Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]OS(=O)=O.[H-].[Na+].[C:8]1(=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][NH:9]1.[Na+].[Cl-]>CN(C)C=O.O1CCCC1>[NH2:1][N:9]1[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:8]1=[O:19]
Reactant: NO[SH](=O)=O
Reactant: O=C1NCCCc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NN1CCCc2ccccc2C1=O
Reaction time: 1 h

Procedure:
A solution of 2.7 g of O-amino-sulfonic acid and 1.25 g of a 55% oily suspension of sodium hydride in 30 ml of dimethylformamide and 30 ml of tetrahydrofuran was gradually added at a temperature of 10° C. to a suspension of 9.66 g (0.0176 mol) 4,5-dihydro-2-benzazepine-1(2H,3H)-one. After standing for 1 hour at room temperature the mixture was poured into a saturated aqueous solution of NaCl, then the organic layer was separated and the mother liquors were extracted with 300 ml (3×100 ml) of an 1:1 (v:v) mixture of tetrahydrofuran and dimethylformamide. The organic phases were combined and brought to dryness. The obtained residue was subsequently taken up with 500 ml of ethyl acetate and the resulting organic solution was extracted with 200 ml (5×40 ml) of a 3% aqueous solution of HCl. The acidic extract was made alkaline with 5% aqueous sodium hydroxide and subsequently extracted with ethyl acetate. After evaporating the solvent, an oily residue was obtained which was distilled under reduced pressure. Yield: 10 g. of the title compound. B.p. 120° C./0.2 mmHg
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:26][C:27]1[C:28](=[O:34])[NH:29][C:30](=[O:33])[NH:31][CH:32]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:26][C:27]2[C:28](=[O:34])[NH:29][C:30](=[O:33])[NH:31][CH:32]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1)Nc1c[nH]c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
1.87 g (0.01M) p-chlorophenoxyacetic acid is suspended with stirring in 30 ml dry dimethylformamide and dissolved by addition of 1. g (0.01M) triethylamine. The reaction mixture is cooled to 0° to 5° C. internal temperature, mixed with 1.1 g (0.1M) chloroformic acid ethyl ester and stirred one minute at its reaction temperature. To the reaction mixture of the mixed anhydrides one rapidly adds a solution of 1.27 g (0.01M) 5-aminouracil in dry dimethylformamide and stirs for 30 minutes. Subsequently the reaction mixture is poured into 1 liter ice water, the precipitate is filtered with suction, dried and recrystallized from water in the ratio 1:1.
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:29][CH2:28][C@@H:27]([C:30]([CH3:32])=[CH2:31])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:26])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C@@H:12]([OH:25])[CH2:11][CH2:10]3)[CH2:7][CH2:6]1.C[N+]1([O-])CCOCC1>C(#N)C.C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:26])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12](=[O:25])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:27]([C:30]([CH3:32])=[CH2:31])[CH2:28][CH2:29][C@:3]1([CH:2]=[O:1])[CH2:20][CH2:19]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To suspension of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol (20 g, 45.2 mmol) in acetonitrile (200 mL) and DCM (300 mL) was added 4 angstrom molecular sieves (5 g) and the mixture was stirred for 10 minutes at rt. To the mixture was then added NMO (15.88 g, 136 mmol) and TPAP (0.794 g, 2.259 mmol). The dark green mixture was stirred under nitrogen overnight. Additional NMO (2.0 g) and TPAP (0.08 g) were added and the mixture was stirred at rt for 7 h. The mixture was filtered through a pad of silica gel and celite which was washed with dichloromethane then 25% EtOAc in hexanes. The filtrate was concentrated under reduced pressure and purified using a Thomson 240 g silica gel column and a 15-20% ethyl acetate in hexanes gradient. The title product was isolated as a white foam (17.6 g, 40.1 mmol, 89%). 1H NMR (400 MHz, chloroform-d) δ=9.68 (d, J=1.5 Hz, 1H), 4.77 (d, J=2.0 Hz, 1H), 4.66-4.63 (m, 1H), 2.89 (td, J=11.2, 5.8 Hz, 1H), 2.56-2.36 (m, 2H), 2.16-2.03 (m, 2H), 1.97-1.84 (m, 2H), 1.71 (s, 3H), 1.08 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 1.83-0.87 (m, 18H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[C:29]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:15][CH2:14]2)[CH2:3][CH2:2]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C2CCN(CCC3CCNc4ccccc43)CC2)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(CCC3CCN(C(C)=O)c4ccccc43)CC2)cc1OC
Reaction time: 2 h

