Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.1 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60.9 mg, 53%).
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:31]=[C:32]([CH:42]4[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]4)[NH:33][C:34]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:29][C:24]=2[O:23][CH2:22]1>C1COCC1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:31]=[C:32]([CH:42]4[CH2:47][CH2:46][CH:45]([NH:48][S:8]([CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:10])=[O:9])[CH2:44][CH2:43]4)[NH:33][C:34]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Cc1cccc(-c2[nH]c(C3CCC(N)CC3)nc2-c2ccc3c(c2)OCO3)n1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2[nH]c(C3CCC(NS(=O)(=O)Cc4ccccc4)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.4 %

Procedure:
α-Toluenesulfonyl chloride (0.023 g, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 4-[4-benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl] cyclohexylamine (see Example 19; 0.038 g, 0.10 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.005 g (9%) of the title compound as a yellow solid. MS (ESP+) m/z 531.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.67 (m, 1H), 7.41 (m, 6H), 7.30 (m, 1H), 7.22 (m, 1H), 7.01 (m, 2H), 6.07 (s, 2H), 4.34 (s, 2H), 3.05 (m, 2H), 2.63 (s, 3H), 2.13 (m, 2H), 1.95 (m, 2H), 1.72 (m, 2H), 1.43 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([N:14]5[CH2:15][CH2:16][O:17][CH2:18][CH2:19]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[O:39][N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCOCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M3) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (29 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[N:16]#[C:17][NH2:18].[N+:19]([O-:22])([OH:21])=[O:20].NC(N)=N>>[N+:19]([O-:22])([O-:21])=[O:20].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]([NH2:18])=[NH2+:16])=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#CN
Reactant: Nc1ccc(OCCn2cncn2)cc1
Reactant: O=[N+]([O-])O
Agent: N=C(N)N
Product: NC(=[NH2+])Nc1ccc(OCCn2cncn2)cc1
Product: O=[N+]([O-])[O-]

Procedure:
The title compound was prepared from 4-[2-(1,2,4-triazol-1-yl)ethoxy]aniline (5.30 g, 25.9 mmol), cyanamide (1.86 g, 44.11 mmol) and concentrated HNO3 (1.88 mL, 28.54 mmol) in a manner similar to the guanidine of Example 1 to give the desired material (6.62 g) as an off-white solid, m.p. 280-282°. δH (d6DMSO) 9.33 (1H, bs), 8.56 (1H, s), 7.97 (1H, s), 7.17 (4H, bs), 7.16-7.12 (2H, s), 6.98-6.94 (2H, m), 4.58 (2H, t, J 5.0 Hz) and 4.34 (2H, t, J 2.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]2[C:5]([CH2:6]C3C4C=C(Cl)C=CC=4[NH:9][C:8]=32)=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([C:26]([O:28]O)=O)[CH:20]=1.C([O-])(O)=[O:31].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:26](=[O:28])[C:21]3[CH:22]=[C:23]([Cl:25])[CH:24]=[CH:19][C:20]=3[NH:9][C:8](=[O:31])[C:17]=2[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2[nH]c3c(c2c1)Cc1ccc(Br)cc1-3
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C(=O)Cc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution 3-Bromo-8-chloro-5,10-dihydro-indeno[1,2-b]indole (4.2 g, 13 mmol) in chloroform (150 mL) and 5% aqueous NaHCO3 (56 mL) was added mCPBA (7.5 g, 43 mmol) in chloroform (150 mL) dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 2 hours and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered and concentrated. The resulting oil was triturated with ether and filtered. The filter cake was washed with ether and dried in vacuo to give 8-Bromo-2-chloro-5H,11H-dibenzo[b,f]azocine-6-12-dione (2.0 g, 43%). 1HNMR (CDCl3) δ 7.67 (d, 1H, J+2.20 Hz), 7.59 (d, 1H, J=1.76 Hz), 7.42 (dd, 1H, J=7.92, 1.76 Hz), 7.32 (dd, 1H, J=8.01, 2.20 Hz), 7.02 (m, 2H), 4.44 (d, 1H, J=15.40 Hz), 3.85 (d, 1H, J=14.96 Hz). HPLC Rt=3.65 min.
Reaction SMILES: [Li+].[CH3:2][C:3]1[S:7][CH:6]=[C:5]([S:8]([O-:11])(=O)=[O:9])[CH:4]=1.C([O-])(=O)C.[Na+].[NH2:17]OS(O)(=O)=O>O>[CH3:2][C:3]1[S:7][CH:6]=[C:5]([S:8]([NH2:17])(=[O:11])=[O:9])[CH:4]=1
Reactant: NOS(=O)(=O)O
Reactant: Cc1cc(S(=O)(=O)[O-])cs1
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(S(N)(=O)=O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of the above prepared 5-methyl-thiophene-3-sulfonic acid lithium salt (1.100 g, 6.03 mmol) in 5.0 ml of water was added 0.792 g of sodium acetate (1.6 eq.) and 1.024 g of hydroxylamine-O-sulfonic acid (1.5 eq.), and this mixture was stirred for 2 h at room temperature. HPLC showed complete conversion to the product. The reaction mixture was then partitioned between ethyl acetate and water, the layers were separated, the organic phase was washed with citric acid (10% in water), water and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica column chromatography (SiO2, hexane/ethyl acetate), to yield finally 0.745 g of the title compound as light yellow solid of mp. 105-106.5° C.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN(C=[O:31])C>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH:24]=[C:23]([O:31][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 70 °C
Yield: 62 %

