Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[O:18]=[C:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O1C2C=CC(O)=CC=2OC1.[CH:45]1[C:54]2[CH2:53][CH2:52][CH2:51][CH2:50][C:49]=2[CH:48]=[CH:47][C:46]=1[OH:55]>>[OH:28][C:27]1([C:47]2[C:46]([OH:55])=[CH:45][C:54]3[CH2:53][CH2:52][CH2:51][CH2:50][C:49]=3[CH:48]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]1=[O:18]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: CCOC(=O)CN1C(=O)C(=O)c2ccccc21
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 5,6,7,8-tetrahydronapthalen-2-ol, the title compound was obtained (81%): 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 7.54 (dd, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.80 (d, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 4.45 (ABq, 2H), 4.21 (q, 2H), 4.18-4.14 (br, 1H), 2.73-2.47 (m, 4H), 1.77-1.63 (m, 4H), 1.24 (t, 3H); MS (ES+) m/z 364 (M−17), 404 (M+23)
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1B(O)O>>[F:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Product: N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Yield: 55 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate A-11) was reacted with 2-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as brown viscous oil in 55% yield. MS: 311.1 (M+H+).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[Si:8]([O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCCN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a DMF (4 ml) solution of 60% sodium hydride (0.21 g, 5.2 mmol) was dropwise added a DMF (4 ml) solution of 2-(tert-butyldimethylsilyloxymethyl)piperidine (1.00 g, 4.4 mmol) at room temperature. The mixture was stirred at room temperature for 30 min., to which was then dropwise added a THF (1 ml) solution of benzyl bromide (0.75 g, 4.4 mmol). After stirring at room temperature for additional 30 min., a reaction solution was poured onto water followed by extraction with diethyl ether (30 ml). The extract was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1.30 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[OH:18])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(C(OC(C)(C)C)=O)CCNCC1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[O:18][C:9]2=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1CCCCC1O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC2CCCCC2C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3-chlorophenyl)(2-hydroxycyclohexyl)acetic acid (Reference Example 2-d) (1.25 g, 4.66 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.1 g, 7.0 mmol), and tert-butyl 1-piperazinecarboxylate (0.87 g, 4.66 mmol) in methylene chloride (12 mL) was treated with triethylamine (0.98 mL, 7.0 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 25% EtOAc/hexane) to yield 0.97 g (83%) the lactone, 3-(3-chlorophenyl)hexahydro-1-benzofuran-2(3H)-one as a clear oil. HRMS: calcd for C14H15ClO2+H, 251.0861; found (ESI, [M+H]+), 251.0844.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O-:9])=[O:8])=[CH:5][S:4][N:3]=1.[OH-].[Na+].Cl.[CH2:13]1COCC1.CO.O>>[CH2:1]([C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1)[CH3:13]
Reactant: C1CCOC1
Reactant: Cc1nscc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nscc1C(=O)O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylate (G-3) (4.73 g, 30.1 mmol) in THF-MeOH-H2O (2:1:1, 50 mL), NaOH (3.61 g, 90.3 mmol) is added and the resulting mixture is stirred at 40° C. for 16 h. The mixture is allowed to cool to RT and then acidified with concentrated HCl to adjust the pH to 2-3. The precipitate is collected by filtration, rinsed with water and dried in vacuo to afford the product, 3 ethylisothiazole-4-carboxylic acid (G-4).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>C(OCC)(=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: NCCCn1ccnc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1NCCCn1ccnc1
Temperature: 125 °C
Reaction time: 15 h

Procedure:
1-(3-Aminopropyl)imidazole (4.55 ml) was added to 2-chloronitrobenzene (3.000 g) and stirred for 15 hours at 125° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution, and extracted with 1N hydrochloric acid aqueous solution. The extract was alkalified with 1N sodium hydroxide aqueous solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (4.442 g) as orange oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][C:7]([CH3:11])(O)[CH:8]=[CH2:9])([CH3:3])[CH3:2].[C:12](O)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(OCC)=C>[CH:1]([O:4][CH2:5][CH2:6][C:7]([CH3:11])=[CH:8][CH2:9][CH2:13][CH:12]=[O:14])([CH3:3])[CH3:2]
Reactant: C=CC(C)(O)CCOC(C)C
Reactant: CC(=O)O
Agent: C=COCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=CCCC=O)CCOC(C)C

Procedure:
15.8 g (0.1 mol) of 5-isopropoxy-3-methyl-1-penten-3-ol and 20.0 g of mercuric acetate in 180 cc of ethyl vinyl ether are maintained at reflux temperature over the course of 4 days. 0.9 cc of glacial acetic acid is added at 20° to the turbid solution. After 3 hours 150 cc of 5 % potassium carbonate solution are added and the product is extracted with hexane. The hexane extract is dried with sodium sulphate and evaporated. The residue is heated to 165°-168° over the course of 11/2 hours without further purification and in an atomosphere of nitrogen; the residue is subsequently distilled at reduced pressure. The 7-isopropoxy-5-methyl-4-heptenal has a B.P. of 70°-73°/0.8 mm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([CH3:12])=[N:7]2.[CH3:14]I.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([CH2:12][CH3:14])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Reactant: CI
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cccc(Br)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 54.3 %

