[ CAS No. 57297-29-7 ] {[proInfo.proName]}

Name: 57297-29-7|Cyclopropanecarboximidamide hydrochloride|97%
Brand: Ambeed
SKU: A264831
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Quality Control of [ 57297-29-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 57297-29-7 ]

Product Details of [ 57297-29-7 ]

CAS No. :	57297-29-7	MDL No. :	MFCD00053010
Formula :	C₄H₉ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JRYOZJIRAVZGMV-UHFFFAOYSA-N
M.W :	120.58	Pubchem ID :	2781916
Synonyms :

Calculated chemistry of [ 57297-29-7 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	2.0
Molar Refractivity :	32.49
TPSA :	49.87 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) :	-6.69 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.49
Log Po/w (WLOGP) :	1.07
Log Po/w (MLOGP) :	0.5
Log Po/w (SILICOS-IT) :	0.37
Consensus Log Po/w :	0.49

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.83
Solubility :	17.8 mg/ml ; 0.148 mol/l
Class :	Very soluble
Log S (Ali) :	-1.11
Solubility :	9.43 mg/ml ; 0.0782 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.1
Solubility :	95.1 mg/ml ; 0.789 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.48

Safety of [ 57297-29-7 ]

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

Application In Synthesis of [ 57297-29-7 ]

* 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 [ 57297-29-7 ]
Downstream synthetic route of [ 57297-29-7 ]

[ 57297-29-7 ] Synthesis Path-Upstream 1~3

1
[ 5500-21-0 ]
[ 57297-29-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: With hydrogenchloride; methanol In toluene at 15 - 23℃; for 18 h; Stage #2: With ammonia In methanol; toluene at 5 - 25℃; for 1.16667 h;	A l-L reactor equipped with a thermocouple, subsurface gas feed line, hydrogen chloride cylinder, cylinder balance and nitrogen bubbler was flushed with nitrogen and charged with cyclopropanecarbonitrile (100 g, 1.5 mol), methanol (48 g, 1.5 mol) and toluene (400 mL). The reaction mixture was maintained at 15 °C under slight nitrogen positive pressure while feeding anhydrous hydrogen chloride (57 g, 1.55 mol) below the reaction mixture surface over 2 h. Then the reaction mixture was stirred for 16 h at 23 ⁰C. EPO <DP n="24"/>Excess hydrogen chloride was purged by bubbling nitrogen below the reaction mixture surface and venting the effluent gas through a water scrubber over 2 h. The mixture was cooled to 5 °C, and then a solution of ammonia in methanol (240 mL of a 7 M solution, 1.7 mol) was added over 10 minutes while maintaining the temperature below 25 °C. After being allowed to stand an additional 1 h, the reaction mixture was distilled at reduced pressure to remove the excess methanol. The product was filtered, washed with toluene (100 mL), and suction-dried to give 17O g (94 percent yield) of the title compound as a solid. ¹H NMR (DMSO-J₆) δ 8.8 (br s, 4H), 1.84 (m, IH), 1.1 (m, 4H).
79.5%	Stage #1: With hydrogenchloride In ethanol at 20℃; for 24 h; Stage #2: With ammonia In ethanol at 23℃; Cooling with ice	Cyclopropylcarboxamidine hydrochloride (1) A solution of cyclopropanecarbonitrile (70 g, 1 .04 mol) in ethanol (50 mL) was added to a saturated solution of dry HCI gas in dry ethanol (93 g) along with slight cooling. The resulting mixture was then stirred at RT for 24 h. The thick suspension formed was diluted with ethanol (25 mL) and cooled with an ice-water bath. An ethanolic ammonia solution (103.2 g) was added slowly to the ethanol mixture over ~ 30 min. The cooling bath was then removed, and the mixture was stirred at 23 °C for another 24 h. The precipitated ammonium chloride by-product was filtered off, and washed with ethanol (25 mL). The filtrates were concentrated and diluted with methanol (25 mL). The product was precipitated from the methanol mixture by the addition of diethyl ether (100 mL). The suspension was stirred for 4 h, the precipitate was filtered off, washed with diethyl ether (50 mL), and dried under vacuum to afford 100 g (79.5percent) of the amidine (1 ). LCMS m/z 85 (M+1 ). H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 2H), 8.72 (s, 2H), 1.84 (m, 1 H), 1.15-1 .06 (m, 4H).
67%	Stage #1: With hydrogenchloride; methanol In diethyl ether at 0℃; for 2 h; Stage #2: With ammonia In methanol for 1 h; Cooling with ice	Hydrogen chloride gas was bubbled through a stirred solution of cyclopropylcarbonitrile (10.0 g, 0.15 mol) and methanol (6 ml, 0.15 mol) in dry ether (60 ml) at 0°C for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue dissolved in methanol (125 ml). The solution was added to an ice-cold mixture of methanol (125 ml) and liquid ammonia (15 ml) and the mixture stirred for 1 hour. The resulting clear solution was evaporated to leave cyclopropylcarboxamidine hydrochloride salt as a white solid (12.0 g, 67percent). Characterising data for the compound are as follows: ¹H nmr (400 MHz, d₆-DMSO) δ_H 8.75 (2H, s), 8.64 (2H, s), 1.81 (1 H, quintet), 1.11 (4H, s) ppm.

67%

Stage #1: With hydrogenchloride In methanol; diethyl ether at 0℃; for 2 h;
Stage #2: With ammonia In methanol; diethyl ether for 1 h; Cooling with ice

Hydrogen chloride gas was bubbled through a stirred solution of cyclopropylcarbonitrile (10.0 g, 0.15 mol) and methanol (6 ml, 0.15 mol) in dry ether (60 ml) at 0⁰C for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue dissolved in methanol (125 ml). The solution was added to an ice-cold mixture of methanol (125 ml) and liquid ammonia (15 ml) and the mixture stirred for 1 hour. The resulting clear solution was evaporated to leave cyclopropylcarboxamidine hydrochloride salt as a white solid (12.0 g, 67percent). 1H nmr (400 MHz, de-DMSO) δ_H 8.75 (2H, s), 8.64 (2H, s), 1.81 (1 H₁ quintet), 1.11 (4H₁ s) ppm.

Reference： [1] Patent: WO2006/121648, 2006, A2, . Location in patent: Page/Page column 22-23
[2] Patent: WO2011/58478, 2011, A1, . Location in patent: Page/Page column 31
[3] Patent: WO2009/81112, 2009, A2, . Location in patent: Page/Page column 113-114
[4] Patent: WO2010/92339, 2010, A1, . Location in patent: Page/Page column 83
[5] Patent: US2003/139415, 2003, A1,
[6] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 19, p. 3155 - 3160

2
[ 63190-44-3 ]
[ 57297-29-7 ]

Reference： [1] Patent: WO2006/124657, 2006, A1, . Location in patent: Page/Page column 13

3
[ 57297-29-7 ]
[ 40876-98-0 ]
[ 858956-25-9 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: for 0.333333 h; Stage #2: at 70℃; Stage #3: With hydrogenchloride In water at 20℃;	A solution of sodium hydroxide (2.85 g, 71.3 mmol) in water (3 ml) was added to a stirred solution of diethyl oxaloacetate sodium salt (8.7 g, 50 mmol) in water (50 ml) and the mixture stirred for 20 minutes. Cyclopropylcarboxamidine hydrochloride salt (5.0 g, 40 mmol) was added to the solution and the mixture was heated at 70 ⁰C overnight, then cooled to ambient temperature and acidified to pH1 by the cautious addition of concentrated hydrochloric acid. The precipitate was isolated by filtration and dried to yield 2-cyclopropyl-4-hydroxypyrimidine-6-carboxylic acid (4.7 g, 63percent). Characterising data for the compound are as follows: ¹H nmr (400MHz, d₆-DMSO) δ_H 13.30 (1H, br s), 12.97 (1H, br s), 6.59 (1H, s), 1.94 (1H, quintet), 1.04 (4H, m) ppm.
63%	Stage #1: With sodium hydroxide In water for 0.333333 h; Stage #2: at 70℃; Stage #3: With hydrogenchloride In water at 20℃;	A solution of sodium hydroxide (2.85 g, 71.3 mmol) in water (3 ml) was added to a stirred solution of diethyl oxaloacetate sodium salt (8.7 g, 50 mmol) in water (50 ml) and the mixture stirred for 20 minutes. Cyclopropylcarboxamidine hydrochloride salt (5.0 g, 40 mmol) was added to the solution and the mixture was heated at 70 ⁰C overnight, then cooled to ambient temperature and acidified to pH1 by the cautious addition of concentrated hydrochloric acid. The precipitate was isolated by filtration and dried to yield 2-cyclopropyl-4-hydroxypyrimidine-6-carboxylic acid (4.7 g, 63percent). 1H nmr (400MHz, d₆-DMSO) δ_H 13.30 (1 H, br s), 12.97 (1 H, br s), 6.59 (1 H, s), 1.94 (1 H, quintet), 1.04 (4H, m) ppm.

