Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[Cl:34])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=1[Cl:34])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.0 g), 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxopentanoic acid methyl ester (2.1 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 130° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1 by volume) to afford title compound, 1.6 g.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1.[NH4+].[Cl-]>>[CH3:7][C:6]1[N:5]([CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])[N:4]=[CH:3][C:2]=1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1
Reactant: Cc1c(I)cnn1C[C@H](O)CO
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-(4-Iodo-5-methylpyrazol-1-yl)-propane-1,2-diol (20.0 mg, 0.0709 mmol) in THF (1 mL, 10 mmol) was added 2 M isopropylmagnesium chloride in THF (0.18 mL, 0.36 mmol) at 0° C., and the reaction was allowed to warm to rt over 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.070 mL, 0.43 mmol) was then added, and the mixture was stirred at rt for 30 min. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil. It was used in the Suzuki coupling without further purification.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12]([N:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH3:16])(=[O:14])=[O:13]>O.C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12]([N:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:16])(=[O:13])=[O:14]
Reactant: COC(=O)CCCCN(C)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCCC(=O)O)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 18 h

Procedure:
A solution of lithium hydroxide (18.2 mg, 0.76 mmol) in water (3 ml) was added to a solution of methyl 5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoate (178 mg, 0.45 mmol) in THF (5 ml), and stirring was carried out for 18 h at room temperature. THF was then concentrated in vacuo, water was added to the residue, and extraction with DCM (2×20 ml) was carried out. The aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[C:32]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[C:33]([CH:41]=[CH:42][CH:43]=2)[O:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:14]=1.[F:49][C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[C:46]([CH2:45][CH2:44][C:32]1[C:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[CH:14]=[C:9]([C:54]3[CH:53]=[CH:52][CH:51]=[C:50]([F:49])[CH:55]=3)[CH:10]=2)=[CH:43][CH:42]=[CH:41][C:33]=1[O:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])([OH:48])=[O:47]
Reactant: CN(C)c1ccc(-c2cc(Br)cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)c2)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)c1ccc(-c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(-c3cccc(F)c3)c2)cc1
Temperature: 90 °C

Procedure:
In a reaction vessel charged with 4 mL of toluene and 1 mL of water, was added 45 mg (0.072 mmol) of 4-[3-[6-(5-bromo-4′-dimethylamino-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid, 3-fluorophenylboronic acid (20 mg, 0.144 mmol), and potassium phosphate (35.9 mg, 0.144 mmol). This mixture was put under an atmosphere of nitrogen and 4.16 mg of tetrakis(triphenylphosphine)palladium(0) was added. This mixture was stirred and was heated overnight at 90° C. At this time, analysis of an aliquot by LC-MS, indicated the formation of the desired product. To the reaction mixture was added 2N HCl to effect pH=˜6. The aqueous phase was thrice extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to provide a solid which was purified by preparative HPLC to provide 46 mg of product. Example 57 was characterized by low resolution mass spectrometry where signals corresponding to the following were observed: ES(+)=598+Na, ES(−)=597. Example 57 was also characterized by high resolution mass spectrometry where signals corresponding to the following were observed: m/e calculated for C37H39FO6 598.273068; found compatible with (M+Na)1+=621.2624.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[CH2:15][OH:16].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[CH2:15][O:16][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1
Reactant: OCc1ncccn1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ncccn2)n1
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
Into 3.6 g of N,N-dimethylformamide were dissolved 304 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 200 mg of 2-pyrimidylmethyl alcohol, 87 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 15 minutes. After stirring for 1.5 hour at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 278 mg of 5-(2-pyrimidylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (36)).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:3]([O:13][CH3:18])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Yield: 83.7 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (10.0 g, 37.9 mmol), dimethyl sulfate (4.31 mL, 45.5 mmol) and potassium carbonate (10.5 g, 75.9 mmol) in acetone (200 mL) was heated at reflux overnight. After evaporation to dryness, the mixture was diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexane, to yield the desired product (8.8 g, 84%). LCMS calculated for C10H11BrClO2 (M+H)+: m/z=227.0. found: 277.0.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:13]([C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])([O-:15])=[O:14].Cl>C(O)C.C(OCC)C.C(Cl)(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:17]=1[C:18]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:19])([O-:15])=[O:14]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 96.2 %

Procedure:
A mixture of magnesium turnings (4.94 g) and carbon tetrachloride (2 ml) in ethanol (35 ml) was warmed to 50° C. until the reaction started. Diethyl ether (150 ml) was then added cautiously, with stirring. A solution of diethyl malonate (32.5 g) in diethyl ether (50 ml) was then added dropwise, then stirred and heated at reflux for 2 hours. After cooling the mixture, diethyl ether (150 ml) was added. A solution of 2-nitro-4-trifluoromethylbenzoyl chloride (50.7 g) in diethyl ether (100 ml) was added dropwise. The mixture was heated at reflux for 2 hours. After cooling, hydrochloric acid (2M,200 ml) was added and the layers were separated. The organic layer was washed with water, dried (anhydrous sodium sulphate), and filtered. The filtrate was evaporated to dryness, to give diethyl 2-nitro-4-trifluoromethylbenzoylmalonate (72.6 g), in the form of an off-white solid, m.p. 60° C.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH:6]1[CH:10]=[CH:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([SnH](CCCC)CCCC)CCC.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:9]1[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]2[CH2:5][O:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[CH:10]12
Reactant: CC(C)(C)OC(=O)N1CC=CC1COc1ccccc1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC2c3ccccc3OCC21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Tert-butyl 2-[(2-bromo-phenoxy)methyl]-2,5-dihydro-1H-pyrrole-1-carboxylate (14.2 g, 0.38 mol) was dissolved in toluene (707 mL) and heated at 50° C. for 20 min. To this solution was added AlBN (688 mg, 0.049 mol) and tributyltin hydride (16 mL, 0.61 mol) at room temperature. The reaction mixture was stirred at 80° C. for 16 h and then DBU (9.5 mL, 0.62 mol) was added. The resulting suspension was filtered through a pad of silica gel (100 g) and the solids washed with methyl tert-butylether. The filtrate was evaporated. The crude product was purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 10% ethyl acetate in 10 minutes, then 20% ethyl acetate for 15 min) to provide the title product. MS m/z 299 [M+Na]+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+].O>CO>[N:10]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:11]=[N-:12]
Reactant: CCOC(=O)CCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCCN=[N+]=[N-]
Yield: 98.5 %

Procedure:
A solution of ethyl 4-bromobutyrate (10.0 g, 51.3 mmol), NaN3 (6.66 g, 102 mmol) and 25 ml of water in 75 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water. After drying and evaporation of solvent, ethyl 4-azidobutyrate (7.94 g, 98.6%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH:19]([CH3:29])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C(OC1C=CC(/C=C2/C(=O)N(CCCNC(=O)OC(C)(C)C)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH:19]([CH3:29])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: CC(Br)CNC(=O)OC(C)(C)C
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCCNC(=O)OC(C)(C)C)C2=O)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(C(C)CNC(=O)OC(C)(C)C)C2=O)cc1
Yield: 15.4 %

Procedure:
The title compound 21c was prepared from compound 2 (300 mg, 1.20 mmol) and tert-butyl (2-bromopropyl)carbamate (286 mg, 1.20 mg) in a manner similar to that described for 21a. Yield=15.4%, 75 mg.
Reaction SMILES: [CH2:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][C@H:7]([CH:12]([CH3:14])[CH3:13])[C:6]([O:15][CH3:16])=[N:5]1)[CH:2]=[CH2:3].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]I)=[C:20]([Cl:27])[CH:19]=1.O>O1CCCC1>[CH2:1]([C@:4]1([CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][C:20]=2[Cl:27])[C:9]([O:10][CH3:11])=[N:8][C@H:7]([CH:12]([CH3:14])[CH3:13])[C:6]([O:15][CH3:16])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1N=C(OC)[C@@H](C(C)C)N=C1OC
Reactant: Clc1cc(Br)ccc1CCI
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@]1(CCc2ccc(Br)cc2Cl)N=C(OC)[C@@H](C(C)C)N=C1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Under an argon atmosphere, an n-butyllithium-hexane solution (1.60 mol/L, 11.16 mL) was added at −78° C. to a solution of (5R)-2-allyl-3,6-dimethoxy-5-isopropyl-2,5-dihydropyrazine (3.64 g) in tetrahydrofuran (60 mL) to form a reaction solution. This reaction solution was then stirred at −78° C. for 30 minutes. A solution of 4-bromo-2-chloro-1-(2-iodoethyl)benzene (6.73 g) in tetrahydrofuran (20 mL) was added to the reaction solution, and the reaction solution was stirred at −78° C. for 30 minutes and then at 0° C. for 1 hour. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=70:1) to obtain the target product (6.04 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10]>[Cu].[Zn].S([O-])([O-])(=O)=O.[Cu+2].[Zn].O>[F:8][C:7]1[CH:2]=[C:3]([F:10])[CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: Fc1cc(F)c(Cl)c(F)c1
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Fc1cc(F)cc(F)c1
Temperature: 330 °C
Reaction time: 32 h
Yield: 42 %

Procedure:
An autoclave was charged with 6.68 g of 2-chloro-1,3,5-trifluorobenzene, 0.5 g of water and 7.5 g of 3-5% zinc-copper couple (prepared by adding an aqueous solution of copper sulfate to an aqueous dispersion of zinc powder (copper/zinc weight ratio of 3 to 5%), allowing the mixture to stand, filtering out the solid component under reduced pressure, and washing, drying and pulverizing the solid component in a mortar), and the content was heated at 330° C. with high speed stirring for 32 hours. After the reaction, the content was distilled off, and a fraction distilled off at 74° to 77° C. was dried over sodium sulfate to obtain 1,3,5-trifluorobenzene in an amount of 2.19 g (yield 42%).
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Si:10]([O:17][CH2:18][CH:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:20]Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[Br:1][C:2]1[N:3]([CH2:20][CH:19]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:18][O:17][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:12])[CH3:11])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Br)n1
Reactant: CC(C)(C)[Si](C)(C)OCC(CCl)OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(Cn1cc([N+](=O)[O-])nc1Br)OC1CCCCO1
Temperature: 110 °C
Reaction time: 12 h
Yield: 70.3 %

Procedure:
2-Bromo-4-nitroimidazole (7.63 g) and 1-(tert-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane (12 g) were dissolved in N,N-dimethylformamide (80 ml), then potassium carbonate (6.6 g) and sodium iodide (6.3 g) were added thereto, and the reaction mixture was heated and stirred at 110° C. for 12 hours. Ice-water (240 ml) was added, extracted twice with ethyl acetate (150 ml), and the extracts were combined together and washed with an aqueous solution being saturated with sodium chloride (100 ml), then dried over anhydrous magnesium sulfate. After being filtrated under a reduced pressure, the filtrate was concentrated under a reduced pressure. The residue obtained was purified by use of a silica gel column chromatography (eluent: dichloromethane/ethyl acetate=100/1), there was obtained 2-bromo-1-[3-(t-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl]-4-nitroimidazole (12.69 g, yield: 68.7%)
Reaction SMILES: C=[C:2]1[CH:7](Cl)[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[CH:3]1[CH2:11][CH2:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O=O.OP([O-])([O-])=O.[K+].[K+]>CO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:10][C:4]1([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]2[CH:3]1[CH2:11][CH2:12][C:13](=[O:23])[C:14]=2[CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17]
Reactant: C=C1C(Cl)CCC(C)(C)C1CCC(=O)CCC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: O=O
Agent: O=P([O-])([O-])O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC1=C2CCCC(C)(C)C2CCC1=O
Reaction time: 264 h
Yield: 52.3 %

Procedure:
190 g (0.55 mol) of tert.butyl 6-(2-methylidene-6,6-dimethyl-3-chlorocyclohex-1-yl)-4-oxo-hexanoate was dissolved in 1.7 l of methanol in a gasification flask, cooled to -70° and ozonized (O2 flow=200 l/h) for 1 hour and 45 minutes. 108 g (1.65 mol) of CuSO4 -activated zinc powder, 200 ml of deionized water and 150 ml of a solution of 115 g of K2HPO4 in 300 ml of H2O was placed in a 4 l four-necked flask fitted with a stirrer, thermometer, condenser and dropping funnel. The cold ozonization mixture was rapidly added dropwise and the resulting grey suspension was heated under reflux. After 17 hours the remainder of the K2HPO4 solution was added and the mixture was heated under reflux. After 4 days the pH value of the mixture was adjusted with saturated K2HPO4 solution to ~7, after 5 days to pH 7.5 and after 6 days to pH 8. After a total of 11 days the grey mixture was left to cool and the phases were separated. The aqueous phase was extracted 3 times with hexane. The combined organic phases were washed neutral 3 times with saturated NaCl solution, dried over MgSO4 and evaporated. 84.17 g of tert.butyl 2-[5,5-dimethyl-2-oxo-2,3,4,4a,5,6,7,8-octahydronaphth-1-yl]acetate was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(OCC)(=O)C.O.CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 105.1 %

Procedure:
To an N,N-dimethylformamide solution (20 mL) of 4′-hydroxy-2′-methylacetophenone (3.06 g, 20 mmol) were added potassium carbonate (3.66 g, 26.4 mmol), benzyl bromide (2.7 mL, 22.4 mmol), and n-Bu4NI (0.75 g, 2.03 mmol), and the mixture was stirred for 14 hours at room temperature. To the reaction solution cooled in ice were added a saturated solution of ammonium chloride, subsequently water and ethyl acetate to separate an organic layer. The organic layer was washed with 20% aqueous solution of sodium thiosulfate and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=8:1 to 6:1) to obtain the title compound (5.05 g, quant.) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:16]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:16][O:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc2ccccc2cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc2ccccc2cc1OC
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2CO3 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp. overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): 1H-NMR DMSO-d6) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC>COCCOC.CCOC(C)=O.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-c3ncccn3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 4-(4-Bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (355 mg; 1.002 mmol); 2-tributylstannanyl-pyrimidine (1.1 g; 2.98 mmol); triphenylphosphine palladium dichloride (35 mg, 0.049 mmol) was stirred in DME (4 ml) at 100° C. overnight. Reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml) and water (50 ml). Separated organic layer, washed with brine, dried over Na2SO4, then chromatographed on silica gel eluting with 70% v/v EtOAc/Hexanes yielding product at solid (110 mg; 31%)