Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:22]>O.CO>[ClH:22].[NH2:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CO
Solvent: O
Product: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 12.9 g of 10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 650 ml of 2N aqueous hydrochloric acid solution is heated to boiling for 2 hours, cooled and then concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 80° C. 4 g (of the 14.8 g obtained in total) are dissolved in 250 ml of distilled water and the solution is stirred for 16 hours at a temperature in the region of 20° C. The crystals formed are separated out by filtration, washed successively with 25 ml of distilled water and 25 ml of methanol and then air-dried at a temperature in the region of 20° C. The product obtained (3.5 g) is stirred in suspension for 10 minutes in 100 ml of boiling methanol and, after cooling and storing for 1 hour at 5° C., is isolated by filtration, washed with 20 ml of chilled methanol and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 2.1 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one hydrochloride are thus obtained, decomposing without melting at about 240° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 5.70 (broad s, 1H: CH--N+ --Cl-); 7.48 and 7.58 (2t, J=7.5 Hz, 1H each: --H7 and --H8); 7.72 and 8.76 (2s, 1H each: --H of the imidazole); 7.98 and 8.09 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 9.47 (cplx, 3H: N+ H3Cl-); 12.80 (cplx, 1H: --NH--)].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[O:6].[CH3:25][O:26]C1C=CC(C(Cl)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:26][C:24]1[CH:23]=[CH:22][C:4]([C:5]([NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[O:6])=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc[nH]4)c3c2)cc1
Yield: 102.9 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) (from Example 25) was coupled with 4-methoxy-benzoyl chloride (0.4 mmol) and triethylamine in DCM at 0° C. to give 130 mg of the titled compound as a white solid.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=O)=[CH:14][CH:13]=1.[OH-].[K+]>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:6]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:10])[CH:7]=3)[NH:8][CH:19]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(NN)cc1
Reactant: O=CCc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2[nH]cc(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Yield: 47 %

Procedure:
A mixture of p-tolyl hydrazine hydrochloride (3 g, 0.0189 mol), 4-fluorophenyl acetaldehyde (3 g, 0.0227 mol) and ethanol (50 mL) was heated at 80° C. for 1 h. After completion of reaction (monitored by TLC), the mixture was cooled to RT, basified with potassium hydroxide solution, and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (15% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a brown colored oil (2 g, 47% yield).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:12])=[C:6](N)[C:7]([F:10])([F:9])[F:8])C.[CH3:14][NH:15][NH2:16]>C(=O)([O-])O.[Na+]>[CH3:14][N:15]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([CH3:12])[C:4]([OH:3])=[N:16]1
Reactant: CCOC(=O)C(C)=C(N)C(F)(F)F
Reactant: CNN
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(O)nn(C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
3-Amino-4,4,4-trifluoro-2-methyl-but-2-enoic acid ethyl ester (25.5 g, 124 mmol) was cooled to 0° C. and methyl hydrazine (7 ml, 132 mmol) was added dropwise. The mixture was allowed to warm to room temperature and heated to 50° C. for 20 hours. The mixture was allowed to cool to room temperature and was stirred for 16 hours. The mixture was cooled to 0° C. and saturated aqueous sodium hydrogencarbonate solution (50 ml) was added. The solid was removed by filtration and washed with cold water (0° C.) to give the product as a white solid (8.46 g, 38% yield over two steps).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.N1([C:23](N2C=CN=C2)=[O:24])C=CN=C1>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[C:23](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(Nc1nc(Br)cnc1N)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(c1ccccc1)n1c(=O)[nH]c2ncc(Br)nc21
Reaction time: 20 h
Yield: 85.1 %

Procedure:
To a solution of 5-bromo-N3-(1-phenylethyl)pyrazine-2,3-diamine (1.77 g, 6.04 mmol) in anhydrous tetrahydrofuran (30 mL) was added diimidazol-1-ylmethanone (1.47 g, 9.06 mmol) at room temperature. After stirring for 20 h, the reaction was concentrated under reduced pressure. Purification of the resultant residue by flash chromatography [silica gel; hexanes/ethyl acetate (2:1)] afforded 6-bromo-1-(1-phenylethyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one as a red brown solid (1.64 g, 85%). 1H NMR (300 MHz, DMSO): δ 12.31 (s, 1H), 8.04 (s, 1H), 7.40-7.27 (m, 5H), 5.61 (q, J=7.2 Hz, 1H), 1.90 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]1[N:26]([CH2:27][C:28](O)=[O:29])[N:25]=[C:24]([C:31]([F:34])([F:33])[F:32])[CH:23]=1>>[Br:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:31]([F:34])([F:33])[F:32])=[N:25]3)[CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1sc(C2CCNCC2)nc1CCc1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(CCc3ccccc3)c(Br)s2)CC1

