Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC)=O)=NC(OC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[S:41]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]O)[S:42]1>O1CCCC1.C1(C)C=CC=CC=1>[S:41]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[S:42]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCCCC1CCSS1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.6 %

Procedure:
3.25 ml of dimethyl azodicarboxylate were added dropwise to a solution of 5.77 g of triphenylphosphine in 20 ml of tetrahydrofuran, whilst ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. 3.24 g of phthalimide were then added to the reaction mixture, after which a mixture of 20 mmol of 5-(1,2-dithiolan-3-yl)pentanol (prepared as described in Preparation 1) in 30 ml of toluene and 10 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for one hour. The reaction mixture was allowed to stand overnight at room temperature, after which 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were added. The resulting mixture was stirred at room temperature for 7 hours and 30 minutes. 0.88 g of phthalimide, 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were then added to the reaction mixture. The reaction mixture was allowed to stand at room temperature for 4 days. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:6 and 1:4 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was removed from the eluate by distillation under reduced pressure, and 30 ml of toluene were added to the residue. 1 ml of the resulting mixture was weighed, and the solvent was removed from it by distillation under reduced pressure, to give 165 mg of the title compound as an orange oil having an Rf value of 0.35 (silica gel thin layer chromatography; using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH2:1]([O:17][CH:18]1[O:23][CH:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[CH:20]=[CH:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:28]Cl.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:17][CH:18]1[O:23][CH:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[C:20]([Cl:28])=[CH:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClCl
Reactant: CCCCCCCCCCCCCCCCOC1C=CC(=O)C(C(C)C)O1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC1C=C(Cl)C(=O)C(C(C)C)O1
Yield: 99.4 %

Procedure:
In 50 ml of carbon tetrachloride was dissolved 3.8 g of 6-cetyloxy-2-isopropyl-2H-pyran-3(6H)-one with stirring. Into the solution was gradually introduced chlorine gas (0.71 g) at a temperature below 10° C. and after the subsequent stirring for 30 minutes was added dropwise 0.8 g of pyridine maintaining the temperature below 15° C. A crystal from the reaction mixture was separated by suction filter. The filtrate was washed with 5% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. By the distillation of solvent was obtained 4.12 g of 6-cetyloxy-4-chloro-2-isopropyl-2H-pyran-3(6H)-one [compound 2] in a yellow viscous oily form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH2:15][Br:16])=[C:13]([C:17]#[N:18])[CH:12]=[N:11]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br-:16].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH2:15][N+:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([C:17]#[N:18])[CH:12]=[N:11]1
Reactant: N#Cc1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1CBr
Reactant: c1ccncc1
Product: N#Cc1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1C[n+]1ccccc1
Product: [Br-]

