Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([I:16])=[C:10]2[C:6]=1[CH:7](O)[N:8](C(C)(C1C=CC=CC=1)C)[C:9]2=[O:17].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([I:16])=[C:10]2[C:6]=1[CH2:7][NH:8][C:9]2=[O:17]
Reactant: COCOc1c(OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(I)c2c(c1O)CNC2=O
Yield: 70.7 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methoxymethoxy-5-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (763 mg, 1.58 mmol) was dissolved in nitromethane (12 mL), and the solution was treated with trifluoroacetic acid (1.22 mL, 15.8 mmol) and triethylsilane (2.55 mL, 15.8 mmol), followed by purification by slurry using chloroform to obtain 4-hydroxy-5-methoxy-7-iodoisoindolinone (341 mg, yield 71%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:20])=[O:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol) and sulfamic acid (7.3 g, 75 mmol) were dissolved in glacial acetic acid (50 ml) and the solution added with a solution of sodium chlorite (8.2 g, 75 mmol) in water (15 ml). The reaction mixture was stirred at room temperature for 1 hr then water (300 ml) was added so obtaining the precipitation of a solid that was filtered and dried at 40° C. under vacuum (12 g, 48 mmol, 97% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(NC(C)C)(C)C.[Li].CN(C)CCN(C)C.I[CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:3]([O:2][CH3:1])=[O:16])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CI
Agent: CN(C)CCN(C)C
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C[Si](C)(C)C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
A solution of 5.58 g (25 mmol) of N-benzyloxycarbonyl glycine methyl ester in dry THF (70 ml) is added dropwise to a solution at -78° C. of lithium diisopropylamine (8.76 ml, 62.5 mmol) and tetramethylethylene diamine (9.43 ml, 62.5 mmol) in dry THF (100 ml), under nitrogen. After the addition is complete, the solution is stirred for 2 hours at -78° C., then 15 minutes at -30° C. and cooled to -78° C. A solution of 5.36 g (25 mmol) of iodomethyl-trimethylsilane in dry hexamethylphosphoramide (39 ml) is added dropwise to the resultant syrupy mixture. After the addition is complete, the reaction mixture is warmed up to -50° C., kept at this temperature for 1 hour and cooled to -78° C., just before hydrolysis. The reaction mixture is quenched by addition of water and ammonium chloride and diluted with ether. The organic layer is washed with 1N potassium hydrogen sulfate, twice with water and dried over sodium sulfate. The solvent is evaporated and the residue obtained (8.03 g) is purified by flash chromatography (silica gel,ethyl acetate/petroleum ether: 2/8). 4.30 g of the title compound are obtained (yield: 56%) (colorless oil). Rf : 0.51 (ethyl acetate/petroleum ether: 2/8).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[C:5]([CH3:20])[CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[C:5]([CH3:20])[CH:4]=1
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)c(C)c1
Agent: BrB(Br)Br
Product: Cc1cc(O)ccc1-c1ccc2cc(O)ccc2c1

Procedure:
The title compound was prepared by reacting 6-(4-methoxy-2-methylphenyl)-2-naphthol (420 mg, 1.59 mmol) with boron tribromide (4.53 mL of 1.0 M solution in CH2Cl2, 4.53 mmol) according to method D to yield 400 mg (quantitative yield) of a yellowish solid: mp 191–193° C.; 1H NMR (DMDO-d6): δ 6.68 (1H, dd, J=8.41 Hz, J=2.21 Hz), 6.72 (1H, d, J=2.21 Hz), 7.07–7.11 (2H, m), 7.14 (1H, d, J=2.21 Hz), 7.33 (1H, dd, J=8.41 Hz, J=2.21 Hz), 7.64 (1H, d, J=0.885 Hz), 7.68 (1H, d, J=8.41 Hz), 7.77 (1H, d, J=9.29 Hz), 9.33 (1H, s), 9.69 (1H, s); 13C NMR (DMDO-d6): δ 108.34, 112.82, 116.84, 118.68, 125.47, 127.13, 127.56, 128.02, 129.26, 130.71, 132.26, 133.02, 135.63, 135.90, 155.11, 156.31; MS (ESI) m/z 249 (M−H)−.
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([N:14](CCO)[CH2:15][CH3:16])[CH3:13]>>[N:1]1([CH2:6][C:7]([O:9][CH2:10][CH2:11][N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CCO
Reactant: CCOC(=O)CN1CCCC1
Product: CCN(CC)CCOC(=O)CN1CCCC1

