Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[C:6](=[O:11])([O:9][CH3:10])OC.CO.[C:14](=O)(OC)[O:15][CH3:16]>C[O-].C[O-].C([Sn+2]CCCC)CCC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:11])[O:9][CH2:10][CH2:14][O:15][CH3:16]
Reactant: COC(=O)OC
Reactant: COCCO
Agent: CCCC[Sn+2]CCCC
Agent: C[O-]
Solvent: CO
Product: COCCOC(=O)OCCOC
Temperature: 102 °C
Yield: 87.5 %

Procedure:
A total of 76.1 grams (1 mole) of 2-methoxyethanol, 67.6 grams (0.75 moles) of dimethyl carbonate, and 0.5 grams of dibutyltin dimethoxide were combined in a 250 milliliter round bottom three-neck flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux at an initial temperature of 73° C. at the head and 102° C. in the kettle. After 7 minutes at reflux, a methanol/dimethyl carbonate azeotrope was slowly removed overhead. A total of 55.9 grams of material was removed overhead (64° C.-88° C.) over a period of about 21 hours after which time the kettle temperature rose to 145° C. After this time, the flask contents were cooled and put under vacuum. The desired product was collected at a temperature of 97° C.-105° C. at 3 mm Hg. A total of 77.98 grams (87.5 percent yield) of bis(2-methoxyethyl)carbonate was obtained at a purity of greater than 99 percent as analyzed by capillary gas chromatography on a DB-1701 column.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[OH2:19].S(=O)(=O)(O)[OH:21]>C(O)C>[CH3:10][CH:9]([C:5]1[C:6](=[O:21])[NH:7][C:2](=[O:19])[NH:3][C:4]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:11]
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cc1ccccc1
Reactant: O=S(=O)(O)O
Reactant: O
Solvent: CCO
Product: CC(C)c1c(Cc2ccccc2)[nH]c(=O)[nH]c1=O

Procedure:
50 g of compound of Example 12 are brought to reflux for 16 hours in a mixture of 200 ml of ethanol, 50 ml of water and 50 ml of sulphuric acid. At the end of the reaction, the ethanol is distilled off under atmospheric pressure, 100 ml of water are added and then the pH of the medium is brought to 2/3 by running in 30% sodium hydroxide solution. The precipitate obtained is filtered off, washed with water and washed with acetone in order to lead, after drying, to 30.6 g of 5-(1-methylethyl)-6-(phenylmethyl)pyrimidine-2,4-(1H,3H) -dione.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[O:22])=[CH:23][CH:24]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: NCCCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(COc1ccc(Cl)cc1)NCCCCCn1ccnc1
Reaction time: 2 h

Procedure:
1,1'-Carbonyldiimidazole (6.48 g) was added to a solution of 4-chlorophenoxyacetic acid (7.46 g) in THF (144 ml.) at ambient temperature. The mixture was stirred for 2 hours and then 1-(5-aminopentyl)imidazole (6.1 g) was added. The mixture was stirred at ambient temperature for 18 hours and then worked up as described in Example 9a to give an oil which was purified by flash chromatography on silica using ethyl acetate/methanol/triethylamine, 18:2:1 as the mobile phase to give 2-(4-chlorophenoxy)-N-[5-(imidazol-1-yl)pentyl]acetamide as an oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1.S(Cl)(Cl)=O.Cl.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23](=[O:39])[N:24]([CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38])[C:25]2=[O:30].C(N(CC)CC)C>C1COCC1>[O:38]=[C:32]1[CH:31]([N:24]2[C:23](=[O:39])[C:22]3[C:26](=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20][NH:19][C:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][N:9]=3)=[O:13])[C:25]2=[O:30])[CH2:36][CH2:35][C:34](=[O:37])[NH:33]1
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCCc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Yield: 64.7 %

