Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[I-:10].[Na+].ClOC(C)(C)C>C(#N)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([I:10])[C:3]=1[OH:9]
Reactant: [I-]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: CC(C)(C)OCl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1c(Cl)cc(Cl)cc1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6.52 g (40 mmol) of 2,4-dichlorophenol and 7.76 g (52 mmol) of sodium iodide in 80 mL of acetonitrile and 16 mL of water at room temperature add 5.64 g (52 mmol) of tert-butyl hypochlorite dropwise over a period of 30 minutes. Stir the reaction mixture for 3 hours at ambient temperature. Dilute the reaction mixture with 200 mL of ethyl acetate. Wash the resulting organic solution successively with 5% aqueous sodium thiosulfate solution and brine and dry over anhydrous magnesium sulfate. Remove the solvent and then crystallize from hexanes to yield 5.9 g (51%) of (P9) as a slightly colored solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=3)[S:10][C:3]=12.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CC(C)n1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 195 °C
Yield: 88.3 %

Procedure:
To a solution of 123 (1.16 g, 4.18 mmol) in Ph2O (20 ml) was added 2-fluoro-4-nitrophenol (1.31 g, 8.37 mmol) and potassium carbonate (2.31 g, 16.72 mmol). The reaction mixture was heated to 195° C. for 18 hrs then cooled to room temperature. The residue was purified by column chromatography, eluents EtOAc/Hex (9/1 to 5/5), then MeOH/CH2Cl2 (98/2), to afford title compound 124 (1.47 g, 88% yield) as a yellow solid. MS (m/z): 399.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 1-chloro-4-iodobenzene according to the general procedure C. Obtained as a yellow solid (779 mg).
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[CH3:9][Si:10]([CH2:13][CH2:14][O:15][CH2:16]Cl)([CH3:12])[CH3:11]>C1COCC1>[Br:1][C:2]1[N:6]=[CH:5][N:4]([CH2:16][O:15][CH2:14][CH2:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:3]=1
Reactant: Brc1cnc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-1H-imidazole (1.0 eq.) in thy THF (0.4 M solution) was added NaH (60%, 1.2 eq.) portionwise at 0° C. The mixture was stirred for 2 hr at 0° C., then SEMCl (1.2 eq.) was added and the mixture was stirred for 12 hr at RT. The reaction was quenched by the addition of sat. aq. NH4Cl solution and the mixture extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel eluting with 20-50% EtOAc/petroleum ether to obtain E1 as an oil. 1H NMR (300 MHz, CDCl3) δ: 7.45 (1H, s), 7.00 (1H, s), 5.21 (2H, s), 3.47 (2H, t, J=8.2 Hz), 0.89 (2H, t, J=8.2 Hz), 0.00 (9H, s). MS (ES) C9H17BrN2OSi requires: 276/278, found: 277/279 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]#[N:15])=[C:4]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:5](OCC)=[O:6]>CCO.[Ni]>[Cl:1][C:2]1[C:3]2[CH2:14][NH:15][C:5](=[O:6])[C:4]=2[CH:10]=[C:11]([CH3:13])[N:12]=1
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1C#N
Agent: [Ni]
Solvent: CCO
Product: Cc1cc2c(c(Cl)n1)CNC2=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 11.1 %

