference： [1] Archiv der Pharmazie, 1995, vol. 328, # 6, p. 487 - 495
[2] Tetrahedron Asymmetry, 1993, vol. 4, # 11, p. 2307 - 2310

6
[ 41365-74-6 ]
[ 41365-75-7 ]

Reference： [1] Journal of medicinal chemistry, 1973, vol. 16, # 1, p. 1 - 5

7
[ 35573-93-4 ]
[ 41365-75-7 ]
[ 854253-50-2 ]

Reference： [1] Chemische Berichte, 1901, vol. 34, p. 1917

[ 41365-75-7 ] Synthesis Path-Downstream 1~72

1
[ 35573-93-4 ]
[ 41365-75-7 ]

Yield	Reaction Conditions	Operation in experiment
	With ethanol; ammonia
	With sodium azide; hydrogen 1.) DMF, 2.) C₂H₅OH, 4 d; Yield given. Multistep reaction;
	Multi-step reaction with 2 steps 1: NaN₃ / dimethylsulfoxide / 16 h / 50 °C 2: 8.2 g / H₂ / 5 percent Pd/C / methanol / 2 h / 20 °C / 2585.74 Torr

Multi-step reaction with 2 steps 1: 83 percent / dimethylformamide / 5 h / 145 °C 2: 87 percent / hydrazine / methanol / 2 h / Heating

Reference： [1]Albers et al. [Chemische Berichte, 1944, vol. 77/79, p. 617,626]
[2]Durrwachter, John R.; Wong, Chi-Huey [Journal of Organic Chemistry, 1988, vol. 53, # 18, p. 4175 - 4181]
[3]Xun, Jin; Huang, Haidong; Vogel, Kurt W.; Drueckhammer, Dale G. [Bioorganic Chemistry, 2005, vol. 33, # 2, p. 90 - 107]
[4]Carroll; Berrang; Linn [Journal of Heterocyclic Chemistry, 1981, vol. 18, # 5, p. 941 - 946]

2
[ 2453-90-9 ]
[ 41365-75-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With hydrazine; In methanol; dichloromethane;	2. Preparation of 3,3-diethoxypropylamine (Compound 2), A solution of N-(3,3-diethoxypropyl)phthalimide (1) (16.5 g, 59.5 mmol) and hydrazine (3.8 g, 120 mmol) in methanol (300 ml) was stirred at reflux for 4 hours (a mechanical stirrer was necessary as the mixture thickened considerably). The mixture was cooled with continued stirring, and filtered, washing the precipitate with methanol. The filtrate was evaporated to a semi-solid mass, which was taken up in methylene chloride (150 ml) and filtered again. The filtrate was concentrated and the residue was distilled in vacuo to provide Compound 2 as a colorless liquid (6.5 g, 70%). (The reported boiling point is ca. 60 C. at 4 mm of Hg, ca. 70 C. at 20 mm of Hg.).

Reference： [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 941 - 946
[2]Patent: US5171754,1992,A

3
[ 41365-75-7 ]
[ 24424-99-5 ]
[ 153815-24-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	In dichloromethane; at 20℃; for 2h;	Step 1: tert-Butyl (3,3-diethoxypropyl)carbamate A solution of di-tert-butyl dicarbonate (6.74 g, 31.0 mmol) in DCM (50 mL) was added to a solution of 1-amino-3,3-diethoxypropane (5.0 g, 34.0 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 10% aqueous potassium hydrogen sulfate and the organic phase dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title product (8.13 g, 100%). 1H NMR (400 MHz, CDCl3): delta 5.00 (s, 1H), 4.56-4.53 (m, 1H); 3.69-3.62 (m, 2H); 3.54-3.46 (m, 2H); 3.24-3.20 (m, 2H); 1.84-1.80 (m, 2H); 1.49 (s, 9H); 1.23-1.19 (m, 6H).
94%	With triethylamine; In dichloromethane; at 0 - 20℃; for 16.25h;	3,3-diethoxypropan-1-amine (1) (5.24 g, 35.6 mmol) was diluted in a mixture of dichloromethane (80 mL) and triethylamine (5.12 mL). The solution was cooled to 0 C., and a solution of di-tert-butyl-dicarbonate (7.85 g, 35.97 mmol) in dichloromethane (20 mL) was slowly added over a 15-minute period. The mixture was stirred for 16 h, at room temperature. The organic phase was washed with 1N HCl (1×100 mL), 0.5N HCl (1×100 mL), and brine (2×100 mL) before it was dried with anhydrous magnesium sulphate, filtered and concentrated. Le crude product was purified by flash chromatography on silica gel (eluent:hexanes/ethyl acetate 7:3). The protected amine was obtained as a yellow oil (8.36 g, 94%). 1H NMR (300 MHz, CDCl3) delta (ppm) 4.93 (s, 1H), 4.53 (t, 1H, J=5.5 Hz), 3.56 (d-quint, 4H, J=38.9 Hz, J=2.3 Hz), 3.20 (q, 2H, J=6.2 Hz), 1.79 (q, 2H, J=6.2 Hz), 1.42 (s, 9H), 1.19 (t, 6H, J=7.1 Hz). 13C NMR (75.5 MHz, CDCl3) delta (ppm) 155.9, 101.9, 78.9. 61.5, 36.7, 33.4, 28.4, 15.3. IR (CHCl3) v (cm-1) 3363 (br), 2979, 2920, 2880, 1708, 1514, 1448, 1393, 1365, 1171, 1139, 1065.
90%	With triethylamine; In 1,4-dioxane; water;	a-5-1) 1-tert-Butoxycarbonylamino-3,3-diethoxypropane A mixture of di-tert-butyl dicarbonate (9 g, 40 mmol.) in dioxane (40 ml) is added drop by drop, with stirring and at 0 C., to a solution of 1-amino-3,3-diethoxypropane (5.52 g, 37 mmol) and Et3N (4.04 g, 40 mmol) in 5 ml dioxane. After 2 hrs, the mixture is stirred at ambient temperature for 12 hrs then the solvent is evaporated. The residual oil is taken up in 10 ml of water, acidified with 30 ml HCl (1%), then extracted with ethyl acetate (60 ml*3). The organic phases are dried (MgSO4) and evaporated to give 8.89 g of 1-tert-butoxycarbonylamino-3,3-diethoxypropane (90%). 1H NMR (CDCl3): 1.20 (t, 6H, J=8.8 Hz, CH3), 1.40 (s, 9H, C(CH3)3), 1.60-2.00 (m, 2H, CH2C), 3.00-3.80 (m, 6H, OCH2+NHCH2), 4.50 (t, 1H, J=6.4 Hz, CH), 5.05-5.10 (br, 1H, NH).

