[ CAS No. 109-85-3 ] {[proInfo.proName]}

Name: 109-85-3|2-Methoxyethylamine|98%
Brand: Ambeed
SKU: A799079
Rating: 95 (32 reviews)

,{[proInfo.pro_purity]}

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

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3d Animation Molecule Structure of 109-85-3

Structure of 109-85-3 * Storage: {[proInfo.prStorage]}

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Quality Control of [ 109-85-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 109-85-3 ]

SDS Specification

Alternatived Products of [ 109-85-3 ]

Product Details of [ 109-85-3 ]

CAS No. :	109-85-3	MDL No. :	MFCD00008180
Formula :	C₃H₉NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ASUDFOJKTJLAIK-UHFFFAOYSA-N
M.W :	75.11	Pubchem ID :	8018
Synonyms :

Calculated chemistry of [ 109-85-3 ]

Physicochemical Properties

Num. heavy atoms :	5
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	20.33
TPSA :	35.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.37 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.28
Log Po/w (XLOGP3) :	-0.86
Log Po/w (WLOGP) :	-0.41
Log Po/w (MLOGP) :	-0.63
Log Po/w (SILICOS-IT) :	-0.46
Consensus Log Po/w :	-0.22

Druglikeness

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

Water Solubility

Log S (ESOL) :	0.37
Solubility :	175.0 mg/ml ; 2.33 mol/l
Class :	Highly soluble
Log S (Ali) :	0.6
Solubility :	300.0 mg/ml ; 3.99 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.33
Solubility :	35.4 mg/ml ; 0.471 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 109-85-3 ]

Signal Word:	Danger	Class:	3,8
Precautionary Statements:	P210-P280-P305+P351+P338-P310	UN#:	2733
Hazard Statements:	H225-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 109-85-3 ]

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

Upstream synthesis route of [ 109-85-3 ]
Downstream synthetic route of [ 109-85-3 ]

[ 109-85-3 ] Synthesis Path-Upstream 1~6

1
[ 111-46-6 ]
[ 110-91-8 ]
[ 109-86-4 ]
[ 75-04-7 ]
[ 109-85-3 ]
[ 929-06-6 ]

Reference： [1] Patent: JP2005/527516, 2005, A, . Location in patent: Page/Page column 20
[2] Patent: JP2005/527516, 2005, A, . Location in patent: Page/Page column 20

2
[ 141-43-5 ]
[ 77-78-1 ]
[ 38256-93-8 ]
[ 3030-44-2 ]
[ 109-85-3 ]

Reference： [1] Canadian Journal of Chemistry, 1985, vol. 63, p. 288 - 290

3
[ 117-80-6 ]
[ 109-85-3 ]
[ 22272-22-6 ]

Yield	Reaction Conditions	Operation in experiment
96.1%	With triethylamine In N,N-dimethyl-formamide for 1 h;	To an ice-cold stirred solution of compounds 1 (10 mmol) andtriethylamine (1 mL) in DMF (20 mL) was added dropwise 2-methoxyethylamine (12.5 mmol). After the mixture color turnedfrom light yellow to red, the reaction continued at room temperaturefor 1 h, then poured into 300 mL water to form an orange redprecipitate. The resulting precipitated solid was filtered, washedwith cooled water, and dried.Yield: 96.1percent; orange powder; mp: 82-83 °C; 1H NMR (DMSO-d6,400 MHz) δ: 7.98(m, 2H), 7.75-7.87(m, 2H), 7.25(s, 1H),3.92-3.94(m, 2H), 3.57(t, J 5.7 Hz, 2H), 3.29-3.38(s, 3H); ESI-MS:m/z 266.1 [M+H]⁺, C13H12ClNO3 (MW=265.1).
87.8%	With triethylamine In ethanol at 20℃; for 18 h;	To 2,3-dichloro-1,4-naphthoquinone (0.341g, 1.50mmol) in 1.5mlof ethanol was added 2-methoxyethylamine (0.124g, 1.65mmol) and triethylamine (0.227g,2.25mmol) and the mixture stirred at r. t. for 18h. The red precipitate formedwas filtered under suction, washed with distilled water and dried to afford (4) as a dark red solid, 87.8percent.¹H (CDCl₃) δ 8.15 (dd, 1H, J=0.94, 7.68Hz), 8.03 (dd, 1H, J=0.99, 7.67Hz), 7.72 (dt, 1H, J=1.31, 7.59Hz), 7.62 (dt, 1H, J=1.28, 7.55Hz), 6.36 (br s, 1H), 4.06(dd, 2H, J=5.60, 10.62Hz), 3.63(t, 2H, J=5.17Hz), 3.42 (s, 3H); ¹³C(CDCl₃) δ 180.42, 176.84, 144.37, 134.85, 132.67, 132.44, 129.88,126.80, 77.20, 71.22, 58.95, 44.50.
53%	With triethylamine In diethyl ether at 20℃; for 24 h;	2, 3 a-Dichloro provided 1, 4 a-napthoquinone 1g (4. 4mmol) diethylether 30 ml a melting solution 2 a-Methoxyethylamine 568 micro l (6. 6mmol), triethylamine 610 micro l some excellent. 24 hours at room temperature then evaporated in pressure with respect to the stirring mixture. (Hexanes: EtOAc=20:1) column chromatography compound to a positive number (NQ 25) to compounds of formula 25 to obtained.Yield: 53percent

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 504 - 516
[2] MedChemComm, 2017, vol. 8, # 6, p. 1318 - 1321
[3] European Journal of Medicinal Chemistry, 2015, vol. 104, p. 42 - 56
[4] Patent: KR101761848, 2017, B1, . Location in patent: Paragraph 0317-0320
[5] ChemMedChem, 2016, p. 1944 - 1955

4
[ 79099-07-3 ]
[ 109-85-3 ]
[ 710972-40-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: With sodium cyanoborohydride; acetic acid In methanol at 25℃; for 12 h; Stage #2: With sodium carbonate In methanol; water	To a solution of 1 ,1-dimethylethyl 4-oxo-1 -piperidinecarboxylate (1 g, 5.0 mmol), acetic acid (0.3 ml_, 5.0 mmol) and [2-(methyloxy)ethyl]amine (0.44 ml_, 5.0 mmol) in MeOH (20 mL) were added NaCNBH₄ (346 mg, 5.5 mmol). After 12 h at 25 ⁰C, the solution was diluted with the aqueous solution of Na₂CO₃. The aqueous solution was extracted several times with ethyl acetate. The organic fractions were combined, concentrated and purified with chromatography separation (silica, 0-10percent MeOH in DCM) yielding the title compound (1.2 g, 93percent) as a yellow oil: LC/MS (ES) m/e 259 (M+H)⁺
37%	Stage #1: With triethylamine; zinc(II) chloride In methanol at 65℃; for 7 h; Stage #2: With sodium cyanoborohydride In methanol at 25℃; for 17 h;	Intermediate 1, tert-butyl 4-oxopiperidine-1-carboxylate (1.0 g, 5.02 mmol), was dissolved in methanol (15 mL) and treated with Intermediate 118, 2-methoxyethylamine (490 mg, 6.53 mmol), triethylamine (2.1 mL, 15.1 mmol) and ZnCI2 (68 mg, 0.50 mmol). The reaction mixturewas stirred at 65 C for 7 h, then NaBH3CN (949 mg, 15.1 mmol) was added portionwise. The resulting reaction mixture was stirred at 25 C for 17 h. The solvents were removed in vacuo, and the residue was partitioned between H20 (150 mL) and EtOAc (120 mL). The aqueous layer was extracted with EtOAc (2 x 120 mL), and the organic layers were combined, dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by columnchromatography (Normal basic activated alumina, 40 percent to 50 percent EtOAc in hexane) to give tertbutyl 4-[(2-methoxyethyl)amino]piperidine-1-carboxylate (480 mg, 37 percent) as a liquid.LCMS (Method I): mlz 203 (M+H-56) (ES), at 3.60 mi UV active.

