Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.Cl[C:6]1C=CC(N2C(C)=C(CCC)C(=O)C(C(O)=O)=N2)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:37][C:36](=[O:43])[C:35]([C:44]([OH:46])=[O:45])=[N:34]2)=[CH:29][CH:28]=1.O>CO>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:37][C:36](=[O:43])[C:35]([C:44]([O:46][CH3:6])=[O:45])=[N:34]2)=[CH:29][CH:28]=1
Reactant: CCCCc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Reactant: CCCc1c(C)n(-c2ccc(Cl)cc2)nc(C(=O)O)c1=O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCCCc1cc(=O)c(C(=O)OC)nn1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 25 ml of methanol, cooled to -5° C., there is added 2.38 g (0.02 mol) of thionyl chloride. To the ice cooled solution is added 2.85 g (0.0093 mol) of the mixture of 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-n-propyl-6-methyl pyridazine-3-carboxylic Acid and 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-n-butyl pyridazine-3-carboxylic Acid dissolved in 25 ml of methanol. The solution is stirred at 0° C. for 1/2 hr. and at room temperature for 18 hrs. To the solution is added 250 ml of water and the oil suspension formed is stirred at room temperature for 1 hr. The suspension is extracted with 3 (100 ml) portions of methylene dichloride and the extract is dried over magnesium sulfate and concentrated in vacuo to afford 2.9 g of mixed products (oil). The mixture is separated using a silica gel dry column and ethyl acetate as eluent to afford 0.5 g (17% yield of example 30 (oil) and 0.5 g (17% yield) of example 29 (semi-solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:17][C:16]=1[NH2:26])([O-:14])=[O:13].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:26][C:16]2[CH:17]=[C:18]([C:21]3[NH:22][CH:23]=[CH:24][CH:25]=3)[CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1cc(-c2ccc[nH]2)ccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccc[nH]3)ccc2[N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A solution of 4-methoxybenzoyl chloride (145, 0.175 g, 1.0 mmol), aniline 144 (79.2 mg, 0.39 mmol) and 4-(dimethylamino)pyridine (catalytic amount) was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM, treated with saturated NaHCO3, stirred for 3 h and diluted with AcOEt. Organic phase was collected, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated to provide compound 146 (0.133 g, 100% yield).
Reaction SMILES: C1(S(O[C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)(=O)=O)C=CC=CC=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CS(C)=O>[N:28]1([C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn2c3c(c(OS(=O)(=O)c4ccccc4)ccc3c1=O)CCC2
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Yield: 10 %

Procedure:
18.5 g of 8-benzenesulfonyloxy-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under flow of nitrogen at 10 atm. at a temperature of 160° to 170° C. for 20 hours while stirring. Treatment in the same manner as in Example 15 gave 1.5 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267° to 268° C.
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([CH3:15])[CH:6]=1)(=O)C.[OH-].[Na+].CCOC(C)=O>O.CO>[CH3:15][C:7]1[CH:6]=[C:5]([OH:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CC(=O)Oc1cc(C)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cc(O)c2c(c1)CCCC2
Yield: 93.7 %

Procedure:
A solution of 5,6,7,8-tetrahydro-3-methyl-1-naphthyl acetate (11.00 g) and NaOH (6.50 g) in a mixture of water (50 ml) and MeOH (150 ml) was refluxed for 5 hours. MeOH was removed under reduced pressure to give a residue. AcOEt was added to the residue and c-HCl was added dropwise under ice-cooling. The organic phase was washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 5,6,7,8-tetrahydro-3-methyl-1-naphthol as a solid (8.19 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[F:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>O1CCCC1>[F:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH:18]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[OH:19]
Reactant: COc1cccc(Br)c1
Reactant: O=Cc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(F)cc2F)c1
Reaction time: 0.17 h
Yield: 102.7 %