81%	With triethylamine; In 1,4-dioxane; at 0 - 20℃;	3,3-diethoxypropan-1-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in1,4-dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then cooled to 0C. (Boc)20 (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1,4- dioxane was added drop-wise. The solution was agitated 2 hours at 0C then overnight at ambient temperature before being neutralised with 10 mL of water. The pH was adjusted to 5 with HC1 (1 %). The solution was extracted 3 times with 50 mL of EtOAc.The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 8.21 g (81 %) of compound 1ZD in the form of a pale yellow oil.
81%	With triethylamine; In 1,4-dioxane; at 0 - 20℃;	3,3-diethoxypropan-1-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in1,4-dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then cooled to 0C. (Boc)20 (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1,4- dioxane was added drop-wise. The solution was agitated 2 hours at 0C then overnight at ambient temperature before being neutralised with 10 mL of water. The pH was adjusted to 5 with HC1 (1 %). The solution was extracted 3 times with 50 mL of EtOAc.The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 8.21 g (81 %) of compound 1ZD in the form of a pale yellow oil.
81%	With triethylamine; In 1,4-dioxane; at 0 - 20℃;	3,3-diethoxypropan-1-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in1,4-dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then cooled to 0C. (Boc)20 (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1,4- dioxane was added drop-wise. The solution was agitated 2 hours at 0C then overnight at ambient temperature before being neutralised with 10 mL of water. The pH was adjusted to 5 with HC1 (1 %). The solution was extracted 3 times with 50 mL of EtOAc.The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 8.21 g (81 %) of compound 1ZD in the form of a pale yellow oil.
81%	With triethylamine; In 1,4-dioxane; at 0℃;	Compound 1ZD: tert-butyl N-(3 ,3-diethoxypropyl)carbamate 3,3-diethoxypropan-1-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in1,4-dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then cooled to 0C. (Boc)20 (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1,4- 25 dioxane was added drop-wise. The solution was agitated 2 hours at 0C then overnightat ambient temperature before being neutralised with 10 mL of water. The pH was adjusted to 5 with HC1 (1 %). The solution was extracted 3 times with 50 mL of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 8.21 g (81 %) of compound 1ZD in the form of a pale yellow oil.
81%	With triethylamine; In 1,4-dioxane; at 0 - 20℃;	Compound 1ZD: tert-butyl N-(3,3-diethoxypropyl)carbamate 3,3-diethoxypropan-l-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in 1,4-dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then cooled to 0C. (Boc)20 (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1,4- dioxane was added drop-wise. The solution was agitated 2 hours at 0C then overnight at ambient temperature before being neutralised with 10 mL of water. The pH was adjusted to 5 with HC1 (1 %). The solution was extracted 3 times with 50 mL of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 8.21 g (81 %) of compound 1ZD in the form of a pale yellow oil.
81%	With triethylamine; In 1,4-dioxane; at 0 - 20℃;	3,3-diethoxypropan-l-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in 1 ,4-dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then cooled to 0C. (Boc)20 (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1 ,4- dioxane was added drop-wise. The solution was agitated 2 hours at 0C then overnight at ambient temperature before being neutralised with 10 mL of water. The pH was adjusted to 5 with HC1 (1 %). The solution was extracted 3 times with 50 mL of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 8.21 g (81 %) of compound 1ZD in the form of a pale yellow oil.
81%	With triethylamine; In 1,4-dioxane; at 0 - 20℃;	Compound 1ZD: tert-butyl N-(3,3-diethoxypropyl)carbamate 3,3-diethoxypropan-1-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in 1,4-dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then cooled to 0 C. (Boc)2O (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1,4-dioxane was added drop-wise. The solution was agitated 2 hours at 0 C. then overnight at ambient temperature before being neutralised with 10 mL of water. The pH was adjusted to 5 with HCl (1%). The solution was extracted 3 times with 50 mL of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 8.21 g (81%) of compound 1ZD in the form of a pale yellow oil.
81%	With triethylamine; In 1,4-dioxane; at 0 - 20℃;	3,3-diethoxypropan-1-amine (6 g, 40.76 mmol, 1.00 equiv) was dissolved in 1,4- dioxane (30 mL) in the presence of TEA (4.45 g, 43.98 mmol, 1.08 equiv), then cooled to0C. (Boc)20 (9.6 g, 43.99 mmol, 1.08 equiv) diluted in 20 mL of 1,4-dioxane was added drop-wise. The solution was agitated 2 hours at 0C then overnight at ambient temperature before being neutralised with 10 mL of water. The pH was adjusted to 5 with HC1 (1 %). The solution was extracted 3 times with 50 mL of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 8.21 g (81 %) of compound 1ZDin the form of a pale yellow oil.
		To (3,3-diethoxypropyl)amine (1.00 equiv) in THF (2 volumes) was charged di-t-butyldicarbonate (1.05 equiv) in THF (3 volumes). The reaction was heated to 45 C. and held for ½ h. Analysis showed the disappearance of starting material, and the resulting solution was heated to 65 C. p-Toluene sulphonic acid (0.1 equiv) and water (5 volumes) were charged over 10 mins, heating continued at 65 C. and held for ½ hour. Analysis showed disappearance of tert-butyl (3,3-diethoxypropyl)carbamate. Toluene (15 volumes) charged, layers separated and washed with water (5 volumes). A fraction of the solution obtained (0.95 equivs) was charged to a solution containing 6-(1-amino-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (Method 18) (1 equiv), toluene (5 volumes) and molecular sieves (1 weight equivalent). The reaction mixture was stirred overnight at room temperature until the reaction was complete. THF (2.5 volumes) were charged followed by sodium acetoxyborohydride (2.0 equiv) and the resulting mixture held overnight until reaction was complete. Aqueous acetic acid (20% v/v, 2.5 volumes) were charged over 10 minutes, stirred at room temperature for 10 minutes, filtered and washed with water (2.5 volumes). The layers were separated and the organic layer was concentrated under vacuo at 50 C. Further toluene was charged (2.5 volumes) and the solvent removed. The product was obtained as an orange oil (typical yield 92%). m/z 486 (MH+).
	With triethylamine; In tetrahydrofuran; at 0 - 20℃;	Triethylamine (26.1 mL, 187 mmol) was added to a solution of l-amino-3,3- diethoxypropane (27.5 mL, 170 mmol) in tetrahydrofuran (75 mL). The solution was chilled in an ice/water bath and then a solution of di-tert-butyl dicarbonate (40.8 g, 187 mmol) in tetrahydrofuran (125 mL) was added dropwise over a few hours. The reaction mixture was allowed to slowly warm to ambient temperature and then stirred at ambient temperature. After 15 hours the reaction mixture was concentrated under reduced pressure to provide a yellow oil. The oil was dissolved in ethyl acetate (200 mL). The solution was washed sequentially with water (2 x 50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow oil. This material was dried under high vacuum to provide 42.0 g of tert-butyl (3,3- diethyoxypropyl)carbamate.
	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A A solution of 1-amino-3,3-diethoxypropane (5.00 mL, 30.9 mmol) in 5 mL of tetrahydrofuran (THF) was treated with triethylamine (4.51 mL, 34.0 mmol) under an atmosphere of nitrogen and cooled to 0 C. The reaction mixture was then treated dropwise with a solution of di-tert-butyl dicarbonate (7.42 g, 34.0 mmol) in 25 mL of THF. The reaction mixture was stirred for 2 h at 0 C. and then allowed to come to room temperature. After 15 h, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water (2*) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl (3,3-diethoxypropyl)carbamate (8.40 g) as a clear, faintly yellow oil.
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 17h;	Part A A solution of 1-amino-3,3-diethoxypropane (5.00 ML, 30.9 mmol) in 5 ML of tetrahydrofuran (THF) was treated with triethylamine (4.51 ML, 34.0 mmol) under an atmosphere of nitrogen and cooled to 0 C. The reaction mixture was then treated dropwise with a solution of di-tert-butyl dicarbonate (7.42 g, 34.0 mmol) in 25 ML of THF. The reaction mixture was stirred for 2 h at 0 C. and then allowed to come to room temperature.After 15 h, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water (2*) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl (3,3-diethoxypropyl)carbamate (8.40 g) as a clear, faintly yellow oil.
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 17h;	Part A; A solution of l-amino-3,3-diethoxypropane (5.00 mL, 30.9 mmol) in 5 niL of tetrahydrofuran (TEtaF) was treated with triethylamine (4.51 mL, 34.0 mmol) under an atmosphere of nitrogen and cooled to 0 0C. The reaction mixture was then treated dropwise with a solution of di-tert-butyl dicarbonate (7.42 g, 34.0 mmol) in 25 mL of TEtaF. The reaction mixture was stirred for 2 h at 0 0C and then allowed to come to room temperature. After 15 h, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water (2X) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl (3,3-diethoxypropyl)carbamate (8.40 g) as a clear, faintly yellow oil.

Reference： [1]Bioorganic Chemistry,2010,vol. 38,p. 229 - 233
[2]Patent: US2014/163066,2014,A1 .Location in patent: Paragraph 0404-0406
[3]Patent: US9809621,2017,B2 .Location in patent: Page/Page column 29
[4]Synthesis,1994,p. 37 - 39
[5]Patent: US2011/44974,2011,A1
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[15]European Journal of Organic Chemistry,2005,p. 1302 - 1310
[16]Journal of Organic Chemistry,2005,vol. 70,p. 10701 - 10708
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[23]Journal of the American Chemical Society,2012,vol. 134,p. 11400 - 11403

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[ 41365-75-7 ]

Reference： [1]Archiv der Pharmazie,1995,vol. 328,p. 487 - 495
[2]Tetrahedron Asymmetry,1993,vol. 4,p. 2307 - 2310

5
[ 41365-75-7 ]
[ 501-53-1 ]
[ 73870-54-9 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1980,vol. 53,p. 508 - 511
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 3919 - 3922
[3]Journal of the American Chemical Society,2012,vol. 134,p. 11400 - 11403

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[ 41365-75-7 ]
[ 5535-49-9 ]
[ 221100-43-2 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 1149 - 1152

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[ 41365-75-7 ]
[ 1794-48-5 ]
[ 574754-64-6 ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 7942 - 7947

8
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[ 3479-47-8 ]
[ 473710-07-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3345 - 3350

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[ 83793-44-6 ]
[ 615537-50-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3345 - 3350

10
[ 41365-75-7 ]
[ 98-59-9 ]
[ 164532-58-5 ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 54 - 55
[2]Tetrahedron Letters,2009,vol. 50,p. 3306 - 3310
[3]Journal of the American Chemical Society,2012,vol. 134,p. 11400 - 11403
[4]Organic and Biomolecular Chemistry,2015,vol. 13,p. 11351 - 11361

11
[ 41365-75-7 ]
[ 1187-34-4 ]
[ 952402-34-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	In water; at 80℃; for 0.166667h;	Preparation 34 : 1-(3,3-Diethoxy-propyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5- carbonitrile (Prep34); <n="82"/>(2-Cyano-3-ethoxy-acryloyl)-carbamic acid ethyl ester (Prep 33, 300 mg, 1.42 mmol) was suspended in water (20 ml_); 3,3-diethoxypropylamine (460 mul, 2.84 mmol) was added and the mixture warmed at 800C for 10 minutes. The reaction mixture was lyophilized and the residue was purified by flash chromatography with petroleum ether-ethyl acetate (1-1 ) to give 350 mg of the title compound (91% yield) MS (ES) (mlz): 268.3 [M+H]+.1H-NMR (DMSO-Cl6) delta:11.93 (br. s., 1 H), 8.63 (s, 1 H), 4.55 (t, 1 H), 3.79 (t, 2 H), 3.49 - 3.60 (m, 2 H), 3.35 - 3.46 (m, 2 H), 1.86 - 1.99 (m, 2 H), 1.09 (t, 6 H).

