Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:21](O)=[O:22])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:44][O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[NH2:48].Cl>O.CN(C=O)C>[CH3:44][O:45][C:46](=[O:51])[C:47]([NH:48][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[O:10][CH2:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22])([CH3:50])[CH3:49]
Reactant: COC(=O)C(C)(C)N
Reactant: COc1ccc(COc2c(C(=O)O)ccc3ccccc23)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to 150 mg 1-[6-methoxy-pyridin-3-ylmethoxy]-naphthalene-2-carboxylic acid in 2 mL of abs. DMF 130 mg EDC, 72 mg 1-hydroxybenzotriazole and 81 mg N,N-diisopropylethylamine were added. After 30 min at 0° C. 89 mg of 2,2-dimethylglycine methyl ester hydrochloride and 81 mg N,N-diisopropylethylamine were added. The mixture was stirred for 1 h at room temperature. The mixture was poured into cold water, acidified to pH 3 with 2 M HCl, extracted with ethyl acetate twice, washed with sat. sodium hydrogen carbonate solution and brine. The combined organic layers were dried over magnesium sulphate, filtrated and concentrated in vacuo to provide 191 mg of 2-{[1-(6-methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][CH:17]=[O:18])([CH:14]=[CH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:42]([O:44]CC)C>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]([O:44][CH3:42])=[O:18])([CH:14]=[CH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: C=CC1(CC=O)CCN(Cc2ccccc2)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CO
Product: C=CC1(CC(=O)OC)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.486 g of (1-benzyl-4-vinylpiperidin-4-yl)acetaldehyde in N,N-dimethylformamide (10 ml) were added 0.48 g of methanol and 4.50 g of pyridinium dichromate and the resulting mixture was stirred at room temperature for 20 hours. After adding 100 ml of diethyl ether, the reaction mixture was filtered through celite. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.321 g of the title compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[H][H]>CO.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3F)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCNCC4)cc3F)oc12
Yield: 32.7 %

Procedure:
2-(2-Fluoro-4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (300 mg, 0.9 mmol) and platinum (IV) oxide (150 mg) in methanol (20 mL) was purged with hydrogen (2.5 MPa) at 45° C. for two days. Then the mixture was filtered and the filtrate was concentrated. The crude was purified by prep-HPLC to obtain 2-(2-fluoro-4-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (100 mg, yield 32%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.93-2.03 (m, 2H), 2.15-2.18 (m, 2H), 2.94-3.20 (m, 3H), 3.52-3.55 (m, 2H), 7.32-7.37 (m, 2H), 7.51-7.55 (t, J=7.6 Hz, 1H), 7.93-7.95 (t, J=7.6 Hz, 2H), 8.29-8.33 (t, J=7.6 Hz, 1H); LC-MS (ESI) m/z: 340 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-hydroxy-phenyl acetic acid (10.0 g, 65.72 mmol) in DMF (70 mL) at rt were added Cs2CO3 (47.11 g, 144.5 mmol) and benzyl bromide (17.29 mL, 144.5 mmol). The reaction mixture was stirred overnight at room temperature, heated at 100° C. for 1 h and cooled to rt. The solvent was removed under reduced pressure and poured into H2O. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallization in hexanes to afford (4-benzyloxy-phenyl) acetic acid benzyl ester as a yellow solid. (20.5 g, 94%): 1H NMR (300 MHz, CDCl3): δ 7.25-7.34 (m, 10H), 7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 5.50 (s, 2H), 5.12 (s, 2H), 3.61 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: C([O:5]C(N1CCC[C@H]1CO)=O)(C)(C)C.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC(=O)NC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[C:28]1([P:21](=[O:5])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=c1ccnc[nH]1