Procedure:
4-[5-Bromo-4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine (II-3, 127 mg) is reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (118 mg). After chromatographic purification, this gives 1-{4-[5-bromo-4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (52 mg).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:10]([OH:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7]CC)=[O:6])=[N+:2]=[N-:3].[Li+].[OH-]>CO.C1COCC1>[N:1]([C@@H:4]([C@@H:10]([OH:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@@H](N=[N+]=[N-])[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](N=[N+]=[N-])C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Ethyl (2S,3S,4S)-2-azido-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenylpentanoate (22 mg, 0.058 mmol) in 50% MeOH/THF (800 μL) was added aqueous 1N LiOH (70 μL, 0.070 mmol). The reaction was stirred at rt overnight and concentrated in vacuo. The resulting residue was suspended in EtOAc (30 mL) and washed with aqueous 10% KHSO4 solution (15 ml) and brine (15 mL), and the organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel using an isocratic elution of 10% (10% AcOH/MeOH)/CH2Cl2 and collection and concentration of the appropriate fractions yielded the compound as a yellow residue. 1H NMR (400 MHz, CD3OD) δ 7.23 -7.15 (m, 5H), 4.23-3.87 (m, 3H), 3.21-3.08 (m, 1H), 2.66-2.57 (m, 1H), 1.29 (s, 9H); ES MS (M+23)=373.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:27]=[C:26]([CH3:28])[O:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:27]=[C:26]([CH3:28])[O:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(N)no1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cc(C)on2)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 37.2 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al., J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-amino-5-methylisoxazol (96 mg, 0.978 mmol) was added. The resulting mixture was stirred, at room temperature for four days and the final product was collected by filtration and washed with diethylether to yield the title compound (35 mg, 37.2% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:17]1[C:21](=[O:22])[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (2 mmol, Example 1, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 70% yield.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[O:37][C:38]([CH:41]2[O:45][CH2:44][CH2:43][O:42]2)=[CH:39][CH:40]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[O:37][C:38]([CH:41]5[O:45][CH2:44][CH2:43][O:42]5)=[CH:39][CH:40]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(C2OCCO2)o1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccc(C2OCCO2)o1
Reaction time: 2 h
Yield: 81 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-(1,3-dioxolane-2-yl)furan-2-sulfonamide (12 mg, 0.020 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 9 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-5-(1,3-dioxolane-2-yl)furan-2-sulfonamide (percentage yield: 81%), was obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[CH:17]=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.C(O)(=O)C.C([BH3-])#N>C(O)C>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:24][C:23]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[CH:17]=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Nc1ccc(Cc2c[nH]c3ncncc23)c(F)n1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(CNc2ccc(Cc3c[nH]c4ncncc34)c(F)n2)cc(OC)c1OC

Procedure:
In a 2 mL microwave vial, 6-fluoro-5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-ylamine (68, 9.72 mg, 0.04 mmol) and 3,4,5-trimethoxy-benzaldehyde (69, 15.7 mg, 0.08 mmol) were dissolved in 600 μL of 95:5 ethanol:acetic acid, and silica supported cyanoborohydride (50 mg, 1 mmol/g, 0.05 mmol) was added. The reaction was irradiated for 10 minutes at 160° C. in a microwave. The vial was centrifuged to condense the silica and the supernatant was removed by pipette into another vial. The residual silica was rinsed with 500 μL of ethanol, centrifuged and the supernatant added to the first supernatant. The solvents were removed under vacuum and the resulting material dissolved in dimethyl sulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=424.3.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5]
Reactant: C[O-]
Reactant: Cc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cc(C(F)(F)F)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (1 g, 4.5 mmol) in anhydrous methanol (20 mL) was added sodium methoxide (540 mg, 10 mmol). After stirring at room temperature for 2 hours, the resultant mixture was concentrated to give a residue. And the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give 2-methoxy-6-methyl-4-(trifluoromethyl)nicotinonitrile (0.9 g, 92%). LRMS (M+H) m/z: calcd 216.05. found 216.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1.Cl>C(O)C.[OH-].[Na+]>[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26])([OH:21])=[O:20]
Reactant: NCCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
In a mixture of 50 ml of ethanol and 25 ml of 1N aqueous sodium hydroxide solution, 18-aminooctadecanoic acid (400 mg, 1.33 mmoles) was dissolved at 40° C. To the obtained solution, being maintained at 40° C., was gradually added maleic anhydride (1.97 g, 20.0 mmoles) over a period of 2 hours. The reaction mixture was stirred for 30 minutes, then acidified with hydrochloric acid under ice-cooled condition and subjected to centrifugation. The precipitate was collected by filtration, sufficiently washed with water and then dried under reduced pressure, to give N-(17-carboxyheptadecyl)maleamic acid (436 mg, 88%) having the following properties.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Cl:33][C:34]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:35]=1[CH:36]=O>>[Cl:33][C:34]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:35]=1[CH:36]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Br-]
Product: O=C(O)CCCCCCCCC=Cc1ccc(Cl)cc1Cl
Yield: 61.2 %

