Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[C:23]([Cl:24])=[CH:22][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=2)=[O:13])=[C:10](F)[CH:9]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=1OC>CN1C(=O)CCC1>[Cl:7][C:8]1[C:23]([Cl:24])=[CH:22][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=2)=[O:13])=[C:10]([O:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][C:29]=2[O:4][CH3:1])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(O)ccc1F
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1cc(Cl)c(Cl)cc1F
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
Cs2CO3 (97.7 mg, 0.3 mmol) was added to a solution of 4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (30.1 mg, 0.1 mmol) and 4-fluoro-3-methoxyphenol (42.6 mg, 0.3 mmol) in NMP (0.5 mL) and the reaction was stirred at 90° C. for 2 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) and HCl as a modifier to yield 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (114) (13.2 mg, 30%). ESI-MS m/z calc. 422.02. found 423.3 (M+1)+; Retention time: 1.57 minutes (3 minutes run).
Reaction SMILES: O[C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S([O:18][CH3:19])(OC)(=O)=O.[CH3:20]C(C)=O>>[I:11][C:10]1[C:2]([O:18][CH3:19])=[C:3]([CH:7]=[C:8]([I:12])[CH:9]=1)[C:4]([O:6][CH3:20])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc(I)cc(I)c1O
Reactant: CC(C)=O
Product: COC(=O)c1cc(I)cc(I)c1OC

Procedure:
A mixture of 2-hydroxy-3,5-diiodobenzoic acid (3.9 g, 10.0 mmol) potassium carbonate (4.15 g, 30.0 mmol) and dimethyl sulfate (2.77 g, 22.0 mmol) in acetone (33 ml) was heated at reflux for 16 h, cooled and concentrated. The residue was dissolved in EtOAc and washed with water, brine, dried (Na2SO4), filtered and concentrated to give an off-white solid (4.2 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12]C)=[C:10]([O:14]C)[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:16]>ClCCl.CO>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:16]
Reactant: COc1cc2c(c(Cl)c1OC)CCNC2=O
Solvent: ClCCl
Solvent: CO
Product: O=C1NCCc2c1cc(O)c(O)c2Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To the solution of 5-chloro-6,7-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one (700 mg, 2.90 mmol) in dichloromethane (DCM) (2 mL) at −78° C. was added borontribromide (0.821 mL, 8.69 mmol). Mixture was allowed to warm up to room temperature and stirred at room temperature for 1 hour. Mixture was diluted with methanol and stripped several times to give 5-chloro-6,7-dihydroxy-3,4-dihydroisoquinolin-1(2H)-one (619 mg, 2.90 mmol, 100% yield) LCMS (M+H)+: 214.0
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:19])[CH3:18])[N:10]=1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)[C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)[C:22]=1[C:23]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:18])[CH3:19])[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:24]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: COc1cc(N2CC3CNCC3C2)nc(N(C)C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)nc(N(C)C)n1
Yield: 80.7 %

Procedure:
A mixture of [4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine (60.0 mg, 0.23 mmol), 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness to yield crude title compound (354.0 mg, 343%). The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (84.0 mg, 81.5%). MS (ESI) mass calcd. for C22H25FN8O2,452.49; m/z found 453.3 [M+H]+. 1H NMR (CDCl3): 7.88-7.79 (m, 2H), 7.72 (d, J=6.7, 1H), 7.54-7.41 (m, 1H), 7.19-7.08 (m, 1H), 5.02-4.92 (m, 1H), 3.96-3.86 (m, 1H), 3.87-3.83 (m, 3H), 3.81-3.50 (m, 5H), 3.43-3.19 (m, 2H), 3.15-3.09 (m, 6H)), 3.09-2.91 (m, 2H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
(187) A solution of 2-(oxazol-5-yl)pyridine (100 mg, 0.68 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.75 mmol, 0.30 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.40 mmol, 2.8 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.68 mmol, 130 mg) was added, and the solution was stirred for 10 min at 0° C. Decanoyl chloride (2 equiv, 1.4 mmol, 270 mg, 0.29 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)decan-1-one (187) (80 mg, 0.27 mmol, 40% yield) as a light brown powder: mp 56-57° C.; 1H NMR (CDCl3, 250 MHz) d 8.69-8.62 (m, 1H), 7.87-7.75 (m, 3H), 7.33-7.25 (m, 1H), 3.08 (t, J=7.7 Hz, 2H), 1.81-1.69 (m, 2H), 1.41-1.19 (m, 12H), 0.86 (br t, J=7.0 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.5, 157.3, 153.1, 150.0, 146.2, 136.9, 127.8, 124.1, 120.3, 39.1, 31.8, 29.4, 29.3, 29.2, 29.1, 24.0, 22.6, 14.0; IR (KBr) umax 2930, 2845, 1697, 1601, 1422, 1380 cm−1; MALDI-FTMS (DHB) m/z300.1911 (C18H24N2O2+H+ requires 301.1910).
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][CH2:3]1.S(=O)(=O)(O)[OH:14].[C:18](#[N:20])[CH3:19]>>[C:18]([NH:20][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][CH2:3]1)(=[O:14])[CH3:19]
Reactant: O=S1(=O)NCC(O)c2ccsc21
Reactant: O=S(=O)(O)O
Reactant: CC#N
Product: CC(=O)NC1CNS(=O)(=O)c2sccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (10.26 g, 0.05 mol) in acetonitrile (100 ml) was cooled to 0° C. Then concentrated sulfuric acid (26.6 ml, 0.50 mol) was added dropwise over 1/2 hr. at 0° to 5° C. The reaction mixture was stirred for 1/2 hr. at 5° C. and for 4 hrs. at ambient temperature. The resulting solution was poured into ice water (200 ml). A pale beige solid precipitated and was filtered and dried. Wt. was 10.2 g. Yield 83%.
Reaction SMILES: [I-:1].[Na+].[CH3:3][C:4](=O)[CH2:5][CH3:6]>>[CH2:3]([C:4]1[CH:3]=[CH:3][C:4]([CH2:5][CH2:6][I:1])=[CH:6][CH:5]=1)[CH2:4][CH2:5][CH2:6][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCC(C)=O
Reactant: [I-]
Agent: [Na+]
Product: CCCCCCCCc1ccc(CCI)cc1
Yield: 80 %

