Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)CCl>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:18]([C:17]2[C:12]([NH:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:20])=[CH:24][CH:23]=1
Reactant: O=C(O)c1cccnc1Nc1ccc2ncccc2c1
Reactant: Nc1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1Nc1ccc2ncccc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-(6-quinolylamino)pyridine-3-carboxylic acid (250 mg, from Step A) and 4-chloroaniline (120 mg) and DIEA (220 ul) in DMF (15 ml) was added EDC (220 mg) and HOBt (130 mg). The reaction was stirred at 50° C. for 3 h. The solution was evaporated under reduced pressure and mixed with CH2Cl2 (50 ml). The resulting solution was washed with 1N HCl, saturated NaHCO3, H2O and brine. The organic layer was dried over Na2SO4, evaporated under reduced pressure and triturated with CH2Cl2. The precipitate was filtered and washed with EtOH to give the titled compound. MS (ES+): 375 (M+H)+; (ES−): 373 (M−H)−. Calc'd for C21H15ClN4O—374.8.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28]OS(C)(=O)=O)[O:25][C:24]4=[O:34])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:36].[CH:37]([OH:40])(C)[CH3:38]>O1CCCC1.C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][NH:36][C:37](=[O:40])[CH3:38])[O:25][C:24]4=[O:34])=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)C(=O)O1
Reactant: CC(C)O
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)C(=O)O1
Temperature: 95 °C

Procedure:
A mixture of (R)-(-)-3,6-dihyro-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 4, 935 mg) and concentrated aqueous ammonium hydroxide (4 mL) in isopropanol (4 mL) and tetrahydrofuran (4 mL) is placed in a sealed tube and immersed in an oil bath maintained at 95° C. for 18 hours. The mixture is then diluted with methylene chloride (40 mL), washed with saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the 5-aminomethyl-2-oxazolidinone intermediate (Rf =0.34 by TLC, methanol/chloroform, 10/90). A solution of this intermediate (783 mg) and pyridine (1.55 mL) in dry methylene chloride (19 mL) at 0° C. under N2 is treated with acetic anhydride (0.90 mL), and the resulting solution is allowed to warm to ambient temperature with stirring over 1.5 hours. The mixture is then diluted with methylene chloride (20 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (2×10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 75 g), eluting with a gradient of methanol/methylene chloride (1/99-2/98). Pooling and concentration of those fractions with an Rf =0.26 by TLC (methanol/chloroform, 5/95) gives the title compound, mp 166-169° C.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:2]5[CH2:3][CH2:4][CH2:5][S:1]5(=[O:7])=[O:6])=[CH:14][N:13]=4)=[O:16])[CH2:22][CH2:21]3)=[N:24][CH:25]=2)[CH2:31][CH2:32]1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cn2)CC1
Yield: 40.8 %

Procedure:
Using isothiazolidine 1,1-dioxide (94 mg) and (5-bromopyridin-2-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (310 mg) described in Preparation Example 135 and by the reaction and treatment in the same manner as in Example 1, the title compound (139 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]#[N:9])=[N:5][CH:4]=1.C[O-].[Na+].[Cl-:13].[NH4+:14]>>[ClH:13].[CH3:1][O:2][C:3]1[S:7][C:6]([C:8](=[NH:14])[NH2:9])=[N:5][CH:4]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COc1cnc(C#N)s1
Agent: C[O-]
Agent: [Na+]
Product: COc1cnc(C(=N)N)s1
Product: Cl
Yield: 50.1 %

Procedure:
5-methoxythiazole-2-carbonitrile (0.74 g, 5.26 mmol) was reacted with sodium methoxide (0.28 g, 5.26 mmol) and ammonium chloride (0.6 g, 11 mmol) according to the procedure as described in Example 61, Step B to give the title compound as a white solid (0.51 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH-:1].[CH2:2]([CH:4]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[O:6])[CH3:3].[CH2:11]=O>>[CH2:7]([C:4]([CH2:2][CH3:3])([CH2:11][OH:1])[CH2:5][OH:6])[CH2:8][CH2:9][CH3:10]
Reactant: [OH-]
Reactant: C=O
Reactant: CCCCC(C=O)CC
Product: CCCCC(CC)(CO)CO