Reference： [1]Patent: WO2007/113232,2007,A1 .Location in patent: Page/Page column 79-80

12
2-propanol-water [ No CAS ]
[ 41365-75-7 ]
[ 125971-96-2 ]
1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-LH-pyrrole-3-carboxamide [ No CAS ]
1-(3,3-diethoxypropyl)-5-(4-fluoropheny)-2-(1-methylethy)-N,4-diphenyl-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With nitrogen; Trimethylacetic acid In toluene	2.C Method A Step C: Preparation of 1-(3,3-Diethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide. To a nitrogen purged flask equipped with a mechanical stirrer is added 130 kg (311 mol) of (+-)4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R,R)], [R-(R,S)], [S-(R,R)]and [S-(R,S)]isomers, 5%0 L of heptanes and 60 L of toluene, 59 kg (400 mol) of 3-amino-1,1-diethoxypropane, and 22.3 kg (218 mol) of pivalic acid. The mixture is stirred and heated 1o reflux, removing water with a Dean Stark trap. The mixture is refluxed 32 hours and slowly cooled to 60°-65° C., diluted with 500 L of 2-propanol-water (3:2), seeded, and cooled to 20°-25° C. The product is isolated by filtration, washed with 300 L of 2-propanol, and dried in vacuo to yield 133.5 kg of 1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-lH-pyrrole-3-carboxamide; mp 125.1°-127.7° C. after recrystallization from ethanol HPLC: (acetonitrile:tetrahydrofuran:water) (40:25:55) 1.5 mL/min 25 nm Econosil C18 μ 25 cm R.T.=37.70 min 99.4% (area) NMR: ((CD3)2 CO) δ1.04 (6H, m, t), 1.47 (6H, d), 1.82 (2H, m), 3.40 (5H, m), 3.99 (2H, m), 4.43 (1H, brt), 6.90-7.50 (14H, m), 8.26 (1H, brs)

Reference： [1]Current Patent Assignee: ROKEBY; WAANAA RANBAATO; PFIZER INC - US5003080, 1991, A

13
[ 41365-75-7 ]
[ 75-36-5 ]
[ 581814-43-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In dichloromethane; at 0 - 20℃; for 14h;	Route to WBH02142 iV-(3,3-Diethoxypropyl)acetamide WBH02111C9H19NO3, MoI. Wt: 189.25To a solution of l-amino-3,3-diethoxypropane (5 g, 33.95 mmol) in DCM (250 ml) at O0C, was added triethylamine (5.15 g, 50.95 mmol) followed by acetyl chloride (2.93 g, 37.35 mmol). This mixture was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (100 ml) and extracted with DCM (3 x 75 ml). The combined organics were dried EPO <DP n="226"/>(MgSO4), filtered and concentrated in vacuo to afford the desired product as a transparent oil (6.1 I g5 95%).1H NMR (270 MHz, CDCl3): delta 1.20 (6H, t, J= 6.9 Hz, 2 x CH3), 1.79 (2H, q, J = 7.4, 11.0 Hz, CH2), 1.93 (3H5 s, CH3), 3.32 (2H, q, J= IA, 11.0 Hz, CH2), 3.42-3.53 (2H5 m, CH2), 3.60-3.71 (2H, m, CH2), 4.54 (IH, t, J= 5.2 Hz5 CH), 6.15 ppm (IH, br s, NH).

Reference： [1]Patent: WO2007/3934,2007,A2 .Location in patent: Page/Page column 223-224
[2]Journal of the American Chemical Society,2009,vol. 131,p. 378 - 386

14
[ 864228-16-0 ]
[ 41365-75-7 ]
[ 917814-21-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	Intermediate 6; EPO <DP n="27"/>To a solution of Intermediate 4 (1.40 g, 3.49 mmol), 1 -amino-2,3-diethoxypropane (513 mg, 3.49 mmol), and DIPEA (2.25 g, 17.45 mmol) in DMF (50 ml) was added HATU (1.592 g, 4.19 mmol). The solution was allowed to stand at RT for 2 h and the DMF was evaporated. The residue was partitioned between EtOAc (150 ml) and sat. aqueous NaHCO3 (200 ml). The organic layer was separated and the aqueous was extracted further with EtOAc (2 x 150 ml). The combined extracts were washed with water (200 ml), brine (100 ml), dried (Na2SO4) and evaporated. The crude product was purified on an lsolute SPE Si Il cartridge (20 g) eluting with 40-60% EtOAc in pentane and then 100% EtOAc to afford a cream solid.Yield: 1.59 g (86%)LC-MS (Method 3): Rt 3.06 min, m/z 553 [MNa]+

Reference： [1]Patent: WO2006/136857,2006,A1 .Location in patent: Page/Page column 25-26

15
[ 215941-14-3 ]
[ 41365-75-7 ]
[ 878798-94-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; In dichloromethane;	To the solution 3,3-bis(ethyloxy)-1-propanamine (379 mg, 2.576 mmol) in CH2CI2 (8 ml_) were added /V-(1 -benzothien-2-ylcarbonyl)-L-leucine (847 mg, 2.91 mmol), HOOBt (21 mg, 0.13 mmol), and Lambda/-methylmorpholine (0.37 ml, 3.35 mmol). The mixture was stirred several minutes whereupon EDCHCI (568 mg, 2.96 mmol) was added. The reaction mixture was stirred overnight at RT. Added cold saturated aqueous NH4CI solution to the reaction mixture and extracted with dichloromethane twice. The combined organic layer was washed by saturated aqueous NaHCO3 solution and brine. The organic solution was dried over MgSO4 and concentrated. The resultant residue was purified by flash column chromatography on silica gel (Biotage, 0%-1.5% CH2CI2ZMeOH) to provide 0.65 g of the title compound (60%).

Reference： [1]Patent: WO2006/29210,2006,A2 .Location in patent: Page/Page column 83-84

16
[ 161790-45-0 ]
[ 41365-75-7 ]
[ 1075748-17-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 23h;	1.1 N-(3,3-Diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide5 g of 3-methoxy-2-methoxymethyl-2-methyl-propionic acid (prepared as described in EP609058) were dissolved in 49 mL of DCM and 12 mL of THF. 11.4 mL of DIPEA, 5.84 g of HOBt, 7.07 g of EDC and 5.45 g of 3,3-diethoxy-propylamine were added sequentially. The mixture was stirred for 23 h at rt, diluted with DCM and washed with sat. NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using Hept/EtOAc from 3/1 to 0/1 as eluant to yield 7.25 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellowish oil.1H-NMR (CDCl3): 7.04 (s, 1H), 4.51 (t, 1H), 3.45-3.7 (m, 4H), 3.43 (s, 4H), 3.32 (s, 6H), 3.30 (dd, 2H), 1.79 (dd, 2H), 1.19 (t, 6H), 1.12 (s, 3H).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 23h;	5 g of 3-methoxy-2-methoxymethyl-2-methyl-propionic acid (prepared as in EP609058) were dissolved in 49 mL of DCM and 12 mL of THF. 11.4 mL of DIPEA, 5.84 g of HOBt,7.07 g of EDCI and 5.45 g of 3,3-diethoxy-propylamine were added sequentially. The mixture was stirred for 23 h at rt, diluted with DCM and washed with sat. NaHCO3. The <n="86"/>organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 3/1 to 0/1 as eluant to yield 7.25 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellowish oil. 1H-NMR (CDCI3): 7.04 (s, 1 H), 4.51 (t, 1 H), 3.45-3.7 (m, 4H), 3.43 (s, 4H), 3.32 (s, 6H), 3.30 (dd, 2H), 1.79 (dd, 2H), 1.19 (t, 6H), 1.12 (s, 3H).

Reference： [1]Patent: US2011/207815,2011,A1 .Location in patent: Page/Page column 8
[2]Patent: WO2008/132679,2008,A1 .Location in patent: Page/Page column 84-85

17
[ 41365-75-7 ]
[ 100-52-7 ]
[ 1099778-15-0 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 11783 - 11788

18
[ 41365-75-7 ]
[ 456-48-4 ]
[ 1099778-13-8 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 11783 - 11788

19
[ 41365-75-7 ]
[ 946513-93-5 ]
[ 1173565-35-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 20℃;	Example 35; 3-(l-(((35,4/f)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)pi peridin-4-yl)-l-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrimidiii-2(lH)-oneStep ACyclopentyl((3R,4S)-4-((4-(3,3-diethoxypropylamino)piperidin-l-yl)methyl)-3-hydroxy-3-p henylpyrrolidin-l-yl)methanone <n="43"/>Following the procedure in Scheme 6, a mixture of l-(((3S,4R)-l-(cyclopentanecarbonyl) - 4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-one (1.0 g, 2.7 mmol), acetic acid (0.16 mL, 2.7 mmol), NaBH(OAc)3 (0.86 g, 4.05 mmol) and 3,3-diethoxypropan-l-amine (0.48 mL, 2.97 mmol) in diy THF (8 mL) was stirred at room temperature overnight. After this time, the mixture was diluted with EA and washed sequentially with NaOH, NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated to yield crude amine which was used without further purification in the next step. MS (ESI, Pos. 1.5 kV) m/z 502.5 (M+H)+, 524.5 (M+Na)+.
	With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 20℃;	Following the procedure in Scheme 6, a mixture of l-(((3S,4R)-l-(cyclopentanecarbonyl) - 4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-one (1.0 g, 2.7 mmol), acetic acid (0.16 niL, 2.7 mmol), NaBH(OAc)3 (0.86 g, 4.05 mmol) and 3,3-diethoxypropan-l-amine (0.48 mL, 2.97 mmol) in dry THF (8 mL) was stirred at room temperature overnight. After this time, the mixture was diluted with EA and washed sequentially with NaOH, NaHCCbeta and brine. The organic phase was dried over Na2SO4 and concentrated to yield crude amine which was used without further purification in the next step. MS (ESI, Pos. 1.5 kV) m/z 502.5 (M+H)+, 524.5 (M+Na)+.

