Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.S1(CCCC1)(=O)=O.B(OC)(OC)OC.C[C:21]([O:23][CH2:24][C:25]1[CH2:34][S:33][C@@H:28]2[C@H:29]([NH2:32])[C:30](=[O:31])[N:27]2[C:26]=1[C:35]([OH:37])=[O:36])=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.N>>[NH2:32][CH:29]1[C:30](=[O:31])[N:27]2[C:26]([C:35]([OH:37])=[O:36])=[C:25]([CH2:24][O:23][CH3:21])[CH2:34][S:33][C@H:28]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: N
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 19.5 %

Procedure:
4.1 ml of concentrated sulfuric acid was added to 80 me of sulfolane and the resulting mixture was cooled to about 0° C. 8.2 ml of trimethyl borate was added dropwise thereto and 10 g of 7-aminocephalosporanic acid was added thereto in small portions. 8.4 ml of antimony pentachloride was added dropwise thereto at about 0° C., stirred at 0 ° C. for additional 6 hours, and then, the resulting mixture was added to ice-water. The pH of the mixture was adjusted to 3.4 with aqueous ammonia. The ocherous solid formed was isolated by filtration and washed with water. The wet solid was dispersed in water and the pH of the resulting mixture was adjusted to 8 with aqueous ammonia to dissolve the solid in water, and then, the pH of the resulting mixture was adjusted to 3.5 with 3N hydrochloric acid. The resulting mixture was filtered to obtain crystals which were washed with water, and then, dried overnight in a vacuum to give 1.75 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid as an ocherous solid (Yield: 20% and Purity: 94.3%). H-NMR data was equal to that of the compound prepared in Example 1.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:29])=[N:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(F)cc2)cc1C(Nc1ccc(C(=O)O)nc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(F)cc3)oc2C)C2CCCCC2)cn1
Yield: 29.7 %

Procedure:
A solution of 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid (694 mg), ethyl 3-(methylamino)propanoate (223 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), hydroxybenzotriazole monohydrate (260 mg) and triethylamine (237 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give ethyl 3-[{[5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (263 mg) as an amorphous compound. Ethyl 3-[{[5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (246 mg, 30%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[N:8]1([C:6]2[N:7]=[C:2]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(=O)N1CCc2c(Cl)nc(N3CCOCC3)nc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(-c3ccncc3)nc(N3CCOCC3)nc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 112.9 %

Procedure:
1-(4-Chloro-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-ethanone (J-01-D, 217 mg), 4-(4,4,5,5-tetramethyl-[1,3]dioxaborolan-2-yl)-pyridine (189 mg), palladium acetate (8.6 mg), S-Phos (32 mg) and potassium phosphate (326 mg) were suspended in DMF (7.6 ml), followed by stirring at 100° C. for 3 hours. To the reaction mixture, water (50 ml) was added, followed by extraction five times with ethyl acetate/THF (40 ml/10 ml). The combined extracts were washed with saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/0 to 50/1), to obtain the desired compound (D-323) as a pale yellow powder (282 mg, 100%).
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.CC1C=C(N2CCN(C)CC2)C=CC=1N.CN1CCNCC1.CC1C=CC(N2CCOCC2)=CC=1N.[CH3:77][C:78]1[CH:83]=[C:82]([N:84]2[CH2:89][CH2:88][N:87]([CH3:90])[CH2:86][CH2:85]2)[CH:81]=[CH:80][C:79]=1[NH:91][C:92]([N:94]1[C:98]2[N:99]=[C:100]([N:128]3[CH2:133][CH2:132][O:131][CH2:130][CH2:129]3)[N:101]=[C:102]([C:103]3[CH:104]=[N:105][C:106]([N:109](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[N:107][CH:108]=3)[C:97]=2[CH2:96][CH2:95]1)=[O:93]>>[CH3:77][C:78]1[CH:83]=[C:82]([N:84]2[CH2:89][CH2:88][N:87]([CH3:90])[CH2:86][CH2:85]2)[CH:81]=[CH:80][C:79]=1[NH:91][C:92]([N:94]1[C:98]2[N:99]=[C:100]([N:128]3[CH2:133][CH2:132][O:131][CH2:130][CH2:129]3)[N:101]=[C:102]([C:103]3[CH:104]=[N:105][C:106]([NH2:109])=[N:107][CH:108]=3)[C:97]=2[CH2:96][CH2:95]1)=[O:93]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccc(N4CCN(C)CC4)cc3C)cn2)cc1
Agent: CN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: Cc1cc(N2CCN(C)CC2)ccc1N
Product: Cc1cc(N2CCN(C)CC2)ccc1NC(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Yield: 75 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg), and 2-methyl-4-(4-methyl-piperazin-1-yl)-phenylamine (63 mg) obtained using 1-methyl-piperazine instead of morpholine in the same manner as Step A and Step B in Example 1-D-240, instead of 2-methyl-5-morpholin-4-yl-phenylamine, in the same manner as Step C in Example 1-D-237, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [2-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 2, to obtain the desired compound (D-241) (110 mg, 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[C:7]=1[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:7]1[N:6]2[C:9]([CH:12]=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=[CH:3][C:2]=1[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(Br)ccc2ncc(C=O)n12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccnc2)ccc2ncc(C=O)n12
Yield: 40 %

