Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+:2].C[O:4][C:5](=[O:13])[C:6]([F:12])([F:11])[S:7](F)(=[O:9])=[O:8]>O>[C:5]([C:6]([F:12])([F:11])[S:7]([O-:1])(=[O:9])=[O:8])([OH:4])=[O:13].[Na+:2]
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(F)(F)S(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound, triphenylsulfonium (1-pyrrolidonemethoxycarbonyl)-difluoromethanesulfonate was prepared as depicted in Scheme 1 above and as follows: Sodium hydroxide (6.400 g, 160 mmol) was placed in a 100 mL round-bottom flask fitted with a condenser and water (30 mL) was added. The suspension was stirred magnetically for 30 min, then cooled down to 0° C. with an ice-bath. Methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (9.605 g, 50 mmol) was added dropwise over 15 min. When the addition was complete, the mixture was left stirring under reflux for 18 hours. After this time, the mixture was cooled down to room temperature, filtered on a Buchner funnel to remove salts and the filtrate was acidified to pH=2 with aqueous HCl. The water was then removed under reduced pressure at 55° C. to give a colorless oil of sodium carboxydifluoromethanesulfonate. The next step was carried out assuming 100% conversion. 13C NMR (125 MHz, D2O) δ 113.69 (t), 165.53; 19F NMR (282 MHz, D2O) δ −108.83
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([O:11]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl.N1C=CC=CC=1>O>[F:1][C:2]1[C:9]([F:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(F)c1F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1ccc(O)c(F)c1F
Temperature: 170 °C
Yield: 6759.9 %

Procedure:
Combine 2,3-difluoro-4-methoxy-benzaldehyde (2.76 g, 16.0 mmol) and pyridine hydrochloride (18.5 g, 160 mmol) in a round bottom flask equipped with nitrogen inlet. Heat the mixture at 170° C. two hours, cool to near ambient temperature and dilute with water. Extract aqueous with EtOAc (2×), wash extract with 0.1 N aq. HCl (2×), water (2×) and brine, dry (MgSO4) and concentrate. Purify on silica gel (20% EtOAc/Hexane) to give 2,3-difluoro-4-hydroxy-benzaldehyde (171 g) as a yellow solid. 1HNMR (CDCl3): 10.18 (s, 1H), 7.59 (t, 1H), 6.90 (t, 1H), 6.14 (s, 1H).
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[I:15]N1C(=O)CCC1=O>C(#N)C>[I:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cn2ccccc2n1
Solvent: CC#N
Product: CCOC(=O)c1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
2.405 g (12.16 mmol) of ethyl imidazo[1,2-a]pyridine-2-carboxylate were dissolved in 60 ml of acetonitrile with magnetic stirring, to this solution were added 3.01 g (13.38 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 1 h. The reaction mixture was treated with 50 ml of 100 mg/ml Na2S2O5 aqueous solution. The aqueous phase was extracted with 2×100 ml of ethyl acetate. The aqueous phase was neutralized by adding NaHCO3 portionwise and then extracted with 3×100 ml of ethyl acetate. The whole of the organic phases was combined and then washed with 200 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo in order to obtain 1.59 g (yield=41%) of ethyl 3-iodoimidazo[1,2-a]pyridine-2-carboxylate as a pale yellow solid. LC-MS: m/z=317 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.45 (d, J=6.9 Hz, 1H), 7.66 (d, J=9.1 Hz, 1H), 7.46 (d, J=7.0 Hz, 1H), 7.15 (d, J=6.6 Hz, 1H), 4.30 (d, J=7.1 Hz, 2H), 1.36 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[S-:24][C:25]#[N:26].[Na+].BrBr.O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[S:24][C:25]#[N:26])[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2nc3n(c2SC#N)CCS3)cc(C(C)(C)C)c1O
Yield: 37.9 %

Procedure:
In 10 ml of acetic acid was dissolved 1.35 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and after adding thereto 0.64 g of sodium thiocyanate, 0.7 g of bromine was added dropwise to the solution under ice-cooling. After performing the reaction for one hour at room temperature, 30 ml of water was added to the reaction mixture to precipitate crystals, which were recovered by filtration. The crystals were added to a mixture of 20 ml of chloroform and 10 ml of an aqueous 10% potassium carbonate solution followed by stirring. The chloroform layer thus formed was dried and concentrated, and the residue thus formed was purified by silica gel column chromatography using chloroform as the eluent and further recrystallized from ethanol to provide 0.6 g 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-thiocyanato-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15](O)[CH2:14]1>>[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14]1