Reference： [1]Patent: WO2009/89659,2009,A1 .Location in patent: Page/Page column 41-42
[2]Patent: WO2009/92293,2009,A1 .Location in patent: Page/Page column 42

20
[ 934187-35-6 ]
[ 41365-75-7 ]
N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane at 20℃; for 23h;	1.1 5 g of 3-methoxy-2-methoxymethyl-2-methyl-propionic acid (prepared as described inEP609058) were dissolved in 49 mL of DCM and 12 mL of THF. 11.4 mL of DIPEA, 5.84 g of HOBt, 7.07 g of EDC and 5.45 g of 3,3-diethoxy-propylamine were added sequentially.The mixture was stirred for 23 h at rt, diluted with DCM and washed with sat. NaHCO3.The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using Hept/EtOAc from 3/1 to 0/1 as eluant to yield7.25 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellowish oil.1H-NMR (CDCI3): 7.04 (s, 1 H), 4.51 (t, 1 H), 3.45-3.7 (m, 4H), 3.43 (s, 4H), 3.32 (s, 6H),3.30 (dd, 2H), 1.79 (dd, 2H), 1.19 (t, 6H), 1.12 (s, 3H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2010/46869, 2010, A2 Location in patent: Page/Page column 18

21
[ 41365-75-7 ]
[ 1570-05-4 ]
[ 1264499-32-2 ]

Reference： [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 10210 - 10213

22
[ 41365-75-7 ]
[ 1162654-55-8 ]
[ 1358769-17-1 ]

Yield	Reaction Conditions	Operation in experiment
		f) Preparation of intermediate (10)H To a stirred solution of intermediate (9) (287 mmol) in CHC13 (2000 ml) was added 3,3-diethoxy-l-propanamine (474 mmol) at 0C in portions. After the addition, the reaction mixture was stirred at 0C for 1 hour and then at 15C for 2 hours. Thin Layer Chromatography (petroleum ether/ethyl acetate= 5/1) showed that the reaction was completed. The reaction mixture was washed by saturated Na2S03 aqueous (four times with 600 ml) and then saturated NaHC03 aqueous was added until pH = 7. The aqueous layer was extracted by CH2C12 (500 ml). The combined organic phases were washed with brine (800 ml), dried over Na2S04 and concentrated to give the crude product. The crude product was washed by tert-butyl methylether (three times 500 ml) to give 87 g of intermediate (10) (mp. 100.8 - 103.8C).
	In chloroform; at 0 - 15℃; for 3h;	[0080] To a stirred solution of intermediate (9) (287 mmol) in CHCl3 (2000 ml) was added 3,3-diethoxy-1-propanamine (474 mmol) at 0 C. in portions. After the addition, the reaction mixture was stirred at 0 C. for 1 hour and then at 15 C. for 2 hours. Thin Layer Chromatography (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed. The reaction mixture was washed by saturated Na2SO3 aqueous (four times with 600 ml) and then saturated NaHCO3 aqueous was added until pH=7. The aqueous layer was extracted by CH2Cl2 (500 ml). The combined organic phases were washed with brine (800 ml), dried over Na2SO4 and concentrated to give the crude product. The crude product was washed by tert-butyl methylether (three times 500 ml) to give 87 g of intermediate (10) (mp. 100.8-103.8 C.).

Reference： [1]Patent: WO2012/17030,2012,A1 .Location in patent: Page/Page column 14-15
[2]Patent: US2013/109694,2013,A1 .Location in patent: Paragraph 0080

23
[ 100-48-1 ]
[ 41365-75-7 ]
[ 21202-42-6 ]

Reference： [1]New Journal of Chemistry,2013,vol. 37,p. 204 - 211

24
[ 107833-73-8 ]
[ 41365-75-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 7600.51 Torr; for 12h;	To a solution of 5 (17.7 g, 0.1 mol) in MeOH (20 mL) was added Pd/C (10%, 15 mg) and stirred at rt for 12 h under 10 atmospheres of H2. The filtrate through Celite was concentrated under reduced pressure to give 6 (14.4 g, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta = 1.14 (t, 6H, J = 6.8 Hz), 1.29 (br s, 2H), 1.71 (q, 2H, J = 6.4 Hz), 2.73 (t, 2H, J = 6.4 Hz), 3.45 (q, 2H, J = 7.2 Hz), 3.60 (q, 2H, J = 7.2 Hz), 4.53 (t, 1H, J = 5.2 Hz). IR (neat): 3385, 2953, 2831, 1621, 1389 cm-1; MS (EI): m/z: 147 [M+]

Reference： [1]Tetrahedron Asymmetry,2013,vol. 24,p. 207 - 211

25
[ 41365-75-7 ]
[ 125971-96-2 ]
1-(3,3-diethoxypropyl)-5-(4-fluoropheny)-2-(1-methylethy)-N,4-diphenyl-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With Trimethylacetic acid; In n-heptane; toluene; for 14h;Reflux;	Diketone 2 (12.51 g, 30 mmol), compound 6 (5.88 g, 40 mmol), and pivalic acid (2.14 g, 21 mmol) were dissolved in heptane (54 mL) and toluene (6 mL). The mixture was heated at reflux with azeotropic removal of water for 14 h and then cooled to rt, filtered, washed with heptane (3 × 30 mL), and dried to give 7 (13.15 g, 83%) as a white powder. Mp 125.0-126.3 C (Lit.11 125.1-127.7 C); 1H NMR (400 MHz, CDCl3): delta = 1.11 (t, 6H, J = 6.8), 1.54 (d, 6H, J = 7.2), 1.80-1.84 (m, 2H), 3.26-3.32 (m, 2H), 3.42-3.47 (m, 2H), 3.58-3.63 (m, 1H), 3.95-3.99 (m, 2H), 4.33 (t, J = 4.8 Hz, 1H), 6.86 (s, 1H), 6.98-7.20 (m, 14H); IR (KBr): 3412, 2975, 1665, 1596, 1433 cm-1. MS (ESI) m/z: 529 [M+H+]

Reference： [1]Tetrahedron Asymmetry,2013,vol. 24,p. 207 - 211
[2]Angewandte Chemie - International Edition,2014,vol. 53,p. 4186 - 4190

26
[ 956317-36-5 ]
[ 41365-75-7 ]
[ 1410040-78-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;	HATU (1.94 g, 5.09 mmol) was added to a solution of 3,3-diethoxypropan-1-amine (0.50 g, 3.40 mmol), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.83 g, 4.08mmol) and N,N-diisopropylethylamine(DIPEA) (2.97 mL, 17.0 mmol) in DMF (5 mL), followedby stirring at room temperature for 15 h. An aqueous NaHCO3solution was added to the reaction solution, followed by extractionwith EtOAc. The organic layer was washed with brine and wasdried with MgSO4. The desiccant was then removed by filtration,and the solvent was distilled off under reduced pressure.The resulting residue was purified by column chromatography(20-80% EtOAc in hexanes) to yield N-(3,3-diethoxy-propyl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide 14 as a brown oil(1.13 g, 100%).
1.6 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;	HOBt.H2O (1.1 g, 7.4 mmol) and EDC.HCl (1.4 g, 7.4 mmol) were added to a solution of 3,3-diethoxypropan-1-amine (0.96 mL, 5.9 mmol) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.0 g, 4.9 mmol) in DMF (18 mL), followed by stirring at room temperature for 3 hours. An aqueous NaHCO3 solution was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with water and brine and was dried with Na2SO4. The desiccant was then removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (KP-Sil: 25 g, hexane/EtOAc=85/15 to 0/100) to give the titled compound (1.6 g, colorless solid). MS (ESI pos.) m/z: 333 [M+H]+

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 1260 - 1275
[2]Patent: US2014/81025,2014,A1 .Location in patent: Paragraph 0275; 0276; 0277

27
[ 41365-75-7 ]
[ 15780-63-9 ]
[ 1587714-55-3 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 2108 - 2110

28
[ 41365-75-7 ]
[ 1610535-31-3 ]
[ 1610534-70-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 60℃; for 2h;	N-[4-(3,3-Diethoxy-propylamino)-6-prop-2-ynylamino-[ 1,3,5] triazin-2-yl]-0,N- dimethyl-hydroxylamine (133): A mixture of of N-(4-chloro-6-prop-2-ynylamino-[l,3,5]triazin-2-yl)- Omicron,Nu-dimethyl-hydroxylamine (127) (350 mg, 1.54 mmol), N,N- diisopropylethylamine (266 muEpsilon, 1.54 mmol) and 3,3-diethoxy-propylamine (498 muEpsilon, 3.08 mmol) in 1,4-dioxane (6 mL) was heated at 60C for 2 h. A saturated NaHC( solution (50 mL) was added, and the resulting suspension was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (75 mL), then with a brine solution (75 mL), and lastly dried over solid anhydrous Na2S04. After filtration, the solvent was removed under reduced pressure to yield N-[4-(3,3- diethoxy-propylamino)-6-prop-2-ynylamino-[l,3,5]triazin-2-yl]-0,N-dimethyl- hydroxylamine (133) in quantitative yield. 400 MHz 1H NMR (CDC13, ppm) 5.28 (1H, s), 5.02 (1H, br s), 4.59 (1H, t, J=5.6 Hz), 4.25-4.13 (2H, m), 3.76 (3H, s), 3.71- 3.62 (2H, m), 3.55-3.42 (4H, m), 3.28 (3H, s), 2.19 (1H, t, J=2.5 Hz), 1.93-1.86 (2H, m), 1.22 (6H, t, J=7.0 Hz). ESI-MS (m/z): 3 39 [M+H]+.