Procedure:
Using the method of Example 5, ethyl 1-pyrrolidineacetate was reacted with 2-(N,N-diethylamino)ethanol to provide 2-(N,N-diethylamino)ethyl 1-pyrrolidineacetate, b.p. 92° C. at 250 μmHg.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32](=[O:38])[O:33][CH2:34][CH2:35][O:36][CH3:37]>CC(C)=O>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:32]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[CH2:23][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:38]
Reactant: COCCOC(=O)Nc1cccc(C)c1CCl
Reactant: Cc1nc2c(N)cccn2c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOC(=O)Nc1cccc(C)c1CNc1cccn2c(C=O)c(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
A mixture of 2.0 g (11.41 mmol) of 8-amino-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde, 1.21 g (11.41 mmol) of anhydrous sodium carbonate, 0.17 g (1.14 mmol) of sodium iodide and 3.5 g (13.6 mmol) of 2-methoxyethyl 2-chloromethyl-3-methylphenylcarbamate in 30 ml of acetone is stirred at RT for 24 h and concentrated in a Rotavapor. The residue is treated with 100 ml of water and extracted with ethyl acetate, and the organic phase is dried with magnesium sulphate and concentrated in vacuo. The residue is recrystallized from toluene. 3.31 g (73%) of the title compound of m.p. 153°-155° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])OC(=O)[CH:3]=1.[C:15]1([CH:21]=[CH:22]N2CCOCC2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCOCC1>C1(C)C=CC=CC=1>[CH3:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:3])[CH:1]=[CH:22][C:21]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Reactant: C(=CN1CCOCC1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: CCOC(=O)c1c(C)ccc(-c2ccccc2)c1C
Temperature: 25 °C
Yield: 18.1 %

Procedure:
Under a dry nitrogen atmosphere a solution of commercial ethyl 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylate (19.6 g, 0.1 mole) in toluene (20 ml) was added dropwise to a stirred solution of 4-(2-phenylethenyl)morpholine (14.3 g, 0.076 mole) in toluene (200 ml). Preparation of the morpholine derivative is described in U.S. Pat. No. 3,922,237. After the addition, the reaction mixture was heated at reflux for approximately 20 hours. The reaction mixture was then cooled and concentrated under reduced pressure, leaving a residue. The residue was heated at 170° under a dry nitrogen atmosphere for 3.5 hours, allowed to cool to room temperature, and then filtered. The filtrate was purified by column chromatography on silica gel, elution first with n-hexane: ethyl acetate, and finally ethyl acetate, to give ethyl 2,4-dimethyl-[1,1'-biphenyl]-3-carboxylate (3.5 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7](F)=[CH:8][CH:9]=1)[CH:5]=O.Cl.O(N)C.C(=O)([O-])[O-].[K+].[K+].[NH2:23][NH2:24]>COCCOC.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:7](=[CH:8][CH:9]=1)[NH:24][N:23]=[CH:5]2
Reactant: NN
Reactant: COc1c(Br)ccc(F)c1C=O
Agent: CON
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1c(Br)ccc2[nH]ncc12
Temperature: 20 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
A solution of 3-bromo-6-fluoro-2-methoxybenzaldehyde (0.727 g, 3.12 mmol) and methoxylamine hydrochloride (0.260 g, 3.12 mmol) in 1,2-dimethoxyethane (4 mL) was treated with potassium carbonate (0.472 g, 3.42 mmol) and stirred at 20° C. for 5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. This residue was dissolved in 1,2-dimethoxyethane (4 mL), the resultant solution was treated with hydrazine (4 mL), warmed to 100° C. and stirred at that temperature for 15 h. The reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue. This residue was triturated with ether to give the desired product (185 mg, 26%) as a gray solid. LCMS calculated for C8H8BrN2O (M+H)+: m/z=227.0, 229.0. found: 226.9, 229.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19](O)=[O:20])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.[CH3:24][O:25][NH2:26].Cl.CN(C)CCCN=C=NCC>O1CCCC1.O.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:26][O:25][CH3:24])=[O:20])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CONC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 1, Step 1, 150 mg, 0.483 mmol) and O-methylhydroxylamine hydrochloride (61 mg, 0.724 mmol) in tetrahydrofuran/water (1/1, 4.8 mL) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (278 mg, 1.45 mmol), and the resulting mixture is stirred at ambient temperature for 30 minutes and is then diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase is washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with methanoumethylene chloride (2.5/97.5). Pooling and concentration of those fractions with an Rf=0.53 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 206-208° C. (decomp.); MS (ESI+) for C15H18FN3O5 m/z 340 (M+H)+; [α]25D=−56° (c 0.92, DMSO).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>C1COCC1.CCO.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: Cc1cc2ccc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]c1=O
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2ccc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]c1=O
Reaction time: 4 h
Yield: 50.9 %

Procedure:
A solution of 7-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3-methyl-1H-[1,8]naphthyridin-2-one (0.43 g, 0.94 mmol) in THF was added to a slurry of Raney Ni in EtOH. The mixture was hydrogentated for 4 h at 40 psi. The reaction mixture was filtered through a small celite bed and rinsed with CH2Cl2 and mMeOH. The filtrate was concentrated and purified by column chromatography on silica (10% MeOH/EtOAc) to afford the title compound as a pale yellow solid (0.22 g, 51.4%). mp: 157–158° C.; 1H NMR (400 MHz, CDCl3) δ 9.00 (br s, 1H), 7.75 (d, 1H), 7.50 (s, 1H), 7.15 (m, 2H), 7.00–6.90 (m, 2H), 3.10 (br s, 4H), 2.80 (t, 2H), 2.60 (br s, 4H), 2.42–2.38 (m, 2H), 2.20 (s, 3H), 1.82–1.80 (m, 2H), 1.70–1.60 (m, 4H); MS: ES+: 459.01 (M+H)+, 460.97 (Exact mass: 458.16).
Reaction SMILES: [C:1]([C:5]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([O:22][CH3:23])[C:6]=1[O:24][CH3:25])([O:3][CH3:4])=[O:2].[OH-].[Na+].[CH:28](O)=O>C=O>[C:1]([C:5]1[C:15]2[CH2:14][CH2:13][N:12]([CH3:28])[CH2:11][CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[CH:8]=[C:7]([O:22][CH3:23])[C:6]=1[O:24][CH3:25])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1c2c(cc(OC)c1OC)C(c1ccccc1)CNCC2
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1c2c(cc(OC)c1OC)C(c1ccccc1)CN(C)CC2

Procedure:
A solution of 3.7 g of 6-carbomethoxy-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml of formic acid and 10 ml of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give 6-carbomethoxy-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: C([NH:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The mixture of 1.4 g of 4-(4-acetamidophenoxy)-3-benzylamino-5-sulfamoylbenzoic acid and 14 ml of 2N aqueous sodium hydroxide is refluxed for one hour under nitrogen. After cooling to room temperature it is filtered and the filtrate acidified with glacial acetic acid to pH = 4. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-aminophenoxy)-3-benzylamino-5-sulfamoylbenzoic acid of the formula ##SPC12##
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]2[C:20]3[N:21]=[C:22]([CH3:24])[NH:23][C:19]=3[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:32]([O:34][CH2:35]Cl)[CH3:33]>O1CCCC1.C(OCC)C>[C:26]1([CH2:25][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11]2[C:20]3[N:21]=[C:22]([CH3:24])[N:23]([CH2:35][O:34][CH2:32][CH3:33])[C:19]=3[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (0.064 g, 2 mmole) in tetrahydrofuran (15 mL) was cooled in an ice bath. N,N-bis(phenylmethyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.32 mmole) was added and the reaction mixture was allowed to warm to room temperature for 20 minutes. Chloromethyl ethyl ether was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with diethyl ether, washed twice with water, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with methylene chloride) to provide 0.43 g of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [Na].Cl.[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>C(O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[NH:10][C:13](=[O:20])[CH2:14][C:15](=[O:16])[N:9]=2)=[CH:6][CH:5]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)NC(c2ccc(Cl)cc2)=N1

Procedure:
To a stirred solution of 56.4 g. of sodium metal in one liter of absolute ethanol there is added 156 g. of p-chlorobenzamidine hydrochloride followed by the dropwise addition of 144 g. of diethyl malonate over a thirty minutes period. The reaction mixture is heated under reflux for five hours. The solution is filtered and the filter cake is dissolved in water. The ethanol filtrate is evaporated to dryness and the solid residue added to the water solution. Upon acidification of the aqueous solution to pH2 with concentrated hydrochloric acid, a solid precipitates which is removed by filtration. Washing this material several times with water affords 2-(4-chlorophenyl)-4,6-(1H,5H)-pyrimidinedione.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:17])=[N:3]1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][N:2]1[C:6]([O:7][C:21]2[CH:22]=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=2)=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:17])=[N:3]1
Reactant: Cc1nn(C)c(O)c1Cc1ccc(Cl)cc1Cl
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(C)c(Oc2ccnc(Cl)n2)c1Cc1ccc(Cl)cc1Cl
Yield: 42.5 %

Procedure:
In 10 ml of acetonitrile were stirred 2.7 g (10 mmol) of 1,3-dimethyl-4-(2,4-dichlorobenzyl)-5-hydroxypyrazole, 1.5 g (10 mmol) of 2,4-dichloropyrimidine and 1.5 g (11 mmol) of potassium carbonate with refluxing for 3 hours. After completing the reaction, the reaction mixture was purified as the same manner as described in Example 4 to give 1.63 g of 1,3-dimethyl-4-(2,4-dichlorobenzyl)-5-(2-chloropyrimidine-4-yloxy)pyrazole.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][CH:23]=[C:24]([C:26]([OH:29])([CH3:28])[CH3:27])[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8]2=[O:31])[C:4]([CH3:32])=[N:3]1.I[CH2:34][CH3:35].IC>>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][CH:23]=[C:24]([C:26]([O:29][CH2:34][CH3:35])([CH3:28])[CH3:27])[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8]2=[O:31])[C:4]([CH3:32])=[N:3]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C(C)(C)O)c4)cc3c21
Reactant: CCI
Solvent: CI
Product: CCOC(C)(C)c1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 104 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 215.2, 0.063 mmol) and iodethane as replacement for the iodomethane to give the title compound as a film. (HPLC: tR 2.30 min (Method A); M+H=457 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.69-8.67 (m, 1H), 8.63-8.61 (m, 1H), 8.16-8.12 (m, 2H), 8.03-7.98 (m, 1H), 7.77-7.74 (m, 1H), 7.63-7.61 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.21 (q, 2H), 1.97 (s, 3H), 1.55 (s, 3H), 1.54 (s, 3H), 1.09 (t, 3H))
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[N+:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)([O-:33])=[O:32]>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:31]([O-:33])=[O:32])[CH:39]=1)[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1cccc([N+](=O)[O-])c1
Yield: 21.4 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-nitro-phenylboronic acid (43 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (12 mg, 22%). LC-MS m/e 432.31 (M+H+)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(O)(=O)C.[Pt]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH2:11][CH2:10][NH:13][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NCCN
Agent: [Pt]
Solvent: CC(=O)O
Product: Oc1ccc(CNCCNCc2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
24.16 g of a bisazomethine prepared from 2 mols of p-hydroxybenzaldehyde and 1 mol of ethylenediamine and with a melting point of 215°-216° C. (decomposition) are hydrogenated in 150 ml of glacial acetic acid with 0.5 g of 10% platinum/charcoal at 25° C. in a hydrogenation flask. After 24 hours no further H2 is taken up. The catalyst is filtered off and the filtrate is concentrated in a rotary evaporator. The residue is crystalline and is stirred with 90 ml of isopropanol at 60° C.; the crystals do not dissolve. They are filtered off at room temperature, washed with isopropanol, and dried at 80° C. in vacuo. Yield 30.65 g (86.8% of theory) of the diacetate of N,N'-bis-(4-hydroxybenzyl)-1,2-diaminoethan with a melting point of 152°-155° C. The NMR spectrum confirms the structure of the diacetate.