Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])[CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-c1cc(CBr)ccn1
Product: O=c1n(Cc2ccnc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 89, 261 mg (0.85 mmol) of the compound from Example 5A and 240 mg (0.85 mmol) of the compound from Example 65A were reacted with one another. This gave 249 mg (54% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([F:10])[CH:8]=O)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]S(F)(=O)=O)=[CH:19][C:18]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([F:10])[CH:8]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(F)Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of p-chloro-β-cyclopropyl-α-fluoro-cinnamaldehyde (224.6 mg, 1 mmol), (4-fluoro-3-phenoxyphenyl)methanesulfonyl fluoride (312.7 mg, 1.1 mmol), potassium carbonate (552.8 mg, 4 mmol), and 18-crown-6 (13.2 mg, 0.05 mmol) in acetonitrile is stirred at room temperature overnight, quenched with water, and extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product (380 mg, 94% pure by GC analysis, 93% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([N:25]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(Cl)c2c1
Reactant: NCc1ccccc1
Solvent: O
Product: CN(C)c1ccc2nc(N)c(C#N)c(N=Cc3ccccc3)c2c1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 mL of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 2.3 g of the title compound is obtained, m.p.: 265° C.
Reaction SMILES: [SH:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([OH:11])=[N:4][N:3]=1.[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[S:22][CH2:23][C:24]([NH:26][CH:27]1[C:42](=[O:43])[N:29]2[C:30]([C:39]([OH:41])=[O:40])=[C:31]([CH2:34]OC(=O)C)[CH2:32][S:33][C@H:28]12)=[O:25].[Na]>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[S:22][CH2:23][C:24]([NH:26][CH:27]1[C:42](=[O:43])[N:29]2[C:30]([C:39]([OH:41])=[O:40])=[C:31]([CH2:34][S:1][C:2]3[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([OH:11])=[N:4][N:3]=3)[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: CCn1c(S)nnc(O)c1=O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSc3cc(Cl)ccc3Cl)[C@H]2SC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CCn1c(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CSc4cc(Cl)ccc4Cl)[C@H]3SC2)nnc(O)c1=O

Procedure:
To 12 ml. of water were added with stirring 571 mg. of 3-mercapto-4-ethyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine. The pH of the resulting mixture was 2.3 and was adjusted to 6.6 by addition of 2.9 ml. of 1 N sodium hydroxide. 7-(2,5-Dichlorophenylthio)acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid, sodium salt (1.54 g., 3 mmol.) was added, and the resulting mixture was treated in accordance with the procedure described in Example 8 to obtain 7-(2,5-dichlorophenylthio)acetamido-3-(4-ethyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-ylthio)methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[O:8]2.C[N+]1([O-])CC[O:29]CC1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH2:5][C:6](=[O:29])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[O:8]2
Reactant: COc1cc(OC)c2c(c1)OC(c1ccc(OC)c(OC)c1)C=C2
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(c1)OC(c1ccc(OC)c(OC)c1)C(=O)C2
Temperature: 25 °C
Reaction time: 36 h
Yield: 30 %