Procedure:
A mixture of fusaric acid (0.36 g, 2.0 mmol) and thionyl chloride (10 mL) was heated to reflux for 1 hour. Excess thionyl chloride was removed under vacuum. To the acid chloride, was then added 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), THF (30 mL) and triethylamine (0.61 g, 6.0 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the crude residue was chromatographed using a methylene chloride-methanol gradient, eluting the product with 95:5 methylene chloride-methanol. This material was further purified by preparative HPLC, eluting with 1:1 acetonitrile-water, providing 0.58 g of the purified product in 64% yield: mp 137-139° C.; 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.24-1.39 (m, 2H), 1.54-1.65 (m, 2H), 2.06-2.10 (m, 2H), 2.51-2.72 (m, 4H), 2.84-2.97 (m, 1H), 4.94 (d, J=6.4 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.66-7.71 (m, 1H), 7.77-7.86 (m, 3H), 7.97 (d, J=8.0 Hz, 1H), 8.54 (d, J=1.7 Hz, 1H), 9.43 (t, J=6.4 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 13.7, 21.6, 22.0, 31.0, 31.7, 32.6, 38.5, 48.9, 121.8, 121.9, 127.2, 131.6, 133.0, 134.8, 137.3, 139.2, 141.2, 147.5, 148.5, 164.5, 167.0, 167.6, 169.9, 172.8; Anal. calcd for C24H24N4O5.0.3H2O: C, 63.51; H, 5.46; N, 12.34. Found: C, 63.52; H, 5.55; N, 12.05.
Reaction SMILES: C([CH:3]([OH:14])[CH2:4][CH2:5][C:6]1[C:7]([Cl:13])=[N:8][C:9](Cl)=[CH:10][CH:11]=1)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:34]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[C:32](B4OC(C)(C)C(C)(C)O4)=[CH:31][C:25]=3[C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1(C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[Cl:13][C:7]1[N:8]=[C:9]([C:32]2[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][C:24]3[O:23][C:22]([C:19]4[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=4)=[C:26]([C:27]([NH:29][CH3:30])=[O:28])[C:25]=3[CH:31]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][OH:14]
Reactant: CCC(O)CCc1ccc(Cl)nc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: c1ccc(-c2ccccc2)cc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCCO)c(Cl)n3)cc12
Temperature: 70 °C

Procedure:
To a mixture of ethyl 3-(2,6-dichloropyridin-3-yl)propan-1-ol (180 mg, 0.873 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (439 mg, 0.873 mmol), XantPhos Biphenyl precatalyst (78 mg, 0.087 mmol), and cesium carbonate (854 mg, 2.62 mmol) was added 1,4-Dioxane (7.3 mL) and water (1.5 mL). A steady stream of N2 was bubbled through the reaction mixture for 5 minutes then the mixture was heated to 70° C. for 4 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc/CH2Cl2 as eluent. Further purification by preparative TLC using 50% EtOAc/CH2Cl2 as eluent provided the title compound. 1H NMR δ (ppm) (CHCl3-d): 8.01˜7.96 (3H, m), 7.72 (1H, d, J=7.68 Hz), 7.68 (1H, s), 7.56 (1H, d, J=7.70 Hz), 7.23 (2H, t, J=8.6 Hz), 5.95 (1H, br s), 3.78 (2H, q, J=5.76 Hz), 3.24 (3H, s), 3.03 (3H, d, J=4.88 Hz), 2.93 (2H, t, J=7.76 Hz), 2.88 (3H, s), 2.03˜1.97 (2H, m). MS (M+H)+: 545.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)[C:20]=1[CH3:36]>CN(C)C=O>[ClH:25].[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)[C:20]=1[CH3:36]
Reactant: COCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 15.3 %