Procedure:
To a solution of ethyl 2-chloro-3-cyano-6-methylisonicotinate (1.0 g, 4.5 mmol) in EtOH (14.8 mL) is added Raney nickel (100 mg, RANEY 2800 NICKEL), and the mixture is stirred at 60° C. under hydrogen atmosphere for 2 days. After cooling to rt, the reaction mixture is filtered through a pad of Celite™. The filtrate is concentrated, and the residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1), and the collecting sample is recrystallized from THF/n-hexane to give 91 mg (11% yield) of the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[N+:5]([O-])=[CH:6][C:7]=1[Br:8].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:14].CO.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Cl:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([CH2:10][OH:14])[CH:3]=1
Reactant: Cc1cc(Cl)c(Br)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OCc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of 4-chloro-5-bromo-2-picoline-N-oxide (23.9 g) in dichloromethane (250 ml) was cooled to 10° and trifluoroacetic anhydride (25 ml) added over 20 minutes. The mixture was allowed to warm to ambient temperature, and stand for 7 days. After cooling to 10°, methanol (100 ml) was added, and the solution stripped. The residue was treated with water (150 ml), basified with saturated aqueous sodium carbonate to pH 10, and extracted with ethyl acetate (2×150 ml). The combined extracts were dried (MgSO4). stripped, and triturated with ether to give 4-chloro-5-bromo-2-hydroxymethylpyridine, 16.58 g. m.p. 109°-10°.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]2[CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=[CH:20][C:10]1=2>C(O)C.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:10]2[N:9]([CH2:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]=2[CH:17]=1
Reactant: CN1CCCC1CCN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CN1CCCC1CCN1C(=O)CCCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
A solution of 2 (600 mg, 1.89 mmol) in dry ethanol (10 mL) was treated with Pd—C (˜0.06 g) and purged with hydrogen gas. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) overnight (18 h). The mixture was filtered through a celite bed and washed with methanol (3×25 mL). The combined organic fractions were concentrated to give a brown residue. The product was purified by dry column chromatography (2 N NH3 in MeOH:CH2Cl2, 5:95) to give compound 3 (435 mg, 80%) as a colourless foam. 1H-NMR (DMSO-d6, 300 MHz) δ: 1.29-1.38 (m, 2H), 1.54-1.60 (m, 2H), 1.66-1.82 (m, 2H), 1.89-2.10 (m, 10H), 2.38-2.45 (m, 2H), 2.84-2.91 (m, 1H), 5.07 (brs, 2H), 6.36-6.52 (m, 2H), 6.85-6.98 (m, 1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>O1CCCC1.CN(C)C=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under cooling with ice, 1-benzhydrylazetidin-3-ol (718 mg) in tetrahydrofuran (8 mL) was added dropwise to a suspension of 60% sodium hydride (144 mg) in N,N-dimethylformamide (8 mL), and the resultant mixture was stirred for 20 minutes. Methyl iodide (0.23 mL) was added to the reaction mixture, followed by stirring at room temperature overnight. The reaction mixture was partitioned between cold saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as an oily product (680 mg, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:37][C:38]([F:48])([F:47])[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[N:17]2[CH2:43][C:42]2[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:46][CH:45]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccc(C(F)(F)F)cc2)c1
Temperature: 150 °C
Yield: 50 %

Procedure:
4-Methyl-2-[4′-trifluoromethyl-5-(6-trifluoromethyl-piperidin-2-yl)-biphenyl-3-yl]-pentanoic acid ethyl ester 7b (37 mg, 0.072 mmol), 4-trifluoromethylbenzyl bromide (86 mg, 0.36 mmol), DIEA (125 μl, 0.72), and tetrabutylammonium iodide (TBAI)(10 mg, 0.096 mmol) were combined and heated under microwave conditions to 150° C. After several additions of the starting materials and ˜90 minutes under microwave, ˜50% product was formed. The reaction was diluted with EtOAc, washed with brine, sat. NaHCO3, and brine, dried over magnesium sulfate and filtered. Purification by silica gel chromatography gave the product as yellow oil. (25 mg, 52%) (M+H) 73.65, Found 674.4
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(N(C)CCO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N(C)CCO)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-[(3-Methyl-4-nitrophenyl)-N-methylamino]ethanol (0.70 g, 3.3 mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon (0.050 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 2-[(4-amino-3-methylphenyl)-N-methylamino]ethanol as solid (0.58 g, y. 97%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][CH:25]=1)[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Product: COC(=O)C(CN1C(=O)c2ccc(Br)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.48 g, 57 mmol) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.62 g, 2.75 mmol) and 4-bromophthalic anhydride (0.62 g, 2.75 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O.O.NN>C(O)COCCO>[CH:8]1([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(c1ccc[nH]1)C1CCCCC1
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: c1c[nH]c(CC2CCCCC2)c1
Yield: 69.3 %

Procedure:
A mixture of cyclohexyl pyrrol-2-yl ketone (17.7 g.) and 99% hydrazine hydrate (6.0 ml.) was heated under reflux in diethylene glycol (70 ml.) for 1.5 hours. The excess hydrazine hydrate and water were distilled off and the mixture was cooled. Potassium hydroxide (12.0 g.) was added portionwise and the mixture was then heated under reflux for 4 hours, cooled and poured into water (500 ml.). The mixture was extracted with ether (3×100 ml.) and the combined etheral extracts were washed with water (3×100 ml.) and dried over sodium sulphate. Evaporation of the ether gave an oil which was distilled to give 2-cyclohexylmethylpyrrole (11.3 g.), B.P. 137°-140° at 15 mm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1N1CCN(C)CC1
Yield: 47.5 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-(4-methylpiperazin-1-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.120 g; 0.314 mmol), sodium hydroxide 10N (0.314 mL; 3.14 mmol) in methanol (3 mL) to afford 0.055 g (48%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=3)[N:4]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Yield: 88 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.500 g, 1.54 mmol) in 15 mL of ethylene glycol dimethyl ether, was added 3-aminophenyl boronic acid (0.358 g, 2.31 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.178 g, 0.098 mmol), and potassium phosphate (1.63 g, 7.7 mmol). The reaction mixture was heated to reflux temperature of the solvent for 18 hours. The solvent was then removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The title compound was purified by column chromatography (SiO2, 6% MeOH in CH2Cl2) (0.457 g, 88% yield): ES-MS (m/z) 337 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH2:9]([NH:11][C:12]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:13])[CH3:10]
Reactant: CCN=C=O
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
N-hydroxysuccinimide (11.5 g, 0.1 mol) was dissolved in 100 g of sufficiently dried tetrahydrofuran. To the solution was added dropwise 7.1 g (0.1 mol) of ethyl isocyanate, and then a catalytic amount of triethylamine was added. After stirring at room temperature overnight, the reaction solution was decolored with active carbon and concentrated. The deposited crystal was filtered and washed with a small amount of ether to obtain 16.1 g of N-(ethylcarbamoyloxy)succinimide represented by the following formula, yield 86.6%.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41].O>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[C:40]([C:36]1[O:35][CH:39]=[CH:38][CH:37]=1)=[O:41]
Reactant: O=C(Cl)c1ccco1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccco3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. 2-Furancarbonyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 7 hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (34 mg, yield 33%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:9]=[C:8]1[CH3:21])(=[O:3])[CH3:2].CN(C)C=O.P(Cl)(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([Cl:29])[C:10]=2[N:9]=[C:8]1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1c(C)nc2c[n+]([O-])c3ccccc3c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCCn1c(C)nc2c(Cl)nc3ccccc3c21
Reaction time: 0.5 h