Procedure:
(2R)-3-[(2R,3S)-5,7,3′,4′-tetrakis(methyloxy)-3-hydroxyflavan)]-5,7,3′,4′-tetramethoxyflavan-3-ene (6) (20 mg, 0.030 mmol) was dissolved in THF (5 mL) and OsO4 (0.9 mg, 0.004 mmol) and N-methylmorpholine-N-oxide (16.3 mg, 0.139 mmol) was added. The reaction mixture is stirred 1-2 days at r.t. under argon (TLC monitoring of consumption of starting material). Solution of sodium metabisulfite (10% aq.) was added and reaction mixture was stirred for 30 minutes. Then was made the extraction 3× with dichloromethane, washed with NaHCO3 (sat. aq.), NaCl (sat. aq.) and dried over MgSO4. Evaporation left crude material which was purified on preparative TLC plates (toluene acetone 6:4) to afford (2S,3S)-3-[(2R,3S)-5,7,3′,4′-tetrakis(methyloxy)-3-hydroxyflavan)]-5,7,3′,4′-tetramethoxyflavan-3-one (7) (Rf 0.19, 6 mg, 0.009 mmol, 30%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C[Si]([C:27]#[N:28])(C)C.[OH-].[NH4+]>C(O)(=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)([C:27]#[N:28])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of 1-Benzyl-piperidin-4-one (2.68 g, 14.20 mmol) in acetic acid (13 ml, glacial) was added 4-Chloro-phenylamine (1.99 g, 15.6 mmol). The reaction was cooled in a cool temperature water bath. Trimethylsilylcyanide (1.89 ml, 14.20 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and stir overnight under N2. The reaction was cooled to 0° C. Concentrated ammonium hydroxide (15 ml) was added slowly. Next added was cold water. The pH of the mixture was ≈10. The mixture was extracted three times with methylene chloride, and the organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Ether was added to the residue, and the white solid was filtered off and dried under high vacuum to give the titled compound (3.73 g, 81%)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[CH3:18][Mg]Br.CCOCC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C:5](=[CH2:18])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2ccc(I)cc12
Reactant: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1c2cc(Br)ccc2Oc2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 500 ml RB flask was charged with 2-bromo-7-iodo-9H-xanthen-9-one (16.030 g, 40.0 mmol) and THF (150 mL). The mixture was stirred for 10 min at RT and the resulting suspension was placed in water-ice bath for another 10 min. Methylmagnesium bromide, 3.0 M in Et2O (20.0 ml, 60.0 mmol) was added dropwise. After 1 hr, the mixture was carefully quenched with sat NH4Cl (150 mL) at 0° C. and diluted with EtOAc. The organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo. The material was dissolved in 100 mL of methylene chloride, treated with PPTS (0.201 g, 0.800 mmol), and heated to reflux for 2 hr. The mixture was cooled to RT, diluted with methylene chloride, and washed with saturated sodium bicarbonate and brine. The organic fraction was dried over sodium sulfate and concentrated in vacuo to afford crude 2-bromo-7-iodo-9-methylene-9H-xanthene as a light orange solid that was advanced without further purification. MS: MH+=399.0/401.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6](Br)[N:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O)C.C(OCC)(=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>[NH2:9][C:3]1[C:2]([Br:1])=[N:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ncc(Br)nc1Br
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: [Cs+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccccc2)nc1Br
Temperature: 75 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
To a stirred solution of 3,5-dibromo-2-aminopyrazine (200 mg; 0.79 mmol) and phenyl boronic acid (106 mg; 0.87 mmol) in dioxane (4 mL) and ethanol (2 mL) was added cesium carbonate (571 mg; 1.75 mmol in 2 mL of water) followed by Pd(PPh3)4 (46 mg; 0.04 mmol). The reaction was heated to 75° C. and stirred for 12 hours. The reaction was cooled to room temperature, diluted with 50 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×50 mL), brine (50 mL), then dried (MgSO4), and filtered. The material was purified using a biotage 12L cartridge eluting with hexanes and ethyl acetate (3:1) to yield an off white solid (88% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH2:23])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].CCN(CC)CC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:34](=[O:35])[O:36][CH2:37][CH3:38])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC1(C(=O)Nc2ccc(N(CC)CC)cc2)CCc2ccccc2C1
Reaction time: 8 h
Yield: 24.4 %

Procedure:
The amine from Example 8A (34 mg, 0.1 mmol) was dissolved in THF (0.5 mL) and Et3N (15 mg, 0.1 mmol) and ethyl chloroformate (13 mg, 0.12 mmol) were added at 0° C. after which the mixture was allowed to stir overnight. HPLC purification gave the titled compound (10 mg, 24%). 1H NMR (300 MHz, DMSO-D6) δ 9.14 (s, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.08 (m, 4H), 7.08 (s, 1H), 6.61 (d, J=9.0 Hz, 2H), 3.96 (m, 2H), 3.28 (q, J=6.6 Hz, 4H), 3.02 (d, J=16.5 Hz, 1H), 2.73 (m, 2H), 2.36 (m, 1H), 2.05 (m, 1H), 1.13 (t, J=6.9 Hz, 3H), and 1.05 (t, J=7.2 Hz, 6H). (one proton (ArCHnHbC(C═O)) overlapped with water)). MS (ESI) positive ion 410 (M+H)+; negative ion 408 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:41])[N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:41]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Yield: 61 %

