Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:10][OH:11])[CH3:7])(=[O:4])=[O:3].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([O:5][CH:6]([CH:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][CH:10]=[O:11])[CH3:7])(=[O:4])=[O:3]
Reactant: CC(OS(C)(=O)=O)C(CCO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(OS(C)(=O)=O)C(CC=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
1.2 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(H)-one (Dess-Martin Periodinane) was added to a solution of 490 mg of 5-hydroxy-3-phenylpentan-2-yl methanesulfonate in 5 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with a sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/10 to 1/1), so as to obtain 414 mg of 5-oxo-3-phenylpentan-2-yl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: [C:1]1([SnH2:7][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.[C:14]([O:17][CH:18]=[CH2:19])(=[O:16])[CH3:15]>C1CCCCC1>[C:14]([O:17][CH2:18][CH2:19][Sn:7]([CH2:19][CH2:18][O:17][C:14](=[O:16])[CH3:15])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])[CH3:15]
Reactant: C=COC(C)=O
Reactant: c1ccc([SnH2]c2ccccc2)cc1
Solvent: C1CCCCC1
Product: CC(=O)OCC[Sn](CCOC(C)=O)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Stoichiometric amounts of diphenyltin dihydride and vinyl acetate were placed in a Pyrex® tube containing anhydrous cyclohexane. The reactionmixture was exposed to ultraviolet radiation for 1 hour at 30° C. The solvent was then eliminated at ambient temperature under vacuum. The product was obtained quantitatively and had the following formula:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29][C@@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCNC[C@H]1O
Agent: Cl
Product: CCC(=O)N1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)[C@@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4S*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f11) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]2[CH2:18][C:17]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:16]=2[Cl:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:19]([NH:26][C:27]([N:16]1[CH2:17][CH2:18][N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCNCC2)cc1
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 50 °C
Yield: 47.5 %

Procedure:
To a solution of 1-(4-Nitro-benzenesulfonyl)-piperazine (1.0 g, 2.6 mmol) in pyridine (10 ml) was added benzyl isocyanate (0.35 ml, 2.85 mmol) in one portion. The resulting mixture was then heated at 50° C. for 2 hours before being cooled to room temperature and concentrated under vacuum. The resulting residue was dissolved in ethyl acetate (50 ml) and washed with 1M HCl (100 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.5 g, 47% yield) as a yellow solid which was used without further purification. Tr=1.86 min, m/z (ES+) (M+H)+ 405.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH:13]=[C:14]1[NH:18][C:17](=[O:19])[CH2:16][S:15]1>>[NH:13]=[C:14]1[NH:18][C:17](=[O:19])[C:16](=[CH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[N:4]3)[S:15]1
Reactant: N=C1NC(=O)CS1
Reactant: O=Cc1ccc2nccnc2c1
Product: N=C1NC(=O)C(=Cc2ccc3nccnc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH2:14][C:15]([CH3:19])([NH2:18])[CH2:16][OH:17]>>[OH:13][CH2:14][C:15]([NH:18][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])([CH3:19])[CH2:16][OH:17]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and 1,3-dihydroxy-2-methyl-2-amino-propane comparable as in Example A. A resin-like, colorless product was obtained.