Reference： [1]Patent: WO2014/78575,2014,A2 .Location in patent: Page/Page column 213-214

29
[ 41365-75-7 ]
[ 1647153-57-8 ]
[ 1647153-58-9 ]

Yield	Reaction Conditions	Operation in experiment
77%		A solution of 19 (280 mg, 0.871 mmol, 1.0 equiv) in dry THF (5 mL) was treated at room temperature under argon atmosphere with HOBt (131 mg, 0.970 mmol, 1.1 equiv) and EDC hydrochloride (186 mg, 0.970 mmol, 1.1 equiv) and stirred for 30 min. Subsequently, 3,3-diethoxy-1-aminopropane (20, 0.18 mL, 1.1 mmol, 1.3 equiv) and DIPEA (0.22 mL, 1.3 mmol, 1.5 equiv) were added and stirring was continued for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (1 × 10 mL), aq. HCl (1 M, 1 × 10 mL), aq. sat. NaHCO3 solution (1 × 10 mL) and water (1 × 10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resultant residue was purified byS15column chromatography (petroleum ether/EtOAc 2:1) yielding 301 mg (0.668 mmol, 77%) of 21 as a white foam. TLC Rf 0.25 (petroleum ether/EtOAc 2:1); mp 93 C; 1H NMR (300 MHz, DMSO-d6, 100 C): 0.93 (d, 3H, J = 6.6 Hz, CH(CH3)2), 0.97 (d, 3H, J = 6.6 Hz, CH(CH3)2), 1.12 (t, 3H, J = 7.0 Hz, OCH2CH3), 1.13 (t, 3H, J = 7.0 Hz, OCH2CH3), 1.48 (s, 3H, 2-CH3), 1.60-1.79 (m, 3H, CH(CH3)2, 2'-H2), 1.67 (s, 3H, 2-CH3), 3.00-3.25 (m, 2H, 1'-H2), 3.39-3.63 (m, 4H, OCH2CH3), 3.83 (dd, 1H, J = 9.0, 6.0 Hz, 5-H), 4.31 (d, 1H, J = 6.0 Hz, 4-H), 4.50 (t, 1H, J = 5.5 Hz, 3'-H), 5.03 (d, 1H, J = 12.8 Hz, CHaHbPh), 5.11 (d, 1H, J = 12.8 Hz, CHaHbPh), 7.25-7.40 (m, 5H, Ph-H), 7.41-7.49 (m, 1H, NH); 13C NMR (126 MHz, DMSO-d6, 35 C, rotamers): 15.2, 19.4, 19.4, 23.6, 24.8, 25.0, 26.2, 27.8, 27.9, 33.2, 33.3, 34.7, 34.7, 60.6, 60.7, 60.8, 61.8, 62.6, 65.4, 66.3, 81.0, 81.5, 92.8, 93.1, 100.3, 126.7, 127.3, 127.5, 127.7, 128.0, 128.2, 136.5, 151.0, 168.1; IR (ATR) nu 3327, 2975, 1710, 1402, 1346, 1257, 1221, 1124, 1049, 883, 767, 696; UV (MeCN) lambdamax (log epsilon) 252 (2.30), 258 (2.34); [alpha]D20 -15.1 (c 0.32, CHCl3); MS (ESI+) m/z 473.3 (M+Na+); HRMS (ESI+) m/z calcd for C24H38N2NaO6 473.2622 (M+Na+), found 473.2624.

Reference： [1]Beilstein Journal of Organic Chemistry,2014,vol. 10,p. 1135 - 1142

30
[ 41365-75-7 ]
[ 1268621-10-8 ]
N-(3,3-diethoxypropyl)-5-{4-[4-([(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 151N-(3,3-diethoxypropyl)-5-{4-[4-([(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxamideTo a stirred solution of 5-{4-[4-([(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (Example 115) (700mg, 1.64mmol) in 10ml of anhydrous DMF were added HATU (684mg, 1.84mmol) and N,N-diisopropylethylamine (426mg, 3.3mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (294mg, 2.0mmol). The mixture was stirred at room temperature for another 10 minutes and poured into 150ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-{4-[4- ([(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 910mg, 100%. 1H NMR (DMSO-d6): 11.81 (br. s., 1H), 8.77 (s, 1H), 8.60 (s, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.82 (t, J = 5.7 Hz, 1H), 7.53 - 7.60 (m, 2H), 7.35 (dd, J = 3.1, 1.6 Hz, 1H), 7.30 (s, 1H), 7.12 - 7.26 (m, 5H), 7.03 (t, J = 2.2 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 6.70 (dd, J = 5.9, 2.3 Hz, 1H), 4.53 (t, J = 5.4 Hz, 1H), 3.51 - 3.63 (m, 2H), 3.43 (dq, J = 9.7, 7.0 Hz, 2H), 3.16 - 3.24 (m, 2H), 2.28 (s, 3H), 1.68 - 1.78 (m, 2H), 1.11 (t, J = 7.0 Hz, 6H) LR MS (ES-): 556 (M-H)

Reference： [1]Patent: WO2015/69287,2015,A1 .Location in patent: Page/Page column 177

31
[ 41365-75-7 ]
[ 1268619-84-6 ]
N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		Example 204N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamideTo a stirred solution of 5-[4-(2-fluoro-5-[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (200mg, 0.45mmol) in 10ml of anhydrous DMF were added HATU (205mg, 0.54mmol) and N,N- diisopropylethylamine (128mg, 0.99mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (100mg, 0.68mmol), and stirring was continued for another 10 minutes. The mixture was poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide as white solid. Yield: 250mg, 97%. 1H NMR (DMSO-d6): 11.81 (br. s., 1H), 10.12 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.96 - 7.98 (m, 1H), 7.79 (t, J = 5.6 Hz, 1H), 7.63 (t, J = 9.5 Hz, 1H), 7.36 (dd, J = 2.8, 1.9 Hz, 1H), 7.33 - 7.35 (m, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 10.3, 8.5 Hz, 1H), 7.10 (s, 1H), 7.01 - 7.07 (m, 1H), 6.80 (dd, J = 5.9, 2.3 Hz, 1H), 4.51 (t, J = 5.4 Hz, 1H), 3.54 (dq, J = 9.4, 7.0 Hz, 2H), 3.41 (dq, J = 9.4, 7.1 Hz, 2H), 3.15 - 3.21 (m, 2H), 2.26 (s, 3H), 1.65 - 1.76 (m, 2H), 1.08 (t, J = 7.0 Hz, 6H) LR MS (ES-): 577 (M-H)

Reference： [1]Patent: WO2015/69287,2015,A1 .Location in patent: Page/Page column 219

32
[ 41365-75-7 ]
[ 1268619-99-3 ]
N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		Example 203N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxamideTo a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxylic acid (300mg, 0.71mmol) in 10ml of anhydrous DMF were added HATU (324mg, 0.85mmol) and N,N-diisopropylethylamine (200mg, 1.55mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3- diethoxypropane (157mg, 1.06mmol), and stirring was continued for another 10 minutes. The mixture was poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3- methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide as white solid. Yield: 380mg, 97%. 1H NMR (DMSO-d6): 11.79 (br. s., 1H), 9.71 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.79 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.57 (dd, J = 6.3, 3.1 Hz, 1H), 7.39 (t, J = 9.4 Hz, 1H), 7.34 (dd, J = 2.8, 1.6 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.06 - 7.09 (m, 1H), 7.04 - 7.06 (m, 1H), 6.72 (dd, J = 5.6, 2.3 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 4.51 (t, J = 5.6 Hz, 1H), 3.54 (dq, J = 9.5, 7.1 Hz, 2H), 3.41 (dq, J = 9.4, 7.1 Hz, 2H), 3.18 (q, J = 7.0 Hz, 2H), 2.28 (s, 3H), 1.71 (q, J = 6.5 Hz, 2H), 1.08 (t, J = 7.0 Hz, 6H) LR MS (ES+): 551 (MH+) LR MS (ES-): 549 (M-H)

Reference： [1]Patent: WO2015/69287,2015,A1 .Location in patent: Page/Page column 218

33
[ 41365-75-7 ]
[ 98-09-9 ]
N-(3,3-diethoxypropyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium carbonate; In dichloromethane; water; at 0℃; for 2h;	Compound 28: To a suspension of sodium carbonate (31 g, 0.37 mol) in water (50 ml) was added a solution of 1-amino-3,3-diethoxypropane (10.00 mL, 61.81 mmol) in DCM (50 mL) followed by cooling to 0 C. benzenesulfonyl chloride (7.65 mL, 60.0 mmol) was added at 0 C. with vigorous stirring followed by warming to 20 C. and continued stirring for 2 h after which time MTBE (150 mL) was added. Organic layer was separated, washed with 1.0 M of HCl (50 mL), saturated NaHCO3 (50 g), water (50 g), concentrated and azeotroped to dry two times with MTBE (150 mL×2) to provide N-(3,3-diethoxypropyl)benzenesulfonamide, 28 (17.34 g, 60.34 mmol, 97% yield) as light yellow clear oil.

