Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH3:32])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH3:32])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3CCOCC3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3CCOCC3)CS[C@H]12)c1csc(N)n1
Yield: 51 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydropyran-4-yl)methylthio-3-cephem-4-carboxylate (200 mg) as prepared in Example 31(b) was reacted with iodomethyl pivalate (181 mg) similarly to Example 28 for the esterification reaction. The resulting reaction solution was post-treated and the produced compound was recovered and purified similarly to Example 28 to give the titled compound (120 mg; 51%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:33])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C>[CH3:7][O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:33])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:30][CH:31]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Yield: 60 %

Procedure:
Potassium carbonate (162 mg) was added to 221 mg of 2-(2-(4-(4-hydroxyphenyloxy)phenyl)acetylamino)benzoic acid methyl ester obtained by the Reference Example 24, the mixture was suspended in dried DMF (5 ml), t-butyl bromoacetate (130 μl) was added little by little to the suspension at room temperature, and the mixture was stirred as it is over a night at room temperature. After completing the reaction, DMF was distilled out under reduced pressure and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of potassium bisulfate and dried with anhydrous magnesium sulfate. After removing the solvent by distillation, the residue was purified by silica gel column chromatography (developing liquid: hexane:ethyl acetate 4:1 to 1:1) to obtain 174 mg of the subject compound. The 1H-NMR of the compound was consistent with the above structure.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH:33]([CH3:35])[CH3:34])[CH:26]=[CH:25][C:24]=1[OH:36].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:36][C:24]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][O:32][CH:33]([CH3:34])[CH3:35])=[CH:28][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CC(C)OCCOc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Oc2ccc(OCCOC(C)C)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 118.2 %

Procedure:
Mixture of 4-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (147 mg, 0.47 mmole), 2-fluoro-4-(2-isopropoxy-ethoxy)-phenol (0.47 mmole, 1 eq) and K2CO3 (0.75 mmole, 1.5 eq) in 2 mL DMSO was heated under microwave irradiation at 150° C. for 40 minutes. Mixture was purified by HPLC to give compound C184 as a yellow oil (273 mg, 96%). 1H NMR (DMSO-d6, 400 MHz) δ 1.23 (d, 6H), 1.27 (d, 6H), 1.79-1.86 (m, 2H), 1.97-2.04 (m, 1H), 2.20 (s, 3H), 3.43-3.50 (m, 2H), 3.73-3.79 (m, 3H), 3.82 (t, 2H), 4.09 (t, 2H), 4.95 (sep, 1H), 5.33-5.36 (m, 1H), 6.70-6.78 (m, 2H), 7.08 (t, 1H), 8.27 (s, 1H). Exact mass calculated for C25H34FN3O6 491.2, found 492.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].C(=O)([O-])[O-].[K+].[K+].CI.C1(C)C=CC=CC=1>O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1CO
Reaction time: 16 h

Procedure:
To a solution of 2,6-dimethylbenzoic acid (10 g, 66.5 mmol) and potassium carbonate (9.18 g, 66.5 mmol) in dimethylfonnamide (67 ml), was added methyl iodide (8.28 ml, 133.16 mmol) in an ice bath, and the mixture was stirred for 16 hours. To the reaction mixture was added toluene and water, and the organic layer was washed with 3% K2CO3, 1N HCl, and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The oily residue was redissolved in dry THF (135 ml), added to LiAIH4 (3.7 g, 99.8 mmol), and stirred for 4 hours in an ice bath. To the reaction mixture was added 1N HCl slowly followed by ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The oily residue was used without further purification.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(Br)(=O)C.[CH3:8][N:9]([C:13]([NH2:15])=[NH:14])[CH2:10][CH2:11][OH:12].[C:16](O)(=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[C:16]([O:12][CH2:11][CH2:10][N:9]([CH3:8])[C:13]([NH2:15])=[NH:14])(=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN(CCO)C(=N)N
Reactant: CCCCCCCCCC(=O)O
Agent: CC(=O)Br
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OCCN(C)C(=N)N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 10.60 mL (125 mmol) of acetyl bromide and 25 mL of dry DCM. The flask is charged with 35.14 g (300 mmol) of Creatinol and 150 mL of dry DCM, and cooled with an ice-water bath to about 0° C., under a nitrogen atmosphere. The acetyl bromide solution is then added slowly with stirring, over a period of 10 minutes, to the Creatinol solution. The solution is stirred for another 15 minutes, after which 9.64 mL (50 mmol) of Decanoic acid is added in one portion and the reaction is slowly heated to about 65° C. for about 6 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 1/5) to yield pure 2-(1-methylguanidino)ethyl decanoate.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:23](=[O:30])[NH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: BrCCc1ccccc1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CCc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from 2-bromoethylbenzene and compound 1 as described for compound 78. Purified by chromatography [ethyl acetate: petroleum ether (60°-80° C.)/1:3]. Crystallized from methanol. M.p. 99°-100° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[Br:33]N1C(=O)CCC1=O>C(#N)C>[Br:33][C:14]1[N:13]=[C:12]([C:15]([NH2:17])=[O:16])[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=2)=[N:10][C:9]=1[NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)cnc2C(N)=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Br)nc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL), N-bromosuccinimide (69 mg) was added and stirred at room temperature for 2 hours. To the reaction liquid, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol=10:0:0 to 10:1). The resulting crude product was solidified with ethyl acetate and washed with ethyl acetate to give 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (130 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>COC(C)(C)C>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:9]
Reactant: Cc1ccccc1OCc1ccccc1C(=O)Cl
Reactant: C1CCNC1
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Yield: 84.6 %

Procedure:
At 20 to 30° C., 15.6 g (0.06 mol) of 2-(2-methylphenoxymethyl)benzoyl chloride (EP-A 493 711, page 22) are added dropwise to a solution of 8.53 g (0.12 mol) of pyrrolidine in 40 ml of t-butyl methyl ether. The mixture is admixed with water and the organic phase is separated off, dried over sodium sulphate and concentrated under reduced pressure. The residue crystallizes when stirred with diisopropyl ether. 15 g (84.6% of theory) of N-[2-(2-methylphenoxymethyl)-benzoyl]-pyrrolidine are obtained.
Reaction SMILES: C(C1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[C:5]([F:16])[CH:4]=1)#N.C1COCC1.CO.[OH-].[Na+].CC[O:28][C:29]([CH3:31])=[O:30]>>[CH2:12]([N:9]([CH2:10][CH3:11])[C:7]([C:6]1[CH:14]=[CH:15][C:31]([C:29]([OH:28])=[O:30])=[CH:4][C:5]=1[F:16])=[O:8])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=O)c1ccc(C#N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(=O)O)cc1F
Temperature: 65 °C
Yield: 66 %

Procedure:
To 4-cyano-2-fluoro-benzoic acid (2.0 g, 12.1 mmol) in DMF (18 mL) at room temperature was added N-ethylethanamine (1.5 g, 2.1 mL, 13.3 mmol) followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.6 g, 12.1 mmol) and diisopropylethylamine (3.9 g, 5.3 mL, 30.3 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with EtOAc and washed with brine solution. The organics were separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc-DCM (10-100%) as eluent to give 4-cyano-N,N-diethyl-2-fluoro-benzamide (2.0 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=7.8, 1.3 Hz, 1H), 7.47-7.37 (m, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.16 (q, J=7.1 Hz, 2H), 1.24 (td, J=7.1, 2.0 Hz, 4H). To 4-cyano-N,N-diethyl-2-fluoro-benzamide (1.75 g, 7.9 mmol) was added a 2:1 mixture of THF:MeOH (15 mL), followed by 4 N NaOH solution (10 mL, 39.6 mmol) and the reaction mixture was heated at 65° C. for 2.5 hours. The reaction mixture was cooled, diluted with EtOAc and washed with 2 M HCl solution. The organics were separated, dried and concentrated in vacuo to give 4-(diethylcarbamoyl)-3-fluoro-benzoic acid (1.91 g, 66%) as a solid. ESI-MS m/z calc. 239.24. Found 240.2 (M+1); Retention time: 0.99 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:12][C:11]1[C:4]2[N:3]=[C:2]([O:27][C:20]3[C:21]([CH3:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=3[Cl:18])[N:6]([CH3:7])[C:5]=2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(C)c12
Reactant: Cc1cc(Cl)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 100 °C
Yield: 63.7 %

Procedure:
A solution of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (5.5 g, 20.2 mmol), 2,4-dichloro-6-methylphenol (10 g, 56.5 mmol) and potassium carbonate (8.4 g, 60.8 mmol) in N,N-dimethylformamide (55 mL) was heated at 100° C. for 9 h. To the mixture was added 2,4-dichloro-6-methylphenol (5 g, 28.3 mmol) and potassium carbonate (4.2 g, 30.4 mmol) and heated at 100° C. for 16 h. Additional 2,4-dichloro-6-methylphenol (5 g, 28.3 mmol) and potassium carbonate (4.2 g, 30.4 mmol) were added and heated at 100° C. for 9 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH silica gel eluting with a 12.5% ethyl acetate/n-hexane. The resulting solids were recrystallized from a 10% ethyl acetate/n-hexane to give 5.3 g (64%) of the title compound as a colorless crystal.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:16]=1)=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCc1cc(-c2cc(C(=O)O)ccn2)c(C)[nH]c1=O
Product: CCCCNC(=O)c1ccnc(-c2cc(CC)c(=O)[nH]c2C)c1

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-4-carboxylic acid and n-butyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])(=O)=O.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:6][CH2:7][N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:17])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)OCCn1c(=O)[nH]c2ccccc21
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 5.6 parts of 2-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl methanesulfonate, 4.9 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 8 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 7 hours with water-separator. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 4.3 parts of 1-{2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 163.6° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.O.[Pd]>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(NCCCN2CCOCC2)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1cccc(NCCCN2CCOCC2)c1
Reaction time: 12 h
Yield: 90.8 %

Procedure:
40 g N-3-(morpholin4-yl)propyl-3-nitroaniline was dissolved in 450 ml ethanol and 50 ml water, and 0.5 Pd/C (5%) was added. After purging with nitrogen, hydrogenation was performed for 12 h at 50° C. under 50 bar of hydrogen pressure. After cooling, nitrogen purging was repeated, the catalyst was filtered off, and the filtrate was reduced in a rotary evaporator. 32.2 g of pasty black oil was obtained; this was distilled in a ball tube (220–232° C., 0.06–0.08 mbar). The product obtained was a crystalline orange material.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:48][CH2:47][CH2:46][CH2:45][CH2:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCCCCc1ccccc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCCCc4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 61 %

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-phenylbutylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound (61% yield) as a yellow powder, m.p. 154-159° C. MS [(+)ESI, m/z]: 584 [M+H]+
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:25][CH2:26][OH:27])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O[N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C:30]1=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]([CH2:25][CH2:26][OH:27])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([O:20][N:29]2[C:33](=[O:34])[CH2:32][CH2:31][C:30]2=[O:35])=[O:19])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: Cn1c(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)ccc(C(=O)O)c1=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)ccc(C(=O)ON2C(=O)CCC2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of 4.43 g. of 6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinic acid and 1.34 g. of N-hydroxysuccinimide in 60 ml. dimethylformamide was cooled in ice and treated dropwise with a solution of 2.56 g. of N,N'-dicyclohexylcarbodiimide in 5 ml. dimethylformamide. The solution was allowed to warm to room temperature over 16 hours. The mixture was cooled and the N,N'-dicyclohexylurea filtered off. Addition of 180 ml. of isopropanol to the filtrate precipitated the 6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester, which was collected by filtration.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=3[O:20][N:19]=2)=[CH:14][C:13]=1[O:28][CH3:29]>C1COCC1>[CH3:29][O:28][C:13]1[CH:14]=[C:15]([C:18]2[C:22]3[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=3[O:20][N:19]=2)[CH:16]=[CH:17][C:12]=1[NH:11][CH:1]=[O:3]
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-c2noc3c2CCCC3=O)ccc1NC=O
Reaction time: 1 h

Procedure:
To formic acid (6.24 g, 135.6 mmol) was added dropwise 3.96 g (38.8 mmol) of acetic anhydride (exothermic, cooling with tap water was used). The reaction mixture was stirred for 1 hr. The resulting mixture was transferred via cannula into another reaction flask containing a solution of 3-(4-amino-3-methoxyphenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one in 50 ml of THF (Cooling with tap water was used). The mixture was stirred for 2 hr, extracted with DCM, washed with water and brine, dried over sodium sulfate and concentrated to furnish 2.65 g of the title compound, MS(M+H)+=287.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>O>[CH2:32]([O:31][C:29]([N:4]([CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:17]=[CH:18][CH:19]=[CH:20]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2][OH:1])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(CNCCO)cc(-n2cccc2)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CN(CCO)C(=O)OCc2ccccc2)cc(-n2cccc2)c1
Reaction time: 2 h

Procedure:
To a mixture of methyl 3-(2-hydroxyethylaminomethyl)-5-(pyrrol-1-yl)benzoate (0.8 g) and triethylamine (0.48 ml) was added benzyl chloroformate (0.46 ml) under ice cooling. After stirring for 2 hours under ice cooling, the reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with the mixture of chloroform and methanol (15:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-[N-benzyloxycarbonyl-N-(2-hydroxyethyl)aminomethyl]-5-(pyrrol-1-yl)benzoate (1.11 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:14][C:15]([CH2:17][CH2:18][CH3:19])=[CH:16][C:3]1=2.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:17]([C:15]1[S:14][C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([C:12]4[NH:22][N:21]=[N:20][N:13]=4)=[CH:8][N:7]3[C:2](=[O:1])[C:3]=2[CH:16]=1)[CH2:18][CH3:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1

Procedure:
From 0.85 g (0.0032 mol) of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile, (Example 29), 0.68 g (0.011 mol) of sodium azide and 0.62 g (0.012 mol) of ammonium chloride in 80 ml of dimethylformamide, following the procedure of Example 34, there is obtained 0.46 g of 2-propyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 288°-292° C. (dec) after recrystallization from pyridine.