Reactant: C[C@@H]1CCC[C@H](O)C1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CCC[C@H](C)C1)C(C)=O

Procedure:
Ethyl (Z)-2hydroxyimino-3-oxobutyrate (2.65 g, 16.7 mmol) was converted into the title compound by reaction with cis 3-methylcyclohexanol (1.9 g, 16.7 mmol) as described in Example 4a method 3. After purification the title compound was obtaind as a colourless oil (0.57 g, 11%) νmax (CHCl3) 1735, 1680, and 1590 cm-1 ; δH (CDCl3) 0.8-1.3 (1H, m,. partially obscured by d, δ 0.9); 0.90 (3H, d, J 6.5 Hz), 1.1-1.4 (1H, m, partially obscured by t, δ 1.33 ), 1.33 (3H, t, J 7.11 Hz), 1.4-1.8 (2H, m, partially obscured by s, δ 1.55 ), 1.55 (3H, s), 1.85-2.1 (2H, m), 2.4 (3H, s), 4.36 (2H, q, J 7.1 Hz), and 4.50-4.64 (1H, m), δ13C (CDCl3), 14.19, 20.32, 22.28, 25.13, 26.74, 29.55, 34.16, 38.13, 61.74, 81.96, 150.2, 161.51, and 193.01.
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH:3]=[CH:4][CH:5]([OH:7])[CH3:6].[CH:9](=O)[CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:10]([CH:9]1[O:8][CH:2]([CH3:1])[CH:3]=[CH:4][CH:5]([CH3:6])[O:7]1)[CH2:11][CH3:12]
Reactant: CC(O)C=CC(C)O
Reactant: CCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1OC(C)C=CC(C)O1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 580 g (5 moles) of hex-3-ene-2,5-diol, 3 g of p-toluenesulfonic acid, 360 g (5 moles) of n-butanal and 1 l of toluene was refluxed, and the resulting water of reaction (108 ml) was removed in the course of 3 h. Thereafter, the mixture was left to cool to room temperature, 10 ml of a 25% strength aqueous sodium hydroxide solution were added, the mixture was washed neutral with a little water and the toluene was removed under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 681 g (4 moles) of 2-propyl-4,7-dimethyl-4,7-dihydro-1,3-dioxepin of boiling point 70° C./0.1 mbar.
Reaction SMILES: [F:1][C:2]1([F:20])[C:8]2([CH2:9][O:10]CC3C=CC(OC)=CC=3)[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[F:1][C:2]1([F:20])[C:8]2([CH2:9][OH:10])[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: COc1ccc(COCC23CCCCC2C3(F)F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: OCC12CCCCC1C2(F)F
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a solution of 7,7-difluoro-1-((4-methoxybenzyloxy)methyl)- bicyclo[4.1.0]heptane (2.50 g, 8.90 mmol) in dichloromethane (20 mL) and water (3.0 mL) was added DDQ (3.00 g, 13.3 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 3 hour. Water (1.5 mL) was added followed by sodium sulfate (10 g). The resulting suspension was filtered through a short pad of silica gel column with ethyl acetate in hexanes (30%) to afford the title compound as a colorless liquid (0.90 g, 62%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>COCCOC.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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:14]
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccccc1-c1ccccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Under air, to 2-bromopyridine (4.54 g, 28.7 mmol, 1.00 equiv) in DME—H2O (1:1, 100 mL) at 23 ° C. was added K2CO3 (5.96 g, 43.1 mmol, 1.50 equiv), 2-aminophenylboronic acid pinacol ester (6.30 g, 28.7 mmol, 1.00 equiv), and tetrakis(triphenylphosphine)palladium (1.66 g, 1.44 mmol, 5.00 mol%). The reaction mixture was stirred at 100 ° C. for 3.0 h. After cooling to 23 ° C., the phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (100 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 4:1 (v/v) to afford 4.20 g of the title compound as a red-brown oil (86%). Rf=0.38 (hexanes/EtOAc 3:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.61-8.60 (m, 1H), 7.78-7.75 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.51 (dd, J=7.6 Hz, 1.4 Hz, 1H), 7.19-7.16 (m, 2H), 6.80-6.76 (m, 2H), 5.72 (br s, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 159.5, 147.9, 146.6, 136.9, 129.9, 129.4, 122.2, 122.2, 121.0, 117.6, 117.2.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-].[Na+].S(=O)(=O)(O)[OH:16]>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:16]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Temperature: 40 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1.77 kg (10 mol) of 2,3,4-trifluoronitrobenzene are added to 2 l of water, and the mixture is warmed to 40° C. and vigorously stirred. 