Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](CC1C=CC(OC)=CC=1)[C:7](=[O:21])[NH:6][C:5]2([CH2:26][NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:22]([F:25])([F:24])[F:23].[N+]([O-])([O-])=O.[NH4+].[Ce].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:21])[NH:6][C:5]2([CH2:26][NH:27][C:28](=[O:36])[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:22]([F:25])([F:23])[F:24]
Reactant: COc1ccc(CN2C(=O)NC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Br)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring solution of N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}-4-fluorobenzamide (260 mg, 0.46 mmol) in acetonitrile (6 mL), an aqueous solution (1 mL) of cerium ammonium nitrate (755 mg, 1.38 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 4 hours. Sodium pyrosulfite was added to the reaction solution, and the solution was stirred for 30 minutes, and then diluted with ethyl acetate and the organic layer was separated. The organic layer was washed sequentially with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1), whereby the objective compound (150 mg, 73%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][C:19]=2[F:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:35][N:36]1[C:45]2[NH:44][C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[NH:41][CH2:40][C:39]=2[CH:38]=[N:37]1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:41]3[CH2:40][C:39]4[CH:38]=[N:37][N:36]([CH3:35])[C:45]=4[NH:44][C:43]4[CH:46]=[CH:47][CH:48]=[CH:49][C:42]3=4)=[O:26])=[CH:20][C:19]=2[F:27])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(=O)O)cc2F)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of 4-[3-(4-carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (865 mg, 2.3 mmol) in dichloromethane (50 ml) was treated with triethylamine (to pH9), WSCD (865 mg, 4.5 mmol) and DMAP (276 mg, 2.3 mmol), and the mixture was stirred at room temperature for 10 min. 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (541 mg, 2.7 mmol) was added. The mixture was heated at reflux for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (615 mg, 48%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH3:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[P:17]([Cl:20])(Cl)Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH3:15])[C:6]=1[O:16][P:17]([Cl:20])[O:16][C:6]1[C:7]([CH3:15])=[CH:8][C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: ClP(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1OP(Cl)Oc1c(C)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
890.3 g (4 mol) of 2,4-di-tert-butyl-6-methylphenol, 4.2 g of dimethylformamide and 170.0 g of xylene are introduced into a four-neck flask which has been flushed with nitrogen and is fitted with a thermometer, dropping funnel, reflux condenser and distillation attachment. 274.9 g (2 mol) of phosphorus trichloride are added dropwise with stirring over the course of 1.5 hours at a temperature of 50° C. The reaction mixture is warmed to 130° C. and refluxed at this temperature for 1 hour. The reaction mixture is kept at 120° C. for 1 hour under a vacuum of 0.15 bar. Xylene is subsequently removed by distillation under a greater vacuum. After the vacuum has been broken using nitrogen, 959.5 g (1.9 mol) of the title compound are obtained as supercooled, yellow-orange, clear melt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:16])[CH3:15])=[O:31]
Reactant: CNc1cnccc1-c1ccc(F)cc1C
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 4-(4-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (60 mg, 0.28 mmol, example 23, intermediate a) and DIPEA (97 μL, 0.56 mmol) was added 3,5-dichlorobenzoyl chloride (87 mg, 0.42 mmol, CAS RN 2905-62-6) in CH2Cl2 (2 mL). After stirring for 16 hours, the reaction mixture was loaded directly onto a silica gel column and elution with EtOAc gave the title compound (43 mg, 40%). MS (ESI): m/z=388.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25]Cl)(=[O:22])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Temperature: 60 °C
Reaction time: 0.02 h
Yield: 46 %

Procedure:
To a solution of 5-bromo-3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-1H-indazole-7-carboxamide (Intermediate 7) (200 mg, 0.432 mmol) in DMF (5 mL) was added K2CO3 (120 mg), sodium iodide (2 mg), and pyrrolidine (0.15 mL). The reaction mixture was heated to 60° C. for 2 hrs. The solution was filtered. The filtrate was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 40% B to 80% B in 3.2 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (40 mg, 46%)
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.S(C1C=CC(CCl)=CC=1)(=O)(=O)N.[S:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)(=[O:30])(=[O:29])[NH2:28].S(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:32][CH:33]=2)=[CH:8][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CN(C)CCOc1ccc(CN)cc1
Agent: NS(=O)(=O)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCOc1ccc(CNC(=O)c2ccc(S(N)(=O)=O)cc2)cc1
Yield: 40.8 %