Procedure:
A solution of 2.5 g of 1-(2-(1,2,3,4-tetrahydroquinolin-4-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine (dihydrochloride, m.p 235°-236°) in 35 ml of THF is treated with a solution of 0.9 g of a acetyl chloride in ml of THF, stirred for 2 hours at-50°, evaporated and worked up in the customary manner. 1-(2-(1,2,3,4-Tetrahydro-1-acetylquinolin-4-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[C:20]3[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[C:20]3[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[CH:14]=[CH:13][CH:12]=2)([OH:10])[C:26]([F:28])([F:27])[F:25])=[C:4]([Cl:24])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C(=O)c1cccc2c1OCC(=O)N2C)c1ccc(Br)cc1Cl
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1cccc2c1OCC(=O)N2C)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 8-[2-(4-bromo-2-chloro-phenyl)-propionyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=476 [M−H+].
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2c(OCc3ccccc3)cccc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a mixture of 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (Uchiyama M. et al Org. Lett. 2006, 8(24), 5517-5520) (2.0 g, 10.4 mmol) and benzyl bromide (1.78 g, 10.4 mmol) in DMF in an ice bath was added sodium hydride (60% dispersed in mineral oil, 624 mg, 15.6 mmol). Resulting mixture was stirred at 0° C. for 10 min and then at rt for 6 h. Reaction mixture was quenched with water (250 mL), neutralized using 1 N HCl to pH=6-7 and extracted with EtOAc (2×). Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Crude product was triturated with hexanes (50 mL). Solid was collected and dried in vacuo to provide the title compound 2.5 g. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.54 (m, 2H), 7.37 (m, 4H), 6.57 (m, 2H), 5.25 (s, 2H), 1.71 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17]Br.O>CN(C)C=O>[CH3:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14])=[CH:11][CH:12]=1)([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1ccc(C(C)(C)C)cc1)OC
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To a mixture of 5.33 g (0.133 mol.) of sodium hydride (60%) and 200 ml of anhydrous N,N-dimethylformamide, there was added dropwise a solution of 20.00 g (0.133 mol.) of 4-(1,1-dimethylethyl)phenol in 50 ml of anhydrous N,N-dimethylformamide with stirring at a temperature of from 5° C. to 10° C. for 10 minutes. Then the reaction mixture was stirred at the same temperature for 30 minutes. To the above mixture, there was added dropwise 24.75 g (0.146 mol.) of bromoacetoaldehyde dimethylacetal in 50 ml of anhydrous N,N-dimethylformamide with stirring at the same temperature for 30 minutes. The reaction mixture was then stirred at room temperature for 20 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. Then the residue was washed three times with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 30.00 g of 2-[4-(1,1-dimethylethyl)phenoxy]-1,1-dimethoxyethane as a light-yellowish oily substance (nD22.8 1.4911).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CCCCCC.C([Li])CCC.[CH3:22][C:23]([CH3:25])=[O:24]>O1CCCC1>[OH:24][C:23]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:25])[CH3:22]
Reactant: CC(C)=O
Reactant: Cn1ccc2ccccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)O)cc2ccccc21
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
5.0 g of 1-methylindole was dissolved in 30 ml of anhydrous tetrahydrofuran. Thereto was dropwise added 30 ml of 1.5 M n-butyllithium hexane solution, at -30° C. in 5 minutes with stirring. The mixture was stirred at 0° C. for 30 minutes. Thereto was dropwise added 4.2 ml of acetone in 10 minutes at the same temperature, and the resulting mixture was stirred at room temperature for 10 minutes. The solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of ethyl acetate and 50 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=50/1 to 20/1), followed by recrystallization from n-hexane, to obtain 3.25 g (yield: 45%) of 2-(1-hydroxy-1-methylethyl)-1-methylindole as colorless crystals.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[C:10]([F:15])[C:9]=1[F:16])(=[O:3])[CH3:2].Cl[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:11]=[C:10]([F:15])[C:9]=1[F:16])(=[O:3])[CH3:2]
Reactant: Clc1ccccn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cc(F)c1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccccn2)cc(F)c1F

Procedure:
By carrying out the operation analogously to example 58, starting from 5-bromo-2,3-difluorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 2-chloropyridine, the expected compound is obtained in the form of a crude product used without further purification in the deacetylation stage.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]=[N:12]2)[C:8]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:36])[CH3:34])[N:28]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3F)cc2=O)n1
Yield: 69 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 43) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.48 g, 69%); ES+-HRMS m/e calcd for C25H30N5O4F [M+H+] 484.2355 found 484.2355. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.25-1.75 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.1, J=10.7 Hz, 1H), 5.80 (d, J=2.7 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.28-7.52 (m, 4H), 7.52 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.CCN(C(C)C)C(C)C.[CH:16]1([CH2:21][CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](Cl)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[CH:16]1([CH2:21][CH:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1nncs1
Reactant: O=C(Cl)C(CC1CCCC1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nncs1)C(CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 2-amino-1,3,4-thiadiazole (220 mg, 21 mmol), 0.4 mL DIEA and 7 mL of DCM is added a solution of the title C compound, 3-cyclopentyl-2-phenylpropionyl chloride (500 mg, 21 mmol) in 2 mL of DCM. The mixture is stirred at ambient temperature for 2-3 h, the mixture is evaporated, and the residue is treated with 10 mL 1 N HCl and extracted twice with ethyl acetate. The combined extracts are washed with brine, saturated sodium bicarbonate solution, and brine and dried over anhydrous magnesium sulfate. Filtration and evaporation afford 3-cyclopentyl-2-phenyl-N-[1,3,4]thiadiazol-2-yl-propionamide as an orange foam: 1H NMR (400 MHz, DMSO-d6) δ 11 (m, 2H), 1.4 (m, 2H), 1.5 (m, 3H), 1.7(m, 3H), 2.1 (ddd, J=13.3, 7.8, 7.7 Hz, 1H), 4.0 (dd, J=8.1, 7.1 Hz, 1H), 7.2 (s, 1H), 7.3 (m, 4H), 9.1 (s, 1H), 12.8 (s, 1H); LC/MS 302 (M+1), 300 (M−1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([CH3:19])=[CH:10][N:9]=2)[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([CH3:19])=[CH:10][N:9]=3)[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCOC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ncc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)ncc1C

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-methylpyridine-4-carboxylate obtained in Example (180b) (26.1 mg, 0.09 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (14.8 mg, 0.08 mmol), WSC hydrochloride (48.8 mg, 0.25 mmol) and HOBt (11.5 mg, 0.08 mmol), to obtain 28.8 mg of the title compound as a yellow oily substance (76%).
Reaction SMILES: [C-:1]1([C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17].P(Cl)(Cl)[Cl:19]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([C:6]([CH3:11])([CH3:10])[C:7]([Cl:19])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17]
Reactant: CC(C)(C(=O)O)[c-]1cccc1
Reactant: ClP(Cl)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C(=O)Cl)[c-]1cccc1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 2-ferrocenyl-2-methylpropionic acid (7.55 g) and pyridine (15 drops) in 500 cm3 of dry benzene was slowly added 25 cm3 of phosphorous trichloride. The resulting mixture was stirred for 3 h at 60° to 70° C. After this time the solution was decanted off and the solvent removed under vacuum. The red-brown viscous residue obtained was twice more evaporated from dry benzene to give 6.91 g (85%) of 2-ferrocenyl-2-methylpropanoyl chloride, a red brown solid, which was recrystallised from light petroleum (40° to 60° C.). The ferrocenyl acid chloride (6.91 g) was dissolved in 10 cm3 of dichloromethane and added to a mixture of 6-aminopencillanic acid (5.18 g) and triethylamine (4.85 g) in 100 cm3 of dichloroethane at 2° C. The resulting mixture was stirred for 1 hour at 15° C., filtered and filtrate evaporated cold `in vacuo`. The residue was dissolved in a mixture of water and ethyl acetate and the aqueous phase adjusted to pH 2.5 with 2M HCl. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts of ethyl acetate were washed several times with water, dried and filtered. To the dry ethyl acetate solution was added 10 cm3 of a 40% solution of sodium 2-ethylhexanoate in 4-methylpentan-2-one. The mixture was concentrated under vacuum and then poured into 600 cm3 of dry ether. The product, which separated as a pale yellow solid, was collected by filtration and dried to yield 8.43 g (72%) of the penicillin. The i.r. spectrum showed a strong β-lactam carbonyl absorption at 1760 cm-1. A thin layer silica gel chromatogram (chloroform/acetone/acetic acid) showed a single substance.
Reaction SMILES: [OH:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C(NCC)C>C(O)C>[NH2:18][C:14]1[O:1][C:2]2[CH2:3][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=2[C:15]=1[C:16]#[N:17]
Reactant: CCOC(=O)N1CCC(=O)C(O)C1
Reactant: N#CCC#N
Solvent: CCO
Solvent: CCNCC
Product: CCOC(=O)N1CCc2c(oc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
Ethyl 3-hydroxy-4-oxopiperidine-1-carboxylate from Example 35A (4.00 g, 21.4 mmol) was dissolved in ethanol (10 mL), and propanedinitrile (1.41 g, 21.4 mmol) was added. Within 10 min, diethylamine (1.56 g, 21.4 mmol) was added dropwise, whilst the temperature was kept below 35° C. Subsequently, the reaction mixture was stirred for 20 h at rt. The precipitate was collected by suction filtration and washed with ethanol and diethyl ether to yield 2.00 g (39%) of the title compound.
Reaction SMILES: Cl.[CH2:2]([CH:4]([C:7]1[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[C:9]([O:16][CH3:17])[CH:8]=1)[CH2:5][CH3:6])[CH3:3].[OH:18][C:19]1[C:28]([CH2:29][CH2:30][CH3:31])=[CH:27][C:22]([C:23]([NH:25]O)=[NH:24])=[CH:21][C:20]=1[CH3:32]>>[CH2:5]([CH:4]([C:7]1[N:12]=[C:11]([C:13]2[O:15][N:25]=[C:23]([C:22]3[CH:27]=[C:28]([CH2:29][CH2:30][CH3:31])[C:19]([OH:18])=[C:20]([CH3:32])[CH:21]=3)[N:24]=2)[CH:10]=[C:9]([O:16][CH3:17])[CH:8]=1)[CH2:2][CH3:3])[CH3:6]
Reactant: CCC(CC)c1cc(OC)cc(C(=O)O)n1
Reactant: CCCc1cc(C(=N)NO)cc(C)c1O
Agent: Cl
Product: CCCc1cc(-c2noc(-c3cc(OC)cc(C(CC)CC)n3)n2)cc(C)c1O
Yield: 3.1 %

