Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.BrC[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30].[C:31](=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]([CH:21]=[C:22]([O:29][CH3:30])[CH:23]=1)[CH2:31][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=1)(=[O:8])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccccc2O)cc1
Reactant: COc1ccc(CBr)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(COc2ccccc2OS(=O)(=O)c2ccc(C)cc2)cc(OC)c1

Procedure:
Toluene-4-sulfonic acid, 2-hydroxyphenyl ester (0.64 g, 2.42 mmol), 4-bromomethyl-1,3-dimethoxy-benzene (0.56 g, 2.42 mmol), potassium carbonate (0.36 g, 2.62 mmol) and 18-crown-6-ether (0.06 g, 0.24 mmol) were stirred together at room temperature in acetone (20 cm3, 99%) under nitrogen for 28 hours. The solution was evaporated under reduced pressure, and the residue was taken up in dichloromethane (20 cm3) and water (20 cm3). The aqueous layer was extracted with dichloromethane (2×20 cm3), and the combined extracts were washed with water (2×50 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was chromatographed (SiO2, dichloromethane) to give the ether, (0.84 g, 83%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1F
Temperature: 25 °C
Reaction time: 50 h
Yield: 90.9 %

Procedure:
A mixture of 2,4-difluoro-5-nitroaniline (3.00 g, 17.23 mmol) (see EP0379894 A3), phenylboronic acid (6.30 g, 51.69 mmol), copper(II) acetate (3.13 g, 17.23 mmol) and 4 Å molecular sieves (3.0 g) in dichloromethane (170.0 mL) and triethylamine (12.01 mL, 43.08 mmol) was placed in a round bottomed flask. The resulting suspension was stirred under at room temperature under a dry ambient atmosphere 50 h. The mixture was filtered through diatomaceous earth and the solvent was evaporated. Additional phenylboronic acid (6.30 g, 51.69 mmol), copper(II) acetate (3.13 g, 17.23 mmol), molecular sieves (3.00 g) triethylamine (12.01 mL, 43.08 mmol), and dichloromethane (170.00 mL) were added and the slurry was stirred for 12 h. The mixture was again filtered through diatomaceous earth and the solvent was evaporated. The resulting residue was re-dissolved in EtOAc, adsorbed on silica and flash chromatographed (15% EtOAc/hexanes) to give 2,4-difluoro-5-nitro-N-phenylaniline as an orange solid (3.92 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:14](=O)(O)[O-].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
1.9 g of 2-chloro-4-hydroxybenzoic acid was dissolved in 20 ml dimethylformamide, and 1.8 g of methyl iodide and 1.2 g of potassium bicarbonate were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 1.7 g of methyl 2-chloro-4-hydroxybenzoate was obtained.
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]2[C:9]3[CH2:15][CH2:14][N:13]([C:16]([O:18]C(C)(C)C)=O)[CH2:12][C:10]=3[S:11][C:5]=2[N:4]=[C:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1.N([O-])=O.[Na+].[C:47](=O)([O-])O.[Na+]>C(O)(=O)C.O>[C:16]([N:13]1[CH2:14][CH2:15][C:9]2[C:6]3[C:7](=[O:8])[NH:2][C:3]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:42]=[CH:41][C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=5)[CH2:31][CH2:32]4)=[N:4][C:5]=3[S:11][C:10]=2[CH2:12]1)(=[O:18])[CH3:47]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc(CCCCN4CCN(c5ccc6ccccc6n5)CC4)n(N)c(=O)c23)C1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c(sc3nc(CCCCN4CCN(c5ccc6ccccc6n5)CC4)[nH]c(=O)c23)C1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
In a mixture of 5 ml of acetic acid with 2 ml of water 60 mg of 3-amino-7-tert-butoxycarbonyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-pyrido[4′3′:4,5]thieno[2,3-d]pyrimidin-4-one was dissolved, and into the solution, a solution of 10 mg of sodium nitrite in 2 ml of water was dropped under cooling with ice. After 30 minutes' stirring, the reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and the resulting precipitate was extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography to provide 52 mg (99%) of 7-acetyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-pyrido[4′3′:4,5]thieno-[2,3-d]pyrimidin-4-one.
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:19]([O:20][CH3:21])=[CH:18][C:8]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])=[O:10])=[C:7]([N+:22]([O-])=O)[C:6]=1[O:25][CH3:26].[H][H]>CO.[Ni]>[NH2:22][C:7]1[C:6]([O:25][CH3:26])=[C:5]([CH3:4])[C:19]([O:20][CH3:21])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: [H][H]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Hydrazine hydrate (1.26 g, 39.37 mmol) was added dropwise to a solution of 190 (2.13 g, 6.56 mmol) in methanol (50 mL) gently refluxing over Raney nickel (1 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the product as a brown glass (191) (1.91 g, 6.50 mmol) which was protected directly as the troc-carbamate.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([OH:18])[CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1.C1(C)C=C[C:22]([S:25](Cl)(=[O:27])=[O:26])=CC=1>N1C=CC=CC=1>[CH3:22][S:25]([O:17][CH2:16][C@@H:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=1)[OH:18])(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](O)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC[C@H](O)c1cccc(Cl)c1

