Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[S:13])[C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1.Cl[C:16](OC(Cl)(Cl)Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:14][C:5]1[C:6]2[C:7](=[S:13])[C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[C:2]([N:1]=[C:16]=[O:17])=[CH:3][CH:4]=1
Reactant: CC1(C)Oc2c(N)ccc(Cl)c2C1=S
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)Oc2c(N=C=O)ccc(Cl)c2C1=S

Procedure:
By the method of Example 1, Step F, 2.51 g (0.011 mole) of 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-3-thione is reacted with 2.18 g (0.011 mole) of trichloromethyl chloroformate in 65 mL of toluene, yielding 4-chloro-2,3-dihydro-2,2-dimethyl-3-thioxobenzofuran-7-yl isocyanate.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([N+:10]([O-:12])=[O:11])=[C:6]2[NH:13]N=N[N:5]2[C:4]1=[O:16])[CH3:2].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[N+:10]([O-:12])[O:11][N:13]=[C:6]2[NH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCn1c(=O)c([N+](=O)[O-])c2[nH]nnn2c1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCn1c(=O)[nH]c2no[n+]([O-])c2c1=O
Yield: 77 %

Procedure:
20.0 g of 6-ethyl-8-nitrotetrazolo[1,5-c]pyrimidine-5,7(1H,6H)-dione are heated at 120° C. for 7 hours with 200 ml of glacial acetic acid in 2000 ml of xylene. A small undissolved portion is filtered off, the filtrate is concentrated in vacuo and the oily residue is made to crystallise by trituration with methylene chloride. 13.5 g (77%) of 6-ethyl-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione-1-oxide are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:13]1[S:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)=[O:19])=[CH:16][N:17]=1)(=O)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:13]2[S:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]34[CH2:32][CH:27]5[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]5)[CH2:24]3)[CH2:30]4)=[O:19])=[CH:16][N:17]=2)[CH2:3]1
Reactant: CCS(=O)(=O)c1ncc(C(=O)NCCC23CC4CC(CC(C4)C2)C3)s1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for ten minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfonyl-5-[2-(adamant-1-yl)ethylaminocarbonyl]thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained at 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-[5-(2-[adamant-1-yl]ethylaminocarbonyl)thiazol-2-yloxy]propane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[C:9]([O:14]C)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1.Br.C([O-])(O)=O.[Na+]>CC(O)=O>[NH2:1][C:2]1[C:7]([C:8]2[C:9](=[O:14])[NH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:4][C:3]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(NS(C)(=O)=O)cc2)c1N
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(CCc2ccc(NS(C)(=O)=O)cc2)c(N)c(-c2ccc[nH]c2=O)c1
Temperature: 70 °C
Yield: 66.2 %

Procedure:
step 5—A mixture of 86 (0.050 g, 0.11 mmol), 48% HBr (0.050 mL) and AcOH (2 mL) in a sealed tube was heated overnight at 70° C. The reaction mixture was cooled to RT, carefully poured into a cold saturated aqueous NaHCO3 and then extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated. The crude residue was purified by SiO2 chromatography and eluted with 10% MeOH/DCM to afford 32 mg (66%) of N-(4-{2-[2-amino-5-tert-butyl-3-(2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-ethyl}-phenyl)-methanesulfonamide (88) as a solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:6]([C:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:4][CH2:3][OH:2])[CH3:7]
Reactant: CCC(CC)(CC)CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(CC)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Step D To a solution of 3,3-diethyl-pentanoic acid methyl ester (1.9 g, 11 mmol) in anhydrous tetrahydrofuran (50 mL) at 0° C. was added a tetrahydrofuran solution (2 M) of LiAlH4 (9 mL, 18 mmol) under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentan-1-ol as a yellow oil (1.4 g, 90%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13]COC)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[N:7]=[CH:8][C:9]([OH:13])=[C:10]([F:12])[CH:11]=2)[CH2:2][CH2:3]1
Reactant: COCOc1cnc(OCC2CC2)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnc(OCC2CC2)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 2-(cyclopropylmethoxy)-5-(methoxymethoxy)pyridine (789 mg, 3.77 mmol) obtained in Reference Example 266 in THF (10 mL) was added 1.6 M n-butyllithium-hexane solution (3.10 mL, 4.90 mmol) at −78° C., and the mixture was stirred at the same temperature for 30 min. To this solution was added N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (1.78 g, 5.66 mmol), and the mixture was stirred at room temperature for 10 min. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give 2-(cyclopropylmethoxy)-4-fluoro-5-(methoxymethoxy)pyridine as an oil. The 2-(cyclopropylmethoxy)-4-fluoro-5-(methoxymethoxy)pyridine was dissolved in THF (10 mL), 6N hydrochloric acid (2.90 mL, 17.4 mmol) was added thereto and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=17:3 to 1:1) to give the title compound (279 mg, yield 40%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([O:17][C:28](=[O:30])[CH3:29])([CH3:16])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C)(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.9 %

