Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:9])[C:4](=[O:29])O1.C=O.[CH3:33][NH2:34].[CH3:35]O>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:10]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:8]([C:7]2[CH2:33][N:34]([CH3:35])[C:4](=[O:29])[C:5]=2[OH:6])=[O:9])=[CH:27][CH:26]=1
Reactant: CN
Reactant: CO
Reactant: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)OCCCN2CCOCC2)O1
Agent: C=O
Product: CN1CC(C(=O)N(Cc2ccc(F)cc2)OCCCN2CCOCC2)=C(O)C1=O
Yield: 35 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-(3-morpholin-4-yl-propoxy)-acetamide (0.080 g, 0.18 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 method 44B) gave 0.027 g (35% yield) of the title compound as a white solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); 1.61 (2H, m, CH2), 2.23 (2H, t, J=7.0 Hz, NCH2), 2.28 (4H, broad, 2×NCH2), 2.93 (3H, s, NCH3), 3.54 (4H, broad, 2×OCH2), 3.76 (2H, broad t, OCH2), 3.97 (2H, s, NCH2), 4.88 (2H, s, NCH2), 7.13 (2H, m, aromatics), 7.40 (2H, m, aromatics). HRMS (MAB N2) calculated for C20H26FN3O5: [M]+: 407.185650. found: 407.184331.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[N:13]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[C:16]([F:26])[C:15]=2[F:27])[N:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[C:5]([NH:8][C:9]1[N:13]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[C:16]([F:26])[C:15]=2[F:27])[N:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
250 ml (0.26 mol) of acetic anhydride are added to 60 g (0.20 mol) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 170 ml glacial acetic acid, whereupon the reaction temperature rises from 20° C. to about 35° C. The mixture is stirred at room temperature for 16 hours and then poured onto 800 ml of water. The crystalline solid which has precipitated out is filtered off with suction, washed freely with water and acetic acid and dried in vacuo. 59.8 g (87.7% of theory) of 5-acetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 102° C. -104° C. are obtained.
Reaction SMILES: [OH-].[K+].[C:3]([NH2:8])(=[O:7])[C:4]([CH3:6])=[CH2:5].Cl[CH2:10][CH2:11][C:12]#[N:13].[CH:14]1C2NC3C(=CC=CC=3)SC=2C=CC=1>CN(C)C=O>[C:12]([CH2:11][CH2:10][N:8]([CH3:14])[C:3](=[O:7])[C:4]([CH3:6])=[CH2:5])#[N:13]
Reactant: C=C(C)C(N)=O
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: N#CCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)N(C)CCC#N
Reaction time: 3 h

Procedure:
To 150 ml of N,N-dimethylformamide, were added 28 g of potassium hydroxide, 17 g of methacrylamide, 23 g of 3-chloropropionitrile and 0.05 g of phenothiazine. A reaction was carried out at 40° C. for 3 hours with stirring.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[H][H]>[Pd].CCO>[OH:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(O)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(O)c1N

Procedure:
A suspension of 10% palladium on carbon (0.045 g) and 2-hydroxy-4-methyl-3-nitropyridine (0.600 g, 3.89 mmol, 1 equiv) in EtOH (20 mL) was subjected to one atmosphere of hydrogen for 16 hours. After purging the reaction vessel with argon, the mixture was filtered through Whatman #3 paper and the filtrate was evaporated to give 2-hydroxy-4-methyl-3-aminopyridine which was used without further purification. This crude material was stirred in THF (18 mL) at 23° C. Benzyl chloroformate (0.611 mL, 4.28 mmol, 1.1 equiv) and Na2CO3 (0.907 g, 8.56 mmol, 2.2 equiv) were added and the reaction mixture was stirred for 60 h, but TLC showed the reaction to be only 25% complete. The reaction mixture was heated to reflux for 24 h. More benzyl chloroformate (0.611 mL, 4.28 mmol, 1.1 equiv) and Na2CO3 (0.454 g, 4.28 mmol, 1.1 equiv) were added. The reaction mixture was heated to reflux for 24 h more, allowed to cool, diluted with EtOAc (200 mL), washed with half-saturated brine (2×40 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography (gradient elution, 3→5% CH3OH in CH2Cl2) to provide the title intermediate (0.363 g, 35%) as a white solid: 1H NMR (DMSO-d6) δ 2.02 (s, 3H), 3.31-3.35 (m, 2H), 5.06 (s, 2H), 6.83 (d, 1H, J=6.7), 7.17 (d, 1H, J=6.7), 7.28-7.39 (m, 5H); Anal. C14H14N2O3: C, H, N.
Reaction SMILES: [C:1]([C:3]([C:15]#[N:16])=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)#[N:2].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[F:17][C:18]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([NH:22][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[C:15]#[N:16])[CH:6]=[CH:7][C:8]=2[OH:14])[CH:23]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:25]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#CC(C#N)=Cc1ccc(O)c(C(=O)O)c1
Product: N#CC(C#N)=Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 9.1 %