Procedure:
Sodium iodide (18.13 g) was added to a solution (500 ml) of the above-mentioned compound (31.5 g) in 2-butanone and the mixture was refluxed under heating for 4 hours. The reaction mixture was concentrated and poured into ice water. The resultant mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate: hexane=1:20) to give 27.5 g of the subject compound as an oily substance (yield 80%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])(=[O:23])=[O:22]>ClCCl>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][S:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Cc1ccc(CCOCCN)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step c) as the hydrochloride salt (1.50 g) was stirred under nitrogen in dichloromethane (25 ml). Triethylamine (2.21 ml) was added followed by methyl 3-(chlorosulphonyl)propanoate (1.18 g). The mixture was stirred at room temperature overnight. The solution was diluted with a further amount of dichloromethane and the organics washed with dilute hydrochloric acid then water, then dried (MgSO4). The mixture was filtered and the volatiles removed in vacuo to give the subtitle compound as an oil (1.4 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.C(OC)(OC)OC.[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.[BH4-].[Na+]>CO.O>[CH2:18]([N:14]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:21]=[CH:22][C:3]([CH2:2][NH:1][CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:4][CH:5]=1)[CH2:19][CH3:20]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: O
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CNCc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 111.1 %

Procedure:
The compound (538 mg) obtained in Example 20-2 was dissolved in anhydrous methanol (10 ml), added with trimethyl orthoformate (600 μl) at room temperature under a nitrogen atmosphere, and then added with a methanol solution (2.0 ml) containing 1-methyl-2-imidazole carboxaldehyde (240 mg). The whole was stirred at room temperature for 36 hours and then added with sodium borohydride (140 mg) under ice-cooling. The whole was warmed to room temperature and stirred for 1 hour. After completion of the reaction, the resultant was added with water under ice-cooling while the whole was stirred. The solvent was distilled off under reduced pressure and the residue was dissolved in chloroform and added with water, followed by extraction of the aqueous layer with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (782 mg) as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:13][S:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>CN(C=O)C>[CH3:13][S:14][C:15]1[N:20]=[C:19]([N:8]2[C:4]3[CH:3]=[C:2]([NH2:1])[CH:10]=[CH:9][C:5]=3[N:6]=[CH:7]2)[CH:18]=[CH:17][N:16]=1.[CH3:13][S:14][C:15]1[N:20]=[C:19]([N:6]2[C:5]3[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cnc3cc(N)ccc32)n1
Product: CSc1nccc(-n2cnc3ccc(N)cc32)n1

Procedure:
To a stirred solution of 5-aminobenzimidazole (700 mg, 5.26 mmol, 1 eq) in DMF (21 mL) was added NaH (231 mg, 5.78 mmol, 1.1 eq, (60% suspension in oil)). The mixture was allowed to stir until gas evolution ceased. To the DMF solution was added 2-methylthio-4-chloropyrimidine (0.612 mL, 5.26 mmol, 1 eq) dropwise via syringe. The mixture was allowed to stir overnight. The DMF was removed under reduced pressure and the residue was diluted with water and extracted 3× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by preparative thin layer chromatography (eluted 2× with 3.5% MeOH/CH2Cl2) to give 149 mg 2-methylthio-4-[6-aminobenzimidazol-1-yl]pyrimidine (faster regioisomer) and 89 mg 2-methylthio-4-[5-aminobenzimidazol-1-yl]pyrimidine (slower regioisomer).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C([O-])([O-])=O.[K+].[K+].CCCCCC.CCOC(C)=O>CN(C=O)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4ccnc4)=C(C=O)C[C@@H]32)C1
Temperature: 80 °C
Yield: 95.8 %

Procedure:
A mixture of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (Compound 3) (500 mg, 1.329 mmol), imidazole (136 mg, 2.0 mmol) and K2CO3 (551 mg, 3.99 mmol) in dry DMF was heated at about 80° C. under N2 for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-cold water (100 ml), and the resulting white precipitate was filtered, washed with water, and dried to give a white solid. This was titrated with boiling mixture of hexane/EtOAc to give Compound 9 (520 mg, 92%), mp 218-220° C. 1H NMR (300 MHz, CDCl3): δ 1.08 (6H, s, 18 and 19-Me), 2.04 (3H, s, 3β-OAc), 4.61 (1H, m, 3α-H), 5.42 (1H, d, J=4.8 Hz, 6-H), 7.11 (1H, s, 4'-H), 7.23 (1H, s, 5'-H), 7.63 (1H, s, 2'-H) and 9.74 (1H, s, 16-CHO). Analysis calculated for C25H32O3N2 : C, 73.49; H, 7.90; N, 6.88; Found: C, 73.34; H, 8.05; N, 6.65. HRMS calcd. for C25H32O3N2 408.2413, found 408.2426.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[C:22]([NH:25][CH2:26][CH:27]1[O:32][CH2:31][CH2:30][NH:29][CH2:28]1)(=[O:24])[CH3:23].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]2[CH2:30][CH2:31][O:32][CH:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(=O)NCC1CNCCO1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1
Yield: 49.2 %

Procedure:
A mixture of 1 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.15 g of 2-acetylaminomethylmorpholine, 1 g of triethylamine and10 ml of pyridine was heated under reflux for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and ethyl acetate was added to the residue. The resulting crystals were collected byfiltration, and suspended in 20 ml of water. The suspension was extracted with chloroform, and the extract was dried and concentrated. Recrystallization of the residue from ethanol gave 720 mg of 5-amino-7-(2-acetylaminomethylmorpholino)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 228°-229° C.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:52][C:51]([CH3:53])=[C:50]([C:54](=O)[CH3:55])[C:49]=2[CH:57]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:52][C:51]([CH3:53])=[C:50]([C:54]3[CH:55]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)[C:49]=2[CH:57]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)c1c(C)oc2ccc(OCc3ccccc3)cc12
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc2ccc(OCc3ccccc3)cc2c1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 49 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(5-benzyloxy-2-methyl-benzofuran-3-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (75 mg, 49% yield). MS: 608.25 (M+H+); HPLC Procedure A, retention time=17.24 min.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[F:15][C:16]([F:26])([F:25])[C:17](=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[C:2]1([CH:1]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:16]([F:15])([F:25])[F:26])[NH:9][C:10]3=[N:11][NH:12][CH:13]=[C:14]23)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1ccccc1

Procedure:
The title compound was prepared from benzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(Cl)Cl)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][CH2:27][N:28]([S:31]([C:34]3[CH:35]=[C:36]([OH:41])[C:37]([OH:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[CH2:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:40][C:37]3[CH:38]=[CH:39][C:34]([S:31]([N:28]4[CH2:27][CH:26]=[C:25]([C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=5)[CH2:30][CH2:29]4)(=[O:33])=[O:32])=[CH:35][C:36]=3[O:41]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(O)c(O)c1)N1CC=C(c2ccc(F)cc2)CC1
Reactant: Cc1ccc(C(Cl)(Cl)c2ccc(Cl)cc2)cc1
Product: Cc1ccc(C2(c3ccc(Cl)cc3)Oc3ccc(S(=O)(=O)N4CC=C(c5ccc(F)cc5)CC4)cc3O2)cc1

Procedure:
Using 4-chlorophenyl-4-methylphenyl-dichloromethane (57 mg, 0.2 mmol) and 4-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-benzene-1,2-diol (69 mg, 0.2 mmol) as a starting material, the title compound was obtained as an off-white crystalline solid (90 mg, 80%) after taking the residue up in hexane/ethyl acetate (4/1), stirring for 10 minutes, filtering the solid and drying.
Reaction SMILES: [I:1][CH3:2].[F:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][C:12]([CH3:15])=[N:11]2)[C:7]([O:16][CH3:17])=[CH:6][C:5]=1[NH:18][C:19]([NH2:21])=[S:20]>C(O)C>[IH:1].[F:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][C:12]([CH3:15])=[N:11]2)[C:7]([O:16][CH3:17])=[CH:6][C:5]=1[NH:18][C:19]([S:20][CH3:2])=[NH:21]
Reactant: CI
Reactant: COc1cc(NC(N)=S)c(F)cc1-n1cnc(C)n1
Solvent: CCO
Product: COc1cc(NC(=N)SC)c(F)cc1-n1cnc(C)n1
Product: I
Temperature: 70 °C
Yield: 105.1 %

