Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[C:15][C:25]3[CH:26]=[CH:27][C:22]([C:21]([O:20][CH2:18][CH3:19])=[O:29])=[CH:23][CH:24]=3)[CH:8]=2)[O:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1cc2c(cc1C)OC(C)(C)CC2(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)OC(C)(C)CC3(C)C)cc1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
Nitrogen was bubbled for 15 min through a solution of 200 (0.877 mmol) of 2,2,4,4,7-pentamethyl-6-ethynylchroman (Compound 9) and 245.3 mg (0.888 mmol) of ethyl 4-iodobenzonate (Compound 97) in 2 ml of triethylamine. The mixture was then placed under an argon atmosphere and treated with a finely ground mixture of 50 mg (0.2625 mmol) of cuprous iodide and 100 mg (0.1425 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction vessel was then fitted with a reflux condenser and the mixture was heated at 55 degrees C. under argon for 72 hours. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica, 5% ethyl acetate in hexane) to give the title compound as a yellow oil. PMR (CDCl3) : & 1.32 (12H, s), 1.37 (3H, t, J~7.0 Hz), 1.80 (2H, s) 2.40 (3H, s), 4.36 (2H, q, J~7.0 Hz), 6.66 (1H, s, 7.42 (1H, s), 7.54 (2H, d, J~8.6 Hz), 7.99 (2H, d, J~8.6 Hz). MS exact mass, m/e 376.2 038 (calcd. for C25H28O3, 376 2038).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([C:30](=[O:39])[CH2:31][C:32]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)=[O:33])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51]([OH:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1>CO>[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([C:30](=[O:39])[CH2:31][C:32]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)=[O:33])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCc1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A solution of 0.390 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-2′-[2-(1-imidazoyl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.143 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 1 hour and evaporated. The residue was triturated with diethyl ether, filtered and dried to give 0.320 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-2′-[2-(1-imidazoyl)acetyl]-2′-isobutyl-4-methylvalerohydrazide p-toluenesulphonate in the form of a pale pink solid.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:17])[N:10]=[C:9]3[C:3]([NH2:27])([CH2:4][O:5]2)[CH2:2]1.[CH3:28][N:29]([CH3:35])[C:30](=[O:34])[C:31](O)=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:28][N:29]([C:30]([C:31]([NH:27][C:3]12[CH2:4][O:5][CH:6]([CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:17])[N:10]=[C:9]31)[CH2:1][CH2:2]2)=[O:32])=[O:34])[CH3:35]
Reactant: CN(C)C(=O)C(=O)O
Reactant: NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(=O)NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-(epoxymethano)pyrimido[1,2-a]azepine-2-carboxamide (70 mg, 0.187 mmol) and 2-(dimethylamino)-2-oxoacetic acid (32.8 mg, 0.280 mmol) in DMF (3 mL) was added diisopropyl-ethylamine (0.175 mL, 1.002 mmol), 4-(dimethylamino)pyridine (DMAP) (4.57 mg, 0.037 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (107 mg, 0.280 mmol) and the resulting mixture stirred at room temperature for 3 h. After work-up the crude was purified by preparative HPLC to afford the title compound as an off-white solid (35 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ: 12.11 (s, 1H), 8.73 (brs, 1H), 7.47 (s, 1H), 7.34 (dd, 2H, J=8.39 & 5.34 Hz), 6.98-7.03 (m, 2H), 4.62-4.70 (m, 2H), 4.53 (d, 2H, J=6.71 Hz), 4.49-4.52 (m, 1H), 4.29 (d, 1H, J=11.6 Hz), 4.08 (d, 1H, J=16.79 Hz), 3.21 (s, 3H), 2.89 (s, 3H), 2.46-2.53 (m, 1H), 2.33-2.38 (m, 1H), 1.86-1.92 (m, 1H), 1.53-1.58 (m, 1H). LCMS (M+H)=474.24. HPLC purity>95%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[C:22]3[CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[CH2:26][CH2:27]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Reactant: CC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)CCCN1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
9.2 g of sodium carbonate are added to a solution of 10 g of 4-(10,11-dihydro-5-dibenzo[a,d]cycloheptenylidene)piperidine in 100 cc of chloroform, a solution of 7.2 g of 5-bromo-2-pentanone in 50 cc of chloroform is then added dropwise within 20 minutes, and the mixture is subsequently boiled at reflux for 17 hours. After cooling, the precipitate is filtered off, the filtrate is extracted twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is filtered over a column of 170 g of silica gel. The fraction eluted with chloroform containing 1% of methanol is dissolved in acetone and acidifed with hydrogen chloride in ether. After the addition of more ether, the hydrochloride of the title compound crystallizes. M.P. 235°-238°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([CH2:21][NH:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:4]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([CH2:21][N:22]([CH3:29])[N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:4]=1
Reactant: COCn1c(=O)c2c(c3c(OC)cc(CNN4CCOCC4)cc31)NCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COCn1c(=O)c2c(c3c(OC)cc(CN(C)N4CCOCC4)cc31)NCCC2
Temperature: 0 °C
Reaction time: 18 h
Yield: 7.5 %