Procedure:
The method of Example 1, Step G, using 20.7 g of the mixture from Step D above dissolved in 90 mL of warm pyridine, yielded 11.1 g of N-[1-(2,4,6-trichlorophenyl)-4-cyano-1H-pyrazol-5-ylmethyl]pyridinium bromide, which was used without further purification in Step F.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 31.5 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.250 g, 0.546 mmol) obtained in step 2 and benzylamine (0.150 mL, 1.37 mmol), the title compound (0.091 g, 31%) was obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]([S:20]([O-:23])(=O)=[O:21])=[CH:12][CH:11]=1)(=[O:8])[CH3:7].[NH+]1C=CC=CC=1>CN1CCCC1=O>[C:6]([NH:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]([S:20]([Cl:3])(=[O:23])=[O:21])=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)[O-])c2cccnc12
Agent: c1cc[nH+]cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)c2cccnc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
In a 1 liter 3-neck round bottomed flask, fitted with a mechanical stirrer and a calcium chloride drying tube, phosphorus oxychloride (360 ml) was chilled to less than 10° C. N-methylpyrrolidone (20 ml) was added (slight exotherm). When the temperature returned to <5° C., finely ground pyridinium 8-acetamido-5-quinolinesulfonate (36.0 g, 0.104 mole) was added. The reaction mixture was thoroughly packed in ice and stirred for 20 hrs. The resulting brown slurry was slowly added to ca. 2500 ml ice/water (cooled by an external ice-salt bath) with vigorous stirring. After stirring for one hour the product was collected by filtration and yielded 27.9 g (94 percent) of a tan powder, m.p. 203°-204° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C1COCC1.[OH-].[Na+].C(OCC)(=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Ethyl cyanoacetate (5 mmol), and p-chloro-acetophenone (5 mmol) are dissolved in toluene (5 mL). Morpholine (5 mmol) is added followed by activated molecular sieves (4A). The reaction is stirred at 80° C. for 12 hours. The reaction is cooled to room temperature, filtered and concentrated. The residue is taken up in toluene (5 mL), ethanol (5 mL) and sulfur is added (0.16 g; 5 mmol). The reaction mixture is heated with mixing at 70° C. for 12 hours. The reaction is cooled to room temperature and the solvents are evaporated. The residue is purified by HPLC to provide ethyl 2-amino-4-(4-chlorophenyl)-thiophene-3-carboxylate. Ethyl 2-amino-4-(4-chlorophenyl)-thiophene-3-carboxylate (5 mmol) is treated with 4-fluorobenzoyl chloride (5 mmol) in THF (10 mL). The reaction is stirred at room temperature for 10 hours. The reaction is diluted with 1N NaOH (10 mL) and ethyl acetate (15 mL). The layers are separated, the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography to provide ethyl 2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylate. Ethyl 2-(fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylate is hydrolyzed under a variety of conditions (e.g. LiOH, water; LiOH, H2O2, water; or NaOH, water) to provide 2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1.[H-].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:11]=[C:10]([CH:9]=[CH:8][C:6]=1[OH:7])[O:12][C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1[N+](=O)[O-]
Yield: 32.5 %

Procedure:
In a similar manner to that described in Reference Example 6 a reaction was carried out using t-butylhydroquinone (1.66 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=4/1 to give t-butyl N-[5-(3-t-butyl-4-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (1.35 g), of which Rf value was 0.45 in thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=3/1 and t-butyl N-[5-(2-t-butyl-4-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (1.11 g), of which Rf value was 0.35 in thin layer chromatography on a silica gel plate using n-hexane/ethyl acetate=3/1.
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]#[C:17][C:18]([O:20]C)=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:23][NH2:24]>C(O)C>[OH:20][C:18]1[NH:24][N:23]=[C:16]([C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=23)[CH:17]=1
Reactant: NN
Reactant: COC(=O)C#Cc1c(-c2ccccc2)nn2ccccc12
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Yield: 42.7 %

Procedure:
A mixture of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propiolate (1.50 g), hydrazine monohydrate (0.544 g) and ethanol (15 ml) was heated under reflux for 2 hours. Ethanol was evaporated in vacuo. Water (50 ml) was added to the residue and the mixture was acidified with 1N hydrochloric acid. The resultant precipitates were collected by filtration and washed with water. Recrystallization from a mixture of N,N-dimethylformamide and water gave crystals of 3-(5-hydroxypyrazol-3-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.64 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[C:8]([F:26])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][C:9]3[CH:24]=[CH:25][C:6]([Cl:5])=[CH:7][C:8]=3[F:26])=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
1,2-Dibromoethane (725 mg, 4 mmol) was added by portions of 70 μl every 30 minutes to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (320 mg, 1 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (552 mg, 4 mmol) in DMF (5 ml) heated at 35° C. The mixture was stirred for a further 30 minutes after the completion of the addition and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with petroleum ether/ether, the solid was collected by filtration and dried under vacuum to give 7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (200 mg, 47%). 1H NMR Spectrum: (DMSOd6) 3.89(t, 2H); 3.96(s, 3H); 4.51(t, 2H); 7.23(s, 1H); 7.35(dd, 1H); 7.55(dd, 1H); 7.59(t, 1H); 7.83(s, 1H); 8.36(s, 1H); 9.57(s, 1H) MS-ESI: 428 [MH]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15]>CO>[CH3:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Product: CNc1ccc(C(C)=O)cc1[N+](=O)[O-]
Yield: 100 %