Procedure:
Add n-butyl lithium solution (2.5 M, 140 mL, 350 mmol) to 3-bromoanisole (44.6 mL, 352.2 mmol) in cold (−78° C.) tetrahydrofuran (anhydrous, 500 mL), dropwise. Let stir for 10 minutes and add 2,4 difluorobenzaldehyde (50 g, 351 mmol), dropwise, and stir for an additional 1 hour. After 1 hour the reaction is complete. Quench the reaction mixture with cold water, extract with ethyl acetate, dry (MgSO4), and concentrate to give the crude, title compound (Compound 7) (90.21 g, >100% Yield). Use compound in a crude form or purify by column chromatography (20% ethyl acetate in heptane). NMR agrees with the final, desired compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1>CN(C=O)C>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCCO
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
3-Amino-1-propanol (6.92 mL, 90.5 mmol) was added dropwise to a stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (20.0 g, 90.5 mmol) and triethylatnine (18.9 mL, 136 nmuol) in DMF (300 mL) at room temperature. After 16 hours, the solvent was removed under reduced pressure and the resulting oil was partitioned between ethyl acetate (450 mL) and water (50 mL). The layers were separated and the organic layer was washed with water (3×50 mL). The combined aqueous layers were back-extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid was triturated with hexanes/ethyl acetate (2: 1) and was isolated by filtration to yield 12.43 g of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]([CH:12]=[O:13])=[C:10]([Cl:14])[N:9]=[C:8]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[Mg].[CH3:24]I.OS([O-])(=O)=O.[Na+]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH:12]([OH:13])[CH3:24])=[C:10]([Cl:14])[N:9]=[C:8]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:21][CH:22]=1
Reactant: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.8 g of 3-(4-bromobenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde are dissolved in 50 ml of THF and a Grignard solution, prepared from 385 mg of magnesium turnings and 990 μl of methyl iodide in 50 ml of diethyl ether, is slowly added by syringe at RT. The mixture is stirred at RT for 3 days, then 200 ml of a 5% aqueous NaHSO4 solution are added und the mixture is extracted twice using 200 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. 3.7 g of a colorless oil are obtained.
Reaction SMILES: COC1C=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:7]=[CH:6]2.Cl.CCOCC.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(N(CC)C(C)C)(C)C.[C:61]([O:64][C:65](=O)[CH3:66])(=[O:63])[CH3:62]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:23]1([CH2:22][CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:9]3[C:8]([O:29][S:30]([C:33]([F:36])([F:34])[F:35])(=[O:32])=[O:31])=[CH:7][CH:6]=[C:5]4[C:10]=3[CH:11]=[CH:12][C:65]([O:64][C:61](=[O:63])[CH3:62])=[CH:66]4)=[CH:19][CH:18]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: BrB(Br)Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
Charge a flask with trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (10.0 g, 19.0 mmol) and dissolve in methylene chloride (100 mL). Add 2M HCl in ether (19 mL, 38 mmol) and remove solvent in vacuo. Redissolve in dry methylene chloride (200 mL) and cool to 0° C. under nitrogen. Add BBr3 (9.0 mL, 95 mmol) slowly, and stir at 0° C. for 30 minutes. Pour reaction slowly into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate in vacuo. Dissolve crude material in methylene chloride (200 mL) and add N,N-diisopropylethylamine (16.5 mL, 95 mmol) and 4-dimethylaminopyridine (120 mg, 1.9 mmol) and stir at room temperature. Add acetic anhydride (3.6 mL, 38 mmol). Stir for 20 minutes and pour into saturated aqueous sodium bicarbonate. Extract with methylene chloride. Wash the organic layer with water, dry over sodium sulfate, filter and concentrate in vacuo to yield 10.5 g (100%) of acetic acid 5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-6-trifluoromethanesulfonyloxy-naphthalen-2-yl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=O)[C:6]=2[CH:22]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:32]2)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[S:32])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN(C)C(=S)c1cc(F)ccc1-2
Reaction time: 1 h