Reference： [1] Patent: WO2009/81112, 2009, A2, . Location in patent: Page/Page column 114
[2] Patent: WO2010/92339, 2010, A1, . Location in patent: Page/Page column 83-84

[ 57297-29-7 ] Synthesis Path-Downstream 1~88

1
[ 57297-29-7 ]
[ 123-06-8 ]
[ 23662-47-7 ]

Reference： [1]Journal of Medicinal Chemistry,1981,vol. 24,p. 382 - 389

2
[ 57297-29-7 ]
[ 4222-24-6 ]

Reference： [1]Tetrahedron Letters,1980,vol. 21,p. 947 - 950
[2]Journal of the American Chemical Society,1986,vol. 108,p. 134 - 140
[3]Journal of the American Chemical Society,1992,vol. 114,p. 959 - 963
[4]Journal of Organic Chemistry,1993,vol. 58,p. 5802 - 5810
[5]Journal of the American Chemical Society,2007,vol. 129,p. 10019 - 10028

3
[ 57297-29-7 ]
[ 56147-49-0 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 959 - 963

4
[ 4360-68-3 ]
[ 5815-08-7 ]
[ 57297-29-7 ]
2-cyclopropyl-4-phenyl-pyrimidine [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2003,vol. 1,p. 1638 - 1640

5
[ 2648-51-3 ]
[ 98-17-9 ]
[ 57297-29-7 ]
2-cyclopropyl-4-(3-trifluoromethylphenoxy)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In 1,2-dimethoxyethane; for 3h;Heating / reflux;	Example 14 Preparation of 2-cyclopropyl-4-(3-trifluoromethylphenoxy)pyrimidine 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a cyclopropylcarbamidine hydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional cyclopropylcarbamidine hydrochloride (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers / ethyl acetate: 20 / 1) to yield 2.1 g (75 percent) of the pure product having as a colorless liquid; 1H NMR (CDCl3); delta = 2.10 ppm (m, N=C(=N)-CH).
2.1 g (75%)	With potassium carbonate; In 1,2-dimethoxyethane;	EXAMPLE 14 Preparation of 2-cyclopropyl-4-(3-trifluoromethylphenoxy)pyrimidine 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a cyclopropylcarbamidine hydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional cyclopropylcarbamidine hydrochloride (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers/ethyl acetate: 20/1) to yield 2.1 g (75percent) of the pure product having as a colorless liquid; 1H NMR (CDCl3); delta=2.10 ppm (m, N=C(=N)-CH).

Reference： [1]Patent: EP1200414,2005,B1 .Location in patent: Page/Page column 7
[2]Patent: US6281358,2001,B1

6
[ 6249-74-7 ]
[ 57297-29-7 ]
5-benzyloxy-6-hydroxy-2-cyclopropyl-pyrimidine-4-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		EXAMPLE 2 Preparation of 5-benzyloxy-6-oxo-2-cyclopropyl-1,6-dihydropyrimidine-4-carboxylic Acid tert-butyl Ester NaOMe (6.8 mL, 25 wt percent solution in MeOH, 30 mmol) was added to a solution of cyclopropane-1-caboximidamide HCl (1.21 g, 10.0 mmol) and fumarate reagent 1a (4.60 g, 15.0 mmol) in MeOH (16.6 mL) at 0° C. The mixture was warmed to room temperature, then stirred for 30 hours. After dilution with MeOH (5 mL) and cooling to 0° C., 1N HCl (40 mL) was added and the product was precipitated from the mixture. The solid was washed with 10 mL of cold 9:1H2OMeOH and dried giving 3.14 g of the title product (92percent isolated yield) of >98percent pure (HPLC area percent purity at 210 nm) as a white crystalline solid with a melting point of 164.0-164.5° C. 1H-NMR (400 MHz, CDCl3) d 12.98 (1H, br s), 7.46-7.49 (2H, m), 7.30-7.38 (m, 3h), 5.24 (2H, s), 1.89-1.95 (1H, m), 1.52 (9H, s), 1.24-1.29 (2H, M), 1.05-1.10 (2H, m); 13C NMR (100 MHz, DMSO-d6) 164.3, 159.7, 159.5, 145.7, 139.4, 137.3, 128.6, 128.3 (2 peaks), 82.6, 73.4, 27.9, 13.5, 10.0 ppm.

Reference： [1]Patent: US2005/90668,2005,A1 .Location in patent: Page/Page column 10-11

7
[ 404569-73-9 ]
[ 57297-29-7 ]
2-cyclopropyl-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium acetate;	EXAMPLE 62 Synthesis of 2-cyclopropyl-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 100 mg (0.266 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide, 48.1 mg (0.399 mmol) of cyclopropyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of sodium acetate, in the same manner as that of Example 61. Yield: 90.4 mg (0.205 mmol) (77percent) MS (ESI, m/z) 440 (M+H)+ 438 (M-H)- 1H-NMR (CDCl3): 1.06-1.14 (2H, m), 1.17-1.22 (2H, m), 1.73 (2H, quint), 2.22-2.30 (1H, m), 2.48 (2H, t), 2.53 (3H, s), 3.31 (2H, q), 5.48 (1H, br t), 7.06-7.08 (2H, m), 7.15-7.20 (1H, m), 7.24-7.29 (2H, m), 7.39-7.40 (1H, m), 7.66-7.68 (2H, m).
	With sodium acetate;	Example 62 Synthesis of 2-cyclopropyl-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 100 mg (0.266 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide, 48.1 mg (0.399 mmol) of cyclopropyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of sodium acetate, in the same manner as that of Example 61. Yield: 90.4 mg (0.205 mmol) (77percent) MS (ESI, m/z) 440 (M+H)+ 438 (M-H)- 1H-NMR (CDCl3): 1.06-1.14 (2H, m), 1.17-1.22 (2H, m), 1.73 (2H, quint), 2.22-2.30 (1H, m), 2.48 (2H, t), 2.53 (3H, s), 3.31 (2H, q), 5.48 (1H, br t), 7.06-7.08 (2H, m), 7.15-7.20 (1H, m), 7.24-7.29 (2H, m), 7.39-7.40 (1H, m), 7.66-7.68 (2H, m).

Reference： [1]Patent: US2004/9991,2004,A1 .Location in patent: Page/Page column 28
[2]Patent: EP1318147,2003,A1

8
[ 404570-24-7 ]
[ 57297-29-7 ]
4-(3-chloro-4-methoxyphenyl)-2-cyclopropyl-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With sodium acetate;	EXAMPLE 90 Synthesis of 4-(3-chloro-4-methoxyphenyl)-2-cyclopropyl-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 150 mg (0.419 mmol) of 2-acetyl-3-(3-chloro-4-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 76.0 mg (0.629 mmol) of cyclopropyl-carbamidine hydrochloride and 68.9 mg (0.840 mmol) of sodium acetate, in the same manner as that of Example 1. Yield: 54.7 mg (0.125 mmol) (31percent) MS (ESI, m/z) 436 (M+H)+ 1H-NMR (CDCl3): 1.04-1.11 (2H, m), 1.17-1.22 (2H, m), 1.72 (2H, quint), 2.23-2.32 (1H, m), 2.45 (2H, t), 2.54 (3H, s), 3.32 (2H, q), 3.85 (3H, s), 5.47 (1H, br s), 6.90 (1H, d), 7.04-7.07 (1H, m), 7.15-7.20 (1H, m), 7.23-7.26 (3H, m), 7.70 (1H, dd), 7.88 (1H, d).
	With sodium acetate;	Example 90 Synthesis of 4-(3-chloro-4-methoxyphenyl)-2-cyclopropyl-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 150 mg (0.419 mmol) of 2-acetyl-3-(3-chloro-4-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 76.0 mg (0.629 mmol) of cyclopropyl-carbamidine hydrochloride and 68.9 mg (0.840 mmol) of sodium acetate, in the same manner as that of Example 1. Yield: 54.7 mg (0.125 mmol) (31percent) MS (ESI, m/z) 436 (M+H)+ 1H-NMR (CDCl3): 1.04-1.11 (2H, m), 1.17-1.22 (2H, m), 1.72 (2H, quint), 2.23-2.32 (1H, m), 2.45 (2H, t), 2.54 (3H, s), 3.32 (2H, q), 3.85 (3H, s), 5.47 (1H, br s), 6.90 (1H, d), 7.04-7.07 (1H, m), 7.15-7.20 (1H, m), 7.23-7.26 (3H, m), 7.70 (1H, dd), 7.88 (1H, d).

