Name: 16588-74-2|3,5-Bis(trifluoromethyl)phenylisocyanate|98%
Brand: Ambeed
SKU: A926179
Rating: 94 (26 reviews)

1
[ 3380-34-5 ]
[ 16588-74-2 ]
[ 28395-87-1 ]

Reference： [1]Patent: DE2004302,1970,
Chem.Abstr.,1970,vol. 73

2
[ 454-81-9 ]
[ 16588-74-2 ]
[ 25761-42-6 ]

Reference： [1]Patent: CH506240,1971,
Chem.Abstr.,1971,vol. 75

3
[ 401-94-5 ]
[ 16588-74-2 ]
[ 55225-68-8 ]

Reference： [1]Patent: DE2334355,1975,
Chem.Abstr.,1975,vol. 82

4
[ 16588-74-2 ]
[ 3280-68-0 ]
[ 25790-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In acetone Heating;

Reference： [1]Current Patent Assignee: BASF SE; NOVARTIS AG; Novartis (w/o Sandoz) - CH506240, 1971, A [Chem.Abstr., 1971, vol. 75, # 117485][Chem.Abstr., 1971, vol. 75, # 117485] Current Patent Assignee: BASF SE; NOVARTIS AG; Novartis (w/o Sandoz) - DE1912553, 1969, A1 [Chem.Abstr., 1970, vol. 72, # 43228][Chem.Abstr., 1970, vol. 72, # 43228]

5
[ 16588-74-2 ]
[ 50547-51-8 ]
1-(3,5-bis-trifluoromethyl-phenyl)-3-(2-ethyl-4-oxo-4<i>H</i>-quinazolin-3-yl)-urea [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1149 - 1152

6
[ 320778-92-5 ]
[ 16588-74-2 ]
[ 820242-14-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	In tetrahydrofuran at 20℃; for 16h;
	In benzene at 20℃; for 3h;
	In benzene at 20℃; for 1h;	1.B Example 1B (R,R)-trans-1-[3,5-bis (trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]urea To a solution (0.60 ml) of 3,5-bis(trifluoromethyl)phenylisocyanate (0.26 ml, 1.5 mmol) in dry benzene was added (R,R)-trans-N,N-dimethyl-1,2-diaminocyclohexane (213 mg, 1.5 mmol) under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH=20/1-7/1) to give the title compound as a white amorphous solid. [α]D25 -35.3 (c 0.93, CHCl3); 1H-NMR (500MHz, DMSO-d6) δ 9.39 (s, 1H), 8.02 (s, 2H), 7.51 (s, 1H), 6.21 (d, J=5.5Hz, 1H), 3.35 (ddd, J=15.2, 10.5, 4.3Hz, 1H), 2.28 (dt, J=3.1, 10.2Hz, 1H), 2.18 (brs, 1H), 2.15 (s, 6H), 1.85-1.66 (m, 2H), 1.63-1.52 (m, 1H), 1.31-0.96 (m, 4H) ppm; 13C-NMR (126MHz, DMSO-d6) δ 154.9, 142.9, 131.3, 131.1, 130.8, 130.5, 126.9, 124.7, 122.5, 120.4, 117.12, 117.09, 113.4, 113.3, 65.6, 50.9, 39.9, 33.2, 24.9, 24.5, 21.4 ppm; IR (CHCl3) v 3424, 3332, 2939, 2864, 2792, 1695, 1549, 1473 cm-1; MS (FAB+) 398 (MH+, 100); Elemental analysis Calculated (for C17H21F6N3O): C, 51.38; H, 5.33; N, 10.57; F, 28.69. Found: C, 51.30; H, 5.22; N, 10.58; F, 28.46.

Reference： [1]Berkessel, Albrecht; Mukherjee, Santanu; Mueller, Thomas N.; Cleemann, Felix; Roland, Katrin; Brandenburg, Marc; Neudoerfl, Joerg-M.; Lex, Johann [Organic and Biomolecular Chemistry, 2006, vol. 4, # 23, p. 4319 - 4330]
[2]Okino, Tomotaka; Hoashi, Yasutaka; Furukawa, Tomihiro; Xu, Xuenong; Takemoto, Yoshiji [Journal of the American Chemical Society, 2005, vol. 127, # 1, p. 119 - 125]
[3]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP1640361, 2006, A2 Location in patent: Page/Page column 13

7
[ 387350-79-0 ]
[ 16588-74-2 ]
4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidine-1-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	In dichloromethane at 20℃; for 4h;	16 EXAMPLE 16; 4-[Cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidine-l-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (111)(4-Benzenesulfonyl-methyl-amino)-piperidine-l -carboxylic acid (3,5-bis- trifluoromethylphenyl)-amide (112) ;[0600] General procedure for the synthesis of compounds 111 and 112: Compound 110 (80 mg, 0.31 mmol, Aldrich) was added to a solution of compound 19 or 19e (0.31 mmol) in 2 mL of DCM at room temperature. After 4 hours at room temperature, the reaction mixture was poured to a column (silica gel, EtOAc/hexane 1/1) to give the title compounds 111 and 112.[0601] 4-[Cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]-piperidine- 1 - carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (111, white solid, 140 mg, yield 82%): 1H NMR (400 MHz, CDCl3): δ 8.13 (s, IH), 8.06 (d, IH, 7.9Hz), 7.89 (d, IH, 7.9 Hz), 7.83 (s, 2H), 7.72 (dd, IH, 7.7, 7.8 Hz), 7.46 (s, IH), 7.14 (br, IH, NH), 4.16 - 4.21 (m, 2H), 4.02 - 4.09 (m, IH), 2.86 - 2.92 (m, 2H), 1.86 - 1.99 (m, 3H), 1.65 - 1.69 (m, 2H), 0.89 - 0.93 (m, 2H), 0.77 - 0.81 (m, 2H); LC: 100%; MS: m/z = 604 (M+l).

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2007/118853, 2007, A1 Location in patent: Page/Page column 198-199

8
[ 16588-74-2 ]
9-amino-9-deoxyepicinchonine [ No CAS ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-[(R)-(quinolin-4-yl)((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In dichloromethane at 20℃; for 10h;
75%	In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere;	4.2. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-[(R)-(quinolin-4-yl)((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl]urea 1f A solution of 9-amino(9-deoxy) epicinchonine2(a) and 2(p) (448 mg, 1.53 mmol) in dry THF (1 mL/0.17 mmol) was added slowly to bis(trifluoromethyl)isocyanate (291 μL, 1.68 mmol) in dry THF (1 mL/0.19 mmol) at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 3 h until analysis by TLC indicated that all of the amine had been consumed. Purification by flash column chromatography [EtOAc/MeOH/Et3N (100:2:3-100:10:3) afforded catalyst 1h as a colourless solid (629 mg, 75% yield). Mp 200-204 °C; IR νmax(film)/cm-1 2937 (N-H), 1678 (CO), 1594 and 1551 (CC); 1H NMR (500 MHz, CD3OD) δH 8.83 (d, 1H, J = 4.7, Ar-H), 8.50 (d, 1H, J = 8.4, Ar-H), 8.06 (d, 1H, J = 7.9, Ar-H), 7.89 (s, 2H, Ar-H), 7.76 (t, 1H, J = 7.6, Ar-H), 7.68 (t, 1H, J = 7.6, Ar-H), 7.62 (d, 1H, J = 4.7, Ar-H), 7.41 (s, 1H, Ar-H), 5.89 (ddd, 1H, J = 17.1, 10.5, 6.4, CH2CH), 5.62 (br s, 1H, NH-CH), 5.15-5.11 (m, 2H, CH2CH), 3.21 (dd, 1H, J = 18.5, 9.0, CH-N), 3.12 (dd, 1H, J = 13.5, 7.5, CH-N), 3.05-2.95 (m, 3H, CH-N), 2.29 (dd, 1H, J = 15.8, 7.7, quinuclidine-H), 1.58-1.53 (m, 3H, quinuclidine-H), 1.21-1.17 (m, 1H, quinuclidine-H), 0.96-0.93 (m, 1H, quinuclidine-H); 13C NMR (125 MHz, CD3OD) δC 156.7, 151.0, 149.1, 143.2, 141.5, 133.1 (q, J = 33, 2× Ar), 131.0, 130.1, 128.8, 128.2, 125.5 (q, J = 272, 2 × CF3), 125.0, 119.0, 119.0, 115.5 (br q, J = 4, 3 × Ar), 115.3, 61.3, 61.2, 50.2, 48.1, 40.5, 28.9, 27.4, 26.4; MS m/z (ES+) 549 (98%, MH+). [HR-MS (ES+): MH+, 549.2097. [C28H27N4OF6]+ requires 549.2089]; (c 1.00, CHCl3).
	In tetrahydrofuran at 20℃;

Reference： [1]Amere, Mukkanti; Lasne, Marie-Claire; Rouden, Jacques [Organic Letters, 2007, vol. 9, # 14, p. 2621 - 2624]
[2]Location in patent: experimental part Jakubec, Pavol; Cockfield, Dane M.; Hynes, Peter S.; Cleator, Ed; Dixon, Darren J. [Tetrahedron Asymmetry, 2011, vol. 22, # 11, p. 1147 - 1155]
[3]Miyaji, Ryota; Asano, Keisuke; Matsubara, Seijiro [Organic Letters, 2013, vol. 15, # 14, p. 3658 - 3661]

9
[ 16588-74-2 ]
[ 1640227-33-3 ]
[ 1005003-44-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	In dichloromethane at 20℃; for 24h;
85%	In dichloromethane at 20℃; for 24h;

Reference： [1]Liu, Xu-Guang; Jiang, Jia-Jun; Shi, Min [Tetrahedron Asymmetry, 2007, vol. 18, # 23, p. 2773 - 2781]
[2]Shi, Min; Liu, Xu-Guang [Organic Letters, 2008, vol. 10, # 6, p. 1043 - 1046]

10
[ 706778-81-6 ]
[ 16588-74-2 ]
[ 706778-83-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	In ethyl acetate at 20℃; for 16h;	13.A Step A: 2- [3- (BENZYLOXYFORMYLAMINO)- (2R)-CYCLOPENTYLMETHYL-PROPIONYL]-TETRAHYDROPYRIDAZINE- 1-carboxylic acid (3, 5-BIS- (TRIFLUOROMETHYL) PHENYL) amide To a solution OF N-BENZYLOXY-N-[(2R)-CYCLOPENTYLMETHYL-3-OXO-3- (TETRAHYDROPYRIDAZIN-1-YL) PROPYL] formamide (53 mg, 0.14 MMOL) in EtOAc (2 ml) at rt under argon was added 3, 5-BIS- (TRIFLUOROMETHYL) PHENYL isocyanate (36 mg, 0.14 MMOL). The resulting mixture was stirred for 16 h at rt and then concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with 70-100% EtOAc/hexanes to give the title compound as a colourless oil (76 mg, 85%). 1 H-NMR ; B (CD30D), 8.25-7. 88 (3H, m, ArH and CHO), 8.60-7. 20 (6H, m, ArH), 5.01-4. 75 (2H, m, CH2Ph), 4.60-2. 90 (7H, m), 1.80-1. 05 (13H, m), 1.00-0. 90 (2H, m). LRMS: +ve ion: 651 [M+23], 400.

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2004/50638, 2004, A1 Location in patent: Page 24

11
[ 16588-74-2 ]
[ 95-85-2 ]
C₁₅H₉ClF₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.4%	In tetrahydrofuran; toluene at 100℃; for 1h;	309 3,5-Bis(trifluoromethyl)phenylisocyanate(180 µL, 1.04mmol) was added to a solution of 2-amino-4-chlorophenol(143.6mg, 1mmol) in a mixed solvent of tetrahydrofuran/toluene(0.5mL+4.5mL), and the mixture was stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=1:1) and crystallized by isopropyl ether/n-hexane to give the title compound(288.5mg, 72.4%) as a light yellowish brown powder.1H-NMR(DMSO-d6): δ 6.84-6.91(2H, m), 7.67(1H, s), 8.06(2H, s), 8.14(1H, d, J=2.1Hz), 8.45(1H, s), 10.10(1H, s), 10.44(1H, s).
72.4%	In tetrahydrofuran; toluene at 100℃; for 1h;	309 3,5-Bis(trifluoromethyl)phenylisocyanate(180 µL, 1.04mmol) was added to a solution of 2-amino-4-chlorophenol(143.6mg, 1mmol) in a mixed solvent of tetrahydrofuran/toluene(0.5mL+4.5mL), and the mixture was stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=1:1) and crystallized by isopropyl ether/n-hexane to give the title compound(288.5mg, 72.4%) as a light yellowish brown powder.1H-NMR(DMSO-d6): δ 6.84-6.91(2H, m), 7.67(1H, s), 8.06(2H, s), 8.14(1H, d, J=2.1Hz), 8.45(1H, s), 10.10(1H, s), 10.44(1H, s).
72.4%	In tetrahydrofuran; toluene at 100℃; for 1h;	309 3,5-Bis(trifluoromethyl)phenylisocyanate(180 µL, 1.04mmol) was added to a solution of 2-amino-4-chlorophenol(143.6mg, 1mmol) in a mixed solvent of tetrahydrofuran/toluene(0.5mL+4.5mL), and the mixture was stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=1:1) and crystallized by isopropyl ether/n-hexane to give the title compound(288.5mg, 72.4%) as a light yellowish brown powder.1H-NMR(DMSO-d6): δ 6.84-6.91(2H, m), 7.67(1H, s), 8.06(2H, s), 8.14(1H, d, J=2.1Hz), 8.45(1H, s), 10.10(1H, s), 10.44(1H, s).

72.4%

In tetrahydrofuran; toluene at 100℃; for 1h;

309 3,5-Bis(trifluoromethyl)phenylisocyanate(180 µL, 1.04mmol) was added to a solution of 2-amino-4-chlorophenol(143.6mg, 1mmol) in a mixed solvent of tetrahydrofuran/toluene(0.5mL+4.5mL), and the mixture was stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=1:1) and crystallized by isopropyl ether/n-hexane to give the title compound(288.5mg, 72.4%) as a light yellowish brown powder.1H-NMR(DMSO-d6): δ 6.84-6.91(2H, m), 7.67(1H, s), 8.06(2H, s), 8.14(1H, d, J=2.1Hz), 8.45(1H, s), 10.10(1H, s), 10.44(1H, s).

Reference： [1]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1510207, 2005, A1 Location in patent: Page/Page column 163-164
[2]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1512396, 2005, A1 Location in patent: Page/Page column 162
[3]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC; IYAKU BUNSHI SEKKEI KENKYUSHO - EP1514544, 2005, A1 Location in patent: Page/Page column 168
[4]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1510210, 2005, A1 Location in patent: Page/Page column 164

12
[ 56341-37-8 ]
[ 16588-74-2 ]
N-[3,5-Bis(trifluoromethyl)phenyl]-6-chloro-2-hydroxyindole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40.7%	With triethylamine In tetrahydrofuran at 20℃; for 4h;	77 A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added to a solution of 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) in tetrahydrofuran(5mL) under argon atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6):δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%	With triethylamine In tetrahydrofuran at 20℃; for 4h;	77 A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added to a solution of 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) in tetrahydrofuran(5mL) under argon atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6):δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%	With triethylamine In tetrahydrofuran at 20℃; for 4h;	77 A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added to a solution of 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) in tetrahydrofuran(5mL) under argon atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6):δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).

40.7%	With triethylamine In tetrahydrofuran at 20℃; for 4h;	28 Under argon atmosphere, 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) was dissolved in tetrahydrofuran(5mL). A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%	With triethylamine In tetrahydrofuran at 20℃; for 4h;	28 Under argon atmosphere, 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) was dissolved in tetrahydrofuran(5mL). A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).
40.7%	With triethylamine In tetrahydrofuran at 20℃; for 4h;	28 Under argon atmosphere, 3,5-bis(trifluoromethyl)phenylisocyanate(255mg, 1.0mmol) was dissolved in tetrahydrofuran(5mL). A solution of 6-chloro-oxindole(184mg, 1.1mmol) in tetrahydrofuran(5ml) and triethylamine(0.3mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(172.2mg, 40.7%) as a pink solid.1H-NMR(DMSO-d6): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1Hz), 7.41(1H, d, J=8.1Hz), 7.88(1H, s), 8.04(1H, d, J=2.1Hz), 8.38(2H, s), 10.93(1H, s).