Procedure:
LDA(Aldrich) (1.7M in heptane/THF/ethylbenzene; 0.60 mL, 1.01 mmol) was added (dropwise, over 1 min) to a solution of 5-bromo-3-chloro-2-methylquinoxaline (126e) (238 mg, 0.92 mmol) in THF (8.0 mL) in an oven-dried flask under argon at −78° C., and the resulting solution was stirred at −78° C. for 7 min. Methyl iodide (0.12 mL, 1.85 mmol) was then added, and the resulting solution was stirred at −78° C. for 15 min, then warmed to 23° C. and stir at 23° C. for 16 h. The reaction mixture was subsequently cooled to 0° C., water (0.5 mL) was added, and the reaction mixture was concentrated onto silica gel and chromatographically purified (silica gel, 0-15% EtOAc/hexanes) to provide 5-bromo-3-chloro-2-ethylquinoxaline (136 mg, 0.50 mmol, 54% yield) as a light-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, d, J=3.1 Hz), 8.02 (1H, d, J=2.3 Hz), 7.60 (1H, t, J=8.0 Hz), 3.20 (2H, q, J=7.4 Hz), 1.44 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 271.0/272.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12]
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CC(C)(C)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.7 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 12.5 ml of benzene and 1.23 ml of tert.-butanol were reacted to obtain 1.05 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate melting at 67° C. with a specific rotation of [α]D20 =+75.5°±2° (c=0.5% in chloroform).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[NH:35][C:36]1[N:37]=[CH:38][C:39]2[CH2:45][NH:44][CH2:43][CH2:42][C:40]=2[N:41]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[NH:35][C:36]1[N:37]=[CH:38][C:39]2[CH2:45][N:44]([C:23](=[O:25])[CH2:22][CH2:21][NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:43][CH2:42][C:40]=2[N:41]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.69 g; 1.5 equiv; 14.06 mmoles) to a flask containing 3-(tert-butoxycarbonylamino)propanoic acid (1.8 g; 1.0 equiv; 9.37 mmoles), N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (2.50 g; 1.0 equiv; 9.37 mmoles) and N,N-dimethyl-4-pyridinamine, (0.229 g; 0.2 equiv; 1.87 mmoles) in dichloromethane (30 mL). Stir the mixture for 2 hours, then load the solution directly onto a silica gel column and purify by column chromatography (30 to 100% ethyl acetate in dichloromethane) to give tert-butyl {3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}carbamate (3.42 g; 83%) as a colorless foam: MS (m/z): 438(M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=[O:20])[CH2:13][CH2:12]1>C1COCC1>[OH:20][CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[N:14]1[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]1)[CH:5]1[S:6][CH2:7][CH2:8][NH:3][C:4]1=[O:9]
Reactant: O=C1CSCCN1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccccc2C(O)C2SCCNC2=O)CC1
Temperature: 25 °C

Procedure:
Sodium hydride (930 mg, 23.3 mmol of 60% oil dispersion) was washed with hexanes under a nitrogen atmosphere and suspended in 100 mL of anhydrous THF. Thiomorpholin-3-one (1.0 g, 8.55 mmol) was added, followed immediately by 2-(4-methylpiperazin-1-yl)-benzaldehyde (1.58 g., 7.75 mmol). The reaction was then heated to reflux overnight, cooled to room temperature and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with aqueous ammonium chloride (NH4Cl) and saturated brine and then dried with MgSO4. Purification using flash chromatography gave 2-{hydroxy-[2-(4-methylpiperazin-1-yl)phenyl]-methyl}-thiomorpholin-3-one as a white solid, m.p. 137-139° C. Mass spectrum 322 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1.ClCCl>C(N(CC)CC)C>[CH3:1][S:2]([O:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(CN2N=C3CC(OS(C)(=O)=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reaction time: 2 h
Yield: 93 %

Procedure:
Methanesulfonyl chloride (39 μL) was added dropwise to a mixture composed of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (240 mg), dehydrated dichloromethane (6 mL) and triethylamine (88 μL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for two hours. After confirming that the raw material disappeared, the reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane and hexane were added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (253 mg, 93%). The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8](Br)([CH3:10])[CH3:9].[Cl:14][C:15]1[C:20]([OH:21])=[CH:19][C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[C:17]([F:35])[CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([O:21][C:20]1[CH:19]=[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:17]([F:35])=[CH:16][C:15]=1[Cl:14])([CH3:10])[CH3:9]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: COC(=O)CCNC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)C(C)(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Yield: 63.8 %