Procedure:
By the similar procedure of compound B7, B2 (2.25 g, 4.38 mmol) and 2,4-dichlorobenzaldehyde (500 mg, 2.86 mmol) were used as starting materials to afford (10 E or 10Z))-11-(2,4-dichlorophenyl)undec-10-enoic acid (B9) (576 mg, 1.75 mmol, 61%). Then this compound (210 mg, 0.638 mmol) was dissolved in ethyl acetate (10 mL) and Pd/BaSO4 (21 mg) was then added. The mixture was stirred at room temperature under hydrogen for 12 h. The mixture was filtered through Celite pad and washed with ethyl acetate. The combined filtrate was concentrated and dried in vacuum to afford compound B16 (210 mg, 0.634 mmol, 99%) as white solids. mp: 78° C. 1H-NMR (CDCl3, 400 MHz) δ 7.32 (d, J=1.9 Hz, 1H), 7.09-7.15 (m, 2H), 2.65 (t, J=7.8 Hz, 2H), 2.33 (t, J=7.5 Hz, 2H), 1.53-1.63 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 180.00, 162.19, 159.80, 130.90, 125.31, 110.69, 103.44, 34.11, 30.15, 29.44, 29.36, 29.33, 29.19, 29.16, 29.03, 28.41, 24.69. HRMS (ESI) calculated for C17H24Cl2O2Na [M+Na]+: 353.1051, found: 353.1046.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8]Cl)(=[O:5])=[O:4].[CH3:11][NH:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC#N.O>[CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8][N:12]([CH3:13])[CH3:11])(=[O:5])=[O:4]
Reactant: CNC
Reactant: CN(C)S(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)CCCS(=O)(=O)N(C)C
Temperature: 65 °C
Yield: 68.6 %

Procedure:
A solution of 3-chloro-propane-1-sulfonic acid dimethylamide (0.55 g, 3.00 mmol) in MeCN (5 mL) was treated with dimethylamine (2 M in THF; 10 mL, 20 mmol), potassium carbonate (455 mg, 3.30 mmol) and a catalytic amount of potassium iodide (50 mg, 0.03 mmol). This mixture was heated in a sealed tube at 65° C. for 18 hours, then cooled and diluted with water and extracted into EtOAc. The organic extract was washed with brine then dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a pale brown oil (0.40 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:28]=[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:16][CH:17]=1)[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 84.4 %

Procedure:
In a manner similar to Example 12, Step (b), (4-trifluoromethyl-phenyl)boronic acid (1.285 g, 0.00676 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with chloroform to give 1.42 g of 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid, methyl ester as a white solid; mp 140-142° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH:18]([OH:21])[CH2:19][CH3:20])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(N(CC)CC)C>CCO>[OH:21][CH:18]([C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[C:3]1=[O:22])[CH2:19][CH3:20]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CCC(Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A solution of (S)-3-amino-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (47.6 mg, 0.153 mmol) in EtOH (3 mL) was charged with 4-chloro-6-(trifluoromethyl)quinazoline (46.3 mg, 0.2 mmol) and triethylamine (0.064 mL, 0.46 mmol). The mixture was heated for 30 min at 100° C. in the microwave oven. Solvent was evaporated off, and the residue was purified by flash chromatography on silica gel with elution by 0.8:7.2:92 cNH4OH—MeOH—CH2Cl2 to afford the titled compound 1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (47.3 mg) as a solid. MS found: (M+H)+=508.3
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:17][CH2:18][CH3:19])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([OH:16])=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22](=[O:23])[C:21]([CH3:28])([O:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:17][CH2:18][CH3:19])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15]2)[CH3:27])[CH3:26]
Reactant: CCCn1c(-c2ccccc2)cc2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(-c2ccccc2)cc2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-phenyl-1-propyl-1H-indole-5-ol and ethyl 2-bromo-2-methyl-propanoate using a procedure analogous to that of Example 10.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[CH2:13][O:12][CH2:11][CH2:10][NH:9][CH2:8]1.Cl.[F:15][C:16]1[C:22](F)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1.O>CN(C=O)C>[F:15][C:16]1[C:22]([N:9]2[CH2:8][CH2:7][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: C1CNCCOC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N2CCCOCC2)c(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 88.7 %

Procedure:
19.4 g of potassium carbonate and 11.9 g of homomorph-oline hydrochloride are added to a solution of 5 g of 4,5-difluoro-2-nitroaniline in 98 mL of anhydrous DMF. The reaction medium is heated at 80° C. using an oil bath for 2 hours. The reaction medium is cooled to ambient temperature, then 300 mL of water are added thereto, and precipitation occurs. The precipitate is filtered through sintered glass. The yellow solid is rinsed with 3 times 100 mL of water. The solid is dried in an oven at 70° C. 6.5 g of 4-fluoro-2-nitro-5-perhydro-1,4-oxazepin-4-ylphenylamine are obtained in the form of an orange solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.91 (m, 2H); from 3.52 to 3.61 (m, 4H); 3.66 (m, 2H); 3.74 (m, 2H); 6.28 (d, J=8.5 Hz, 1H); 7.24 (broad s, 2H); 7.61 (d, J=15.5 Hz, 1H).