Reference： [1]Patent: US2004/9991,2004,A1 .Location in patent: Page/Page column 33
[2]Patent: EP1318147,2003,A1

9
[ 404570-25-8 ]
[ 57297-29-7 ]
2-cyclopropyl-4-(2,4-dimethylphenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium acetate;	EXAMPLE 92 Synthesis of 2-cyclopropyl-4-(2,4-dimethylphenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 150 mg (0.467 mmol) of 2-acetyl-3-(2,4-dimethylphenyl)-N-(3-phenylpropyl) acrylamide, 84.4 mg (0.700 mmol) of cyclopropyl-carbamidine hydrochloride and 77.1 mg (0.940 mmol) of sodium acetate, in the same manner as that of Example 1. Yield: 92.9 mg (0.233 mmol) (49percent) MS (ESI, m/z) 400 (M+H)+ 1H-NMR (CDCl3): 1.01-1.07 (2H, m), 1.13-1.18 (2H, m), 1.37-1.47 (2H, m), 2.22-2.30 (9H, m), 2.55 (3H, s), 3.15 (2H, q), 5.22 (1H, br t), 6.97-7.05 (3H, m), 7.13-7.28 (5H, m).
	With sodium acetate;	Example 92 Synthesis of 2-cyclopropyl-4-(2,4-dimethylphenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 150 mg (0.467 mmol) of 2-acetyl-3-(2,4-dimethylphenyl)-N-(3-phenylpropyl) acrylamide, 84.4 mg (0.700 mmol) of cyclopropyl-carbamidine hydrochloride and 77.1 mg (0.940 mmol) of sodium acetate, in the same manner as that of Example 1. Yield: 92.9 mg (0.233 mmol) (49percent) MS (ESI, m/z) 400 (M+H)+ 1H-NMR (CDCl3): 1.01-1.07 (2H, m), 1.13-1.18 (2H, m), 1.37-1.47 (2H, m), 2.22-2.30 (9H, m), 2.55 (3H, s), 3.15 (2H, q), 5.22 (1H, br t), 6.97-7.05 (3H, m), 7.13-7.28 (5H, m).

Reference： [1]Patent: US2004/9991,2004,A1 .Location in patent: Page/Page column 33-34
[2]Patent: EP1318147,2003,A1

10
[ 57297-29-7 ]
[ 10495-09-7 ]
[ 858956-23-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol;	EXAMPLE 1 Preparation of ethyl 6-amino-5-bromo-2-cyclopropyl-4-pyrimidinecarboxylate (Compound 1) and methyl 6-amino-5-bromo-2-cyclopropyl-4-pyrimidinecarboxylate (Compound 2) Step A: Preparation of 2-cyclopropyl-6- (diethoxymethyl)-4 (lI)-pyrimidinone To a mixture of ethyl 4,4-diethoxy-3-oxobutanoate (prepared according to the method of E. Graf, R. Troschutz, Synthesis, 1999,7, 1216; 10.0 g, 46 mmol) and cyclopropane- carboximidamide monohydrochloride (Lancaster Synthesis, 5.0 g, 41 mmol) in methanol (100 mL) was added a methanol solution of sodium methoxide (5. 4 M, 8.4 mL, 46 mmol). The reaction mixture was stirred overnight. The solvent was removed with a rotary evaporator. Dichloromethane was added and the mixture was filtered. The solvent from the filtrate was removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC) (35-100percent ethyl acetate in hexanes as eluant) to afford the title compound as a white solid (4.67 g). 1H NMR (CDC13) 8 6.55 (s, 1H), 5.10 (s, 1H), 3.61 (m, 4H), 1.91 (m, 1H), 1.23 (m, 8H), 1.09 (m, 2H). Additionally 3.24 g of an undehydrated product was obtained. This material could be converted to the title compound by refluxing it in methanol with a catalytic amount of pyridinium p-toluenesulfonate.

Reference： [1]Patent: WO2005/63721,2005,A1 .Location in patent: Page/Page column 27-28

11
[ 57297-29-7 ]
2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		A 500-mL jacketed reactor equipped with a pH meter, temperature probe and metering addition funnel was charged with denatured ethanol (contained 5 percent 2-propanol, 3O mL) and water (150 mL). The reaction mixture was stirred while diethyl oxalacetate, sodium salt (70 g, 0.33 mol) was added over 10 minutes. A solution of 25 percent aqueous NaOH (14 g, 56 mL, 0.35 mol) was metered into the stirring vortex over 1 h while maintaining the temperature in a range of 25 to 30 °C. The reaction mixture was stirred for an additional 30 minutes at 30 °C, and <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> (32 wt percent solution in water, 32 g, 0.267 mol) was added. A solution of 25 percent aqueous NaOH (31 g, 0.19 mol) was added at a temperature ranging from 30 to 35 0C over about 1 h so as to maintain the pH in the range of 10.5-11.5. Then the resulting orange mixture was gradually heated to 60 0C over a period of 1 h and held at the same temperature for additional 30 minutes. The reaction mixture was cooled to 45-50 0C, and hydrochloric acid (37 wt. percent in water, 50 mL, 0.60 mol) was added over 1 h at about 45 0C (CAUTION: foaming) until the pH reached to about 1.5. The reaction mixture was cooled to 5 °C and filtered. The resulting wet cake was washed with water (3 x 20 mL), suction-dried, and dried in a vacuum-oven at 70 0C for 16 h to afford 42 g (85 percent yield) of the title compound as a beige solid (97 percent purity by HPLC assay) decomposing at 235-236 0C.1H NMR (DMSO-J6) 6 6.58 (s, IH), 1.95 (m, IH), 1.0 (m, 4H). 13C NMR (DMSO-J6) delta 169.2, 169.0, 157.3, 116.8, 17.7, 14.1.

Reference： [1]Patent: WO2006/121648,2006,A2 .Location in patent: Page/Page column 23

12
N-(2-benzyloxy-3-(dimethylamino)-2-propenylidene)-N-methylmethanaminium tetrafluoroborate [ No CAS ]
[ 57297-29-7 ]
[ 866602-89-3 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium methylate; In methanol; for 3.5h;Heating / reflux;	The title compound was prepared following a procedure described in US 4, 558, 039 using the tetrafluoroborate of Arnold's salt (N- (2-benzyloxy-3- (dimethylamino)-2- propenylidene)-N-methylmethanaminium tetrafluoroborate-Holy, A., Arnold, Z, Collect. Czech. Chem. Commun., EN, 38, 1973, 1371-1380). Cyclopropanecarboxamidine hydrochloride (2.0 g, 16.6 mmol) was dissolved in MeOH (10 mL). To this solution was added Arnold's salt (5.85 g, 18.3 mmol). A solution of NaOMe (2.15 g, 39.8 mmol) in MeOH (20 mL) was added in small portions and the reaction mixture was heated under argon to reflux temperature. After 3.5 h, the reaction mixture was allowed to cool to room temperature and the solvents were removed by evaporation. The solid material was washed with water, filtered off and dried under reduced pressure to give the subtitle compound (2.4 g, 64percent). APCI-MS m/z: 227.1 [MH +I. 'H-NMR (DMSO-D6): 6 8.44 (2H, s), 7.49-7. 29 (5H, m), 5.21 (2H, s), 2.14 (1H, m), 0.95 (2H, m), 0.89 (2H, m) ppm.

