Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[NH2:8][C:6]1[CH:5]=[C:4]([OH:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1cc(O)cc(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
3-Chloro-5-nitrophenol from Example 63A (3.00 g, 17.3 mmol) and zinc powder (5.65 g, 86.4 mmol) in ethanol (80 mL) were heated to 60° C., and a solution of ammonium chloride (1.85 g, 34.6 mmol) in water (16 mL) was added dropwise. The reaction was stirred for further 3 h at 60° C. It was then filtered through Celite®, and the solvent was removed in vacuo. The residue was dissolved in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with DCM, and the precipitate was collected by suction filtration to yield 1.97 g (77%) of the title compound as yellowish crystals.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][CH3:22])([C:7]#[N:8])[C:5]#[N:6]
Reactant: CCCI
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.3 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.3 g of 1-iodopropane were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.1 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-propylmalononitrile (hereinafter, referred to as the present compound (82)).
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][C@@H:15]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.CCOC(C)=O.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][C@@H:15]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:11][N:10]=[CH:9]2)=[CH:42][CH:43]=1)#[N:2]
Reactant: CS(=O)(=O)CC[C@@H](CN(Cc1cccc(Cl)c1)C(=O)OCc1ccccc1)NCc1cncn1Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)CC[C@@H](CNCc1cccc(Cl)c1)NCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
To a solution of the product from Step F (163 mg, 0.262 mmol) in 3 mL of methanol and 3 mL of EtOAc was added at room temperature 10% palladium on carbon (10 mg). A balloon of hydrogen gas was introduced to the solution via syringe needle, and the reaction was stirred for ca. 20 minutes. The solution was filtered through celite to remove the catalyst, then concentrated in vacuo. The resulting product was purified by silica gel chromatography (4% MeOH/CH2Cl2 with 1% NH4OH) to provide the titled compound (63 mg).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:16]1=[O:17].[F:26][C:27]([F:40])([F:39])[S:28]([O:31]S(C(F)(F)F)(=O)=O)(=[O:30])=[O:29]>ClCCl>[F:26][C:27]([F:40])([F:39])[S:28]([O-:31])(=[O:30])=[O:29].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:23]2[CH:24]=[C:25]3[C:20]([CH:19]=[CH:18][C:16](=[O:17])[O:15]3)=[CH:21][CH:22]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1ccc2ccccc2o1
Reactant: O=S(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: O=c1ccc2ccc([S+](c3ccccc3)c3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To 160 ml of dichloromethane were dissolved 20.2 g (0.1 mol) of diphenylsulfoxide and 17.5 g (0.12 mol) of coumarin, and 28.2 g (0.1 mol) of trifluoromethanesulfonic anhydride was added dropwise thereto at −70 to −60° C., followed by gradually warming to room temperature and reacting with stirring for 2 hours. After completion of the reaction, the obtained reaction solution was washed with water (160 ml×5 times) and concentrated under reduced pressure, followed by purifying the resulting crude product by a column chromatography to obtain 32.1 g of objective substance as pale yellow glassy substance (yield: 67%).