Reaction SMILES: CO[CH:3]([O:10]C)[C@@H:4]1[O:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(C(O)=O)(F)(F)F.[OH-].[Na+].[BH4-].[Na+]>O1CCOCC1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:9][C@@H:6]2[CH2:7][O:8][C@@H:4]([CH2:3][OH:10])[CH2:5]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COC(OC)[C@H]1C[C@H](O)CO1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@@H](CO)C2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3S-trans)-tetrahydro-5-(dimethoxymethyl)-3-furanol-4-methylbenzenesulfonate, (Compound IV(e), 10.0 g, 31.6 mmole), 1% CF3CO2H (50 mL), and dioxane (80 mL) in a 250 mL round bottom flask fitted with a reflux condenser was warmed to 80° C. for five hours. After cooling to room temperature, the solution was adjusted to pH 7.0 using 1N NaOH, treated with NaBH4 (1.2 g, 31.7 mmole), and allowed to stir at room temperature for an additional 30 minutes. The solvent was partially removed, then extracted with EtOAc (100 mL×3). The organic fraction was dried over MgSO4, filtered, evaporated and purified by flash column chromatorgraphy (60% EtOAc/40% Hexane) to afford 3.6 g or recovered starting material and 2.7 g (49% based on recovered starting material) of Compound IV(c).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)[N:7]=1)=[O:5])C.[CH:24]([OH:27])([CH3:26])[CH3:25]>>[CH:24]([O:27][C:20]1[N:19]=[CH:18][C:17]([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:6]([C:4]([OH:3])=[O:5])=[N:7]2)=[CH:22][CH:21]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(Cl)nc2)n1
Reactant: CC(C)O
Product: CC(C)Oc1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cn1
Yield: 81 %

Procedure:
The general procedure of Referential Example 125 was repeated through use of the 1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carboxylic acid ethyl ester (1.05 g) prepared in Referential Example 123-3) and isopropanol, to thereby give the title compound as a powder (840 mg, 81%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:25])[C@H:12]([CH2:14][S:15][CH2:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[NH2:13])[CH3:9].[C:26]([O:30][C:31](=[O:35])[CH:32](Br)[CH3:33])([CH3:29])([CH3:28])[CH3:27]>CN(P(N(C)C)(N(C)C)=O)C>[C:26]([O:30][C:31](=[O:35])[C@H:32]([CH3:33])[NH:13][C@H:12]([C:11]([O:10][CH2:8][CH3:9])=[O:25])[CH2:14][S:15][CH2:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H](N)CSCC(=O)NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)[C@H](CSCC(=O)NC1CCCC1)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A 2.8 ml of triethylamine was added to a solution of 5.5 g of S-cyclopentylcarbamoylmethyl-L-cysteine ethyl ester and 4.2 g of 2-bromopropionic acid t-butyl ester in 10 ml of HMPA. The mixture was stirred at room temperature for 30 hours. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a 10:1 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound from the first eluate as a colorless oil. Yield 1.36 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[CH:12]=[C:13](N2CCCC2)[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][CH2:22][O:23][C:24](/[C:26](/Cl)=[N:27]\[OH:28])=[O:25].O>ClCCl>[CH3:14][C:13]1[O:28][N:27]=[C:26]([C:24]([O:23][CH2:22][CH3:21])=[O:25])[C:12]=1[C:11](=[O:20])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: CC(=CC(=O)Nc1ccc([N+](=O)[O-])cc1)N1CCCC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1noc(C)c1C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A suspension of 12.38 g (45 mmol) of the crude N-(4-nitrophenyl)-3-pyrrolidyl-2-butenamide in 200 ml of dry dichloromethane was cooled to 0° C. and 7.50 g (49.5 mmol) of ethyl chlorooximidoacetate were added in one portion. The reaction mixture was stirred at -5° C. to 0° C. for 2 hours and was then poured into 200 ml of water. The aqueous layer was extracted with 100 ml of dichloromethane and the combined organic extract was washed with 100 ml of 10% HCl, 5% NaHCO3 solution and then dried over MgSO4. Evaporation of the solvent gave 10.91 g (76%) of ethyl 5-methyl-4-[N-(4-nitrophenyl)]carbamoyl-3-isoxazolecarboxylate as a white crystalline solid melting at 151°-53° C. (from ethyl acetate);
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1.CCOC(C)=O>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](CCSC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of (S)-2-amino-4-(methylthio)butanoic acid (1.0 g, 6.7 mmol) in dioxane at 0° C. was added NaOH (11.06 g, 22.12 mmol) followed by dropwise addition of methyl chloroformate (1.04 mL, 13.4 mmol) and the solution was warmed to room temperature with stirring over 2 h. The solution was diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (1.3 g, 6.27 mmol, 94%). 1H NMR (400 MHz, CDCl3) δ ppm 1.95-2.07 (m, 1H) 2.07-2.13 (m, 3H) 2.14-2.28 (m, 1H) 2.59 (t, J=7.4 Hz, 2H) 3.71 (s, 3H) 4.52 (br s, 1H) 5.33 (br s, 1H).
