Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:30][NH2:31]>>[CH3:5][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:1])[CH2:3][NH:31][CH3:30]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Reactant: CN
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNC)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with methylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.0, 26.5, 26.6, 36.0, 37.2, 43.1, 46.0, 53.2, 58.8, 62.6, 102.6, 102.8, 103.1, 105.1, 112.3, 112.6, 131.6, 137.8, 138.8, 162.0, 164.5, 169.2, 169.3; MS m/z 422.2 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:33]([O-:36])([O-:35])=[O:34].[Na+:37].[Na+]>C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:33]([O-:36])(=[O:35])=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:37]
Reactant: BrCCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Yield: 14.3 %

Procedure:
A solution of 1,4,5-triphenyl-2-(7-bromoheptyloxy)-imidazole (2.0 g) in ethanol (10 ml) was refluxed with a solution of sodium sulphite (0.55 g) in water (5 ml) for 20 hours. More sodium sulphite (0.2 g) in water (1 ml) was added and refluxed a further 20 hours. The mixture was evaporated to dryness, boiling ethanol added and filtered hot. Chromatography of the filtrate on silica gel (dichloromethane/methanol 5:1) followed by crystallisation from ethanol/isopropanol gave sodium 7-(1,4,5-triphenylimidazol-2-yloxy)heptanesulphonate (0.3 g, 15%) as a colourless solid, m.p. 246°-8° C. Found: C, 64.47; H, 5.85; N, 5.09; S, 5.50%; C28H29N2NaO4S+2% isopropanol +2% water, Requires: C, 64.19; H, 5.96;N, 5.25; S, 6.01%.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([Cl:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CC(C)([O-])C.[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>CS(C)=O>[CH2:1]([C:4]1[N:8]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([Cl:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1nc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.27 g (10.0 mMol) of 2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazole are dissolved in 50 ml of dimethylsulphoxide, 1.23 g (11.0 mMol) of potassium tert.butoxide are added in batches thereto and the resulting mixture is stirred for 30 minutes at ambient temperature. Then 3.38 g (11.0 mMol) of methyl 4'-bromomethyl-biphenyl-2-carboxylate are added in batches thereto. The reaction mixture is then stirred for 3 hours at ambient temperature, stirred into ice water and extracted 3 times with ethyl acetate. The combined organic phases are washed with saline solution and dried over magnesium sulphate. Then the solvent is removed in vacuo and the residue is chromatographed on silica gel (particle size 0.032-0.063 mm), using as eluant first petroleum ether and then mixtures of petroleum ether and ethyl acetate of increasing polarity (9:1, 4:1 and 7:3). The uniform fractions are combined and evaporated down.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C:26](=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:22])[C:19]([O:21][CH3:26])=[O:20])=[CH:10][C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 74 %

Procedure:
A mixture of α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid (0.5 g.), methanol (5 ml.) and concentrated sulphuric acid (4 drops) was heated under reflux for six hours. The mixture was then poured into water (10 ml.), and the resulting mixture was neutralised with sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3×5 ml.) and the combined extracts were washed successively with sodium bicarbonate solution (5 ml.) and water (5 ml.), and then dried with sodium sulphate. The solvent was evaporated in vacuo and the residue crystallised from cyclohexane to give methyl α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionate m.p. 90°-92.5° C., in 74% yield.
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)CC1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C1C=CC=CC=1.[CH2:35]([O:37][C:38](=[O:61])[CH:39](OC(=O)C)[C:40]1[O:44][C:43]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[CH:42][CH:41]=1)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:61])[CH2:39][C:40]1[O:44][C:43]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[CH:42][CH:41]=1)[CH3:36]
Reactant: CCOC(=O)C(OC(C)=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 61 %