Procedure:
{(1R)-1-{N-Methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester (2.4 g, 4.2 mmol) was dissolved in a mixture of trifluoroacetic acid (40 ml) and dichloromethane (40 ml) at 20° C. After 10 min the reaction mixture was concentrated in vacuo and coevaporated from dichloromethane (80 ml). The residue was crystallised from ethyl acetate to give 1.19 g of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:10]([F:29])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[NH2:8][C:9]1[C:10]([F:29])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1
Reactant: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)ccn1
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N)c2F)ccn1

Procedure:
To a solution of {4-[3-(3-dibenzylamino-2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-pyridin-2-yl}-methyl-amine (408 mg, 0.849 mmol) in toluene (4.30 mL) trifluoro-methanesulfonic acid (4.30 mL) was added and the mixture was irradiated in the microwave oven at 120° C. for 30 minutes. The reaction was then poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 5% methanol in methylene chloride (60% over 4 steps).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C>[CH2:6]([NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][O:14][CH:15]([F:16])[F:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N[C@H](COC(F)F)C(=O)NCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
A solution of (2R)-2-amino-N-benzyl-3-(difluoromethoxy)propanamide (113 mg, 0.46 mmol) in ethyl acetate was cooled in an ice bath. To the cooled solution was added triethylamine (139 mg, 1.38 mmol) followed by methanesulfonylchloride (63 mg, 0.55 mmol). The reaction mixture was stirred for 15 minutes and then quenched with water, extracted with ethyl acetate and washed with brine. The organic layer was dried, concentrated and triturated with diethyl ether to give the product (33 mg, 22%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.31 (m, 5H), 6.73 (br, 1H), 6.24 (t, 1H), 5.21 (d, 1H), 4.48 (d, 2H), 4.21 (m, 3H), 3.01 (s, 3H)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C(C1C=CC(O)=CC=1)C.C1(O)C=CC=CC=1.C1C(O)=CC=C(C)C=1.N(C(C)(C)C(OC)=O)=NC(C)(C)C(OC)=O>CO.O>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Agent: CCc1ccc(O)cc1
Agent: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Agent: Cc1ccc(O)cc1
Solvent: O
Solvent: CO
Solvent: Oc1ccccc1
Product: C#Cc1ccc(O)cc1

Procedure:
To 536.3 g of a p-vinylphenol fraction obtained by the same vacuum flash distillation as in Example 1, containing 32.9% of p-vinylphenol, 49.1% of p-ethylphenol, 1.6% of phenol, 7.0% of p-cresol and 9.4% of water were added 160.9 g of methanol as a solvent and 5.36 g of dimethyl 2,2′-azobisisobutyrate as an initiator. The resulting mixture was subjected to a polymerization reaction at 80° C. for 5 hours. The reaction mixture was treated in the same manner as in Example 1 to obtain 98.2 g of a poly(p-vinylphenol). The polymer had a Mw of 8,800, a Mn of 5,200 and a light transmittance at 248 nm, of 76.9%.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:7].[NH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(CC)CC)C>CO>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:10][C@H:9]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:7]
Reactant: NN1CCOCC1
Reactant: CS(=O)(=O)OCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCNN2CCOCC2)C[C@H]1Cc1c[nH]c2ccccc12
Yield: 27.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-methylsulfonyloxyethyl)piperazine (200 mg), 4-aminomorpholine (36 mg) and triethylamine (52 mg) in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) as an eluent to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[2-(morpholinoamino)ethyl]piperazine (55 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8](OCC)=O.CC1C=CC(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=1.[NH3:28]>>[F:14][C:2]([F:1])([F:13])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:28]=[CH:25][NH:26][CH:27]=1
Reactant: CCOC(=O)c1ccoc1C(F)(F)F
Reactant: N
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Product: FC(F)(F)c1occc1-c1c[nH]cn1