Procedure:
1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol (2.0 g, 5.97 mmol) was dissolved in DMF (20 ml), sodium hydride (716 mg, 17.9 mmol) was added and the mixture stirred at RT for 20 min. Acetic anhydride (913 mg, 8.95 mmol) was added dropwise at the same temperature and stirring continued for 1.5 h. The reaction was monitored by TLC and LCMS. The reaction mixture was poured into 250 mL ice water and extracted with EtOAc (3×200 mL), washed with water (3×300 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by column chromatography (silica gel: 100-200 mesh, eluent:−6-8% MeOH in DCM) to obtain 110 mg of acetic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-1-pyridin-3-yl-ethyl ester, which was followed by chiral separation. 1H NMR (CD3OD, Free base) δ (ppm): 8.38 (d, 1H), 8.15 (s, 1H), 7.45 (d, 1H), 7.22 (t, 1H), 7.1 (s, 1H), 7.0 (s, 1H), 6.8 (d, 1H), 4.43 (d, 1H), 4.2 (d, 1H), 3.7 (d, 1H), 3.5 (d, 1H), 2.8 (m, 2H), 2.53 (m, 1H), 2.5 (s, 3H), 2.4 (s, 3H), 2.2 (m, 1H), 2.07 (d, 6H). Separation by chiral HPLC provided enantiomers II-15a-b.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:31][CH2:30][C:29]1=[O:32]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:31][CH2:30][C:29]3=[O:32])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 17.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 110 and azetidin-2-one (142 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (158 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc2nc(S)[nH]c2c1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)Nc1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
5 g of 5-amino-2-mercaptobenzimidazole was dissolved in 50 ml of pyridine and 7.95 g of dodecanoyl chloride was added dropwise thereto under cooling with ice. After stirring, for 3 hours at room temperature, the solution was poured into ice-water. The formed crystals were filtered off and recrystallized from water-containing methanol to obtain 10.9 g of compound (8).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=1)[CH2:8][C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1COCC1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=1)[CH2:8][CH:9]=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)CN(CCCc1cccc(Br)n1)C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC=O)CCCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 20-7 (14.9 g, 35.7 mmol) and THF (100 ml) at -78° C. was added DIBAL (1.0M/hexanes, 53.6 ml, 53.6 mmol) dropwise over 20 minutes. After 1 h, the mixture was warmed to RT and quenched by the careful addition of 20 mL MeOH. 200 ml of 1.0 M Rochelle's salt was then added followed by the removal of the cooling bath. The mixture was stirred for 1.0 hour and then diluted with Et2O. After another 30 minutes of stirring, the organic portion was separated and dried over MgSO4. Evaporative removal of the solvent gave the crude aldehyde 20-8 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:10]C(=O)[O:8][C:7](=O)[C:6]=2[CH:13]=1.C(OCC)(=O)C.C(O)(=O)C.[CH3:25][NH2:26]>O>[NH2:10][C:5]1[C:4]([CH3:14])=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:26][CH3:25])=[O:8]
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Reactant: CN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Cl)cc(C)c1N
Temperature: 50 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 250-mL flask equipped with a thermometer and nitrogen bubbler was charged with 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (9.0 g, 43 mmol) (i.e. the product of Example 1), ethyl acetate (50 mL), and acetic acid (3.8 g, 63 mmol). The mixture was heated to 50° C., and anhydrous methylamine (1.6 g, 50 mmol) was added below the surface of the mixture while maintaining the temperature at 48-52° C. The mixture was held for 1 h at 50° C., then water (65 mL) was added, and the ethyl acetate was removed by distillation. When the pot temperature reached 83° C., the solution was seeded, and the product slurry was cooled over 3 h to 10° C. The solid was collected by filtration and dried to afford the title compound as a white crystalline solid (7.94 g, >98.5 wt. % purity by HPLC assay, 93% yield) melting at 143-145° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[CH:2].[Li][CH2:25]CCC.CI.Cl>C1COCC1.O>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[CH2:13][CH2:14][CH:9]([CH:6]3[CH2:5][CH2:4][CH:3]([C:1]#[C:2][CH3:25])[CH2:8][CH2:7]3)[CH2:10][CH2:11]2)=[CH:16][CH:17]=1)[CH2:22][CH3:23]
Reactant: C#CC1CCC(C2CCC(c3ccc(CCC)cc3)CC2)CC1
Reactant: [Li]CCCC
Agent: Cl
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CC#CC1CCC(C2CCC(c3ccc(CCC)cc3)CC2)CC1
Reaction time: 3 h