Procedure:
According to the procdure described in Example 13 for the preparation of (4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 2-acetoxy-2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester was hydrogenolyzed to provide in 61% yield 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester as a white solid, mp 77-78° C. 1H NMR: δ 7.71 (d, 2H, J=8.5 Hz), 7.63-7.59 (m, 4H), 7.45 (t, 2H, J=7.4 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.64 (d, 1H, J=2.9 Hz), 6.34 (d, 1H, J=3.3 Hz), 4.22 (q, 2H, J=7.2 Hz), 3.76 (s, 2H), 1.30 (t, 3H, J=7.2 Hz). Anal. Calculated for C20H18O3: C, 78.41; H, 5.92. Found: C, 78.16; H, 5.92.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCOCC1
Temperature: 175 °C
Yield: 66.8 %

Procedure:
2,6-Dichloro-3-nitropyridine (0.222 g, 1.15 mmol), 4-aminotetrahydropyran (0.109 g, 1.08 mmol) and DIEA (0.300 mL, 1.72 mmol) were taken up in ethanol (3.0 mL) and heated to 175° C. for 15 minutes in a heavy walled sealed tube under microwave irradiation. The solvent was removed under reduced pressure and the residual solid was purified by preparative HPLC to give the title compound (0.186 g). LCMS m/z=258.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.60-1.75 (m, 2H), 2.8 (d, J=12.4 Hz, 2H), 3.60 (t, J=11.4 Hz, 2H), 4.02 (d, J=11.8 Hz, 2H), 4.30-4.45 (m, 1H), 6.63 (d, J=8.6 Hz, 1H), 8.29 (d, J=5.8 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[CH:8]1([NH2:11])[CH2:10][CH2:9]1>C1COCC1>[CH:8]1([NH:11][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])[CH2:10][CH2:9]1
Reactant: O=S1(=O)CCCO1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCNC1CC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
To a solution of 1,3-propane sultone (2.246 g, 18.39 mmol) in THF (20.0 mL) was added cyclopropanamine (1.214 mL, 17.51 mmol) at room temperature. Upon completion of addition, the reaction mixture was stirred at 40° C. for 30 min, at which point the mixture became a thick white paste. At the conclusion of this period, the reaction mixture was vigorously stirred at 65° C. for 2 h. After cooling to room temperature, the resulting solid was collected by filtration to afford the tilted compound (0.522 g, 17% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (br. s, 1H), 3.12 (t, J=6.9 Hz, 2H), 2.72-2.63 (m, 1H), 2.60 (t, J=6.8 Hz, 2H), 2.51-2.46 (m, 1H), 1.97-1.85 (m, 2H), 0.79-0.70 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+]([O-])=O)[C:5]=1[C:6]#[N:7])([O-:3])=[O:2].[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(F)(F)F)cc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of 3 g (11.49 mmol) 2,6-dinitro-4-trifluoromethyl-benzonitrile (CAS: 35213-02-6) in 30 ml methanol at 0° C. under nitrogen, was added 2.3 ml (11.49 mmol) of a 5M sodium methoxide in methanol. The reaction mixture was stirred at 0° C. for 1.5 hours then poured into ice water, stirred for 60 minutes and the product was collect by filtration. The crude solid was purified on silica (Eluent: heptane/ethyl acetate 0 to 30%) to provide 2.24 g (79%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)c(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C(=O)c2ccc(C)cc2)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56 mg), 2-hydroxy-4-methoxy-4′-methylbenzophenone (242 mg), and 4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-hexane to give the title compound (46 mg, yield 43%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1)#[N:2].[CH3:21][CH2:22][CH:23]([NH2:26])[CH2:24][CH3:25]>>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:26][CH:23]([CH2:24][CH3:25])[CH2:22][CH3:21])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Reactant: CCC(N)CC