Procedure:
Furanyl-imidazoles were prepared by the TosMIC reaction from aldehydes, which can be obtained either by reduction of acids, esters or amides; or by oxidation of primary alcohols. These procedures are well known in the literature. For example, ethyl 2-trifluoromethyl-furan-3-carboxylate (Scheme 17) prepared from literature procedures (U.S. Pat. No. 5,405,865, Apr. 11, 1995) was converted to an aldehyde by reduction of a Weinreb amide. The aldehyde was then reacted with the TosMIC and methanolic ammonia to yield 4-(2-trifluoromethyl-furan-3-yl)-imidazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([NH2:10])=O)[NH:6][CH:7]=1)#[N:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:20]2)=CC=1>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:8](=[S:20])[NH2:10])[NH:6][CH:7]=1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1c[nH]c(C(N)=O)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(C(N)=S)c1
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A mixture of 4-cyanopyrrole-2-carboxamide (1.35 g, 10.0 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (4.0 g, 9.9 mmol) in toluene is heated at 100° C. for 41/2 hours, diluted with tetrahydrofuran and heated at reflux for 20 minutes. The reaction mixture is then cooled and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate mixture gives the title product as a yellow solid (0.9 g, mp 253° C. dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]N=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]1([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Cc1ccccn1
Reactant: c1ccncc1
Product: c1ccc(C2CCCNC2)cc1

Procedure:
Pyridine and 2-methylpyridine
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:45]([NH:46][C:47](=[O:56])[CH2:48][O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44](=[O:57])[N:26]2[C:27]=1[C:28]([O:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(OCC)(=O)C>[Br-:20].[C:38]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:30][C:28]([C:27]2[N:26]3[C:44](=[O:57])[C@@H:45]([NH:46][C:47](=[O:56])[CH2:48][O:49][C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@H:25]3[S:24][CH2:23][C:22]=2[CH2:21][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:29])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Product: [Br-]
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of triphenylphosphine (0.90 g, 1.5 equiv.) in ethyl acetate (10 ml) was added to a stirred solution of diphenylmethyl 3-bromomethyl-7β-phenoxyacetamidoceph-3-em-4-carboxylate (ca. 1.49 g, 2.515 mmole) in ethyl acetate (25 ml). The mixture was stirred in the absence of light for 16 hours, and the precipitated solid was filtered off, washed with ethyl acetate and dried to give the title phosphonium salt (1.585 g, 74%), λmax. (EtOH) 268.5 nm (ε 10,700) and 275.5 nm (ε 9,850), νmax. (CHBr3), 3415 (NH), 1788 (azetidin-2-one), 1710 (CO2R), 1692 and 1620 (CONH) and 1440 cm-1 (P+ --C6H5).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[CH2:12](I)[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6])[CH3:13]
Reactant: CCI
Reactant: O=Cc1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(O)c1O

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3,4,5-trihydroxybenzaldehyde with ethyl iodide in DMF using K2CO3 as base. MS (ISN): 181.1 [M−H]−.
Reaction SMILES: [NH2:1][S:2]([C:5]1[N:6]([CH3:14])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25](=O)[O:26]C2C=CC=CC=2)[N:18]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25]([NH:1][S:2]([C:5]2[N:6]([CH3:14])[CH:7]=[CH:8][C:9]=2[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3])=[O:26])[N:18]=1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1ccn(C)c1S(N)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccn(C)c1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Methyl 2-(aminosulfonyl)-1-methyl-1H-pyrrole-3-carboxylate (0.10 g, 0.46 mmol) and 0.13 g (0.50 mmol) of phenyl (4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate were combined in 2 mL of acetonitrile and 0.075 mL of DBU was added and the resulting amber solution was stirred at ambient temperature for 30 min. The reaction mixture was diluted with 15 mL of water and acidified with 0.5 mL 1N HCl and the resulting precipitate was collected by filtration and rinsed successively with water and ether, then dried to afford 0.13 g of the title compound as a white solid, m.p. 189°-190° C. (dec).