Procedure:
After 4-fluoroaniline(0.43 ml, 4.5 mmol) and triethylamine(0.63 ml, 4.5 mmol) were added to a solution of 6-methoxymethyl-5-methyl-2-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.9 g, 3 mmol) in dimethylformamide (5 ml), 190 mg of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:7].[ClH:15].NO.C[N:19]([CH:21]=O)C>O>[Cl:15][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:7][C:21]#[N:19]
Reactant: CC(=O)c1ccccc1
Reactant: CN(C)C=O
Reactant: Cl
Agent: NO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#CC=C(Cl)c1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To an ice cold (0-5° C.) dimethylformamide (2.56 mL, 33.32 mmol) was added phosphorous oxychloride (1.56 mL, 16.66 mmol) dropwise with stirring for 15 min. To this cold mixture, acetophenone (1.0 g, 8.3 mmol) was added dropwise maintaining the temperature of the reaction mixture between 45-55° C. for 10 min. The reaction mixture was slowly allowed to rt and stand for 30 min. To the reaction mixture, 0.5 mL of a total solution of hydroxylamine hydrochloride (2.31 g, 33.32 mmol) in dry DMF (3.3 mL) was added and the mixture was stirred at 70-80° C. for 5 min. Then the remaining solution of hydroxylamine hydrochloride in DMF was added thereafter at such a rate that the temperature of the reaction mixture rise above 145-155° C. After completion of the addition, the reaction mixture was allowed to rt for 30 min and diluted with cold water (100 mL). The solution was extracted with chloroform (3×100 mL) and the chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel using hexane-ethyl acetate (98:2) as eluent to give the product as an oil (0.72 g, 53%). 1H NMR (400 MHz, CDCl3): δ 7.64-7.67 (2H, m, Ar—H), 7.43-7.53 (3H, m, Ar—H), 6.02 (1H, s, ═CH).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[O+:14][C:13]1[C:8](=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[CH:12]=1)[C:7]=2[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([NH2:29])[C:21]=1[C:30]([OH:32])=[O:31].C(N(C(C)C)CC)(C)C.[C:43]([O:46][CH2:47][Br:48])(=[O:45])[CH3:44]>ClC(Cl)C>[Br-:48].[CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[O+:14][C:13]1[C:8](=[CH:9][CH:10]=[C:11]([N:17]([CH3:18])[CH3:19])[CH:12]=1)[C:7]=2[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([NH2:29])[C:21]=1[C:30]([O:32][CH2:47][O:46][C:43](=[O:45])[CH3:44])=[O:31]
Reactant: CN(C)c1ccc2c(-c3ccc([N+](=O)[O-])c(N)c3C(=O)O)c3ccc(N(C)C)cc3[o+]c2c1
Reactant: CC(=O)OCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(=O)OCOC(=O)c1c(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)ccc([N+](=O)[O-])c1N
Product: [Br-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 13.6 %

Procedure:
3,6-Bis(dimethylamino)-9-(3-amino-2-carboxy-4-nitrophenyl)xanthylium intramolecular salt (2.44 g) prepared by the method disclosed in WO99/01447 was dissolved in 120 ml of dichloroethane, and the solution was added with 1 ml of diisopropylethylamine. The mixture was further added with acetoxymethyl bromide (0.55 ml), and stirred at room temperature. The progress of the reaction was monitored every day by TLC, and additional diisopropylethylamine and acetoxymethyl bromide were added in amounts half of those used for the first addition. After 4 days, the reaction mixture was added with dichloroethane and washed with water, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 3,6-bis(dimethylamino)-9-(2-acetoxymethoxycarbonyl-3-amino-4-nitrophenyl)xanthylium bromide (0.445 g, 13.6%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@H:10]2[C@@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@@H:13]3[C@@H:12]([CH2:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH:37]([O-])([O-])OCC>C(O)(=O)C>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:37][N:9]2[C@H:10]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@@H:13]2[C@@H:12]([CH2:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:11]1
Reactant: CN(CCCN1C(=O)c2ccccc2C1=O)C[C@H]1C[C@@H](Nc2ncnc(Cl)c2N)[C@@H]2OC(C)(C)O[C@H]12
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)O
Product: CN(CCCN1C(=O)c2ccccc2C1=O)C[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of 2-(3-((((3aR,4R,6R,6aS)-6-((5-amino-6-chloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)isoindoline-1,3-dione (0.22 g, 0.39 mmol) in ethyl orthoformate (2.3 mL, 14 mmol) was treated with acetic acid (8 drops) and heated at reflux for 3.25 h; HPLC indicated nearly complete consumption of starting material. The reaction mixture was cooled to rt, diluted with toluene (10 mL), and concentrated in vacuo to remove most of the volatiles, and further concentrated under the flow of air. The resulting clear, dark brown oil was purified by column chromatography (2×22 cm silica; 0-1% 7 N NH3 in CH3OH/CH2Cl2) to afford the title compound (0.19 g, 85%) as a pale yellow foam: MS (ESI+) for C26H29ClN6O4 m/z 525.2 [M+H]+; HPLC purity 92% (ret. time, 2.917 min).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:23][C@H:22]2[C@H:18]([CH2:19][CH2:20][CH2:21]2)[C@H:17]1[CH:24]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(=O)OCC.CCCCCCC>[C:9]([O:13][C:14]([N:16]1[CH2:23][C@H:22]2[C@H:18]([CH2:19][CH2:20][CH2:21]2)[C@H:17]1[CH2:24][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1CNCc1ccccc1
Reaction time: 2 h