Procedure:
10.7 g (35.3 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 7.13 g (17.6 mmol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide in 100 ml of toluene are heated to boiling under reflux for 22 hours. The mixture is subsequently concentrated in vacuo until crystallisation begins and is then left to stand in an ice-bath for 1 hour. The crystallised-out material is filtered off under suction and washed with a small amount of toluene. The mixture is separated on silica gel with ethyl acetate/chloroform (1:9). After recrystallisation from ethyl acetate, there is obtained pure ethyl 8-fluoro-5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 157°-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[N+:12]([O-])=O>[Pd].C(O)C>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:12]
Reactant: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1c(N)cccc1N
Reaction time: 8 h
Yield: 105.9 %

Procedure:
A mixture of 2-methoxy-1,3-dinitro-benzene (1.49 g) and palladium on carbon (10%, 150 mg) in ethanol (75 mL) was stirred under hydrogen atmosphere (1 atm.) overnight. The catalyst was filtered off on a CELITE™ pad and the filter cake was washed with ethanol. The filtrate was evaporated under reduced pressure to afford 1.1 g of 2-methoxy-benzene-1,3-diamine as a light yellow solid without further purifications.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:13])[C:8]([CH3:12])=[C:9]([OH:11])[N:10]=[C:5]2[S:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][O:11][C:9]3[N:10]=[C:5]4[S:4][CH:3]=[C:2]([CH3:1])[N:6]4[C:7](=[O:13])[C:8]=3[CH3:12])=[CH:34][CH:35]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: Cc1c(O)nc2scc(C)n2c1=O
Reactant: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(COc3nc4scc(C)n4c(=O)c3C)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
To a solution of 3,6-dimethyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (537 mg) and potassium carbonate (745 mg) in DMF (10 ml) was added 4-(4-methoxybenzoyl)benzyl bromide (970 mg) and the mixture was stirred at 80° C. for 2 hours. This reaction mixture was concentrated and the residue was diluted with water-ethyl acetate and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (hexane: ethyl acetate =2:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (106 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]([NH2:26])=[O:25])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:35][C:36]1[CH:37]=[C:38]([CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH:39]=[CH:40][C:41]=1OS(C(F)(F)F)(=O)=O>COCCOC.C(O)C.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:24]([C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:41]3[CH:40]=[CH:39][C:38]([CH2:50][C:51]([O:53][CH3:54])=[O:52])=[CH:37][C:36]=3[Cl:35])=[CH:13][CH:14]=2)[C:6]([CH3:8])=[N:7][C:2]=1[CH3:1])(=[O:25])[NH2:26]
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: Cc1nc(C)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
To a degassed solution of 3,5-dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carboxamide (Intermediate 7-6; 196 mg, 0.55 mmol) in DME (6 mL), ethanol (1.5 mL) and water (1.5 mL) was added tripotassium phosphate (141 mg, 0.67 mmol), methyl 2-(3-chloro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 1-2; 185 mg, 0.55 mmol) followed by (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (36.5 mg, 0.04 mmol). The resulting mixture was stirred at 80° C. under nitrogen for 4 hours. The reaction mixture was allowed to cool to ambient temperature, evaporated and partitioned between EtOAc (75 mL) and saturated brine (50 mL) then filtered through celite. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetate (110 mg, 48.4%) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[O:19][C:18](=[O:20])[C:17]([C:21](=[O:24])[CH2:22][CH3:23])=[C:16](O)[CH:15]=1)[CH3:13])(C(C)(C)C)(C)C.C([O-])(O)=[O:27].[Na+]>CC(O)=O.C1COCC1.O>[OH:27][C:15]1[CH:16]=[C:17]([C:21](=[O:24])[CH2:22][CH3:23])[C:18](=[O:20])[O:19][C:14]=1[CH:12]([CH3:13])[CH2:11][CH2:10][CH2:9][OH:8]
Reactant: O=C([O-])O
Reactant: CCC(=O)c1c(O)cc(C(C)CCCO[Si](C)(C)C(C)(C)C)oc1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(=O)c1cc(O)c(C(C)CCCO)oc1=O