Procedure:
To a cooled solution of 1.50 g of 4-[2-(dimethylamino)ethoxy]benzylamine and 0.87 g of triethylamine in 10 ml of chloroform was added 1.87 g of 4-sulfamoylbenzyl chloride, which was prepared from 1.71 g of 4-sulfamoylbenzoic acid with 16.3 g of thionyl chloride in the usual way, with stirring. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was washed with ethyl acetate to give 1.19 g of pale yellow crystals, which were recrystallized from ethanol to give colorless crystals, m.p. 173.5°-174.5° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[CH:29]=3)=[C:26]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+]>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:29]=3)=[C:26]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Cl)c2)CC1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Nc3ccccc3)c2)CC1
Temperature: 120 °C

Procedure:
To a suspension of NaH (130 mg, 3.3 mmol) in DMA (2 mL) was added aniline (0.58 mL, 6.1 mmol) and stirred until bubling ceased. To this solution was added 1-(1-t-butoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-chloro-4-pyridinyl)imidazole (0.30 g, 0.66 mmol) and the resulting solution was heated at 120° C. until no evidence of starting material was observed by mass spectroscopy (1-3 days). To the cooled reaction mixture 1M NaOH was added and the resulting mixture extracted three times with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure to afford a yellow residue which was chromatographed with 50-80% EtOAc/hexanes. The resulting solid was triturated with Et2O to give the title compound as a light yellow solid; yield 180 mg (53%): ESMS m/z=514(M+ +H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1nccs1
Product: O=C(NC(=S)NCCSCc1nccs1)c1ccccc1

Procedure:
By the procedure of Example 18, 2-[(2-aminoethyl)thiomethyl]thiazole is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-thiazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18, gives N-[2-(2-thiazolylmethylthio)ethyl]thiourea. Treating this compound with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH2:13][C:14]2([C:24]3[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=3)[CH2:19][CH2:18][N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH2:13][C:14]2([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([C:31]#[N:32])[CH:38]=4)=[CH:26][CH:25]=3)[CH2:19][CH2:18][N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1)c1ccc(F)c(Cl)c1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cccc(-c2ccc(C3(CNS(=O)(=O)c4ccc(F)c(Cl)c4)CCN(CC4CC4)CC3)cc2)c1
Temperature: 25 °C
Yield: 450.7 %

Procedure:
To a flask containing 3-chloro-N-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-4-fluorobenzenesulfonamide (0.047 g, 0.04 mmol) was added Pd(PPh3)4 (0.005 g, 0.004 mmol, 10 mol %), 3-cyanophenylboronic acid (0.01 g, 0.06 mmol, 1.5 eq.) and Na2CO3 (0.106 g, 1 mmol). The mixture was suspended in toluene (1.5 mL), EtOH (0.75 mL) and H2O (0.5 mL) and heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (5 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), saturated brine (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brown solid which was purified by HPLC to give 3-chloro-N-[4-(3′-cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-ylmethyl]-4-fluoro-benzenesulfonamide (0.097 g, 45%). MS (ESI): 538.2/540.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13].[C:14](Cl)(=[O:16])[CH3:15].Cl>>[CH3:15][C:14]([C:9]1[C:10]([F:12])=[CH:11][C:6]([Br:5])=[C:7]([F:13])[CH:8]=1)=[O:16]
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(F)c(Br)cc1F
Temperature: 60 °C
Yield: 31 %

Procedure:
Anhydrous aluminum chloride was mixed (5 grams, 37.5 millimoles, 2.4 equivalents) with 1-bromo-2,5 difluorobenzene in a dry, round-bottom flask blanketed with nitrogen and fitted with a condenser. The mixture was heated to 60° C. and acetyl chloride (1.7 milliliters, 23.3 millimole, 1.5. equivalents) was added by syringe. The wet yellow solid changed then into a scarlet solution and was heated at 90° C. for 1 hour. The reaction mixture was poured onto 38 grams of ice, HCl was added (3 milliliters, 37% concentration) and the mixture was extracted with ether. The crude material was dried over magnesium sulfate and evaporated down. The crude material was purified by column chromatography or distilled. The product (1.2 grams, 31%) was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH3:26])[N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:27]>CO.O>[CH3:26][C:13]1[N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:27])[C:11]=2[N:12]=1
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Reactant: N
Solvent: O
Solvent: CO
Product: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 150 °C

Procedure:
A suspension of 4-chloro-2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline (1.80 g, 4.55 mmol) in a solution of ammonia in methanol (7 M, 18 mL) in a high pressure vessel was heated at 150° C. for 14 hours. The vessel was allowed to cool to room temperature. A solid was isolated by filtration, washed with methanol, and purified by flash chromatography (silica gel, eluted with 10% methanol in dichloromethane) to provide a white solid. The solid was stirred in water (100 mL) for 1 hour, isolated by filtration, washed with water, and dried to yield 0.84 g of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 253-255° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Br[C:38]1[CH:47]=[C:42]([C:43]([O:45][CH3:46])=[O:44])[C:41]([OH:48])=[CH:40][CH:39]=1.ClCCl>C([O-])(O)=O.[Na+].C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[C:38]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[C:31]([CH3:32])=[CH:36][CH:33]=[CH:34][CH:35]=4)(=[O:29])=[O:28])[C:12]3=[N:13][CH:14]=2)[CH:39]=[CH:40][C:41]=1[OH:48]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1cc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccccc2C)ccc1O
Temperature: 90 °C
Yield: 90.8 %