Reaction SMILES: [C:1]([O-])(C)(C)C.[K+].CI.[CH2:9]([O:11][C:12](=[S:18])[CH2:13][C:14]([CH2:16][CH3:17])=[O:15])[CH3:10]>O1CCCC1>[CH2:9]([O:11][C:12](=[S:18])[CH:13]([CH3:1])[C:14]([CH2:16][CH3:17])=[O:15])[CH3:10]
Reactant: CCOC(=S)CC(=O)CC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=S)C(C)C(=O)CC
Temperature: 60 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
First 12.3 g (0.11 mol) of potassium tert.-butanolate and then 15.6 g (0.11 mol) of methyl iodide were added to a solution of 17.6 g (0.1 mol) of 4-methylthioacetoacetic acid ethyl ester in 100 ml of tetrahydrofuran, while cooling. The mixture was subsequently stirred at 60° C. for 12 hours, the solvent was then distilled off in vacuo, 200 ml of methylene chloride were added to the residue and the solution was extracted by shaking twice with 100 ml of water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was distilled in vacuo. 14 g (74% of theory) of 2-methyl-4-methylthioacetoacetic acid ethyl ester with a boiling point of 95°-99° C./2 mm Hg were thus obtained. ##STR6##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]([CH2:31][CH3:32])[C:28](O)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][C:28](=[O:29])[CH:27]([N:19]3[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[N:22]=[C:18]3[CH3:17])[CH2:31][CH3:32])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC(C(=O)O)n1cc(C(F)(F)F)nc1C
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C)n1cc(C(F)(F)F)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]butanoic acid (0.032 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.034 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.47 (q, J=1.2 Hz, 1H), 7.34-7.24 (m, 2H), 7.21-7.11 (m, 2H), 6.98 (s, 1H), 4.65 (dd, J=10.1, 5.3 Hz, 1H), 3.00-2.88 (m, 1H), 2.49 (ddd, J=14.4, 7.4, 5.3 Hz, 1H), 2.45 (s, 3H), 2.13-2.00 (m, 1H), 1.11-0.97 (m, 9H); MS: (ES) m/z calculated for C21H23F4N5O [M+H]+ 438.2, found 438.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH3:18])([CH3:17])[CH:14]([CH3:16])[CH3:15])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH3:17])([CH3:18])[CH:14]([CH3:15])[CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)C(C)(C)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C(C)(C)N=C=Nc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 2.3 g of N-(3,5-dichlorophenyl)-N'-(1,1,2-trimethylpropyl)thiourea produced in Example A-4 in 50 ml of dichloromethane were added 3.9 g of triphenylphosphine, 2.4 g of carbon tetrachloride and 1.5 g of triethylamine. The mixture was refluxed for 3 hours and evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-(3,5-dichlorophenyl)-N'-(1,1,2-trimethylpropyl)carbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 1.3 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 120° C. for 12 hours, cooled to room temperature and poured into 600 ml of water. The resulting crystals were collected by filtration and purified by silica gel column chromatography using chloroform as a solvent to yield 1.6 g of crude product. Recrystallization from benzene-cyclohexane mixture gave 1.2 g of the title compound as colorless platelets melting at 167.0°-170.0° C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:13][NH:14][C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O1CCCC1>[C:6]1([C:5]2[O:22][C:15]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CCC(=O)NNC(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1nnc(-c2ccccc2)o1
Reaction time: 3 h
Yield: 64.6 %

Procedure:
Thionyl chloride (0.34 mL, 4.7 mmol) was added to the mixture of methyl 4-(2-benzoylhydrazino)-4-oxobutanoate (900 mg, 4 mmol), Pyridine (0.87 mL, 0.011 mol) in tetrahydrofuran (20 mL) at room temperature. After stirring for 3 hours, the reaction mixture was concentrated. The residue was mixed with toluene (20 mL) and refluxed overnight. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to yield the desired product (600 mg, 72%). LCMS calculated for C12H13N2O3 (M+H): 233.1. found: 233.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Br[C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2.CCN(CC)CC>C(Cl)Cl>[C:32]1([C:19]2([NH:1][C@@H:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:4])[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: COC(=O)C[C@H](N)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
Pb(NO3)2 (6.06 g, 18.3 mmol) was added over 1 min to a CH2Cl2 (80 mL) solution of (S)-1-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol), 9-bromo-9-phenyl-9H-fluorene (6.44 g, 20.0 mmol) and Et3N (3.0 mL, 21.5 mmol), and the heterogeneous mixture was stirred at ambient condition for 48 hr. The mixture was filtered and the filtrate was treated with MgSO4 and filtered again, and the final filtrate was concentrated. The resulting crude material was submitted to a BIOTAGE® purification (350 g silica gel, CH2Cl2 elution) to afford (S)-1-benzyl 4-methyl 2-(9-phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorless oil (7.93 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 7.82 (m, 2H), 7.39-7.13 (m, 16H), 4.71 (d, J=12.4, 1H), 4.51 (d, J=12.6, 1H), 3.78 (d, J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partially overlapped with solvent). LC (Cond. 1): RT=2.16 min; LC/MS: Anal. Calcd. for [M+H]+ C31H28NO4: 478.20; found 478.19.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.[NH:24](C(OCC1C=CC=CC=1)=O)[C@H:25]([C:36]([NH:38][C@H:39]([C:43](O)=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1>>[NH2:24][C@@H:25]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:36]([NH:38][C@@H:39]([CH:40]([CH3:41])[CH3:42])[C:43]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:44])=[O:37]
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Method B, Example 12, and employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-Trp-Val-OH as the staring materials, which yielded the title compound as a white powder. 1H NMR (CD3OD, 300 MHz): δ 7.65-7.62 (d, 1H), 7.38-7.35 (d, 1H), 7.17-7.01 (m, 3H), 4.26-4.20 (m, 1H), 4.17-4.14 (d, 1H), 4.05 (m, 1H), 3.46-3.20 (m, 4H), 2.00 (m, 1H), 1.9-1.88 (m, 2H), 1.77-1.54 (m, 8H), 1.34-1.16 (m, 3H), 1.05-0.94 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 42.89. LCMS m/z: [M+H]+=521.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]=[C:20]1[NH:29][C:28](=S)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1>CN(C)C=O>[O:19]=[C:20]1[N:29]=[C:28]([NH:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=c1[nH]c(=S)c2ccccc2[nH]1
Solvent: CN(C)C=O
Product: O=c1nc(NCCCOc2cc(CN3CCCCC3)ccn2)c2ccccc2[nH]1

Procedure:
3-[4-(Piperidinomethyl)pyrid-2-yloxy]propylamine (2.03 g) and 2-oxo-4-thiono-1,2,3,4-tetrahydroquinazoline (1.24 g) were stirred in dimethylformamide (5 ml) at ambient temperature for 5 days. The reaction mixture was filtered to afford a solid that was washed with cold dimethylformamide and diethyl ether to yield the title product (1.25 g), m.p. 189°-192° C. (recrystallised from isopropanol).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[CH:16]=1)[CH:11]=[CH:10]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc(CN)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: COc1cccc(CNc2ccc3cc(NCc4ccccc4)ccc3n2)c1

Procedure:
The title compound, MS: m/e=370.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-methoxybenzylamine and benzylamine.
Reaction SMILES: CN(C)C=O.FC(F)(F)S(O[C:12]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][C:15]([C:25]([O:27][CH3:28])=[O:26])=[CH:14][N:13]=1)(=O)=O.[C:31]([C:33]1([OH:41])[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1)#[CH:32].N>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.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:18]([C:17]1[C:12]([C:32]#[C:31][C:33]2([OH:41])[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[N:13][CH:14]=[C:15]([C:25]([O:27][CH3:28])=[O:26])[CH:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COC(=O)c1cnc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
50 ml of N,N-dimethylformamide was added to a mixture of 2.0 g of 3-benzyl-5-methoxycarbonyl-2-pyridyl trifluoromethanesulfonate, 742 mg of 3-ethynyl-3-quinuclidinol, 1.5 g of tetrakis(triphenylphosphine)palladium(0), 374 mg of cuprous iodide and 2.7 ml of triethylamine, followed by heating under stirring for one hour in an oil bath kept at 60° C. in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using chloroform/methanol/aqueous 36% ammonia (46:3:0.3) as an eluent for separation and purification, to give 1.1 g of the target compound.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8](=[CH:12][CH2:13][CH:14]1[CH2:19][CH:18]2[C:16]([CH3:20])([CH2:17]2)[C:15]1([CH3:22])[CH3:21])[C:9](=[O:11])[CH3:10].CI.O>O1CCCC1>[CH3:7][C:8]([CH3:1])([CH:12]=[CH:13][CH:14]1[CH2:19][CH:18]2[C:16]([CH3:20])([CH2:17]2)[C:15]1([CH3:22])[CH3:21])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)C(C)=CCC1CC2CC2(C)C1(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CC(=O)C(C)(C)C=CC1CC2CC2(C)C1(C)C