Procedure:
Into toluene (30 ml) were added (R)-2-(3-chlorophenyl)-2-hydroxyethanol obtained in 1) above (7 g), pyridine (8.0 g) and further, under ice-cooling and dropwise, p-toluenesulfonyl chloride (9.3 g), and then the resulting mixture was stirred at the same temperature for 24 hours. The solid thus precipitated was filtered off, the filtrate was concentrated, and the residue was dissolved in toluene (40 ml) and then washed with dilute hydrochloric acid. The organic layer was collected by layer separation, washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether and hexane to obtain a colorless oily compound mentioned above (10.6 g, 80.0%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([NH2:34])[C:28]=2[CH:27]=[N:26]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:34][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:28]=3[CH:27]=[N:26][NH:25]4)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc2[nH]ncc12
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc3[nH]ncc23)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 230 mg; 0.98 mmol) in DCM (5 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) and triethylamine (0.41 ml; 2.9 mmol) followed by 1H-indazol-4-amine (Key Organics, 150 mg; 1.12 mmol). After stirring at RT for 72 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH3:39])[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C.[C:47](O)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[CH3:39][N:38]([C:47]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:54])[CH:35]1[CH2:36][CH2:37][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:33][CH2:34]1
Reactant: O=C(O)c1ccccc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottomed flask benzoic acid (0.627 g, 5.13 mmol, commercially available from e.g. Sigma-Aldrich) and HATU (2.129 g, 5.60 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 30 minutes before 1-boc-4-methylaminopiperidine (1 g, 4.67 mmol, commercially available from e.g. Apollo, Fluorochem or Astatech) was added followed by triethylamine (1.626 mL, 11.67 mmol). The reaction was stirred at room temperature overnight. Solvent was removed in vacuo and the crude dissolved in DCM then organic phase was extracted with a saturated NaHCO3 solution (twice), a 10% citric acid solution (twice) then washed with brine and dried over MgSO4. Solvent was removed in vacuo and the crude purified on a silica column (40+M) eluting with DCM/MeOH; 90/10. Fractions containing desired compound were joined and solvents were removed in vacuo, to give title compound D14 as a pale yellow oil in 1.66 g. LCMS [M+H]+319.13 [M+H-tBu]+263.03@1.01 min (2 min run)
Reaction SMILES: [I-].[Li+].COC([C:7]1([CH2:31][CH:32]=[CH2:33])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=O.C(OCC)(=O)C>N1C=CC=CC=1.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:10]=2[NH:9][C:8](=[O:30])[CH:7]1[CH2:31][CH:32]=[CH2:33]
Reactant: C=CCC1(C(=O)OC)C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCC1C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Reaction time: 6.5 h
Yield: 104.7 %

