Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11](Cl)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)C=Cc1ccc(F)c(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
The unpurified 3-(3-bromo-4-fluoro-phenyl)-acryloyl chloride (3.5 g, 13.3 mmol) prepared in Step 2, N,O-dimethylhydroxylamine hydrochloride (1.4 g, 14.0 mmol), and pyridine (2.4 mL, 29.4 mmol) were added at 0° C. to dichloromethane (20.0 mL). The reaction mixture was stirred at room temperature for 12 hours, quenched with a 1N hydrochloric acid solution, and then extracted with diethyl ether two times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was recrystallized from diethyl ether and n-hexane to give 3.2 g of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: Oc1ccc(F)cc1Br
Reactant: COCOC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCOc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
2-Bromo-4-fluorophenol (25.0 g, 0.13 mol) was dissolved in dry dichloromethane (100 mL) and dimethoxymethane (115 mL, 1.30 mol). Phosphorus pentoxide (110.8 g, 0.39 mol) was added portion-wise to the solution such that the reaction temperature remained below 40° C. The mixture was stirred vigorously at room temperature for 2 hours and then carefully poured into 1N aqueous NaOH (50 mL). The organic layer was separated, washed with water and then brine, dried over anhydrous MgSO4, filtered and concentrated to give 2-bromo-4-fluoro-1-methoxymethoxy-benzene (30.1 g) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH2:3][CH2:2][O:1][C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:32]
Reactant: COc1cccc(N=C=O)c1
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2cccc(OC)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Br[C:2]1[N:3](C(OC(C)(C)C)=O)[C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:10]=[C:9]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:8]=2)=[CH:5][CH:6]=1.[NH:37]1[CH:41]=[CH:40][C:39](B(O)O)=[N:38]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:28][O:27][CH2:26][C@H:25]([CH3:29])[O:24][C:9]1[CH:8]=[C:7]([C:4]2[NH:3][C:2]([C:41]3[CH:40]=[CH:39][NH:38][N:37]=3)=[CH:6][CH:5]=2)[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[CH:10]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(Br)n2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3cc[nH]n3)[nH]2)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 50.8 %

Procedure:
t-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (375 mg, 0.446 mmol) synthesized in Example (13c) and commercially available 1H-pyrazol-3-ylboronic acid (120 mg, 1.00 mmol) were dissolved in a mixed solvent of 1,2-dimethoxyethane (20 mL) and water (5 mL), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (28 mg, 0.034 mmol) and an aqueous potassium carbonate solution (3M, 0.65 mL, 1.95 mmol) were added, and stirring was carried out at 100° C. for 7 days under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-80%) to afford the desired compound (106 mg, yield 35%) as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:20])=[C:13]([S:16](Cl)(=[O:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)(=O)C>>[CH3:1][N:2]([CH3:3])[S:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:7]2)=[CH:11][C:12]=1[Br:20])(=[O:18])=[O:17]
Reactant: CNC
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Product: CN(C)S(=O)(=O)c1cc2c(cc1Br)CCN2

Procedure:
Starting with dimethylamine and 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonyl chloride, the title compound was prepared by using similar methods to those described for Preparation 27.1H NMR (DMSO-d6): 7.40 (1H, s), 7.01 (1H, s), 3.51 (2H, t), 3.01 (2H, t), 2.77 (6H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl>C(O)CCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: C1CNCCN1
Agent: Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Yield: 70 %

Procedure:
A solution of 1-chloro-4-nitrobenzene (15 g, 94.5 mmol) in 1-butanol (75 mL) was added over 20-30 minutes to a refluxing solution of anhydrous piperazine (24.4 g, 284 mmol) in 1-butanol (75 mL) and the mixture maintained at reflux overnight. The solvent was removed under reduced pressure to afford a solid, to which was added 2N hydrochloric acid (400 mL). The aqueous layer was washed twice with ethyl acetate, cooled to below 10° C. and basified with a cold solution of 40% sodium hydroxide to pH 10, keeping temperature below 20° C. The mixture was extracted with ethyl acetate (4×200 mL) then the combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded 1-(4-nitro-phenyl)-piperazine (13.7 g, 70%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH:6]=1.C([O:9][CH:10]=[C:11]([C:17]#[N:18])[C:12](OCC)=O)C>C(O)C>[C:17]([C:11]1[C:10](=[O:9])[N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[N:1][CH:12]=1)#[N:18]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NC1=CCCN1
Solvent: CCO
Product: N#Cc1cnc2n(c1=O)CCC2
Temperature: 25 °C
Yield: 42.5 %