Reaction SMILES: O=O.[O:3]=[O+][O-].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:17]1([CH:23]([O:30][C:31]([C@@H:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=C)=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CSC>CO>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1.[C:24]1([CH:23]([O:30][C:31]([C@@H:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=[O:3])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[O+][O-]
Reactant: C=C1CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=O
Solvent: CSC
Solvent: CO
Product: N[C@@H]1C(=O)N2[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Temperature: -12 °C
Reaction time: 0.08 h

Procedure:
A stream of oxygen and ozone (containing 0.35 mmol of ozone per minute) is passed for 4 minutes through a solution, cooled to -60° C, of 0.553 g of the 4-methylphenylsulphonate of 7β-amino-3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester in 50 ml of methanol. After a further 5 minutes, 0.3 ml of dimethyl sulphide is added to the solution which is pale blue in colour. The mixture is stirred for 15 minutes at -70° C, for 1 hour at -12° C and for one hour in an ice bath and is then evaporated. The residue is taken up in a small quantity of methylene chloride, diethyl ether is then added until the mixture turns cloudy, and the mixture is left to stand. The micro-crystalline pulverulent precipitate, which is reddish in colour, is filtered off and gives the 4-methylphenylsulphonate of 7β-amino-cepham-3-one-4α-carboxylic acid diphenylmethyl ester, which is principally in the enol form as the 4 -methylphenylsulphonate of 7β-amino-3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester, melting point 143°-145° C (with decomposition); thin layer chromatogram (silica gel) Rf~0.28 (system: ethyl acetate/pyridine/water, 85:10:5); ultraviolet absorption spectrum (in ethanol): λmax = 262 mμ (ε = 3,050) and 282 mμ (ε = 3,020); infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58 μ, 5.77 μ (shoulder), 6.02 μ and 6.22 μ.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([SH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1>>[CH3:8][C:9]1[CH:10]=[C:11]([S:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: Ic1ccccc1
Product: Cc1cc(C)cc(Sc2ccccc2)c1

Procedure:
The general procedure was used to convert iodobenzene and 3,5-dimethylthiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (417 mg, 97% yield). 1H NMR (300 MHz, CDCl3) δ 7.17–7.01 (m, 5H; Hc, Hc′, Hd, Hd′, He), 6.84 (s, 2H; Ha, Ha′), 6.72 (s, 1H; Hb), 2.10 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 138.81 (C3, C5), 136.35 (C9), 134.69 (C1), 130.44 (C10, C14), 129.10 (C11, C13), 129.02 (C2, C6), 128.68 (C4), 126.61 (C12), 21.13 (C7, C8). Anal. Calcd. for C14H14S: C, 78.45; H, 6.58; S, 14.96; Found C, 78.53; H, 6.62; S, 14.89.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:26])[C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4].[CH3:35][N:36](C)C=O>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-]#N.[Zn+2].[C-]#N>[CH2:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:26])[C:14]([C:35]#[N:36])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCOC(=O)CC1c2ccc(OS(=O)(=O)C(F)(F)F)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCCOC(=O)CC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-5-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 17; 837 mg, 1.64 mmol) in N,N-dimethylformamide (6 ml) was degassed under vacuum for 15 min. Tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.164 mmol) and zinc cyanide (251 mg, 2.13 mmol) were then added and the resulting orange mixture stirred at 100° C. for 4 h. The mixture was cooled to room temperature and insoluble material filtered off and washed with ethyl acetate. The mother liquors were concentrated in vacuo and the residue dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate and the aqueous phase further extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5-25% ethyl acetate in cyclohexane, gave the title compound (600 mg) as a colourless oil.