Procedure:
The compound (40 mg, 0.10 mmol) prepared in step 3 of Example 96 and potassium carbonate (22 mg, 0.15 mmol) were dissolved in acetonitrile (5 ml), added with iodo methane (0.008 ml, 0.12 mmol). The resulting mixture was heated to reflux temperature and stirred for 18 hours. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (dichloromethane:methanol=15:1) to obtain the title compound (3 mg, yield: 8%, yellow solid).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(=O)([O-])O.[Na+].C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:21][CH2:20][C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)=[O:7]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NCc1cccnc1)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 20 h

Procedure:
3-Fluoro-4-nitrobenzoic acid 2.78 g, 3-pyridylmethylamine 1.55 mL, N,N-diisopropylethylamine 2.61 mL, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 4.31 g, 1-hydroxybenzotriazole monohydrate 2.98 g and acetonitrile 39 mL were mixed and stirred for 20 hours. The reaction liquid was poured in saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine by the order stated, and dried over magnesium sulfate. Distilling the solvent off, 4.09 g of the title compound was obtained.
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1)=[O:2].Cl[CH2:13][O:14][CH3:15]>>[CH:1]([C:3]1[N:4]([CH2:13][O:14][CH3:15])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1)=[O:2]
Reactant: COC(=O)c1c[nH]c(C=O)c1
Reactant: COCCl
Product: COCn1cc(C(=O)OC)cc1C=O

Procedure:
reacting a methyl 2-formyl-4-pyrrolcarboxylate with chloromethyl-methyl-ether in the presence of a base and a suitable organic solvent, obtaining as a reaction product methyl 2-formyl-N-methoxymethyl-4-pyrrolcarboxylate;
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:14][CH3:15])(=[O:13])[CH3:12].CO.C(OC)(=O)CC(C)=O>>[C:1]([CH2:12][C:11]([O:14][CH3:15])=[O:13])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)=O
Reactant: COC(=O)c1ccccc1
Agent: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)CC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A 1-L flask fitted with a mechanical stirrer, reflux condenser, and nitrogen sweep (to protect the Na), was immersed in a water bath to control temperature (i.e., to provide heat and to cool if need be). In the flask was placed 272.3 g (2 moles) of methyl benzoate; 74.1 g (1 mole) of methyl acetate; 1 gm. atom--23 g., Na; and 32 g (1 mole) of methanol (to react with the Na and to initate the reaction). The flask was purged with nitrogen and was maintained under a positive nitrogen pressure throughout the reaction. The solution was heated to 80°-85° C. overnight, during which time all the Na metal was consumed. The resulting yellow heterogeneous solution was cooled to room temperature and poured into a separatory funnel containing 130 ml of concentrated hydrochloric acid and 200 g. of crushed ice. This was shaken and the lower aqueous phase removed. (In this step the Na in the Na methyl benzoyl acetate reacts with the HC1 and is removed as NaCl.) The residual material was then washed with water, 2×100 mls, saturated NaHCO3 solution, 2×100 mls. and finally 2×100 mls of saturated brine (NaCl). (Byproduct methanol leaves with the water in the water washes). The residual yellow organic phase was then transferred to a distilling flask and fractionated through a 12-inch Vigreux column at 0.5 mm Hg pressure. A forerum containing methyl benzoate and methyl acetoacetate was collected at 37°-42° C. at 0.5 mm Hg. This was followed by a fraction of 82.5 methyl benzoyl acetate boiling at 81°-84° C. at 0.5 mm Hg. Yield of the pure product methyl benzoyl acetate based on Na was 46.3%, as a water white liquid.
Reaction SMILES: Cl.C(O)C.[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[N+:25]([O-])=O.[OH-].[Na+]>C(OCC)(=O)C>[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[NH2:25]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1Br
Temperature: 90 °C
Yield: 98 %