Procedure:
Trimethylsilyl chloride (25 ml) and triethylamine (50 ml) were added to a stirred solution of N-Boc piperidinone (30 g) in DMF (40 ml) and the mixture was heated at 70° C. for 16 h. The solution was cooled to room temperature and diluted with hexanes (300 ml), the solution was washed with sodium bicarbonate solution (3×100 ml), dried (MgSO4) and evaporated to give a colourless oil. The product was purified on silica eluting with 10% ethyl acetate/hexanes to give the title compound as colourless oil (25 g, 62%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O[N:15]1[C:19](=O)[CH2:18][CH2:17][C:16]1=O.C1([N:28]=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:17][CH2:16][NH:15][CH2:19][CH2:18][NH:28][C:9]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1]([CH3:2])=[O:3])=[CH:13][CH:12]=1)=[O:11]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCNCCNC(=O)c1ccc(NC(C)=O)cc1
Temperature: 4 °C
Reaction time: 18 h

Procedure:
Desethyl-N-acetylprocainamide was prepared by dissolving 1.0 g of p-acetamidobenzoic acid and 0.7 g N-hydroxysuccinimide in 20 ml pyridine. To this solution was added 1.4 g of N,N'-dicyclohexylcarbodiimide. The reaction mixture was placed at 4° C. for 18 hours, at which time the crystals were removed by filtration. The filtration was brought to room temperature and with stirring, 0.51 g N-ethylethylenediamine ethylethylenediamine was added. Stirring continued for 3 hours, the solution was cooled to 4° C. and allowed to react for an addition 24 hours at 4° C. The second crop of crystals was removed by filtration, dissolved in 25 ml of distilled water. The pH was adjusted to 10 with sodium hydroxide to form a white precipitate of desethyl-N-acetylprocainamide. The resultant precipitate was dried in vacuo and stored at -20° C. in a desiccator.
Reaction SMILES: [CH2:1](C1CCCCC1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1Cc1ccccc1
Reactant: O=C1CCCCC1Cc1ccccc1
Product: c1ccc(CNC2CCCCC2Cc2ccccc2)cc1