Procedure:
6-(5-(t-Butyldimethylsilyloxy)pentan-2-yl)-4-hydroxy-3-propionyl-2-H-pyran-2-one (IV; 3 g; 8.15 mmol) in 100 ml AcOH/THF/water (3/1/1, v/v/v) was stirred for 18 h at 25° C. The reaction mixture was neutralized with saturated NaHCO3, extracted with 3×50 ml EtOAc, dried with anhydrous Na2SO4, and evaporated to an oil. The product was purified via silica chromatography (40% EtOAc in hexanes).
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](Cl)=[O:27])=[CH:22][CH:21]=1>CCCCCC.O1CCCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:26](=[O:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][C:20]([CH3:19])=[CH:21][CH:22]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: Cc1ccc(OCC(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (8.83 ml) and N,N-dimethylformamide (3 drops) were added at room temperature to a solution of 4-methylphenoxyacetic acid (6.73 g) in dichloromethane (70 ml), and the reaction mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, then the resulting acidic gas was removed as the toluene azeotrope, and the product was dried under reduced pressure to give 4-methylphenoxyacetyl chloride. A 1.61N solution of n-butyl lithium in hexane (25.2 ml) was added dropwise at −78° C. to a solution of (S)-4-benzyl-2-oxazolidinone (7.08 g) in tetrahydrofuran (70-ml), and after the completion of the dropwise addition, the reaction mixture was stirred at −78° C. for 30 minutes. To this resulting solution was added at −78° C. a solution of 4-methylphenoxyacetyl chloride obtained above in tetrahydrofuran (70 ml) followed by stirring at 0° C. for 1 hour. The resulting reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed successively with a 1N aqueous solution of hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate =3/1˜1/1) to afford the target compound (9.00 g) as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]I>C1COCC1>[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)CI
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C)Cc1ccco1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of furan (8.16 g, 0.13 mol) in dry THF (100 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (28.0 mL, 2.5 M, 70.0 mmol) was then added dropwise. After addition, the reaction mixture was stirred at −78° C. for additional 1 hour, before a solution of (S)-2-methylbutyliodide (10.0 g, 50.5 mmol) in dry THF (20 mL) was added slowly. This mixture was stirred at −78° C. for 2 hours, and then allowed to warm to room temperature slowly and stirred at room temperature overnight. The reaction was quenched by water (20 mL) and the mixture was poured into water (200 mL), and the resulting mixture was extracted with ether (300 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as eluent, leading to a colorless oil as the product. (6.18 g, 88.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C=CC(OC)=CC=1C=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:21][CH3:20])=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1ccc(OC)c(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 88.6 %

Procedure:
According to the preparation of 42, 2,5-dimethoxybenzaldehyde (38) (1.2 g, 7.3 mmol) was used to afford 47 (1.8 g, 88.6%) as pale yellow prism crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][OH:16])[CH:5]=[CH:4][C:3]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)C>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][O:16][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 99.2 %

Procedure:
400 mg of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanol dissolved in 25 ml of THF absolute were treated with 382 mg of triphenylphosphine, 242 mg of ethyl 4-hydroxybenzoate and 0.24 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 1 portion of 50 ml of diethylether and washed with 2 portions of 25 ml of water and 1 portion of 50 ml of a saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 591 mg of (RS)-ethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptyloxy]-benzoate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2.[CH2:17]([S:33](Cl)(=[O:35])=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O>N1C=CC=CC=1>[CH2:17]([S:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2)(=[O:35])=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: Nc1ccc2[nH]c(-c3ccccc3)cc2c1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20.8 g of 5-amino-2-phenylindole are dissolved in 200 ml of pyridine, and 32.45 g of hexadecylsulfonyl chloride are added. After stirring for 2 hours at room temperature, a precipitate is obtained by the addition of water. The precipitate is suction filtered and washed with water. It is then stirred into methanol in the cold, suction filtered and recrystallized from ethanol with the addition of a saturated aqueous sodium dithionite solution. The precipitate is suction filtered, washed with water and a little methanol and dried. 47.4 g of the above mentioned compound are obtained.