Procedure:
Lithium iodide (1.08 g; 8.04 mmole) was added to 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-3-(2-propenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one (870 mg; 2.01 mmole) in pyridine (14 ml), three drops of water were added, and the mixture was refluxed with stirring for 6.5 hours. The solution was dissolved into ethyl acetate and washed with 1N hydrochloric acid (three times). The organic layer was dried (magnesium sulfate) and concentrated giving 0.79 g of solid. The crude material was used "as is" in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:32](I)([CH3:34])[CH3:33]>C1COCC1.CN(C=O)C>[CH:32]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12)([CH3:34])[CH3:33]
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(O)cccc4C3=C2)cn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCc1cn(C2=NCC(=O)N3CCc4c(OC(C)C)cccc4C3=C2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
Example 142. To a stirred suspension of 9-hydroxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (50 mg, 0.148 mmol) and cesium carbonate (120 mg, 0.369 mmol) in THF (1 mL) and DMF (0.35 mL), isopropyl iodide (55 mg, 0.325 mmol) was added. The mixture was stirred at rt for 17 h and poured onto H2O. The mixture was extracted with DCM and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by by SFC (column: PPU 5 μm, 250×30 mm, 60 A, Princeton; eluent: 5% MeOH/CO2 isocratic run for 20 min; flow 100 mL/min; UV detection at 220 nm). The residue was crystallized from diethyl ether and gave the title compound as white crystals (27 mg). UPLC-MS: MS 381.2 (M+H+); UPLC rt 0.98 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.11 Hz, 6 H), 2.80 (t, J=6.11 Hz, 2 H), 3.23 (s, 3 H), 3.82 (br. s., 2 H), 4.22 (br. s., 2 H), 4.27 (s, 2 H), 4.64 (dt, J=12.04, 6.08 Hz, 1 H), 7.14 (d, J=8.07 Hz, 1 H), 7.22 (s, 1 H), 7.31 (t, J=8.19 Hz, 1 H), 7.63 (s, 1 H), 7.66 (d, J=7.82 Hz, 1 H), 8.20 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][N:16]([CH3:29])[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=O)=[CH:19][CH:18]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:15][N:16]([CH3:29])[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=3)[N:1]=2)=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc2nc(-c3ccc(N(C)C)c4ccccc34)[nH]c(=O)c2cc1OC
Yield: 56 %

Procedure:
2-(4-(Dimethylamino)naphthalen-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxy-benzamide and 4-Dimethylamino-naphthalene-1-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(dimethylamino)naphthalen-1-yl)-6,7-dimethoxy-quinazolin-4(3H)-one (159 mg, 56%) was isolated as a white solid. Selected data: MS (m/z): 376.13; MP 235.5-236.5° C.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[CH:24]1[C:37]2[C:36]3([CH2:39][N:40]4[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]4)[CH2:38][CH:29]([C:30]4[C:35]3=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:28]=2[CH:27]=[CH:26][CH:25]=1>O1CCCC1.N1C=CC=CC=1>[CH:34]1[C:35]2[C:36]3([CH2:39][N:40]4[CH2:45][CH2:44][C:43]([C:23]5[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=5)([OH:46])[CH2:42][CH2:41]4)[CH2:38][CH:29]([C:28]4[C:37]3=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccn1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a cooled solution (-72° C.) of t-butyllithium (1.7M in pentane, 5.38 mL, 9.15 mmol, 2.8 eq) in tetrahydrofuran (24 mL) under nitrogen was added dropwise bromomesitylene (0.64 mL, 4.18 mmol, 1.3 eq). The metal-halogen exchange reaction was stirred for an additional hour during which time a white precipitate forms. 2-Methoxypyridine (0.50 g, 4.38 mmol, 1.4 eq) was added to this suspension and the resulting reaction was warmed to room temperature and stirred at that temperature for 4 h. The metallated pyridine solution was recooled to -72° C. and a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (1.00 g, 3.3 mmol) in tetrahydrofuran (3 mL) was added. The reaction was warmed to room temperature over 1.5 h. After stirring for 18 h, the reaction was quenched with the addition of water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried with anhydrous sodium sulfate, filtered, and reduced to an oil. The product was purified by flash chromatography over silica gel (100 mL, eluent: 30% ethyl acetate in hexane) to yield 0.99 g (73%) of the title compound as a white solid. TLC analysis (Rf 0.23, 30% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 8.05 (dd, J=4.9, 1.7 Hz, 1H), 7.49 (dd, J=7.5, 5.7 Hz, 1H), 7.22 (m, 4H), 6.92 (m, 5H), 4.27 (s, 1H), 4.02 (s, 3H), 3.78 (s, 1H), 3.48 (s, 2H), 2.83 (m, 4H), 2.61 (d, J=1.4 Hz, 2H), 2.00 (m, 4H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,13), 395 (24). The free base was dissolved in methylene chloride, diluted with ether and acidified with ethereal HCl. The resulting hydrochloride salt was filtered, rinsed with fresh ether, and dried in vacuo (50° C., 10 pascal, 18 h) to yield a white solid, mp 225°-228° C. (dec).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared according to the method described in Example 24a) from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 4-hydrochloride (0.764 g), 4-dimethylaminopyridine (0.488 g), morpholine (0.35 ml) and a solution of 3-bromophenylacetic acid (0.43 g) in dichloromethane (10 ml). The mixture was stirred overnight at room temperature. The reaction mixture was washed with 2M hydrochloric acid (3×100 ml), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The sub-title compound was obtained as a solid (0.550 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: BrCc1ccccc1
Product: COC(=O)c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 120.2 %

Procedure:
Crude methyl 4-(benzyloxy)-3,5-dichlorobenzoate (2) (16.9 g) was prepared from methyl 3,5-dichloro-4-hydroxybenzoate (1) (10 g, 45.2 mmol) and benzyl bromide (15.5 g, 90 mmol) using a procedure essentially the same as in Step (i) for AAA-001, except that the mixture was stirred at RT for 18 h. The crude product was partially purified by silica gel chromatography (330 g, 0-10% EtOAc/isohexane) to afford a white solid. The material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1.[Cl:1][C:2]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:3]=1[C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: Clc1ccccc1
Product: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Product: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
2,4'-dichloro-4-nitro-biphenyl was prepared by dissolving 2-chloro-4-nitroaniline (2.6 g, 15 mmol) in chlorobenzene (20 mL, 200 mmol), heated to 120° C. under a nitrogen atmosphere. i-Amylnitrite (3.4 mL, 25 mmol) was added to the solution slowly over 1 h via a syringe pump and canula. After stirring for 12 h the reaction mixture was cooled to ambient temperature and the excess chlorobenzene was removed in vacuo. The residue after evaporation was chromatographed by filtration through silica gel as in Example 1A, using mixture of hexane and ethyl acetate (80:20) as the eluent. Further purification was achieved by chromatography [Chromatotron®, 4 mm silica gel, hexanes/methylene chloride, 80:20, 20 mL/min] which yielded the title compound (1.75 g). Mass spectrum: m/z at 267 for C12H7Cl2NO2.
Reaction SMILES: C[O:2]C.[F:4][C:5]([F:12])([F:11])[C:6]([F:10])=[C:7](F)[F:8].C[O-].[Na+]>CO>[F:10][CH:6]([C:5]([F:12])([F:11])[F:4])[C:7]([F:8])=[O:2]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: COC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(F)C(F)C(F)(F)F
Yield: 82 %

Procedure:
The above methyl ether (49.5 g, prepared from the reaction of hexafluoropropene with sodium methoxide in methanol) in a still pot was cooled in a Dry Ice-acetone bath and 2.70 g of SbF5 was added. The mixture was stirred on a still with a Dry Ice-acetone trap attached and the cooling bath removed. Evolution of CH3F was vigorous below room temperature. The mixture was warmed until all of the product had collected in the Dry Ice-acetone trap. Material in the trap was redistilled in a low-temperature still to give 33 g (82%) of 2,3,3,3-tetrafluoropropionylfluoride, b.p. 25°.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C@@H:16]([OH:25])[C@H:17]1[O:22][C:20](=[O:21])[C:19]([OH:23])=[C:18]1[OH:24])=[O:13]>C(#N)C>[CH2:15]([OH:14])[C@@H:16]([OH:25])[C@H:17]1[O:22][C:20](=[O:21])[C:19]([OH:23])=[C:18]1[OH:24].[C:12]([OH:14])(=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)O
Product: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Yield: 99 %
Yield: 99 %

Procedure:
Erythorbic acid (≧99.0%, Fluka, Sigma-Aldrich) and lauric acid (≧99.0%, Fluka, Sigma-Aldirch) were prepared as raw materials for the synthesis of erythorbyl laurate, and acetonitrile (J. T. Baker Co., Philips burg, NJ USA) was used.