Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][CH:10]=1.[C:30](Cl)(=O)[CH3:31].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[N:14]=[C:30]([CH3:31])[O:16][N:15]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)Cl
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)no1
Reaction time: 4 h

Procedure:
100 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxybenzamidine are placed in 2 ml of toluene. 20 mg of acetyl chloride and 2 ml of pyridine are added, and heating is carried out for 4 hours at 120° C. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and washed with dilute hydrochloric acid and water. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.10).
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH:1]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(OCc1ccccc1)C1CCCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1

Procedure:
Benzyl pipecolate was routinely generated by treating an ethyl acetate suspension of this salt with saturated sodium bicarbonate until dissolution of the organic material. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were dried with MgSO4 and evaporated to yield (S)-Benzyl pipecolate (15) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1>C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(F)c(Cc2ccncc2)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COc1ccc(F)c(CC2CCNCC2)c1
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxybenzyl)pyridine (7.7 g, 35.5 mmole) and platinum oxide (0.7 g) in acetic acid (75 ml) was hydrogenated for 3 hr. The catalyst was removed and the acetic acid removed in vacuo. The residue was dissolved in water and the solution basified with sodium hydroxide. The basic mixture was extracted with ether. The extracts were dried and concentrated in vacuo. The residue was vacuum distilled to give the product (6 g, 75.9%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CN1CCCC1=O.O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)nccc12
Temperature: 110 °C
Yield: 75 %

Procedure:
To a solution of 1-chloro-5-nitroisoquinoline (1.0 g, 4.8 mmol) in N-methylpyrrolidinone (2 mL) was added 3-(trifluoromethyl)aniline (917 mg, 5.7 mmol). The reaction mass was heated at 110° C. for 2 h. The reaction mass was diluted with water and was extracted with chloroform. The organic layer was dried, filtered, concentrated and purified by column chromatography to afford 1.2 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, J=7.8 Hz, 1H), 8.33-8.29 (m, 2H), 7.96-7.89 (m, 3H), 7.68 (t, J=8.1 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.26 (m, 1H).
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([S:22]([CH:25]([CH2:29][CH3:30])[C:26](O)=[O:27])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=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][CH3:15].CN(C)C=O.S(Cl)([Cl:38])=O>C(OCC)(=O)C>[CH2:1]([C:16]1[CH:17]=[C:18]([S:22]([CH:25]([CH2:29][CH3:30])[C:26]([Cl:38])=[O:27])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=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][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cccc(S(=O)(=O)C(CC)C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCc1cccc(S(=O)(=O)C(CC)C(=O)Cl)c1
Temperature: 70 °C

Procedure:
2-[(3-Pentadecylphenyl)sulfonyl]butanoic acid (84.6 g, 0.193 Mole) was suspended in ethyl acetate (700 mL) to which was added dimethylformamide (0.5 mL) and thionyl chloride (70 mL, 0.964 Mole). The mixture was heated at 70° C. for 1.5 hours, cooled, concentrated under reduced pressure, co-evaporated with ethyl acetate (2×100 mL) and the oil so obtained used as such in the next step of the reaction sequence.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24](O)=[O:25])[C:13]2=[O:27])=[O:10])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:63])[C@H:58]1[CH2:62][CH2:61][NH:60][CH2:59]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:60]3[CH2:61][CH2:62][C@H:58]([N:57]([CH3:63])[CH3:56])[CH2:59]3)=[O:25])[C:13]2=[O:27])[CH:7]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Reactant: CN(C)[C@H]1CCNC1
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: ClCCl
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CC[C@H](N(C)C)C3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (50 mg, 0.11 mmol), HATU (46.6 mg, 0.12 mmol), and dimethyl-(S)-pyrrolidin-3-yl-amine (14.0 mg, 0.12 mmol) DCM (2 ml) is added. The mixture is treated with DIPEA (48.6 μL, 2.79 mmol) and stirred at RT for 1 hour. DCM (5 ml) is added to the mixture and washed with 1M HCl. The acidic aqueous phase is treated with 1M NaOH until the pH is adjusted to pH of 7-8. The product is extracted from the aqueous phase with EtOAc (3×10 ml). The organic portions are combined, washed with water (10 ml), dried (MgSO4), filtered and concentrated to afford the title compound, [M+H]+ 544
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][S:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][S:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])[C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([Cl:34])=[CH:36][CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.7 %

Procedure:
A reaction mixture of 33 (350 mg, 0.74 mmol), 4-chlorobenzoyl chloride (390 mg, 2.29 mmol) and Et3N (412 μl, 2.96 mmol) in CH2Cl2 was stirred at room temperature for 14 h. The mixture was purified by silica gel column directly to give 34 (301 mg, 67%). 34 had an analytical HPLC retention time=4.41 min. (Column: YMC S5 Combiscreen 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:17][N:18]=1)[C:7]([O:9]C)=[O:8])([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:17][N:18]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)c([N+](=O)[O-])c1
Yield: 62.2 %