Reference： [1]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1535609, 2005, A1 Location in patent: Page/Page column 90
[2]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1535610, 2005, A1 Location in patent: Page/Page column 89-90
[3]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1555018, 2005, A1 Location in patent: Page/Page column 88
[4]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1510207, 2005, A1 Location in patent: Page/Page column 119 Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1510210, 2005, A1 Location in patent: Page/Page column 119
[5]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1512396, 2005, A1 Location in patent: Page/Page column 117
[6]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC; IYAKU BUNSHI SEKKEI KENKYUSHO - EP1514544, 2005, A1 Location in patent: Page/Page column 123

13
[ 869733-91-5 ]
[ 16588-74-2 ]
6-chloro-3,4-dihydro-2-(4-fluorobenzyl)-3-oxo-2H-1,2-benzothiazine-4-(3,5-bis-(trifluoromethyl))carboxanilide 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	Stage #1: 6-chloro-3,4-dihydro-2-(4-fluorobenzyl)-3-oxo-2H-1,2-benzothiazine 1,1-dioxide; 3,5-ditrifluoromethylisocyanate With triethylamine In dimethyl sulfoxide at 20℃; for 2.5h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide	16 At room temperature 76 mg (0.75 mmol) triethylamin were added to a mixture of 250 mg (0.74 mmol) 6-chloro-3,4-dihydro-2-(4-f(uorobenzyl)-3-oxo-2H-1,2-benzothiazine 1,1-dioxide and 192 mg (0.75 mmol) 3,5-bis(trifluoromethyl)-phenylisocyanate dissolved in 3 mL DMSO. After stirring for 2.5 hrs the resulting mixture was quenched with dilute HCI in an ice bath and then extracted with methylenechloride (2 times). The combined extracts were washed, dried and concentrated to give 390 mg crude product. This material was recrystallized from methylenechloride/hexane to give 303 mg 6-chloro-3,4-dihydro-2-(4-fluorobenzyl)-3-oxo-2H-1,2-benzothiazine-4-(3- trifluoromethyl) carboxanilide 1,1-dioxide. Yield: 69 % Melting point: 233 - 234 °C Structure was confirmed by elementary analysis (C23H14F4ClN2O4S: C,H,N) and mass- spectroscopy.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2005/110422, 2005, A2 Location in patent: Page/Page column 78

14
[ 74896-14-3 ]
[ 16588-74-2 ]
N-[3,5-bis(trifluoromethyl)phenyl]-2,4-dioxobicyclo[3.2.1]octane-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 50℃; for 25h;	Example 23 N-[3,5-bis(trifluoromethyl)phenyl]-2,4-dioxobicyclo[3.2.1]octane-3-carboxamide A solution of <strong>[74896-14-3]bicyclo[3,2,1]octane-2,4-dione</strong> (0.34 g, 2.5 mmole), 3,5-bis(trifluoromethyl)phenyl isocyanate (0.86 ml, 5.0 mmole), and 60% sodium hydride in mineral oil (0.11 g, 2.75 mmole) in dimethylformamide (100 mL) was stirred at 0 C. for 1 hour and heated at 45-50 C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N aqueous HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (30% dichloromethane/hexane) to give a clear oil as the expected product. The oily product was crystallized by triturated with hexane in a dry ice bath and collected at room temperature to give the title compound as a white solid, mp=88-90 C.; (-) ESI m/z=392 (M-H)-. Analysis for C17H13F6NO3 Calculated: C, 51.92; H, 3.33; N, 3.56. Found: C, 51.74; H, 3.38; N, 3.47.

Reference： [1]Patent: US2006/4108,2006,A1 .Location in patent: Page/Page column 16

15
(1S)-1,8,8-trimethyl-bicyclo[3.2.1]octane-2,4-dione [ No CAS ]
[ 16588-74-2 ]
(1S)-N-[3,5-bis(trifluoromethyl)phenyl]-1,8,8-trimethyl-2,4-dioxobicyclo[3.2.1]octane-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With dmap; triethylamine In dichloromethane at 0 - 30℃;	1 (1S)-N-[3,5-bis(trifluoromethyl)phenyl]-1,8,8-trimethyl-2,4-dioxobicyclo[3.2.1] octane-3-carboxamide Example 1 (1S)-N-[3,5-bis(trifluoromethyl)phenyl]-1,8,8-trimethyl-2,4-dioxobicyclo[3.2.1] octane-3-carboxamide To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-bis-(trifluoromethyl)phenyl isocyanate (0.51 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.36 g, 42% yield), mp=68-72° C.; MS (-) ESI m/z=434 (M-H)-; [α]D25=-21.0° (c=1, EtOH). Analysis for C20H19F6NO3 Calculated: C, 55.18; H, 4.40; N, 3.22. Found: C, 55.43; H, 4.28; N, 3.12.

Reference： [1]Current Patent Assignee: PFIZER INC - US2006/4108, 2006, A1 Location in patent: Page/Page column 12

16
[ 872875-92-8 ]
[ 16588-74-2 ]
(1R)-N-[3,5-bis(trifluoromethyl)phenyl]-1,8,8-trimethyl-2,4-dioxobicyclo[3.2.1]octane-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With dmap; triethylamine In dichloromethane at 0 - 30℃;	12 (1R)-N-[3,5-bis(trifluoromethyl)phenyl]-1,8,8-trimethyl-2,4-dioxobicyclo [3.2.1]octane-3-carboxamide Example 12 (1R)-N-[3,5-bis(trifluoromethyl)phenyl]-1,8,8-trimethyl-2,4-dioxobicyclo [3.2.1]octane-3-carboxamide To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-bis-(trifluoromethyl)phenyl isocyanate (0.51 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a yellow solid (0.44 g, 51% yield), mp=68-71° C.; MS (-) ESI m/z=434 (M-H)-; [α]D25=+22.8° (c=1, EtOH). Analysis for C20H1 9F6NO3 Calculated: C, 55.18; H, 4.40; N, 3.22. Found: C, 54.99; H, 4.25; N, 3.95.

Reference： [1]Current Patent Assignee: PFIZER INC - US2006/4108, 2006, A1 Location in patent: Page/Page column 14

17
[ 108-91-8 ]
[ 16588-74-2 ]
[ 192049-20-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	In dichloromethane	83 1-Cyclohexyl-3-(3,5-Bis trifluoromethyl-phenyl)-urea EXAMPLE 83 1-Cyclohexyl-3-(3,5-Bis trifluoromethyl-phenyl)-urea Cyclohexylamine 4.98 g (49.3 mmol) was added to 120 ml of anhydrous dichloromethane in a 500 ml round bottomed flask. This stirred solution was cooled to 0° C. using an ice water bath. 3,5-Bis(trifluoromethyl)phenyl isocyanate 12.33 g (48.3 mmol) was added drop wise over a period of 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred at ambient temperatures for 18 hours. During this time a heavy precipitate was formed. This solid was collected by filtration on a Buchner funnel, and was re-suspended in 250 ml of dichloromethane. After approximately 30 minutes of stirring, the solid was again filtered on a Buchner funnel and then placed under vacuum at 40° C. to dry for a period of 24 hours to give 15.4 g of a white solid (90% yield). 1H NMR (400 MHz DMSO) δ9.10 (s 1H) 8.10 (s 2H) 7.53 (s 1H) 6.43 (d 1H) 3.49 (m 1H) 1.81 (t 2H) 1.68 (m 2H) 1.54 (m 1H) 1.25 (m 5H). MS: m/z 355 (M+1).
79%	In tetrahydrofuran at 20℃; for 16h; Inert atmosphere;
	In tetrahydrofuran

Reference： [1]Current Patent Assignee: SANOFI - US2004/19113, 2004, A1
[2]Yang, Ting; Ferrali, Alessandro; Sladojevich, Filippo; Campbell, Leonie; Dixon, Darren J. [Journal of the American Chemical Society, 2009, vol. 131, # 26, p. 9140 - 9141]
[3]Lin, Binhong; Waymouth, Robert M. [Journal of the American Chemical Society, 2017, vol. 139, # 4, p. 1645 - 1652]

18
[ 16588-74-2 ]
[ 593284-15-2 ]
[ 919112-98-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	In tetrahydrofuran at 20℃; for 16h;

Reference： [1]Berkessel, Albrecht; Mukherjee, Santanu; Mueller, Thomas N.; Cleemann, Felix; Roland, Katrin; Brandenburg, Marc; Neudoerfl, Joerg-M.; Lex, Johann [Organic and Biomolecular Chemistry, 2006, vol. 4, # 23, p. 4319 - 4330]

19
[ 1040405-79-5 ]
[ 16588-74-2 ]
[ 1040405-77-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	In pyridine at 50℃; for 5h;	1 To a mixture of INT-1 (0.686 g, 1.64 mmol of free hydrazine derivative) in pyridine (5 ml), 3,5-bis(trifluoromethyl)phenylisocyanate is added drop wise (0.418 g, 1.64 mmol) and the resulting reaction mixture is first heated (5O0C) for 5 hours and then evaporated to dryness (0.94 g, yield -100%), to afford Compound 1. LC-MS, basic conditions, r.t 2.02 min, > 95%. Purification has been carried out by prep LC- MS. LC-ESI-HRMS of [M-H]- shows 574.1052 Da. CaIc. 574.103785 Da, dev. 2.5 ppm.

Reference： [1]Current Patent Assignee: NEUROSEARCH A/S - WO2008/87177, 2008, A1 Location in patent: Page/Page column 13

20
[ 16588-74-2 ]
[ 77815-14-6 ]
[ 438243-39-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	In 1,4-dioxane at 20℃; for 16h;	25 To a solution of 2-amino-4-(4-fluorophenyl)thiazole (0.54 g, 2.00 mmol) in dioxane (20.0 ml.) was added 3,5-bis(trifluoromethyl)phenyl isocyanate (1.04 g, 4.08 mmol), followed by catalytic amount of triethyl amine (0.2 ml_). The pale yellow reaction solution was stirred at ambient temperature for 16 h, upon which time precipitate was formed. After removing the solvent under reduced pressure, the residue was crystallized from ether to afford 1-(3,5-t»/s-trifluoromethylphenyl)-3-[4-(4- fluorophenyl)thiazol-2-yl]urea (0.83 g, 92%) as a colourless solid: Rf = 0.33 (diethyl ether in hexane, 1 :1 ); mp > 260 0C; 1H NMR (300 MHz, acetone-cf6) δ 10.30 (br, 1 H), 9.22 (br, 1H), 8.23 (s, 1 H), 8.19 (s, 1 H), 7.99-7.87 (m, 2H), 7.67 (d, J = 10.2 Hz, 1H), 7.43 (s, 1 H), 7.21-7.08 (m, 2H); 13C NMR (75 MHz, acetone-d6) δ 164.0, 160.8, 159.2, 151.5, 148.6, 141.4, 141.0, 132.0, 131.9, 131.5, 131.4, 131.1 , 127.8, 127.7, 125.3, 121.7, 118.7, 115.8 (m), 115.4, 115.1 , 106.8; MS (ES+) m/z 450 (M + 1 ).

Reference： [1]Current Patent Assignee: XENON PHARMACEUTICALS INC - WO2008/101029, 2008, A2 Location in patent: Page/Page column 92; 93

21
[ 74896-15-4 ]
[ 16588-74-2 ]
N-[3,5-bis(trifluoromethyl)phenyl]-2,4-dioxobicyclo[3.2.2]nonane-3-carboxamide sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: bicyclo[3.2.2]nonane-2,4-dione With sodium hydride In tetrahydrofuran at 20 - 60℃; for 17h; Stage #2: 3,5-ditrifluoromethylisocyanate In tetrahydrofuran at 20℃; for 72h; Stage #3: With sodium methylate In methanol	37 Example 37 N-[3,5-bis(trifluoromethyl)phenyl]-2,4-dioxobicyclo[3.2.2]nonane-3-carboxamide Into an oven-dried 25 mL three-neck round bottom flask under a nitrogen atmosphere was placed sodium hydride (0.06 g, 1.50 mmol, 60% suspension in mineral oil). The mineral oil was removed by washing with dry hexane and the resulting material was suspended in dry tetrahydrofuran (3 mL). To the stirred suspension was added a solution of Intermediate II (0.20 g, 1.32 mmol) in dry tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature under nitrogen overnight (16 hr) and then warmed at 60° C. for 1 hour. To the cooled reaction mixture was then added 3,5-bis(trifluoromethyl)phenylisocyanate (0.46 mL, 2.64 mmol) via syringe. The resulting mixture was stirred at room temperature under nitrogen for 3 days. The tetrahydrofuran was removed on a rotary evaporator and the residue was partitioned between dichloromethane (100 mL) and 1N aqueous HCl (100 mL). The aqueous layer was extracted with two additional portions (25 mL) of dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (25% hexane/dichloromethane). It was converted to its sodium salt in methanol by treatment with one equivalent of sodium methoxide in methanol and recrystallized from diethyl ether/hexane to afford the desired product as a white solid (0.40 g, 73%), mp=286-288° C.; MS (-) ESI m/z=406 (M-H)-. Analysis for C18H15F6NO3.Na.1.0H2O Calculated: C, 48.33; H, 3.61; N, 3.13. Found: C, 48.01; H, 3.51; N, 3.05.

Reference： [1]Current Patent Assignee: PFIZER INC - US2006/4108, 2006, A1 Location in patent: Page/Page column 19

22
[ 1201659-62-2 ]
[ 16588-74-2 ]
[ 1201659-67-7 ]

Yield	Reaction Conditions	Operation in experiment
56%	In tetrahydrofuran
56%	In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	General Procedure for Synthesis of Compounds Ia-d General procedure: To a solution of compound 8a, b (30.0 mg, 0.1 mmol) in anhydrous tetrahydrofuran (THF) (3 mL), a solution of the appropriate aryl isocyanate (0.1 mmol) in anhydrous THF (3 mL)was added dropwise at room temperature under N2 atmosphere. The reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, and purification was carried out by flash column chromatography using the appropriate proportion of ethyl acetate and hexane as mobile phase.

Reference： [1]Location in patent: scheme or table Jung, Myung-Ho; Kim, Hwan; Choi, Won-Kyoung; El-Gamal, Mohammed I.; Park, Jin-Hun; Yoo, Kyung Ho; Sim, Tae Bo; Lee, So Ha; Baek, Daejin; Hah, Jung-Mi; Cho, Jung-Hyuck; Oh, Chang-Hyun [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 23, p. 6538 - 6543]
[2]El-Gamal, Mohammed Ibrahim; Oh, Chang-Hyun [Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 1, p. 25 - 34]

23
[ 1058062-64-8 ]
[ 16588-74-2 ]
[ 1263296-31-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	In tetrahydrofuran at 23℃; Inert atmosphere;

Reference： [1]So, Sonia S.; Burkett, Julie A.; Mattson, Anita E. [Organic Letters, 2011, vol. 13, # 4, p. 716 - 719]

24
[ 1058062-64-8 ]
[ 16588-74-2 ]
[ 1263296-30-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrahydrofuran / 23 °C / Inert atmosphere 2: potassium hydrogenfluoride / methanol / 1 h / 50 °C / Inert atmosphere

Reference： [1]So, Sonia S.; Burkett, Julie A.; Mattson, Anita E. [Organic Letters, 2011, vol. 13, # 4, p. 716 - 719]

25
[ 16588-74-2 ]
[ 191171-55-8 ]
[ 1263296-29-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	In tetrahydrofuran at 23℃; Inert atmosphere;
83%	In acetonitrile at 23℃; for 4h; Inert atmosphere;
83%	In acetonitrile at 23℃; for 4h; Inert atmosphere;

83%	In acetonitrile at 23℃; for 4h; Inert atmosphere;
83%	In acetonitrile at 23℃; for 4h; Inert atmosphere;
81%	In dichloromethane at 20℃;
	In acetonitrile at 23℃; for 4h; Inert atmosphere;

Reference： [1]So, Sonia S.; Burkett, Julie A.; Mattson, Anita E. [Organic Letters, 2011, vol. 13, # 4, p. 716 - 719]
[2]So, Sonia S.; Auvil, Tyler J.; Garza, Victoria J.; Mattson, Anita E. [Organic Letters, 2012, vol. 14, # 2, p. 444 - 447]
[3]So, Sonia S.; Mattson, Anita E. [Journal of the American Chemical Society, 2012, vol. 134, # 21, p. 8798 - 8801]
[4]Nickerson, David M.; Angeles, Veronica V.; Auvil, Tyler J.; So, Sonia S.; Mattson, Anita E. [Chemical Communications, 2013, vol. 49, # 39, p. 4289 - 4291] Couch, Erica D.; Auvil, Tyler J.; Mattson, Anita E. [Chemistry - A European Journal, 2014, vol. 20, # 27, p. 8283 - 8287]
[5]Hardman, Andrea M.; So, Sonia S.; Mattson, Anita E. [Organic and Biomolecular Chemistry, 2013, vol. 11, # 35, p. 5793 - 5797]
[6]Wu, Huabin; Handoko; Raj, Monika; Arora, Paramjit S. [Organic Letters, 2017, vol. 19, # 19, p. 5122 - 5125]
[7]Auvil, Tyler J.; So, Sonia S.; Mattson, Anita E. [Angewandte Chemie - International Edition, 2013, vol. 52, # 43, p. 11317 - 11320][Angew. Chem., 2013, vol. 125, # 43, p. 11527 - 11530,4]

26
[ 87120-72-7 ]
[ 16588-74-2 ]
[ 1275064-22-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	In dichloromethane at 20℃;	5 Example 5: Synthesis of l-(3,5-bis(trifluoromethyl)phenyI)-3-(piperidin-4- yl)urea (17)[00154] To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (15) (1.11 g, 5.54 mmol) in CH2CI2 (100 mL) was added slowly l-isocyanato-3,5- bis(trifluoromethyl)benzene (12) (0.96 mL, 5.54 mmol). The reaction was stirred at room temperature overnight. The reaction was then concentrated, and the residue was purified by automated flash chromatography (Rf = 0.65 in 1 :1 PE:EtOAc) to provide the title compound in quantitative yield as a white foam. .H NMR (300 mHz, CDCI3) δ 1.24 (m, 2 H), 1.48 (s, 9 H), 1.98 (d, 2 H, J = 11.9 Hz), 2.91 (d, 2 H, J = 11.4 Hz), 3.86 (br s, 1 H), 4.02 (d, 2 H, J = 13.6 Hz), 5.37 (br s, 1 H), 7.47 (s, 1 H), 7.86 (s, 2 H). LRMS (ESI) calcd for Ci4Hi5F6N30 [M - BOC + 2] 356.3, found 356.0, calcd for C29H23F6 303 [M + Na] 478.4, found 478.0].

Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/32291, 2011, A1 Location in patent: Page/Page column 46

27
[ 16588-74-2 ]
[ 144222-22-0 ]
[ 1274835-24-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	In dichloromethane at 0℃; for 4h;	4 Example 4: Synthesis of l-(3,5-bis(trifluoromethyl)phenyl)-3-(piperidin-4- ylmethyl)urea (14)[00152] To a solution of tert-butyl 4-(aminomethyl)piperidine-l-carboxylate (11) (2.05 g, 9.57 mmol) in CH2C12 (1 10 mL) at 0 °C was added slowly l-isocyanato-3,5- bis(trifluoromethyl)benzene (12)(1.65 mL, 9.57 mmol). The reaction was stirred for 4 hours; at this time, the reaction was concentrated and purified by automated flash chromatography ( f = 0.6 in 1 : 1 PE:EtOAc) to provide the title compound as a white solid (3.93 g, 88%). NMR (300 mHz, CDC13) δ 1.12 (m, 2 H), 1.47 (s, 9 H), 1.72 (m, 4 H), 2.74 (t, 2 H, J = 12.8 Hz), 3.20 (m, 2 H), 4.13 (d, 2 H, J - 11.7 Hz), 5.74 (br s, 1 H), 7.45 (s, 1 H), 7.88 (s, 2 H). LRMS (ESI) calcd for C15Hi7F6N30 [M - Boc + 2] 370.3, found 370.0, calcd for C2oH25F6N303 [M + Na] 492.4, found 492.0].

Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/32291, 2011, A1 Location in patent: Page/Page column 45

28
[ 16588-74-2 ]
[ 328-74-5 ]
[ 3824-74-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran at 50℃; for 48h;
91%	In tetrahydrofuran at 20℃; for 48h; Schlenk technique; Inert atmosphere;
89%	In tetrahydrofuran at 20℃; for 16h; Inert atmosphere;

78%	In 1,4-dioxane at 55℃; Inert atmosphere;	General Procedure A for the Synthesis of compounds 1-9 General procedure: 1,3-bis(3,4-dichlorophenyl)urea (1). 3,4-dichlorophenylisocyanate (200 mg, 1.064 mmol) and 3,4-dichloroaniline (172 mg, 1.064 mmol) were dissolved in 10 mL of anhydrous dioxane. The reaction mixture was warmed to 55 °C, stirred under nitrogen over night and then cooled to room temperature (RT). The solvent was removed under vacuum and the crude was crystallized twice in ethyl acetate/hexane to afford 1 (181 mg, 49%).
70%	In acetonitrile at 20℃; for 1h;
70%	With trimethylamine In acetonitrile at 20℃; for 4h; Inert atmosphere;
	In dichloromethane at 20℃; Inert atmosphere;
	In dichloromethane at 20℃;
	In tetrahydrofuran at 50℃; for 48h;
	In tetrahydrofuran

Reference： [1]Liedtke, Theresa; Spannring, Peter; Riccardi, Ludovico; Gansäuer, Andreas [Angewandte Chemie - International Edition, 2018, vol. 57, # 18, p. 5006 - 5010][Angew. Chem., 2018, vol. 130, p. 5100 - 5104,5]
[2]Pongener, Imlirenla; Nikitin, Kirill; McGarrigle, Eoghan M. [Organic and Biomolecular Chemistry, 2019, vol. 17, # 32, p. 7531 - 7535]
[3]Lee, Yong-Jay; Liu, Kuang-Shun; Lai, Chien-Chen; Liu, Yi-Hung; Peng, Shie-Ming; Cheng, Richard P.; Chiu, Sheng-Hsien [Chemistry - A European Journal, 2017, vol. 23, # 41, p. 9756 - 9760]
[4]Denoyelle, Séverine; Chen, Ting; Chen, Limo; Wang, Yibo; Klosi, Edvin; Halperin, José A.; Aktas, Bertal H.; Chorev, Michael [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 402 - 409]
[5]Andreoli, Federico; Doukara, Abdallah Larbi; Mehdid, Mohammed Amine; Vanthuyne, Nicolas; Roussel, Christian; Dessolin, Jean; Kraus, Jean-Louis [Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 1, p. 153 - 162]
[6]Sun, Lifeng; Wu, Xiaowei; Xiong, De-Cai; Ye, Xin-Shan [Angewandte Chemie - International Edition, 2016, vol. 55, # 28, p. 8041 - 8044][Angew. Chem., 2016, vol. 128, # 28, p. 8173 - 8176]
[7]Kim, Hun Young; Oh, Kyungsoo [Organic Letters, 2011, vol. 13, # 6, p. 1306 - 1309]
[8]Schoen, Eva-Maria; Marques-Lopez, Eugenia; Herrera, Raquel P.; Aleman, Carlos; Diaz, David Diaz [Chemistry - A European Journal, 2014, vol. 20, # 34, p. 10720 - 10731]
[9]Vallavoju, Nandini; Selvakumar, Sermadurai; Pemberton, Barry C.; Jockusch, Steffen; Sibi, Mukund P.; Sivaguru, Jayaraman [Angewandte Chemie - International Edition, 2016, vol. 55, # 18, p. 5446 - 5451][Angew. Chem., 2016, vol. 128, # 18, p. 5536 - 5541,6]
[10]Lin, Binhong; Waymouth, Robert M. [Journal of the American Chemical Society, 2017, vol. 139, # 4, p. 1645 - 1652]

29
[ 202341-04-6 ]
[ 16588-74-2 ]
NS₅₈₀₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With triethylamine In tetrahydrofuran at 20℃; for 12h;	1 To a solution (3.0 mL) of 2,4-dibromo-6- (1H-tetrazol-5-yl) aniline (0.5 mmol, 157.5 mg) and triethylamine (1.5 mL) in 3,5-ditrifluoro Methylphenyl isocyanate (0.5 mmol, 87.0 μL) was added and stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain UA-14 (NS5806: 57.4 mg, yield 20%) as a white solid.

Reference： [1]Current Patent Assignee: TOHOKU UNIVERSITY - JP2019/137678, 2019, A Location in patent: Paragraph 0037; 0038
[2]Location in patent: body text Lundby; Jespersen; Schmitt; Grunnet; Olesen; Cordeiro, Jm; Calloe [British Journal of Pharmacology, 2010, vol. 160, # 8, p. 2028 - 2044]

30
[ 41564-26-5 ]
[ 16588-74-2 ]
C₁₈H₁₉F₆NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With benzophenone In benzene-d6 at 20℃; for 9h; Inert atmosphere; Irradiation; stereoselective reaction;	15 Procedure for photoinduced carbamoylation of ethereal C-H bonds: General procedure: To a C6D6 (660 μL) solution of cis-1,2-cyclohexanediol isopropylidene ketal 4a (20.6 mg, 132 μmol) in a 5-mm NMR tube were added benzophenone (24.1 mg, 132 μmol) and pentafluorophenyl isocyanate (140 μL, 1.07 mmol) at rt. The mixture was degassed by freeze-thaw for 3 times. The NMR tube was placed at 5 cm distance from a UV-lamp and irradiated with a Riko 100 W medium-pressure mercury lamp at rt for 9 h. The reaction was quenched with n-butylamine (100 μL). Volatile materials were removed by evaporation and the residue was purified with flash column chromatography (hexane/AcOEt 30:1) to give N-(perfluorophenyl)amide 5e in 48% yield (23.1 mg).

Reference： [1]Kamijo, Shin; Hoshikawa, Tamaki; Inoue, Masayuki [Tetrahedron Letters, 2011, vol. 52, # 22, p. 2885 - 2888]

31
[ 1218764-05-6 ]
[ 16588-74-2 ]
[ 1218761-02-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran at 10 - 35℃; for 4h;	142 tert-butyl (3S,4R)-3-([3,5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate Example 142 tert-butyl (3S,4R)-3-([3,5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate To a solution of the compound (20 g) obtained in Reference Example 19 in THF (300 mL) was added dropwise a solution of 3,5-bis(trifluoromethyl)phenyl isocyanate (19.1 g) in THF (50 mL), and the mixture was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent gradient; 0→33% ethyl acetate/hexane) to give the title compound (40 g, 100%) as a white powder. MS(ESI+): 480 (M-tBu+2H)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2336105, 2011, A1 Location in patent: Page/Page column 131

32
[ 1218764-10-3 ]
[ 16588-74-2 ]
[ 1218760-99-6 ]

Yield	Reaction Conditions	Operation in experiment
83%	With triethylamine In acetonitrile at 10 - 35℃; for 3h;	138 tert-butyl (3R,4S)-3-([3,5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate Example 138 tert-butyl (3R,4S)-3-([3,5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate The compound (0.25 g) obtained in Reference Example 20 was dissolved in acetonitrile (5 mL), 3,5-bis(trifluoromethyl)phenyl isocyanate (0.17 mL) and triethylamine (0.14 mL) were added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hr, poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give the title compound (0.36 g, 83%) as a white powder. MS (ESI+) : 480 (M-tBu+2H)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2336105, 2011, A1 Location in patent: Page/Page column 130

33
[ 1218764-25-0 ]
[ 16588-74-2 ]
[ 1218761-46-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran at 10 - 35℃; for 3h;	189 tert-butyl (3S,4R)-3-([3,5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-4-(5-fluoropyridin-2-yl)pyrrolidine-1-carboxylate Example 189 tert-butyl (3S,4R)-3-([3,5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-4-(5-fluoropyridin-2-yl)pyrrolidine-1-carboxylate To a solution of the compound (1.9 g) obtained in Reference Example 28 in THF (22 mL) was added dropwise a solution of 3,5-bis(trifluoromethyl)phenyl isocyanate (1.3 mL) in THF (2.0 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0→60% ethyl acetate/hexane) to give the title compound (3.3 g, 91%) as a white powder. MS(ESI+): 537(M+H)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2336105, 2011, A1 Location in patent: Page/Page column 139

34
(3R*,4R*)-1-[(1-acetylpiperidin-4-yl)carbonyl]-3-(3,4-dichlorophenyl)-N-methylpiperidine-4-amine [ No CAS ]
[ 16588-74-2 ]
1-[(3R*,4R*)-1-[(1-acetylpiperidin-4-yl)carbonyl]-3-(3,4-dichlorophenyl)piperidin-4-yl]-3-[3,5-bis(trifluoromethyl)phenyl]-1-methylurea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	In tetrahydrofuran at 10 - 35℃; for 48h;	10 1-[(3R,4R)-1-[(1-acetylpiperidin-4-yl)carbonyl]-3-(3,4-dichlorophenyl)piperidin-4-yl]-3-[3,5-bis(trifluoromethyl)phenyl]-1-methylurea Example 10 1-[(3R,4R)-1-[(1-acetylpiperidin-4-yl)carbonyl]-3-(3,4-dichlorophenyl)piperidin-4-yl]-3-[3,5-bis(trifluoromethyl)phenyl]-1-methylurea To a solution of the compound (0.21 g) obtained in Reference Example 11 in THF (4.0 mL) was added 3,5-bis(trifluoromethyl)phenyl isocyanate (0.13 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 0→10% methanol/ethyl acetate) to give the title compound (0.32 g, 94%) as a white powder. MS(ESI+): 667(M+H)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2336105, 2011, A1 Location in patent: Page/Page column 94

35
tert-butyl (3R*,4R*)-4-amino-3-(4-fluorophenyl)piperidine-1-carboxylate p-toluenesulfonate [ No CAS ]
[ 16588-74-2 ]
tert-butyl (3R*,4R*)-4-([3, 5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-3-(4-fluorophenyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine In tetrahydrofuran at 10 - 35℃; for 96h;	1 tert-butyl (3R, 4R) -4- ([3, 5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-3-(4-fluorophenyl)piperidine-1-carboxylate Example 1 tert-butyl (3R, 4R) -4- ([3, 5-bis(trifluoromethyl)phenyl]carbamoyl}amino)-3-(4-fluorophenyl)piperidine-1-carboxylate The compound (0.93 g) obtained in Reference Example 4 was dissolved in THF, 3,5-bis(trifluoromethyl)phenyl isocyanate (0.38 mL) and triethylamine (0.36 mL) were added dropwise at room temperature. The reaction mixture was stirred at room temperature for 4 days, poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give the title compound (0.99 g, 90%) as a white powder. MS (ESI+) : 494 (M-tBu+2H)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2336105, 2011, A1 Location in patent: Page/Page column 92

36
[ 3575-32-4 ]
[ 16588-74-2 ]
[ 1325760-92-6 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 12910 - 12913

37
[ 912541-99-2 ]
[ 16588-74-2 ]
[ 1334318-82-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	In tetrahydrofuran at 20℃; for 10h;
36%	In tetrahydrofuran at 20℃; for 20h;
36%	In tetrahydrofuran at 20℃; for 19h; Cooling with ice;	2.O The compound 2 (94.9 mg, 0.176 mmol) was dissolved in 4 mL of anhydrous THF. The mixture was ice cold stirred for 20 minutes. 32 μΙ_ (0.185 mmol) of 3,5-bis(trifluoromethyl) phenylisocyanate was then added. The reaction mixture is stirred at room temperature for 19 hours and was concentrated under vacuum. The residual solid was purified and washed with diethyl ether (3 x 1 mL).Another way of synthesis of the 6b (FC10) compound is as follows: 3,5-bis(trifluoromethyl)- phenylisocyanayte was added dropwise to an excessive quantity of diethylamine. The resulting monoamineurea was then stirred at room temperature following general synthesis of amides in point 1.Yield: 36%. Rf = 0.30 (DCM/MeOH: 95/5). RP-HPLC: purity = 99%, tR = 8.40 min 1H-NMR characteristic protons (300MHz, CD3OD): δ (ppm) = 8.02 (s, 2H, Ar-H35, H39), 7.42 (s, 1 H, Ar-H37), 5.61 (s, 1 H, CH-12), 3.62-3.22 (m, 4H, NHCH2CH2NH), 3.15 (dd, 1 H, J = 7.0 Hz , 5.1 Hz, CH-3), 2.66 (dt, 1 H, J = 13.0 Hz, 3.0 Hz CH-1), 2.37 (s, 1 H, CH-9), 1.38 (s, 3H, Me- H27), 1.10 (s, 3H, Me-H29), 1.05 (s, 3H, Me-H25), 0.98 (s, 3H, Me-H23), 0.94 (s, 3H, Me- H26), 0.78 (s, 3H, Me-H24), 0.74 (s, 3H, Me-H28). NMR (CD3OD): δ (ppm) = 202.4 (C11), 179.4 (C30), 172.6 (C13), 157.6 (C33), 143.4 (C34), 133.0 (q, J = 33.0 Hz, C36/C38), 128.9 (C12), 124.8 (q, J = 270.1 Hz, CF3), 118.8 (q, J = 3.0 Hz, C35/C39), 115.3 (q, J = 7.0 Hz, C37), 79.4 (C3), 63.1 (C9), 56.2 (C5), 49.3 (C18), 46.6 (C14), 44.9 (C20), 44.5 (C8), 42.6 (C19), 41.1 (C31/C32), 40.6 (C31/C32), 40.3 (C1), 40.2 (C4), 38.7 (C22), 38.3 (C10), 33.7 (C7), 32.9 (C17), 31.9 (C21), 29.6 (C29), 29.1 (C28), 28.7(C23), 27.8 (C2), 27.6 (C15/C16), 27.4 (C15/C16), 23.7 (C27), 19.1 (C26), 18.6 (C6), 16.8 (C25), 16.3 (C24).*attribution may be reversedIR (KBr): v (cm"1): 3360 (OH), 2932 (CH aliphatic), 1643 (C=0), 1544, 1467, 1386.Mp: 201 °C.HRMS (ESI-QTOF) calcd for C41 H55F6N304 (M+H+) 768.4167, obsd 768.4170

Reference： [1]Location in patent: scheme or table Asakawa, Chiharu; Ogawa, Masanao; Fujinaga, Masayuki; Kumata, Katsushi; Xie, Lin; Yamasaki, Tomoteru; Yui, Joji; Fukumura, Toshimitsu; Zhang, Ming-Rong [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3594 - 3597]
[2]Lallemand, Benjamin; Chaix, Fabien; Bury, Marina; Bruyère, Céline; Ghostin, Jean; Becker, Jean-Paul; Delporte, Cédric; Gelbcke, Michel; Mathieu, Véronique; Dubois, Jacques; Prévost, Martine; Jabin, Ivan; Kiss, Robert [Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6501 - 6513]
[3]Current Patent Assignee: UNIVERSITE LIBRE DE BRUXELLES - WO2012/22780, 2012, A1 Location in patent: Page/Page column 63; 64

38
[ 16867-03-1 ]
[ 16588-74-2 ]
[ 1257423-77-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	In 1,4-dioxane at 55℃; Inert atmosphere;	General procedure E for the synthesis of compounds 26-28. General procedure: 3-(3,4-dichlorophenyl)-1-(3-hydroxypyridin-2-yl)urea (26). 3,4-dichlorophenylisocyanate (250 mg, 1.330 mmol) and 2-amino-3-hydroxypyridine (146 mg, 1.330 mmol) were dissolved in 10 mL of anhydrous dioxane. The reaction mixture was warmed to 55 °C, stirred under nitrogen over night and then cooled to RT. The crude was purified twice by crystallization in EtOH to afford 26 (178 mg, 45%).

Reference： [1]Denoyelle, Séverine; Chen, Ting; Chen, Limo; Wang, Yibo; Klosi, Edvin; Halperin, José A.; Aktas, Bertal H.; Chorev, Michael [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 402 - 409]

39
[ 1374771-59-1 ]
[ 16588-74-2 ]
[ 1374771-87-5 ]

Yield	Reaction Conditions	Operation in experiment
39%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h;	16 To a stirred solution of 4-((3- (piperazin-l-yl)pyridin-2-yloxy)methyl)pyrimidin-2-amine prepared in Example 15 (0.171 mmol), diisopropylamine (0.12 ml, 0.683 mmol) and dichloromethane (1 ml) at room temperature was added 3,5-bis(trifluoromethyl)phenyl isocyanate (52.4 mg, 0.205 mmol) in dichloromethane (1 ml). After stirring for 30 min, the resulting mixture was concentrated under reduced pressure and purified by preparative HPLC to give 4-(2-((2-Aminopyrimidin- 4-yl)methoxy)pyridin-3-yl)-N-(3,5-bis(trifluoromethyl)phenyl)piperazine-l-carboxamide (36.0 mg, 39%) as a white solid. XH-NMR (400MHz, DMSO-d6) δ 9.30 (s, 1H), 8.24 (s, 2H), 8.23 (d, 1H), 7.76 (dd, 1H), 7.62 (s, 1H), 7.31 (dd, 1H), 6.98 (dd, 1H), 6.67 (s, 2H), 6.60 (d, 1H), 5.23 (s, 2H), 3.70 - 3.66 (m, 4H), 3.14 - 3.10 (m, 4H). MS (EI) for C23H21F6 702: 542.2 (MH+).

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2012/61337, 2012, A1 Location in patent: Page/Page column 67

40
[ 1375062-48-8 ]
[ 16588-74-2 ]
[ 1375062-49-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	In dichloromethane at 20℃; Inert atmosphere;
98%	In dichloromethane at 20℃; Inert atmosphere;	1; 2 Synthesis of Urea 6 To a stirred solution of amine 5 (720 mg, 3 mmol) in 20 mL CH2Cl2 was added 780 μL (4.6 mmol) of 3,5-Bis(trifluoromethyl)phenyl isocyanate. The reaction was allowed to stir overnight under argon atmosphere at room temperature. The solvent was removed in vacuo and the crude was chromatographed (silica gel, 9:1 CH2Cl2/EtOAc then 4:1 CH2Cl2/EtOAc) to obtain urea 6 (1.46 g, 98%). Analytical data for title compound: 1H NMR (400 MHz, MeOD) δ 8.29 (d, J=8.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.92 (s, 3H), 7.81 (d, J=8.2 Hz, 1H), 7.54-7.36 (m, 3H), 7.31 (m, 1H), 2.75 (s, 3H) (see FIG. 7A); 13C NMR (100 MHz, MeOD) δ 161.26, 155.33, 148.00, 143.14, 138.90, 138.53, 136.61, 135.85, 133.58, 133.26, 132.78, 132.09, 129.98, 129.56, 129.08, 128.55, 126.45, 125.56, 124.22, 119.46, 116.26, 25.04 (see FIG. 7B); HRMS (EI) calc. for [C25H17F6N3O]+ 489.1276. found 489.1281; IR (NaCl) ν 3342, 3152, 1724, 1661, 1501, 1418, 1252, 1144, 1067.

Reference： [1]Mortezaei, Shahab; Catarineu, Noelle R.; Canary, James W. [Journal of the American Chemical Society, 2012, vol. 134, # 19, p. 8054 - 8057]
[2]Current Patent Assignee: NEW YORK UNIVERSITY - US2015/112066, 2015, A1 Location in patent: Paragraph 0086; 0088

41
[ 615-43-0 ]
[ 16588-74-2 ]
[ 1022042-74-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	In diethyl ether for 12h;
91%	In diethyl ether for 12h;
79%	In dichloromethane at 20℃; for 5h;	1-(3,5-Bis(trifluoromethyl)phenyl)-3-(2-iodophenyl)urea, 10. A solution of 8 (1.27 g, 5.78 mmol) and 7 (983 mg, 3.85 mmol) in dichloromethane (7 mL) was stirred at room temperature for 5 hours. The precipitate was collected by vacuum filtration and suspended in cold dichloromethane. The suspension was stirred for 10 minutes, filtered and the residue was dried under vacuum to give 1.4 g (3.03 mmol, 79%) of a white solid.

Reference： [1]Nickerson, David M.; Mattson, Anita E. [Chemistry - A European Journal, 2012, vol. 18, # 27, p. 8310 - 8314]
[2]Nickerson, David M.; Angeles, Veronica V.; Auvil, Tyler J.; So, Sonia S.; Mattson, Anita E. [Chemical Communications, 2013, vol. 49, # 39, p. 4289 - 4291]
[3]De los Santos, Zeus A.; Yusin, Georgy; Wolf, Christian [Tetrahedron, 2019, vol. 75, # 11, p. 1504 - 1509]

42
[ 1402743-81-0 ]
[ 16588-74-2 ]
[ 1402743-82-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: tert-butyl ((1R,2R)-2-(2-amino-4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-1-yl)carbamate; 3,5-ditrifluoromethylisocyanate In tetrahydrofuran at 0 - 20℃; for 0.75h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 0 - 20℃; for 16h;
92%	Stage #1: tert-butyl ((1R,2R)-2-(2-amino-4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-1-yl)carbamate; 3,5-ditrifluoromethylisocyanate In tetrahydrofuran at 0 - 20℃; for 2.5h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 0 - 20℃; for 16h;	1-(2-(((1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl)oxy)-5-(trifluoromethyl)phenyl)-3-(3,5-bis(trifluoromethyl)phenyl)urea 12 (Cas No. 1402743-82-1) A solution of compound 11 (6.98 g, 17.1 mmol) in THF (21 mL) was cooled to 0 °C and 3,5-bis(trifluoromethylphenyl) isocyanate (4.57 g, 17.9 mmol) was added dropwise. The reaction mixture was allowed to warm up to r.t. and stirred for 2.5 h. Then the reaction mixture was cooled to 0 °C, TFA (34 mL, 444 mmol) was added and stirred for 16 hours at r.t. The reaction mixture was concentrated, a saturated solution of NaHCO3 (170 mL) was added and extracted with CH2Cl2 (4 × 100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude solid product was triturated with CHCl3 and hexane, filtered and washed with hexane to give the urea 13 (8.85 g, 15.7 mmol, 92 %) as an off-white solid. Mp 202-203 °C; [α]D20 = -78.1 (c = 0.51, MeOH). 1H NMR (400 MHz, [D6]DMSO) δ 10.16 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.40 (bs, 1H), 8.08 (s, 2H), 7.67 (s, 1H), 7.51 - 7.33 (m, 3H), 7.31 - 7.18 (m, 3H), 4.89 (dt, J = 7.1, 5.3 Hz, 1H), 4.52 (d, J = 4.7 Hz, 1H), 3.60 (dd, J = 16.4, 7.1 Hz, 1H), 3.35 (s, 2H), 2.93 (dd, J = 16.3, 5.5 Hz, 1H). 13C NMR (101 MHz, [D6]DMSO) δ 152.1, 149.3, 144.4, 141.4, 138.6, 130.8 (q, J = 32.6 Hz), 129.1, 127.6, 127.0, 124.6, 124.5 (q, J = 271.5 Hz), 124.2, 123.2 (q, J = 272.3 Hz), 121.2 (q, J = 31.8 Hz), 119.8 - 119.5 (m), 118.0 - 117.7 (m), 115.1 - 114.9 (m), 114.8 - 114.6 (m), 113.3, 88.1, 62.2, 36.2.

Reference： [1]Probst, Nicolas; Madarász, Údám; Valkonen, Arto; Pápai, Imre; Rissanen, Kari; Neuvonen, Antti; Pihko, Petri M. [Angewandte Chemie - International Edition, 2012, vol. 51, # 34, p. 8495 - 8499]
[2]Kaasik, Mikk; Kaabel, Sandra; Kriis, Kadri; Järving, Ivar; Kanger, Tõnis [Synthesis, 2019, vol. 51, # 10, p. 2128 - 2135]

43
[ 32315-10-9 ]
[ 328-74-5 ]
[ 16588-74-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran
	In 1,4-dioxane at 80℃; for 24h;
	In dichloromethane for 0.75h; Cooling with ice;	4.1.27. N-(2-fluorophenyl)-N0-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (11a) General procedure: Triphosgene (0.80 g, 2.7 mmol) was dissolved in anhydrousCH2Cl2 (20 mL) and the mixture was stirred on the ice-bath for15 min. A solution of 2-fluoroaniline (0.76 g, 6.8 mmol) in anhydrousCH2Cl2was added dropwise to the above mixture and stirringwas continued for 30 min. Then triethanolamine (0.83 mL,8.2 mmol) diluted with CH2Cl2 (10 mL) was then added onto themixture. Stirring was continued for 20 min, a solution of triethanolamine(0.83 mL, 8.2 mmol) and intermediate (10) (1.50 g,6.8 mmol) in anhydrous CH2Cl2 (10 mL) was added. After completionof the action, the reaction was quenched with dilute NaHCO3.The organic layer was washed with water and brine, and dried overNa2SO4. After filtration and concentration in vacuo, the residueswas purified by silica gel flash chromatography (PE/AcOEt 3:1)gave as white solid (11a) (1.06 g, 43.3%).

	In dichloromethane at 0℃; for 0.25h; Alkaline conditions;	4.16.2 4.2.16.2 (3-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido) phenyl)boronic acid (15) General procedure: Triphosgene (0.94 g, 3.2 2 mmol) was dissolved in anhydrous CH2Cl2 (20 mL) and the mixture was stirred on the ice-bath for 5 min. A solution of 4-chloro-3-(trifluoromethyl)aniline (1.40 g, 7.16 mmol) in anhydrous CH2Cl2 was added dropwise to the above mixture and stirring was continued for 15 min. Then triethanolamine (1.20 mL,17.18 mmol) diluted with CH2Cl2 (10 mL) was then added onto the mixture. Stirring was continued for 15 min, a solution of triethanolamine (1.20 mL, 17.18 mmol) and 3-aminophenylboronic acid 14 (0.89 g,5.73 mmol) in anhydrous CH2Cl2 (10 mL) was added and continued stirring for 20min. Subsequently, the ice bath was removed, and the mixture was reacted at room temperature overnight. After completion of the action, the reaction was quenched with dilute NaHCO3.The organic layer was washed with water and brine, and dried overNa2SO4. After filtration and concentration in vacuo, the residue was purified by silica gel flash chromatography (PE/AcOEt = 5:1) yielding 15 as white solid (0.84 g, 32.68%).
	In dichloromethane at 0 - 5℃; Reflux;
	In dichloromethane at 0℃; for 1h;	General procedure: Aniline (140mg, 1.5mmol) and Et3N (202mg, 2mmol) were dissolved in 5mL of dichloromethane and slowly added dropwise to a solution of triphosgene (BTC) (223mg, 0.75mmol) in 10mL of dichloromethane at 0°C. The mixture was then stirred at 0°C for 1h. Then, 5a (300mg, 1mmol) in 1mL of DMF was added at 0°C, and the mixture was then stirred at room temperature for 30min, and the solvent was distilled with a rotary evaporator. The residue was washed with water (10mL×3) and purified via silica gel flash column chromatography to afford 1-(3-((2S,5S)-5-((1H-indol-3-yl)methyl)-3,6-dioxopiperazin-2-yl)propyl)-3-phenylurea (6a) as a pale powder in 74% yield. Compounds 6b-v, 7a-k and 8a-k were prepared similar to 6a.

Reference： [1]Yang, Ling-Ling; Li, Guo-Bo; Ma, Shuang; Zou, Chan; Zhou, Shu; Sun, Qi-Zheng; Cheng, Chuan; Chen, Xin; Wang, Li-Jiao; Feng, Shan; Li, Lin-Li; Yang, Sheng-Yong [Journal of Medicinal Chemistry, 2013, vol. 56, # 4, p. 1641 - 1655]
[2]Zhao, Yan-Fang; Liu, Zi-Jian; Zhai, Xin; Ge, Dan-Dan; Huang, Qiang; Gong, Ping [Chinese Chemical Letters, 2013, vol. 24, # 5, p. 386 - 388]
[3]Shan, Yuanyuan; Gao, Hongping; Shao, Xiaowei; Wang, Jinfeng; Pan, Xiaoyan; Zhang, Jie [European Journal of Medicinal Chemistry, 2015, vol. 103, p. 80 - 90]
[4]Li, Chuansheng; Shan, Yuanyuan; Sun, Ying; Si, Ru; Liang, Liyuan; Pan, Xiaoyan; Wang, Binghe; Zhang, Jie [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 506 - 518]
[5]Sun, Shaofeng; He, Zuopeng; Huang, Mindong; Wang, Ningning; He, Zongzhong; Kong, Xiangkai; Yao, Jianwen [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2381 - 2391]
[6]Sun, Haiyang; Li, Hui; Wang, Jiayi; Song, Gonghua [Chinese Chemical Letters, 2018, vol. 29, # 6, p. 977 - 980]

44
[ 1365699-34-8 ]
[ 16588-74-2 ]
[ 1449741-67-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	In dichloromethane at 0 - 20℃; for 1h;	9 6.9. N1-((5S,5aS,8aR,9R)-8-oxo-9-(3,4,5-Trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydro[1,3]dioxolo[4',5':4,5]benzo[f]isobenzofuran-5-yl)-4-(((3,5-di(trifluoromethyl)anilino)carbonyl)amino)benzamide (11g) To a solution of N1-((5S,5aS,8aR,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydro[1,3]dioxolo[4',5':4,5]benzo[f]isobenzofuran-5-yl)-4-aminobenzamide (10), (200 mg, 0.37 mmol) in dry CH2Cl2 (10 mL), 3,5-bis(trifluoromethyl)phenyl isocyanate (g), (115 mg, 0.56 mmol) was added at 0 °C and the stirring was continued for 1 h at the room temperature. After 1 h, the formed solid was filtered and washed with CH2Cl2 thoroughly to obtain the pure compound 11g in 220 mg, 77% yield. Mp 213-215 °C; [α]25D = -76.9 (c 0.5 in CHCl3); 1H NMR (300 MHz, CDCl3): δ 2.91-2.99 (m, 2H), 3.74 (s, 3H), 3.78 (s, 6H), 4.20-4.26 (m, 1H), 4.30-4.48 (m, 2H), 5.40-5.46 (m, 1H), 5.90 (d, 2H, J = 12.2 Hz), 6.30 (s, 2H), 6.71 (s, 1H), 7.30 (d, 2H, J = 8.43 Hz), 7.50 (s, 1H), 7.62 (d, 2H, J = 8.43 Hz), 7.90 (d, 2H, J = 8.10 Hz), 8.41 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 41.1, 43.3, 47.7, 55.6, 60.6, 68.5, 101.2, 107.6, 109.0, 109.5, 116.4, 116.9, 119.4, 121.9, 124.1, 125.6, 126.2, 128.2, 129.1, 131.9, 131.6, 134.4, 137.2, 137.5, 137.9, 142.4, 146.9, 151.8, 152.3, 166.1, 174.3. MS (ESI): m/z 788 [M+H]+.

Reference： [1]Kamal, Ahmed; Suresh, Paidakula; Ramaiah, M. Janaki; Srinivasa Reddy; Kapavarapu, Ravi Kumar; Rao, Bolla Narasimha; Imthiajali, Syed; Lakshminarayan Reddy; Pushpavalli; Shankaraiah, Nagula; Pal-Bhadra, Manika [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 17, p. 5198 - 5208]

45
[ 1467714-04-0 ]
[ 16588-74-2 ]
[ 1467714-22-2 ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	General Method for Synthesis of the Target Urea Derivatives 2a-g General procedure: To a mixture of compound 9 (34 mg, 0.1 mmol) and cesium carbonate (33 mg, 0.1 mmol) in anhydrous THF (3 mL), a solution of the appropriate aryl isocyanate (0.1 mmol) in anhydrous THF (3 mL) was added dropwise at room temperature under N2 atmosphere. The reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, and purification was carried out by flash column chromatography using the appropriate proportion of ethyl acetate and hexane as mobile phase.

Reference： [1]Kim, Hyun-Jin; El-Gamal, Mohammed I.; Lee, Yong Sup; Oh, Chang-Hyun [Bulletin of the Korean Chemical Society, 2013, vol. 34, # 8, p. 2480 - 2486]

46
3-(3-(4-chloro-3-methoxyphenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)benzenamine [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(3-(4-chloro-3-methoxyphenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;	4.5. General procedure for synthesis of diarylurea derivatives 9-13 General procedure: To a solution of compound 8 (50 mg, 0.1 mmol) in anhydrous THF (1 mL), a solution of the appropriate aryl isocyanate (0.1 mmol) in THF (1 mL) was added dropwise at room temperature under N2. The reaction mixture was stirred at room temperature for 12 h. The mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexanee ethylacetate 1:5 v/v) to yield the target compounds 9-13.

Reference： [1]El-Gamal, Mohammed I.; Park, Yi Seul; Chi, Dae Yoon; Yoo, Kyung Ho; Oh, Chang-Hyun [European Journal of Medicinal Chemistry, 2013, vol. 65, p. 315 - 322]

47
3-(8-nitroquinolin-4-yl)benzenamine [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(8-nitroquinolin-4-yl)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran at 20℃; for 2h;	4.7. General procedure for preparation of compounds 13a,b General procedure: To a solution of 3-(8-nitroquinolin-4-yl)benzenamine (9, 29 mg,0.11 mmol) in anhydrous THF, the appropriate isocyanate (0.12 mmol) was added. The mixture was stirred at room temperature for 2 h. Upon completion, the reaction mixture was filtered and washed with ethyl acetate to afford the target compounds 13a,b.

Reference： [1]Koh, Eun Jeong; El-Gamal, Mohammed I.; Oh, Chang-Hyun; Lee, So Ha; Sim, Taebo; Kim, Garam; Choi, Hong Seok; Hong, Jun Hee; Lee, Sang-Gi; Yoo, Kyung Ho [European Journal of Medicinal Chemistry, 2013, vol. 70, p. 10 - 21]

48
[ 16588-74-2 ]
(8R,9R)-9-amino(9-deoxy)epicinchonin [ No CAS ]
[ 945985-98-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	In tetrahydrofuran at 20℃;	Representative Procedure for the Preparation of Amino Urea Catalyst1 General procedure: To a solution of A (1.0 mmol, 1.0 eq) in THF (5 mL) was added phenyl isocyanate (1.0 mmol, 1.0 eq) in oneportion at room temperature. The reaction was stirred for 16 h. After evaporation of THF, the residue waspurified by flash column chromatography (MeOH/EtOAc 1:10) to afford amino urea catalyst 5a 384.5 mg,87% yield;
40%	Stage #1: (8R,9R)-9-amino(9-deoxy)epicinchonin With diphenyl phosphoryl azide; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 50℃; for 34h; Stage #2: With triphenylphosphine In tetrahydrofuran at 50℃; for 15h; Stage #3: 3,5-ditrifluoromethylisocyanate In tetrahydrofuran at 20℃;

Reference： [1]Gan, Min; He, Hailong; Jiang, Xiaojian; Liu, Shenghui; Yi, Peng [Synlett, 2019, vol. 30, # 12, p. 1474 - 1478]
[2]Miyaji, Ryota; Asano, Keisuke; Matsubara, Seijiro [Organic and Biomolecular Chemistry, 2014, vol. 12, # 1, p. 119 - 122]

49
[ 16588-74-2 ]
cis-1,2-diaminocyclohexane [ No CAS ]
[ 1648911-53-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	In dichloromethane at 20℃; for 6.5h; Inert atmosphere;	1,1'-((1R,2S)-Cyclohexane-1,2-diyl)bis(3-(3,5bis(trifluoromethyl)phenyl)urea) (1) 3,5-Bis(trifluoromethyl)phenyl isocyanate (0.62mL,3.6mmol) and cis-1,2-diaminocyclohexane (0.21 mL,1.8 mmol) were dissolved in dichloromethane (DCM) (40 mL) and stirred for 6.5 h at rt under a nitrogen atmosphere. A white precipitate was isolated by filtration in a 71% yield after washing with excess DCM. 1HNMR (DMSO-d6, 300 MHz): d 1.30-1.75 (m, 8H), 3.91 (br s,2H), 6.40 (d, 2H, J 6.0 Hz), 7.52 (s, 2H), 7.99 (s, 4H), 9.16 (s, 2H). 13C{1H} NMR (DMSO-d6, 100 MHz): d 21.7 (CH2), 28.6 (CH2), 48.7 (CH), 113.4 (Ar CH), 117.1 (Ar CH), 123.3 (q, CF3, J 270.9 Hz), 130.6 (q, Ar CZCF3, J 32.2 Hz), 142.3 (Ar C), 154.4 (CvO).19F{1H} NMR (DMSO-d6, 282 MHz): d 61.86. LR-MS ES2 (m/z): 623 [M 2 H]2. HR-MS ES (m/z): Act. 647.1293 [M Na]. Calcd 647.1287 [M Na], err. (ppm) 20.9 m.p. (8C): 275.7-275.9.

Reference： [1]Karagiannidis, Louise E.; Hiscock, Jennifer R.; Gale, Philip A. [Supramolecular Chemistry, 2013, vol. 25, # 9-11, p. 626 - 630]

50
[ 16588-74-2 ]
trans-1,2-cyclohexanediamine [ No CAS ]
[ 896429-25-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	In dichloromethane at 20℃; for 72h; Inert atmosphere;	1,1'-((1S,2S)-Cyclohexane-1,2-diyl)bis(3-(3,5bis(trifluoromethyl)phenyl)urea) (3) 3,5-Bis(trifluoromethyl)phenyl isocyanate (0.62mL,3.6 mmol) and (^)-trans-1,2-diaminocyclohexane (0.21mL, 1.8mmol) were dissolved in DCM (40mL) and stirred for 72 h at rt under a nitrogen atmosphere. A white precipitate was isolated by filtration in a 96% yieldafter washingwithexcessDCM. 1HNMR (DMSO-d6,300 MHz): d 1.30 (brs,4H),1.70(br s, 2H), 1.87 (br s, 2H), 3.48 (br s, 2H), 6.24 (d, 2H, J 8.29 Hz), 7.37 (s, 2H), 7.90 (s, 4H), 9.211 (s, 2H).13C{1H} NMR (DMSO-d6,75 MHz): d 24.6 (CH2),32.2 (CH2), 53.7 (CH), 113.2 (Ar CH), 116.8 (Ar CH),123.2 (q, CF3, J 271.3 Hz),130.4 (q,ArCZCF3, J 31.9), 142.3 (Ar C), 155.0 (CvO). 19F{1H} NMR (DMSO-d6, 282 MHz): d 61.72. LR-MS ES (m/z): 625 [M H].HR-MS ES (m/z): Act. 647.1289 [M Na]. Calcd 647.1287 [M Na],err.(ppm)20.3 m.p. (8C): 305.3 -305.5.

Reference： [1]Karagiannidis, Louise E.; Hiscock, Jennifer R.; Gale, Philip A. [Supramolecular Chemistry, 2013, vol. 25, # 9-11, p. 626 - 630]

51
[ 163061-73-2 ]
[ 16588-74-2 ]
1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In dichloromethane at 20℃;

Reference： [1]Schoen, Eva-Maria; Marques-Lopez, Eugenia; Herrera, Raquel P.; Aleman, Carlos; Diaz, David Diaz [Chemistry - A European Journal, 2014, vol. 20, # 34, p. 10720 - 10731]

52
[ 16588-74-2 ]
[ 286454-86-2 ]
(S)-1-[3,5-bis(trifluoromethyl)phenyl]-3-(1-(diphenylphosphaneyl)-3,3-dimethylbutan-2-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	In dichloromethane at 20℃; for 2h;

Reference： [1]Lou, Yan-Peng; Zheng, Chang-Wu; Pan, Ren-Ming; Jin, Qiao-Wen; Zhao, Gang; Li, Zhong [Organic Letters, 2015, vol. 17, # 3, p. 688 - 691]

53
[ 16588-74-2 ]
[ 114715-38-7 ]
1-[(3S)-1-benzylpyrrolidin-3-yl]-3-[3,5-bis(trifluoromethyl)phenyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In tetrahydrofuran at 20℃;	1-[(3S)-1-benzylpyrrolidin-3-yl]-3-[3,5-bis(trifluoromethyl)phenyl]urea To a solution of (S)-1-benzyl-3-aminopryrrolidine (11) 250mg (1.42 mmol) in THF (2.5 ml)was added 1-isocyanato-3,5-bis(trifluoromethyl)benzene 255 μL (1.49 mmol) atroom temperature. After stirring for overnight, the mixture was concentratedunder reduced pressure. Theresidue was added n-heptane (5 mL) and the slurry was stirred for 3 h. Theprecipitate was filtered to give 1-[(3S)-1-benzylpyrrolidin-3-yl]-3-[3,5-bis(trifluoromethyl)phenyl]urea (5) 567mg (1.31 mmol, 92% yield) as a white solid. 1H-NMR (CDCl3,400 MHz) δ (ppm) = 2.02 (2H, s), 2.19-2.38 (2H, m), 2.47 (1H, dd, J = 10.0, 6.8Hz), 2.89 (1H, brd, J = 9.2 Hz), 3.07(1H, brs), 3.65 (2H, s), 4.06 (1H, brs),5.98 (1H, d, J = 7.6 Hz), 7.22-7.33 (5H, m), 7.46 (1H, s), 7.80 (2H, s). 13C-NMR(CDCl3, 100 MHz) δ (ppm) = 32.30, 49.86, 53.22, 60.15, 60.90, 115.84, 118.96,121.93, 124.64, 127.71, 128.65, 129.15, 131.94 (q), 140.93, 154.95. MS-EI (m/z) = 431 (M+). Anal. Calcdfor C20H19F6N3O: C, 55.69; H, 4.44;N, 9.74; F, 26.42. Found: C, 55.36; H, 4.38; N, 9.71; F, 26.84. [α]D20 42.3 (c 0.104, CH2Cl2).

Reference： [1]Kawazoe, Souichirou; Yoshida, Kazuki; Shimazaki, Yuichi; Oriyama, Takeshi [Tetrahedron Letters, 2015, vol. 56, # 2, p. 410 - 413]

54
[ 1029438-85-4 ]
[ 16588-74-2 ]
4-(4-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)phenoxy)phenylboronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In 1,2-dichloro-ethane at 70℃; for 17h;	Synthesis of 4-(4-(3-(3,5- bis(trifluoromethyl)henyl)ureido)rhenoxy)rhenylboronic acid (EJ1 -36, Scheme 5) [0209] (4-(4-aminophenoxy)phenyl)boronic acid (10 mg, 0.0386 mmol )was placed in a vial. Dichloroethane (3 mL) was added to the vial. 1-isocyanato-3,5-bis(trifluoromethyl)-benzene (14 pL, 2 eq) was then added tothe solution. The solution was stirred at 7000 for 17 hours. After 17 hours, the solvent was evaporated under vaccuo. A minimal amount of dichloromethane was added to the mixture, and was purified by using a TLC preparatory plate with one run in 100:1 DCM: Methanol to provide the desired product (EJI-36) (4-(4-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)phenoxy)phenyl)boron ic acid (16.95 mg, 0.035 mmol, 91 %) as a dark yellow oil; 1 H-NMR(CDCI3, 400MHz, ppm).933 (5, 2H), 67.576 (5, 1H), 67.041 (5, 2H), 67.866-6.821 (m, 2H), 6 6.628-6.517 (m, 3H), 6 6.027 (5, 1 H); MS (APOI-’-, Mi-i) 484.68.

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2015/51149, 2015, A1 Location in patent: Paragraph 0209

55
4-((5-chloroquinolin-8-yl)oxy)aniline [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(5-chloroquinolin-8-yloxy)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.7%	In 1,2-dichloro-ethane at 70℃; for 17h;	Synthesis of 1 -(3,5-bis(trifluoromethyl)rjhenyl)-3-(4-(5-chloroguinolin-8- yloxy)rjhenyl)urea (EJ1 -35, Scheme 6) [0219] 4-((5-chloroquinolin-8-yl)oxy)aniline (30 mg, 0.lllmmol ) was placed in a vial. Dichloroethane (3 mL) was added to the vial. 1-isocyanato- 3,5-bis(trifluoromethyl)benzene (33 uL, 2 eq) was then added to the solution. The solution was stirred at 70°C for 17 hours. After 17 hours, the solutioncontained a pink precipitate. The solvent was evaporated under vacuum. A minimal amount of dichloromethane was added to the mixture, and was purified by using a TLC preparatory plate with two runs in 100:1 DCM:Methanol, to provide the desired product (EJI-35) 1-(3,5- bis(trifluoromethyl)phenyl)-3-(4-((5-chloroqu inol in-8-yl)oxy)phenyl)urea (45.4 mg, 0.086 mmol, 77.7%) as a pink powder; 1 H-NMR(CDCI3, 400MHz, ppm) 6 9.014-9.004 (d, 1H), 68.743-8.722 (d, 1H), 68.381(s, 1H), 67.712-7.681 (m, 2H), 6 7.606-7.585 (d, 1H), 6 7.495 (5, 1H), 6 7.182-7.123 (d, 2H), 6 7.123-7.103 (d, 1H), 66.942-6.921 (d, 2H); MS (APCI-’-, M-’-1)536.20.

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2015/51149, 2015, A1 Location in patent: Paragraph 0219

56
[ 117401-33-9 ]
[ 16588-74-2 ]
1-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-3-(3,5-bis(trifluoromethyl)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	In 1,2-dichloro-ethane at 70℃; for 17h;	Synthesis of 1 -(4-(benzo[dl[1 ,31dioxol-5-yloxy)rhenyl)-3-(3,5- bis(trifluoromethyl)rhenyl)urea (EJ2-02, Scheme 8) [0237] 4-(benzo[d][1 ,3]dioxol-5-yloxy)aniline (50mg, 0.21 8mmol ) was dissolved in dichloroethane. 1 -isocyanato-3,5-bis(trifluoromethyl)benzene (45uL, 0.30 mmol, 1 .2 eq) was then added to the solution. The solution was stirred at 70 00 for 17 hours. After 17 hours, the solution was a medium yellow color. The solvent was evaporated under vacuum. A minimal amount of dichloromethane was added to the mixture, and was purified by using a TLC preparatory plate with one run in 5:2 Hexanes:EtOAc, to provide the desiredproduct (EJ2-02) 1 -(4-(benzo[d][1 ,3]dioxol-5-yloxy)phenyl)-3-(3,5-bis(trifluoromethyl)phenyl)urea (17.9 mg, 0.O37mmol, 17%) as a light yellow oil. 1H-NMR(0D013,400MHz,ppm) 6 7.98 (m, 5H), 6 7.68 (m, 2H), 6 7.42-7.39 (d, 2H), 6 7.22-7.19 (d, 2H), 66.82-6.79 (m, 1H), 6 6.73-6.52 (m, 2H), 6 6.07 (5, 2H); MS (APOI-’-, Mi-i) 485.

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2015/51149, 2015, A1 Location in patent: Paragraph 0237

57
4-(2-((3r,5r,7r)-adamantan-1-yl)ethoxy)aniline [ No CAS ]
[ 16588-74-2 ]
C₂₇H₂₈F₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	In 1,2-dichloro-ethane at 70℃; for 17h;	Synthesis of 1 -(4-(2-(adamantan-1 -yl)ethoxy)rhenyl)-3-(4-(trifluoromethoxy)- rhenyl)urea (EJ2-06, Scheme 8) [0242] 4-(2-((3r,5r,7r)-adamantan-1 -yl)ethoxy)aniline (35 mg, 0.129 mmol ) was dissolved in dichloroethane (3 mL). 1-isocyanato-3,5- bis(trifluoromethyl)benzene (27 uL, 1 .2 eq) was then added to the solution. The solution was stirred at 70 00 for 17 hours.[0243] The solvent was evaporated under vacuum. A minimal amount of dichloromethane was added to the mixture, and was purified by using a TLC preparatory plate with one run in 5:2 Hexanes:EtOAc to provide the desired product (EJ2-06) 1 -(4-(2-(adamantan-1 -yl)ethoxy)phenyl)-3-(4- (trifluoromethoxy)phenyl)urea ( 50.0 mg, 0.095 mmol, 74%) as light yellow powder. 1H-NMR(0D013, 400MHz, ppm) 6 7.924 (5, 5H), 6 7.90-7.89 (d, 2H), 67.59 (5, 3H), 6 3.85 (5, 9H), 6 1 .78-1 .62 (m, 3H), 6 1 .57 (5, 5H); MS (APCI+, M+1) 527.

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2015/51149, 2015, A1 Location in patent: Paragraph 0242; 0243

58
[ 1372625-07-4 ]
[ 16588-74-2 ]
2-(Z)-triisopropylsilylmethylidene-4-{3,5-bis(trifluoromethyl)phenyl}-6-methoxy-2H-1,4-benzoxazin-3(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With zinc diacetate; palladium diacetate; tricyclohexylphosphine In toluene at 130℃; for 27h; Inert atmosphere;	4.3 Palladium-catalyzed insertion/annulation of alkynyl aryl ethers with arylisocyanates 4.3. 1 A general procedure General procedure: An alkynyl aryl ether (0.50mmol), an isocyanate (0.75-1.0mmol), and decane (an internal standard, 7.0mg, 0.049mmol) were added sequentially to a solution of Pd(OAc)2 (5.6mg, 25μmol), Zn(OAc)2 (1.6mg, 25μmol) and PCy3 (7.0mg, 25μmol) in toluene (1.0mL) prepared in a 3mL-vial in a dry box. The vial was closed with a screw cap, taken outside the dry box, and heated at 120°C. The resultant mixture was filtered through Celite, and the filtrate was evaporated and dried in vacuo. The desired products were obtained in yields listed in this paper by preparative thin-layer chromatography. 2-(Z)-Triisopropylsilylmethylidene-4-{3,5-bis(trifluoromethyl)phenyl}-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (3am) (0032) Pale yellow prisms, mp 115-121°C (hexane), Rf 0.52 (hexane-ethyl acetate=10:1). 1H NMR (400MHz, CDCl3) δ 1.13 (d, J=7.2Hz, 18H), δ 1.33 (sex., J=6.8Hz, 3H), δ 3.66 (s, 3H), δ 5.79 (d, J=2.8Hz, 1H), δ 6.18 (s, 1H), δ 6.58 (dd, J=8.8, 2.8Hz, 1H), δ 6.99 (d, J=8.8Hz, 1H), δ 7.26 (s, 1H), δ 7.85 (s, 2H), δ 8.02 (s, 1H); 13C NMR (101MHz, CDCl3) δ 11.7, 19.0, 55.9, 102.7, 108.3, 109.8, 116.8, 122.8 (q, J=274.3), 123.3 (quin, J=3.7), 128.5, 130.0, 130.0, 133.8 (q, J=34.5), 136.3, 137.6, 151.5, 155.2, 156.4; IR (KBr) 3067, 2945, 2867, 1686, 1630, 1597, 1514, 1467, 1383, 1346, 1308, 1279, 1230, 1213, 1182, 1142, 1106, 1079, 1042, 1019, 997, 884, 860, 848, 796, 769, 741, 716, 700, 681, 652, 553cm-1. MS (EI, 70eV) m/z (%) 559 (M+, 6), 516 (100), 463 (5), 430 (45), 392 (5), 377 (4), 358 (5).HRMS calcd for C27H31F6NO3Si (M+H) 560.2056, found 560.2082.

Reference： [1]Minami, Yasunori; Kanda, Mayuko; Sakai, Megumi; Hiyama, Tamejiro [Tetrahedron, 2015, vol. 71, # 26-27, p. 4522 - 4534]

59
(S)-4-(2-hydroxyethyl)-3-methylenedihydrofuran-2(3H)-one [ No CAS ]
[ 16588-74-2 ]
(S)-2-(4-methylene-5-oxotetrahydrofuran-3-yl)ethyl(3,5-bis(trifluoromethyl)phenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.2%	With triethylamine In dichloromethane at 20℃; for 1h;	1 Compound 4s - 9: yellow solid; compound at room temperature 3s (35.5 mg, 0 . 25mmol) with 3, 5 - 23 fluorine methyl phenyl isocyanate (1.2eq) is dissolved in methylene chloride, dropping triethylamine (1.2eq), reaction time is one hour, the reaction solution washing, dichloromethane extraction, the combined organic phase, drying and condensing column to obtain the product 80.6 mg, the yield of 81.2%.
	With triethylamine In dichloromethane at 20℃; for 1h;

Reference： [1]Current Patent Assignee: SECOND MILITARY MEDICAL UNIVERSITY - CN104926761, 2017, B Location in patent: Paragraph 0148; 0149; 0150; 0151; 0152
[2]Shao, Wen-Hao; Chen, Bing-Yang; Cheng, Xiang-Rong; Yuan, Hu; Chen, Hao; Chang, Wan-Lin; Ye, Ji; Lin, Shan; Sun, Qing-Yan; Zhang, Wei-Dong [European Journal of Medicinal Chemistry, 2015, vol. 93, p. 274 - 280]

60
4-((2-aminoquinolin-5-yl)oxy)-N-methylpicolinamide [ No CAS ]
[ 16588-74-2 ]
4-((2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)quinolin-5-yl)oxy)-N-methylpicolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere;	3 4.10. General procedure for synthesis of compounds 9a-k General procedure: A solution of the suitable aryl isocyanate (0.187 mmol) in anhydrous DCM (2 mL) was added drop wise to a stirred solution ofcompound 7 (0.05 g, 0.170 mmol) in DCM (4 mL) under argon atmosphereat 0 °C. The reaction mixture was stirred at rt for 24 h, then the resulting solid was collected by filtration, washed with DCM and dried to yield the target compounds 9a-k in pure form. 4.10.3 4-((2-(3-(3,5-Bis(trifluoromethyl)phenyl)ureido)quinolin-5-yl)oxy)-N-methylpicolinamide (9c) White solid; yield 89%; mp 258-260 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.98 (br. s, 1H), 10.43 (br. s, 1H), 8.80 (q, J = 4.4 Hz, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.36 (s, 2H), 8.28 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 7.8, 0.8 Hz, 1H), 7.25 (q, J = 2.4 Hz, 1H), 2.79 (d, J = 5.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 166.19, 164.12, 153.11, 152.97, 152.77, 151.12, 149.27, 146.92, 141.22, 133.26, 131.45, 131.13, 125.35, 125.10, 122.39, 119.86, 118.52, 116.45, 114.84, 114.68, 109.50, 26.47; HRMS (ESI-TOF) m/z calcd for C25H17F6N5O3Na [M+Na]+: 572.1134, found: 572.1145.

Reference： [1]El-Damasy, Ashraf Kareem; Seo, Seon Hee; Cho, Nam-Chul; Kang, Soon Bang; Pae, Ae Nim; Kim, Key-Sun; Keum, Gyochang [European Journal of Medicinal Chemistry, 2015, vol. 101, p. 754 - 768]

61
[ 38088-36-7 ]
[ 16588-74-2 ]
(3R)-3-C-[(3,5-bis(trifluoromethyl)phenyl-ureidomethyl)]-1,2:5,6-di-O-isopropylidene-α-D-allofuranose [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In dichloromethane at 40℃; for 4h;	11 4.1.11 (3R)-3-C-[(3,5-Bis(trifluoromethyl)phenylureidomethyl]-1,2:5,6-di-O-isopropylidene-α-d-allofuranose hemihydrate 19 Bis(3,5-trifluoromethyl)phenyl isocyanate (0.041 mL, 0.159 mmol, 1.15 equiv) was added to a solution of amino alcohol 5 (40.0 mg, 0.138 mmol, 1 equiv) in CH2Cl2 (1.5 mL). After stirring at reflux at 40 °C for 4 h, the solvent was removed under reduced pressure. Purification by column chromatography (EtOAc/Hex 25%) yielded 19 (76.0 mg, 75%). Rf = 0.39 (EtOAc/Hex 2:3); [α]D25 = +26 (c 1.2, CHCl3); mp = 95-99 °C (Hex/EtOAc); IR (KBr): 3370, 2993, 2141, 1664, 1571, 1389, 1280, 1182, 1132; 1H NMR (CDCl3, 300 MHz) δ: 7.84 (s, 2H, H-C(Ar)), 7.59-7.39 (br s, 2H, H-C(Ar), H-N-C(Ar)), 5.84 (d, 1H, 3J = 3.6 Hz, H-C(1)), 5.67 (dd, 1H, 3J = 5.6, 5.0, Hz, H-N-C(3')), 4.39 (d, 1H, 3J = 3.6 Hz, H-C(2)), 4.20-4.12 (m, 2H, H-C(5)), Ha-C(6)), 3.99-3.92 (m, 1H, Hb-C(6)), 3.80 (d, 1H, 3J = 8.2 Hz, H-C(4)), 3.68-3.53 (m, 2H, H-C(3')), 3.24-3.15 (br s, 1H, HO-C(3)), 1.75 (1H, 0.5H2O), 1.57, 1.45, (2s, 6H, (H3C)2C-O-C(1)), 1.34 (1s, 6H, (H3C)2C-O-C(5)); 13C NMR (CDCl3, 75.5 MHz) δ: 155.5, 140.5, 132.3 (q, 2JC-F = 34 Hz), 123.2 (q, 1JC-F = 273 Hz), 118.7 (q, 3JC-F = 3.3 Hz), 116.1 (sept, 3JC-F = 3.8 Hz), 113.0, 110.1, 103.7, 81.3, 80.4, 79.9, 73.0, 68.1, 41.2, 26.8, 26.2 (2C), 25.2; Elemental analysis: calcd C22H26F6N2O7·0.5H2O (553.17): C, 47.74; H, 4.92; N, 5.06; found C, 47.98; H, 4.80; N, 4.81.

Reference： [1]Turks, Maris; Rolava, Evija; Stepanovs, Dmitrijs; Mishnev, Anatoly; Markovi, Dean [Tetrahedron Asymmetry, 2015, vol. 26, # 17, p. 952 - 960]

62
[ 38088-37-8 ]
[ 16588-74-2 ]
(3S)-3-C-[(3,5-bis(trifluoromethyl)phenyl-ureidomethyl)]-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	In dichloromethane at 40℃; for 4h;	14 4.1.14 (3S)-3-C-[(3,5-Bis(trifluoromethyl)phenylureidomethyl]-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose hydrate 22 Bis(3,5-trifluoromethyl)phenyl isocyanate (0.101 mL, 0.398 mmol, 1.15 equiv) was added to a solution of amino alcohol 6 (0.100 g, 0.346 mmol, 1 equiv) in CH2Cl2 (3 mL). After stirring at reflux at 40 °C for 4 h, the solvent was removed under reduced pressure. Purification by column chromatography (EtOAc/Hex 25%) yielded 22 (0.162 g, 83%). Rf = 0.48 (EtOAc/Hex 2:3); [α]D25 = +31 (c 0.5, CHCl3); mp = 93-98 °C (Hex/EtOAc); IR (KBr): 3359, 3123, 2992, 2941, 1673, 1573, 1475, 1388, 1280, 1181, 1133, 1074; 1H NMR (CDCl3, 300 MHz) δ: 7.84 (s, 2H, H-C(Ar)), 7.51 (s, 1H, H-C(Ar)), 7.20-7.06 (br s, 1H, H-N-C(Ar)), 5.90 (d, 1H, 3J = 3.6 Hz, H-C(1)), 5.66 (dd, 1H, 3J = 6.6, 6.0, Hz, H-N-C(3')), 4.58-5.45 (br s, 1H, HO-C(3)), 4.42 (d, 1H, 3J = 3.6 Hz, H-C(2)), 4.39 (ddd, 1H, 3J = 8.2, 6.4, 4.9 Hz, H-C(5)), 4.15 (dd, AB syst., 1H, 2J = 8.9 Hz, 3J = 6.4 Hz, Ha-C(6)), 4.04 (dd, AB syst., 1H, 2J = 8.9 Hz, 3J = 4.9 Hz, Hb-C(6)), 3.90 (dd, AB syst., 1H, 2J = 14.9 Hz, 3J = 6.0 Hz, Ha-C(3')), 3.80 (d, 1H, 3J = 8.2 Hz, H-C(4)), 3.47 (dd, AB syst., 1H, 2J = 14.9 Hz, 3J = 6.6 Hz, Hb-C(3')), 1.81 (br s, 2H, H2O), 1.53, 1.43, 1.35, 1.31 (4s, 12H, (H3C)2C-O-C(1,5)); 13C NMR (CDCl3, 75.5 MHz) δ: 155.7, 0.2, 132.4 (q, 2JC-F = 34 Hz), 124.7 (q, 1JC-F = 274 Hz), 118.9 (q, 3JC-F = 4 Hz), 116.5 (sept, 3JC-F = 4 Hz), 113.0, 109.7, 104.7, 86.0, 82.9, 82.3, 72.6, 67.6, 43.6, 27.2, 26.9, 26.5, 25.2; Elemental analysis: calcd C22H26F6N2O7·H2O (562.18): C, 46.98; H, 5.02; N, 4.98; found C, 46.62; H, 4.90; N, 5.00.

