Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O.CS(O)(=O)=O>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[C:5]2[C:4]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:17]
Reactant: COc1cc(C)cc(CCCC(=O)O)c1OC
Agent: CS(=O)(=O)O
Product: COc1cc(C)c2c(c1OC)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A mixture of 4-(2,3-dimethoxy-5-methylphenyl)butyric acid (50.7 g, 0.21 mole) and methanesulfonic acid (507 g, 355 mL) was stirred at 0° for 1 hour and overnight at room temperature. The reaction mixture was poured onto ice, and the solution was extracted with CH2Cl2. The combined CH2Cl2 layers were washed with 1N KOH, water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield 20.2 g tan solid, (44%); mp 58°-62°; M+ 204.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:12][C@@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:16]=[CH:15]/[CH2:14][C@H:13]([OH:17])[CH3:12])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: C=CC[C@@H](C)O
Reactant: CC(C)Oc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Oc1cncc(/C=C/C[C@@H](C)O)c1
Temperature: 140 °C
Yield: 84.9 %

Procedure:
A mixture of 5-isopropoxy-3-bromopyridine (10.26 g, 47.50 mmol), (2R)-4-penten-2-ol (4.91 g, 57.00 mmol), palladium(II) acetate (106 mg, 0.47 mmol), tri-o-tolylphosphine (578 mg, 1.90 mmol), triethylamine (28.46 mL, 204.25 mmol), and acetonitrile (30 mL) were heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give a pale-yellow oil (8.92 g, 85.0%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH2:6][NH:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)=[O:9].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][C:32](O)=[O:33])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH2:6][NH:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:32](=[O:33])[CH2:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:29][CH2:28]2)[CH2:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: COC(=O)CCNC(=O)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)C1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
To a mixture of N-[(3-piperidyl)carbonyl]-β-alanine methyl ester hydrochloride (1.57 g),3-(1-tert-butoxycarbonyl-4-piperidyl)propionic acid (1.61 g) and 1-hydroxybenztriazole (0.96 g) in N,N-dimethylformamide (16 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.14 ml) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with (CHCl3:MeOH 100:1) to give N-[1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-β-alanine methyl ester as an oil (2.19 g).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([Mg]Cl)(C)C.CON(C)[C:19]([C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)(=[O:30])=[O:29])=[CH:25][C:24]([Cl:42])=[CH:23][N:22]=1)=[O:20]>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([NH:27][C:26]2[C:21]([C:19]([C:2]3[C:3]4[CH:4]=[N:5][NH:6][C:7]=4[N:8]=[CH:9][CH:10]=3)=[O:20])=[N:22][CH:23]=[C:24]([Cl:42])[CH:25]=2)(=[O:30])=[O:29])=[CH:32][C:33]=1[C:38]([F:39])([F:41])[F:40]
Reactant: Ic1ccnc2[nH]ncc12
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ncc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-7-azaindazole (Potashman et.al., WO2005070891) (123 mg) in THF (2 mL) at 0° C. was added isopropylmagnesium chloride (2 M solution in THF, 0.5 mL). The mixture was stirred at 0° C. for 30 min and 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (114 mg) was added. The reaction mixture was warmed to room temperature, stirred for 2 h and quench by saturated aqueous NH4Cl solution (2 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica) to afford the title compound as a white powder. MS (M+H)+: 515.9.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[F:16])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: ClCCCn1ccnc1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 122 %