Procedure:
A mixture of methyl 3-nitro-4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (2.00 g), 1 M aqueous sodium hydroxide solution (10 ml) and tetrahydrofuran (10 ml) was heated under reflux for 1 hr. After cooling, 1 M hydrochloric acid was added to acidify the reaction mixture. The crystals were collected by filtration and dissolved in ethyl acetate-tetrahydrofuran. This solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3-nitro-4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (1.20 g, yield 62%). Recrystallization from hexane-tetrahydrofuran gave pale-yellow prism crystals. melting point: 254–255° C.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12]Br)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:14][NH:15][CH3:16]>C(#N)C>[C:1]([O:10][CH2:11][CH2:12][N:15]([CH3:16])[CH3:14])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)OCCBr
Reactant: CNC
Solvent: CC#N
Product: CCCCCCCC(=O)OCCN(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.8 %

Procedure:
2-Bromoethyl octanoate (0.2 g, 0.72 mmol) and 40% aqueous dimethylamine (4.2 mL, 36 mmol) were dissolved in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 48 hours. After removal of acetonitrile under vacuum, chloroform (30 mL) was added. The chloroform layer was extracted with potassium carbonate solution (20 mL, 0.01N) and water (2×20 mL), then was dried over sodium sulfate. The drying agent was suction filtered, and the chloroform removed in vacuo. The resulting material was applied to a silica gel column (discontinuous gradient of chloroform/methanol 95:5, 8:2 as eluent) affording 0.13 g pure product. Yield 77%; liquid; 1H NMR (CDCl3) 0.85-0.95 (t, CH3 (CH2)4), 1.20-1.40 (m, CH3 (CH2)4), 1.55-1.70 (m, CH2 CH2 CO), 2.25-2.40 (t, CH2 CH2 CO), 2.45-2.55 (s, (CH3)2 N) 2.75-2.85 (t, O CH2 CH2 N), 4.25-4.35 (t, O CH2 CH2 N).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[BrH:27].[S:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][S:28][CH2:33][CH2:32]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCSCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(thiomorpholino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrobromide is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-thiomorpholinobutyric acid hydrobromide in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9](O)=[O:10])[C:6](=[O:12])[C:5]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][C:16](=[O:17])[C:4]1=2)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([NH:35][C:36]2[NH:40][N:39]=[N:38][N:37]=2)=[O:10])[C:6](=[O:12])[C:5]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][C:16](=[O:17])[C:4]1=2)[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCn1cc(C(=O)O)c(=O)c2c3ccccc3oc(=O)c21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2c3ccccc3oc(=O)c21
Yield: 56 %

Procedure:
Prepared by the method described for Ex. 17 from 4-ethyl-1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (2.2 g, 0.0077 mole), 1,1'-carbonyldiimidazole (2.4 g, 0.0148 mole) and 5-aminotetrazole monohydrate (0.76 g, 0.0076 mole) in dimethylformamide (30 ml). Recrystallization from dimethylformamide gives pale yellow crystals (1.5 g, 55%), m.p. above 300.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([O:40]C)=[O:39].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([OH:40])=[O:39]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(F)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1N1C(N2CCN(c3cccc(F)c3)CC2)=Nc2c(F)cccc2C1CC(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In 15 ml of dioxane, 117 mg (0.2 mmol) of methyl {8-fluoro-2-[4-(3-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 34A) are mixed with 0.61 ml of 1N aqueous sodium hydroxide solution, and the mixture is stirred at 50° C. for 3 hours. After removal of the solvent, the residue is taken up in water and the mixture is adjusted to pH 34 using 1N hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:16]([CH:19]=O)[CH:17]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:21][NH2:22].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:19]=[N:21][NH:22][CH:17]=1
Reactant: NN
Reactant: O=CC(C=O)C(c1ccccc1)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: O
Product: Clc1ccc(C(c2ccccc2)c2cn[nH]c2)c(Cl)c1

Procedure:
Two grams of [(2,4-dichlorophenyl)phenylmethyl]malonaldehyde in 10 ml of ethanol were heated with 3 ml of anhydrous hydrazine on a steam bath for two hours. The reaction mixture was poured into water and extracted with ether. The ether extract was dried, filtered, and evaporated. The residue was crystallized twice from Skelley B/acetone to provide 1.2 g of the desired title product, m.p. 131° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.C[O-].[Na+].C[CH2:29][O:30]C(C)=O.O>CN1C(=O)CCC1.[Cu]I>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[O:30][CH3:29]
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CCOC(C)=O
Agent: [Cu]I
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 100 °C