1760 g (22 mol) of 31.7% strength sodium hydroxide solution are then added dropwise in such a way that the temperature does not rise above 60° C. After about 2 h, GC checking no longer shows any starting compound. The reaction mixture is brought to pH 2.5 using 70% strength sulfuric acid. Steam is then passed into the solution, the product passing over with the steam. The separated solution is cooled to 10° C. with stirring and the precipitated solid is filtered off with suction. The water having a residual content of about 0.1% of 2,3-difluoro-6-nitrophenol can be used in a subsequent batch. 1.48 kg of 2,3-difluoro-6-nitrophenol having a purity >99.9% (GC) are obtained after drying (melting point 64° C.), which corresponds to a yield of 85% of theory.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[Cl:20][C:21]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][C:22]=1[CH:23]=O>>[Cl:20][C:21]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][C:22]=1[CH2:23][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cc(-c2ccccn2)ccc1Cl
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(-c2ccccn2)ccc1Cl

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-chloro-5-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 437.10 g/mol.
Reaction SMILES: CS(O[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16](=[O:20])[CH2:17][CH2:18][Cl:19])[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)(=O)=O.[H][H]>C(O)C.[Pd]>[Cl:19][CH2:18][CH2:17][C:16]([C:15]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=[O:21])[NH:12]2)=[CH:7][CH:6]=1)=[O:20]
Reactant: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCCl)NC(=O)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2ccc(C(=O)CCCl)cc2N1

Procedure:
3.0 Grams of 6-methylsulfonyloxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril and 0.5 g of palladium black were suspended in 200 ml of ethanol and the suspension was subjected to catalytic reduction under 3 atmospheric pressure of hydrogen gas at a room temperature for 5 hours under stirring condition. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure to obtain a residue. The residue was recrystallized from ethanol to obtain a 1.2 g of 7-(3-chloropropionyl)-3,4-dihydrocarbostyril in colorless powdery-like crystals. Melting point: 159°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][OH:16])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:28])=[CH:25][CH:24]=1.O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][O:16][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:28])=[CH:39][CH:40]=2)=[CH:17][CH:18]=1
Reactant: O=C(OCCOc1ccccc1)c1ccc(CCl)cc1
Reactant: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NOCc1ccc(C(=O)OCCOc2ccccc2)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
2.0 Grams (0.008 mole) of 5-(4-fluorophenoxy)-1,3-dimethylpyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethyl sulfoxide, and after adding 0.65 g (0.0116 mole) of powdery potassium hydroxide, the resulting solution was stirred at 30° C. for 30 minutes. To this solution was added 2.5 g (0.00865 mole) of 2-phenoxyethyl 4-chloromethylbenzoate, and reaction was carried out at from 50° to 60° C. for 1 hour. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 3.0 g of the desired compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:12])[CH3:11])[C:3]1=[O:17].[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:16]([O:15][C:13]([NH:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:12])[CH3:11])[C:3]1=[O:17])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: c1ccccc1
Solvent: C1COCCO1
Product: C=CC[C@@H]1[C@@H](NC(=O)OCc2ccccc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
5.05 g (21.2 mmol) of (3R,4R)-3-amino-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-4-(2-propenyl)-2-azetidinone [6] was dissolved in 30 ml of dioxane, and a dioxane solution (60 ml) of 6.4 g (23.3 mmol) of S-4,6-dimethylpyrimidin-2-ylthiocarbonate was added dropwise to the solution at room temperature. The mixture was stirred at room temperature for 16 hours. Benzene (100 ml) was added to the reaction solution, and the insoluble materials were separated by filtration. The filtrate was concentrated, and the resulting syrup was dissolved in a small amount of methylene chloride. The solution was adsorbed on a column of silicas gel (500 g), and the column was eluted stepwise with benzene and benzene/ethyl acetate (10/1, 5/1 and 3/1). Fractions in the eluates which showed a UV absorption at an Rf of 0.20 in TLC developed with benzene/ethyl acetate (4:1) were collected and concentrated under reduced pressure to give 7.66 g (97%) of the captioned compound as a colorless syrup.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH:6]=C.[O:23]=[O+][O-].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:23]