Reference： [1] Patent: WO2007/16610, 2007, A2, . Location in patent: Page/Page column 49; 50
[2] Patent: WO2017/21730, 2017, A1, . Location in patent: Page/Page column 59
[3] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 56; 58
[4] Patent: CN107814792, 2018, A, . Location in patent: Paragraph 0223; 0224
[5] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 94-95; 101-102

5
[ 124-63-0 ]
[ 109-85-3 ]
[ 1234356-69-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With sodium hydroxide In 2-methyltetrahydrofuran at 20 - 25℃; for 1 h; Large scale Stage #2: With triethylamine In 2-methyltetrahydrofuran at 0 - 25℃; for 6 h; Large scale Stage #3: at 50 - 55℃; for 13 h; Large scale	Starting material: Compound 4 Methanesulfonyl chloride (MsCl) [CAS 124-63-0] 2-Methoxyethylamine [CAS 109-85-3] Reagents: Sodium Chloride (NaCl) 50percent Sodium Hydroxide (NaOH) Triethylamine (Et3N) (0258) Solvents: n-Heptane Isopropyl Acetate (zPrOAc) 2-Methyl Tetrahydrofuran (2-MeTHF) A 100-gallon reactor was charged with Compound 4 (10.4 kg, 23.2 mol, 1.0 eq) and 2- methyltetrahydrofuran (2-MeTHF, 132.6 kg, 155.2 L, 15 vol). A solution of 1.0 M NaOH (48.5 L, 48.5 mol, 2.1 eq) was added in one portion to the slurry and the resulting biphasic mixture was allowed to stir at 20-25 °C for 1.0 h. The phases were allowed to settle, the lower aqueous layer was removed and the organic layer was washed with 2.5percent NaCl (52 L, 5 vol). The organic layer was concentrated down to 104 L (10 vol) and chased with 2-MeTHF (44.0 kg, 51.5 L, 5 vol) a total of five times to achieve the desired water content of <0.1percent (0.08percent). After pohsh-filtering the 2-MeTHF solution into a clean 100-gallon reactor, triethylamine (Et3N, 3.5 kg, 4.9 L, 34.8 mol, 1.5 eq) was added and the mixture was cooled to 0-5 °C. Methanesulfonyl chloride (MsCL 4.0 kg, 2.7 L, 34.8 mol, 1.5 eq) was added over a period of 1 h while keeping the internal temperature < 20 °C. Once the addition of MsCl was complete, the reaction temperature was adjusted to 20-25 ''C and the mixture was stirred for 2 h. Analysis by HPLC indicated the presence of 3.7percent Compound 4. Additional Et3N (0.4 kg, mL, 0.55 L, 4.0 mol, 0.2 eq) and MsCl (0.4 kg, 0.27 L, 3.5 mol, 0.15 eq) were charged and the mixture was stirred at 20-25 °C for 1.5 h. At this point, 0.57percent Compound 4 was detected by HPLC. Additional Et3N (0.1 kg, mL, 0.14 L, 1.0 mol, 0.05 eq) and MsCl (0.1 kg, 0.07 L, 1.0 mol, 0.05 eq) were charged and the mixture was stirred at 20-25 °C for 1.5 h. Water (93.5 kg, 9 vol) was added and the biphasic mixture was stirred for 2.5 h. The phases were allowed to settle for 1 h and the aqueous layer was then transferred to a clean 200-gallon reactor. The aqueous layer was back-extracted with 2-MeTHF (44.6 kg, 52.2 L, 5 vol) and the upper layer was transferred to the 100-gallon reactor to combine organic layers before being washed with 5percent NaCl (51.6 kg, 5 vol). The resulting 2-MeTHF solution was concentrated down to -104 L (10 vol) and then chased with 2-MeTHF (44.0 kg, 51.5 L, 5 vol) a total of five times to achieve the desired water content of <0.1percent (0.02percent). After polish-filtering the 2-MeTHF solution into a clean 100-gallon reactor, the solution containing Compound 5 was concentrated down to 52 L (5 vol). 2-methoxyethylamine (35.8 kg, 41.4 L, 4 vol) was added, and the resulting reaction mixture was heated to 50-55 °C. The reaction mixture was allowed to stir at temperature for 13 h and HPLC analysis indicated complete conversion. Once the transformation was deemed complete, isopropylacetate (iPrOAc, 117.8 kg, 135L, 13 vol) and water (104 kg, 10 vol) were charged to the reactor while maintaining a temperature of 50-55 °C. After stirring for 1.5 h, the water layer was transferred to a clean 200-gallon reactor and extracted with iPrOAc (61.8 kg, 70.9 L, 7 vol). The upper layer was transferred to the 100- gallon reactor to combine organic layers and then re-equilibrated at 50-55 °C. The combined organic layer was washed with water (4x20.8 kg, 4x2 vol) before being vacuum distilled down to 63L (6 vol). The resulting slurry was chased with w-heptane (3x85.0 kg, 3x124 L, 3x12 vol) down to ~6 vol to achieve < 8.5 wtpercent of residual iPrOAc (1.1 wtpercent). The slurry was diluted with n-heptane (42.7 kg, 62.4 L, 6 vol) and stirred at 20-25 °C for 16.0 h before being filtered. The filter cake was washed with heptane (2x28.4 kg, 2x41.5 L, 2x4 vol) and then dried at 40-45 °C for 30 h. Compound A was obtained (9.4 kg, 86percent yield, 96.6percent AUC by HPLC) as a cream colored solid. Example 4. Preparation of ARQ 087-2 HC1 Crystalline Form D

Reference： [1] Patent: WO2017/106639, 2017, A1, . Location in patent: Page/Page column 38; 39

6
[ 32779-36-5 ]
[ 109-85-3 ]
[ 886365-79-3 ]

Yield	Reaction Conditions	Operation in experiment
92.3%	With potassium carbonate In acetonitrile at 100℃; for 6 h;	To a solution of 5-bromo-2-chloropyrimidine (4 g, 20.68 mmol) in acetonitrile (40 mL) was added 2-methoxyethanamine (5.5 mL, 63 mmol) and potassium carbonate (14 g, 100 mmol) . The mixture was heated at 100 and stirred for 6 h. The reaction mixture was concentrated to remove solvent. The residue was diluted with water (30 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 9/1 to give a colorless oily product (4.43 g, 92.3) .[1798]MS (ESI, pos. ion) m/z: 233.2 [M+1]⁺.

Reference： [1] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00725

[ 109-85-3 ] Synthesis Path-Downstream 1~88

1
[ 5577-13-9 ]
[ 109-85-3 ]
[ 99982-78-2 ]

Reference： [1]Patent: DE1011413,1957,

2
[ 627-42-9 ]
[ 109-85-3 ]
[ 111-95-5 ]

Reference： [1]Patent: US2876243,1955,

3
[ 97-08-5 ]
[ 109-85-3 ]
4-chloro-N-(2-methoxyethyl)-3-nitrobenzenesulfonamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 10126 - 10140
[2]Patent: US2422029,1942,

4
[ 400-70-4 ]
[ 75-04-7 ]
[ 109-85-3 ]
[ 35232-89-4 ]

Reference： [1]Patent: DE2058224,1972,
Chem.Abstr.,1972,vol. 77
[2]Patent: GB1279389,1972,
Chem.Abstr.,1972,vol. 77

5
[ 42267-27-6 ]
[ 109-85-3 ]
[ 58191-16-5 ]

Reference： [1]Journal of Organic Chemistry,1976,vol. 41,p. 1340 - 1343

6
[ 40381-90-6 ]
[ 109-85-3 ]
[ 56112-94-8 ]

Reference： [1]Angewandte Chemie,1980,vol. 92,p. 390 - 391

7
[ 33263-43-3 ]
[ 109-85-3 ]
[ 76254-79-0 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 299 - 304

8
[ 6630-30-4 ]
[ 109-85-3 ]
[ 66031-97-8 ]

Reference： [1]Liebigs Annalen der Chemie,1982,p. 762 - 779

9
[ 71149-52-5 ]
[ 109-85-3 ]
[ 85251-02-1 ]

Reference： [1]Journal of Medicinal Chemistry,1983,vol. 26,p. 838 - 844

10
[ 1397-89-3 ]
[ 109-85-3 ]
C₅₀H₈₀N₂O₁₇ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1995,vol. 117,p. 6249 - 6253

11
[ 104-53-0 ]
[ 6575-13-9 ]
[ 109-85-3 ]
(S)-1-[Carboxy-(4-methoxy-phenyl)-methyl]-pyrrolidine-2-carboxylic acid methyl ester [ No CAS ]
(S)-1-[[[1-(2,6-Dimethyl-phenylcarbamoyl)-3-phenyl-propyl]-(2-methoxy-ethyl)-carbamoyl]-(4-methoxy-phenyl)-methyl]-pyrrolidine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2003,vol. 44,p. 603 - 605

12
[ 6575-13-9 ]
[ 109-85-3 ]
[ 590-86-3 ]
[ 531512-51-3 ]
2-[[2-Azocan-1-yl-2-(4-methoxy-phenyl)-acetyl]-(2-methoxy-ethyl)-amino]-4-methyl-pentanoic acid (2,6-dimethyl-phenyl)-amide [ No CAS ]

Reference： [1]Tetrahedron Letters,2003,vol. 44,p. 603 - 605

13
[ 90-34-6 ]
[ 79-08-3 ]
[ 109-85-3 ]
[ 100-46-9 ]
{(CH₂-CH₂-CH₂-CHMe-NH-(6-methoxyquinolin-8-yl))Gly-(2-methoxyethyl)Gly-(PhCH₂)Gly}5-NH₂ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 8841 - 8845

14
[ 90-34-6 ]
[ 79-11-8 ]
[ 109-85-3 ]
[ 100-46-9 ]
{(CH₂-CH₂-CH₂-CHMe-NH-(6-methoxyquinolin-8-yl))Gly-(2-methoxyethyl)Gly-(PhCH₂)Gly}5-NH₂ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 8841 - 8845

15
[ 35998-96-0 ]
[ 98-88-4 ]
[ 75318-43-3 ]
[ 109-85-3 ]
6-benzamido-2-cyano-3-(2-methoxyethyl)quinazolin-4(3H)-one [ No CAS ]