Procedure:
In a series of procedures similar to preparations A and B, 2-benzyl cyclohexanone was converted into 1-amino-2-benzylcyclohexane in 65% via the intermediate oxime. This material (3.05 g, 16.1 mmol) was then converted to the title compounds in a procedure similar to preparation C, isolated as an oil:
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[CH2:9][O:10][C:6]=2[C:5]([CH3:20])=[C:4]([CH3:21])[C:3]=1[NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCCCCC.[C:36](OCC)(=[O:38])C>>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:7]3[C:2]([O:38][CH3:36])=[C:3]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]([CH3:21])=[C:5]([CH3:20])[C:6]=3[O:10][CH2:9]2)=[CH:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(Br)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Product: COc1c(NC(=O)CC(C)(C)C)c(C)c(C)c2c1C(c1ccc(C(C)C)cc1)CO2
Yield: 21 %

Procedure:
Using N-(4-bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 63, the title compound was synthesized in the same manner as in Example 36. Yield: 21%. Melting point: 161-162° C. (hexane-ethyl acetate).
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[CH3:29][NH2:30]>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:30][CH3:29])[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Reactant: CN
Product: CNc1nccc(-c2cnc3c(NC(C)C)nccn23)n1

Procedure:
Isopropyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and methylamine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.N1C=CC=CC=1>ClCCCl>[CH2:11]([O:10][C:8]([C:7]1[C:2]([N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)=[N:3][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:18]([O-:20])=[O:19])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC

Procedure:
A mixture of 0.379 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine, 0.2 g of (1H-1,2,4-triazole, 0.2 ml of pyridine and 15 ml of 1,2-dichloroethane was reacted at 80° C. for 18 hours. After the reaction mixture was concentrated, the concentrate was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (eluent:dichloromethane/ethyl acetate 4:1), to give 0.19 g of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([N:25]3[CH2:29][C:28]4=[CH:30][N:31]=[C:32]([CH3:33])[N:27]4[C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:16])([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.ClC(Cl)(Cl)[C:37]([N:39]=C=O)=[O:38].CO.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[C:37](=[O:38])([O:16][C:13]([CH3:14])([CH3:15])[CH:12]([NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])[C:17]([N:19]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:29][C:28]3=[CH:30][N:31]=[C:32]([CH3:33])[N:27]3[C:26]2=[O:34])[CH2:21][CH2:20]1)=[O:18])[NH2:39]
Reactant: Cc1ncc2n1C(=O)N(N1CCN(C(=O)C(NC(=O)Nc3ccc(Cl)cc3)C(C)(C)O)CC1)C2
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1ncc2n1C(=O)N(N1CCN(C(=O)C(NC(=O)Nc3ccc(Cl)cc3)C(C)(C)OC(N)=O)CC1)C2
Yield: 62 %

Procedure:
To a solution of N—(4-chlorophenyl)—N′—(2-hydroxy-2-methyl-1-((4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperazinyl)carbonyl)propyl)urea (0.18 g) obtained in Example 34 in dichloromethane (15 ml) was added trichloroacetyl isocyanate (0.065 ml) at 0° C., and the temperature of the mixture was elevated to room temperature and mixed at room temperature for 6 hours. To the reaction mixture were added methanol (5 ml), water (5 ml) and potassium carbonate (0.15 g), and then mixed at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound as colorless powder (0.12 g, 62%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.Cl[CH2:33][CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38].[CH3:40][NH:41][CH3:42].[I-].[K+]>ClCCl.C(O)C.C(N(CC)CC)C>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:14](=[O:31])[CH:3]([NH:2][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][N:41]([CH3:42])[CH3:40])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNC
Reactant: O=C(Cl)CCCCCl
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)CCCCC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 96 h

Procedure:
A solution containing the compound of Example 11 (1.1 g) in dichloromethane (50 ml) was treated with chlorovaleryl chloride (0.52 ml) and triethylamine (0.64 ml) for 16 hours. The reaction was diluted with dichloromethane, washed with dilute hydrochloric acid and aqueous sodium bicarbonate, dried (Na2SO4) and concentrated to give an oil. To a solution containing the forgoing oil in ethanol (5 ml) was added dimethylamine (5 ml of a 33% solution in ethanol) and potassium iodide (50 mg). After stirring for 4 days the mixture was partitioned between ethyl acetate and water. The ethyl acetate solution was separated, dried and concentrated and the residue purified by chromatography on silica gel eluting with ethyl acetate-methanol (95:5) to give the title compound, mp 140° C.; found: C, 59.31; H, 5.47; N, 7.37. C28H31F6N3O.0.5H2O requires: C, 59.57; H, 5.71; N, 7.44.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=O)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl.[NH2:31][OH:32]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=[N:31]\[OH:32])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccnnc1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccnnc1)c1ccc(Br)cc1
Temperature: 120 °C
Yield: 89.4 %