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), sodium methoxide (70 mg), CuI (5 mg) in NMP (1.0 ml) was heated at 100° C. for 2.5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH-IPE to give 5-(5-amino-6-methoxy-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (58 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:48][CH2:47]1.Cl>O>[C:57]([C:56]1[CH:55]=[CH:54][C:53]([CH2:52][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[CH2:51][CH2:50]2)=[CH:60][CH:59]=1)#[N:58]
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C(=O)NC2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred mixture of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added triethylamine (2.6 ml, 18.32 mmol), HATU (2.32 g, 6.11 mmol), and 4-((4-aminopiperidin-1-yl)methyl)benzonitrile as its HCl salt (1.6 g, 5.55 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration, purified by column chromatography to yield 0.91 g (44%) of methyl 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate as a white solid. LCMS (m/z): 379 (MH+).
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[CH3:5][C:6]12[CH2:19][C:10]1([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[N:9]1[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][N:25]3[CH:29]=[N:28][N:27]=[N:26]3)[C@H:8]1[S:7]2>ClCCl>[CH3:5][CH:6]1[CH:19]=[C:10]([C:11]([O:13][CH2:14][C:15]([Cl:17])([Cl:18])[Cl:16])=[O:12])[N:9]2[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][N:25]3[CH:29]=[N:28][N:27]=[N:26]3)[C@H:8]2[S:7]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cn3cnnn3)[C@H]1S2
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cn3cnnn3)[C@H]2S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
A solution of aluminum bromide (0.4 g.) in dried dichloromethane (5 ml.) was dropwise added under ice-cooling to a suspension of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-{2-(1H-tetrazol-1-yl)acetamido}penam-3-carboxylate (0.46 g.) in dried dichloromethane (10 ml.). After stirring for 4 hours at room temperature, the reaction mixture was washed in turn with 2% hydrochloric acid three times, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was crystallized from ethanol to give 2,2,2-trichloroethyl 2-methyl-7-{2-(1H-tetrazol-1-yl)acetamido}-3-cephem-4-carboxylate (0.24 g.), mp 168° to 170° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH3:32])[CH:26]=4)[CH:22]=[C:21]([CH3:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([CH3:33])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][C:27]=1[CH3:32]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.54 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (10 ml) was added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (THF/diethyl ether) to yield the title compound as a white solid (0.24 g, 52%). MS (ISP) 445.9 [(M+H)+]; mp 267° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:7]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15])[CH3:6])=[O:4].Cl.N([O-])=O.[Na+].[N-:26]=[N+:27]=[N-].[Na+]>O.CCOCC>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:8]1[C:13]([N:14]=[N+:26]=[N-:27])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15])[CH3:6])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COCC(=O)N(c1c(C)cccc1N)C(C)C(=O)OC
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COCC(=O)N(c1c(C)cccc1N=[N+]=[N-])C(C)C(=O)OC
Temperature: 0 °C

Procedure:
10.0 g of N-(1'-methoxycarbonyl-ethyl)-N-methoxyacetyl-2-methyl-6-aminoaniline were strirred up with 75 g of ice and 15 ml of conc. hydrochloric acid at 0° to 5° C. until a clear solution was formed. At 0° to 5° C. where then added dropwise, within 10 minutes, 2.5 g of sodium nitrite dissolved in 10 ml of water. The reddish-brown solution was stirred for a further 30 minutes at the above temperature, and 100 ml of ether were subsequently added. There was thereupon added dropwise at 0° to 5° C., within 15 minutes, a solution of 2.5 g of sodium azide in 10 ml of water, and the temperature was allowed to rise in the course of 30 minutes to room temperature. The reaction mixture was extracted with ether; the organic phase was then washed with sodium hydrogen carbonate/water, dried with magnesium sulfate, and the solvent was evaporated off. The resulting oil was dried at 40° C. in vacuo; nD26 : 1.5396. nD28.5 : 1.5389.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[C:16]([Br:20])=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[C:16]([Br:20])=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2c(Br)cccc2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Brc1cccc2c1CN(Cc1ccccc1)CCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 9.5 %

Procedure:
To a solution of 4-benzyl-6-bromo-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (4.94 g, 14.9 mmol) in tetrahydrofuran (60 ml) was added 1M borane-tetrahydrofuran solution (61.5 ml, 61.5 mmol), and the mixture was stirred at 80° C. for 2 hr. Under ice-cooling, methanol (140 ml) and sodium hydroxide (13.2 g, 331 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The residue was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the desired product (450 mg, 9.5%) as an oil.