Product: CCC(CC)NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)c2)cc1
Yield: 55 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid (example 21a) and 3-pentanamine. Yield 55%. 1H NMR (400 MHz, DMSO): δ 0.69-0.73 (t, 6H), 1.27 (m, 2H), 1.36 (m, 2H), 1.47 (s, 6H), 3.56 (m, 1H), 6.90-6.93 (d, 1H), 7.43-7.45 (d, 2H), 7.77-7.79 (d, 2H), 8.63-8.64 (t, 1H), 8.96-8.98 (d, 1H), 9.17-9.18 (d, 1H). MS (M+H, 336).
Reaction SMILES: [C:1]([N:4]1[CH:8]=[CH:7]N=C1)(=[O:3])[CH3:2].N[C:10]1[CH:15]=[C:14](CC)[N:13]=[C:12]([CH2:18][CH3:19])[CH:11]=1>C1(C)C=CC=CC=1>[C:1]([NH:4][C:8]1[CH:7]=[C:14]([CH2:15][CH3:10])[N:13]=[C:12]([CH2:18][CH3:19])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(N)cc(CC)n1
Reactant: CC(=O)n1ccnc1
Solvent: Cc1ccccc1
Product: CCc1cc(NC(C)=O)cc(CC)n1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
N-acetylimidazole (0.61 g) was added to a solution of 4-amino-2,6-diethylpyridine (0.61 g) in toluene (10 ml) and the mixture was heated at reflux for 16 hours. The mixture was cooled to ambient temperature and solvent was removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate to give 4-(N-acetylamino)-2,6-diethylpyridine (B) (0.66 g) as a solid, m.p. 74°-78° C.; NMR (CDCl3): 1.26(t, 6H), 2.18(s, 3H), 2.74(q, 4H), 7.18(s, 2H), 7.75(broad s, 1H); mass spectrum (chemical ionisation, ammonia): 193(M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([OH:7])[CH3:14])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: C[Mg+]
Reactant: COc1cc(C=O)cc(OC)c1Br
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
An oven-dried flask under argon was charged with 4-bromo-3,5-dimethoxybenzaldehyde (10.08 g, 41.1 mmol) and anhydrous THF (70 mL). The mixture was cooled over a −78° C. bath then a solution of MeMgBr (3.0 M in diethyl ether, 17.8 mL, 53.4 mmol) was added dropwise from an addition funnel over a period of 45 min. After stirring for 20 min, the mixture was allowed to warm to room temperature and stirred for 19 hours. After quenching with a solution of aqueous NH4Cl, it was diluted with H2O and EtOAc then cooled over an ice bath. After the mixture was cooled, the layers were separated. The organics were washed with H2O and brine then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dichloromethane and concentrated in vacuo again to give 1-(4-bromo-3,5-dimethoxyphenyl)ethanol as a white solid (10.8 g, quantitiative yield). The product was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: Nc1cc(O)ccc1Cl
Product: Oc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-chloro-5-hydroxyaniline (33 mg, 0.231 mmol) similar to Example 190 and was isolated as a solid (6 mg). 1H NMR (CDCl3): 9.72 (d, J=1.5 Hz, 1H), 8.78 (dd, J=5.7, 1.5 Hz, 1H), 8.73 (d, J=1.2 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.05 (s, 1H), 7.04 (d, J=8.7 Hz, 1H), 6.73 (dd, J=8.7, 2.7 Hz, 1H), 6.29 (d, J=2.7 Hz, 1H), 6.19 (dd, J=8.4, 2.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:25])=[CH:4][CH:3]=1.[CH2:27]([CH:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28]>>[CH2:27]([CH:29]([CH2:33][CH3:34])[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:26])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:25])=[CH:6][CH:7]=1)=[O:31])[CH3:28]
Reactant: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(N)cc2)C1=O
Reactant: CCC(CC)C(=O)Cl
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(NC(=O)C(CC)CC)cc2)C1=O