Procedure:
3-(2-Bromo-2-methylpropionylamino)propionic acid methyl ester (224 mg) and 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-1H-pyrimidin-2,4-dione (250 mg) were dissolved in acetonitrile 5 ml. After addition of K2CO3 (204 mg), the reaction mixture was heated for 12 hours under reflux, cooled and diluted with ethyl acetate (50 mL). After washing with water (50 mL), thus obtained organic layer was dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (240 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)/[CH:7]=[CH:8]/[C:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=2[S:11][CH:10]=1.[CH3:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[NH2:18][C:17]1[C:12]2[S:11][CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]3[CH:19]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([N:25]5[CH:26]=[C:22]([CH3:21])[N:23]=[CH:24]5)[CH:28]=4)[CH:3]=[CH:4][C:5]=3[CH3:20])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Reactant: Cc1ccc(N)cc1/C=C/c1csc2c(N)ncnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(/C=C/c4csc5c(N)ncnc45)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
(E)-7-(5-amino-2-methylstyryl)thieno[3,2-d]pyrimidine-4-amine (100 mg, 0.354 mmol) and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzoic acid (96 mg, 0.354 mmol) were dissolved in DMF (1.5 mL), HATU (404 mg, 1.063 mmol) and TEA (0.248 mL, 1.7728 mmol) were added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The resulting mixture was purified by silica gel chromatography to obtain the title compound (142 mg, 75% yield).
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][N:12]=[C:11]([C:17]([O:19]C)=[O:18])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][N:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cc(OC2CCCC2)c(OC)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cnc(C(=O)O)cc1OC1CCCC1
Reaction time: 45 h
Yield: 36.2 %

Procedure:
A solution of potassium hydroxide (4.71 g) in water (32 mL) is added to a solution of methyl 4-cyclopentyloxy-5-methoxypyridine-2-carboxylate (7.03 g) in methanol (188 mL) and the mixture allowed to stand for 45 hours. After concentrating in vacuo the residue is dissolved in water, washed with ethyl acetate and basified to pH 5 with concentrated aqueous hydrochloric acid. The mixture is extracted with dichloromethane, the extracts dried (MgSO4) and evaporated to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.4 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(Cl)(Cl)=O.[CH2:16](N(CC)CC)C>ClCCCl>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CCN(CC)CC
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1C

Procedure:
To a suspension of 4-bromo-2-methylbenzoic acid (10.0 g, 0.0465 mol) in 1,2-dichloroethane (60 mL) was added thionyl chloride (28 g, 0.23 mol) and the mixture heated to reflux for 1 hour. The mixture was concentrated to dryness and vacuum dried. The crude acid chloride was dissolved in methanol (100 mL) and the solution was treated with triethylamine (4.7 g, 0.046 mol). The mixture was heated to reflux for an hour and then concentrated to dryness. The crude ester was dissolved in EtOAc, washed consecutively with sat. sodium bicarbonate solution and water. The organic phase was dried and concentrated to obtain the title ester.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:34])[CH3:33]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
A solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (212 mg) in acetic anhydride (10 mL) was stirred at room temperature for 16 hours. The solution was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2 and washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The oily residue was crystallized from AcOEt to give the title compound (130 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:29]1[C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]2[C:38]([O:40][C:41](=O)[C:31]=2[CH:30]=1)=[O:39]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:38](=[O:39])[C:32]3[C:31](=[CH:30][CH:29]=[C:34]([C:35]([OH:37])=[O:36])[CH:33]=3)[C:41]2=[O:40])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc(C(F)(F)F)cc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(C(F)(F)F)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(4-trifluoromethylphenyl)benzoxazole (90 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (45 mg, 0.23 mmol) the title compound was obtained (102 mg, 79%). 1H NMR (DMSO) δ 13.74(s, 1H), 8.43(d, 1H), 8.33(s, 1H), 8.22(d, 1H), 8.20(d, 1H), 8.10(d, 1H), 7.99(d, 2H), 7.93(d, 1H), 7.83(m, 3H), 7.72(dd, 1H), 7.48(d, 1H), 4.03(s, 3H). MS 559.3 m/z (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6]1.Cl[C:27]1[N:32]=[C:31]([NH2:33])[C:30]([N+:34]([O-:36])=[O:35])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:33][C:31]1[N:32]=[C:27]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=3)[C:7]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:6]2)[CH:28]=[CH:29][C:30]=1[N+:34]([O-:36])=[O:35]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCc1ccc(-c2cn(CCCN)cc2NC(=O)OC(C)(C)C)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(-c2cn(CCCNc3ccc([N+](=O)[O-])c(N)n3)cc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
N-[1-(3-aminopropyl)-4-(4-ethylphenyl)pyrrol-3-yl](tert-butoxy)carboxamide (1 eq) and 6-chloro-3-nitro-2-pyridylamine (1.2 eq) were dissolved in DMA with stirring under argon at rt. Hünig's Base (1.5 eq) was added to the clear dark brown solution which was heated to 60° C. for 12 hours until completion was determined by LC/MS and TLC, eluting with EtOAc/Hexane (3:2, v/v) (Rf=0.3). EtOAc was added to the reaction mixture which was then washed with water, brine, dried (Na2SO4), filtered, and concentrated to dryness to give the crude brown product. The brown residue was purified by silica column chromatography eluting with EtOAc/Hexane (24:26, v/v). After collecting the purified fractions and concentrating, the product was isolated as a light yellow solid (75% yield).