Reactant: C=CCC(C(=O)OC)c1ccc(OCc2ccccc2)cc1
Reactant: O=[O+][O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(CC=O)c1ccc(OCc2ccccc2)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 2-(4-benzyloxy-phenyl)-pent-4-enoic acid methyl ester (750 g; 2.53 mol) is dissolved in ethyl acetate (7.5 L), and the resulting mixture cooled to −70° C. Ozone is introduced subsurface into the reaction for 3 h causing the reaction mixture to turn blue. The reaction mass is purged subsurface with nitrogen for 0.5 h to displace any residual ozone. At this point HPLC analysis indicates complete consumption of the starting material. The reaction mixture is warmed to −30° C. and held. In a separate vessel, zinc (450 g; 6.88 mol) and aqueous acetic acid (500 mL in 500 mL water) are combined and cooled to 0° C. The contents of the ozonolysis reactor are added to the aqueous acidic zinc mixture at such a rate as to maintain a reaction temperature of ≦0° C. After the addition is complete and the mixture has been held for 2 h, HPLC indicates conversion of intermediates to the desired aldehyde. The reaction mixture is filtered through Celite®, washed with water (2×4.5 L), and water (4.5 L) is added to the organic phase. Sodium bicarbonate (150 g; 1.79 mol) is added to the mixture, and stirring for 0.25 h gives a pH of >7. The aqueous layer is removed, and the volume is reduced to 2.25 L by reduced pressure distillation. The mixture is held at 50° C., and heptane (3L) is added to slowly provide a precipitate. The resulting slurry is cooled to 20° C. over 2 h, the solids are filtered, washed with heptane (3 L), and dried to constant weight at 45° C. and ˜25″ Hg. The title aldehyde, compound A (513 g; 68% isolated yield) is afforded as a tan solid.
Reaction SMILES: [C:1]([CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1)#[N:2].[CH2:19](N)[CH2:20][NH2:21].S.O>CCOCC>[NH:2]1[CH2:19][CH2:20][N:21]=[C:1]1[CH:3]1[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4]1
Reactant: N#CC1CC2c3ccccc3C1c1ccccc12
Reactant: NCCN
Agent: S
Solvent: O
Solvent: CCOCC
Product: c1ccc2c(c1)C1CC(C3=NCCN3)C2c2ccccc21
Temperature: 130 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g), ethylenediamine (1.5 g) and hydrogen sulfide (about 100 mg) is stirred at 130° C. for 20 hours. The reaction mixture is mixed with water and ether to be distributed in two layers. The ether layer is washed with water, dried, and evaporated to remove the ether. The residue is recrystallized from ether to give 11-(2-imidazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (5.0 g) as crude crystals. IR (KBr), 1621 cm-1 (N--C=N).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:31]([CH2:40][CH3:41])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:43].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:31]([CH2:40][CH3:41])=[N:30][C:25]=3[C:26]([NH2:43])=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [NH4+]
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
mCPBA (2.0 g of 60%, 6.97 mmol) was added to a solution of 7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (2.8 g, 6.97 mmol) in chloroform (50 mL). After 30 minutes an additional equivalent of mCPBA was added and the reaction mixture was stirred for an additional hour. Ammonium hydroxide (20 mL) was added and the reaction mixture was stirred for 10 minutes. p-Toluenesulfonyl chloride (1.33 g, 6.97 mmol) was added in a single portion and the reaction mixture was stirred for 16 hours. The layers were separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The organics were combined, washed with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (40+M cartridge eluting with a gradient of 2 to 25% CMA in chloroform). The residue was combined with acetonitrile and allowed to stand overnight. A solid was isolated by filtration and rinsed with acetonitrile to provide 1.96 g of 7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=O)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(#N)C>[CH:1]1([NH:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[O:15])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc(NC2CCCC2)ncn1
Reactant: Nc1ccc(O)cc1
Solvent: CC#N
Product: O=C(Nc1ccc(O)cc1)c1cc(NC2CCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclopentyl)amino]pyrimidine-4-carboxylic acid (Intermediate 5) and 4-aminophenol (Aldrich), the title compound was obtained as a yellow solid after trituration in acetonitrile.