Reference： [1]Turks, Maris; Rolava, Evija; Stepanovs, Dmitrijs; Mishnev, Anatoly; Markovi, Dean [Tetrahedron Asymmetry, 2015, vol. 26, # 17, p. 952 - 960]

63
N-[3-(3-aminophenyl)imidazo[1,2-a]pyridin-8-yl]benzamide [ No CAS ]
[ 16588-74-2 ]
N-{3-[3-([3,5-bis(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]imidazo[1,2-a]pyridin-8-yl}benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With pyridine at 20℃; for 2h;	N-{3-[3-([3,5-bis(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]imidazo[1,2-a]pyridin-8-yl}benzamide (7f) General procedure: A mixture of compound 5 (100 mg, 0.31 mmol), anhydrouspyridine (2 ml) and the aryl isocyanate (0.34 mmol) was stirred atroom temperature for 2 h.Method A: The solvent was evaporated and the residue wastaken up in chloroform. The organic layer was washed with water (2), dried over sodium sulphate, filtered and concentrated underreduced pressure. The crude product was triturated with diisopropylether, filtered and washed with acetonitrile to give thedesired products.Method B: The solvent was evaporated. The residue was trituratedwith diisopropyl ether, filtered and washed with acetonitrileto give the desired products

Reference： [1]Garamvölgyi, Rita; Dobos, Judit; Sipos, Anna; Boros, Sándor; Illyés, Eszter; Baska, Ferenc; Kékesi, László; Szabadkai, István; Szántai-Kis, Csaba; Kéri, György; Örfi, László [European Journal of Medicinal Chemistry, 2016, vol. 108, p. 623 - 643]

64
[ 885677-91-8 ]
[ 16588-74-2 ]
C₂₀H₂₅F₆N₃O [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 260 - 263

65
[ 16588-74-2 ]
[ 259537-92-3 ]
C₁₉H₂₃F₆N₃O₃ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 1020 - 1024
Angew. Chem.,2015,vol. 128,p. 1032 - 1036,5

66
2-aminophenylboronic acid pinacol ester [ No CAS ]
[ 16588-74-2 ]
[ 1263296-29-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	In acetonitrile at 23℃; for 4h; Inert atmosphere;	1-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea A flame-dried round-bottom flask under N2 was charged with 2-aminophenylboronic acid pinacol ester (600 mg, 2.74 mmol). Freshlydistilled MeCN (30 mL) was added to create a colorless solution. Last,3,5-bis-trifluoromethylphenyl isocyanate (473 μL, 2.74 mmol) wasintroduced to the reaction flask dropwise by syringe. Shortly after additionof the isocyanate, a white precipitate began to form. The reactionmixture was allowed to stir at 23 °C for 4 h. The pure boronateurea pinacol ester was isolated as a white solid after vacuum filtrationfollowed by washing with hexanes. The solid was dried under vacuum.Yield: 1.08 g (83%); Rf = 0.94 (EtOAc-hexanes-MeOH, 4:4:1); mp215.2-216.9 °C.IR (NaBr): 3415, 3132, 2985, 1640, 1600, 1581, 1476, 1184, 1129 cm-1.1H NMR (400 MHz, DMSO-d6): δ = 9.93 (br s, 1 H), 9.19 (br s, 1 H), 8.16(s, 2 H), 7.69 (s, 1 H), 7.52-7.50 (m, 1 H), 7.42-7.34 (m, 2 H), 7.08-7.04 (m, 1 H), 1.24 (s, 12 H).13C NMR (100 MHz, DMSO-d6): δ = 154.0, 142.2, 141.7, 134.7, 131.2(q, J = 33 Hz, CCF3), 130.8, 123.8 (q, J = 271 Hz, CF3), 123.4, 119.7,119.4, 115.6, 83.0, 25.5. The carbon bonded to boron was not seendue to broadening.1611B NMR (160 MHz, DMSO-d6): δ = 26.0 (br s).HRMS (ESI): m/z [M + H]+ calcd for C21H21BF6N2O3: 475.1622; found:475.1614.

Reference： [1]Bernardim, Barbara; Couch, Erica D.; Hardman-Baldwin, Andrea M.; Burtoloso, Antonio C. B.; Mattson, Anita E. [Synthesis, 2016, vol. 48, # 5, p. 677 - 686]

67
1-methyl-4-(3-methylpyridin-2-yl)isatin [ No CAS ]
[ 16588-74-2 ]
C₂₂H₁₅F₆N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With chloro(1,5-cyclooctadiene)rhodium(I) dimer; triphenyl-arsane In 1,4-dioxane at 160℃;

Reference： [1]Zeng, Rong; Chen, Peng-Hao; Dong, Guangbin [ACS Catalysis, 2016, vol. 6, # 2, p. 969 - 973]

68
[ 5580-80-3 ]
[ 16588-74-2 ]
C₁₅H₆F₁₀N₂O [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 5446 - 5451
Angew. Chem.,2016,vol. 128,p. 5536 - 5541,6

69
[ 1867654-07-6 ]
[ 16588-74-2 ]
[ 1938090-72-2 ]

Yield	Reaction Conditions	Operation in experiment
1.24 g	With triethylamine In dichloromethane at 20℃; for 4h; Inert atmosphere;

Reference： [1]Sun, Lifeng; Wu, Xiaowei; Xiong, De-Cai; Ye, Xin-Shan [Angewandte Chemie - International Edition, 2016, vol. 55, # 28, p. 8041 - 8044][Angew. Chem., 2016, vol. 128, # 28, p. 8173 - 8176]

70
[ 947383-62-2 ]
[ 16588-74-2 ]
[ 1938090-73-3 ]

Yield	Reaction Conditions	Operation in experiment
1.06 g	With triethylamine In dichloromethane at 20℃; Inert atmosphere;

Reference： [1]Sun, Lifeng; Wu, Xiaowei; Xiong, De-Cai; Ye, Xin-Shan [Angewandte Chemie - International Edition, 2016, vol. 55, # 28, p. 8041 - 8044][Angew. Chem., 2016, vol. 128, # 28, p. 8173 - 8176]

71
[ 78525-34-5 ]
[ 16588-74-2 ]
1,1′,1″,1‴-(ethene-1,1,2,2-tetrayltetrakis(benzene-4,1-diyl))tetrakis(3-(3,5-bis-(trifluoromethyl)phenyl)urea) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane for 3.5h; Reflux;

Reference： [1]Xu, Suying; Bai, Xilin; Ma, Jingwen; Xu, Minmin; Hu, Gaofei; James, Tony D.; Wang, Leyu [Analytical Chemistry, 2016, vol. 88, # 15, p. 7853 - 7857]

72
[ 16588-74-2 ]
[ 100-46-9 ]
[ 13571-42-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	In dichloromethane at 0 - 20℃; for 0.166667h;
57%	In dichloromethane at 20℃; Inert atmosphere;	2.1 1-Benzyl-3-[3,5-bis(trifluoromethyl)phenyl]urea (L1) To a well stirred solution of benzylamine 1 (0.55 ml, 5.0 mmol) in dry CH2Cl2 (10 ml) was added 3,5-bis(trifluoromethyl)phenyl isocyanate 2 (1.24 ml, 6 mmol) under N2. The reaction mixture was stirred at rt. overnight, concentrated to reduced pressure and purification by column chromatography (SiO2; CH2Cl2 100% to CH2Cl2:MeOH=98:2) provided L1 (1.03 g, 57%) as a white solid. TLC (CH2Cl2)=Rf: 0.35 (UV, KMnO4); Mp: 189-190 °C; 1H NMR (200 MHz, DMSO-d6, δ in ppm): 4.32 (d, J=5.7 Hz, 2H), 7.03 (t, J=5.7 Hz, 1H), 7.30 (s, 5H), 7.53 (s, 1H), 8.10 (s, 2H), 9.39 (s, 1H). 13C NMR (50 MHz, DMSO-d6, δ in ppm): 43.2, 126.5, 127.2, 127.5, 128.7, 130.7, 131.4, 140.4, 143.0, 155.3. FTIR (film, cm-1): 3327, 1655, 1560, 1272, 1168, 877. MS (ESI): 361.1 (100%) [M-\|-H]-; Anal. Calcd. For C16H12F6N2O (362.09): C, 53.05; H, 3.34; N, 7.73; Found: C 53.01; H, 3.41; N, 7.75.

Reference： [1]Wang, Hongyu; Man, Yunquan; Wang, Kaiye; Wan, Xiuyan; Tong, Lili; Li, Na; Tang, Bo [Chemical Communications, 2018, vol. 54, # 78, p. 10989 - 10992]
[2]Formica, Mauro; Fusi, Vieri; Giorgi, Luca; Piersanti, Giovanni; Retini, Michele; Zappia, Giovanni [Tetrahedron, 2016, vol. 72, # 44, p. 7039 - 7049]

73
[ 57605-80-8 ]
[ 16588-74-2 ]
6-O-[(N-(3,5-bis-(trifluoromethyl)phenyl)carbamoyl)]-(1S,2E,4S,7E,11E)-2,7,11-cembratriene-4,6-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18.3%	With triethylamine In toluene at 70℃; for 24h; Reflux;	18 4.4. Synthesis of analogs 3-20 General procedure: To stirring solutions of 1 (50 mg, 0.16 mmol) in 10 mL toluene, 300 μL of Et3N were added and the mixture was then left to stir for 15 min at 70 °C. Different isocyanates (0.16 mmol) were then added to each stirring mixture. Reaction mixtures were then left for 24 h under reflux and periodically monitored by TLC, using n-hexanes and EtOAc (6:4) as mobile phase. After reactions completion, solvents were then evaporated under reduced pressure, and the residues were partitioned between 2% aq HCl and EtOAc (10 mL, each). Organic layers were pooled, washed with brine and finally dried over anhydrous Na2SO4. Concentrated organic layers were loaded on celite and then purified over Si gel columns using mixtures of n-hexanes and EtOAc to yield pure analogs.

Reference： [1]Ebrahim, Hassan Y.; Mohyeldin, Mohamed M.; Hailat, Mohammad M.; El Sayed, Khalid A. [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5748 - 5761]

74
[ 16588-74-2 ]
[ 6159-55-3 ]
1,2,3,9-tetrahydropyrrolo-[2,1-b]-quinazolin-3-yl N-(3,5-bis(trifluoromethyl)phenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In tetrahydrofuran; dichloromethane at 20℃;	1,2,3,9-tetrahydropyrrolo-[2,1-b]-quinazolin-3-(3,5-bis(trifluoromethyl)phenyl)carbamate (3) To a stirred solution of vasicine (0.5 mmol) in THF: DCM (3 ml, 2: 1) was added solution of 3,5-bis(trifluoromethyl)phenylisocyanate (0.55 mmol) in THF (1 ml) and the mixture was allowed to stir at room temperature. The progress of the reaction was monitored by TLC. After completion of reaction, the solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel mesh 100-200 using ethyl acetate as eluent. The product was obtained in 85% yield aswhite coloured solid. [α]D27 -68.1(c = 0.22, CHCl3: MeOH (1:1)); 1H NMR (600 MHz, CDCl3 + MeOD): δ 8.17 (s, 2H), 7.68 (s, 1H), 7.38-7.35 (m, 1H),7.24-7.22 (m, 2H), 7.14-7.12 (m, 1H), 5.78-5.76 (m, 1H), 4.86-4.71 (m, 2H),3.60-3.53 (m, 2H), 2.85-2.82 (m, 1H), 2.31-2.29 (m, 1H); 13CNMR (150 MHz, CDCl3 + MeOD): δ 158.6, 152.7, 141.2, 140.0, 131.6 (q, J = 33.8 Hz), 128.1,125.6, 124.6, 123.2, 122.8 (q, J = 271.8 Hz), 118.5, 117.7, 115.4, 73.2, 47.7,46.5, 26.7. HRMS (ESI-TOF) m/z:[M+H]+ calcd for C20H16F6N3O2 444.1136 Found 444.1147.

Reference： [1]Sharma, Sushila; Kumar, Manoranjan; Bhatt, Vinod; Nayal, Onkar S.; Thakur, Maheshwar S.; Kumar, Neeraj; Singh, Bikram; Sharma, Upendra [Tetrahedron Letters, 2016, vol. 57, # 45, p. 5003 - 5008]

75
[ 1000152-08-8 ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-3-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	In tetrahydrofuran; dichloromethane at 20℃;	1-(3,5-Bis(trifluoromethyl)phenyl)-3-(1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-3-yl)urea (4) To a stirred solution of 1′ (0.5mmol) in THF: DCM (3 ml, 2: 1) was added solution of 3,5-bis(trifluoromethyl)phenyl isocyanate (0.55 mmol) in THF (1 ml) and the mixture was allowed to stir at room temperature. The progress of the reaction was monitored by TLC. After completion of reaction, the solvent was removed under reduced pressure and the product was purified by column chromatography over silica gel mesh 100-200 using EtOAc: MeOH (8: 2) as eluent. The product was obtained in 88% yield as off white colored solid. [α]D27-25.0 (c = 0.22, CHCl3:MeOH (1: 1)); 1H NMR (600 MHz, CDCl3): δ 9.57 (brs, 1H), 7.53 (s,2H), 7.36 (brs, 1H), 7.20 (s, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.98-6.94 (m, 2H), 6.88 (d, J = 7.3 Hz, 1H), 5.11 (s,1H), 4.59 (q, J = 16.2 Hz, 2H), 3.33-3.29 (m, 1H), 3.23-3.20 (m,1H), 2.47-2.42 (m, 1H), 1.80 (brs, 1H); 13CNMR (150 MHz, CDCl3): δ 162.8, 155.0, 141.4, 140.8, 131.3 (q, J = 33 Hz), 128.9, 126.4,125.1, 123.2 (q, J = 270 Hz), 122.4, 118.8, 117.8, 114.9, 51.7, 48.1,47.2, 27.9. HRMS (ESI-TOF) m/z: [M+H]+calcd for C20H17F6N4O 443.1307 Found 443.1298.

Reference： [1]Sharma, Sushila; Kumar, Manoranjan; Bhatt, Vinod; Nayal, Onkar S.; Thakur, Maheshwar S.; Kumar, Neeraj; Singh, Bikram; Sharma, Upendra [Tetrahedron Letters, 2016, vol. 57, # 45, p. 5003 - 5008]

76
[ 1452849-33-0 ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-((6,7-dimethoxy-2-methylquinolin-3-yl)oxy)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;	4.3. Synthesis of 1-(4-(6,7-dimethoxy-2-methylquinolin-3-yloxy)phenyl)-3-phenylurea (1a) General procedure: To a solution of compound 9a (31 mg, 0.1 mmol) in anhydrousTHF (5 mL), the phenyl isocyanate (12 mg, 0.1 mmol) and anhydrouspotassium carbonate (28 mg, 0.2 mmol) were added. Thereaction mixture was stirred at room temperature under nitrogenatmosphere for 12 h. After reaction completion, the inorganicmaterial was filtered off and washed with THF, the organic solventwas evaporated under reduced pressure, and the residue was purifiedby column chromatography (silica gel, using the proper ratioof hexane and ethyl acetate) to get the compound 1a as a pureproduct.

Reference： [1]El-Gamal, Mohammed I.; Khan, Mohammad Ashrafuddin; Tarazi, Hamadeh; Abdel-Maksoud, Mohammed S.; Gamal El-Din, Mahmoud M.; Yoo, Kyung Ho; Oh, Chang-Hyun [European Journal of Medicinal Chemistry, 2017, vol. 127, p. 413 - 423]

77
4-(6,7-dimethoxy-2-methylquinolin-3-ylthio)benzenamine [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-((6,7-dimethoxy-2-methylquinolin-3-yl)thio)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;	4.3. Synthesis of 1-(4-(6,7-dimethoxy-2-methylquinolin-3-yloxy)phenyl)-3-phenylurea (1a) General procedure: To a solution of compound 9a (31 mg, 0.1 mmol) in anhydrousTHF (5 mL), the phenyl isocyanate (12 mg, 0.1 mmol) and anhydrouspotassium carbonate (28 mg, 0.2 mmol) were added. Thereaction mixture was stirred at room temperature under nitrogenatmosphere for 12 h. After reaction completion, the inorganicmaterial was filtered off and washed with THF, the organic solventwas evaporated under reduced pressure, and the residue was purifiedby column chromatography (silica gel, using the proper ratioof hexane and ethyl acetate) to get the compound 1a as a pureproduct.

Reference： [1]El-Gamal, Mohammed I.; Khan, Mohammad Ashrafuddin; Tarazi, Hamadeh; Abdel-Maksoud, Mohammed S.; Gamal El-Din, Mahmoud M.; Yoo, Kyung Ho; Oh, Chang-Hyun [European Journal of Medicinal Chemistry, 2017, vol. 127, p. 413 - 423]

78
[ 2576-47-8 ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-bromoethyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With triethylamine In dichloromethane at 0℃; for 4h;	2.2.8. Synthesis of 1-(3,5-Bis(trifluoromethyl)phenyl)-3-(2-bromoethyl)urea (6) 2-Bromoethylamine hydrobromide (1 g, 4.88 mmol), 3,5-bis(trifluoromethyl)phenyl isocyanate (0.93 mL, 5.37 mmol) and triethylamine (0.748 mL, 5.37 mmol) were dissolved in dichloromethane (20 mL) at 0 °C and the resulting mixture was stirred for 4 h, after which all volatiles were evaporated. The product was purified on silica gel using a 30:70 mixture of ethyl acetate:hexanes, yielding, after evaporation and vacuum drying, 0.9 g (2.34 mmol, 48 %). 1H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.08 (s, 2H), 7.56 (s,1H), 6.73 (t, J = 5.2 Hz, 1H), 3.61-3.45 (m, 4H). 13C NMR (101 MHz, DMSO) δ 155.11, 142.83, 131.26, 130.94,117.81, 114.17, 41.76, 33.47.