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 7477 - 7481

16
[ 16523-31-2 ]
[ 109-85-3 ]
5-hydroxy-2-(2-methoxy-ethylamino)-4-(2-methoxy-ethylimino)-cyclohexa-2,5-dienone [ No CAS ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 7237 - 7246

17
[ 1187-59-3 ]
[ 109-85-3 ]
[ 1001346-35-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	In ethanol; at 140℃; for 0.666667h;Microwave;	N-Methylacrylamide (ABCR; 500 mg, 5.87 mmol), 2-Methoxyethylamine (Aldrich; 441 mg, 5.87 mmol), and EtOH (2 mL) were combined and heated in a microwave at 140 C. for 40 minutes. The reaction mixture was cooled and added to a 5 g SCX-2 column pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) then the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated in vacuo to give the title compound as a clear oil (608 mg, 65%)1H NMR (399.902 MHz, CDCl3) delta2.35 (m, 2H), 2.79 (m, 5H), 2.88 (m, 2H), 3.37 (s, 3H), 3.49 (m, 2H), 7.55 (s, 1H)
65%	In ethanol; at 140℃; for 0.5h;Microwave irradiation;	General procedure: A solution of <strong>[1187-59-3]N-methylacrylamide</strong> (2) (1.88 g, 22.0 mmol) and cyclopentylamine (1.98 mL, 20.0 mmol) in MeOH (14 mL) was heated under microwave irradiation to 140 C for 30 min (Biotage Initiator). The volatiles were removed under reduced pressure, the residue diluted with MeOH (20 mL) and purified by strong cation exchange filtration (50 g SCX-2 cartridge) washing with MeOH (100 mL) and eluting with 7 M methanolic NH3 (100 mL). The eluted product was concentrated under reduced pressure to afford the title compound 3 as a brown oil (3.09 g, 18.2 mmol, 91%). This was used directly with no further purification.

Reference： [1]Patent: US2008/9482,2008,A1 .Location in patent: Page/Page column 122
[2]Tetrahedron Letters,2012,vol. 53,p. 5049 - 5055

18
[ 50-00-0 ]
[ 1139-83-9 ]
[ 109-85-3 ]
3-(2-methoxyethyl)-3,4-dihydrobenzo[3,4]chromeno[8,7-e][1,3]oxazin-6-one [ No CAS ]

Reference： [1]Chemistry of Natural Compounds,2007,vol. 43,p. 15 - 18

19
[ 117103-53-4 ]
[ 109-85-3 ]
[ 710323-13-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	In methanol; at 25℃; for 5h;	Example 72 2 (R)- (3-CHLORO-4-METHANESULFONYL-PHENYL)-3-CYCLOPENTYL-N- [5- (2-METHOXY- ethylamino)-pyrazin-2-yl]-propionamide [000336] A mixture of <strong>[117103-53-4]2-bromo-5-nitropyrazine</strong> (500 mg, 2.45 mmol) and 2- METHOXYETHYLAMINE (276 mg, 3.67 mmol) in methanol (15 ML) was stirred at 25C for 5 h. After such time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 40/60 to 20/80 hexanes/ethyl acetate) afforded (2-methoxy-ethyl)- (5-nitro-pyrazin-2-yl) -amine (291 mg, 60%) as a yellow solid: mp 116.0-117. 3C ; EI- HRMS m/e calcd for C7HLON403 (M+) 198.0753, found 198. 0751.

Reference： [1]Patent: WO2004/52869,2004,A1 .Location in patent: Page 192 - 193

20
[ 15365-25-0 ]
[ 109-85-3 ]
[ 659737-49-2 ]

Yield	Reaction Conditions	Operation in experiment
30%	With triethylamine; for 2.0h;Heating / reflux;	A mixture of <strong>[15365-25-0]2-bromomethyl-4-methoxy-benzoic acid methyl ester</strong> (1.0 g, 3.9 mmol), tri- ethylamine (391 mg, 3.9 mmol) and 2-methoxy-ethylamine (348 mg, 4.6 mmol) was heated under reflux for 2 h. After cooling to RT the mixture was filtered and evaporated. The residue was purified by chromatography (SiOz, Heptane: EtOAc 1: 1 to EtOAc) to afford the title product (260 mg, 30%) as a light yellow solid. MS m/e = 221.3 (M+).

Reference： [1]Patent: WO2004/14856,2004,A1 .Location in patent: Page 18

21
[ 6271-78-9 ]
[ 109-85-3 ]
[ 672324-66-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium carbonate; In i-Amyl alcohol; at 25 - 130℃; for 16h;	To a SOLUTION OF 6-CHLORONICOTINAMIDE (1G, 6.39 MMOL) in isoamyl alcohol (15 mL) at rt was added NA2CO3 (0. 81 G, 7.67 MMOL) followed by METHOXYETHYLAMINE (0. 67 mL, 7.67 MMOL). The mixture was heat at 130 C for 16h, cooled to rt, and was filtered thru a medium GLASS-FRITTED filter. The resulting filtrate was concentrated under reduced pressure and the resultant solid was triturated with Et20 (2 x 10 mL). The crude solid was placed under high vacuum to afford 1.2 g (96%) of a light yellow solid. M+H = 196.

Reference： [1]Patent: WO2004/22561,2004,A1 .Location in patent: Page 92

22
[ 3970-39-6 ]
[ 109-85-3 ]
[ 860466-30-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; at 180℃; for 0.416667h;	c) (2-Methoxy-ethyl)- (2-methoxy-6-nitro-phenyl)-amine; A mixture of 7.5g (40mol) <strong>[3970-39-6]2-chloro-1-methoxy-3-nitro-benzene</strong>, 14ml diisopropylethylamine and 35ml 2-methoxyethyl amine is heated (180C oil bath temperature) in a closed steel reactor for 25 min. Then the reaction mixture is cooled to room temperature and is concentrated in vacuo (3 x coevaporation with toluene) to obtain ca. 20g (which contains 85% of the title compound) of a red oil which is used without further purification in the next step.

Reference： [1]Patent: WO2005/68433,2005,A1 .Location in patent: Page/Page column 39
[2]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5161 - 5164

23
[ 4565-31-5 ]
[ 109-85-3 ]
[ 910915-87-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; for 2h;	5-Formyl-thiophene-2-carboxylic acid (740 mg, 4.7 mmol), methoxyethylamine (412 muL, 4.7 nnnnol), HATU (4.5 g 11.8 nnnnol), ethyldiisopropylamine (4 ml) and DMF (2 m) in DCM (20 ml) was stirred for 2 hrs. The mixture was extracted with DCM and aq. bicarbonate. The organic layer was dried and concentrated. This residue was oxidized in t-BuOH (4ml) by the addition of sodium phosphate buffer (0.5M, 2 ml) and aq. KMnO4 (1M, 2ml). After 10 min. addition of sat. aq. Na2SO4 (2ml) was done and pH was adjusted to 3 with aq. HCI. Extracted with EtOAc. Organic layer was dried and concentrated.
		Example 1 Synthesis of the present aldehyde derivative is described in Examples 1-1 to 1-15.Example 1-1 Synthesis of the present aldehyde derivative [Compound No. (a)] To a solution of 1.56 g of 5-formylthiophene-2-carboxylic acid in 40 ml of tetrahydrofuran was added 2.11 g of carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours and 30 minutes. To the mixture was added 1 ml of 2-methoxyethylamine. The mixture was stirred at room temperature for 1 hour and 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in 70 ml of ethyl acetate, washed with 2N hydrochloric acid and then an aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.88 g of 5-formylthiophene-2-carboxylic acid 2-methoxyethylamide [Compound No. (a)] as a white solid. 1H-NMR(270MHz,DMSO-d6) delta (ppm): 3.27 (s, 3H), 3.38~3.50 (m, 4H), 7.89 (d, 1H, J=4.1Hz), 8.01 (d, 1H, J=4.1Hz), 8.91 (broad, 1H), 9.95 (s, 1H).
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; for 2h;	4.50 5-(2-Methoxy-ethylcarbamoyl)-thiophene-2-carboxylic acid; delta-Formyl-thiophene^-carboxylic acid (740 mg, 4.7 mmol), methoxyethylamine (412 mul_, 4.7 mmol), HATU (4.5 g 1 1.8 mmol), ethyldiisopropylamine (4 ml) and DMF (2 m) in DCM (20 ml) was stirred for 2 hrs. The mixture was extracted with DCM and aq. bicarbonate. The organic layer was dried and concentrated. This residue was oxidized in t-BuOH (4ml) by the addition of sodium phosphate buffer (0.5M, 2 ml) and aq. KMnO4 (1 M, 2ml). After 10 min sat. aq. Na2SO4 (2 ml) was added and the pH was adjusted to 3 with aq. HCI. Extracted with EtOAc. The organic layer was dried and concentrated.

Reference： [1]Patent: WO2006/64286,2006,A1 .Location in patent: Page/Page column 120
[2]Patent: EP1857455,2007,A1 .Location in patent: Page/Page column 98
[3]Patent: WO2007/144379,2007,A1 .Location in patent: Page/Page column 56

24
[ 133357-62-7 ]
[ 109-85-3 ]
[ 900157-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 20℃;	Intermediate 102.5; A mixture of 3-Bromomethyl-5-methoxy-benzoic acid methyl ester (300 mg, 1.16 mmol) (see e.g. Tetrahedron Lett, 1993, 31, 6313) , 2-Methoxy-ethylamine (260 mg, 3.47 mmol) and K2CO3 (0.32 g, 2.32 mmol) in CH3CN (5 mL) are stirred at RT. for over night. After adding H2O (20 mL), the reaction mixure is extracted with CH2CI2 (20 mL, 2x). The combined organic phases are washed with H2O, brine and dried (Na2SO4), concentrated under reduced EPO <DP n="155"/>to give 3-Methoxy-5-[(2-methoxy-ethylamino)-methyl]-benzoic acid methyl ester as an oil (217 mg, 0.85 mmol; 85%; ES-MS: M+H = 254 ; HPLC: tRtheta, = 2.29 minutes). This crude material is used without purification. To a mixture of this crude material and Et3N (0.48 ml, 3.47 mmol), (BOC)2O (380 mg, 1.74 mmol) in DCM (5 mL) is added at RT. After stirring for 1 h, the reaction mixture is quenched by adding H2O, and mixture is extracted with DCM. The combined organic phases are washed with H2O, brine and dried (MgSO4), concentrated under reduced pressure and silica gel flash chromatography to give Intermediate 102.5 as white amorphous; Rf = 0.47 (AcOEt:n-Hex=1:2) 1H NMR (400 MHz, CDCI3); J1.40-1.55 (brs, 9H), 3.30 (s, 3H), 3.35-3.55 (m, 4H), 3.80 (s, 3H), 3.90 (s, 3H), 4.45 (brs, 2H), 6.95-7.0 (brs, 1H), 7.40 (m, 1H), 7.50 (m, 1H).

Reference： [1]Patent: WO2006/74924,2006,A1 .Location in patent: Page/Page column 153-154

25
[ 135748-35-5 ]
[ 357404-66-1 ]
[ 109-85-3 ]
4-Chloro-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(2-methoxyethyl)amino]propyl}oxy)benzonitrile oxalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; oxalic acid; triethylamine; In tetrahydrofuran; water; N,N-dimethyl-formamide; mineral oil;	b 4-Chloro-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(2-methoxyethyl)amino]propyl}oxy)benzonitrile oxalate (R)-alpha-(2-Chloroethyl)-3-furanmethanol (100 mg, 0.62 mmol) was dissolved in tetrahydrofuran (5 ml) at room temperature. To this solution was added sodium hydride as a 60% suspension in mineral oil (3 7 mg, 0.93 mmol) and the mixture was stirred for 10 minutes before solid <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (107.6 mg, 0.62 mmol) was added in one portion. The resultant mixture was stirred for 1 h before water (2 ml) was added and the mixture concentrated in vacuo. The residues were partitioned between dichloromethane and water. The organics were collected, dried over magnesium sulphate, filtered and concentrated to dryness in vacuo. The resultant residue was dissolved in N,N-dimethylformamide (2 ml) and treated with sodium iodide (93 mg, 0.62 mmol), triethylamine (172 mul, 1.24 mmol) and 2-methoxyethanamine (107 mul, 1.24 mmol) before being heated to 60 C. for 72 h. After being allowed to cool the mixture was filtered and purified via reverse phase HPLC to give the title compound as a free base which was treated with a 50% saturated solution of oxalic acid in ether. The resultant white solid was collected via filtration to yield the title compound (61 mg, 28%). MS APCI+ve m/z 353/355 [(M+H)+]. 1H NMR 300 MHz (d6-DMSO) 8.02 (1H, d), 7.82 (1H, s), 7.70 (1H, s), 7.59 (1H, s), 5.72 (2H, t), 3.57 (2H, m), 3.31 (3H, s), 3.16 (2H, m), 3.09-2.98 (2H, b), 2.37 (1H, bm), 2.27 (1H br m).

Reference： [1]Patent: US2003/158185,2003,A1

26
[ 135748-35-5 ]
[ 32541-33-6 ]
[ 109-85-3 ]
4-Chloro-2-[1-ethyl-3-[(2-methoxyethyl)amino]propoxy]-5-fluorobenzonitrile Oxalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; oxalic acid; triethylamine; In tetrahydrofuran; methanol; water; N,N-dimethyl-formamide; mineral oil;	EXAMPLE 25 4-Chloro-2-[1-ethyl-3-[(2-methoxyethyl)amino]propoxy]-5-fluorobenzonitrile Oxalate 1-Chloro-3-pentanol (1 g, 8.15 mmol) was dissolved in tetrahydrofuran (20 ml) and treated with sodium hydride as a 60% suspension in mineral oil (480 mg, 12.2 mmol) followed after 10 minutes by <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (1.41 g, 8.15 mmol). The mixture was stirred at room temperature for 18 h before being treated with methanol (1 ml) and then water (10 ml). The tetrahydrofuran was then removed via heating the vessel to 80 C. and applying a nitrogen stream. Once the tetrahydrofuran was evaporated off, the residue was extracted into dichloromethane, dried over magnesium sulphate and concentrated in vacuo. The resultant material was re-dissolved into N,N-dimethylformamide (8 ml) and treated with sodium iodide (305 mg, 2.03 mmol), triethylamine (565 mul, 4.06 mmol) and 2-methoxyethanamine (352 mul, 4.06 mmol) before being heated to 60 C. for 5 days. The mixture was filtered and purified via RP-HPLC on the crude reaction material. The purified compound was then treated with 50% saturated oxalic acid in ether to produce a white powder which was collected via filtration. (378 mg, 15%). MS APCI+ve m/z 315 ([M+H]+). 1H NMR 300 MHz (d6-DMSO) 8.03 (1H, d), 7.65 (1H, d), 4.66 (1H, m), 3.56 (2H, m), 3.30 (3H, s), 3.14-3.06 (2H, m), 3.06-2.97 (2H, m), 2.03 (2H, m), 1.65 (2H, m), 0.92 (3H, t).

Reference： [1]Patent: US2003/65174,2003,A1

27
[ 16490-02-1 ]
[ 109-85-3 ]
Pyrimidine 4,6-dicarboxylic acid di-(2-methoxyethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; triethylamine; In N-methyl-acetamide; dichloromethane; toluene;	Example 1 Pyrimidine 4,6-dicarboxylic acid di-(2-methoxyethyl)-amide (formula I: R1 =CH2 -CH2 -OCH3; R2 =H) 1.7 g of <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> are suspended in 20 ml of toluene, and 2.4 g of thionyl chloride and 0.2 ml of dimethylformamide are added. The mixture is heated to the reflux temperature until no further evolution of gas is to be observed (about 3 hours). About 5 ml of solvent are distilled off, the mixture is cooled to 0-10 C. and 1.9 g of 2-methoxyethylamine and 2.8 ml of triethylamine, dissolved in 10 ml of toluene, are added. The solution is heated slowly to room temperature, stirred at room temperature for 12 hours and evaporated to dryness. The residue is taken up in 50 ml of methylene chloride, the mixture is extracted 3 times by shaking with saturated sodium bicarbonate solution and the organic phase is washed with water, dried with magnesium sulfate and evaporated. The solid is recrystallized from diisopropyl ether. Yield: 2.1 g; melting point: 85-86 C.

Reference： [1]Patent: US5130317,1992,A

28
[ 31938-07-5 ]
[ 109-85-3 ]
[ 259537-80-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; triphenylphosphine;palladium diacetate; In tetrahydrofuran; dichloromethane; pentane;	Preparation 40 3-(Cyanomethyl)- N -(methoxymethyl)benzamide 2-(3-Bromophenyl)acetonitrile (40g, 0.20mol) was added to a solution of 2-methoxyethylamine (61.3g, 0.81mol), triphenylphosphine (8.0g, 0.03mol), palladium acetate (4.0g, 0.01mol) and triethylamine (62g, 0.61mol) in tetrahydrofuran (400ml). The reaction mixture was heated to 100C in a sealed vessel under carbon monoxide a 100psi for 18hrs, after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:pentane (90:10) changing to dichloromethane (100%) and then to dichloromethane:methanol (98:2) to afford the title compound, 14.57g (33%). 1H-NMR (300MHz, DMSO): delta [ppm] 3.26 (3H, s), 3.41 (4H, m), 4.09 (2H, s), 7.65-7.43 (2H, m), 7.78 (1H, m), 7.83 (1H, s), 8.55 (1H, bs). LRMS: m/z = 219 (MH+).
	With triethylamine; triphenylphosphine;palladium diacetate; In tetrahydrofuran; dichloromethane; pentane;	Preparation 40 3-(Cyanomethyl)-N-(methoxymethyl)benzamide 2-(3-Bromophenyl)acetonitrile (40 g, 0.20 mol) was added to a solution of 2-methoxyethylamine (61.3 g, 0.81 mol), triphenylphosphine (8.0 g, 0.03 mol), palladium acetate (4.0 g, 0.01 mol) and triethylamine (62 g, 0.61 mol) in tetrahydrofuran (400 ml). The reaction mixture was heated to 100 C. in a sealed vessel under carbon monoxide a100 psi for 18 hrs, after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:pentane (90:10) changing to dichloromethane (100%) and then to dichloromethane:methanol (98:2) to afford the title compound, 14.57 g (33%). 1H-NMR (300 MHz, DMSO): delta [ppm] 3.26 (3H, s), 3.41 (4H, m), 4.09 (2H, s), 7.65-7.43 (2H, m), 7.78 (1H, m), 7.83 (1H, s), 8.55 (1H, bs). LRMS: m/z=219 (MH+).

Reference： [1]Patent: EP997474,2000,A1
[2]Patent: US6180627,2001,B2

29
[ 3939-13-7 ]
[ 109-85-3 ]
[ 945347-61-5 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In tetrahydrofuran; at 20℃; for 18h;	To a solution of <strong>[3939-13-7]3-cyano-2-fluoropyridine</strong> (15a) (100 mg, 0.82 mmol) in tetrahydrofuran (1.6 mL) was added cesium carbonate (267 mg, 0.82 mmol) and 2-methoxyethylamine (68 mg, 0.9 mmol). The mixture was stirred at room temperature for 18 h, and then concentrated. The residue was taken up in dichloromethane/water, absorbed onto diatomaceous earth, and eluted with dichloromethane. The eluate was concentrated to provide compound 15b.
	With caesium carbonate; In tetrahydrofuran; at 20℃; for 18h;	To a solution of <strong>[3939-13-7]3-cyano-2-fluoropyridine</strong> (15a) (100 mg, 0.82 mmol) in tetrahydrofuran (1.6 ml_) was added cesium carbonate (267 mg, 0.82 mmol) and 2-rnethoxyethylamine (68 mg, 0.9 mmol). The mixture was stirred at room temperature for 18h, and then concentrated. The residue was taken up in dichloromethane/water, absorbed onto diatomaceous earth, and eluted with dichloromethane. The eluate was concentrated to provide compound 15b.
	With caesium carbonate; In tetrahydrofuran; at 20℃; for 18h;	To a solution of <strong>[3939-13-7]3-cyano-2-fluoropyridine</strong> (15a) (100 mg, 0.82 mmol) in tetrahydrofuran (1.6 mL) was added cesium carbonate (267 mg, 0.82 mmol) and 2-methoxyethylamine (68 mg, 0.9 mmol). The mixture was stirred at room temperature for 18 h, and then concentrated. The residue was taken up in dichloromethane/water, absorbed onto diatomaceous earth, and eluted with dichloromethane. The eluate was concentrated to provide compound 15b.

Reference： [1]Patent: US2008/269225,2008,A1 .Location in patent: Page/Page column 38
[2]Patent: WO2007/79214,2007,A2 .Location in patent: Page/Page column 105
[3]Patent: US2011/319400,2011,A1 .Location in patent: Page/Page column 38

30
[ 104-53-0 ]
[ 1197-58-6 ]
[ 109-85-3 ]
[ 18591-57-6 ]
[ 1033514-10-1 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 3208 - 3211

31
[ 78238-12-7 ]
[ 109-85-3 ]
[ 1050514-17-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;	Intermediate 74 : 3"Methoxv-N-(2-methoxyethvl)-S-nJtrobenzamide; To a solution of S-methoxy-S-nitrobcnzoic acid (1 g: 5.1 mmol; 1 cq) in DCM (40 mL) is added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (972 mg; 5.1 mmol; 1 eq). After 5 niin, 2-methoxyethylaminc (381 mg; 5.1 mmol; 1 cq) is added and the reaction mixture is stirred at room temperature for 2 h. The reaction mixture is then quenched with water and the expected product extracted with EtOAc. The organic phase is washed with an aqueous solution Of Na2CCb then dried over MgSO4. The solvent is evaporated to dryness to afford 1.3 g (100percent) of the title compound as an orange oil. ElPLC (max plot) 73.0percent; Rt 2.9H min.

Reference： [1]Patent: WO2008/101979,2008,A1 .Location in patent: Page/Page column 84

32
[ 1878-69-9 ]
[ 109-85-3 ]
[ 1127329-44-5 ]

Yield	Reaction Conditions	Operation in experiment
89%		Scheme 12; 156 tert-Butyl 3-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenethyl(2- methoxyethyl)carbamate (156); Step 1 : 2-(3-Iodophenyl)-N-(2-methoxyethyl)acetamide (151); To a solution of 3 iodophenylacetic acid (1.12 g, 4.3 mmol) in dichloromethane (50 mL) was added oxalyl chloride (0.75 mL, 8.6 mmol) and DMF (0.05 mL). The mixture was stirred for 1 h at room temperature and concentrated. The residue was dissolved in dry THF (40 mL) and 2-methoxyethylamine (2.0 mL, 23 mmol) was added. The mixture was stirred for 2 h and concentrated. The residue was partitioned between water and ethyl acetate, the organic phase was collected, washed with IM HCl, water, saturated NaHCO3, brine, dried (MgSO4), filtered and concentrated to afford pure 151 (1.23 g, 89 %). 1H NMR (400 MHz, CDCl3) delta (ppm): 7.64- 7.61 (m, 2H), 7.26-7.24 (m, 1H), 7.10-7.06 (m, 1H), 5.81 (br s, 1H), 3.49 (s, 2H), 3.44-3.40 (m, 4H), 3.32 (s, 1H). MS (m/z): 320.1 (M+H).

Reference： [1]Patent: WO2009/26717,2009,A1 .Location in patent: Page/Page column 116-117

33
[ 111-71-7 ]
[ 39546-47-9 ]
[ 76041-72-0 ]
[ 109-85-3 ]
[ 1115577-09-7 ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 5974 - 5987

34
[ 119072-55-8 ]
[ 76041-72-0 ]
[ 109-85-3 ]
[ 590-86-3 ]
[ 1115577-04-2 ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 5974 - 5987

35
[ 931-53-3 ]
[ 34946-82-2 ]
[ 76041-72-0 ]
[ 109-85-3 ]
[ 590-86-3 ]
[ 1219036-57-3 ]

Reference： [1]Synlett,2010,p. 153 - 157

36
[ 65189-15-3 ]
[ 109-85-3 ]
[ 1243559-55-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In 1,4-dioxane; at 20℃; for 24h;	A mixture of 2-methoxyethyl amine (4.11 ml_, 43.9 mmol), TEA (6.11 ml_, 43.9 mmol) and <strong>[65189-15-3]5,6-dichloronicotinonitrile</strong> (Bionet GC-0755, 7.6 g, 43.9 mmol) was prepared in dioxane and stirred at RT for 24 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. The residue taken up with EtOAc (100 ml.) and washed with water (3x100 ml_). The organic layer was dried (Na2SC>;4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder (6.9 g, 75%). LC/MS, M+(ESI): 212.1. 1H NMR (DMSO-d6. 400 MHz) delta 8.42 (1 H, d), 8.07 (1 H, d), 7.48 (1 H, t), 3.58 (2H, m), 3.47 (2H, m), 3.23 (3H, s).

Reference： [1]Patent: WO2010/100142,2010,A1 .Location in patent: Page/Page column 76-77

37
[ 1027345-08-9 ]
[ 109-85-3 ]
4-(2-methoxyethylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 55℃; for 3h;	(0137) 4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.536 g, 5 mmol), 2-methoxyethanamine (0.376 g, 5 mmol), and triethylamine (1.939 g, 15 mmol) in anhydrous tetrahydrofuran (30 ml) solution was heated at 55 C. for 3 hours. The solution was diluted with ethyl acetate, washed with water and brine, and dried (Na2SO4), filtered and the filtrate was concentrated. The crude material was used in the next step without further purification.

Reference： [1]Patent: US10213433,2019,B2 .Location in patent: Page/Page column 25-26

38
[ 65001-21-0 ]
[ 109-85-3 ]
[ 1010120-57-6 ]

Yield	Reaction Conditions	Operation in experiment
27%	In tetrahydrofuran; at 20℃; for 16h;	A solution of <strong>[65001-21-0]5-bromopyridine-3-sulfonyl chloride</strong> (1.5 g, 5.8 mmol)) and 2-methoxyethanamine (1.3 g, 18 mmol) in THF (40 mL) was stirred at room temperature for 16 h. After this time, the resulting reaction mixture was partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic solution was dried and evaporated. The resulting residue was purified by flash column chromatography using ethyl acetate/hexanes to yield 5-bromo-N-(2- methoxyethyl)pyridine-3 -sulfonamide (460 mg, 27 %). LCMS Method T: Retention time 1.13 min; [M+l] =295, 297.

