Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7]([NH2:9])=[O:8].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)C>[C:24]([O:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7]([NH2:9])=[O:8])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=O
Solvent: CCOCC
Product: CCCCCC(CCCN(CCCCCCC(=O)O)C(N)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[1-(4hydroxynonyl)ureido]heptanoic acid (9.9 g., 0.03 mole) (Example 1, Step C) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is cooled and taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basis solution is separated and acidified with concentrated hydrochloric acid. The oil that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. Thus there is obtained 7-[1-(4-acetoxynonyl)ureido] heptanoic acid as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]([N:16]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([NH:26]C(=O)C)[C:18]=3[CH2:17]2)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl>C1COCC1>[NH2:26][C:19]1[C:18]2[CH2:17][N:16]([CH:14]([C:4]3[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])=[C:2]([CH3:1])[CH:3]=3)[CH3:15])[C:24](=[O:25])[C:23]=2[CH:22]=[CH:21][N:20]=1
Reactant: CC(=O)Nc1nccc2c1CN(C(C)c1cnc(OCC(F)(F)F)c(C)c1)C2=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C(C)N2Cc3c(ccnc3N)C2=O)cnc1OCC(F)(F)F
Temperature: 80 °C
Reaction time: 6 h
Yield: 130.9 %

Procedure:
To a solution of N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (159 mg, 0.39 mmol, Example-2, single enantiomer) in THF (3.0 mL) is added 2 M aqueous hydrochloric acid (3.0 mL) at rt. The mixture is stirred at 80° C. for 6 hours. The reaction mixture is concentrated to give 187 mg (>99% yield) of the title compound as orange solid. A part of the sample is purified by preparative LC-MS to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 337 g of 4-nitro-3-(4-chlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(4-chlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [N:1]1[S:2][CH:3]=[C:4]2[C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[N:1]1[S:2][CH:3]=[C:4]2[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)c1cccc2nscc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2nscc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of methyl 2,1-benzisothiazole-4-carboxylate (5.00 g, 25.9 mmol) in tetrahydrofuran (129 mL) was added diisobutylaluminum hydride (1 M hexane solution, 78.0 mL, 78.0 mmol) at −78° C., and the mixture was stirred at room temperature for 3 hr. The reaction solution was cooled to 0° C., and water was added. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (4.2 g, yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 41.8 %

Procedure:
An anhydrous methylene chloride solution of 20.0 g of ethyl 3-(2,6-dichloro-4-trifluoromethylphenyl)-3-hydroxypropionate (8) was added to a suspension of 19.6 g of pyridinium chlorochromate and 15 g of Celite in 100 ml of methylene chloride at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with 200 ml of ether and thereafter applied to a column packed with 100 g of silica gel. Ether was used for elution, and the eluent was concentrated under reduced pressure, giving 8.3 g of the desired compound in the form of a pale brown oil (yield 41.91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][N:15](C)[CH2:14][CH2:13]1.[C:19](OCC)(=O)C>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[CH3:19]
Reactant: CCOC(C)=O
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Agent: [Pd]
Product: COc1cc(N)ccc1N1CCNCC1C
Reaction time: 16 h
Yield: 71 %

Procedure:
Dissolve 1-(2-methoxy-4-nitro-phenyl)-4-methyl-piperazine (1.05 g, 4.18 mmol) in ethyl acetate (50 mL) and add 10% Pd/C (0.20 g). Hydrogenate the slurry at room temperature under a hydrogen filled balloon for 16 h. Filter the slurry through a pad of Celite® and rinse with ethyl acetate. Concentrate the filtrate in vacuo to give a reddish solid (0.66 g, 71% yield). MS/ES m/z 220.0 (M+1)+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([N:8]1[CH2:29][CH2:28][CH2:27][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH:40]1[C:46]([NH2:47])=[N:45][C:43](=[O:44])[N:42]([C@@H:48]2[O:52][C@H:51]([CH2:53][OH:54])[C@@H:50]([OH:55])[C@@H:49]2[OH:56])[CH:41]=1>CO.[Pd]>[NH2:1][C@H:2]([C:6]([N:8]1[CH2:29][CH2:28][CH2:27][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH:40]1[C:46]([NH2:47])=[N:45][C:43](=[O:44])[N:42]([C@@H:48]2[O:52][C@H:51]([CH2:53][OH:54])[C@@H:50]([OH:55])[C@@H:49]2[OH:56])[CH:41]=1
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of the corresponding Ara-C-tetrapeptide-Z-protected (D) (24.7 mg, 0.03 mmol) in methanol containing Pd/C (10% wt/wt) (11.5 mg) was hydrogenated at 25 psi at room temperature for 2 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness, under reduced pressure, to give D (90% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>CS(C)=O>[C:8]1([C:6]2[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)NCCNc1cc(Cl)nc(-c2ccccc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(N2CCNCC2)nc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 49.3 %

Procedure:
N-{2-[(6-Chloro-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (27) (1.5 g) and piperazine (4.44 g) were dissolved in DMSO. To this was added sodium hydrogencarbonate (2.16 g) and the mixture heated to 110° C. for 3 hrs. The reaction mixture was cooled to ambient temperature then partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous layer was washed with ethyl acetate (2×200 ml) and the combined organics washed with brine (100 ml), dried over magnesium sulfate then filtered. Removal of the solvent in vacuo furnished the title compound (0.865 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[Cl:23][C:24]([Cl:29])([Cl:28])[C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[C:18]([C:25](=[O:26])[C:24]([Cl:29])([Cl:28])[Cl:23])[NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1[nH]cc2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2)C(Cl)(Cl)Cl

Procedure:
A mixture of 0.7 g (2.2 mmol) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine and 2.0 ml (18 mmol) of trichloroacetyl chloride in 20 ml of methylene chloride was refluxed for 7 days. The resulting precipitate was collected by filtration and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a white solid mp 240°-245° (dec).
Reaction SMILES: [Na].C[O:3][C:4]([C@H:6]1[C@H:10]([C:11]([O:13]C)=[O:12])[O:9][C:8]([CH:28]([Br:30])[CH3:29])([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[C:21]=3[Br:25])[CH:16]=2)[O:7]1)=[O:5]>O.CO>[Br:30][C@H:28]([C:8]1([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[C:21]=3[Br:25])[CH:16]=2)[O:9][C@@H:10]([C:11]([OH:13])=[O:12])[C@H:6]([C:4]([OH:5])=[O:3])[O:7]1)[CH3:29]
Reactant: COC(=O)[C@@H]1OC(c2ccc3c(Br)c(OC)ccc3c2)(C(C)Br)O[C@H]1C(=O)OC
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C3([C@H](C)Br)O[C@@H](C(=O)O)[C@H](C(=O)O)O3)ccc2c1Br
Reaction time: 2 h