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[NH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(CO)cc1
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2I)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(-c3ccc(OC)cc3)c(I)c3ccc(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25-mL flask under argon, 4-iodo-7-methoxy-3-(4-methoxyphenyl)isoquinolin 1(2H)-one (500 mg, 1.23 mmol) is dissolved in 15 mL of anhydrous THF. 4-methoxybenzyl alcohol (217 μl, 1.84 mmol), triphenylphosphine (482 mg, 1.84 mmol) and diisopropyl azodicarboxylate (261 μl, 1.84 mmol) are added to the previous solution. After stirring overnight at ambient temperature, the medium is hydrolyzed with 20 mL of water and extracted with 3×20 mL of dichloromethane. The organic phases are washed with 3×10 mL of water, dried over MgSO4 and concentrated under vacuum. Compound 69 is obtained by recrystallization from ether (358 mg, 55%). 1H NMR CDCl3 δ 7.94 (s, 1H), 7.89 (d, 1H), 7.34 (d, 1H), 6.98 (d, 2H), 6.91 (d, 2H), 6.81 (d, 2H), 6.72 (d, 2H), 5.19 (s, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H);
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([NH:21][CH2:22][CH2:23][CH2:24]Br)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[NH:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 4-hydroxy-naphthalene-1-carbaldehyde (15.2 g, 58.1 mmol) in DMF (50 mL) at r.t. was added N-Boc 3-bromo-propylamine (15.2 g, 63.9 mmol), followed by potassium carbonate (12 g, 87.2 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted by CH2Cl2. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from EtOAc/hexane to afford [3-(4-formyl-naphthalen-1-yloxy)-propyl]carbamic acid tert-butyl ester (13.8 g, 72%) as a light yellow solid.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:21]([NH2:23])=[O:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:31]([O:35][C:36]([NH:38][CH2:39][CH:40](C)[C:41](O)=O)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH2:14]([O:13][C:11]([CH2:10][C@H:9]([NH:8][C:6]([CH:40]([CH3:41])[CH2:39][NH:38][C:36](=[O:37])[O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:7])[C:21](=[O:22])[NH2:23])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(N)=O
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(CNC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(N)=O

Procedure:
Benzyl (S)-3-(1-t-butoxyformamido)succinamate was deprotected using trifluoroacetic acid and then coupled with DL-N-(t-butoxycarbonyl)-2-methyl-β-alanine to yield t-Butyl [(RS)-2-[[(S)-2-[(benzyloxy)carbonyl]-1-carbamoylethyl]-carbamoyl]propyl]carbamate, m.p. 135°-136° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15].CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:19]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15]
Reactant: CC(O)CCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The above alcohol (16.17 mmol) was oxidised using methods described in EP-A-164 187 (Swern oxidation, DMSO, oxalyl chloride, triethylamine) to give 8-(3',5'-bistrifluoromethylbenzyloxy)-octan-2-one. The ketone was reacted with triethyl-4-phosphonocrotonate/lithium diisopropylamide to give ethyl 11-(3',5'-bistrifluoromethyl)benzyloxy- 5-methylundeca-2,4-dienoate. The ester was converted into the amide as in Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:14][CH2:13][S:10]([CH3:9])(=[O:12])=[O:11])[CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: C=CS(C)(=O)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1cc(Br)ccc1=O
Temperature: 100 °C
Yield: 29 %

Procedure:
5-Bromopyridin-2-ol (4.0 g, 23.0 mmol) and methylsulfonylethene (2.4 g, 2.0 mL, 23.0 mmol) were combined in N,N-dimethylformamide (DMF, 23 mL) and heated to 100° C. The crude reaction mixture was then evaporated to dryness. The crude material was then dissolved in a minimum of dichloromethane. The solution was then washed twice with an aqueous 1 M solution of hydrochloric acid, two times with a saturated aqueous solution of sodium bicarbonate, two times with a saturated aqueous solution of sodium chloride, and finally by two washes of water. The organic layer was dried over sodium sulfate and then evaporated to dryness to yield the product as a pale brown solid (1.87 g, 6.68 mmol, 29%). ESI-MS m/z calc. 279.0. found 280.0 (M+1)+. Retention time 0.34 minutes.