Procedure:
Reduced iron (84.2 g, 1.51 mol) and 1.5 mol/L hydrochloric acid (605 mL) were added to ethanol (2.5 L) and the mixture was heated to 90° C. with stirring. To this mixture was added (7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine 4 times (30 g each time) every 30 min. The mixture was heated under reflux for 5 hrs and the inner temperature was set to 50° C. 2N Aqueous sodium hydroxide solution (450 mL) and 1N aqueous sodium hydroxide solution were added to adjust the pH thereof to 7-8 and the mixture was stirred for a while. Ethyl acetate (1 L) and Celite (300 g) were added, and after stirring for a while, the mixture was filtered through Celite. The residue was washed with THF-ethyl acetate (1:1, 1 L) and the filtrate was concentrated under reduced pressure. Water (1 L) was added to the concentrate and the product was collected by filtration and dried under reduced pressure at 60° C. overnight to give the title compound (108.76 g, 98%).
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])[CH:8]([CH3:10])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[CH:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:24])=[O:5])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)N(C)C(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(C)C(C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 0.250 g (0.700 mmol) of the product of Example 5 in 1.0 mL of dichloromethane was added 0.5 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of ethyl acetate/hexanes (1:3) to (1:1) to provide 0.211 g (100%) of the carboxylic acid as a colorless oil. Electrospray Mass Spec 300.0 (M−H)−
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:43])[C:23]([CH3:42])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:43])[C:23]([CH3:42])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.8 %

Procedure:
Morpholine (0.025 g, 0.289 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.083 g, 0.434 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-methoxybenzoic acid (0.050 g, 0.145 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) to obtain the titled compound (0.033 g, 0.0794 mmol, 55%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH3:21])=[CH:6][C:7](=[O:20])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(#N)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[O:4][C:5]([CH3:21])=[CH:6][C:7](=[O:20])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:1]
Reactant: CCOC(=O)CCCCCOc1c(CO)oc(C)cc1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CCOC(=O)CCCCCOc1c(C=O)oc(C)cc1=O
Reaction time: 3 h

Procedure:
To a solution of 4.25 g of 2-hydroxymethyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone in 110 ml of acetonitrile was added 12 g of activated manganese dioxide. The resulting suspension was stirred for 3 hr, at which time the mixture was filtered and the filtrate evaporated to an oil, 2-formyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone, weighing 4.0 g (94%). NMR (CDCl3): δ1.23 (3H, t, J=7 Hz), 2.36 (3H, s), 6.32 (1H, s).
Reaction SMILES: [C:1]([C:3](=[C:13]([S:16][CH3:17])SC)[C:4]([C:6]1[O:10][C:9]([C:11]#[N:12])=[CH:8][CH:7]=1)=O)#[N:2].[N+]([O-])(O)=O.[NH2:22][C:23]([NH2:25])=[NH:24].C(N(CC)CC)C.O>CN(C=O)C>[NH2:25][C:23]1[N:24]=[C:4]([C:6]2[O:10][C:9]([C:11]#[N:12])=[CH:8][CH:7]=2)[C:3]([C:1]#[N:2])=[C:13]([S:16][CH3:17])[N:22]=1
Reactant: N=C(N)N
Reactant: CSC(SC)=C(C#N)C(=O)c1ccc(C#N)o1
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Solvent: O
Product: CSc1nc(N)nc(-c2ccc(C#N)o2)c1C#N
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Following the method of Rudorf and Augustin (J. Prakt. Chem. 1978, 320, 576), a solution of 300 mg (1.13 mmol) 5-(2-cyano-3,3-bis-methylsulfanyl-acryloyl)-furan-2-carbonitrile, 166 mg (1,36 mmol) guanidine nitrate and 0.40 ml (2.84 mmol) triethylamine in 5 ml DMF was heated at reflux for 1 h. The reaction mixture was then cooled to room temperature and poured onto 250 ml water, extracted three times with ethyl acetate, and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) afforded 120 mg (41%) 2-amino-4-(5-cyano-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. ES-MS m/e (%): 256 ([M—H]−, 100).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7](C)[CH:8]=[C:9]([CH2:13][NH:14]C(=O)C[Cl:17])[C:10]=2[OH:12])[CH2:5][CH2:4]1.Cl.[CH2:21](O)C>>[ClH:17].[ClH:1].[NH2:2][C:3]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][NH2:14])[C:10]=2[OH:12])[CH2:5][CH2:4]1
Reactant: Cc1cc(CNC(=O)CCl)c(O)c2c1CCC2N
Reactant: CCO
Agent: Cl
Product: CC1(N)CCc2ccc(CN)c(O)c21