Procedure:
Benzylamine (0.263 mL, 1.75 eq) was added to a solution of (1S,2S,5R)-2-formyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (330 mg, 1 eq) in chloroform (10 mL). After 15 min the mixture was treated with NaBH(OAc)3 (292.25 mg, 1 eq), stirred for 2 h and poured into a sat. aq NaHCO3 solution. The layers were separated and the aqueous layer was extracted twice with chloroform. The combined org. extracts were washed with sat. NaHCO3 solution, dried over anh. MgSO4, filtered and concentrated in vacuo to give a crude yellow oil. FC (EA/n-heptane: 3/7 to 7/3) gave the title compound as a colourless oil
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.CN(C)C=O.CS(OC[CH2:44][C:45]1[CH:50]=[C:49]([N+:51]([O-])=O)[CH:48]=[CH:47][C:46]=1[CH3:54])(=O)=O>CN(C)C1C=CN=CC=1.C(#N)C>[NH2:51][C:49]1[CH:48]=[CH:47][C:46]([CH3:54])=[C:45]([CH2:44][CH2:17][N:14]2[CH2:13][CH2:12][CH:11]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:16][CH2:15]2)[CH:50]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: Cc1ccc([N+](=O)[O-])cc1CCOS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N)cc1CCN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 90 °C
Reaction time: 20 h
Yield: 221.3 %

Procedure:
A 100 mL round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (6.6 g, 7.1 mmol), 5-fluoro-3-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-indole (2.7 g, 8.1 mmol), diisopropylethylamine (6.2 mL, 35.6 mmol), 4-dimethylaminopyridine (0.87 g, 7.1 mmol), and dry dimethyl formamide (85 mL). The mixture was stirred at 90° C. for 20 h. After cooling to room temperature, the resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL glass cylinder with a fritte and a three way junction in the bottom. The resin was then treated for 20 min with 80 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2%, w/w), using a flow of nitrogen to agitate the resin (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (25 mL), a 1:1 mixture of dichloromethane:triethylamine (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL round bottom flask. Acetonitrile (70 mL), diisopropylethylamine (5.2 mL, 30 mmol) and 2-(2-methanesulfonyloxyethyl)-1-methyl-4-nitrobenzene (3.67 g, 14 mmol) was added. The reaction mixture was heated to 70° C. for 18 h. After cooling to room temperature, the resin was filtered off and washed with dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL round bottom flask and treated with tin(II) chloride dihydrate (60 mL of an 0.5 M solution in DMF). The reaction mixture was stirred for 18 h. at room temperature. The resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3 ×25 mL). The resin was dried in vacuo (20° C., 20 h) to yield the title resin (6.3 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[C:15](=COC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=[O:40])C.O=[O+][O-]>CO>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([OH:40])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=[O+][O-]
Solvent: CO
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
A solution of 4-nitrobenzyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (1.97 g), ethyl acetate (30 ml) and methanol (7.5 ml) was treated with ozone in a similar manner to that of Example 1 (4) to give 4-nitrobenzyl 7-(2-phenylacetamido)-3-hydroxy-3cephem-4-carboxylate (400 mg.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N(C(C)C)(C(C)C)CC>CN(C=O)C.C(Cl)Cl>[CH2:13]([NH:20][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(Br)cc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To an ice bath cooled mixture of 5-bromo-2-methoxybenzoic acid (439 mg, 1.9 mmol) in 1:1 CH2Cl2:DMF (4 mL) was added benzylamine (0.228 mL, 2.1 mmol), EDCI (438 mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol) and NEtiPr2 (0.496 mL, 2.85 mmol). The mixture was then stirred at room temperature until the reaction was complete. Extractive work up with ethyl acetate, washing with saturated aqueous NaHCO3, H2O, saturated aqueous KHSO4 and brine, gave the title compound (550 mg) after isolation which was carried forward without purification. LCMS (M+H)+ 320, 322.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.Cl.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][N:15]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: BrCCCCBr
Reactant: NCCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Brc1ccc(CCN2CCCC2)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
0.51 mL (4.23 mmol) 1,4-dibromobutane in 20 mL acetonitrile is added slowly to a solution of 1.0 g (4.23 mmol) 4-bromo-phenethylamine hydrochloride, 1.8 g (13.0 mmol) K2CO3 and 200 mg (1.20 mmol) Kl in 100 mL acetonitrile at 75° C. and the reaction mixture is stirred for a further 4 h at 75° C. The reaction solution is diluted with 100 mL water and the aqueous phase is extracted with 100 mL EtOAc. The combined organic extracts are washed with saturated NaCl solution, the organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 9:1:0.1)
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21][C:17]3=[CH:16][N:15]=2)[CH2:9]1.C(N(CC)CC)C.Cl[C:30]1[N:35]=[C:34]([NH2:36])[C:33]([N+:37]([O-:39])=[O:38])=[CH:32][CH:31]=1>C(#N)C>[CH:16]1[N:15]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:30]3[N:35]=[C:34]([NH2:36])[C:33]([N+:37]([O-:39])=[O:38])=[CH:32][CH:31]=3)[CH2:9]2)[N:18]2[CH2:19][CH2:20][CH2:21][C:17]=12
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: c1nc(C2CCCNC2)n2c1CCC2
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2CCCC(c3ncc4n3CCC4)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 3-(piperidin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole trifluoroacetate salt (94 mg) in anhydrous acetonitrile (1.1 mL) at 10° C. was added triethylamine (130 μL, 0.93 mmol). Then 6-chloro-3-nitropyridin-2-amine (39 mg, 0.2 mmol) was added. The reaction mixture was shaken at 80° C. for 2 h and then for 18 h at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (3 mL). The mixture was washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-10% methanol in dichloromethane) to afford 6-(3-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)piperidin-1-yl)-3-nitropyridin-2-amine as a yellow oil (60 mg, 82%). MS (ES+) (M+H) 329.2; LCMS retention time: 1.61 minutes (Method L).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:17]>Cl.C(O)C>[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:17]=[CH:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: CN(N)c1ccccc1
Reactant: COc1ccc2ccccc2c1C=O
Agent: Cl
Solvent: CCO
Product: COc1ccc2ccccc2c1C=NN(C)c1ccccc1

Procedure:
3.7 g of 2-methoxy-1-naphthaldehyde and 4.9 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude 2-methoxy-1-naphthaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 3.7 g (63.8%) of light yellow scalelike crystals which melt at 90.5°-91.5° C.