Procedure:
The title compound (3 mg) is prepared by coupling and cyclizing 6-(1-ethyl-propyl)-4-methoxy-pyridine-2-carboxylic acid hydrochloride (64 mg, 246 μmol) and 4,N-dihydroxy-3-methyl-5-propyl-benzamidine (54 mg, 259 μmol) as described in Example 1; LC-MS**: tR=0.88 min, [M+H]+=396.29.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:54][O:55][CH3:56])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][CH:34]([S:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:35]3(O)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(I)(I)P(I)I.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:54][O:55][CH3:56])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:35]3[C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CSC1SCC2C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N2C1(O)C(=O)OC(C)(C)C
Agent: IP(I)P(I)I
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CSC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2CS1
Reaction time: 1 h
Yield: 44.5 %

Procedure:
1.55 g of the product of Step A dissolved in 30 ml of pyridine and 1.4 g of diphosphorus tetraiodide were stirred under an inert atmosphere for 30 minutes and after a further 0.76 g of diphosphorus tetraiodide were added, the mixture was stirred for 1 hour. 100 ml of ethyl acetate were added followed by filtering and concentrating to dryness under reduced pressure at a temperature below 30° C. The residue was dissolved in ethyl acetate and the solution was filtered, washed first with 0.1N hydrochloric acid, then with a solution of sodium bicarbonate, and then with a sodium chloride solution, after which it was dried and concentrated to dryness. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and acetone (10-0.75). After crystallization from ether, 675 mg of racemic 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(ethoxycarbonylmethylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate melting at 212°-214° C. (decomposes) were obtained.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH:8]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[S:9]1)=[O:7])C.Cl>O.CCO>[CH:21]1[C:11]2[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:8]([C:6]([OH:7])=[O:5])[S:9][C:10]=2[CH:24]=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: CCOC(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Yield: 83.8 %

Procedure:
A solution of KOH (1.64 g, 29 mmol) in water (6 ml) was added to 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid ethyl ester (2.26 g, 7 mmol) in EtOH (16 ml) and the mixture heated to reflux for 2 hr. The reaction mixture was acidified with 2N HCl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to give 1.65 g (80%) of 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid as a yellow foam. 1H NMR (DMSO) δ 12.55 (1H, br s), 11.70 (1H, s), 7.74-7.82 (1H, m), 7.00-7.57 (7H, m), 5.17 (1H, s).