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of N-tert-butoxycarbonyl-L-prolinol (0.81 g, 4 mmol) 18 in dry DCM (10 mL) was added triphenylphosphine (5.24 g, 20 mmol) followed by 4(3H)-pyrimidone (0.77 g, 8 mmol). The solution was cooled in an ice bath and DIAD (3.24 g, 16 mmol) added dropwise over 10 min. After 48 h GC-MS indicated complete conversion of 18 and the reaction mixture was poured onto water (30 mL), the organic fraction collected and the aqueous phase washed with further DCM (2×20 mL). The combined organic fractions were washed with 1M NaOH (2×15 mL) then brine (1×15 mL) and dried over Na2SO4. Removal of bulk solvent yielded an orange gum, addition of hexanes/diethyl ether (1:1) resulted in formation of a precipitate of triphenylphosphine oxide, which was removed by filtration. Chromatography (ethyl acetate) afforded the desired product as a colorless oil (0.77 g, 69%). HRMS (ESI)=280.1655 (M+H)+. Calcd. for C14H22N3O3 280.1656. 1H NMR (600 MHz, CDCl3) δ 8.71 (s, 1H), 8.39 (d, J=6 Hz, 1H), 6.69 (d, J=6 Hz, 1H), 4.45-3.91 (m, 3H), 3.40-3.33 (m, 2H), 2.00-1.82 (m, 4H), 1.42 (s, 9H). TLC (UV254) Rf=0.49 (ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:27][CH2:28][N:29]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:31]3)[S:23][N:22]=2)=[CH:17]1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1cc(-c2nsc(N3CCNCC3)n2)co1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccoc3)ns2)CC1
Yield: 28.5 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (311 mg, 1.15 mmol), 1-[3-(3-furyl)-1,2,4-thiadiazol-5-yl]piperazine (300 mg, 1.27 mmol) and diisopropylethylamine (0.221 ml, 1.27 mmol) in dimethyl sulfoxide (3.8 ml) was stirred at 80° C. for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 117 mg (28.3%) of the desired product as a solid.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:6]=[C:1]([CH2:11][C:12]([OH:14])=[O:13])[C:2]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:4]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1CC(=O)O
Temperature: -10 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a stirred solution of 1,2-phenylenediacetic acid (10.2 g, 52.5 mmol) in conc. sulfuric acid (33 mL), cooled to −10° C., is added over 10 min a mixture of nitric acid (3.9 mL) and sulfuric acid (1.3 mL). After stirring at −10° C. for 4 h, the reaction mixture is poured onto ice (250 cc). The resulting mixture is extracted with ethyl acetate (3×300 mL). The combined organic phases are washed with H2O (100 mL), dried (MgSO4), filtered and concentrated to afford a white solid. The solid is recrystallized from methyl-tert-butyl ether in hexane to give 8.2 g (34.3 mmol, 65%) of the desired product. mp 187-188° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A, and 1-methyl-1 H-imidazole-4-sulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 8.81 (m, 2H), 8.30 (d, 2H), 7.52 (s, 1H), 7.39 (s, 1H), 7.28-7.20 (m, 3H), 7.14 (m, 1H), 7.04-6.63 (m, 3H), 4.46 (s, 2H), 4.43 (s, 2H), 3.72 (s, 3H), 3.65 (s, 3H), 2.83 (t, 2H), 2.52 (t, 2H); MS 506 (M+1).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]([F:20])([CH:17]([F:19])[F:18])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=1>C1COCC1.O>[F:20][C:4]([F:3])([CH:17]([F:19])[F:18])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Lithium hydroxide (469 mg, 19.6 mmol) is added to a solution of methyl 5-(2,2,3,3-tetrafluoropropoxyl)pyridine-2-carboxylate (1.047 mg, 3.92 mmol) in THF (7 mL) and water (7 mL). The reaction mixture is stirred for 1 hour at 60° C., cooled to ambient temperature, quenched with 1 M HCl (20 mL), diluted with brine and extracted with dichloromethane (3 times). The organic layers are combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (921 mg, 93%). ES/MS (m/e): 254.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]1>O>[CH:32]1([O:14][C:13]2[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]1
Reactant: Cc1csc(Nc2ncccc2O)n1
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncccc2OC2C=CCCC2)n1
Reaction time: 3 h
Yield: 37.4 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (0.250 g, 1.21 mmol) and Cs2CO3 (1.18 g, 3.62 mmol) were added to DMF (3 mL). 3-Bromocyclohex-1-ene (0.216 g, 1.21 mmol) was added, and the reaction mixture was stirred for 3 hours. Water was added and the reaction mixture was extracted with ether. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography provide 3-(cyclohex-2-enyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.130 g=37.5%). 1H NMR (d6-DMSO) δ 9.53 (s, 1H), 7.85 (dd, 1H), 7.41 (d, 1H), 6.90 (dd, 1H), 6.58 (s, 1H), 6.00 (m, 1H), 6.88 (m, 1H), 6.88 (m, 1H), 4.99 (m, 1H), 2.24 (s, 3H), 2.05 (m, 2H), 1.87 (m, 3H), 1.62 (m, 1H); Mass spectrum (apci) m/z=288.0 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@:20]([O:52][CH3:53])([NH:21][C:22](=[O:51])[C:23](=[N:30][O:31]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:54])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([NH:21][C:22](=[O:51])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([O:52][CH3:53])[C:19](=[O:54])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CO[C@@]1(NC(=O)C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc2)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO[C@@]1(NC(=O)C(=NO)c2ccccc2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21

Procedure:
t-Butyl (6R,7S)-3-acetoxymethyl-7-methoxy-7-[2-triphenylmethoxyimino-2-phenylacetamido]-ceph-3-em-4-carboxylate (syn isomer) (400 mg, 0.535 mmole) was treated with anisole (2 ml) and trifluoroacetic acid (8 ml) as described in Example 1(b) to give (6R,7S)-3-acetoxymethyl-7-[2-hydroxyimino-2-phenylacetamido]-7-methoxyceph-3-em-4-carboxylic acid (syn isomer) as an electrostatic white solid. (135 mg, 0.30 mmole). This acid was converted into the title compound by dissolving it in water containing sodium bicarbonate (25 mg, 0.298 mmole), filtering the solution and freeze-drying the filtrate to give the product as an amorphous solid (120 mg, 0.255 mmole, 51%), paper chromatography Rf 0.40 Rf/Rf cephaloram 0.78, λmax (pH6 buffer) 254 nm (ε 10,400).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(#N)C.O>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:38])([F:39])([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29])#[N:24]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (3.46 mmol) of the compound of Example 6A, 944 mg (3.46 mmol) of the compound of Example 23A and 1.58 g (4.15 mmol) of HATU were dissolved in 12.1 ml of anhydrous DMF, and 0.72 ml (4.15 mmol) of N,N-diisopropylethylamine was added. The reaction mixture was stirred at RT for 1 h and then stirred into 120 ml of 0.1 M aqueous sodium hydroxide solution. After a further 10 min of stirring at RT, the precipitate formed was filtered off and dried. This crude product was then separated into its components by preparative HPLC (Method 23). The product fractions were combined and concentrated to dryness on a rotary evaporator. The product obtained was suspended in a mixture of 10 ml of acetonitrile and 10 ml of water, made alkaline with a little saturated sodium bicarbonate solution and stirred at RT for 10 min. The solid was filtered off, washed with water and dried. This gave 1.12 g (69% of theory) of the title compound.
Reaction SMILES: CN(C)C=O.[CH:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH2:7].[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][O:32][CH3:33])[N:25]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[C:21]=2[C:20]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[N:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][O:32][CH3:33])[N:25]([CH2:26][C:27]([CH3:28])([OH:29])[CH3:30])[C:21]=2[C:20]2[CH:19]=[CH:18][C:17]([CH:7]=[CH:6][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:16][C:15]=2[N:14]=1
Reactant: C=CS(C)(=O)=O
Reactant: COCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COCc1nc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 70.2 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (12 mg, 0.05 mmol), acetonitrile (20 mL), N,N-dimethylformamide (15 mL) triethylamine (1.10 mL, 7.92 mmol), tri-o-tolylphosphine (48 mg, 0.16 mmol), methyl vinyl sulfone (294 mg, 2.77 mmol) and 1-[4-amino-7-bromo-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (1.00 g, 2.64 mmol). The reaction mixture was purged with nitrogen. The tube was sealed and heated at 120° C. in an oil bath. The reaction was maintained at 120° C. for 18 hours and then cooled to ambient temperature. The reaction was filtered and the filtrate was concentrated under reduced pressure. The resulting solid was partitioned between chloroform (100 mL) and aqueous 1% sodium carbonate (100 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (5×50 mL). The combined organic fractions were concentrated and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-6% gradient of methanol in dichloromethane) to provide 750 mg of 1-{4-amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a yellow semi-solid. MS (ESI) m/z 405 (M+H)+.
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[NH2:7][C:8]([NH2:10])=[NH:9].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[C:21](=O)[C:20](=[CH:23]N(C)C)[CH2:19][C:18](=[O:27])[NH:17][C:16]=2[CH:28]=1>>[NH2:9][C:8]1[N:10]=[CH:23][C:20]2[CH2:19][C:18](=[O:27])[NH:17][C:16]3[CH:28]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=3[C:21]=2[N:7]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2

Procedure:
In a manner similar to that described for method I (NaHCO3 used instead of K2CO3), guanidine hydrochloride and 8-chloro-4-((dimethylamino)methylene)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) were converted to I-23 (72%): HRMS Calcd. for C12H9ClN4O: 261.0543, Found 261.0543.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O=C1C2C(=CC=CC=2)C(CC(O)=O)N1[C:37]1[CH:42]=[CH:41][C:40](Cl)=[CH:39][N:38]=1>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:3]2[CH:4]([CH2:11][C:12]([N:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:37]3)=[O:14])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[CH:16][CH:17]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2CC(=O)O)cc1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1
Product: COc1ccc(N2C(=O)c3ccccc3C2CC(=O)N2CCCCC2)cc1

Procedure:
The above (+) acetic acid ester (B) was worked up in the same manner as (v) to give the following compound:
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[O:4]1.[CH3:18][O:19][CH2:20]CO>>[N+:12]([C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([OH:4])=[C:10]([O:11][CH2:3][CH2:18][O:19][CH3:20])[CH:9]=1)([O-:14])=[O:13]
Reactant: COCCO
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Agent: [OH-]
Product: COCCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Temperature: 45 °C

Procedure:
0.2 mol (13.2 g) of potassium hydroxide pellets (85%) is added to 100 ml of ethylene glycol monomethyl ether which has been heated beforehand to 45° C. 0.1 mol (21.2 g) of 4,5-methylenedioxy-1,2-dinitrobenzene, prepared according to Example 1, is added to this solution in the course of 5 minutes. The heating is maintained for 1 hour.
Reaction SMILES: CO.[N:3]1[N:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[NH:6][CH:7]=1.[OH-].[Li+].Cl>O.O1CCCC1>[N:3]1[N:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[NH:6][CH:7]=1
Reactant: COC(=O)CCCCc1nnc[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCc1nnc[nH]1
Temperature: 0 °C
Yield: 346.4 %

Procedure:
Add methanol (3 mL), tetrahydrofuran (3 mL), and water (2 mL) to a flask containing methyl 5-(4H-1,2,4-triazol-3-yl)pentanoate (0.5 g; 1.0 equiv; 2.73 mmoles). Add lithium hydroxide (0.261 g; 4.0 equiv; 10.92 mmoles) in one portion, and stir at room temperature for 90 minutes. Cool the solution to 0° C. and add 5N hydrogen chloride (2.18 mL; 4.0 equiv; 10.92 mmoles) slowly. Concentrate the mixture and then azeotrope the residue with toluene (4×10 mL). Add dichloromethane (30 mL) followed by magnesium sulfate. Filter, and rinse the filter cake with 100 mL 10% ethanol in dichloromethane. Concentrate to provide 5-(4H-1,2,4-triazol-3-yl)pentanoic acid (1.6 g; >100%) as an alcoholic adduct: MS (m/z): 170 (M+1).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]=1.CS(O[CH2:26][CH2:27][C:28]([CH3:32])=[C:29]([F:31])[F:30])(=O)=O.C(=O)([O-])O.[Na+]>O>[CH3:6][C:7]1[C:11]([C:12]([O:14][CH2:26][CH2:27][C:28]([CH3:32])=[C:29]([F:31])[F:30])=[O:13])=[CH:10][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]=1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: Cc1nn(-c2ccccc2)cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCOC(=O)c1cn(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.57 g (2.8 mmol) of 3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid, obtained in accordance with a method described in J. Chem. Soc., page 2736 (1961), and 0.58 g (2.9 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate, followed by the addition of 0.48 g (5.7 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:6) to obtain 0.66 g (yield: 76%) of 4,4-difluoro-3-methyl-3-butenyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate.