Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23]2)=[CH:20][CH:21]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[ClH:1].[ClH:30].[ClH:1].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[CH:20][CH:21]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC(N(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC(N(C)C)C2)nc1
Product: Cl
Yield: 201.3 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{6-[3-(dimethylamino)pyrrolidin-1-yl]pyridin-3-ylamino}-1,5-naphthyridin-3-yl)ethanone (55 mg, 0.134 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.20 mmol) followed by formation of the trihydrochloride salt to afford the desired product (85 mg, 99%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.41 (s, 1H), 8.54-8.37 (m, 2H), 8.29 (d, J=2.3 Hz, 1H), 7.99 (dd, J=9.5, 2.3 Hz, 1H), 7.39-7.35 (m, 2H), 7.10 (d, J=9.5 Hz, 1H), 4.29-4.11 (m, 2H), 4.03-3.85 (m, 2H), 3.75-3.71 (m, 1H), 3.03 (s, 6H), 2.85 (s, 3H), 2.71-2.82 (s, 1H); ESI MS m/z 521 [M+H]+; HPLC>99% (AUC), tR=8.90 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH2:30].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH:29]([NH:30][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:23])([F:22])[F:24])[CH:4]=1)[C:28]([O:27][CH3:26])=[O:36]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1](=[O:21])([O:17][CH:18](Cl)[CH3:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([O:13][N+:14]([O-:16])=[O:15])[CH2:8][O:9][N+:10]([O-:12])=[O:11].[CH2:22]([C:26]1[N:27]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:28]([C:32]([OH:34])=[O:33])=[C:29]([Cl:31])[N:30]=1)[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:22]([C:26]1[N:27]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[NH:52][N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:28]([C:32]([O:34][CH:18]([O:17][C:1]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([O:13][N+:14]([O-:16])=[O:15])[CH2:8][O:9][N+:10]([O-:12])=[O:11])=[O:21])[CH3:19])=[O:33])=[C:29]([Cl:31])[N:30]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(5R)-5,6-bis(nitrooxy)hexyl 1-chloroethyl carbonate (7.67 g, 23.2 mmol) was added to a stirred solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (6.30 g, 9.3 mmol) and Cs2CO3 (3.02 g, 9.3 mmol) in DMF (186 mL). The solution was stirred at 70° C. for 2 h. Water (50 mL) was added and the solution was extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was redissolved in MeOH (186 mL). After stirring at 70° C. for 2 h, the solution was concentrated in vacuo. The residue was purified by HPLC chromatography (50×100 mm C-18) eluting with 40-100% MeCN/water+0.05% TFA. The diastereomers were then separated by HPLC chromatography on silica gel (ChiralPak AD-H) eluting with 20% MeOH in supercritical CO2 to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.06 (d, J=7.5 Hz, 1H), 7.62 (td, J=7.5, 1.0 Hz, 1H), 7.56 (td, J=6.5, 1.0 Hz, 1H), 7.44 (d, J=6.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 6.87 (q, J=5.5 Hz, 1H), 5.54 (d, J=6.0 Hz, 2H), 5.24 (ddd, J=13.0, 6.2, 3.0 Hz, 1H), 4.73 (dq, J=12.5, 1.5 Hz, 1H), 4.46 (dd, J=13.0, 6.5 Hz, 1H), 4.14-4.04 (m, 1H), 2.76 (t, J=7.7 Hz, 2H), 1.76-1.59 (m, 6H), 1.61 (d, J=5.5 Hz, 3H) 1.55-1.40 (m, 2H), 1.38 (hex, J=7.5 Hz, 2H), 0.90 (t, J=7.5 Hz, 3H); LCMS (M+H) found 731.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37]>C(#N)C>[CH3:34][C:35]([CH3:40])([CH3:39])[C:36]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH2:19]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])=[O:37]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)C(C)(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 41.9 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (180 mg, 0.4 mmol) in acetonitrile (2 mL) was added 2,2-dimethyl-propionyl chloride (0.064 mL, 0.5 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (15 mL) and sodium hydrogen carbonate (15 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-(2,2-dimethyl-propionyloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (90 mg, 42% yield): mp, 146-148° C.; 1H NMR (DMSO-d6) δ 0.87-0.89 (m, 4H, 2CH2), 1.19 (s, 9H, 3CH3), 1.30 (t, J=7 Hz, 3H, CH3), 1.76-1.82 (m, 1H, CH), 3.04 (d, J=8 Hz, 2H, CH2), 3.73 (s, 3H, CH3), 3.97-4.05 (m, 2H, CH2), 4.19 (d, J=18 Hz, 1H, NCHH), 4.58 (d, J=18 Hz, 1H, NCHH), 5.66 (t, J=8 Hz, H, NCH), 6.87-6.94 (m, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.50 (d, J=8 Hz, 1H, Ar), 8.23(d, J=8 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.82 (s, 1H, NH); 13CNMR (DMSO-d6) δ 7.77, 14.69, 15.46, 26.71, 34.63, 37.63, 46.61, 51.03, 55.46, 63.78, 111.91, 112.07, 116.82, 117.32, 117.51, 119.24, 131.24, 132.76, 136.96, 142.24, 147.92, 148.55, 166.66, 168.00, 171.71, 175.41; Anal Calcd for C29H35N3O7: C, 64.79; H, 6.56; N, 7.82. Found: C, 64.91; H, 6.50; N, 7.84.
Reaction SMILES: Cl.[F:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN1CCCC1=O>[ClH:13].[F:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1c(F)ccc2c1NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCc4ccc(F)c(C)c43)c2cc1OC
Yield: 58 %

Procedure:
Utilizing a procedure analogous to that described in Example 47 (with conversion to the HCl salt analogous to Example 2), this product was prepared in 58% yield from 6-fluoro-7-methyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 220°-225° C.; LC-MS: 340 (MH+); anal. RP18-HPLC RT: 4.63 min.).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10](O)(=[O:22])[C:11]1[CH:21]=[C:18]([O:19][CH3:20])[C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:10]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:22])[C:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:16]([OH:17])=[C:18]([O:19][CH3:20])[CH:21]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: CCCCC(CC)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)c1cc(OC)c(O)c(OC)c1

Procedure:
To 13.2 g (0.1 mol) 2-ethyl-1-hexanol in a flask equipped with reflux condenser connected to a Dean-Stark trap was added 9.9 g (0.05 mol) syringic acid, 0.2 g p-toluenesulfonic acid and 75 ml toluene. The mixture was refluxed for 20 h. Excess alcohol and toluene were distilled off under slight vacuum. The dark liquid residue was diluted with CH2Cl2 and extracted with 2% NaHCO3 +15% aqueous NaCl followed by neutral 15% aqueous NaCl solution. The organic layer was dried with anhydrous Na2SO4 and distilled. After removal of all unreacted 2-ethylhexanol the product distilled over as a viscous, colorless liquid, b.p. 204°-209° C./4×102Pa, which crystallized on standing at room temperature to a fine white solid, mp 35°-36° C. Yield: 10.1 g, 65%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[NH:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=O)[C:12]1=[O:13].[OH-:22].[K+]>C(O)C>[CH3:3][C:2]1[C:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:11][C:21]2[C:16]([C:14]=1[C:12]([OH:22])=[O:13])=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: [OH-]
Reactant: CCC(=O)c1ccccc1
Agent: [K+]
Solvent: CCO
Product: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Temperature: 80 °C
Reaction time: 40 h

Procedure:
3-Methyl-2-phenylquinoline-4-carboxylic acid was prepared by a Pfitzinger reaction (J. Org. Chem. 1950, 15:511–516). Propiophenone (3.3 mL, 1.2 equiv.) was added to a solution of isatin (3.00 g, 20.0 mmol) in ethanol (95%, 30 mL), followed by the addition of KOH pellets (86%, 3.91 g, 3 equiv.). The light brown mixture was stirred at 80° C. (oil bath temperature) for 40 hours. Solvent was removed in vacuo and the resulting solid residue was dissolved in water (50 mL), extracted with ether (30 mL×2) to remove any un-reacted starting materials. The aqueous layer was then cooled with an ice bath and acidified with concentrated aqueous HCl until pH˜3. The white precipitate was collected by suction filtration, washed with water and dried in a vacuum oven (30° C.) overnight. The white solid was essentially pure carboxylic acid (5.10 g, 97% yield) and was used for the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 7.50–8.08 (m, 9H), 2.46 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])[P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C.C1COCC1>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:3]([P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])[P:10](=[O:15])([O:11][CH3:12])[O:13][CH3:14])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COP(=O)(OC)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 30 %

Procedure:
Sodium hydride (1.02 g, 25.4 mmol) was added in portions to a stirring solution of tetramethyl methylenebisphosphonate in DMF (40 mL). After 30 min a solution of 4-nitrobenzylbromide (5.00 g, 23.1 mmol) in THF (5 mL) was added and the resulting mixture was stirred at room temperature for 4.5 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl (20 mL). After the addition of water (100 mL) the product was extracted with EtOAc and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated at reduced pressure. The crude product was purified by silica gel chromatography (0% to 10% MeOH in EtOAc) resulting in 12 as a colorless solid (2.55 g, 30%). 1H NMR (400 MHz, CDCl3) δ 2.65 (tt, J=6.5, 23.8, 1H), 3.31 (dt, J=6.5, 16.5, 2H), 3.73 (d, J=7.0, 6H), 3.75 (d, J=7.0, 6H), 7.42 (d, J=8.9, 2H), 8.15 (d, J=8.9, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][S:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C)C=O>[F:38][CH:36]([F:37])[O:35][C:32]1[CH:33]=[CH:34][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:17][C:14]3[CH:13]=[CH:12][C:11]([CH2:10][S:8]([CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[O:9])=[CH:16][CH:15]=3)[N:23]=2)=[CH:30][CH:31]=1
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Reactant: FC(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(OC(F)F)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A solution of 126 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfinylmethyl)-phenol in 4 ml N,N-dimethylformamide was treated at 0° C. with 14 mg (0.55 mmol) sodium hydride and stirred at that temperature for 30 min, then 143 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-difluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued over night at room temperature. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, and purified on silica. Elution with ethyl acetate/methanol (0 to 20%) yielded 123 mg (33%) 1-[2-(4-{2-[2-(E)-(4-difluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl-methanesulfinyl)-ethyl]-1H-[1,2,3]triazole as beige solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[CH2:9]([O:11][C:12](=[O:24])[C:13]1[C:18](F)=[CH:17][CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:14]=1[NH2:23])[CH3:10].Cl>C1COCC1>[CH2:9]([O:11][C:12](=[O:24])[C:13]1[C:18]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[CH:17][CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:14]=1[NH2:23])[CH3:10]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1c(F)ccc([N+](=O)[O-])c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCC(F)(F)F)ccc([N+](=O)[O-])c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
420 mg NaH (60% suspension in oil) were added to a solution of 2.16 mL (29.8 mmol) 2,2,2-trifluoro-ethanol in 5 mL THF. When the gas evolution ceased, 1.0 g (4.38 mmol) 2-Amino-6-fluoro-3-nitro-benzoic acid ethyl ester was added. The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for further 30 minutes. To this mixture were added 2 mL of a 6 M aqueous HCl-solution, and most of the solvent was removed under reduced pressure. The residue was mixed with 20 mL water and the resulting solid was collected and washed with water and then hexane. The obtained yellow crystalline material was dried under reduced pressure at 35° C. Yield: 1.22 g.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]([CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)[CH3:9])[C:5]([OH:7])=[O:6].CI.Cl.[N+](=[CH2:24])=[N-]>O1CCCC1>[O:3]=[C:4]([C:8]([CH3:24])([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)[CH3:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C(=O)C(=O)O)c1ccc(C(=O)O)cc1
Reactant: C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C(=O)C(=O)O)c1ccc(C(=O)O)cc1
Yield: 34 %

Procedure:
A 2N aqueous solution (30 ml) of sodium hydroxide and 50 ml of tetrahydrofuran were added to 2.22 g (10 mmoles) of 2-oxo-3-(p-carboxyphenyl)butanoic acid, and the mixture was stirred until a completely uniform solution formed. Then, 1.5 ml (24 mmoles) of methyl iodide was added, and the mixture reacted at room temperature for 24 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ether. The ether layer was dried. The drying reagent was separated by filtration, and the solvent was evaporated. The NMR spectral analysis of the resulting oily product led to the determination that the desired 2-oxo-3-methyl-3-phenylbutanoic acid formed in a yield of 80 %. This product was converted to a methyl ester by using diazomethane, and isolated and purified by silica gel column chromatography (ethyl acetate:hexane=1:10). Then a 1N aqueous solution of sodium hydroxide was added and the ester was hydrolyzed. The hydrolyzate was acidified with 1N hydrochloric acid and extracted with ether. After drying, the solvent was evaporated to give 0.80 g (3.4 mmoles) of 2-oxo-3-methyl-3-(p-carboxyphenyl)butanoic acid as a white solid in a yield of 34 %.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-ethylthio-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH2:10][C:9](=[O:11])[C:8]([OH:12])=[CH:7][N:6]=1)[CH3:3].C(C(CCCC)C([O-])=O)C.[Na+].[CH:24]([NH:26][C@@H:27]1[C:39](=[O:40])[N:29]2[C:30]([C:36]([OH:38])=[O:37])=[C:31]([CH2:34]Cl)[CH2:32][S:33][C@H:28]12)=[O:25].C(OC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:24]([NH:26][C@@H:27]1[C:39](=[O:40])[N:29]2[C:30]([C:36]([O-:38])=[O:37])=[C:31]([CH2:34][N+:2]([CH3:3])([CH3:1])[CH2:4][C:5]3[NH:6][CH:7]=[C:8]([OH:12])[C:9](=[O:11])[CH:10]=3)[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: CN(C)CC1=NC=C(O)C(=O)C1
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC=O)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Reaction time: 2 h
Yield: 43.2 %

Procedure:
2-(N, N-Dimethylamino) methyl-5-hydroxy-4-pyridone (15.85 g) was dissolved in N,N-dimethylformamide (238 ml) by addition of sodium 2-ethylhexanoate (10.44 g) . To the resulting solution was added dropwise a cooled solution of 7β-formamido-3-chloromethyl-3-cephem-4carboxylic acid (13.04 g) at 5° C. and the mixture was stirred for 2 hours at the same temperature. The mixture was added dropwise to a mixture of ethyl acetate (2.5 l) and diisopropyl ether (2.5 l) and the resulting precipitates were collected by filtration, washed three times with a mixture of ethyl acetate and diisopropyl ether (1:1) and dried in vacuo. The powder was poured into cold water (300 ml) and the mixture was adjusted to pH 3.0 with 1N hydrochloric acid. After the insoluble materials were filtered off, the filtrate was chromatographed on Diaion HP-20 (1300 ml) at 50° C. and the elution was carried out with 10% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-formamido-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo- 1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4carboxylate (8.31 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Cl:9][C:10]1[C:11]([N:15]=[C:16]=[S:17])=[CH:12][S:13][CH:14]=1>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:16]([NH:15][C:11]1[C:10]([Cl:9])=[CH:14][S:13][CH:12]=1)=[S:17]
Reactant: Nc1ccccc1N
Reactant: S=C=Nc1cscc1Cl
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=S)Nc1cscc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.86 g of 1,2-diaminobenzene (o-phenylenediamine) is added to a solution of 1.4 g of 4-chloro-3-thienyl isothiocyanate in 40 ml of anhydrous THF, the mixture is stirred at room temperature for about 20 hours and the solvent is distilled off under reduced pressure. The residue is treated with water and extracted with ethyl acetate, the solvent is distilled off again and the residue is purified using medium-pressure silica gel column chromatography using a 1:1 mixture of ethyl acetate and toluene. Brown-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.Cl[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13].[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([O:30][CH3:31])=[O:29].[Cl-].[Al+3].[Cl-].[Cl-]>C[N+]([O-])=O.ClCCl.O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:16]([NH:15][S:12]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]([CH3:18])[C:20]=2[C:28]([O:30][CH3:31])=[O:29])(=[O:14])=[O:13])=[O:17])[N:7]=1
Reactant: COC(=O)c1cc2ccccc2n1C
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(S(=O)(=O)NC(=O)Nc2nc(C)cc(OC)n2)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
To a stirred suspension of 2.92 g (0.021 mole) of 2-amino-4-methoxy-6-methylpyrimidine in 75 ml dry CH3NO2 at -10° was added dropwise under nitrogen via syringe 2.0 ml (0.023 mole) of chlorosulfonyl isocyanate at such a rate as to maintain the temperature below 0°. The resulting clear solution was stirred 0.5 hour at -5° to -10° and then contacted dropwise with a solution of 3.97 g (0.021 mole) of methyl 1-methyl-1H-indole-2-carboxylate dissolved in 25 ml of dry nitromethane. Upon completion of the addition, 2.95 g (0.022 mole) of aluminum (III) chloride was added in one portion. The reaction mixture was stirred at reflux for 3 hours, then cooled to room temperature and poured into 300 ml H2O. Dichloromethane was added and the layers were separated. The aqueous solution was extracted with two additional portions of CH4Cl2 and the combined organic solutions washed with H2O, dried over MgSO4 and evaporated in vacuo. Chromatography on silica gel with 5% acetone in CH2Cl2 afforded 1.63 g of the desired product as a white solid, m.p. 200°-203° (d). The infrared spectrum of the product included absorptions at 3190 (NH), 1715 (C=O), 1703 (C=O), 1340 and 1150 (SO2) cm-1, 'H NMR (CDCl3 /DMSO-d6) δ2.45 (s, 3H, pyrimidine CH3), 3.95 (s, 3H, OCH3), 4.0 (s, 6H, OCH3N--CH3), 6.37 (s, 1H, pyrimidine CH), 7.23-7.56 (m, 3H, indole CH), 8.18-8.47 (m, 1H, indole CH), 9.50 (s, 1H, NH), 13.08 (br s, 1H, NH). Mass spectral analysis showed m/e 139, ##STR31##