Procedure:
3.5 g (11.3 mmol) of 4-ethynyl-4′-(4-propylphenyl)bicyclohexyl are initially introduced in 30 ml of THF at −20° C., and 8.6 ml (13.6 mmol) of n-BuLi (15% soln. in hexane) are added dropwise. After 1 h at this temperature, 0.85 ml (13.6 mmol) of methyl iodide is metered in, and the batch is left in the cooling bath to thaw for 3 h. Water and dil. hydrochloric acid are added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and sat. sodium chloride soln., and the solution is dried using sodium sulfate. The crude product obtained after removal of the solvents is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=4:1). The further purification is carried out by recrystallisation from n-heptane. This gives 4′-(4-propylphenyl)-4-prop-1-ynylbicyclohexyl as a colourless solid having an m.p. of 70° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH3:21])[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([C:12](=[O:14])[CH:13]=1)[C:7]([O:9]CC)=[O:8])[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([C:3]1[N:4]([CH3:21])[C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]([C:12](=[O:14])[CH:13]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)n(C)c(CC)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Yield: 100.8 %

Procedure:
2.2 g of ethyl 6-ethyl-1-methyl-2-phenyl-4-oxonicotinate is suspended in 35 ml of 5% aqueous sodium hydroxide solution. The resulting suspension is heated on a steambath for 4 hours, cooled and acidified with dilute HCl to yield 2.0 g of 6-ethyl-1-methyl-2-phenyl-4-oxonicotinic acid. mp (CH3CN)=244°-245° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:24])[CH:12]([NH:13][C:14](=[O:23])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH2:16])[C@H:4]2[S:3]1.[OH-].[Na+].[CH3:27][C:28]([CH3:30])=O>O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:24])[CH:12]([N:13]3[C:14](=[O:23])[CH:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:16][C:28]3([CH3:30])[CH3:27])[C@H:4]2[S:3]1
Reactant: CC(C)=O
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2S1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1C=C(C(=O)O)N2C(=O)C(N3C(=O)C(c4ccccc4)NC3(C)C)[C@H]2S1
Reaction time: 24 h

Procedure:
A suspension of 2-methyl-7-(2-phenylglycyl)amino-3-cephem-4-carboxylic acid (1.0 g) in water (10 ml) was adjusted to pH 8.8 by adding dropwise 10% sodium hydroxide. To the suspension was added acetone (10 ml), and the mixture was stirred for 24 hours in an ice bath. Acetone was removed under reduced pressure, and then the aqueous layer was adjusted to about pH 3.5 with 10% hydrochloric acid, and then extracted three times with ethyl acetate (20 ml). The residue obtained by distilling off ethyl acetate was dissolved in a small amount of acetone, and then a small quantity of insoluble material was filtrated off. A great quantity of ether was added to the filtrate, and then the precipitate was collected by filtration to give 2-methyl-7-(2,2-dimethyl-4-phenyl-5-oxoimidazolidin-1-yl)-3-cephem-4-carboxylic acid (0.30 g), mp 160° to 162° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([NH2:12])[CH:4]=1.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:12]=[C:17]([C:16]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:15]=3[O:14][CH3:13])[NH:11][C:6]=2[CH:7]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: COc1cc(N)c(N)cc1OC
Product: COc1cc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2cc1OC