Procedure:
To a microwave vial was added (R)-3-(4-bromophenyl)-1-(pyridazin-4-yl)-3-o-tolylpropan-1-one (30 trig, 79 μmol), sodium hydrogencarbonate (20 mg, 0.24 mmol) and hydroxylamine hydrochloride (16 mg, 0.24 mmol) in ethanol (1 mL) and water (0.02 mL). The vial was capped and heated at 120° C. for 10 min, then the reaction mixture was partitioned between ethyl acetate and poured onto water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient dichloromethane to dichloromethane/methanol/25% aq. anmmonia solution 95:5:0.25) afforded the title compound (28 mg, 90%). White foam, MS: 396.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cncc(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
5-Bromopyridin-3-amine (1.2 g, 6.94 mmol) was dissolved in dichloromethane (30 ml). Diisopropylethylamine (1.45 ml, 8.32 mmol) first and then a solution of 4-methoxybenzoyl chloride (1.18 g, 6.92 mmol) in dichloromethane (20 ml) were added. After stirring 1 h at room temperature the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 2.12 g (80% yield) of the title compound. Purity 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 4-chloroaniline (25.51 g) and triethylamine (69.73 ml) in chloroform (350 ml) were added 2,2-dimethyl-propionyl chloride (25.32 g) over a 30 minutes period. The resulting solution was stirred at r.t. for 1 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 35.8 g of product. M.p. 149-150° C.; Retention Time HPLC 2.83 min; MS (ES+) 212 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=1[NH:26][C:27](=[O:45])[CH2:28][CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]2[O:41][CH2:42][CH2:43][O:44][C:36]=12)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH3:17])([CH3:16])[CH3:15].O>O1CCCC1.CN(C)C=O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:11]2[C:10](=[O:12])[CH2:9][CH2:8][C:7]2=[O:13])=[CH:20][C:19]=1[NH:26][C:27](=[O:45])[CH2:28][CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]2[O:41][CH2:42][CH2:43][O:44][C:36]=12)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCCCCC(CC(=O)Nc1cc(CBr)ccc1C(C)(C)C)c1cccc2c1OCCO2
Reactant: O=C1CCC(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCC(CC(=O)Nc1cc(CN2C(=O)CCC2=O)ccc1C(C)(C)C)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
2 ml (2.00 mmol) of a 1 M potassium t-butoxide solution in tetrahydrofuran were added to a solution of 200 mg (2.02 mmol) of succinimide in 10 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 15 minutes. A solution of 680 mg (1.35 mmol) of N-[2-t-butyl-5-bromomethylphenyl]-3-(2,3-ethylenedioxyphenyl)octanamide (prepared as described in Preparation 70E) in 5 ml of dimethylformamide was then added to the mixture. The mixture was stirred at room temperature for 1 hour, after which water was added, and the aqueous mixture was extracted with diethyl ether. The extract was washed with 10% v/v aqueous hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate and a with saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 565 mg of the title compound as a colorless foam-like substance in a 80% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.C(C1C=CC2C(=CC=CC=2)C=1)(=O)C>CO>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:7]3[CH:8]=[CH:9][C:10](=[O:11])[NH:1][C:2]=3[N:3]=[CH:4][CH:5]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N
Agent: CC(=O)c1ccc2ccccc2c1
Solvent: CO
Product: O=c1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2[nH]1
Yield: 51.8 %

Procedure:
Ethyl(E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (350 mg), 2′-acetonaphthone (50 mg) and methanol (80 ml) were irradiated for 4 hours while stirring, and the precipitated solid was filtered out to obtain 156 mg of a light yellow solid.