Procedure:
Synthesis in analogy to Example 8 starting from enantiomerically pure 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one and 2-ethyl-butyryl chloride to yield (−)-2-ethyl-N-{4-[2-(2-methyl-5-oxo-4-phenyl-4-propyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-butyramide. LC/MS at 254 nm; [M+H] 448; Rt=3.313 min; optical rotation=−8.2°, c=1.0 in methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[I-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(N(C(C)C)C(C)C)C>C(#N)C>[N:1]1([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][NH:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrCCCCCBr
Reactant: Nc1ccc2c(c1)C(=O)NC2
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCc2ccc(N3CCCCC3)cc21
Temperature: 75 °C
Reaction time: 20 h

Procedure:
6-Amino-2,3-dihydro-isoindol-1-one (0.810 g, CAS 675109-45-2) was dissolved in 12 ml of acetonitrile and treated successively with sodium iodide (2.458 g, 3 eq.), 1,5-dibromopentane (1.11 ml, 1.5 eq.), and N-ethyl-diisopropylamine (2.88 ml, 3.1 eq.), and the mixture was stirred at 75° C. for 20 h. Pouring onto crushed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by crystallization from hexane/ethyl acetate yielded 6-piperidin-1-yl-2,3-dihydro-isoindol-1-one (0.669 g) as light brown crystals, MS 217.3 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:15])[C:10](=[O:14])[C:11]([CH3:13])([CH3:12])[C:6]2=[CH:5][CH:4]=1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH3:15][N:9]1[C:7]2=[N:8][C:3]([NH:2][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:4][CH:5]=[C:6]2[C:11]([CH3:12])([CH3:13])[C:10]1=[O:14]
Reactant: O=C(Cl)c1ccncc1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)nc21
Agent: Cl
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3ccncc3)nc21

Procedure:
Prepared in analogy to example 2 from 6-amino-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride and isonicotinoyl chloride hydrochloride. The title compound was obtained as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]([CH:15]1[C:20](=O)[CH2:19][CH2:18][NH:17][CH2:16]1)(OCC)=[O:11]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:20]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[C:10](=[O:11])[O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: Cc1ccc(O)cc1C
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3

Procedure:
In the same way as described for example 1, 0.3m of 3,4-dimethyl phenol, 0.2m of 3-carbethoxy-4piperidone were reacted to give 8.4g of crude product. Crystallization from ethyl acetate afforded analytical material, m.p. 173°-5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])[CH2:11]1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(Br)c2)c(F)c1
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
1-(3-Bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 14, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (13.0 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH:19](=[N:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CS(O)(=O)=O.N>C(#N)C.O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:32][C:31]3[N:27]([N:26]=[CH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:28]=[N:29][N:30]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1nnnn1N=Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: N
Solvent: O
Solvent: CC#N
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N=Cc3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
10.9 g of 7β-aminocephalosporanic acid and 8.2 g of 1-benzylideneamino-5-mercapto-1H-tetrazole were dissolved in 60 ml of acetonitrile, and 19.2 g of methanesulfonic acid were added gradually thereto at a temperature below 30° C. The mixture was stirred at room temperature for 30 minutes and then at 44° C. for 4 hours. After ice-cooling, 400 ml of water were added to the reaction mixture, and said mixture was adjusted to 5.2 with 28% ammonia. The resultant precipitates were collected by filtration, washed with water and tetrahydrofuran, and then dried. 11.53 g of 7β-amino-3-[(1-benzylideneamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid were obtained as pale yellow powder. mp 170° C. (decomp.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][N:10]([CH3:16])[CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C(O)CO>CC(O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:14][CH2:15][CH:11]([N:10]([CH3:16])[CH3:9])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1CCNC1
Reactant: Brc1cccc(I)c1
Agent: [Cu]I
Solvent: CC(C)O
Solvent: OCCO
Product: CN(C)C1CCN(c2cccc(Br)c2)C1
Temperature: 80 °C

Procedure:
1-Bromo-3-iodobenzene (1 eq, 3.53 mmol, 1 g), copper(I) iodide (0.05 eq, 0.177 mmol 0.034 g) and potassium phosphate tribasic carbonate (2 eq, 7.07 mmol, 1.51 g) are dissolved in 2-propanol (15 ml) under an inert atmosphere of nitrogen. Then, N,N-dimethylpyrrolidin-3-amine (2 eq, 7.07 mmol, 0.807 g) and ethylene glycol (2 eq, 7.07 mmol, 0.394 ml) are added and the reaction mixture heated at 80° C., overnight.