Procedure:
A solution of sodium hydroxyde (5.32 g, 0.133 mol) in water (70 ml) was added dropwise in 1 hour, under stirring, to a solution of the diastereoisomer 3 (35.4 g, 0.0665 mol) in methanol (250 ml) at 20° C. The reaction mixture was kept at 20° C. for 2 hours; then methanol was removed under reduced pressure mantaining the initial volume of the solution by addition of water. The aqueous solution, so obtained, was extracted with dichloromethane, acidified with conc HCl to pH 1, and extracted with diethylether (3×100 ml). The combined organic extracts were washed with water, anhydrified over sodium sulfate, filtered, and concentrated in vacuo. Crystallization of the residue from dichloromethane gave the pure 2-(1(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid (diastereoisomer 7).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([O:22][CH3:23])[CH:14]=1)[CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH4+].[OH-]>CCO.C1COCC1.B#[Ni].O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:3]([N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:22][CH3:23])[CH:14]=1)[CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(CN(C)Cc2ccccc2)ccc1[N+](=O)[O-]
Agent: B#[Ni]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CN(C)Cc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Nickel boride Reduction General Method: To a stirred solution of nickel chloride hexahydrate (820 mg, 3.45 mmol) in 12 mL EtOH and 3 mL THF, at 0° C., NaBH4 (130 mg, 3.45 mmol) was added. The resulting black suspension was stirred at 0° C. while N-benzyl-(3-methoxy-4-nitro-benzyl)-methyl amine was added as a solution in 5 mL THF. After several minutes, 260 mg of NaBH4 was added in several portions over 10 minutes, and the reaction mixture was subsequently allowed to warm to room temperature. After 2 h, TLC indicated complete conversion to a new, more polar product. At this point, 1.5 mL of 5% NH4OH was added and the reaction was stirred for about 10 min, until the black solids achieved a granular consistency. The reaction was filtered through a glass fiber filter, rinsing with THF. The clear colorless filtrate was concentrated to about ¼ volume, diluted with 30 mL water and extracted with EtOAc (3×30 mL). The combined extracts were washed with brine, dried over MgSO4 and filtered through a short plug of silica and concentrated in vacuo to afford 575 mg (65%) of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.2-7.4 (m, 5H), 7.85 (s, 1H), 6.85 (s, 1H), 6.74 (d, J=8.2 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 3.87 (s, 3H), 3.73 (br. s, 2H) 3.49 (s, 2H), 3.45 (s, 2H), 2.18 (s, 3H). MS (APCI-pos)M+1=256.9.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:3]1[CH:2]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:4]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1ccc(F)cc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 41, substituting 4-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.93 (s, 2H), 7.88 (dd, J=8.7, 5.9 Hz, 1H), 7.56 (dd, J=9.2, 2.5 Hz, 1H), 7.38-7.30 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>O.[Cl-].C([N+](CC)(CC)CC)C>[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(CSc2ccc(Cl)cc2)cc1

Procedure:
150 g of 4-chlorothiophenol in 200 ml of water, 65 g of potassium hydroxide, 10 g of tetraethylammonium chloride and 140 g of 4-methylbenzyl chloride are initially introduced into a stirred apparatus and are heated under reflux for 4 hours. 300 ml of water are then added, and the mixture is cooled. The solid product is filtered off under suction and washed with water. After the crystals have been dried, 230 g of product of melting point 72° to 73° C. remain.
Reaction SMILES: [OH:1][CH:2]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([CH3:18])[C:11]=1[OH:19])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O.[O]N(S(=O)([O-])=O)S(=O)([O-])=[O:24].[K+].[K+].Cl>[OH-].[Na+]>[CH3:18][C:12]1[C:11](=[O:19])[C:10]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[C:15]([CH3:16])[C:14](=[O:24])[C:13]=1[CH3:17]
Reactant: Cc1cc(C)c(C(O)CCCCC(=O)O)c(O)c1C
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1=C(C)C(=O)C(C(O)CCCCC(=O)O)=C(C)C1=O
Temperature: 0 °C

Procedure:
To a solution of 6-hydroxy-6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formula II-3 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.158 part) in 5% sodium hydroxide solution (2 volume parts) and water (7 volume parts) was added Fremy's salt (1 part) at room temperature with stirring. After being stirred for 1 hour, the mixture was cooled to 0° C., acidified with cold dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was subjected to column chromatography on silica gel and eluted with chloroform-methanol (20:1). The product was recrystallized from ethylacetate-hexane (1:2) to give 2,3,5-trimethyl-6-(5'-carboxy-1'-hydroxypentyl)-1,4-benzoquinone (formula I-3 wherein R=H3C, n=4, in the free form) (0.128 part) as brown needles melting at 130°-131.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C(O)(C)C.[N-:35]=[N+:36]=[N-:37].[Na+].Cl>[Br-].[Zn+2].[Br-].O>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:24]=[CH:23][CH:22]=[C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]4[NH:37][N:36]=[N:35][N:19]=4)=[CH:16][N:15]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(Oc3ccc(C#N)cn3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCc1c(OCc2cccc(Oc3ccc(-c4nnn[nH]4)cn3)c2)ccc(C(C)=O)c1O
Temperature: 130 °C
Yield: 68 %

Procedure:
Mix 6-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenoxy]-nicotinonitrile of Preparation 42, (0.33 g, 0.83 mmol), isopropyl alcohol (5 mL), zinc bromide (1.12 g, 4.98 mmol), sodium azide (0.32 g, 4.98 mmol) and water (5 mL) in a pressure flask. Seal the flask and heat to 130° C. in an oil bath for 6 hr. Allow to cool to ambient temperature and pour into 1N hydrochloric acid (50 mL). Filter the white solid and purify by flash chromatography, using 40:1 chloroformchloroform/methanol+1% acetic acid to 20:1 chloroformchloroform/methanol+1% acetic acid as a gradient eluent to give the title compound (0.25 g, 68%): MS (m/z): 444.2 (M−1). 1H NMR (DMSO-d6) 12.86 (s, 1H), 8.80 (s, 1H), 8.46 (d, J=8.2 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.52 (t, J=8.2 Hz, 1H), 7.37-7.28 (m, 3H), 7.20 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 5.32 (s, 2H), 2.63-2.55 (m, 5H), 1.51-1.41 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:14]C(=O)CC)(=[O:13])[CH2:11][CH3:12].C([O-])(=O)CC.[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([CH3:12])[C:10]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=Cc1ccc(F)cc1
Agent: CCC(=O)[O-]
Agent: [Na+]
Product: CC(=Cc1ccc(F)cc1)C(=O)O
Temperature: 140 °C
Reaction time: 20 h

Procedure:
p-Fluorobenzaldehyde (200 g, 1.61 mol), propionic anhydride (3.5 g, 2.42 mol) and sodium propionate (155 g, 1.61 mol) are mixed in a one liter three-necked flask which had been flushed with nitrogen. The flask is heated gradually in an oil-bath to 140° C. After 20 hours, the flask is cooled to 100° C. and poured into 8 l of water. The precipitate is dissolved by adding potassium hydroxide (302 g) in 2 l of water. The aqueous solution is extracted with ether, and the ether extracts are washed with potassium hydroxide solution. The combined aqueous layers are filtered, are acidified with concentrated HCl, and are filtered. The collected solid, p-fluoro-α-methylcinnamic acid, is washed with water, and is dried and used as obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (581 mg, 1.87 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (865 mg, 4.00 mmol) to afford the desired product (525 mg, 56%): ESI MS m/z 488 [C24H30BrN3O3+H]+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH:31][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1

Procedure:
The title compound is prepared by following Method C, using 4-iodo-benzoic acid (4.46 g, 17.97 mmol), oxalyl chloride (5.2 mL, 59.11 mmol) and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (3.0 g, 11.98 mmol) to afford 3.77 g, 66%). LC/MS, Retention time=5.62 min; (m/z): calcd for C19H211N4OS: 480.4; found: 480.7.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:20])[CH3:4].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>>[ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]1([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[OH:20])[CH3:4]
Reactant: Cc1ccc(CC2CCC(=O)C(CN(C)C)C2)cc1
Reactant: COc1cccc(Br)c1
Agent: Cl
Product: COc1cccc(C2(O)CCC(Cc3ccc(C)cc3)CC2CN(C)C)c1
Yield: 39 %

Procedure:
The base of compound (42) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 7:1 ether/methanol via a silica gel column and was taken up in ether. After adding trimethylchlorosilane/water, compound (44) was obtained in a yield of 39% theoretical.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:54][C:55]1([CH3:62])[C:59]([CH3:61])([CH3:60])[O:58][BH:57][O:56]1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[B:57]1[O:58][C:59]([CH3:61])([CH3:60])[C:55]([CH3:62])([CH3:54])[O:56]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1ccc(OC)cc1Br
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCCCOc1ccc(OC)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 95 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 2-bromo-1-butoxy-4-methoxybenzene (1.2 g, 4.7 mmol), TEA (2.6 mL, 19 mmol), (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.51 g, 0.95 mmol) (Aldrich, CAS# 166330-10-5), palladium(II) acetate (0.11 g, 0.47 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 mL, 14 mmol) (Aldrich, CAS# 25015-63-8) in 1,4-dioxane (5.0 mL) was stirred overnight at 95° C. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ether. The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford compound C.3 (0.60 g, 41% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=3.1 Hz, 1H), 6.91 (dd, J=3.1, 9.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 3.91 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 1.75 (m, 2H), 1.54 (m, 2H), 1.34 (s, 12H), 0.96 (t, J=7.4, 3H).