Procedure:
Step B (5): Iodomethane (0.184 mL, 2.95 mmol) was added to a solution of 1-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (664 mg, 2.36 mmol) in absolute ethanol (100 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the reaction was concentrated in vacuo. The residual volatiles were removed under high vacuum to afford methyl 2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (1.05 g, 105% yield) as a white solid. LC-MS (M+H)+ 296.2. 1H NMR (500 MHz, methanol-d4) δ ppm 7.70 (s, 1 H) 6.57 (d, J=10.68 Hz, 1 H) 6.12 (d, J=6.41 Hz, 1 H) 2.74 (s, 3 H) 1.50 (s, 3 H) 1.17 (s, 3 H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[NH:13][C:12]([CH3:14])=[N:11][C:10]=1[N+:15]([O-])=O.[C:19]([CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24])(=O)[CH3:20]>C(O)C.C(O)(=O)C.[Fe]>[OH:25][CH2:26][CH2:27][C:22]1[C:19]([CH3:20])=[N:15][C:10]2[N:11]([C:12]([CH3:14])=[N:13][C:9]=2[C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:18])[C:23]=1[OH:24]
Reactant: CC(=O)C1CCOC1=O
Reactant: Cc1cc(C)c(-c2[nH]c(C)nc2[N+](=O)[O-])c(C)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCO)c(C)nc23)c(C)c1
Yield: 34.1 %

Procedure:
A solution of 5-mesityl-2-methyl-4-nitro-1H-imidazole (2.1 g, 8.56 mmol), α-acetyl-γ-butyrolactone (1.21 g, 9.42 mmol), and iron powder (2.39 g, 42.8 mmol) in ethanol (40 mL) and acetic acid (10 mL) was stirred at 80° C. for one day. The mixture was filtered through Celite and evaporated. The resulting crystals were washed with ethyl acetate, to give the title compound (0.95 g) as white crystals.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[N+]([O-])([O-])=[O:29].[NH4+].[Ce].[CH3:34][C:35]1([CH3:48])[CH2:44][CH2:43][C:42]([CH3:46])([CH3:45])[C:41]2[CH:40]=[C:39]([CH3:47])[CH:38]=[CH:37][C:36]1=2>C(O)(=O)C>[CH3:34][C:35]1([CH3:48])[CH2:44][CH2:43][C:42]([CH3:46])([CH3:45])[C:41]2[CH:40]=[C:39]([CH:47]=[O:29])[CH:38]=[CH:37][C:36]1=2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Ce+4]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. The CAN in the reaction path stands for cerium ammonium nitrate. To 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-methylnaphthalene (b) (202 mg, 1.00 mol) were added acetic acid (8.2 mL) and cerium ammonium nitrate (2.40 g, 4.37 mol) followed by stirring at 100° C. for 1 hour. The reaction solution was poured into ice water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (15/1) as an elution solvent. The yield was 106 mg (49%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14][C:3]=12.[CH3:19][O:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22]>C1(C)C=CC=CC=1.CCOCC>[F:25][C:24]([F:27])([F:26])[S:21]([OH:23])(=[O:22])=[O:20].[Cl:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:19])[C:4]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14][C:3]1=2
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Clc1c2ccccc2nc2c1oc1ccccc12
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1c2ccccc2C(Cl)c2oc3ccccc3c21
Product: O=S(=O)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 11-chlorobenzofuro[3,2-b]quinoline from Example 55 (0.4 g, 1.6. mol) in anhydrous toluene (15 mL) was added methyltriflate (0.52 g, 0.36 mL, 200 mol %). The reaction mixture was stirred for 20 h at rt, diluted with ether, and stirred for 1 h. The solid product was filtered to afford after drying, 0.41 g (62%) of the title compound, mp 221-223° C. (became "wet" at 200-202° C.); 1H NMR (DMSO-d6) δ 8.90 (q, 2H, J=8), 8.73 (dd, 1H, J=1.2, J=8), 8.40-8.36 (m, 1H), 8.24-8.14 (m, 3H), 7.83 (m, 1H); 13C NMR (DMSO-d6) δ 159.53, 145.04, 142.89, 137.44, 136.69, 134.57, 130.32, 129.93, 127.05, 126.02, 125.43, 125.38, 124.73, 119.23, 116.62, 113.80, 106.93, 40.00; MS (FAB, m/z) 268 (M+)