Reference： [1]Patent: WO2011/28741,2011,A1 .Location in patent: Page/Page column 263

39
[ 74840-38-3 ]
[ 109-85-3 ]
[ 1316122-39-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	In dichloromethane; at 20 - 45℃; for 2.0h;	Step 2: 5-Bromo-2-(2-methoxy-ethylamino)-pyrimidine-4-carboxylic acid ethyl ester2-Methoxyethylamine (0.278 ml, 3.2 mmol) was added at room temperature to a solution of 5- bromo-2-methanesulfonyl-pyrimidine-4-carboxylic acid ethyl ester (0.2 g, 0.65 mmol) in dichloromethane (5 ml). Stirring was continued at 45 C for 2 hours. The solvent was evaporated and the crude product was purified by silica gel chromatography using an ethyl acetate/heptane eluent to yield the title compound as colorless oil (0.175 g, 89 %).MS: M = 304.2 (M+H)+

Reference： [1]Patent: WO2011/89132,2011,A1 .Location in patent: Page/Page column 55

40
[ 63897-12-1 ]
[ 109-85-3 ]
[ 1338346-27-2 ]

Yield	Reaction Conditions	Operation in experiment
39.3%	With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	EXAMPLE 1022-[2-(1 ,3-benzothiazol-5-yl)-1 H-imidazol-4-yl]-6-methyl-1 -[2-(methyloxy)ethyl]-4-(4- mor holinyl)-1 H-imidazo[4,5-c]pyridineStep 1 . 2-chloro-6-methyl-N-[2-(methyloxy)ethyl]-3-nitro-4-pyridinamineTo a solution of <strong>[63897-12-1]2,4-dichloro-6-methyl-3-nitropyridine</strong> (1 g, 4.83 mmol) and triethylamine (0.741 ml, 5.31 mmol) in Nu,Nu-Dimethylformamide (DMF) (1.959 ml) at 0 C was added a solution of 2-methoxyethlyamine (0.424 ml, 4.88 mmol) in Nu,Nu-Dimethylformamide (DMF) (0.535 ml). Removed from ice bath and stirred at rt overnight. LCMS showed mainly desired product along with a small amount of the undesired regioisomer as well as the bis addition product. Quenched with water and diluted with Et20. Separated and extracted twice more with Et20. Washed combined organics with water twice, then with brine, dried on MgS04, filtered and concentrated. Purified via Biotage FCC (0-20% EtOAc / hex) Desired and bis-addition product co-eluted. Combined all product-containing fractions and concentrated resulting in a bright yellow solid. Suspended in hexanes, sonicating to break up large particles. Sonicated for 20 min. Filtered and collected bright yellow solid that was pure desired product: 2-chloro-6-methyl-N-[2-(methyloxy)ethyl]-3-nitro-4- pyridinamine (466 mg, 1.897 mmol, 39.3 % yield). MS (m/z): 246.1 (M+H)+.

Reference： [1]Patent: WO2011/123609,2011,A1 .Location in patent: Page/Page column 81

41
[ 475216-25-2 ]
[ 109-85-3 ]
[ 1338346-13-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 150℃; for 0.25h;Microwave irradiation;	PREPARATION 2N-methyl-4-[2-(methyloxy)ethyl]amino}-3-nitrobenzamideThe <strong>[475216-25-2]4-fluoro-N-methyl-3-nitrobenzamide</strong> (2.63 g, 13.3 mmol) was partially dissolved in ethanol (7 ml.) in a microwave vial and /V,/V-diisopropylethylamine (DIEA) (2.3 ml_, 13.3 mmol) and [2-(methyloxy)ethyl]amine (1.16 ml_, 13.3 mmol) were added. The vial was capped and heated in the microwave at 150C for 15 minutes. Reaction was repeated two times on same scale and all crude reactions were combined. Mixture was cooled to room temperature and left to sit for 2 hours. A solid formed and it was filtered, rinsed with diethyl ether and dried to give the title compound as an orange solid (9.19 g, 86%, >95% purity). Product was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) delta 8.63 (d, J = 2.27 Hz, 1 H), 8.48 (d, J = 4.55 Hz, 1 H), 8.36 - 8.44 (m, 1 H), 7.99 (dd, J = 2.02, 9.09 Hz, 1 H), 7.16 (d, J = 9.09 Hz, 1 H), 3.51 - 3.69 (m, 4H), 3.32 (s, 3H), 2.77 (d, J = 4.55 Hz, 3H); MS (m/z) 254.0 (M+H)+.

Reference： [1]Patent: WO2011/123609,2011,A1 .Location in patent: Page/Page column 43

42
[ 1480-87-1 ]
[ 109-85-3 ]
[ 866010-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; at 150℃; for 0.133333h;Microwave irradiation;	EXAMPLE 722-[2-(1 ,3-benzothiazol-5-yl)-1 H-imidazol-4-yl]-3-[2-(methyloxy)ethyl]-3H-imidazo[4,5- b]pyridineStep 1 . <strong>[1480-87-1]2-fluoro-3-nitropyridine</strong>: Added DIEA (738 muIota, 4.22 mmol) to a solution of 3-fluoro- 2-nitropyridine (500 mg, 3.52 mmol) and 2-(methoxy)ethylamine (333 muIota, 3.87 mmol) in Ethanol (2448 muIota) and heated in a microwave to 150 C for eight minutes. LCMS showed the reaction was complete. Concentrated the reaction and used the material without purification. MS (m/z) 198.1 (M+H)+.

Reference： [1]Patent: WO2011/123609,2011,A1 .Location in patent: Page/Page column 72

43
[ 931-53-3 ]
[ 104-88-1 ]
[ 1701-18-4 ]
[ 109-85-3 ]
[ 1352943-20-4 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 476 - 478

44
[ 6492-86-0 ]
[ 109-85-3 ]
[ 1374035-44-5 ]

Reference： [1]Chemical Communications,2012,vol. 48,p. 4767 - 4769

45
[ 1458-18-0 ]
[ 109-85-3 ]
[ 14340-25-1 ]
[ 1387561-41-2 ]
[ 27314-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3.5h;	a) 3-Amino-6-bromo-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acid methyl esterTo a mixture of <strong>[1458-18-0]3-amino-5,6-dichloro-pyrazine-2-carboxylic acid methyl ester</strong> [CAS 1458-18-0] and 3-amino-6-bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester [CAS 14340-25-1] (799 mg, 3 mmol) in DMF was added 2-methoxy-ethylamine (0.31 ml, 3.6 mmol) and NEt3 (2.09 ml, 15 mmol) and the mixture was stirred at r.t. for 3.5 h. The reaction mixture was poured into water (150 ml) and extracted with toluene (2×150 ml). The organic layers were washed with half-saturated aq. sodium chloride, combined, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc 100:0 to 0:100%) to provide the title compound together with 3-amino-6-chloro-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acid methyl ester (about 1:1) as colorless solid. This mixture was used for the next step.HPLC: RtH4=0.77 min; ESIMS [M+H]+=305.1; (Cl-pyrazine: HPLC: RtH4=0.73 min; ESIMS [M+H]+=261.1).

Reference： [1]Patent: US2012/184539,2012,A1 .Location in patent: Page/Page column 56

46
[ 109-85-3 ]
[ 1970-80-5 ]
[ 482325-76-8 ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 13733 - 13742

47
[ 20577-64-4 ]
[ 27258-33-9 ]
[ 109-85-3 ]
C₁₅H₂₁N₃O₄ [ No CAS ]

Reference： [1]ACS Combinatorial Science,2012,vol. 14,p. 631 - 635

48
[ 5926-51-2 ]
[ 109-85-3 ]
[ 846059-13-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 2408 - 2411

49
[ 60031-08-5 ]
[ 109-85-3 ]
[ 1399849-71-8 ]

Yield	Reaction Conditions	Operation in experiment
1.87 g		To a suspension of <strong>[60031-08-5]1-<strong>[60031-08-5]indanone-6-carboxylic acid</strong></strong> (1.76 g) in N,N-dimethylformamide (50 mL) was added carbonyldiimidazole (3.24 g), and the mixture was stirred at room temperature for 1 hour. Thereto was added a solutionof 2-methoxyethylamine (3.76 g) in dichloromethane (50 mL) under ice-cooling, and the mixture was stired at roomtemperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then dissolved in chloroform.The organic layer was washed with aqueous saturated sodium hydrogen carbonate solution, dried over sodiumsulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (20 mL),and then thereto was added 1-normal hydrochloric acid (20 mL), and the mixture was stired at room temperature for 12hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layerwas washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. Theresulting residue was triturated with isopropyl ether-ethyl acetate (2:1) to give N-(2-methoxyethyl)-3-oxoindan-5-carboxamide[REx(13-1)] (1.87 g) as a brown powder. APCI-MS m/z: 234[M+H]+.