Reference： [1]Patent: WO2005/95362,2005,A1 .Location in patent: Page/Page column 37, 38

13
[ 57297-29-7 ]
[ 920-37-6 ]
[ 265324-26-3 ]

Yield	Reaction Conditions	Operation in experiment
27%	With triethylamine; In ethanol; for 1h;Reflux;	Example 196a 2-cyclopropylpyrimidin-4-amine 196a Cyclopropylcarbamidine hydrochloride (1.0 g, 8.3 mmol) was dissolved in ethanol (25 mL) and triethylamine (1.26 g, 12.5 mmol), followed by the addition of 2-chloroacrylonitrile (870 mg, 10 mmol). The resulting orange-yellow solution was refluxed for 1h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase Combiflash to afford 196a (300 mg, 27percent) as a light brown solid. MS-ESI: [M+H]+ 136
	With triethylamine; In ethanol; for 0.5h;Heating / reflux;Product distribution / selectivity;	Alternative Preparation Method for Step A]: Cyclopropylcarbamidine hydrochloride (7.61 g) was dissolved in ethanol (125 mL) and triethylamine (19.35 mL) and 2-chloro-acrylonitrile (5.52 mL) were added. The resulting orange-yellow solution was refluxed for 30 minutes. The mixture was cooled and left in a refrigerator over night. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/methanol 9:1) to give 2-cyclopropyl-pyrimidin-4-ylamine (4.2 g) as a light brown solid that was still contaminated with an unidentified component, but used without further purification. 1H NMR (delta, DMSO-d6, product signals only): 7.88 (d, 1H), 6.64 (br s, 2H), 6.16 (d, 1H), 1.89-1.82 (m, 1H), 0.87-0.81 (m, 4H).

Reference： [1]Patent: EP2773638,2015,B1 .Location in patent: Paragraph 0747; 0748
[2]Patent: US2005/288308,2005,A1 .Location in patent: Page/Page column 9

14
[ 57297-29-7 ]
[ 54070-74-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; at 20℃; for 0.25h;	Sodium (646 mg, 28 mmol) is dissolved in methanol (50 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (3.40 g, 28 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo. This free base is added to a solution of sodium (1.29 g, 56 mmol) in methanol (50 ml) under a nitrogen atmosphere, at room temperature. Diethylfluoromalonate (5 g, 28 mmol) is added and the mixture is stirred at 60 °C for 5 h. The solvent is evaporated and the yellowish solid obtained is dissolved in 60 ml of water. The pH is adjusted at 6 with a 5 N HC1 solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-5-fluoro- 4, 6-pyrimidinediol 3 (3.6 g, 76 percent) is obtained as a white powder and used in the next step without further purification. 1H NMR (250 MHz, DMSO): 0.95 (m, 4H), 1.83 (m, 1H), 12.1 (bs, 2H); Sodium (0.417 g, 18.1 mmol) is dissolved in methanol (65 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (2.19 g, 18.1 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo to 30 ml. This free base is added to a solution of sodium (0.834 g, 36.2 mmol) in methanol (130 ml) under a nitrogen atmosphere, at room temperature. 2-ethoxy-4, 5-dihydro-3H-pyrrole-3- carboxylic acid ethyl ester (3.4 g, 18.1 mmol) in methanol is added and the mixture is stirred at 60 °C overnight. After cooling, the solvent is evaporated and the solid obtained is dissolved in water. The pH is adjusted at 5 with a 5 N HC1 solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-6,7-dihydro-5H- pyrrolo [2,3-d] pyrimidin-4-ol 48 (1.88 g, 59 percent) is obtained as a white powder and used in the next step without further purification. MS (MH+): 178.

Reference： [1]Patent: WO2003/87064,2003,A1 .Location in patent: Page/Page column 30

15
4-[(Dimethylamino)methylene]-3,4-dihydro-1H-1-benzazepine-2,5-dione [ No CAS ]
[ 57297-29-7 ]
[ 476363-48-1 ]

Yield	Reaction Conditions	Operation in experiment
62%		a 2-Cyclopropyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-one Analogous to Scheme 1from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong>. Yield: 62percent. White solid, m/z (ISP) 252 (MH).

Reference： [1]Patent: US2003/55042,2003,A1

16
[ 5500-21-0 ]
[ 57297-29-7 ]

Yield	Reaction Conditions	Operation in experiment
94%		A l-L reactor equipped with a thermocouple, subsurface gas feed line, hydrogen chloride cylinder, cylinder balance and nitrogen bubbler was flushed with nitrogen and charged with cyclopropanecarbonitrile (100 g, 1.5 mol), methanol (48 g, 1.5 mol) and toluene (400 mL). The reaction mixture was maintained at 15 °C under slight nitrogen positive pressure while feeding anhydrous hydrogen chloride (57 g, 1.55 mol) below the reaction mixture surface over 2 h. Then the reaction mixture was stirred for 16 h at 23 0C. EPO <DP n="24"/>Excess hydrogen chloride was purged by bubbling nitrogen below the reaction mixture surface and venting the effluent gas through a water scrubber over 2 h. The mixture was cooled to 5 °C, and then a solution of ammonia in methanol (240 mL of a 7 M solution, 1.7 mol) was added over 10 minutes while maintaining the temperature below 25 °C. After being allowed to stand an additional 1 h, the reaction mixture was distilled at reduced pressure to remove the excess methanol. The product was filtered, washed with toluene (100 mL), and suction-dried to give 17O g (94 percent yield) of the title compound as a solid. 1H NMR (DMSO-J6) delta 8.8 (br s, 4H), 1.84 (m, IH), 1.1 (m, 4H).
79.5%		Cyclopropylcarboxamidine hydrochloride (1) A solution of cyclopropanecarbonitrile (70 g, 1 .04 mol) in ethanol (50 mL) was added to a saturated solution of dry HCI gas in dry ethanol (93 g) along with slight cooling. The resulting mixture was then stirred at RT for 24 h. The thick suspension formed was diluted with ethanol (25 mL) and cooled with an ice-water bath. An ethanolic ammonia solution (103.2 g) was added slowly to the ethanol mixture over ~ 30 min. The cooling bath was then removed, and the mixture was stirred at 23 °C for another 24 h. The precipitated ammonium chloride by-product was filtered off, and washed with ethanol (25 mL). The filtrates were concentrated and diluted with methanol (25 mL). The product was precipitated from the methanol mixture by the addition of diethyl ether (100 mL). The suspension was stirred for 4 h, the precipitate was filtered off, washed with diethyl ether (50 mL), and dried under vacuum to afford 100 g (79.5percent) of the amidine (1 ). LCMS m/z 85 (M+1 ). H NMR (400 MHz, DMSO-d6) delta 8.86 (s, 2H), 8.72 (s, 2H), 1.84 (m, 1 H), 1.15-1 .06 (m, 4H).
67%		Hydrogen chloride gas was bubbled through a stirred solution of cyclopropylcarbonitrile (10.0 g, 0.15 mol) and methanol (6 ml, 0.15 mol) in dry ether (60 ml) at 0°C for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue dissolved in methanol (125 ml). The solution was added to an ice-cold mixture of methanol (125 ml) and liquid ammonia (15 ml) and the mixture stirred for 1 hour. The resulting clear solution was evaporated to leave cyclopropylcarboxamidine hydrochloride salt as a white solid (12.0 g, 67percent). Characterising data for the compound are as follows: 1H nmr (400 MHz, d6-DMSO) deltaH 8.75 (2H, s), 8.64 (2H, s), 1.81 (1 H, quintet), 1.11 (4H, s) ppm.