Procedure:
Using 5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH2:10][CH:11](OS(C)(=O)=O)[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O-:33])(=[S:32])[CH3:31].[K+].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:29])[CH2:10][CH:11]([S:32][C:30](=[O:33])[CH3:31])[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC(CNC(=O)OCc1ccccc1)CC(=O)OCc1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC(CNC(=O)OCc1ccccc1)CC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg (0.59 mmol) 4-benzyloxycarbonylamino-3-methanesulfonyloxy-butyric acid benzyl ester in 5 ml DMF were added sequentially 68 mg (1.0 equiv.) potassium thioacetate and 101 μl (1.0 equiv.) DIPEA. The reaction mixture was stirred for 2 h at 80° C. under argon and light protection. Further 68 mg (1.0 equiv.) potassium thioacetate and 101 μl (1.0 equiv.) DIPEA were added. After stirring for another 2 h at 80° C., the mixture was poured into 10 ml water and extracted three times with 15 ml ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate) gave pure 3-acetylsulfanyl-4-benzyloxycarbonylamino-butyric acid benzyl ester as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([SH:19])[CH:13]=[CH:12]2.I[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24])[CH:13]=[CH:12]2
Reactant: N#Cc1ccccc1I
Reactant: Fc1ccc(-c2ccc3cc(S)ccc3c2)c(F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: N#Cc1ccccc1Sc1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 20.2 %

Procedure:
6-(2,4-Difluorophenyl)-2-naphthyl hydrosulfide (Step 2, 0.78 g) was dissolved in isopropyl alcohol (15 mL). 2-Iodobenzonitrile (0.66 g, 2.88 mmol), copper(I) iodide (29 mg, 0.15 mmol), potassium carbonate (0.8 g, 5.79 mmol) and ethylene glycol (320 μL) were added and the reaction heated to 80° C. under nitrogen overnight. Ethyl acetate was added to the cooled reaction mixture and stirred for 15 minutes. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10-20% ethyl acetate/isohexane, followed by recrystallisation from ethyl acetate/isohexane, to give 2-{[6-(2,4-difluorophenyl)-2-naphthyl]thio}benzonitrile (216 mg, 20%). 1H NMR (500 MHz, CDCl3) δ 8.04 (1H, s), 7.97 (1H, s), 7.88 (2H, t, J=7.8 Hz), 7.68 (2H, d, J=8.0 Hz), 7.54-7.48 (2H, m), 7.43-7.39 (1H, m), 7.28 (1H, t, J=7.6 Hz), 7.19 (1H, d, J=7.9 Hz), 7.03-6.95 (2H, m).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.[OH:7][PH:8]([OH:10])=[O:9].P(Cl)(Cl)Cl>O>[NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1([P:8]([OH:10])(=[O:7])[OH:9])[P:8]([OH:10])(=[O:7])[OH:9]
Reactant: O=[PH](O)O
Reactant: O=C1CCCN1
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=P(O)(O)C1(P(=O)(O)O)CCCN1
Reaction time: 8 h

Procedure:
85.0 gm of 2-pyrrolidone (1.0 mol) and 164 gm of H3PO3 (2.0 mols) were melted at 80°C. While stirring this melt, 176 ml of PCl3 (2.0 mols) were added thereto. The mixture was stirred for three additional hours and was left standing at 70°C overnight. Then, three liters of H2O were used for the hydrolysis. The solution was boiled with activated carbon; and after filtration, the reaction product was precipitated with acetone. The white substance was dissolved in water, and passed over a cation exchanger. The solution was concentrated; and the substance was separated upon the addition of ethanol. The yield of crystalline azacyclopentane-2,2-diphosphonic acid was 95 gm, or about 41% of the theory. The molecular weight of the compound was determined by titration to be 230 (calculated: 231.09).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Cl)nc1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 17, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 56% yield; NMR Spectrum: (DMSOd6): 2.21 (s, 3H), 3.50-3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, 1H), 7.25 (d, 2H), 7.56 (d, 1H), 7.69 (d, 1H), 7.82 (s, 1H), 8.26 (d, 1H), 8.37 (d, 1H), 8.96 (d, 1H); Mass Spectrum M+H+ 452 and 454.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].C1COCC1.[N:35]1([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1>CCOC(C)=O.CCCCCC>[O:29]=[C:4]1[C:3](=[CH:2][NH:47][C:44]2[CH:43]=[CH:42][C:41]([CH2:40][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:46][CH:45]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 354, 100 mg, 0.2575 mmol) and THF (2.6 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (45.4 mg, 0.258 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 43% yield (0.060 g, 0.11 mmol).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:28])[CH2:23][O:24]C(=O)C)[CH3:21])[C:14]=3[Cl:29])[C:5]2=[N:4][C:3]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+].CO>O1CCCC1>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:28])[CH2:23][OH:24])[CH3:21])[C:14]=3[Cl:29])[C:5]2=[N:4][C:3]=1[CH3:30]
Reactant: CC(=O)OCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A mixture of 3-bromo-8-[3-(N-acetoxyacetyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (1.42 g), potassium carbonate (761 mg), methanol (7 ml) and tetrahydrofuran (7 ml) was stirred at ambient temperature for 1 hour. The mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 3-bromo-8-[2,6-dichloro-3-(N-glycoloyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (1.16 g) as crystals.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:9]([O:13]CCCC)CCC>C1COCC1>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:9]=[O:13].[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCOCCCC
Solvent: C1CCOC1
Solvent: C=CCCCCCC
Product: CCCCCCC(C)C=O
Product: CCCCCCCC
Reaction time: 1 h

Procedure:
A mixture of Rh(CO)2(acac)(3 mg,0.012 mmole), branched polymer3 (insoluble) (26 mg), 1-Octene (98 mg,0.9 mmole), and THF(0.5 ml) was heated at 80 C. under 100 psi of CO/H2(1/1) for 1 hr. Butyl ether(2.6 mg, 0.02 mmole) was added into the mixture as the internal standard and the mixture was analyzed by Gas Chromatograph with Chrompack CP-SIL 8 column(30 m×0.32 mm ID). 98.8% Conversion was obtained with 40.8 wt % of Nonyl aldehyde, 1.3 wt % of 2-Methyl-1-octanal, 6.2 wt % of Octane, and 29.0 wt % of Octene isomers.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: C1CNCCN1
Solvent: CCO
Product: Clc1cc(N2CCNCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
18 g 3,4,6-trichloro-pyridazine and 34 g piperazine are suspended in 100 ml of ethanol and stirred for 30 minutes at ambient temperature. The precipitated solid is suction filtered. 500 ml of water are added to the mother liquor and the precipitated product is suction filtered. 14 g product are obtained as a solid. M.p=111-115° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:31]=[CH:30][C:29]3[NH:28][C:27](=[O:32])[C:26]4[NH:33][CH:34]=[CH:35][C:25]=4[C:24]=3[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]>ClC(Cl)C>[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:31]=[CH:30][C:29]3[NH:28][C:27](=[O:32])[C:26]4[NH:33][CH:34]=[CH:35][C:25]=4[C:24]=3[CH:23]=2)[CH:19]=[CH:20][CH:21]=1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([C:38]([OH:40])=[O:39])[CH3:37]
Reactant: CCC(=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)c1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)O
Product: Nc1cccc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
0.5 mL of trifluoroacetic acid is added to a solution of 120 mg (0.22 mmol) of 8-(3-tert-butoxycarbonylaminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 2 mL of dichloroethane. The solution is stirred at room temperature for 30 minutes then the solvents are evaporated. The residue is triturated with diisopropyl ether then the solid is filtered and washed with dichloromethane to give 86 mg (69%) of 8-(3-aminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate trifluoroacetate in the form of a beige solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[O:10][C:11]([CH2:14][CH3:15])=[CH:12][N:13]=2)=[CH:5][N:6]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([C:11]1[O:10][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:6][CH:5]=2)=[N:13][CH:12]=1)[CH3:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cnc(CSc2cnc(N)s2)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cnc(CSc2cnc(NC(=O)c3ccccc3)s2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
A mixture of 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (48.2 mg, 0.2 mmol), benzoyl chloride (24.4 mg, 0.21 mmol) and triethylamine (35 mg, 0.35 mmol) in methylene chloride (0.5 mL) was stirred at rt for 10 min. The organic solution was washed with water and concentrated. The residue was purified by a flash column (SiO2 ; hexanes: ethyl acetate/2:1) to afford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzamide (41 mg, 59%) as a solid, mp 122-123° C. 1H NMR (CDCl3) δ12.65 (s, 1 H), 7.96 (m, 2 H), 7.61 (m,, 1 H), 7.49 (m, 2 H), 6.88 (s, 1 H), 6.56 (s, 1 H), 3.93 (s, 2 H), 2.61 (q, J=7.6 Hz, 2 H), 1.20 (t, J=7.6 Hz, 3 H); MS m/e 346 (M+H)+ ;
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl.C(OCC)C>[C:1]1([CH:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[O:32][CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCCCCCC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(C(CCCCCCCCC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.53 g of 11,11-diphenylundec-1-ene in 25 mL of dichloromethane was added 1.5 g of 50-60% by wt of m-chloroperbenzoic acid and the mixture was stirred at room temperature for 16 hrs. The solution was diluted with diethyl ether and washed with 10% by wt aqueous solution of sodium hydrogen sulfite, saturated aqueous sodium hydrogen carbonate solution, and brine. The organic layer was dried over sodium sulfate and concentration in vacuo gave 1.5 g of 11,11-diphenylundec-1-ene oxide which is characterized by:
Reaction SMILES: [C:1]1(=[CH:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([OH:24])=O)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:35]>C1(C)C=CC=CC=1.CN(C=O)C.O>[C:1]1(=[CH:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([NH2:35])=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1C=C1CCCC1
Reactant: CC#N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2CCN(C(=O)C(N)=O)CC2)cc1C=C1CCCC1