Temperature: -35 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
5.0 g (43 mmol) of potassium tert-butoxide dissolved in 50 ml of tetrahydrofuran was added to the solution of 8.7 g (40 mmol) of 3-methyl-5-(1,2,2-trimethylbicyclo-[3.1.0]hex-3-yl)pent-3-en-2-one in 50 ml of the same solvent at −40° C. After 5 minutes of stirring at −35° C. 7.0 g (45 mmol) of methyl iodide was added rapidly and stirring continued at −20° C. for 10 minutes. The reaction mixture was poured on 200 ml of water and worked up as usual. Flash chromatography of the crude product (silica gel; eluent: hexane/MTBE 9:1) followed by Kugelrohr distillation at 150° C./0.1 Torr gave 7.3 g (78% yield) of 3,3-dimethyl-5-(1,2,2-trimethylbicyclo[3.1.0] hex-3-yl)pent-4-en-2-one.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[N:5]=1.CO.O.[NH2:25]N>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]=[C:4]([NH:3][NH2:25])[CH2:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[CH:17]=1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 0.67 h

Procedure:
To a suspension of 3.4 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine dihydrochloride in 60 parts by volume of methanol is added 1.25 parts of 80% hydrazine hydrate. The suspension is stirred for 40 minutes, diluted with water and extracted with methylene chloride. The extract is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from a mixture of methylene chloride and benzene to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as colorless prisms. Melting point: around 170° C (browning), 202° C to 204° C (decomposition).
Reaction SMILES: [CH2:1](OP(C#N)(=O)OCC)C.C[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][N:20]=2)=[CH:14][C:13]=1[NH2:31].[C:32]([NH:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:39](O)=[O:40])(=[O:34])[CH3:33].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:32]([NH:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:39]([NH:31][C:13]1[CH:12]=[CH:17][C:16]([CH3:1])=[C:15]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][N:20]=2)[CH:14]=1)=[O:40])(=[O:34])[CH3:33]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CC(=O)Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(C(=O)Nc2ccc(C)c(Nc3nccc(-c4cccnc4)n3)c2)cc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Diethylcyanophosphonate (Aldrich, Buchs, Switzerland; 0.66 mL, 4.0 mmol) is added to a stirred mixture of 4-methyl-N-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine (554 mg, 2.0 mmol), 3-acetylamino-5-(trifluoromethyl)-benzoic acid (495 mg, 2.0 mmol) and triethylamine (1.12 mL, 8.0 mmol) in 10 mL N,N-dimethylformamide at 20° C. under an argon atmosphere. After stirring for 18 hours at 20° C., the mixture is treated with saturated aqueous solution of sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined extracts are dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to afford a crude product. The crude product is purified by column chromatography on silica gel, eluent dichloromethane/methanol/aqueous ammonia. The pure fractions are combined, the solvent is evaporated off under reduced pressure and the residue is crystallised from ethyl acetate-hexane to give the title compound as a cream crystalline solid.
Reaction SMILES: [Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]12)=[O:9].[S:25]([N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(N(CC)CC)C>CN(C)C=O.O>[Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][O:19][C:39](=[O:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[C:36](=[O:45])[NH:35][S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: Cc1ccc(S(=O)(=O)N2C(=O)c3ccccc3C2=O)cc1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)c2ccccc2C(=O)OCC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)Cc4cccs4)[C@H]3SC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
In N,N-dimethylformamide (40 ml) is dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (3.8 g), followed by the addition of N-tosylphthalimide (4.0 g) and triethylamine (2.0 ml) in that order. The mixture is stirred at room temperature for 4 hours. The reaction mixture is poured in water (100 ml) and rinsed with ethyl acetate. The aqueous layer is adjusted to pH 2.0 with dilute phosphoric acid and extracted with ethyl acetate. The extract is dried and, then, a solution of sodium 2-ethylhexanoate in isopropyl alcohol is added. By this procedure is obtained 7β-(2-thienylacetamido)-3-[2-(N-tosylcarbamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid sodium salt (4.0 g).