Reference： [1]Patent: EP2687518,2014,A1 .Location in patent: Paragraph 0107; 0108

50
[ 42237-85-4 ]
[ 109-85-3 ]
[ 1515187-15-1 ]

Yield	Reaction Conditions	Operation in experiment
1.96 g	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 0 - 20℃;Reflux;	Intermediate D3: 3-Amino-5-bromo-N-(2-methoxyethyl)benzamide. To a stirred solution of <strong>[42237-85-4]3-amino-5-bromobenzoic acid</strong> (1.90 g, 8.53 mmol), 2-methoxy- ethanamine (1.50 ml, 17.08 mmol) and triethylamine (3.60 mL, 25.8 mmol) in DCM (30 mL) at 0C was added 50 wt% T3P in EtOAc (7.65 ml, 12.85 mmol). The reaction was stirred at rt overnight then refluxed for 90 min. The reaction was cooled to rt, whereupon a further quantity of triethylamine (3.60 ml, 25.8 mmol) was added. The reaction vessel was then cooled in an ice bath and 50 wt% T3P in EtOAc (7.65 ml, 12.85 mmol) from a fresh bottle was added. The ice bath was removed, the reaction allowed to warm to rt, and stirred at this temperature for 1 h. The reaction was partitioned between sat. NaHC03 (50 mL) and DCM (50 mL). The aqueous phase was back extracted with fresh DCM (50 mL). The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo to afford an orange oil (3.12 g). The crude product was purified by chromatography on silica gel (80 g column, 0- 10% MeOH in DCM) to afford Intermediate D3 (1.96 g) as an orange oil. 1H NMR (DMSO-d6) 400 MHz, delta: 8.37 (t, 1 H), 7.08 (t, 1 H), 7.00-6.99 (m, 1 H), 6.84 (t, 1 H), 5.57 (s, 2H), 3.44-3.41 (m, 2H), 3.39-3.33 (m, 2H), 3.25 (s, 3H). LCMS m/z 273/275 (M+H)+ (ES+)

Reference： [1]Patent: WO2014/27209,2014,A1 .Location in patent: Page/Page column 82

51
[ 5274-99-7 ]
[ 109-85-3 ]
[ 1090476-15-5 ]

Yield	Reaction Conditions	Operation in experiment
3.711 g		To a 250-mL round-bottomed flask equipped with a stirring bar, 12 (3.201 g, 13.723 mmol, 1.0 equiv) and CH2Cl2 (180 mL) were added. Et3N (3.824 mL, 27.446 mmol, 2.0 equiv) was added drop-wise, followed by TBTU (4.406 g, 13.723 mmol, 1.0 equiv). After 30 min, 2-methoxyethylamine(2.355 mL, 27.446 mmol, 2.0 equiv) was added drop-wise, and the reaction mixture was stirred for 23 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with H2O (2 × 200 mL), 0.5 M aq HCl (2 ×200 mL), sat. aq NaHCO3 solution (2 × 200 mL) followed by sat. brine solution (200 mL), dried over anhyd Na2SO4, and evaporated to produce 3.711 g of raw 13a as a white solid. HRMS (ESI+): m/z calcd for C16H23N2O3: 291.1709; found 291.1703.
		To a 250-mL round-bottomed flask equipped with a stirring bar, 12 (3.201 g, 13.723 mmol) and CH2CI2 (180 mL) were added. Et3N (3.824 mL, 27.446 mmol) was added drop-wise, followed by TBTU (4.406 g, 13.723 mmol). After 30 min, 2- methoxyethylamine (2.355 mL, 27.446 mmol) was added drop-wise, and the reaction mixture was stirred for 23 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with H2O (2 chi 200 mL), 0.5 M aq HCI (2 chi 200 mL), sat. aq NaHCO3 solution (2 chi 200 mL) followed by sat. brine solution (200 mL), dried over anhyd Na2SO4, and evaporated to produce 3.71 1 g of crude 1 -benzoyl-A/-(2-methoxyethyl)piperidine-4-carboxamide. This product was used in the next step without further purification.Product appearance: white solid.HRMS (ESI+): m/z calculated for C16H23N2O3: 291 .1709; found: 291 .1703

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 2037 - 2039
[2]Patent: WO2016/151484,2016,A1 .Location in patent: Paragraph 0340
[3]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 633 - 645
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 119 - 139

52
[ 5779-93-1 ]
[ 109-85-3 ]
C₁₂H₁₇NO [ No CAS ]

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 146 - 153

53
[ 63082-45-1 ]
[ 109-85-3 ]
C₁₁H₁₄FNO [ No CAS ]

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 146 - 153

54
[ 3453-33-6 ]
[ 109-85-3 ]
C₁₅H₁₇NO₂ [ No CAS ]

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 146 - 153

55
[ 5381-20-4 ]
[ 109-85-3 ]
[ 105411-19-6 ]

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 146 - 153

56
[ 54605-72-0 ]
[ 109-85-3 ]
C₁₃H₁₅N₃O [ No CAS ]

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 146 - 153

57
[ 3364-80-5 ]
[ 109-85-3 ]
C₇H₁₀N₂OS [ No CAS ]

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 146 - 153

58
[ 58028-76-5 ]
[ 109-85-3 ]
C₁₄H₂₀N₂O₂ [ No CAS ]

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 146 - 153

59
[ 109-85-3 ]
[ 207557-35-5 ]
C₁₀H₁₇N₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3053 - 3074

60
[ 58556-75-5 ]
[ 109-85-3 ]
7-bromo-N-(7-bromonaphthalen-2-yl)-N-(2-methoxyethyl)naphthalene-2-amine [ No CAS ]

Reference： [1]Russian Chemical Bulletin,2014,vol. 63,p. 102 - 108
Izv. Akad. Nauk, Ser. Khim.,2014,p. 102 - 108,7

61
[ 30483-75-1 ]
[ 109-85-3 ]
C₁₃H₂₀N₂O₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2015,vol. 54,p. 1646 - 1650
Angew. Chem.,2015,vol. 127,p. 1666 - 1670

62
[ 109-85-3 ]
[ 195609-18-8 ]
1-(2-methoxyethyl)-5-nitroindolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.7%		A solution of 2-(2-fiuoro-5-nitrophenyl) acetic acid (1.001 g) and 2- methoxyethanamine (1.892 g) in DMSO (5 mL) was stirred at 45 C overnight. Excess 2- metboxyethanamme was removed under reduced pressure before HC1 (2M, 3 mL) was added to the mixture-. The mixture was stirred at 45 C for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SC)4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/petru = 5/1 with drops of AcOH as mobile phase) to give 1 (0.720 g, yield 60.7%) as a yellow solid.

Reference： [1]Patent: WO2015/6754,2015,A2 .Location in patent: Paragraph 00387

63
[ 874279-26-2 ]
[ 109-85-3 ]
4-(dimethoxymethyl)-N-(2-methoxyethyl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 70℃;	General procedure: To the solution of the appropriate methylsulfonyl derivative (Preparation 9a3 1.0 eq.) indry acetonitrile (3m1/mmol) K2C03 (2.0 eq.) and the appropriate amine (1.5 eq.) wereadded, and stirred at 70C until no further conversion was observed. The reaction mixture was cooled, filtered, the precipitate was washed with EtOAc, then the filtrate was concentrated under reduced pressure. Crude product was purified via flash chromatography using heptane and EtOAe as eluents.Starting from 4-(dimethoxymethyl)-2-methylsulfonyl-pyrimidine (Preparation 9a3) and2-methoxyethanamine using General Procedure 9E 4-(dimethoxymethyl)-N-(2-methoxyethyl)pyrimidin-2-amine was obtained.?H NMR (400 MHz, CDCI3): 8.32 (d, tFT), 6.73 (d, 1H), 5.61 (br s, 1H), 5.08 (s, lH), 3.62 (m, 2H) 3.56 (m, 2H), 3.38 (s, 6H), 3.36 (s, 3H).

Reference： [1]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 131; 142

64
[ 117-80-6 ]
[ 109-85-3 ]
[ 22272-22-6 ]

Yield	Reaction Conditions	Operation in experiment
96.1%	With triethylamine; In N,N-dimethyl-formamide; for 1.0h;	To an ice-cold stirred solution of compounds 1 (10 mmol) andtriethylamine (1 mL) in DMF (20 mL) was added dropwise 2-methoxyethylamine (12.5 mmol). After the mixture color turnedfrom light yellow to red, the reaction continued at room temperaturefor 1 h, then poured into 300 mL water to form an orange redprecipitate. The resulting precipitated solid was filtered, washedwith cooled water, and dried.Yield: 96.1%; orange powder; mp: 82-83 C; 1H NMR (DMSO-d6,400 MHz) delta: 7.98(m, 2H), 7.75-7.87(m, 2H), 7.25(s, 1H),3.92-3.94(m, 2H), 3.57(t, J 5.7 Hz, 2H), 3.29-3.38(s, 3H); ESI-MS:m/z 266.1 [M+H]+, C13H12ClNO3 (MW=265.1).
87.8%	With triethylamine; In ethanol; at 20.0℃; for 18.0h;	To 2,3-dichloro-1,4-naphthoquinone (0.341g, 1.50mmol) in 1.5mlof ethanol was added 2-methoxyethylamine (0.124g, 1.65mmol) and triethylamine (0.227g,2.25mmol) and the mixture stirred at r. t. for 18h. The red precipitate formedwas filtered under suction, washed with distilled water and dried to afford (4) as a dark red solid, 87.8%.1H (CDCl3) delta 8.15 (dd, 1H, J=0.94, 7.68Hz), 8.03 (dd, 1H, J=0.99, 7.67Hz), 7.72 (dt, 1H, J=1.31, 7.59Hz), 7.62 (dt, 1H, J=1.28, 7.55Hz), 6.36 (br s, 1H), 4.06(dd, 2H, J=5.60, 10.62Hz), 3.63(t, 2H, J=5.17Hz), 3.42 (s, 3H); 13C(CDCl3) delta 180.42, 176.84, 144.37, 134.85, 132.67, 132.44, 129.88,126.80, 77.20, 71.22, 58.95, 44.50.
53%	With triethylamine; In diethyl ether; at 20.0℃; for 24.0h;	2, 3 a-Dichloro provided 1, 4 a-napthoquinone 1g (4. 4mmol) diethylether 30 ml a melting solution 2 a-Methoxyethylamine 568 micro l (6. 6mmol), triethylamine 610 micro l some excellent. 24 hours at room temperature then evaporated in pressure with respect to the stirring mixture. (Hexanes: EtOAc=20:1) column chromatography compound to a positive number (NQ 25) to compounds of formula 25 to obtained.Yield: 53%