Reference： [1]Stepniak, Pawel; Lainer, Bruno; Chmurski, Kazimierz; Jurczak, Janusz [Carbohydrate Polymers, 2017, vol. 164, p. 233 - 241]

79
C₂HF₃O₂*C₆H₁₄N₄ [ No CAS ]
[ 16588-74-2 ]
(S)-1-(1-azido-4-methylpentan-2-yl)-3-(3,5-di(trifluoromethyl)-phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
894 mg	With triethylamine In dichloromethane at 20℃; for 24h;	2.2.4. Synthesis of urea 4 General procedure: 4 (S)-2-(Boc-amino)-1-azido-4-methylpentane (600 mg, 2.5 mmol) was dissolved in 1:1 mixture of TFA and dichloromethane (5 mL) and the resulting mixture was stirred for 1 h, after which all volatiles were evaporated. In order to neutralize residual TFA and deprotonate the amine, the solid residue was treated with triethylamine (1 mL), which excess was subsequently evaporated. Dichloromethane (20 mL) was added and the solution was treated with the respective isocyanate (1 equiv., 2.5 mmol). After 24 h of stirring at rt the mixture was washed with saturatedsodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried with MgSO4 and the product was purified on silica gel using a 3:97 mixture of methanol:dichloromethane, yielding, after evaporation and vacuum drying, urea 4.

Reference： [1]Stepniak, Pawel; Lainer, Bruno; Chmurski, Kazimierz; Jurczak, Janusz [Carbohydrate Polymers, 2017, vol. 164, p. 233 - 241]

80
4-[3-(3-chloro-5-methoxyphenyl)-1-(3-aminophenyl)-1H-pyrazol-4-yl]pyridine [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(3-(3-chloro-5-methoxyphenyl)-4-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;	General procedure for synthesis of diarylureaderivatives 1a-e General procedure: To a solution of compound 8 (50 mg, 0.1 mmol) in anhydroustetrahydrofuran (THF) (1 mL), a solution of theappropriate aryl isocyanate (0.1 mmol) in THF (1 mL) wasadded dropwise at room temperature under N2. The reactionmixture was stirred at room temperature for 12 h. Aftercompletion of the reaction, the mixture was evaporatedunder reduced pressure, and the residue was purified bycolumn chromatography (silica gel, hexane-ethyl acetate2:1 v/v then switching to 1:5 v/v) to yield the target compound1a-e.
82%	In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;	4.3 Synthesis of the diarylurea derivatives 1a-e General procedure: To a solution of compound 9 (50mg, 0.1mmol) in anhydrous THF (1mL), a solution of the appropriate aryl isocyanate (0.1mmol) in THF (1mL) was added dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane-ethyl acetate mobile phase system) to yield the title compounds.
	In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;	Synthesis of the diarylurea derivatives 1a-e General procedure: To a solution of compound 9 (50 mg, 0.1 mmol) in anhydrous THF (1 mL), a solution of the appropriate aryl isocyanate (0.1 mmol) in THF (1 mL) was added dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane-ethyl acetate mobile phase system) to yield the title compounds.

Reference： [1]Park, Byung-Jun; El-Gamal, Mohammed I.; Lee, Woo-Suck; Shin, Ji-Sun; Yoo, Kyung Ho; Lee, Kyung-Tae; Oh, Chang-Hyun [Medicinal Chemistry Research, 2017, vol. 26, # 9, p. 2161 - 2171]
[2]El-Gamal, Mohammed I.; Park, Byung-Jun; Oh, Chang-Hyun [European Journal of Medicinal Chemistry, 2018, vol. 156, p. 230 - 239]
[3]Tarazi, Hamadeh; El-Gamal, Mohammed I.; Oh, Chang-Hyun [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 4, p. 655 - 663]

81
4-(3,5-dichlorophenoxy)-2-(piperazin-1-yl)pyrimidine [ No CAS ]
[ 16588-74-2 ]
N-(3,5-bis(trifluoromethyl)phenyl)-4-(4-(2, 4-dichlorophenoxy)pyrimidin-2-yl)piperazine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine In dichloromethane for 6h;	4.2.6 Synthesis of compounds 6a-g General procedure: To a solution of intermediate 3 (1mmol) and DIEA (1.1mmol) in dichloromethane (10ml), a solution of R3NCO (1.1 eq) in dichloromethane (2ml) was added dropwise at 0°C for 6h. Upon completion removing the solvent under reduced pressure, the crude product was purified by flash chromatography on silica gel, eluting with dichloromethane/methanol (5%), yield 80-95%.

Reference： [1]Yao, Dahong; Zhou, Yuxin; Zhu, Lingjuan; Ouyang, Liang; Zhang, Jin; Jiang, Yingnan; Zhao, Yuqian; Sun, Dejuan; Yang, Shilin; Yu, Yang; Wang, Jinhui [European Journal of Medicinal Chemistry, 2017, vol. 140, p. 155 - 171]

82
4-(2-methoxy-4-methylphenoxy)-N₂-(4-morpholinophenyl)pyrimidine-2,5-diamine [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(2-methoxy-4-methylphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In dichloromethane at 0 - 50℃; for 12h; Schlenk technique;	4.6 General procedure for preparation of 6a-k General procedure: To an ice-cold solution of the amines 4a-f (0.1mmol) in DCM (5mL) was added appropriate phenyl isocyanate derivative (1.1 eq). The mixture allowed to warm to room temperature and then refluxed at 50°C for 12h. After completion of the reaction, the solvent was evaporated and the residue was purified by flash column chromatography using EtOAc-hexane mixtures (1:3 to 1:1) to obtain the urea 6a-k as white to yellowish white solids.
	In dichloromethane at 0 - 50℃; Schlenk technique;	4.1.1.2 General procedure for preparation of 4h, I, l-q General procedure: Procedure A: To an ice-cold solution of compounds 3a-b or 3d-I (0.1mmol) in DCM (3mL) was added a solution of an appropriate isocyanate derivative (0.12mmol) in 2mL DCM, dropwise. The reaction mixture was allowed to warm to room temperature and refluxed at 50°C for 5h (TLC checked). Upon reaction completion, the reaction mixture was evaporated, and the crude product was purified by column chromatography to obtain the desired compounds.

Reference： [1]Farag, Ahmed Karam; Elkamhawy, Ahmed; Londhe, Ashwini M.; Lee, Kyung-Tae; Pae, Ae Nim; Roh, Eun Joo [European Journal of Medicinal Chemistry, 2017, vol. 141, p. 657 - 675]
[2]Farag, Ahmed Karam; Hassan, Ahmed H.E.; Chung, Kyung-Sook; Lee, Jeong-Hun; Gil, Hyo-Sun; Lee, Kyung-Tae; Roh, Eun Joo [Bioorganic Chemistry, 2020, vol. 103]

83
[ 122-60-1 ]
[ 16588-74-2 ]
3-(3,5-bis(trifluoromethyl)phenyl)-5-(phenoxymethyl)oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With (2-hydroxy-5-methylphenyl)triphenylphosphonium iodide In chlorobenzene at 100℃; for 24h; Inert atmosphere;
91%	With 1,3-bis-(2,6-diethylphenyl)-2-iodoimidazolium chloride In chlorobenzene at 80℃; for 24h; Inert atmosphere;	11 Example 11 Repeat the drying and deoxygenation operations for the pressure tube three times, and pass inert gas for protection,Add catalyst 4 (24.7 mg, 0.05 mmol, 0.05 equiv) and phenyl glycidyl ether (0.135 mL, 1 mmol, 1.0 equiv),Add chlorobenzene solvent (0.5 mL), and finally add 3,5-bistrifluoromethyl phenyl isocyanate (0.19 mL, 1.1 mmol, 1.1 equiv).Tighten the lid and put it in an oil bath at 80°C for 24 hours. After the reaction is completed, it is cooled, purified by column chromatography (petroleum ether: ethyl acetate = 5:1), and spin-dried on a rotary evaporator to obtain a white powder, which is dried to constant weight, with a yield of 91%
80%	With 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride In chlorobenzene at 100℃; for 8h; Inert atmosphere;	9 Example 9 Repeat the drying and deoxygenation operations on the reaction flask three times, and pass inert gas for protection, add catalyst (2) (21.5mg, 0.05mmol, 0.05equiv) and phenyl glycidyl ether (0.135mL, 1mmol, 1.Oequiv) ), add chlorobenzene solvent (1.0 mL), and finally add 3 5-bis(trifluoromethyl)phenyl isocyanate (0.21 mL, 1.2 ol, 1.2 equiv). Insert a balloon filled with inert gas and put it in an oil bath at 100°C to react for 8 hours. After the reaction is completed, cool, column chromatography (petroleumether: ethyl acetate = 4:1), spin-dry on a rotary evaporator to obtain a white powder, dry to constant weight, yield 80%

70%

With 3-hydroxy-N-octylpyridinium iodide In neat (no solvent) at 100℃; for 1h; Microwave irradiation; regioselective reaction;

Reference： [1]Toda, Yasunori; Gomyou, Shuto; Tanaka, Shoya; Komiyama, Yutaka; Kikuchi, Ayaka; Suga, Hiroyuki [Organic Letters, 2017, vol. 19, # 21, p. 5786 - 5789]
[2]Current Patent Assignee: NANJING TECH UNIVERSITY - CN113072517, 2021, A Location in patent: Paragraph 0096; 0097
[3]Current Patent Assignee: NANJING TECH UNIVERSITY - CN112851597, 2021, A Location in patent: Paragraph 0056-0057
[4]Rostami, Ali; Ebrahimi, Amirhossein; Sakhaee, Nader; Golmohammadi, Farhad; Al-Harrasi, Ahmed [Journal of Organic Chemistry, 2022, vol. 87, # 1, p. 40 - 55]

84
C₁₉H₂₉NO₂ [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(3-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl)-2,2-dimethylpent-4-en-1-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	3 In the 0 °C lower, to the stirring of the S - 2 X-ray (about 5.21 mmol) and iPr2NEt (5.21 mmol) of anhydrous CH2Cl2(13.0 ml) slowly adding solution in 1 - isocyanate - 3, 5 - (trifluoromethyl) - benzene-(5.21 mmol). Then the reaction mixture warm to room temperature and stirring for 1 hour. After complete conversion (by TLC monitoring), the crude mixture by silica gel column chromatography (eluant: petroleum ether/CH2Cl2=100/1 to 1/5, step process 100% petroleum ether to remove the CH2Cl2For sample) direct purification, to obtain 1 w (4.3 mmol, 83% yield).
83%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Schlenk technique;

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA - CN107253928, 2017, A Location in patent: Paragraph 0051; 0085
[2]Wang, Fu-Li; Dong, Xiao-Yang; Lin, Jin-Shun; Zeng, Yang; Jiao, Guan-Yuan; Gu, Qiang-Shuai; Guo, Xian-Qi; Ma, Can-Liang; Liu, Xin-Yuan [Chem, 2017, vol. 3, # 6, p. 979 - 990]

85
C₇H₁₄BrN [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-2,2-dimethylpent-4-en-1-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1h;	4 In the 0 °C lower, to the stirring of the S - 2 of AA (4.0 mmol) and iPr2NEt (4.0 mmol) of anhydrous CH2Cl2(10.0 ml) solution slowly adding 1 - isocyanate - 3, 5 - (trifluoromethyl) - benzene-(4.0 mmol). Then the reaction mixture is 0 °C under stirring 60 min. After complete conversion (by TLC monitoring), the crude mixture by silica gel column chromatography (eluant: petroleum ether/EtOAc=100/1 to 10/1, step process 100% petroleum ether to remove the CH2Cl2For sample) direct purification, to obtain 1 aa (3.6 mmol, 90% yield).
90%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Schlenk technique;

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA - CN107253928, 2017, A Location in patent: Paragraph 0103-0107
[2]Wang, Fu-Li; Dong, Xiao-Yang; Lin, Jin-Shun; Zeng, Yang; Jiao, Guan-Yuan; Gu, Qiang-Shuai; Guo, Xian-Qi; Ma, Can-Liang; Liu, Xin-Yuan [Chem, 2017, vol. 3, # 6, p. 979 - 990]

86
2,2-dimethyl-4-(naphthalen-2-yl)pent-4-en-1-amine [ No CAS ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(2,2-dimethyl-4-(naphthalen-2-yl)pent-4-en-1-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h;	5 1 t, 1 z, 1 za, 1 bb - 1 dd synthesis In the 0 °C lower, to the stirring of the S - 2 (2.0 mmol) and iPr2NEt (2.0 mmol) of anhydrous CH2Cl2(5.0 ml) slowly adding solution in 1 - isocyanate - 3, 5 - (trifluoromethyl) - benzene-(2.0 mmol). Then the reaction mixture warm to room temperature and stirring for 1 hour. After complete conversion (by TLC monitoring), the crude mixture by silica gel column chromatography (eluant: petroleum ether/CH2Cl2=100/1 to 1/5, step process 100% petroleum ether to remove the CH2Cl2For sample) direct purification, to obtain 1 t, 1 z, 1 za, 1 bb, 1 cc, 1 dd.
90%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Schlenk technique;

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA - CN107253928, 2017, A Location in patent: Paragraph 0120; 0122; 0131-0135
[2]Wang, Fu-Li; Dong, Xiao-Yang; Lin, Jin-Shun; Zeng, Yang; Jiao, Guan-Yuan; Gu, Qiang-Shuai; Guo, Xian-Qi; Ma, Can-Liang; Liu, Xin-Yuan [Chem, 2017, vol. 3, # 6, p. 979 - 990]

87
[ 16588-74-2 ]
[ 212782-78-0 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-phenylpent-4-en-1-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h;	1 1 m synthesis of S - 1 the m could be based on the literature 2 reported steps.In the 0 °C lower, to the stirring means of S - 1 of m (2.0 mmol) and iPr2NEt (2.0 mmol) of anhydrous CH2Cl2(4.0 ml) solution slowly adding 1 - isocyanate - 3, 5 - (trifluoromethyl) - benzene-(2.0 mmol). Then the reaction mixture temperature to the room temperature and the stirring 1 hour. After complete conversion (by TLC monitoring), the crude mixture by silica gel column chromatography (eluant: petroleum ether/CH2Cl2=100/1 to 1/2, step process 100% petroleum ether to remove the CH2Cl2For sample) direct purification, to obtain the 1 m (1.72 mmol, 86% yield).
86%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Schlenk technique;

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA - CN107253928, 2017, A Location in patent: Paragraph 0049-0057
[2]Wang, Fu-Li; Dong, Xiao-Yang; Lin, Jin-Shun; Zeng, Yang; Jiao, Guan-Yuan; Gu, Qiang-Shuai; Guo, Xian-Qi; Ma, Can-Liang; Liu, Xin-Yuan [Chem, 2017, vol. 3, # 6, p. 979 - 990]

88
[ 22246-07-7 ]
[ 16588-74-2 ]
1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)urea [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2017,vol. 32,p. 885 - 892

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	16588-74-2	MDL No. :	MFCD00013559
Formula :	C₉H₃F₆NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NRSSOFNMWSJECS-UHFFFAOYSA-N
M.W :	255.12	Pubchem ID :	2733314
Synonyms :

Num. heavy atoms :	17
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	8.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.23
TPSA :	29.43 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.27 cm/s

[ CAS No. 16588-74-2 ] {[proInfo.proName]}

Quality Control of [ 16588-74-2 ]

Related Doc. of [ 16588-74-2 ]

Product Details of [ 16588-74-2 ]

Calculated chemistry of [ 16588-74-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 16588-74-2 ]

Application In Synthesis of [ 16588-74-2 ]

[ 16588-74-2 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Log Po/w (iLOGP) :	2.33
Log Po/w (XLOGP3) :	5.05
Log Po/w (WLOGP) :	6.0
Log Po/w (MLOGP) :	3.58
Log Po/w (SILICOS-IT) :	4.16
Consensus Log Po/w :	4.22

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

Log S (ESOL) :	-4.67
Solubility :	0.0055 mg/ml ; 0.0000216 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.41
Solubility :	0.000993 mg/ml ; 0.00000389 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.17
Solubility :	0.0173 mg/ml ; 0.0000679 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.91

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P501-P261-P270-P210-P271-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P310+P330-P304+P340+P311-P403+P233-P403+P235-P405	UN#:	2206
Hazard Statements:	H301+H331-H315-H319-H335-H227	Packing Group:	Ⅲ
GHS Pictogram:

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