Procedure:
6-bromo-5-methylimidazo[1,2-a]pyridine-3-carbaldehyde (125 mg, 0.523 mmol), Pyridine-3-boronic acid (77.5 mg, 0.603 mmol), dichlorobis(triphenylphosphine) palladium (II) (36.7 mg, 0.05 mmol) and 2M aqueous Na2CO3 (2 ml) were dissolved in DMF (3 ml) and refluxed for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to obtain the title compound. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): 69.90(s, 1H), 8.39 (s, 1H), 7.73 (d, 1H, J=9.6 Hz), 7.56 (d, 1H, J=9.3 Hz), 3.11 (s, 3H); MS: m/z 238 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:4]2([CH:8]=[CH:7][CH:6]=[CH:5]2)[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[H][H]>C(O)C>[CH3:1][C:2]1([CH3:14])[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [H][H]
Reactant: CCOC(=O)C1C(C)(C)C12C=CC=C2
Solvent: CCO
Product: CCOC(=O)C1C(C)(C)C12CCCC2

Procedure:
A solution of 1.54 g. of ethyl 2,2-dimethylspiro[2.4]hepta-4,6-diene-1 carboxylate prepared in Example I, above, in 30 ml. of ethanol was catalytically reduced over 50 mg. of pre-reduced platinum oxide. The theoretical amount of hydrogen was taken up over a 3 hr. period. The catalyst was removed by filtration and the alcohol was removed at reduced pressure. The residue, 1.5 g. (100%) could be used directly without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:20]/[C:21](/[CH3:28])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)CCC>[CH3:28][C:21]1[NH:20][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Solvent: CCCCO
Product: CCOC(=O)C1=C(C)NC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
A mixture of 3-(3-nitrophenyl)-1-phenyl-2-propen1-one (2 g), ethyl 3-aminocrotonate (1.2 g) and n-butanol (20 ml) was refluxed for 6 hours. After allowing to cool at ambient temperature, the reaction mixture was evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (150 ml) eluting with a mixture of benzene and ethyl acetate (30:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give ethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (0.6 g).
Reaction SMILES: [Cl:1][C:2]([Cl:18])([Cl:17])[CH:3]([OH:16])[CH:4]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[Cl:18][C:2]([Cl:1])([Cl:17])[CH:3]([O:16][C:19](=[O:21])[CH3:20])[CH:4]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:5](=[O:10])[C:6]([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)(C)C(=O)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Yield: 43 %

Procedure:
314.6 g (1 mol) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one were heated at 95° C. in 1,000 ml of acetic anhydride for 30 hours. The excess anhydride was then distilled off in vacuo, the residue was taken up in 750 ml of methylene chloride and the methylene chloride mixture was washed with 10% strength sodium bicarbonate solution until neutral. The organic phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue was stirred with 150 ml of diisopropyl ether. 153.8 g (43% of theory) of 1,1,1-trichloro-2-acetoxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one were obtained as the pure diastereomer of the A* form of melting point 129°-131° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH3:13]I.[NH4+].[Cl-]>CN(C=O)C>[CH3:13][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:3])[CH:9]=[CH:10]1
Reactant: CI
Reactant: Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cccc2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.3 %

Procedure:
Sodium hydride (1.15 g, 28.7 mmol, 60% in mineral oil) was rinsed with hexanes and then suspended in DMF (20 mL). To this suspension was added 7-methylindole (2.5 g, 19 mmol) portionwise. Gas evolution was allowed to subside between additions. The resulting brown mixture was stirred at room temperature for 15 min and then CH3I (2.71 g, 95.5 mmol) was added in one portion. The exothermic reaction was cooled to 30° C. and stirred for 1 h. Saturated aqueous NH4Cl (10 mL) was added and the mixture was concentrated under reduced pressure. The residue was combined with water (100 mL) and the mixture was then extracted with diethyl ether (3×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.85 g, quantitative) as a red-pink oil which crystallized upon vacuum drying: 1H NMR (300 MHz, CDCl3) δ 7.43 (d, J=7.6 Hz, 1H), 6.97-6.87 (m, 3H), 6.41 (d, J=3.1 Hz, 1H), 4.04 (s, 3H), 2.7 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:20](=[O:25])NCOC)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([CH:20]=[O:25])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COCNC(=O)C(Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C=O)Cc1ccc2ccccc2c1
Temperature: -55 °C
Reaction time: 3 h

Procedure:
To a solution of [1-(methoxymethylcarbamoyl)-2-naphthalen-2-ylethyl]carbamic acid tert-butyl ester, 67, (5.0 g, 13.4 mmol) in THF (40 mL) at −30° C. to −25° C. is added LAH (16.7 mL of a 1M solution in THF) over about 10 minutes and the reaction is then cooled to −55° C. and the stirring is continued for 3 hours. After cooling to −60° C., the reaction is quenched by the addition of citric acid in methanol (1:1 by weight). During quenching the temperature is maintained at about −45° C. The mixture is then allowed to warm to room temperature and partitioned between EtOAc and water and the water phase extracted again with EtOAc. The organic phases are combined and washed with sat NaCl, dried and concentrated in vacuo to afford the crude aldehyde as a white solid which is used without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]3[C:16]([C:7]2=[N:6][C:5]=1[CH3:17])=[CH:15][CH:14]=[CH:13][CH:12]=3)#[N:2].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+].Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH3:17][C:5]1[N:6]=[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]2[C:4]=1[CH2:3][C:1]1[NH:22][N:21]=[N:20][N:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2c3ccccc3ccn2c1CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c3ccccc3ccn2c1Cc1nnn[nH]1
Reaction time: 18 h
Yield: 86.7 %

Procedure:
A mixture of 3-cyanomethyl-2-methylimidazo[2,1-a]isoquinoline (2.8 g), ammonium chloride (0.74 g) and sodium azide (0.9 g) in N,N-dimethylformamide (28 ml) was heated at 120°-125° C. with stirring for 18 hours. The solution was poured into water, acidified with concentrated hydrochloric acid and then neutralized with an aqueous solution of sodium bicarbonate. The resulting precipitates were collected by filtration, washed with water and recrystallized from a mixture of chloroform and methanol to give 2-methyl-3-[(1H- tetrazol-5-yl)methyl]imidazo[2,1-a]isoquinoline (2.9 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10]>CN(C=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9](=[O:10])[CH3:8])[CH:13]=1
Reactant: O=C(CCl)Nc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 7 (200 mg, 0.33 mmol, 1.00 equiv, 50%) in DMF (5 mL) was added potassium carbonate (91.1 mg, 0.66 mmol, 2.00 equiv) and 2-chloro-N-(pyridin-3-yl)acetamide (85.5 mg, 0.50 mmol, 1.50 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (10.0% CH3CN up to 58.0% in 12 min); UV detection at 254/220 nm; Flow rate: 20 mL/mim. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give 2-(((1r,4r)-4-(6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)(methyl)amino)-N-(pyridin-3-yl)acetamide (70 mg) as a white solid. LC-MS (ES, m/z): 437 (M+H+); NMR (400 MHz, DMSO): δ 9.86 (s, 1H), 8.83 (s, 1H), 8.27 (d, 1H), 8.25 (s, 1H), 8.11 (d, 1H), 7.35 (dd, 1H), 5.98 (d, 1H), 4.05-4.15 (m, 1H), 3.31 (s, 2H), 3.07 (t, 2H), 2.92 (t, 2H), 2.38-2.45 (m, 3H), 2.33 (s, 3H), 1.99-2.01 (m, 2H), 1.89-1.92 (m, 2H), 1.40-1.51 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13]1>ClCCCl>[O:22]=[C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nn1cnc2ccccc2c1=O
Solvent: ClCCCl
Product: O=C(Nc1ccc(F)cc1)Nn1cnc2ccccc2c1=O
Temperature: 0 °C

Procedure:
4-Fluorophenyl isocyanate (0.74 mL, 6.51 mmol) is added to a mixture of 3-amino-4(3H)quinazolinone (1.00 g, 6.21 mmol) in 1,2-dichloroethane at reflux. The reaction mixture is heated at reflux for 18 hours, cooled to 0° C. and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 1.64 g (89%), mp 237°-238° C.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O>C(#N)C>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH2:15][S:1][C:2]3[O:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:25][S:24][C@H:19]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1nc2ccccc2o1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4o3)CS[C@H]12
Temperature: 10 °C
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
A 1.66 g quantity of 2-mercaptobenzoxazole, 18 ml of acetonitrile and 2.72 g of 7-ACA were added to 14.9 g of DCPA with stirring under cooling at 10° C., and the reaction was allowed to proceed at 15° to 17° C. for 40 minutes. The reaction solution was cooled with ice and poured into 120 g of ice-water. The precipitate was recovered by filtration, washed with water (20 ml×4) and acetone successively, and dried thereby affording 3.35 g (92.3% of yield) of 7-amino-3-[(benzoxazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.CC(N(C)C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([O:44][C:45]([N:47]1[CH2:51][CH:50]2[CH2:52][CH:53]([CH2:55]OS(C)(=O)=O)[CH2:54][CH:49]2[CH2:48]1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([O:44][C:45]([N:47]1[CH2:48][CH:49]2[CH2:54][CH:53]([CH2:55][O:17][C:11]3[CH:10]=[C:9]4[C:14]([C:5]([O:4][C:3]5[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=5[F:1])=[CH:6][CH:7]=[N:8]4)=[CH:13][C:12]=3[O:15][CH3:16])[CH2:52][CH:50]2[CH2:51]1)=[O:46])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CS(=O)(=O)OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (2.74 g, 6.7 mmol, 1.0 eq.), DMA (30 ml) and cesium carbonate (6.6 g, 20.2 mmol, 3.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 5-methanesulfonyloxymethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (2.6 g, 7.3 mmol, 1.1 eq) was added. The reaction was heated to 75° C. and allowed to stir overnight. After allowing the reaction to cool to room temperature the reaction was poured into water. The solid was filtered and was then dissolved in EtOAc and washed 2× water, 1× brine and dried over NaSO4. The solvent was removed to yield 5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester as a cream solid (3.7 g, 94% yield). 1H NMR (400 MHz), CDCl3): 8.55 (d, 1H), 8.15 (d, 1H), 8.09 (d, 1H), 7.32 (m, 8H), 6.52 (d, 1H), 5.11 (d, 2H), 4.13 (d, 2H), 3.95 (s, 3H), 3.57 (m, 2H), 3.43 (m, 2H), 2.93 (m, 3M, 2.16 (m, 2H), 1.39 (m, 2H); MS (EI) for C32H30FN3O7: 588 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl>O>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)NC(=O)N(CCCCCCCl)C1=O
Reaction time: 0.42 h

Procedure:
128 g of 5,5-dimethyl-hydantoin (1.0 mol), 69 g of anhydrous potassium carbonate (0.5 mol) and 775 g of 1,6-dichlorohexane are reacted at 132°-150°C internal temperature (external temperature 160°C) and the resulting water of reaction is removed continuously by azeotropic circulatory distillation. After 6 hours 25 minutes, the reaction is complete and the reaction mixture is filtered hot to remove the potassium chloride formed. The filtrate is concentrated on a rotary evaporator and dried to constant weight at 100°C and 10-1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc(Cl)cn1
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
In tetrahydrofuran (75 mL) was dissolved methyl 5-chloropyrazin-2-carboxylate (2.589 g), 1M diisobutyl aluminum hydride-tetrahydrofuran solution (30 mL) was added dropwise to the solution at 0° C., and the mixture was stirred at the same temperature for 15 minutes. To the mixture were added water and 1N hydrochloric acid, then, a saturated aqueous sodium bicarbonate solution was added to the same to make the pH to 7. The mixture was filtered through Celite, and then, extracted with chloroform 3 times. The organic layer was separated, dried over anhydrous sodium sulfate, and the residue obtained by concentrating the same under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 65:35 to 50:50) to obtain (5-chloropyrazin-2-yl)methanol (465 mg).