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 144,p. 504 - 516
[2]MedChemComm,2017,vol. 8,p. 1318 - 1321
[3]European Journal of Medicinal Chemistry,2015,vol. 104,p. 42 - 56
[4]Patent: KR101761848,2017,B1 .Location in patent: Paragraph 0317-0320
[5]ChemMedChem,2016,p. 1944 - 1955

65
[ 1160182-44-4 ]
[ 40381-90-6 ]
[ 109-85-3 ]
2-(4-bromo-3-[1,3]dioxolan-2-ylphenoxy)-6-(2-methoxyethylamino)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		2-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-methoxy-ethylamino)-nicotinonitrile (8) (1043) To a solution of compound mixture, 6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile (4+5, 2.5 g, 6.6 mmol) in acetonitrile (anhydrous, 50 mL) was added 2-methoxy-ethylamine (5.7 mL, 66 mmol). The reaction was heated at 80 C. for 2 hours. After the reaction, all volatile components were evaporated under vacuum. Purification was achieved by silica gel chromatography, eluting with 10%-80% EtOAc/hexanes gradient, affording 1.0 g (36% yield) of the title compound. 1H NMR (400 MHz, chloroform-d) delta ppm 7.58-7.47 (m, 2H), 7.41 (d, J=3.1 Hz, 1H), 7.04 (dd, J=8.6, 2.7 Hz, 1H), 6.09-6.03 (m, 2H), 5.37 (t, J=5.1 Hz, 1H), 4.14-3.99 (m, 4H), 3.37 (t, J=5.1 Hz, 2H), 3.31-3.23 (m, 5H).

Reference： [1]Patent: US2015/291629,2015,A1 .Location in patent: Paragraph 1043

66
[ 62068-78-4 ]
[ 109-85-3 ]
6-chloro-2-(2-methoxyethylamino)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	In N,N-dimethyl-formamide; at 60℃; for 7h;Sealed tube;	6-Chloro-2-(2-methoxy-ethylamino)-nicotinamide (2) (1113) Refer to synthesis of D46 for preparation of <strong>[62068-78-4]2,6-dichloro-nicotinamide</strong> (1). A sealed reaction vessel containing <strong>[62068-78-4]2,6-dichloro-nicotinamide</strong> (1) (8.66 g, 45.3 mmol) and 2-methoxy-ethylamine (15.6 mL, 181 mmol) in anhydrous dimethylformamide (40 mL) was heated to 60 C. for 7 h. The reaction was then cooled to room temperature. Dimethylformamide was azeotropically removed by the addition and evaporation of toluene (6×700 mL) by rotary evaporation with water bath at 70 C. An orange oil was obtained (12.2 g). The oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with CH2Cl2 (400 mL) followed by the addition of silica gel (100 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (200 g, 230-400 mesh) and eluted with 50% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound as a white solid (5.37 g, 64% isolated yield). 1H NMR 400 MHz (d6-DMSO) delta7.79 (d, J=7.8 Hz, 1H), 7.30 (s, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 4.04 (br t, J=4.7 Hz, 1H), 3.80 (td, J=5.5, 4.7 Hz, 2H), 3.63 (t, J=5.5 Hz, 2H), 2.94 (s, 3H).

Reference： [1]Patent: US2015/291629,2015,A1 .Location in patent: Paragraph 1113

67
[ 6141-13-5 ]
[ 109-85-3 ]
C₁₁H₁₃N₃O [ No CAS ]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 1035 - 1039

68
[ 848501-94-0 ]
[ 13089-11-7 ]
[ 109-85-3 ]
[ 18672-03-2 ]
N-[10,11-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.0²'⁶]dodeca-1⁽⁸⁾,6,9,11-tetraen-3-yl]-2-[(2-methoxyethyl)amino]-1,3-thiazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27 mg		Example 101 A^-[10,ll-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(8),6,9,ll-tetraen-3-yl]-2-[(2-methoxyethyl)amino]-l,3-thiazole-4-carboxamide (ABR 239601) To a stirred solution of 2-bromo-l ,3-thiazole-4-carboxamide (360 mg, 1.74 mmol) in DMF (15 mL) was added methyl 3,3,3-trifiuoro-2-oxopropanoate (543 mg, 3.48 mmol) followed by pyridine (140 mu, 1.74 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 h. Thionyl chloride (126 mu, 1.74 mmol) was added at 0C and the reaction mixture was then stirred for 1 h. The reaction mixture was concentrated and the residue was filtered through a short pad of silica, eluting with DCM, under nitrogen. The filtrate was concentrated, and the acyl intermediate that remained was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dichloro-lH-l ,3-benzodiazol-2-amine (293 mg, 1.45 mmol) in DMF (10 mL) and triethylamine (231 mu, 1.74 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL), washed with washed with 10% citric acid(aq) (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSC^), filtered and concentrated. The crude product was triturated in DCM to afford a mixture of 2-bromo-N-[10,l 1 -dichloro-4-oxo-3- (trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca-l(8),6,9,l l -tetraen-3-yi]-l ,3-thiazole-4- carboxamide and 2-chloro-N-[10,l l-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (8),6,9,l l-tetraen-3-yl]-l ,3-thiazole-4-carboxamide (746 mg). A microwave tube was charged with a portion of the mixture of 2-bromo-N-[10,l l-dichloro-4- oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca-l(8),6,9,l l-tetraen-3-yl]-l ,3- thiazole-4-carboxamide and 2-chloro-N-[10,l l-dichloro-4-oxo-3-(trifluoromethyl)-2,5,7- triazatricyclo[6.4.0.02'6]dodeca-l (8),6,9,l l-tetraen-3-yl]-l ,3-thiazole-4-carboxamide (80 mg), K2CO3 (64 mg, 0.47 mmol), 2-methoxyethan-l -amine (40 mu, 0.47 mmol) and dioxane (2 mL). Initially, the reaction was heated in the microwave at 130C for 1 h. Then the reaction was then heated for a further 4 h. During this period, additional 2-methoxyethan-l -amine (160 mu, 1.88 mmol) and K2CO3 (256 mg, 1.88 mmol) were added portionwise with the reaction at room temperature during retreatment. Then the reaction mixture was concentrated. The residue was dissolved in EtOAc (25 mL) and washed with water (25 mL), 10% citric acid(aq) (25 mL) and brine (25 mL). The organic phase was dried (MgSC^), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH Method A) to afford the title compound as a white solid (27 mg).

Reference： [1]Patent: WO2015/177367,2015,A1 .Location in patent: Page/Page column 131; 132

69
[ 109-85-3 ]
[ 5071-61-4 ]
N-(2-methoxyethyl)-5-phenyl-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.9%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 18h;	Example 1: N-(2-methoxyethyl)-5-phenyl-lH-pyrazol -3-carboxamide [0118] A solution of 5-phenyl-lH-pyrazole-3-carboxylic acid (0.15 g, 0.79 mmol) in THF (10 mL), 2-methoxy-ethylamine (0.09 g, 1.18 mmol), EDC.HC1 (0.304 g, 1.59 mmol) and HOBt (0.214 g, 1.59 mmol) was stirred for 18 h at room temperature. Voiatiles were removed under vacuum, poured in ice-water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous Na2S04and concentrated under reduced pressure to get a brown liquid. The crude residue was purified by combiflash using 20% MeOH in DCM to give the product (0.15 g, 78.9%) as off white solid; 1NMR (400 MHz, CDC ): delta 12.01 (br, I H), 8.80 (br, IH), 7.61 -7.59 (d, J=7.4 Hz, 2H), 7.46-7.43 (t, 2H), 7.39- 7.36 (t, I H), 7.10 (s, I H), 3.75-3.73 (m, 2H), 3.70-3.63 (m, 2H), 3.46 (s, 3H); LC-MS: [M+H]+246.2; HPLC purity 99.82% at 220 nm and 99.82% at 254 nm.

Reference： [1]Patent: WO2016/105484,2016,A1 .Location in patent: Paragraph 0118

70
[ 35661-60-0 ]
[ 109-85-3 ]
[ 100-46-9 ]
[ 167015-23-8 ]
C₄₉H₆₃N₆O₆PolS [ No CAS ]