Procedure:
16.8 g. of 2-amino-pyrroline are dissolved in 140 ml. of ethanol and the solution is cooled to -5° C. and under stirring added dropwise to a solution of 33.8 g. of ethyl ethoxy-methylene-cyanoacetate in 250 ml. of ethanol. The reaction mixture is allowed to warm up to room temperature, and boiled for an hour. The reaction is then allowed to crystallize under cooling below 0° C. The precipitated crystals are filtered and thus 13.7 g. (42.5%) of 3-cyano-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine are obtained, melting at 119°-121° C. after recrystallization from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][N:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][OH:35]>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:33][CH2:34][OH:35])[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][N:19]=[CH:18][CH:17]=2
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (157 mg) was dissolved in N,N-dimethylformamide (8 ml) to prepare a solution. Potassium carbonate (195 mg) and 2-bromoethanol (0.1 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (147 mg, yield 83%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14](Br)=[C:13]([CH3:19])[N:12]=1.O.Cl>C(O)CO>[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([S:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)=[C:13]([CH3:19])[N:12]=1
Reactant: Cc1nc(N)nc(O)c1Br
Reactant: OCc1ccc(S)cc1
Agent: Cl
Solvent: O
Solvent: OCCO
Product: Cc1nc(N)nc(O)c1Sc1ccc(CO)cc1
Temperature: 155 °C

Procedure:
A stirred mixture of (4-mercaptophenyl)methanol (6.72 g), 2-amino-5-bromo-6-methylpyrimidin-4-ol (10.76 g) and K2 CO3 (7.29 g) in ethylene glycol (120 ml) was heated at 155° C. for 9 h. After cooling the mixture was poured into water (500 ml) and neutralised with conc. HCl. The precipitate was filtered, washed with water then 50% EtOH/ether and dried to give the subtitle compound as a solid, 6.7 g. 1H NMR DMSO-d6: δ11.07 (brs, 1H); 7.18 (d, 2H); 6.99 (d, 2H); 6.87 (brs, 2H); 5.09 (s, 1H); 4.41 (s, 2H); 2.24 (s, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)Cl)[CH3:2].[CH2:19]([O:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])[CH3:20].[Na].N#N>C1COCC1>[CH2:19]([O:21][C:22]([C:23]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[O:17][C:24]=1[NH2:25])=[O:26])[CH3:20]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC#N
Agent: N#N
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N)oc(-c2ccc([N+](=O)[O-])cc2)c1C(=O)OCC

Procedure:
105 g (0.39 mols, 1 eq) of 4-nitrobenzoyl-chloroacetic acid ethyl ester are dissolved in 600 ml of THF. To this solution are added, on a water bath (T=35° C.), in portions, 49.4 g (0.37 mols) of finely ground sodium cyanoacetic acid ethyl ester (preparation: Chem, Ber. 1962, 95, 307-318.). It is stirred over night (under N2), fully concentrated by evaporation, and extracted with H2O and CH2Cl2. The combined CH2Cl2 phase is washed with H2O, and finally dried over MgSO4 and freed from solvent. Crystallisation from toluene yields the title compound, m.p.: 174-177° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:43][C@@H:44]1[CH2:46][O:45]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:43][C@H:44]([OH:45])[CH3:46])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: C[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@@H](C)O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 52.7 %

Procedure:
To a mixture of N-(3-fluoro-4-((7-hydroxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (100 mg, 0.21 mmol) and Cs2CO3 (337 mg, 1.03 mmol) in 10 mL DMF was added (R)-2-methyloxirane (5 mL, 71.60 mmol). The reaction was warmed to 40° C. and stirred for two days. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (1:15 (v/v) MeOH/DCM) to give the title compound as a white solid (60 mg, 54%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccccc1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 22 °C
Reaction time: 19 h
Yield: 93.4 %

Procedure:
To an ice-cooled solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(piperidin-4-yloxy)-phenyl]-urea (82.2 mg, 0.22 mmol), 1-hydroxybenzotriazole (HOBt, 50.1 mg, 0.37 mmol), and benzoic acid (38.8 mg, 0.32 mmol) in dichloromethane-THF (1:1, 2 mL) is added DCC (52.0 mg, 0.25 mmol). The reaction mixture is stirred at 22° C. for 19 hours. The crude product is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a white solid (97.7 mg, 93.4% yield, ES+(m/z) 476.1 [M+H]).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=O)=[C:6]([CH:15]=1)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.O>CC(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:7][C:8]3[C:13]([N:16]=2)=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=3)[CH:15]=1
Reactant: O=Nc1ccc(Br)cc1Nc1ccc(Br)cc1
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2nc3cc(Br)ccc3nc2c1
Yield: 16 %

Procedure:
5-bromo-N-(4-bromophenyl)-2-nitrosoaniline (13-1) (10 g, 28.1 mmol) in AcOH (300 mL) was heated under reflux for 1.5 hrs. Water (400 mL) was then added and the brown precipitate formed was collected by filtration after washing with water (2×200 mL). The product was purified by silica gel chromatography (SiO2, hexanes/DCM=1/1(v/v)) to afford a brown solid, 2,7-dibromophenazine 13-2 (1.52 g, 16% yield). 1H NMR (CDCl3): δ 8.43 (2H, dd, J 2.2, 0.4 Hz), 8.10 (2H, dd, J 9.2, 0.4 Hz), 7.91 (2H, dd, J 9.2, 2.2 Hz) ppm. LC-MS (ESI): m/z 338.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:28])[CH:12]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH2:29](Br)[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:10][C:11](=[O:28])[CH:12]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])=[CH:25][CH:26]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCC(=O)c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)OCC(=O)c1ccccc1)c1ccc(OCC(=O)c2ccccc2)cc1