67%		Hydrogen chloride gas was bubbled through a stirred solution of cyclopropylcarbonitrile (10.0 g, 0.15 mol) and methanol (6 ml, 0.15 mol) in dry ether (60 ml) at 00C for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue dissolved in methanol (125 ml). The solution was added to an ice-cold mixture of methanol (125 ml) and liquid ammonia (15 ml) and the mixture stirred for 1 hour. The resulting clear solution was evaporated to leave cyclopropylcarboxamidine hydrochloride salt as a white solid (12.0 g, 67percent). 1H nmr (400 MHz, de-DMSO) deltaH 8.75 (2H, s), 8.64 (2H, s), 1.81 (1 H1 quintet), 1.11 (4H1 s) ppm.
7.3 g (61%)		EXAMPLE 5A Cyclopropanecarboximidamide Hydrochloride In analogy to the procedure for Example 3A, 6,71 g (100 mmol) cyclopropanecarbonitrile and proportionate amounts of the other reagents are used. Yield: 7.3 g (61percent) GC/MS (method A): retention time 3.42 min., m/z 85,1 [M+H]+

Reference： [1]Patent: WO2006/121648,2006,A2 .Location in patent: Page/Page column 22-23
[2]Patent: WO2011/58478,2011,A1 .Location in patent: Page/Page column 31
[3]Patent: WO2009/81112,2009,A2 .Location in patent: Page/Page column 113-114
[4]Patent: WO2010/92339,2010,A1 .Location in patent: Page/Page column 83
[5]Patent: US2003/139415,2003,A1
[6]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 3155 - 3160

17
4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione [ No CAS ]
[ 57297-29-7 ]
[ 476363-67-4 ]

Yield	Reaction Conditions	Operation in experiment
88%		a 2-Cyclopropyl-10-fluoro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong>. Yield: 88percent. White solid, m/z (ISP) 270 (MH).

Reference： [1]Patent: US2003/55042,2003,A1

18
7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione [ No CAS ]
[ 57297-29-7 ]
[ 476363-79-8 ]

Yield	Reaction Conditions	Operation in experiment
83%		a 10-Chloro-2-cyclopropyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and cyclopropancarboxamidine hydrochloride. Yield: 83percent. White solid, m/z (ISP) 28 (MH).

Reference： [1]Patent: US2003/55042,2003,A1

19
4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione [ No CAS ]
[ 57297-29-7 ]
[ 476364-06-4 ]

Yield	Reaction Conditions	Operation in experiment
88%		a 2-Cyclopropyl-5,7-dihydro-10-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-one Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione and <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong>. Yield: 88percent. White solid, m/z (ISP) 266 (MH).

Reference： [1]Patent: US2003/55042,2003,A1

20
[ 57297-29-7 ]
[ 168626-59-3 ]
4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-isopropoxybenzanilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; potassium carbonate; In chloroform; water; argon;	EXAMPLE 28 A 1.32 g portion of bromine dissolved in 6.6 ml of chloroform was dropwise added gradually (spending about 60 minutes) to 36 ml of chloroform solution containing 3.55 g of 4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-2-isopropoxybenzanilide at room temperature. When disappearance of the color of bromine was confirmed, the reaction solution was washed with a saturated sodium bicarbonate aqueous solution. The resulting organic layer was dried over anhydrous magnesium sulfate, concentrated under a reduced pressure and then evaporated to dryness using a vacuum pump. The thus obtained solid substance was dissolved in 40 ml of chloroform, and the resulting solution was mixed with 5.0 g of cyclopropylcarbamidine hydrochloride and 8.02 g of potassium carbonate and subjected to 20 hours of heating under reflux in a stream of argon. The resulting reaction solution was mixed with water to effect phase separation, and the separated organic layer was dried over anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was crystallized from toluene to obtain 2.96 g of 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-isopropoxybenzanilide.

Reference： [1]Patent: US5723606,1998,A

21
[ 57297-29-7 ]
[ 141642-82-2 ]
tert-butyl 2-cyclopropyl-4-hydroxy-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium ethanolate; In ethanol; at 80℃; for 2h;	Example 1; Preparation of tert-butyl 2-cvclopropyl-4-(3,3,3-trifluoropropoxyl-5,6,8,9-tetrahydro- 7H-pyrimido[4,5-d]azepine-7-carboxylate; [052] Step 1; Preparation of tert-butyl 2-cvclopropyl-4-hvdroxy-5,6,8,9-tetrahydro-7H - pyrimido[4,5-d]azepine-7-carboxylate; [053] Commercially available 1- tert-butyl 4-ethyl 5-oxoazepane-1 ,4-dicarboxylate (6.0 g, 21.0 mmol) and <strong>[57297-29-7]cyclopropanecarboximidamide hydrochloride</strong> (2.54 g, 21.0 mmol) were combined and dissolved in ethyl alcohol (21 mL ). Sodium ethoxide (21 weight percent solution in ethyl alcohol) (7.85 mL , 21.0 mmol) was added, and the mixture was heated at 80°C for 2 h. The contents of the reaction flask were cooled to 0°C and filtered. The solids were washed with cold methanol and dried in a 40°C vacuum oven to provide the title compound as an off-white solid (4.6 g, 72percent).

Reference： [1]Patent: WO2006/44762,2006,A2 .Location in patent: Page/Page column 15

22
[ 884487-29-0 ]
[ 57297-29-7 ]
tert-butyl 2-cyclopropyl-4-hydroxy-9-methyl-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium ethanolate; In ethanol; for 3h;Heating / reflux;	Step 2; Preparation of tert-butyl 2-cvclopropyl-4-hvdroxy-9-methyl-5,6,8,9- tetrahvdro-7/-/-pyrimido[4,5-d]azepine-7-carboxylate; [067] Sodium ethoxide solution (21 weight percent ethanol, 2.24 mL, 1.45 mmol) was added dropwise to a solution of 1- tert-butyl 4-ethyl 6-methyl-5-oxoazepane-1,4-dicarboxylate (290 mg, 0.97 mmol) in ethanol (6 mL). Cyclopropylcarbamidine hydrochloride (175 mg, 1.45 mmol) was added, and the mixture was heated at reflux for 3 h. The contents of the flask were cooled to rt, and the solvent was removed under reduced pressure. The residue was suspended in water and extracted with chloroform (2x). The organic layers were combined and concentrated to afford 200 mg (64percent) of crude product, which was EPO <DP n="21"/>used in the next step without further purification.

Reference： [1]Patent: WO2006/44762,2006,A2 .Location in patent: Page/Page column 19-20

23
[ 57297-29-7 ]
[ 105-45-3 ]
[ 7043-10-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium methylate; In methanol; water;	(a) The 2-cyclopropyl-4-hydroxy-6-methylpyrimidine to be employed as a starting material could be prepared, for example, as follows: STR6 78.3 g (0.65 mol) of cyclopropylamidine hydrochloride and then 76.4 g (0.65 mol) of acetoacetic acid methyl ester were added to a solution of 70 g (1.3 mol) of sodium methylate in 400 ml of methanol at room temperature. The mixture was stirred at room temperature for 18 hours, the solvent was then distilled off in vacuo and the residue was dissolved in 400 ml of water. The solution was adjusted to pH 4 by adding concentrated hydrochloric acid and, after cooling to 5°-10° C., the product which had precipitated was filtered off. 75 g (77percent of theory) of 2-cyclopropyl-4-hydroxy-6-methylpyrimidine were obtained in this manner in the form of a colorless powder with the melting point 187° C. STR7
	With sodium methylate; In methanol; at 20℃; for 18h;	2-Cyclopropyl-6-methylpyrimidin-4-ol (B8.1) (0372) A mixture of <strong>[57297-29-7]cyclopropane-carboximidamide hydrochloride</strong> (2.0 g, 16.7 mmol), methyl 3-oxobutanoate (1.9 g, 16.7 mmol) and CH3ONa (1.8 g, 33.4 mmol) in MeOH (200 mL) was stirred at rt for 18 h. Then the mixture was diluted with Sat. Na2SO3 (50 mL), then concentrated under reduced pressure. The residue was dissolved in 50 mL water, adjusted pH to 4. After cooling to 5° C., the solid was collected and dried in vacuum to give the title compound (2.0 g, 98percent) as a yellow solid. The crude product was used in the next step without further purification. LC-MS: [M+H]+=151.2.
	With sodium methylate; In methanol; at 20℃; for 18h;	A mixture of cyclo propanecarboximidamide hydrochloride (2.0 g, 16.7 mmol), methyl 3-oxobutanoate (1.9 g, 16.7 mmol) and CH3ONa (1 .8 g, 33.4 mmol) in MeOH (200 mL) was stirred at rt for 18 h.Then the mixture was diluted with Sat. Na2503 (50 mL), then concentrated under reduced pressure. The residue was dissolved in 50 mL water, adjusted pH to 4. After cooling to 5°C, the solid was collected and dried in vaccum to give the title compound (2.0 g, 98percent) as a yellow solid. The crude product was used in the next step without further purification. LC-MS: [M+H] = 151.2.

Reference： [1]Patent: US4254113,1981,A
[2]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0371; 0372
[3]Patent: WO2017/221100,2017,A1 .Location in patent: Paragraph 00177

24
[ 324558-30-7 ]
[ 57297-29-7 ]
2-cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	sodium ethanolate; In ethanol;	EXAMPLE 18 2-Cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile In analogy to the procedure described in example 15 the Z and/or E 2-cyano-3-methylsulfanyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acrylic acid ethyl ester [example 13 a)] was treated with cyclopropylcarbamidine hydrochloride in ethanol in the presence of sodium ethylate at reflux to yield the 2-cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile as colorless solid; m.p. >200° C.; MS: [M]+=307.

Reference： [1]Patent: US6218385,2001,B1

Yield	Reaction Conditions	Operation in experiment
		(ii) Cyclopropanecarboxamidine hydrochloride from cyclopropanecarbonitrile. Hydrogen chloride reaction time: 6 days Ammonia reaction time: 16 hours Melting point: 55-58°C 1H NMR CDCl3): 0.85 (m); 1.2 (m); 1.7 (m) Infra red (paraffin mull): 3400, 3200, 1650, 1460, 1380, 1310, 1150, 1040, 940 cm1

26
[ 63190-44-3 ]
[ 57297-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In ethanol; at 20℃;	Ethyl cyclopropanecarboximidate monohydrochloride (40.5 g 0.27 mol) was added portionwise to a saturated solution of ammonia in ethanol (50 mL). A further portion of ethanol (33 mL) was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in ethanol to give the title composition (83 mL).

Reference： [1]Patent: WO2006/124657,2006,A1 .Location in patent: Page/Page column 13

27
sodium salt of ethyl 4,4-diethoxy-3-oxobutanoate [ No CAS ]
[ 57297-29-7 ]
2-cyclopropyl-6-(diethoxymethyl)-4(1H)-pyrimidinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	In ethanol; toluene; at 20℃;Heating / reflux;	A portion (-40.4 mL) of the ethanol solution of <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> as prepared in Example 1 was added to a portion (-210 mL) of the solution of the sodium salt of ethyl 4,4-diethoxy-3-oxobutanoate as prepared in Example 2. The mixture was allowed to stir overnight at room temperature. The mixture was boiled for about 2 h and then allowed to cool to room temperature. The mixture was evaporated under reduced pressure, and the residue was redissolved in toluene (200 mL). A solution of ammonium chloride (0.68 g, 12.7 mmol) in water (30 mL) was added. After stirring for 10 minutes, the aqueous phase was removed. The organic phase was dried and evaporated to leave the product as pale yellow solid (27.27 g, 88 percent yield). Product recrystallized from hexanes melted at 111.5-112.0 °C.IR (nujol) 1674, 1602, 1400, 1316, 1153, 1116, 1099, 1068, 1003, 965, 860 cm-1.- EPO <DP n="16"/>1H NMR (CDCl3) delta 6.54 (d, J= 0.4 Hz, IH), 5.10 (d, J= 0.4 Hz, IH), 3.70-3.57 (m, 4H),1.98-1.92 (m, IH), 1.27-1.05 (m, 10H). MS m/e (M+ + 1) calcd. 239.1396, obsd. 239.1395.

Reference： [1]Patent: WO2006/124657,2006,A1 .Location in patent: Page/Page column 13-14

28
[ 927430-59-9 ]
[ 57297-29-7 ]
[ 927430-65-7 ]

Yield	Reaction Conditions	Operation in experiment
10%	In ethanol; for 120h;Heating / reflux;	To a suspension of 1 g (3.48 mmol) of 2,5-diamino-3-chloro-4-methylamino-benzoic acid methyl ester (synthesis described in example H7) in 153 ml of EtOH, is added 866 mg (6.97 mmol) of <strong>[57297-29-7]cyclopropane carboxamidine hydrochloride</strong>. After 24 hours of reaction under reflux, 866 mg (6.97 mmol) of <strong>[57297-29-7]cyclopropane carboxamidine hydrochloride</strong> were added more and the reaction is stirred under reflux 2 days more. Again 433 mg (3.48 mmol) of <strong>[57297-29-7]cyclopropane carboxamidine hydrochloride</strong> is added and after again 2 days of reaction under reflux, the reaction is stopped and the solvent is evaporated. The residue is suspended in EtOAc and the precipitate is filtrated. The filtrate obtained is evaporated and purified by flash chromatography on silica gel and gives 100 mg (0.36 mmol, 10percent) of a brown solid. LC/MS: 280 / 282

Reference： [1]Patent: WO2007/20050,2007,A2 .Location in patent: Page/Page column 68

29
[ 766-38-1 ]
[ 57297-29-7 ]
[ 304902-95-2 ]

Yield	Reaction Conditions	Operation in experiment
72%		NaH (60percent purity, 41 .9 g,) is added in portions to EtOH (800 mL) at 0 °C. The resulting mixture is warmed to ambient temperature and the cyclopropanecarboxamidine hydrochlorid (93.5 g,) isadded in portions. The reaction is warmed to 50 °C and maintained at this temperature for 0.5 h and then cooled to ambient temperature before mucobromic acid (100 g,) is added in EtOH while keeping the internal temperature below 55 °C. The mixture is allowed to cool to ambient temperature and stirred for additional 16 h. All solid components are removed by filtration and the resulting solution is concentrated under reduced pressure. Aq. HCI (1 mol/L) is added, the aqueous phase is washed with EtOAc (3x), the combined organic extracts are dried over MgSO4 and the solid parts removed by filtration. The residue is concentrated under reduced pressure and the resulting solid titrated with (iPr)20. The solids are collected by filtration and dried yielding the title compound (68.0 g, yield 72 percent) as a colorless solid.1 NMR (400 MHz, CDCI3): 6 = 8.91 (s, 1H), 2.38?2.26 (m, 1H), 1.34?1.14 (m, 4H) ppm; MS (ESI) mlz 244.9 [M + Hj.
72%		NaH (60percent purity, 41 .9 g) is added in portions to EtOH (800 mL) at 0 °C. The resulting mixture is warmed to ambient temperature and the cyclopropanecarboxamidine hydrochlorid (93.5 g,) is added in portions. The reaction is warmed to 50 °C and maintained at this temperature for 0.5 hand then cooled to ambient temperature before mucobromic acid (100 g) is added in EtOH while keeping the internal temperature below 55 °C. The mixture is allowed to cool to ambient temperature and stirred for additional 16 h. All solid components are removed by filtration and the resulting solution is concentrated under reduced pressure. Aq. HCI (1 mol/L) is added, the aqueous phase is washed with EtOAc (3x), the combined organic extracts are dried overMg504 and the solid parts removed by filtration. The residue is concentrated under reduced pressure and the resulting solid titrated with (iPr)20. The solids are collected by filtration and dried yielding the title compound (68.0 g, yield 72 percent) as a colorless solid.1H NMR (400 MHz, CDCl3): 6 = 8.91 (s, 1H), 2.38 ?2.26 (m, 1H), 1.34?1.14 (m, 4H) ppm; MS (ESI) mlz 244.9 [M + Hj.
	With sodium ethanolate; In ethanol; at 20 - 56℃;	5-Bromo-2-cyclopropylpyrimidine was prepared by the method of Budesinsky, Z., Coll.Czech. Chem. Commun., 1949,14, 223-235. Cyclopropanecarboximidamidehydrochloride (2.5 g, 20.7 mmol) was dissolved in EtOH (4 mL), freshly prepared 4.1M"NaOEf irTEtOH (478 niC) was"~added followe'dTSy mucobrbmic aci<T(2'.7 g, 10.3"mm6l)r "The mixture was heated to 56 °C for 30 minutes, more NaOEt in EtOH (4.1M, 3.2 mL)was added and the reaction was stirred at 56 °C for another 15 minutes and then at roomtemperature overnight. The solvent was evaporated off, aqueous HC1 (2M, 10 mL) wasadded and the brown solid was filtered off. The aqueous layer was extracted three timeswith dichloromethane. The combined organic layers were dried and concentrated to give abrown oil that together with the solid gave crude intermediate 5-bromo-2-cyclopropylpyrimidine-4-carboxylic acid (1.6 g). The crude intermediate was heated at140 °C for 8 minutes to give a brown sticky oil that was then partly dissolved indichloromethane. The solution was decanted from the mixture and concentrated to givethe subtitle compound as an oil (673 mg).^-NMR (CDC13): 5 8.61 (2H, s); 2.25 (1H, m); 1.13 (4H, m).APCI-MS m/z: 199/201 1:1 [MH1].

Reference： [1]Patent: WO2018/19552,2018,A1 .Location in patent: Page/Page column 94; 95
[2]Patent: WO2018/229041,2018,A1 .Location in patent: Page/Page column 89
[3]Patent: WO2006/4532,2006,A1 .Location in patent: Page/Page column 21

30
[ 57297-29-7 ]
[ 105-56-6 ]
[ 6287-38-3 ]
[ 945002-67-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; In ethanol;Heating / reflux;	3,4-dichlorobenzaldehyde (2.0 g, 11.43 mmol), ethyl cyanoacetate (1.29 g, 5 11.43 mmol), <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong> (1.38 g, 11.43 mmol), and potassium carbonate (1.58 g, 11.43 mmol) were refluxed in ethanol (40 mL) overnight. The stirbar was removed and water was added. The precipitate was filtered and washed with water to give 2.17 g (62percent) of the title compound as a white powder. MS m/z calculated for (M + H)+ 306, found 306.

Reference： [1]Patent: WO2007/84560,2007,A2 .Location in patent: Page/Page column 184

31
[ 57297-29-7 ]
(E)-2-Acetyl-3-methoxy-but-2-enoic acid methyl ester [ No CAS ]
[ 1056618-41-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In methanol; acetone; tert-butyl alcohol; at 0 - 20℃; for 4h;	EXAMPLE 29; Tetrahydro-furan-3-carboxylic Acid [(S)-3-[5-(2-cyclopropyl-4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-amide (I-48); step 1-; A solution of 126 (0.5 g, 2.904 mmol) and 128 (0.21 g, 1.742 mmol) in MeOH/acetone (1.5 mL/2 mL) was cooled down to 0° C. and a solution of potassium-tert-butoxide solution in tert-butanol (1.75 mL, 3.485 mmol) was added drop wise. After the addition was complete the mixture was slowly warmed to RT. After 4 h the solvent was evaporated. The residue was partitioned between DCM and water. A few drops of 1M HCl were added to bring the pH to ca.7. The layers were separated and the aqueous layer was extracted with DCM. The combined extracts were washed with brine, combined, dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography which afforded a partially purified 130a, which was used in the following step without further purification.

Reference： [1]Patent: US2007/191335,2007,A1 .Location in patent: Page/Page column 44

32
[ 57297-29-7 ]
[ 98977-34-5 ]
[ 1023953-54-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2103 - 2108

33
[ 57297-29-7 ]
[ 866602-89-3 ]

Yield	Reaction Conditions	Operation in experiment
		The subtitle compound was synthesised using the method described in US 4,558,039, starting from cyclopropylcarbamidine hydrochloride. s LC-APCI-MS m/z 227.0 (M+l); Rt = 2.36 min.1H-NMR (DMSO-J0): delta 0.86-0.99 (m, 4H), 2.14 (m, IH), 5.21 (s, 2H), 7.31-7.47 (m, 5H), 8.44 (s, 2H) ppm.

Reference： [1]Patent: WO2008/65393,2008,A1 .Location in patent: Page/Page column 31

34
[ 848360-23-6 ]
[ 57297-29-7 ]
[ 950819-95-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5115 - 5120

35
[ 614-76-6 ]
[ 57297-29-7 ]
[ 16405-79-1 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7841 - 7844

36
[ 614-83-5 ]
[ 57297-29-7 ]
[ 221548-37-4 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7841 - 7844

37
[ 23373-04-8 ]
[ 57297-29-7 ]
[ 5000-77-1 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7841 - 7844

38
[ 21739-93-5 ]
[ 57297-29-7 ]
[ 1129489-79-7 ]

Reference： [1]RSC Advances,2014,vol. 4,p. 50285 - 50294
[2]Angewandte Chemie - International Edition,2009,vol. 48,p. 348 - 351

39
[ 57297-29-7 ]
[ 88-65-3 ]
[ 459796-19-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With copper(l) iodide; TPGS-450-M; caesium carbonate; In water; at 20℃; for 12h;Inert atmosphere; Green chemistry;	General procedure: A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Substituted 2-halobenzoic acid (1, 0.5 mmol) and amidine hydrochloride (2, 0.75 mmol) or bis(guanidine) sulphate (2, 0.38 mmol) in 2 wt percent TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for 12 h (see Table 3 in text). After completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (3:1 to 1:1) as eluent to provide the desired product.

Reference： [1]Applied Organometallic Chemistry,2012,vol. 26,p. 576 - 582,7
[2]Angewandte Chemie - International Edition,2009,vol. 48,p. 348 - 351
[3]Tetrahedron,2015,vol. 71,p. 4853 - 4858
[4]RSC Advances,2015,vol. 5,p. 57235 - 57239

40
[ 57297-29-7 ]
[ 943-14-6 ]
[ 919018-66-9 ]

Reference： [1]RSC Advances,2014,vol. 4,p. 50285 - 50294
[2]Angewandte Chemie - International Edition,2009,vol. 48,p. 348 - 351
[3]RSC Advances,2015,vol. 5,p. 57235 - 57239

41
[ 57297-29-7 ]
[ 40876-98-0 ]
[ 858956-25-9 ]

Yield	Reaction Conditions	Operation in experiment
63%		A solution of sodium hydroxide (2.85 g, 71.3 mmol) in water (3 ml) was added to a stirred solution of diethyl oxaloacetate sodium salt (8.7 g, 50 mmol) in water (50 ml) and the mixture stirred for 20 minutes. Cyclopropylcarboxamidine hydrochloride salt (5.0 g, 40 mmol) was added to the solution and the mixture was heated at 70 0C overnight, then cooled to ambient temperature and acidified to pH1 by the cautious addition of concentrated hydrochloric acid. The precipitate was isolated by filtration and dried to yield 2-cyclopropyl-4-hydroxypyrimidine-6-carboxylic acid (4.7 g, 63percent). Characterising data for the compound are as follows: 1H nmr (400MHz, d6-DMSO) deltaH 13.30 (1H, br s), 12.97 (1H, br s), 6.59 (1H, s), 1.94 (1H, quintet), 1.04 (4H, m) ppm.
63%		A solution of sodium hydroxide (2.85 g, 71.3 mmol) in water (3 ml) was added to a stirred solution of diethyl oxaloacetate sodium salt (8.7 g, 50 mmol) in water (50 ml) and the mixture stirred for 20 minutes. Cyclopropylcarboxamidine hydrochloride salt (5.0 g, 40 mmol) was added to the solution and the mixture was heated at 70 0C overnight, then cooled to ambient temperature and acidified to pH1 by the cautious addition of concentrated hydrochloric acid. The precipitate was isolated by filtration and dried to yield 2-cyclopropyl-4-hydroxypyrimidine-6-carboxylic acid (4.7 g, 63percent). 1H nmr (400MHz, d6-DMSO) deltaH 13.30 (1 H, br s), 12.97 (1 H, br s), 6.59 (1 H, s), 1.94 (1 H, quintet), 1.04 (4H, m) ppm.

Reference： [1]Patent: WO2009/81112,2009,A2 .Location in patent: Page/Page column 114
[2]Patent: WO2010/92339,2010,A1 .Location in patent: Page/Page column 83-84

42
[ 57297-29-7 ]
[ 40876-98-0 ]
2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 Preparation of 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (Compound 135) Step Al : Preparation of 2-cyclopropyl-1, 6-dihydro-6-oxo-4-pyrimidinecarboxylic acid To a mixture of diethyl oxalacetate sodium salt (150 g, 714 mmol) in methanol (300 mL) and water (150 mL) warmed to 30 °C was added 50percent aqueous sodium hydroxide (56 g, 700 mmol) in water (60 mL) over 30 minutes, over which time the temperature remained at 25-30 °C and the pH at 11-12. Then the stirred mixture was heated for an additional 30 min at 35 °C. To this mixture was added <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> (64 g, 530 mol) in portions over 15 minutes. The orange solution was heated to 50 °C over 30 minutes and held at that temperature for 3 h. The reaction mixture was cooled to 35 °C, and concentrated hydrochloric acid (ca. 70 g, 0.7 mol) was added gradually (resulting in foaming) over 30 minutes at 30-40 °C until the pH was about 1.5- 2.5. The mixture was concentrated with a rotary evaporator at 35-40 °C to remove alcohols, stirred for 3-4 h at 25 °C to complete crystallization of the product. After the mixture was cooled to 0 °C the solid was collected by filtration. The solid was washed with water (2 x 60 mL), suction-dried, and then dried in a vacuum-oven at 60 °C to afford the title compound as a beige solid (ca. 60 g). 1H NMR (DMSO-d6) otilde; 6. 58 (s, 1H), 1.95 (m, 1H), 1.0 (m, 4H).; Step A2: Another preparation of 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidine- carboxylic acid To a mixture of diethyl oxalacetate sodium salt (210 g, 950 mmol) in methanol (500 mL) and water (400 mL) was added 50percent aqueous sodium hydroxide (80 g, 1.0 mol) in water (60 mL) over 30 minutes, over which time the temperature remained at 25-30 °C and the pH at 11-12. Then the stirred mixture was heated for an additional 30 min at 30 °C. To this mixture was added <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> (110 g, 910 mol). The orange solution was heated to 50 °C over 30 minutes and held at that temperature for 5 h. The reaction mixture was cooled to 30 °C and concentrated to half volume at reduced pressure at 35-40 °C and concentrated hydrochloric acid (140 g, 1.4 mol) was added gradually (resulting in foaming) over 30 minutes at 25-30 °C until the pH was about 1-2. The mixture was stirred at 5 °C for 1 h to complete crystallization of the product. After the mixture was cooled to 0 °C the solid was collected by filtration. The solid was washed with water (3 x 60 mL), suction-dried, and then dried in a vacuum-oven at 70 °C to afford the title compound as a beige solid (100 g) ; m. p. 235-236 °C (dec. ). 1H NMR (DMSO-d6) 8 6.58 (s, 1H), 1.95 (m, 1H), 1.0 (m, 4H).
60 g		To a mixture of diethyl oxalacetate sodium salt (150 g, 714 mmol) in methanol (300 mL) and water (150 mL) warmed to 30° C. was added 50percent aqueous sodium hydroxide (56 g, 700 mmol) in water (60 mL) over 30 minutes, over which time the temperature remained at 25-30° C. and the pH at 11-12. Then the stirred mixture was heated for an additional 30 min at 35° C. To this mixture was added <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> (64 g, 530 mol) in portions over 15 minutes. The orange solution was heated to 50° C. over 30 minutes and held at that temperature for 3 h. The reaction mixture was cooled to 35° C., and concentrated hydrochloric acid (ca. 70 g, 0.7 mol) was added gradually (resulting in foaming) over 30 minutes at 30-40° C. until the pH was about 1.5-2.5. The mixture was concentrated with a rotary evaporator at 35-40° C. to remove alcohols, stirred for 3-4 h at 25° C. to complete crystallization of the product. After the mixture was cooled to 0° C. the solid was collected by filtration. The solid was washed with water (2*60 mL), suction-dried, and then dried in a vacuum-oven at 60° C. to afford the title compound as a beige solid (ca. 60 g). 1H NMR (DMSO-d6) delta 6.58 (s, 1H), 1.95 (m, 1H), 1.0 (m, 4H).

Reference： [1]Patent: WO2005/63721,2005,A1 .Location in patent: Page/Page column 29
[2]Patent: US2013/303369,2013,A1 .Location in patent: Paragraph 0320-0321

43
[ 65260-58-4 ]
[ 57297-29-7 ]
[ 1192801-25-4 ]

Yield	Reaction Conditions	Operation in experiment
46%	With sodium ethanolate; In ethanol; at 140℃; for 0.333333h;Microwave irradiation;	Preparation 11 : 2-Cvclopropyl-pyrimidine-4-carboxylic acid ethyl ester; <n="23"/> Reference: Riley, T.A.; Hennen, W.J.; Dalley, N.K.; Wilson, B. E.; J. Heterocyclic Chem., 1987, 24, 955-964. Heat a mixture of cyclopropylcarbamidine hydrochloride (2.05 g, 17 mmol), (E)-4-ethoxy-2-oxo-but-3-enoic acid ethyl ester (4.39 g, 25.5 mmol), ethanol (12 mL), and sodium ethoxide (1.16 g, 17 mmol) in a microwave at 140 0C for 20 min. Concentrate the reaction mixture under reduced pressure and partition the residue between ethyl acetate and brine. Separate the organic layer and concentrate under reduced pressure. Purify the residue by silica gel chromatography (10-30% ethyl acetate/hexane) to give 2-cyclopropyl-pyrimidine-4-carboxylic acid ethyl ester (1.5 g, 46%) as light yellow oil. MS (m/z): 193.0 (M+H) +.

Reference： [1]Patent: WO2009/131815,2009,A1 .Location in patent: Page/Page column 21-22

44
[ 623-03-0 ]
[ 57297-29-7 ]
[ 1192469-32-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 24h;Sealed tube;	General procedure: A 5 mL reaction tube was charged with Phen-MCM-41-CuBr (36 mg, 0.025 mmol), amidine 4 (0.75 mmol), nitrile 2 (0.5 mmol), Cs2CO3 (489 mg, 1.5 mmol), and DMSO (1.5 mL) under an air atmosphere. The reaction tube was sealed and placed in an oil bath at r.t. The reaction mixture was stirred at 120 °C for 24 h. After cooling to r.t., the reaction mixture was diluted with EtOAc (10 mL) and filtered. The supported copper catalyst was washed with water (2 5 mL) and acetone (2 5 mL), and reused in the next run. The filtrate was washed with 5percent aqueous NaHCO3 and brine. The organic layer was dried over Mg-SO4 and concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (hexane/EtOAc, 3:2) to provide the desired product 5.

Reference： [1]Synthesis,2019,vol. 51,p. 2014 - 2022
[2]Journal of the American Chemical Society,2009,vol. 131,p. 15080 - 15081

45
[ 26260-02-6 ]
[ 57297-29-7 ]
[ 1208259-27-1 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 758 - 760

46
[ 1086255-91-5 ]
[ 64273-40-1 ]
[ 57297-29-7 ]
[ 1217530-91-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; In ethanol; at 90℃; for 6h;	2-Cyclopropyl-5-nitro-3H-pyrimidin-4-one.To a stirred solution of the nitro olefin mixture (350 mg, 2 mmol) in Ethanol (20 ml) was added the cyclopropyl amidine hydrochloride (301 mg, 2.5 mmol) followed by triethyl amine (2.5mmol).The mixture was heated in oil bath maintained at 90 0C for 6 hours. TLC in 5% methanol in dichloromethane showed mainly a single product and LC-MS showed a peak consistent with the mass of the desired product. After cooling to room temperature, the solvent was evaporated to dryness and the crude was purified by silica gel flash column chromatography, eluded with 3% methanol in dichloromethane. Brownish oil was obtained (310mg, 86%). This material was used as such for the next step.

Reference： [1]Patent: WO2010/30500,2010,A1 .Location in patent: Page/Page column 61-62

47
[ 2042-37-7 ]
[ 57297-29-7 ]
[ 1219036-95-9 ]

Reference： [1]Synlett,2010,p. 101 - 106

48
[ 42872-83-3 ]
[ 57297-29-7 ]
[ 1219036-98-2 ]