Procedure:
To a magnetically stirred suspension of [4-(3-cyclopentylidenemethyl-4-methoxy-phenyl)piperidin-1-yl]-oxo-acetic acid (1.2 mmol, 0.40 g) in dry toluene (15 mL) at room temperature was added oxalyl chloride (2.0M in CH2Cl2 ; 1.3 mmol, 0.65 mL) dropwise over 10 minutes, followed by DMF (3 drops) to promote gas evolution. The resulting homogeneous solution stirred at room temperature for 45 minutes, at which time saturated NH3 /CH3CN (15 mL) was added dropwise over 15 minutes. A white solid precipitated out of solution as the mixture was stirred for another 3/4 hour. At that time, TLC analysis shows reaction to be complete. The solution was diluted with H2O to dissolve the white precipitate and then the THF was removed in vacuo. The aqueous phase was diluted with saturated aqueous NaHCO3 solution (100 mL) and then extracted with EtOAc (2×200 mL). Each organic phase was washed with H2O (1×100 mL) and then the combined organics were dried (Na2SO4) and concentrated to yield a white solid. This compound was purified via column chromatography (SiO2 : 40% EtOAc/hex) to afford a pure white solid of the title compound as a pure white solid, mp 116°-117° C. (0.7 mmol, 0.231 g, 56%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:18][C:19]1[O:20][C:21]([CH3:35])([CH3:34])[CH:22]([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[S:23](=[O:26])(=[O:25])[N:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.CI.[CH3:38][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:38][O:33][C:29]1[CH:28]=[C:27]([CH:22]2[C:21]([CH3:34])([CH3:35])[O:20][C:19]([NH:18][C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][OH:8])=[N:24][S:23]2(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(O)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: COc1cccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3)=NS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 452 mg of 3-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-5-yl}phenol and 148 mg of methyl iodide in THF at 0° C. was added dropwise 0.44 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF. After stirring at constant temperature for 45 minutes and then warming up to room temperature, the reaction solution was stirred for a further 4 hours and then the conversion was checked by LCMS. A further 0.20 ml of the 2 N solution of sodium bis(trimethylsilyl)amide in THF and 114 mg of methyl iodide were added. After stirring at room temperature for 16 hours, the reaction solution was diluted with 60 ml of water, 5 ml of 5% aqueous sodium thiosulfate solution were added and the mixture was extracted twice with 30 ml of ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 5 ml of methanol and, after addition of 0.5 ml of concentrated hydrochloric acid, stirred at room temperature for 1 hour. The reaction solution was diluted with 50 ml of water and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation, and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (41.1 mg) with a molecular weight of 418.5 g/mol (C21H26N2O5S); MS (ESI): m/e=419 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH3:7])=[O:5].[CH:11]1(CO)[CH2:13][CH2:12]1>>[CH3:1][C:2]([CH2:8][CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH2:7][CH:11]1[CH2:13][CH2:12]1)=[O:5]
Reactant: CCCC(C)=CC(=O)OC
Reactant: OCC1CC1
Product: CCCC(C)=CC(=O)OCC1CC1

Procedure:
Prepared from methyl 3-methylhex-2-enoate and cyclopropanemethanol according to the ester preparation method B described above. The Z and E isomer were separated by distillation under vacuum using a 35 cm Fischer Spaltrohr® column.