Reference： [1]Patent: US2015/105370,2015,A1 .Location in patent: Paragraph 0174; 0348

34
[ 41365-75-7 ]
[ 94142-97-9 ]
[ 1608483-52-8 ]

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 426 - 435

35
[ 41365-75-7 ]
dimethyl [(3,5-di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]phosphonate [ No CAS ]
dimethyl {(3,5-di-tert-butyl-4-hydroxyphenyl)-[(3,3-diethoxypropyl)amino]methyl}phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In 1,4-dioxane; at 20℃; for 2 - 3h;Inert atmosphere;	General procedure: A mixture of 0.6 mmol of quinomethane 1a-1c and 0.6 mmol of 3,3-diethoxypropan-1-amine (2) or 4,4-diethoxybutan-1-amine (3) in 1 mL of 1,4-dioxane was stirred for 2-3 h at room temperature under argon. When the reaction was complete, the solvent was removed under reduced pressure (water-jet pump), and the residue was washed with hexane and dried in a vacuum (oil pump) until constant weight.

Reference： [1]Russian Journal of Organic Chemistry,2015,vol. 51,p. 1268 - 1271
Zh. Org. Khim.,2015,vol. 51,p. 1294 - 1297,4

36
[ 41365-75-7 ]
[ 128893-72-1 ]
diethyl {(3,5-di-tert-butyl-4-hydroxyphenyl)-[(3,3-diethoxypropyl)amino]methyl}phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In 1,4-dioxane; at 20℃; for 2 - 3h;Inert atmosphere;	General procedure: A mixture of 0.6 mmol of quinomethane 1a-1c and 0.6 mmol of 3,3-diethoxypropan-1-amine (2) or 4,4-diethoxybutan-1-amine (3) in 1 mL of 1,4-dioxane was stirred for 2-3 h at room temperature under argon. When the reaction was complete, the solvent was removed under reduced pressure (water-jet pump), and the residue was washed with hexane and dried in a vacuum (oil pump) until constant weight.

Reference： [1]Russian Journal of Organic Chemistry,2015,vol. 51,p. 1268 - 1271
Zh. Org. Khim.,2015,vol. 51,p. 1294 - 1297,4

37
[ 41365-75-7 ]
[ 1456553-15-3 ]
dibutyl {(3,5-di-tert-butyl-4-hydroxyphenyl)-[(3,3-diethoxypropyl)amino]methyl}phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In 1,4-dioxane; at 20℃; for 2 - 3h;Inert atmosphere;	General procedure: A mixture of 0.6 mmol of quinomethane 1a-1c and 0.6 mmol of 3,3-diethoxypropan-1-amine (2) or 4,4-diethoxybutan-1-amine (3) in 1 mL of 1,4-dioxane was stirred for 2-3 h at room temperature under argon. When the reaction was complete, the solvent was removed under reduced pressure (water-jet pump), and the residue was washed with hexane and dried in a vacuum (oil pump) until constant weight.

Reference： [1]Russian Journal of Organic Chemistry,2015,vol. 51,p. 1268 - 1271
Zh. Org. Khim.,2015,vol. 51,p. 1294 - 1297,4

38
[ 36603-49-3 ]
[ 41365-75-7 ]
N-(3,3-diethoxypropyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 90℃; for 24h;	Prepared according to General Procedure B from THP-protected bromophenol S1 (10.0 g, 38.9mmol), CuI (0.99 g, 5.84 mmol), L-proline (1.34 g, 11.7 mmol), K2CO3 (10.7 g, 77.8 mmol) andamino-3,3-diethoxypropane (9.43 mL, 58.4 mmol) in DMSO (55 mL). The reaction was stirred at 90C for 24 h and then purified by flash chromatography (SiO2, 0.5% Et3N in 5:1?1:1, 40-60 Cpetroleum ether/diethyl ether) to yield the title compound S2 (10.4 g, 32.2 mmol, 83% yield) as anorange oil; Rf 0.45 (5:1, 40-60 C petroleum ether/diethyl ether); numax/cm-1 (film) 3386, 2971, 2940,2875, 1616, 1510, 1226, 1201; deltaH (400 MHz, CDCl3) 6.92 (2H, d, J = 8.8 Hz), 6.55 (2H, d, J = 8.8Hz), 5.23 (1H, t, J = 3.3 Hz), 4.62 (1H, t, J = 5.5 Hz), 3.99-3.93 (1H, m, J = 3.3 Hz), 3.81 (1H, bs),3.71-3.64 (2H, m), 3.60-3.55 (1H, m), 3.54-3.47 (2H, m), 3.17 (2H, t, J = 7.0 Hz), 2.03-1.91 (3H,m), 1.85-1.81 (2H, m), 1.70-1.56 (3H, m), 1.22 (6H, t, J = 7.0 Hz); deltaC (100 MHz, CDCl3) 149.3,143.7, 118.2, 113.8, 102.2, 97.7, 62.1, 61.5, 40.9, 33.3, 30.6, 25.3, 19.1, 15.3; HRMS (ESI) calculatedfor C18H30NO4 [M+H]+ m/z 324.2169, found 324.2170.

Reference： [1]Synlett,2016,vol. 27,p. 116 - 120

39
[ 72652-32-5 ]
[ 41365-75-7 ]
C₁₂H₁₉BrN₂O₃ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 111 - 115

40
[ 41365-75-7 ]
[ 688317-69-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With copper(ll) sulfate pentahydrate; potassium carbonate; In methanol; at 20℃; for 10h;	The synthesis of 3 was adapted from literature.21 -Amino-3,3-diethoxypropane (5.00 g, 34.0 mmol), potassium carbonate (9.39 g, 68.0 mmol), copper (II) sulphate-5H20 (84.9 mg, 0.340 mmol) and MeOH (30 mL) were introduced into a 100 mL round bottom flask. 2 (8.50 g, 40.1 mmol) was dissolved in MeOH (20 mL) and added to the reaction mixture and the solution was stirred for 10 hours at room temperature. The mixture was diluted with water (30 mL), acidified to pH 6 using acetic acid and extracted into diethyl ether (4 chi 50 mL). The combined organic layers were washed with water (2 chi 50 mL) and brine (2 chi 50 mL), dried over magnesium sulphate and concentrated affording a dark yellow oil 3 (4.52 g, 77 %). 1 H NMR (400 MHz, CDCI3) delta 4.59 (t, J= 5.6 Hz, 1 H), 3.74 - 3.58 (m, 2H), 3.55 - 3.45 (m, 2H), 3.36 (t, J = 6.8 Hz, 2H), 1 .87 (td, J = 6.8, 5.7 Hz, 2H), 1 .20 (t, J = 7.1 Hz, 6H). 13C NMR (400 MHz, CDCI3) delta 103.56, 64.00, 49.85, 32.91 , 15.45.

Reference： [1]Patent: WO2016/24240,2016,A1 .Location in patent: Page/Page column 19; 20

41
[ 41365-75-7 ]
[ 7597-22-0 ]
2-(3,3-diethoxypropylamino)-4,6-dimorpholino-1,3,5-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate; In acetonitrile; for 8h;Reflux;	To a solution of 1.5 g of 2-chloro-4,6-dimorpholino-1,3,5-triazine and 0.77 g of (3,3-diethoxypropyl)amine in 50 mL of acetonitrile was added 2 g of potassium carbonate. The reaction mixture was refluxed for 8 h, then the precipitate was filtered off. The filtrate was evaporated and the residue was dried in a vacuum of 15 mmHg for 3 h. Yield 1.30 g (63%), mp 64 C. 1H NMR spectrum (CDCl3), delta, ppm (J, Hz): 1.20 t (6H, CH3, 3JHH = 7.10), 1.85-1.89 m (2H, CH2), 3.42-3.52 m (4H, CH2O), 3.61-3.64 m (2H, CH2N), 3.65-3.77 br. m [16H, O(CH2CH2)2N], 4.56 t (1H, CH, 3JHH = 5.45). 13C NMR spectrum (CDCl3), deltaC, ppm: 14.82 (CH3), 33.02 (CH2CH), 36.36 (CH2N), 41.10 [O(CH2CH2)2N], 60.87 (CH2O), 66.36[O(CH2CH2)2N], 101.29 (CH), 164.04 (NHC=N), 165.74 (NC=N). Mass spectrum (ESI): m/z 397.4 [M]+. Found, %: C 54.11; H 8.73; N 21.28. C18H32N6O4. Calculated, %: C 54.53; H 8.14; N 21.20.