Procedure:
(a-1) To a stirred and cooled solution of 50 parts of 1-(4-chloro-3-nitrophenyl)ethanone in 240 parts of methanol was added a solution of 40 parts of methanamine in 160 parts of methanol. The reaction mixture was stirred for 12 hours at 60° C. The reaction mixture was evaporated to dry, yielding 50 parts (100%) of 1-[4-(methylamino)-3-nitrophenyl]ethanone as a residue (int. 87).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[C:1]([O:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: OC1CCCC1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CCCC1
Reaction time: 8 h

Procedure:
Acryloyl chloride (75 mL) was added to a stirred solution of cyclopentanol (88 g, 1 mol) and triethylamine (175 mL) in dry THF (500 mL) at a rate slow enough to prevent overheating of the reaction. The reaction mixture was allowed to stand overnight, filtered through a pad of Celite, evaporated to an oil, and distilled to give cyclopentyl acrylate as a colorless liquid (bp 74-79/˜60 mm Hg). The structure of the product was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].B(F)(F)F.CC[O:18][CH2:19][CH3:20].[OH2:21].[Pb](=O)=O>O1CCOCC1>[CH2:10]([C:1]1[C:19](=[O:18])[CH:20]=[CH:5][C:4](=[O:21])[CH:2]=1)/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8]
Reactant: O
Reactant: CCOCC
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: FB(F)F
Agent: O=[Pb]=O
Solvent: C1COCCO1
Product: CC(C)=CCC/C(C)=C/CC1=CC(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.8 %

Procedure:
Geraniol (23.1 g; 150 mmole) was dropwise added to 33.0 g (300 mmole) of 1,4-hydroquinone and 17.0 g (120 mmole) of boron trifluoride ethyl etherate in 300 ml of dioxane at 50° C. over one hour. After stirring the resultant solution at that temperature for 2 hours, the reaction solution was poured into 500 ml of water and was extracted twice with diethyl ether (200 ml). The extract was washed successively with 700 ml of aqueous sodium hydroxide solution (once), 700 ml of water (twice) and 700 ml of saturated aqueous sodium chloride solution (once) and then dried over anhydrous magnesium sulfate. Then the solvent was removed by distillation and the resulting residue was subjected to silica gel column chromatography. The fractions eluted through the column with hexane-ethyl acetate (3:1) was evaporated to dryness in vacuo to thus obtain 6.8 g of waxy substance. This was dissolved in 30 ml of diethyl ether, 33 g (140 mmole) of lead dioxide was added to the solution and the solution was stirred at room temperature for two days. After filtering off lead dioxide, the filtrate was concentrated and the concentrate was chromatographed through a silica gel column. Thus, 1.46 g (5.98 mmole) of 2-geranyl-1,4-benzoquinone was obtained, in an yield of 3.8%, from the fractions eluted with hexane-ethyl acetate (5:1). Then, this compound (1.10 g; 4.50 mmole) was dissolved in 10 ml of pyridine and the solution was heated under reflux for 6 hours. The reaction solution was poured into 75 ml of ice-water and was extracted three times with diethyl ether (25 ml). The extract was washed with 100 ml of water (twice) and 100 ml of saturated aqueous sodium chloride solution (twice) and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting residue was chromatographed through a silica gel column. Thus, 490 mg (2.0 mmole) of 2-methyl-2-(4-methyl-3-pentenyl)-6-chromenol was recovered. Yield=45%. The overall yield from geraniol was 1.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:20]S(C(C)(C)C)=O)[CH2:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.O1CCOCC1>CO>[NH2:20][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) orange solution of ethyl 4-(2,6-dimethoxyphenyl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate (9.210 g; 23.89 mmol) in MeOH (100 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (11.95 ml; 47.80 mmol). The resulting orange mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 3 h. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate as an orange oil. LC-MS (conditions B): tR=0.62 min. and [M+H]+: 282.42 g/mol; tR=0.64 min. and [M+H]+: 282.42 g/mol (mixture of diastereoisomers). Due to transesterification, a reduced amount of methyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate was also detected: tR=0.57 min. and [M+H]+: 268.40 g/mol.
Reaction SMILES: [CH:1]1([N:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]([C:22]1[CH:27]=[C:26]([SH:28])[CH:25]=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]=1[OH:33])([CH3:21])[CH3:20].C(N(CC)CC)C>CO>[CH3:32][C:29]([C:24]1[CH:25]=[C:26]([S:28][CH2:10][CH2:9][C:8]([N:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:11])[CH:27]=[C:22]([C:19]([CH3:21])([CH3:20])[CH3:18])[C:23]=1[OH:33])([CH3:30])[CH3:31]
Reactant: C=CC(=O)N(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)N(C2CCCCC2)C2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
The title compound of Example 3 (1.9 g, 0.008 mole), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol(2 g, 0.008 mole) and triethylamine (0.5 ml) were stirred in methanol (25 ml) for about 12 hours. The solvent was removed in vacuo on a rotary evaporator, the crude material purified by chromatography on silica and recrystallized from hexane, m.p. ca. 168.5°-172° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:18]([O:17][C:16](=[O:22])[NH:15][CH2:12][C:13]#[C:14][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Cc1ncc(C#CCNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (2.81 g, 12.9 mmol) in TEA (25 mL) was added tert-butyl prop-2-yn-1-ylcarbamate (2.58 g, 16.6 mmol). The solution was degassed with argon. To the reaction mixture were added bis(triphenylphosphine)palladium(II) chloride (0.18 g, 0.26 mmol) and copper(I) iodide (0.098 g, 0.52 mmol). The reaction mixture was allowed to stir at 70° C. for 2.5 h and was then concentrated and diluted with EtOAc (100 mL). The mixture was filtered over a pad of Celite® and the resulting filtrate was washed with sat. aq. NaHCO3 (100 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl[3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-yl]carbamate (2.98 g, 79%) as a yellow solid. LCMS (FA): Rt=1.81 min, m/z=292.0 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.C(O)(=O)C>[Zn].O>[CH3:12][C:9]1[CH:10]=[CH:11][C:3]([CH3:2])=[C:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1ccc(C)c2c1CCC2=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)c2c1CCC2
Reaction time: 12 h
Yield: 81.1 %