Procedure:
A mixture of N-tert-butoxycarbonyl-2-(4-hydroxyphenyl)glycine phenacyl ester prepared as above (3.56 g.), phenacyl bromide (1.84 g.) and potassium carbonate (1.28 g.) in an anhydrous acetone (71 ml.) was heated to reflux for 7 hours. The insoluble substances were filtered off and the filtrate was evaporated to dryness under reduced pressure. The residual oil was dissolved in chloroform, washed with water, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was triturated with diisopropyl ether to give crystalline N-tert-butoxycarbonyl-2-(4-phenacyloxyphenyl)glycine phenacyl ester (4.12 g.), which was recrystallized from ethanol to give the pure material, mp 125° to 126.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29]>N1C=CC=CC=1>[Cl:22][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[CH:7][C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:5]([F:21])[CH:4]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NC(=O)c3cccs3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In 5 ml of pyridine was dissolved 0.34 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, and 0.17 g of 2-thiophencarbonyl chloride was added thereto at 5° C. or lower. Thereafter, the temperature was increased to room temperature and the reaction was continued overnight. Then, pyridine was removed by distillation and the residue was dissolved in ethyl acetate. The solution was washed successively with water, diluted hydrochloric acid and a saturated saline solution, and dried over anhydrous sodium sulfate followed by removing ethyl acetate by distillation to obtain a crude product. This was washed with diisopropyl ether to obtain 0.30 g of the desired compound as white crystal.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)C>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cc1ccc(CO)cc1)OCc1ccccc1
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
2.52 g (23.8 mmol) of sodium carbonate and 8.13 g (47.6 mmol) of benzyl bromide were added to a solution of 3.95 g (23.8 mmol) of 4-Hydroxymethylphenylacetic acid [prepared as described in step (i) above] in 40 ml of N,N-dimethylformamide, and the resulting mixture was stirred for 3.5 hours. At the end of this time, the reaction mixture was diluted with diethyl ether, and the diluted mixture was washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by column chromatography through 200 g of silica gel, using a gradient elution method, with mixtures of methylene chloride and ethyl acetate in ratios ranging from 100:5 to 100:10 by volume as the eluent, to give 5.03 g (yield 82%) of the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:24][CH:23]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cc1ccc(NCc2nnn(C)n2)cc1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(C)cc2)[C@H]1O
Yield: 75 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.1 mmol) obtained in step 1 of example 2 and N-(4-methylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (388 mg, yield: 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH:16](O)([CH3:18])[CH3:17]>O>[CH:16]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: CC(C)O
Reactant: O=C(O)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 3-bromo benzoic acid (Aldrich, 2.4 g, 11.9 mmol) in isopropanol (20 mL) was treated with 1 mL of concentrated sulfuric acid and the resulting reaction mixture was refluxed overnight. The reaction mixture was then cooled to ambient temperature and diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as an oil (2.54 g, 88%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH2:10][C:2]2[N:3]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)=[CH:12][CH:13]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cc2nc3ccccc3n2CCc2ccccc2)cc1
Temperature: 100 °C
Yield: 30 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (200 mg, 0.75 mmol) in acetonitrile was treated with (2-bromoethyl)benzene (209 mg, 1.13 mmol) and potassium carbonate (143 mg, 0.90 mmol). The reaction mixture was heated with microwave irradiation at 100° C. for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. Purification of the resultant residue by flash column chromatography (silica, petroleum ether:ethyl acetate 8:2 to 1:1) afforded 4-(1-phenethyl-1H-benzoimidazol-2-ylmethyl)-benzoic acid methyl ester (30%). [M+H] 371.2.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH2:20][CH3:21]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:4]2[C:3]3[C:2]([C:26]4[CH:27]=[CH:28][C:23]([O:22][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:12]=[CH:13]1
Reactant: CC(C)Cn1cnc2cnc3cccc(Br)c3c21
Reactant: CCCOc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2cccc3ncc4ncn(CC(C)C)c4c23)cc1
Yield: 90 %

Procedure:
9-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (1.0 g, 3.4 mmol) and 4-propoxyphenylboronic acid (1.0 g, 5.5 mmol) were coupled according to Part J of Example 1. The palladium (II) acetate (2.5 mg, 0.011 mmol) was added as a 5 mg/mL solution in toluene. The work-up procedure described in Parts 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 1.1 g of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline as a dark brown oil.