Reference： [1]Russian Journal of General Chemistry,2016,vol. 86,p. 761 - 763
Zh. Obshch. Khim.,2016,vol. 86,p. 568 - 570,3

42
[ 10400-19-8 ]
[ 41365-75-7 ]
N-(3,3-diethoxypropyl)pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 0℃;	Step 1 : N-(3,3-diethoxypropyl)pyridine-3-carboxamide (2a) Pyridine-3-carbonyl chloride (10 g, 56.2 mmoles, 1 eq.) was dissolved in DMF (50 mL) and CH3CN (200 mL) with TEA (19.5 mL, 140.4 mmoles, 2.5 eq.). 3,3-diethoxypropan-1 -amine (10.35 g, 70.2 mmoles, 1 .25 eq.) in CH3CN (20 mL) was added at 0C. The solution was stirred overnight then was concentrated, diluted with DCM and washed with sat. NaHC03 and brine. The organic phase was then separated, dried over sodium sulphate and evaporated in vacuum to obtain N-(3,3-diethoxypropyl)pyridine-3- carboxamide 2a (6.8 g, Y= 45%). LC-MS (M-H+): 253.0.

Reference： [1]Patent: WO2016/96631,2016,A1 .Location in patent: Page/Page column 27-28

43
[ 607-69-2 ]
[ 41365-75-7 ]
2-(3,3-diethoxypropylamino)-3H-quinazolin-4-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 8422 - 8440

44
[ 41365-75-7 ]
[ 876-08-4 ]
4-(chloromethyl)-N-(3,3-diethoxypropyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In dichloromethane; at 20℃; for 3h;	To a solution of 4-(chloromethyl)-benzoyl chloride (1.17 g, 6.21 mmol) in DCM (10 mE) was added a solution of 3,3-diethoxypropan-1-amine (0.914 g, 6.21 mmol) and triethylamine (1.04 mE, 7.77 mmol) in DCM (10 mE). The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue dissolved in ethyl acetate. The organic phase was washed with 1 M aqueous sodium hydroxide, brine and dried over anhydrous magnesium sulfate and the filtrate was evaporated under reduced pressure to afford the title compound(1.83 g, 99%). 1H NMR (400 MHz, DMSO-d5); oe 8.45 (dd, J=5.5,5.5 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H),4.81 (s, 2H), 4.56 (dd, J=5.5, 5.5 Hz, 1H), 3.59 (ddd, J=7.1,9.5, 14.1 Hz, 2H), 3.45 (ddd, J=7.1, 9.5, 14.1 Hz, 2H), 3.29 (dd, J=6.0, 7.4 Hz, 2H), 1.79 (dd, J=6.4, 13.6 Hz, 2H), 1.12 (dd, J=7.0, 7.0 Hz, 6H).

Reference： [1]Patent: US2016/235734,2016,A1 .Location in patent: Paragraph 0640; 0641; 0642; 0648; 0649; 0650

45
[ 41365-75-7 ]
(R)-quinuclidin-3-yl 1-(4-((4-(tert-butoxycarbonyl)benzyl)oxy)benzoyl)-3-phenylazetidine-3-carboxylate [ No CAS ]
(R)-quinuclidin-3-yl 1-(4-((4-((3,3-diethoxypropyl)carbamoyl)benzyl)oxy)benzoyl)-3-phenylazetidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		A solution of HC1 in dioxane (4M, 2 mL) added to (i?)-quinuclidin-3-yl 1-(4-((4- (tert-butoxycarbonyl)benzyl)oxy)benzoyl)-3-phenylazetidine-3-carboxylate (0.273 g, 0.46 mmol) and the reaction mixture stirred at room temperature for 72 hours. The solvent was concentrated at reduced pressure to afford the title compound. The residue was dissolved in DMF (10 mL) and triethylamine (0.190 mL, 1.37 mmol) and HATU (0.208 g, 0.55 mmol) added. The reaction mixture was stirred at room temperature for 15 minutes. 3,3-diethoxylpropan-1-amine (0.080 g, 0.55 mmol) was added and the reaction mixture stirred at room temperature for 18 hours. Further HATU (0.104 g) and triethylamine (0.095 mL) was added and the reaction stirred for a further 3 hours. The reaction mixture was dissolved in ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate water and brine (x2). The organic phase was dried over anhydrous magnesium sulfate, the suspension filtered and the filtrate concentrated at reduced pressure. The residue was purified by column chromatography (eluent 100% ethyl acetate to 10% ammonia methanol / ethyl acetate) to afford the title compound (0.283 g, 92%). NMR (400 MHz, CDC13) d 7.79 (d, J=8.4 Hz, 2H), 7.65 - 7.62 (m, 2H), 7.50 - 7.45 (m, 2H), 7.38 (q, J=7.6 Hz, 2H), 7.34 - 7.28 (m, 3H), 7.05 (dd, J=4.9, 4.9 Hz, IH), 6.99 - 6.96 (m, 2H), 5.15 (s, 2H), 5.00 (s, IH), 4.83- 4.81 (m, 2H), 4.67 - 4.59 (m, 3H), 4.12 (q, J=7.1 Hz, IH), 3.77 - 3.48 (m, 6H), 3.14 (s, IH), 2.83- 2.70 (m, 4H), 2.05 - 1.93 (m, 3H), 1.85 - 1.45 (m, 4H), 1.24 (dd, J=7.1 , 7.1 Hz, 6H).

Reference： [1]Patent: WO2016/193241,2016,A1 .Location in patent: Page/Page column 119-120

46
[ 41365-75-7 ]
[ 104-87-0 ]
3,3-diethoxy-N-(4-methylbenzyl)propan-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		To a solution of l-amino-3,3-diethoxypropane (1.0 mL, 6.18 mmol) and p-tolualdehyde (0.807 mL, 6.84 mmol) in DCM (15 mL) was added anhydrous magnesium sulfate. The reaction mixture was stirred at room temperature for 18 hours. The suspension was filtered and the filtrate was concentrated at reduced pressure. The residue was dissolved in ethanol (15 mL) and sodium borohydride (0.466 g, 12.3 mmol) added in portions. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with 10% aqueous potassium carbonate and then extracted with DCM. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated at reduced pressure to afford the title compound (1.18 g, 76%). NMR (400 MHz, CDC13); delta 7.21 - 7.17 (m, 2H), 7.12 (d, J=7.8 Hz, 2H), 4.59 (dd, J=5.7, 5.7 Hz, 1H), 3.74 (s, 2H), 3.64 (ddd, J=7.1, 9.4, 14.1 Hz, 2H), 3.49 (ddd, J=7.1, 9.4, 14.1 Hz, 2H), 2.70 (dd, J=6.8, 6.8 Hz, 2H), 2.33 (s, 3H), 1.86 - 1.80 (m, 2H), 1.19 (dd, J=7.1, 7.1 Hz, 6H).

Reference： [1]Patent: WO2016/193241,2016,A1 .Location in patent: Page/Page column 77

47
[ 41365-75-7 ]
[ 3054-95-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With 2-hydroxynitrobenzene; strontium chloride; sodium sulfite; In acetonitrile; at 135℃; for 9h;	A reaction vessel containing a stirrer, a thermometer and a dropping funnel was charged with 1.36 mol of a 25% sodium sulfite solution, 1.7 mol of a mixture of beta-aminopropanal (2), a mass fraction of 55% Of 2-nitrophenol solution (3) 2.3mol, strontium chloride 0 · 56mol, acetonitrile 300ml, control the stirring speed at 180rpm, raise the temperature of the solution to 135 C, the reaction 9h, static stratification, remove the oil layer , Washed with sodium bromide solution, the mass fraction of 65% isopropyl alcohol, the mass fraction of 75% triethylamine washing, 1.9kPa vacuum distillation, collecting 90-95 C fractions, in the mass fraction of 90% toluene Recrystallization gave 103.43 g of crystalline diethanol acrolein in 83% yield.

Reference： [1]Patent: CN105503547,2016,A .Location in patent: Paragraph 0007; 0015; 0016

48
[ 41365-75-7 ]
4-chloro-6-methoxy-2-(5-methylfuran-2-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline [ No CAS ]
N-(3,3-diethoxypropyl)-6-methoxy-2-(5-methyl-2-furyl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 25 - 110℃; for 12.16h;Inert atmosphere;	To a mixture of intermediate I-05a (300 mg, 748 mumol) and 3,3-diethoxypropan-1-amine (R-04a, 110 mg, 748 mumol) in 1,4-dioxane (10 mL), was added Pd(dba)2 (43 mg, 74 mumol), BINAP (47 mg, 75 mumol) and Cs2CO3 (487 mg, 1 .50 mmol) in one portion at 25C under N2. The mixture was stirred at 25C for 10 minutes and then heated to 110C and stirred for 12 hours. Then, the mixture was concentrated in vacuum and the residue was purified by prep-TLC to afford intermediate I-11a (250 mg, 65%) as yellow solid. ESI-MS (M+1): 512.3 calc. for C29H41N3O5: 511.3.