Procedure:
To a solution of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (502 mg, 1.00 mmol) in 1.5 mL saturated aqueous NaHCO3 and 5.0 mL acetonitrile was added methyl 5-bromosalicylate (253 mg, 1.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1.1) (41 mg, 0.05 mmol) in a microwave vial. The vial was capped, flushed with N2, evacuated under vacuum, and subsequently heated in a microwave at 90° C. for 300 seconds. The material was diluted with ethyl acetate and the organic layer was washed with saturated NaHCO3 (aq) and brine then dried over Na2SO4. The material was filtered, then adsorbed onto silica gel and purified by flash chromatography with a gradient of ethyl acetate and hexane, affording the title compound as a hydroscopic white solid (480 mg, 91% yield). 1H NMR (500 MHz, CD3OD) δ8.55 (d, J=2.0 Hz, 1H), 8.06 (m, 4H), 7.96 (s, 1H), 7.77 (dd. J=2.5, 6.0 Hz, 1H), 7.52 (dd, J=2.0, 6.0 Hz, 1H), 7.40 (m, 3H), 7.16 (d, J=8.5 Hz, 1H), 7.08 (m, 2H), 3.98 (s, 3H), 3.87 (s, 3H), 2.39 (s, 3H). MS: m/z 529.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].C12BC(CCC1)CCC2.Br[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[N:23]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[N:23]=[C:22]([CH2:3][CH2:2][CH2:1][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:27]=1
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cc(Br)nc(C(F)(F)F)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCc1cc(C(F)(F)F)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
To a stirred solution of tert-butyl allylcarbamate (1.95 g, 12.4 mmol) in THF (12 mL), 0.5 mol/L 9-borabicyclo[3.3.1]nonane (29.8 mL, 14.9 mmol) was added under argon atmosphere at room temperature. After stirred at room temperature for 4 h, a solution of 2-bromo-4,6-bistrifluoromethylpyridine (3.65 g, 12.4 mmol) in DMF (12 mL), Pd(OAc)2 (278 mg, 1.24 mmol), DPPF (859 mg, 1.55 mmol) and K2CO3 (2.92 g, 21.1 mmol) were added to the reaction mixture and stirred at room temperature for 7 h. To the reaction mixture, water was added and the crude product was extracted with EtOAc, washed with brine, dried over NaSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 10:1→2:1) to yield tert-butyl 3-(4,6-bistrifluoromethylpyridin-2-yl)propylcarbamate (3.41 g, 74%) as a colorless solid. 1H NMR (CDCl3, 400 MHz) δ 1.44 (9H, s), 1.96-2.03 (2H, m), 2.98-3.02 (2H, m), 3.20-3.25 (2H, m), 4.71 (1H, brs), 7.59 (1H, s), 7.72 (1H, s). CIMS (+) 373 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][O:18]1.[CH3:24][NH:25][CH3:26]>O1CCCC1>[CH3:24][N:25]([CH3:26])[CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1CCCCc1ccccc1OCC1CO1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccccc1CCCCc1ccccc1OCC(O)CN(C)C
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 260 mg of 2-{2-[4-(2-methoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran was treated with 2 ml of 50% by volume aqueous dimethylamine and then worked up. The resulting crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 250 mg (yield 84%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]5([C:39](=[O:46])[NH:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C:38]6[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:47])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:56](Br)[CH:57]=[CH2:58]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]5([C:39](=[O:46])[NH:40][CH:41]([CH2:58][CH:57]=[CH2:56])[C:42]([F:45])([F:43])[F:44])[C:38]6[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=6[C:32]6[C:27]5=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH2:20][CH2:21]4)=[CH:12][CH:13]=3)[C:8]2=[O:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CCBr
Reactant: O=C1c2cc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)ccc2CN1C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC(NC(=O)C1(CCCCN2CCN(c3ccc4c(c3)C(=O)N(C3CCCCC3)C4)CC2)c2ccccc2-c2ccccc21)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
The compound (0.100 g) prepared in Example 92 was dissolved in toluene (5 ml). Sodium hydroxide (0.019 g), potassium carbonate (0.041 g), tetrabutylammonium hydrogen sulfate (0.012 g), and allyl bromide (0.015 ml) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:3) to give the title compound (0.017 g, 16.5%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Yield: 100.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-fluorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4.4 g), the title compound (9 g) was obtained.