Procedure:
Zinc amalgam (prepared by mixing zinc dust (25.0 g), mercuric chloride (2.5 g), concentrated hydrochloric acid (3 ml) and water (50 ml) together for 5 minutes, then decanting the aqueous solution) was added to a mixture of 4,7-dimethylindan-1-one (25.0 g, 156 mmole), acetic acid (50 ml), water (50 ml) and concentrated hydrochloric acid (100 ml). The mixture was refluxed with vigorous stirring for 12 hours, then cooled, poured into water and extracted with diethyl ether. The ether extract was washed successively with water, dilute aqueous sodium bicarbonate solution and water. Then dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography over silica gel (eluant hexane) gave 4,7-dimethylindane (18.5 g, 81.4%) as an oil.
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([CH:23]=O)=[CH:16][C:15]=1[CH2:25][CH2:26][CH3:27])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[Si:6]([O:13][C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([CH:23]=[CH2:1])=[CH:16][C:15]=1[CH2:25][CH2:26][CH3:27])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CCCc1cc(C=O)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=Cc1cc(CCC)c(O[Si](C)(C)C(C)(C)C)c(CCC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a solution of 1.0 g (2.80 mmol) of methyl triphenylphosphonium bromide in 5.0 mL of ether at 0° C. was added 1.12 mL (2.5M, 2.80 mmol) of butyllithium. The reaction mixture was stirred for 30 minutes at 0° C. and then 756 mg (2.33 mmol) of the title compound from Example 14 (Step A) was added. After stirring for 1 h at room temperature, the reaction mixture was poured into ethyl acetate and washed with water and then saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromotography (silica gel, hexane/ethyl acetate 97:3) gave 411 mg of the title compound.