Reference： [1]Patent: WO2017/85053,2017,A1 .Location in patent: Page/Page column 65; 66

49
[ 63810-78-6 ]
[ 41365-75-7 ]
5-bromo-N-(3,3-diethoxypropyl)-2-(methylsulfanyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In N,N-dimethyl-formamide; for 3h;	<strong>[63810-78-6]5-bromo-4-chloro-2-(methylsulfanyl)pyrimidine</strong> (9.2 g, 38.4 mmol), K2003 (6.9 g, 49.9 mmol) and 3,3-diethoxypropan-1-amine (5.65 g, 38.4 mmol) were added to DMF (80 mL). The reaction was stirred for 3 h then quenched with H20 (100 mL), extracted with diethyl ether(2 x 75 mL) and dried over MgSO4. After filtration the filtrate was concentrated under reduced pressure to afford 5-bromo-N-(3,3-diethoxypropyl)-2-(methylsulfanyl)pyrimidin-4-amine 11 a (13.2 g, 98%) as a yellow gum. LC-MS (Method A) 351.9 [M+H] RT 3.32 mm.

Reference： [1]Patent: WO2017/137743,2017,A1 .Location in patent: Page/Page column 73; 74

50
4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidin-1-yl)benzoic acid [ No CAS ]
[ 41365-75-7 ]
4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidin-1-yl)-N-(3-oxopropyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	3,3-diethoxypropan-1-amine (0.117 mL, 0.728 mmol), 4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidin-1-yl)benzoic acid (250 mg, 0.694 mmol), EDC (199 mg, 1.040 mmol) , HOBt (159 mg, 1.040 mmol) and DIEA (0.242 mL, 1.387 mmol) in DMF (2 mL) was stirred at room temperature for 3 hr. The solution was diluted with EtOAc, washed with water and brine, dried over Na2SO4 then concentrated. To the residue was added THF (4 mL) and 4 M HCl (aq) (1 mL) and the solution was stirred at room temperature for 2 hr. The pH was adjusted to ~ 10 with sat. Na2CO3 (aq) then the mixture was extracted with EtOAc three times and the combined organics were washed with brine, dried over Na2SO4 then concentrated to give 4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidin-1-yl)-N-(3-oxopropyl)benzamide (190 mg, 84 % yield) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.53 (d, J=6.7 Hz, 3 H) 1.84 - 1.95 (m, 1 H) 2.11 - 2.24 (m, 1 H) 2.83 (t, J=5.6 Hz, 2 H) 3.05 - 3.10 (m, 1 H) 3.20 - 3.26 (m, 1 H) 3.35 - 3.50 (m, 3 H) 3.68 - 3.73 (m, 2 H) 4.78 (q, J=6.7 Hz, 1 H) 6.40 (d, J=8.79 Hz, 2 H) 7.42 - 7.51 (m, 3 H) 7.58 (d, J=8.8 Hz, 2 H) 7.67 (d, J=6.0 Hz, 1 H) 7.75 (d, J=8.0 Hz, 1 H) 7.82 - 7.93 (m, 1 H) 8.13 - 8.27 (m, 1 H) 9.84 (s, 1 H)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4673 - 4677

51
[ 41365-75-7 ]
2-benzyl-6-(methylcarbamoyl)isonicotinic acid [ No CAS ]
6-benzyl-N<SUP>4</SUP>-(3,3-diethoxypropyl)-N<SUP>2</SUP>-methylpyridine-2,4-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 4.5h;	Intermediate 210: 6-Benzyl-/yt-(3,3-diethoxypropyn-/^-methylpyridine-2,4- dicarboxamide (1150) To a mixture of 2-benzyl-6-(methylcarbamoyl)isonicotinic acid (77.8 mg, 0.29 mmol) and HATU (142.9 mg, 0.38 mmol) in DMF (1.5 mL) was added 3,3-diethoxypropan-l-amine (0.061 mL, 0.37 mmol) and DIPEA (0.151 mL, 0.86 mmol). The mixture was stirred at rt for 4.5 h, after which the volatiles were evaporated under a stream of nitrogen. This was redissolved in DMSO (3 mL) and directly purified by MDAP (high pH). The required fractions were combined and evaporated in vacuo to give 6-benzyl-/V,-(3,3-diethoxypropyl)-Ae-methylpyridine-2,4-dicarboxamide (91.3 mg, 0.23 mmol, 79 % yield) a light brown gum. (1151) LCMS (2 min High pH): Rt = 1.08 min, [MH]+ = 400.4.

Reference： [1]Patent: WO2017/174621,2017,A1 .Location in patent: Page/Page column 135-136

52
[ 41365-75-7 ]
(2S,3S)-2-(fluoromethyl)-7-(methylcarbamoyl)-3-phenyl-2,3-dihydrobenzofuran-5-carboxylic acid [ No CAS ]
(2S,3S)-N5-(3,3-diethoxypropyl)-2-(fluoromethyl)-N’-methyl-3-phenyl-2,3-dihydrobenzofuran-5,7-dicarboxaminde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%		A flask was charged with (2S,3S)-2-(fluoromethyl)-7-(methylcarbamoyl)-3-phenyl-2,3-dihydrobenzofuran-5-carboxylic acid (250 mg, 0.759 mincl) and HATU (346 mg, 0.911 mincl), then wasfilled with DMF (4 mL) and the resulting minxture was treated at rt with DIPEA (0.398 mL, 2.28 mincl) then was stirred at this temperature for 5 min 3,3-Diethoxypropan-1-amine (0.147 mL, 0.911 minol) was then added and the resulting minxture was stirred for 1 h at rt before being diluted with water (50 mL). The aqueous phase was extracted with EtOAc. The combined organics were washed with a 10% w/w LiCI (aq)and filtered through a hydrophobic frit. The solvents were evaporated in vacuo. Purification of the residue obtained by flash chromatography on silica gel (10 g column, gradient: 20 to 100% EtOAc in cyclohexane) gave (2S,3S)-N5-(3,3-diethoxypropyl)-2-(fluoromethyl)-M-methyl-3-phenyl-2,3-dihydrobenzofuran-5,7- dicarboxaminde (306 mg, 88%) as a yellow gum.LCMS (2 min forminc): Rt 1.05 min [M+H] = 458

Reference： [1]Patent: WO2017/174620,2017,A1 .Location in patent: Page/Page column 105; 106

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[ 41365-75-7 ]
C₂₂H₁₉NO₃ [ No CAS ]
[ 79-08-3 ]
[ 98-59-9 ]
C₂₃H₃₁N₂O₆PolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: 3.2. Reaction of Wang Resin 1 with Trichloroacetonitrile and Fmoc-amino Alcohol (Resin 2)Wang resin 1 (1 mmol/g loading, 1 g) was suspended in 10 mL of anhydrous DCM, then 1.5 mL oftrichloroacetonitrile was added, and the resin was left in a freezer for 30 min. Next, a solution of 100 Lof DBU in 2 mL of anhydrous DCM was added, and the slurry was shaken for 1 h. The resin waswashed with anhydrous DCM (3) and anhydrous THF (3). The solution of Fmoc-amino alcohol(3 mmol) in 10 mL of anhydrous THF was added to the resin, followed by the dropwise addition of63 L of a solution of BF3Et2O, and the slurry was shaken for 30 min. Resin 2 was washed THF (3),MeOH (3), and DCM (5). A sample of the resin was washed with MeOH (3) and dried, and10 mg was cleaved with 50% TFA for 30 min, and the product quantified (Fmoc absorbance at 300 nm).Typical loading was between 0.35-0.50 mmol/g.3.3. Acylation with a-Bromocarboxylic Acids (Resins 3 And 13)Resin 2 (1 g) was washed with DCM and DMF, Fmoc was deprotected with 50% piperidine inDMF for 15 min, and the resin was washed with DMF (3) and DCM (5). Reaction of the resinwith a solution of -bromocarboxylic acid (5 mmol) in 10 mL of DCM was carried out in a syringewith a frit, and DIC (2.5 mmol, 386 L) was added. After 5 min, DIU was filtered, and the solutionwas transferred to the syringe with resin 1 and shaken for 1 h. When bromoacetic acid was used,DIEA (2.5 mmol, 436 L) was also added. Then, the resin was washed with DCM (3)._ 3.4. Reaction with Amino-aldehyde Dialkyl Acetal and N-Derivatization (Resin 4)Resin 3 (1 g) was washed with DMF (3), a solution of amino-aldehyde dialkyl acetal (10 mmol)and DIEA (10 mmol, 1.74 mL) in 10 mL of DMF was added, and the slurry was shaken for 2 h.An analytical sample was taken for analysis, reacted with 0.5 M Fmoc-OSu in DCM for 1 h and cleavedwith 50% TFA for 30 min.Resin from the previous step was split into four 250 mg portions, which were washedwith reaction solvent: DCM for sulfonamides (Ns-Cl, Tos-Cl) (1 mmol) and DMSO for 4-fluoro-3-nitrobenzotrifluoride (1 mmol). Then, 3 mL of the reaction solvent and DIEA (1.8 mmol, 174 L) wasadded, and the slurry was shaken for 2 h (in the case of sulfonamides) or overnight (in the case of4-trifluoromethyl-2-nitroaryl). Resin 4 was washed with the reaction solvent (3) and then DCM (3).A sample for analysis was reacted with 0.5 M Fmoc-OSu in DCM for 1 h and cleaved with 50% TFA for30 min.