Procedure:
A process for producing 2-butyl-2-ethyl-1,3-propanediol, comprising feeding a hydroxide compound into a reaction mixture containing 2-ethylhexanal and formaldehyde wherein said hydroxide compound is fed into the reaction mixture continuously and incrementally to produce 2-butyl-2-ethyl-1,3-propanediol such that the reaction mixture is maintained in two phases, an organic phase and an aqueous phase throughout the entire production process.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]([C:21]1([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:23][CH2:22]1)=[O:20])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(N)=O)[CH:7]=1.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[ClH:56].C[N:58](C)C=O>N1C=CC=CC=1>[ClH:56].[NH2:58][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([NH:18][C:19]([C:21]3([C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:33])[CH2:22][CH2:23]3)=[O:20])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reaction time: 33 h
Yield: 54.9 %

Procedure:
4-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide (1.0 g) was dissolved in N,N-dimethylformamide (10 ml) under a nitrogen atmosphere, and water (0.199 ml), [bis(trifluoroacetoxy)iodo]benzene (1.96 g) and pyridine (1.07 ml) were added at room temperature in this order, followed by stirring for 33 hr. The reaction mixture was partitioned after addition of ethyl acetate (30 ml) and a 1N aqueous solution of sodium hydroxide (10 ml). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (10 ml, twice) and brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was dissolved in ethyl acetate (10 ml), 5N hydrochloric acid (0.486 ml, 1.1 equivalents) was added under sonication. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under aeration for 1 hr. The solid was hot air-dried at 80° C. overnight to provide the titled compound as pale brown powder (559.3 mg, 54.9%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:36]1[CH:35]=[CH:34][C:33]([F:32])=[CH:38][C:37]=1[F:39])=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: OB(O)c1ccc(F)cc1F
Product: COC(=O)c1c(-c2ccc(F)cc2F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 2,4-difluorophenylboronic acid. A colorless powder (9 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O.C(Cl)Cl>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (0.332 g, 0.914 mmol) in THF (6 mL) and water (3 mL) was added LiOH (0.066 g, 2.74 mmol). The solution immediately turned from yellow to orange-red. The reaction was stirred vigorously at RT for 16 h. The solution was acidified to pH 2 and diluted with water and CH2Cl2. The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL) and the combined organic fractions were washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated to give the title compound as a tan solid (0.29 g, 91%): mp 228-233° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.55-10.24 (m, 1H), 9.46 (s, 1H), 8.23 (d, J=8.0 Hz, 2H), 8.09 (d, J=7.9 Hz, 4H), 7.64 (d, J=8.5 Hz, 2H); ESIMS m/z 350 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][O:5][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]1[CH2:31][CH3:32])=[O:29]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: CCCOc1cc(F)c(CO)c(F)c1
Product: CCCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(F)c1
Yield: 78 %

Procedure:
This compound was prepared from 2,6-difluoro-4-propoxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (257 mg; 78%); MS (ISP): 465.4 (M+Na)+.
Reaction SMILES: [S:1](Cl)(=[O:4])(=O)[OH:2].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13]C(C)=O)[CH:8]=1.O.[NH3:18]>C1COCC1.C(O)C.Cl>[NH2:13][C:9]1[CH:10]=[CH:11][C:12]([S:1]([NH2:18])(=[O:4])=[O:2])=[C:7]([CH3:6])[CH:8]=1
Reactant: N
Reactant: CC(=O)Nc1cccc(C)c1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(N)ccc1S(N)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To chlorosulfuric acid (20 mL, 302 mmol), m-acetotoluidine (10 g, 67 mmol) was added at room temperature over 20 minutes, and subsequently, the mixture was heated to 70° C. and stirred for 8 hours. The mixture was cooled to room temperature, ice (50 g) was added to the reaction mixture, and the produced solid was collected by removing an aqueous layer by decantation. Subsequently, the obtained solid was washed with water (50 mL) to obtain a crude product. A solution of the obtained crude product in THF (50 mL) was cooled to 0° C., and concentrated ammonia water (20 mL) was added. Subsequently, the temperature of the mixture was raised to room temperature and the mixture was stirred for 2 hours. The reaction mixture was concentrated, water (100 mL) was added to the obtained solid, and filtration was carried out to give a crude product. To a solution of the obtained crude product in ethanol (200 mL), 6N hydrochloric acid (200 mL) was added at room temperature, and the mixture was heated under reflux and stirred for 3 hours. The reaction mixture was concentrated, methylene chloride (200 mL) was added to the obtained solid, and filtration was carried out to give the title compound (7.1 g, yield: 48%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[Br:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: Oc1cccc(Br)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(COc2cccc(Br)c2)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 70.8 %

Procedure:
To a solution of methyl 4-(bromomethyl)benzoate (1 g, 4.4 mmol) in acetone (60 mL) were added 3-bromophenol (1 g, 5.8 mol) and potassium carbonate (1.24 g, 9 mmol). After stirring at 40° C. for 12 hours, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with water (30 mL) and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give methyl 4-((3-bromophenoxy)methyl)benzoate (1 g, 71.4%) as a white solid. LRMS (M+H+) m/z: calcd 320.00. found 320. 1H NMR (300 MHz, d6-DMSO): δ 7.98 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.28-7.22 (m, 2H), 7.15-7.12 (m, 1H), 7.05-7.01 (m, 1H), 5.23 (s, 2H), 3.84 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[CH3:27][CH:28]([CH3:52])[CH2:29][NH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[C:33](OS(C(F)(F)F)(=O)=O)[C:32]=1[N+:49]([O-:51])=[O:50].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:26][CH:25]=2)[C:33]2[C:32]([N+:49]([O-:51])=[O:50])=[C:31]([NH:30][CH2:29][CH:28]([CH3:52])[CH3:27])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: CC(C)CNc1c([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3c(NCC(C)C)c2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
Triethyl amine (40.4 mL, 0.290 mol) and N,N-bis(4-methoxybenzyl)amine (62.0 g, 242 mmol) were sequentially added to a solution of [4-(2-methylpropyl)amino-3-nitroquinolin-2-yl]trifluoromethanesulfonate (Nikolaides et al, U.S. Pat. No. 5,395,937, Example 1, 95.0 g, 242 mmol) in toluene (300 mL) at ambient temperature. The solution was stirred at ambient temperature for a few minutes, heated at reflux for two hours, and allowed to cool to ambient temperature. Ethyl acetate and saturated aqueous sodium bicarbonate (300 mL) were added. The organic layer was separated and washed twice with saturated aqueous sodium bicarbonate. The combined aqueous fractions were filtered to remove a solid, and the filtrate was extracted with ethyl acetate (3×150 mL). The combined extracts were washed once with saturated aqueous sodium bicarbonate. All organic fractions were then combined and dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum for three days to provide N2,N2-bis(4-methoxybenzyl)-N4-(2-methylpropyl)-3-nitroquinoline-2,4-diamine as a red oil, which was used without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.Cl.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.[C:31](=[O:34])([O-:33])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[C:8]([OH:7])(=[O:18])[C:31]([OH:33])=[O:34].[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)=[N:6][O:7][C:8]=2[CH:13]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(CCCc3noc4cc(F)ccc34)CC2)cc1
Product: O=C(O)C(=O)O
Temperature: 90 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To 40 ml of dimethylformamide was added 4.3 g 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 4.0 g of 4-(4-methoxyphenyl)piperazine dihydrochloride, 10.0 g of milled potassium carbonate, and 0.01 g potassium iodide. The mixture was stirred at 90° C. for two hrs, cooled, filtered, and the filtrate evaporated to an oil. The oil was stirred with 100 ml of water and extracted with ether. The ether extract was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, ethereal oxalic acid was added. The precipitate was collected and dried to yield 3.0 g (44%) of product. Two recrystallizations from ethyl acetate/methanol/ether (10:1:5) gave the analytical sample, mp 188°-189° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH2:35][CH3:36]>>[NH2:32][C:23]1[C:22]2[N:21]=[C:20]([CH2:33][CH2:34][CH2:35][CH3:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)(=[O:12])=[O:11])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
According to the general method of Example 5, 3-nitrobenzenesulfonyl chloride and 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine were combined. N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-nitro-1-benzenesulfonamide was isolated as the hydrochloride salt (white solid), m.p. 176.0-178.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (very broad s, 2H), 8.49-8.42 (m, 2H), 8.21-8.17 (m, 2H), 8.06 (t, J=5.7 Hz, 1H), 7.88-7.81 (m, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 4.56 (t, J=7.3 Hz, 2H), 2.94 (t, J=7.7 Hz, 2H), 2.86 (m, 2H), 1.81 (m, 4H), 1.60-1.42 (m, 4H), 0.96 (t, J=7.3 Hz, 3H); IR (KBr) 3096, 2954, 2869, 2771, 1671, 1607, 1528, 1351, 1335, 1163, 1128, 1083, 879, 758, 735, 672, 661 cm−1; MS (EI) m/e 496.1897 (496.1893 calcd for C24H28N6O4S). Anal calcd for C24H28N6O4S*HCl*H2O: C, 52.31; H, 5.67; N, 15.25. Found: C, 52.26; H, 5.46; N, 15.09.
Reaction SMILES: C(O[CH:5]([O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1)[C:6](Cl)([Cl:8])[Cl:7])(=O)C.S(=O)(=O)(O)O.[OH-].[Na+]>CO>[Cl:7][C:6]([Cl:8])=[CH:5][O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OC(Oc1cccc(C)c1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(OC=C(Cl)Cl)c1
Temperature: 15 °C

Procedure:
By an electrochemical reductive dehydrohalogenation method. 1(3-tolyloxy)-2,2,2-trichloroethyl acetate (15.8 g), concentrated sulphuric acid (98% w/v, 9.8 g) and methanol (220 ml) was charged into an electrolytic cell, which was surrounded by a cooling bath set to maintain the temperature at about 15° C, and fitted with a cylindrical diaphragm, stirrer, reference electrode (SCE) and a working electrode. The cathode was a lead plate (surface area about 40 cm2). Using a current density in the range 5 to 10 mA/cm2 the reaction was conducted in the potential range -1100 to 1700 mV (SCE). When reduction was completed the cathodic electrolyte was neutralised with caustic soda and extracted with methylene chloride, the extracts dried over anhydrous sodium sulphate and evaporated to yield a residue of crude 3-tolyl 2,2-dichlorovinyl ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1.Cl>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[CH2:5][CH:6]1[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCC2(CC1)OCCO2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(CC1CCC(=O)CC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-propionic acid methyl ester (667 mg, 1.60 mmol) in acetone (15 mL) was treated with a 10% aqueous hydrochloric acid solution (1.8 mL). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid methyl ester (600 mg, 100%) as a colorless gum which was used without further purification: EI-HRMS m/e calcd for C17H21ClO5S (M+Na)+ 395.0690, found 395.0692.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(O[O:17][C:18]([CH3:21])(C)C)(C)(C)C.[C]=O.[CH2:24]([OH:26])C>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH2:1][C:24]([O:17][CH2:18][CH3:21])=[O:26]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccc2ccccc2c1
Reactant: CCO
Agent: [C]=O
Product: CCOC(=O)Cc1ccc2ccccc2c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
2-Methylnaphthalene (2.13 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 78 mg ethyl 2-naphthaleneacetate was obtained by column chromatography, in a yield of 73%. 1HNMR (400 MHz, CDCl3) δ 1.24 (t, J=6.8 Hz, 3H), 3.78 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 7.41-7.49 (m, 3H), 7.73 (s, 1H), 7.79-7.83 (m, 3H); 13CNMR (100 MHz, CDCl3) δ 14.2, 41.6, 60.9, 125.8, 126.1, 127.4, 127.7, 127.9, 128.2, 131.7, 132.5, 133.5, 171.6; HRMS (ESI) calcd. for C14H14NaO2 [M+Na]: 237.0886. found: 237.0886. The ethyl 2-naphthaleneacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 62 mg product 2-naphthaleneacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 91%.