Procedure:
A dried round bottom flask was charged with a stir bar, 2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (8.7 g, 30.49 mmol), anhydrous dimethylformamide (80 mL), and anhydrous toluene (100 mL) under nitrogen. To this brown mixture was added phosphorus oxychloride (3.1 mL) by syringe at ambient temperature. The reaction solution cleared in a couple of minutes and a slight exotherm was observed. The reaction was judged to be complete after 30 minutes. The volatiles were removed under reduced pressure. The resulting brown solid was partitioned between dichloromethane and 4% aqueous sodium bicarbonate to a pH of 8. The aqueous layer was extracted with dichloromethane (5×). The organic fractions were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure and dried overnight at ambient temperature under reduced pressure to provide 9.2 g of 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate as a brown oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:25])(=[O:24])[NH2:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(S(=O)(=O)N)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([CH2:26][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:24])(=[O:25])[NH2:23])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(S(N)(=O)=O)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: NS(=O)(=O)c1cccc(NCC2CCCC2)c1
Product: NS(=O)(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-sulfamoyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH:4]=O.[C:22]([OH:26])(=[O:25])[CH2:23][SH:24].C(N(CC)CC)C>N1C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[S:24][C:23]([C:22]([OH:26])=[O:25])=[CH:4][C:3]=2[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[CH:16][CH:17]=1
Reactant: O=CC(=C(Cl)c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CS
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cc(-c2ccc([N+](=O)[O-])cc2)c(-c2ccc(F)cc2)s1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 3-chloro-3-(4-fluorophenyl)-2-(4-nitrophenyl)propenal (1.5 g), thioglycolic acid (0.36 ml) and triethylamine (1.5 ml) in pyridine (7.6 ml) was stirred at 70° C. for 1 hour and refluxed for 7 hours. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water and dilute hydrochloric acid, dried and concentrated. The residue (1.6 g) was washed with toluene to give pale brown crystals of 5-(4-fluorophenyl)-4-(4-nitrophenyl)thiophene-2-carboxylic acid (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[S:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]1>>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][CH:15]([CH:12]2[CH2:13][CH2:14][S:9][CH2:10][CH2:11]2)[OH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Br)n1
Reactant: O=CC1CCSCC1
Product: OC(Cc1cccc(Br)n1)C1CCSCC1

Procedure:
The title compound was prepared according to the procedure in Example 158 Step 1 using 2-bromo-6-methylpyridine (1.5 g, 8.72 mmol) and tetrahydro-2H-thiopyran-4-carbaldehyde (2.27 g, 17.4 mmol) as the starting materials.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].O>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]([F:18])([F:17])[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: OC(c1cccnc1)C(F)(F)F
Yield: 90.8 %

Procedure:
3-Pyridinecarboxaldehyde (200 μL, 2.12 mmol) and potassium carbonate (58.6 mg, 0.424 mmol) were suspended in N,N-dimethylformamide (4.0 mL). To this, (trifluoromethyl)trimethylsilane (940 μL, 3.63 mmol) was added dropwise under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 1.5. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure and the residue was dissolved in tetrahydrofuran (4.0 mL). To this, a 1 mol/L aqueous hydrogen chloride solution (5.0 mL) was added at room temperature and the mixture was stirred at the same temperature for 10 minutes. Then, the reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give 3-(2,2,2-trifluoro-1-hydroxyethyl) pyridine (Compound CB) (341 mg, yield: 91%).