Procedure:
5 Grams of 1-amino-4-methyl-6-α-chloroacetylaminomethyl-7-hydroxyindane hydrochloride and 100 ml of ethanol containing 50 ml of concentrated hydrochloric acid were refluxed by heating for 8 hours. The solvent was removed by evaporation and the residue obtained was washed with ethanol. Recrystallized from methanol-ether to obtain 1 g of 1-amino-methyl-6-aminomethyl-7-hydroxyindane dihydrochloride.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:25])([F:24])[C:9]([F:23])([F:22])[C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:34](#[N:38])[CH2:35][C:36]#[N:37].O>CS(C)=O>[F:24][C:8]([F:25])([C:9]([F:22])([F:23])[C:10]([F:20])([F:21])[C:11]([F:18])([F:19])[C:12]([F:16])([F:17])[CH:13]([F:14])[F:15])[CH2:7][CH:35]([C:34]#[N:38])[C:36]#[N:37]
Reactant: N#CCC#N
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
14.6 g of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl trifluoromethanesulfonate was dissolved in 20 ml of dimethyl sulfoxide, and 5.5 g of potassium carbonate was added. 2.6 g of malononitrile dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water 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 2.0 g of 2-(2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl)malononitrile.
Reaction SMILES: [S:1]1[CH:6]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)[S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH3:29])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12>>[S:1]1[CH:6]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]4[N:28]([CH3:29])[N:27]=[N:26][N:25]=4)[CH2:20][S:21][C@H:16]23)=[O:10])[S:4][CH2:3][CH2:2]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)C1=CSCCS1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)C1=CSCCS1

Procedure:
2-(2,3-Dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 1.2 g.) was allowed to react with 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.65 g.) in a similar manner to that of Example 1 to give the captioned compound (2.1 g.), pale yellowish white powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>[Cu]>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([N:15]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 220 °C

Procedure:
A mixture of 65.4 grams of p-iodotoluene, 11.3 grams of copper bronze powder and 55.3 grams of potassium carbonate in 150 milliliters of Soltrol 220 was mechanically stirred in a 250 milliliter round-bottomed flask fitted with a reflux condenser. The mixture was first heated to 160° C. with a heating mantle before 16.92 grams of 4-aminobiphenyl was added. After the addition, the reaction mixture was heated under reflux at 220° C. for five hours. After cooling, the reaction mixture was filtered, and the resulting filter cake was washed with 50 milliliters of heptane. The filtrate was distilled under reduced pressure to remove Soltrol 220. The resulting solid residue was purified by column chromatography on silica gel to afford a white solid. Further purification by recrystallization from isopropanol yielded 16.2 grams of analytically pure bis(p-tolyl)-4-biphenylylamine, melting point, 94° to 95° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:20])[CH3:2]
Reactant: CCc1cc(-c2cccc(C(=O)OC)n2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cc(-c2cccc(C(=O)OC)n2)ccc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a DMF solution of methyl 6-(3-ethyl-4-hydroxyphenyl)pyridine-2-carboxylate were added potassium carbonate and methyl iodide, and the whole was stirred at an oil bath temperature of 70° C. for 2 hours to obtain methyl 6-(3-ethyl-4-methoxyphenyl)pyridine-2-carboxylate, which was then stirred in methanol and a 1M aqueous sodium hydroxide solution at an oil bath temperature of 60° C. for 1 hour to obtain an objective compound.