Procedure:
Prepared analogously to Example 14 from 4,5-dimethoxy-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].Cl.[C:26]([C:29]1[CH:30]=[NH+:31][CH:32]=[CH:33][CH:34]=1)(=[NH:28])[NH2:27].C([O-])(=O)C.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:24][C:20]1[CH:19]=[C:18]([C:17]2[C:4]([C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:6])=[C:1]([CH3:2])[N:28]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:27]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1
Reactant: N=C(N)c1ccc[nH+]c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccnc2)nc(-c2cccc(Cl)c2)c1C(=O)NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.294 mmol) of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propen-1-yl) acrylamide was dissolved in 5 ml of DMF. 60.1 mg (0.381 mmol) of 3-amidinopyridinium hydrochloride and 28.9 mg of (0.353 mmol) of sodium acetate were added thereto and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was stirred at 120° C. overnight, cooled down at room temperature and purified by the silica gel chromatography (hexane/ethyl acetate=1/2) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:35]=[CH:34][C:19]([CH2:20][N:21]5[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:38])[CH:3]=1.[C:39]1([CH2:45][C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CCO.C1(C)C=CC=CC=1>[F:38][C:4]1[CH:3]=[C:2]([NH:1][C:49]([NH:48][C:46](=[O:47])[CH2:45][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[S:50])[CH:37]=[CH:36][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[CH:34][CH:35]=3)[S:15][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cc2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cc4)sc23)c(F)c1
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
Compound 454 (0.3323 g, 0.62 mmol) was suspended in EtOH/toluene (3 mL/3 mL) at RT and stirred for 30 min. 2-Phenylacetyl isothiocyanate (0. 165 g, 0.93 mmol) was added and the reaction mixture was stirred at RT for 1 h, quenched with MeOH (2 mL) and concentrated to dryness. The residue was purified by flash chromatography (eluent 9/1/90 MeOH/NH4OH/DCM) to give compound 450 as a white solid (60 mg, 16% yield). 1H NMR δ(400 MHz, CD3CN): 8.51 (d, J=5.5 Hz, 1H), 7.99 (dd, J=2.5, 12.3 Hz, 1H), 7.84 (s, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.32-7.53 (m, 9H), 6.62 (d, J=4.5 Hz, 1H), 3.81 (s, 2H), 3.54 (s, 2H), 2.30-2.53 (bs, 8H), 2.22 (s, 3H). LCMS: 613 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=[C:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH2:19][CH2:18]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][S:31](O)(=[O:33])=[O:32]>C(Cl)Cl.CCOCC.CCOCC>[CH3:30][S:31]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:20]1[CH2:19][CH2:18][N:17]([C:8]2[N:7]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:11]=[C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=2)[CH2:22][CH2:21]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)O
Reactant: OCCCCCCN1CCN(c2nc(N3CCCC3)nc(N3CCCC3)n2)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)OCCCCCCN1CCN(c2nc(N3CCCC3)nc(N3CCCC3)n2)CC1

Procedure:
A mixture of 4-[4,6-bis(1-pyrrolidinyl)-1,3,5-triazin-2-yl]-1-piperazinehexanol (EXAMPLE 1, 1.22 g) in methylene chloride/ether (1/1, 30 ml) is mixed with a solution of methanesulfonic acid (0.28 g) in ether (15 ml). The mixture is concentrated and the residue crystallized twice from methanol/ether to give the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([O:14][C:15](=[O:29])[CH:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C>[CH2:23]([CH:16]([C:17]1[CH:18]=[CH:19][C:20]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[CH:21][CH:22]=1)[C:15]([OH:29])=[O:14])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC(C(=O)OCC)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)O)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Yield: 18 %

Procedure:
The ethyl ester of the titled product was prepared in 18% yield by reacting phthalic anhydride and α-hexylbenzeneacetic acid ethyl ester in the presence of aluminum chloride in DMF according to the general procedure of Example 55. The title product was then prepared according to the procedure of Example 26 in 45% yield from the intermediate ester, m.p. 118°-121° C.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[OH:9][CH2:10][C:11]([CH3:15])([CH2:13]O)[CH3:12].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH3:12][C:11]1([CH3:15])[CH2:10][O:9][C:4]2([CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]2)[O:7][CH2:13]1
Reactant: CC(C)(CO)CO
Reactant: O=C1CCC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)COC2(CCC(=O)CC2)OC1

Procedure:
1,4 cyclohexane dione (25.0 grams) and neopentyl glycol (23.5 grams) were dissolved in chloroform (200 ml). Then sulfuric acid (4.0 grams) was added to the reaction solution at an ambient temperature and stirred till the reaction substantially completes, accompanied by cooling the reaction mixture to 10–20° C. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) and separated the organic layer from the resulting biphasic mixture. The solvent was distilled off from organic layer till substantial completion under reduced pressure. Hexane (250 ml) was added to the resulting residual mass and followed by cooling the reaction mass to a temperature of 0–5° C. to filter the by-products. Then the solvent from the filtrate was distilled off till the substantial completion under vacuum to yield the desired 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal.