Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C@H:8]([NH:23][C:24]([O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.CO>[CH:30]1[C:29]2[CH:28]([CH2:27][O:26][C:24]([NH:23][C@H:8]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:10])[CH2:7][C:6]([OH:41])=[O:5])=[O:25])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CCCCCCCCCCCNC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCNC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 99.3 %

Procedure:
A solution of (S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-N-undecylsuccinamic acid tert-butyl ester (113 mg, 0.2 mmol) in TFA (2 ml) was stirred at room temperature for 30 min. After completion of the reaction, TFA was removed by evaporation in vacuo. Purification of the residue by silica gel column chromatography (using dichloromethane:methanol=9:1 as an eluent) gave (S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-N-undecylsuccinamic acid (101 mg, 99% yield) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>C1COCC1>[CH2:1]([C:16]1([OH:19])[CH2:17][CH2:18][C:13]2([O:20][CH2:10][CH2:11][O:12]2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: OC1(Cc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A 0° C. solution of 2M benzylmagnesium chloride in THF (20 mL) was treated with a solution of 1,4-cyclohexanedione mono-ethylene ketal (6.24 g, 40 mmol) in THF (50 mL), warmed to room temperature, stirred overnight, quenched with saturated NH4Cl (100 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide the desired product (8.08 g, 81%). MS (CI) m/e 231(M−18)+, 249 (M+H)+, 266.2 (M+18 )+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:23][C:24]1[C:25]([Cl:33])=[CH:26][C:27]([C:30]([OH:32])=O)=[N:28][CH:29]=1.[F:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH2:39][CH2:38]2.O>CN(C=O)C>[Br:23][C:24]1[C:25]([Cl:33])=[CH:26][C:27]([C:30]([N:40]2[C:41]3[C:37](=[CH:36][C:35]([F:34])=[CH:43][CH:42]=3)[CH2:38][CH2:39]2)=[O:32])=[N:28][CH:29]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(O)c1cc(Cl)c(Br)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.75 mg (2.3 mmol) TBTU were added to 0.50 g (2.1 mmol) 5-bromo-4-chloro-pyridine-2-carboxylic acid, 0.29 g (2.1 mmol) 5-fluoro-2,3-dihydro-1H-indole and 0.62 mL (4.4 mmol) TEA in 11 mL DMF and the mixture was stirred overnight at RT. Then the reaction mixture was combined with water, the precipitate formed was suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][NH:12][CH2:13]4)[CH2:9][CH2:8]3.C=O.[BH3-][C:22]#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([CH3:22])[CH2:13]4)[CH2:9][CH2:8]3
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)CCC13CNCC1CCC23
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC13CN(C)CC1CCC23
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
2-Methoxy-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrole (Example 1A, compound 1A-a) (220.0 mg, 0.90 mmol) and paraformaldehyde (810 mg, 2.7 mmol) were stirred in methanol (10 mL) at rt for 30 min. NaBH3CN was added and stirring was continued for 30 min. The mixture was quenched with 1N NaOH (10 mL), extracted with CH2Cl2 (20 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo providing 230.1 mg (98.9%) of the title compound 1B as a white solid.
Reaction SMILES: [O-]CC.[Mg+2:4].[O-]CC.[C:8]([OH:17])(=[O:16])[CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12].CC(C)=O>C(O)C>[C:8]([O-:17])(=[O:16])[CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12].[Mg+2:4].[C:8]([O-:17])(=[O:16])[CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(CCC)C(=O)O
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: CCO
Product: CCCC(CCC)C(=O)[O-]
Reaction time: 0.17 h
Yield: 66 %

Procedure:
11.4 g (0.1 mol) of magnesium ethoxide solid was added to a magnetically stirred, clear, colorless solution of valproic acid (28.8 g; 0.2 mol; Sigma Aldrich Chemical Co.) in 25 mL of absolute ethanol. Residual solid was rinsed into the reaction with 5 mL of absolute ethanol to provide a total volume of 30 mL of absolute ethanol. Within 10 minutes, the slurry became very warm to the touch, and the color of the solution phase changed to pale yellow. Complete dissolution of the magnesium ethoxide solid in ethanol was never achieved, but within minutes the solid phase converted from a slurry of a yellow granular solid to a suspension of white solid that was so thick that stirring stopped. 100 mL of acetone was added, and the thick slurry was stirred for 10 minutes. The precipitate was isolated by filtration, washed with fresh acetone, and dried to constant weight. The product, magnesium valproate, was obtained in 66% yield. Elemental analysis (Table 1) indicated that the product was an inhomogeneous mixture of magnesium valproate and other magnesium salts. The theoretical valproate content (%) of magnesium valproate is 92.2%; the valproate content found by HPLC analysis was 78.4%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:14])=[N-]>CO.C(OCC)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([I:11])[C:2]=1[NH2:1]
Reactant: C=[N+]=[N-]
Reactant: Nc1c(I)cccc1C(=O)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cccc(I)c1N

Procedure:
A solution of 2-amino-3-iodo-benzoic acid (2.5 g, 9.5 mmol) in methanol and diethyl ether mixture (15 mL, 8:2) was added a freshly prepared solution of diazomethane gas in diethyl ether until all the starting material is consumed. Reaction mixture was then evaporated under reduced pressure to obtain a yellow solid which was purified by flash column using. 5% ethylacetate in hexane as an eluent. 1.5 g of the required product was isolated as a yellow viscous liquid.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:20]1([O:26][C:27]2[CH:28]=[C:29]([CH2:33]Br)[CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:12](=[O:19])[CH:13]([CH2:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:28]=3)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(Oc2ccccc2)c1)C(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of sodium (0.31 g, 13.5 mmol) in ethanol (90 mL) is stirred at room temperature until the sodium dissolves. The resultant solution is heated to 70° C., treated dropwise with a solution of ethyl 1-(p-chlorophenyl)-β-oxocyclopropanepropionate (3.4 g, 12.8 mmol) in ethanol, stirred at 70° C. for one hour, treated dropwise with a solution of α-bromo-m-tolyl phenyl ether (4.0 g, 15.2 mmol) in ethanol, stirred at reflux overnight, stirred at room temperature for two days, and concentrated in vacuo to obtain a residue. A solution of the residue in ethyl acetate is washed sequentially with water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Chromatography of the oil using silica gel and a 19:1 hexanes/ethyl acetate solution gives the title product as a colorless oil (5.24 g, 92%) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][N:19]4[C:23]([CH3:25])([CH3:24])[C:22](=[O:26])[NH:21][C:20]4=[O:27])[N:11]=3)=[CH:7][C:6]=2[CH:28]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:24][C:23]1([CH3:25])[N:19]([CH2:18][CH2:17][NH:16][C:12]2[N:11]=[C:10]([C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([NH:1][CH2:29][C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)=[CH:28][C:6]=4[CH:7]=3)[CH:15]=[CH:14][N:13]=2)[C:20](=[O:27])[NH:21][C:22]1=[O:26]
Reactant: O=Cc1ccncc1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(N)ccc3s2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(NCc4ccncc4)ccc3s2)n1
Temperature: 60 °C
Yield: 27.1 %

Procedure:
1-(2-(4-(5-aminobenzothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidin-2,4-dione (300 mg, 0.758 mmol) was suspended in dichloromethane (10 mL). Isonicotinaldehyde (97.4 mg, 0.910 mmol), acetic acid (4-5 drops), and sodium triacetoxyborohydride (321 mg, 1.516 mmol) were added, and the mixture was heated to 60° C. for 16 h. The reaction was cooled to room temperature, diluted with a saturated aqueous solution of sodium bicarbonate (15 mL), and extracted with dichloromethane (4×15 mL). The organic layers were combined and then washed in turn with a saturated aqueous solution of sodium bicarbonate (10 mL), deionized water (15 mL), and a saturated aqueous solution of sodium chloride (15 mL). The organic layer was separated, dried over sodium sulfate (200 mg), filtered through a coarse frit (to remove the sodium sulfate), and concentrated in vacuo to give a white solid (100 mg). The crude material was purified by flash chromatography (MeOH/DCM) to yield the title compound as a white powder (20 mg). MS (M+H)+ 488.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(COc2cccc(N3CCOCC3)c2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 79.8 %

Procedure:
526 mg (2.0 mmol) of 1-(benzyloxy)-3-bromobenzene, 209 μl (2.4 mmol) of morpholine, 283 mg (2.8 mmol) of sodium t-butoxide, 9 mg (0.005 mmol) of tris(dibenzylidine acetone)dipalladium(0) and 19 mg (0.015 mmol) of (±)-BINAP were placed in a flask, 5 ml of toluene was added thereto, and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, 20 ml of ethyl acetate was added thereto, and filtered through Cellite. The resulting filtrate was concentrated under a reduced pressure, and the residue was subjected to column chromatography using 30% ethyl acetate/hexane as an eluent to obtain 430 mg (yield 80%) of 4-(3-(benzyloxy)phenyl)morpholine.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[Br:16]Br.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)(Cl)Cl>[Br:16][CH:8]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: BrBr
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution tert-butyl 4-oxoazepane-1-carboxylate (compound 82.2, 11.0 g, 51.6 mmol) in chloroform (220 mL) at 0° C. was added drop-wise a solution of bromine (3.98 mL, 77.6 mmol) in chloroform (110 mL). The resulting mixture was stirred at room temperature overnight, then the solids that formed were collected by filtration and dissolved in dichloromethane (200 mL). Triethylamine (16.8 mL, 121 mmol) and (Boc)2O (8.70 g, 40.3 mmol) were added to the mixture at 0° C. and the resulting solution was stirred for 3 h at room temperature, and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:10) as the eluent to give 4.0 g (27%) of the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[CH:7]=1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:25]([NH:24][CH:20]1[CH:21]([OH:23])[CH2:22][N:18]([C:11]2[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])=[CH:13][C:12]=2[F:17])[CH2:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CC(O)C(NCc4ccccc4)C3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C(NCc5ccccc5)C4)nc32)c(OC)c1
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 244A (0.049 g) in tetrahydrofuran (3 mL) at 25° C. was treated with a solution of lithium hydroxide monohydrate (0.048 g) in water (3 mL), stirred for 18 hours, concentrated, acidified with HCl (2N in diethyl ether), and filtered.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[C:21](=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:21])=[O:8]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Yield: 87 %

Procedure:
To a solution of 5-hydroxy-4-methoxy-2-nitrobenzoic acid [Sinha J. Ind. Chem. Soc., 47, 925 (1970)] (83.0 g, 0.39 mol) in MeOH (250 ml) was added concentrated H2SO4 (20 ml) and the reaction mixture was heated to reflux for 16 h. On cooling, the reaction mixture was poured into aqueous potassium carbonate solution and acetic acid was added until pH 4 was reached. The mixture was extracted with chloroform, the organic layer washed twice with H2O and dried over MgSO4. Evaporation under reduced pressure afforded the subtitle compound as yellow crystals (77.0 g, 87%). Rf 0.30 (benzene/acetone 4/1, v/v); m.p. 146-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[C:26]2[N:30](COCCOC)[N:29]=[CH:28][CH:27]=2)=[CH:4][C:5]([F:18])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.Cl>CO>[Cl:1][C:2]1[C:3]([O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[C:26]2[NH:30][N:29]=[CH:28][CH:27]=2)=[CH:4][C:5]([F:18])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COCCOCn1nccc1[C@@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Agent: Cl
Solvent: CO
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@@H]2CCCC[C@H]2c2ccn[nH]2)cc1F
Yield: 87 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 158e by using the 5-chloro-2-fluoro-4-{[(1R,2S)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (139 mg, 0.257 mmol) prepared in Example 159c, 6 M HCl (5.0 mL) and methanol (4.0 mL), to yield the title compound (101 mg, 73%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:28])[C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[N:26][CH:25]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(Cl)nc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 6-chloropyridine-3-carbonyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-chloronicotinamide as an off white crystalline solid, m.p. 144.0-148.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.77 (dd, J=2.5, 0.6 Hz, 1H), 8.73 (t, J=5.6 Hz, 1H), 8.22 (s, 1H), 8.16 (dd, J=8.3, 2.5 Hz, 1H), 8.03 (m, 1H), 7.63 (d, J=0.5 Hz, 1H), 7.60 (d, J=0.5 Hz, 1H), 7.45-7.40 (m, 1H), 7.23-7.18 (m, 1H), 6.61 (broad s, 2H), 4.63 (t, J=6.9 Hz, 2H), 3.30 (m,2H), 1.92 (m, 2H), 1.58 (m, 2H). MS (EI) m/e 394.1298 (394.1309 calcd for C20H19N6OCl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[N-:13]=[N+]=[N-].[Na+].FC(F)(F)S(O)(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:13][C:7](=[O:12])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(Br)ccc2CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a cooled solution of 6-bromo-3,4-dihydro-1H-naphthalen-2-one (100 g, 0.44 mol) in toluene was added sodium azide (150 g, 2.2 mol) followed by addition of trifluoromethanesulfonic acid (200 mL) dropwise. When the addition was completed, the ice bath was removed and the mixture was stirred at room temperature overnight. The reaction was poured into ice-water, basified with potassium carbonate to pH >10 slowly, and then extracted with dichloromethane (1000 mL×3). The organic layers were combined and dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was separated by column chromatography on silica gel to give 35 g of crude product. It was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 240.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]([CH3:32])[C:27](=[O:31])[CH2:28][CH2:29][CH3:30])=[C:20]([F:33])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:25][N:26]([CH3:32])[C:27](=[O:31])[CH2:28][CH2:29][CH3:30])=[C:20]([F:33])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCCC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: Cc1ccccc1
Product: CCCC(=O)N(C)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A solution of 2,6-difluorobenzoylisocyanate (2.0 g) in a 1:1 mixture of toluene and petroleum ether (5 ml) was added at room temperature over 30 minutes to a stirred solution of the compound of Example 3 (4.4 g) in the same solvent (20 ml). After stirring at room temperature for 2 hours, the solid product was filtered off and recrystallised from a mixture of diethyl ether and petroleum ether to give 4.3 g of the desired product, melting point 136°-138° C.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)[N+:14]([O-])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:1][S:2]([O:5][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[OH:10])=[CH:19][CH:18]=[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:16]=2)(=[O:4])=[O:3]
Reactant: [O-][n+]1ccc(O)c2ccc(-c3ccccc3)cc21
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1cnc2cc(-c3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonic anhydride (3.05 g) in dichloromethane (10 ml) was added to a mixture of 4-hydroxy-7-phenylquinoline-1-oxide (3.28 g), potassium carbonate (2.13 g) and dichloromethane (160 ml) at 0°, the mixture was stirred at 0° for 2 hours, then allowed to warm to room temperature. Water (250 ml) was added, the layers were separated and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined dichloromethane layer and extracts were dried over magnesium sulphate and the solvent was removed by distillation. The residue was subjected to flash chromatography on two successive silica gel columns eluted with dichloromethane: industrial methylated spirit (19:1) to give crude 4-hydroxy-7-phenylquinol-3-yl methanesulphonate.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:36]([O:35][C:33]([NH:32][C@@H:28]([CH2:27][CH2:26][NH:25][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[C:29]([OH:31])=[O:30])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (15 mg, 0.05 mmol), (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (crude, 0.28 mmol) and sodium methoxide (15 mg, 0.28 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 20 mg. 1H NMR (CD3OD, 200 MHz): δ=8.37 (d, 1H, J=9.0 Hz), 7.64-7.46 (m, 3H), 7.38-7.18 (m, 4H), 4.27-4.14 (m, 1H), 3.56 (t, 2H, J=6.6 Hz), 2.32-1.82 (m, 2H), 1.45 (s, 9H).