Procedure:
To a solution of 1-(3-chloropropyl)-1H-imidazole (1.90 g, 13.14 mmol), cesium carbonate (4.28 g, 13.14 mmol) and a catalytic amount of KI in DMF (30 mL) cooled in an ice-bath was added 2-fluoro-4-nitroaniline (1.38 g, 8.84 mmol) in one portion. At the end of addition, the mixture was refluxed and stirred further for 36 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. To the residue was added water (50 mL) and the resulting mixture was extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL×2) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=15:1) to give the title compound as yellow oil (2.85 g, 82%).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(NCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.7 g (about 7.22 mmol) of tert-butyl 3-[3-(benzylamino)-4-chlorophenyl]-2,2-dimethylpropanoate were dissolved in 150 ml of ethyl acetate, and 100 ml of palladium on carbon (10%) were added. The reaction mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure overnight. The mixture was then filtered off with suction through kieselguhr, the residue was washed thoroughly with ethyl acetate and the combined filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→7:1). This gave 1.49 g (72.7% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1B(O)O.O>C(=O)([O-])[O-].[Na+].[Na+].C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1cccc(C)c1B(O)O
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: CCOC(C)=O
Product: Cc1cccc(C)c1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
3-Bromobenzaldehyde (18.5 g, 100 mmol) and 2,6-dimethylphenylboronic acid (21.0 g, 140 mmol) were dissolved in a mixture of 1 M aqueous sodium carbonate solution (200 mL), ethanol (100 mL) and toluene (200 mL). The air was substituted with argon gas, and tetrakis(triphenylphosphine)palladium(0) (5.78 g, 5.00 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 80° C. for 20 hr. After cooling the reaction mixture, water was added and the mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite. The organic layer in the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound (20.4 g, yield 97%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Br[CH2:14][CH2:15][OH:16]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
4-nitrobenzenethiol (10 g) was dissolved in methanol (100 ml), 3N sodium hydroxide (32.2 ml) was added to the mixture, and 2-bromoethanol (9.7 g) was added dropwise to the mixture. The mixture was stirred for 1 hour at room temperature, the solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane/ethyl acetate, to give 2-[(4-nitrophenyl)sulfanyl]ethanol (10.6 g).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O>[C:15]1([CH:14]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:7])[CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1C(C)c1ccccc1
Reaction time: 0.5 h

Procedure:
Toluene 4423g was charged to a 12 liter bottom outlet Pyrex reactor equipped with a mechanical agitator, heating mantle, addition funnel, cooling coil, thermometer, and a reflux condenser. Sulfuric acid, 981g of 96% was charged in one portion with agitation. Styrene, 3749g, was added dropwise at 80°-85° over 90 min. The mixture was agitated for an additional 30 min. At 80°-85° C. after the styrene addition was complete, the mixture was allowed to settle for 45 min. and the lower sulfuric acid layer was drained off. A solution of sodium hyroxide (80g in 552g of water) was charged and the mixture was allowed to settle for 30 min, and the lower sodium hydroxide layer was drained off at 80° C. Hot water (1440g) was charged and the mixture was agitated for 15 min. then allowed to settle for 30 in. The water wash was separated leaving 7375g of crude phenyltolylethane alkylate. The phenyltolylethane alkylate was vacuum fractionated to remove excess toluene then pure phenyltolylethane, BP 205° C. 100 mmHg.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.C(OP([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (1.50 g), ethyl diethylphosphonoacetate (0.87 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.17 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl (2E)-3-{3-[(4-([2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazol-4-yl)-2-propenoate as colorless crystals (1.60 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:36]([NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CC(C)(C)N=C=O
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: CC(C)(C)NC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-tert-butyl-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and tert-butyl isocyanate (Fluka, Buchs, Switzerland). Analytical HPLC: tR=6.61 min (Grad 2); ES-MS: m/eo=499.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][CH:47]([N:50]5[CH2:55][CH2:54][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:51]5)[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 61.9 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (0.10 g, 0.22 mmol), 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 222, Step D) (0.083 g, 0.22 mmol) and para-toluenesulfonic acid (0.099 g, 0.52 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-3-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamide (0.110 g, 63%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (s, 1H), 9.39 (br. s., 1H), 8.38 (s, 1H), 8.35 (s, 1H), 8.24 (d, J=5.2 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.36-7.52 (m, 3H), 7.16-7.26 (m, 2H), 6.94-7.02 (m, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.45-6.54 (m, 2H), 4.07 (q, J=6.9 Hz, 2H), 3.66-3.79 (m, 2H), 3.04-3.15 (m, 4H), 2.87 (s, 3H), 2.57-2.72 (m, 6H), 2.36-2.47 (m, 1H), 1.78-1.91 (m, 2H), 1.45-1.62 (m, 2H), 1.25 (t, J=7.0 Hz, 3H). MS (M−H, ES−) 806.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:8]=2)[NH:3]1.[OH-].[Na+:20].[O:21]1CCOCC1>O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:8][C:9]=1[CH2:10][C:2]([O-:21])=[O:1].[Na+:20]
Reactant: O=C1Cc2cc(Oc3ccc(Cl)cc3)ccc2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccc(Cl)cc2)cc1CC(=O)[O-]

Procedure:
A mixture of 2-oxo-5-(4-chlorophenoxy)indoline (4.2 g.), sodium hydroxide (2.6 g.), dioxane (20 ml.) and water (40 ml.) was refluxed under heating for 5 days with stirring. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in water (50 ml.) and filtered. The filtrate was washed with diethyl ether and evaporated. The residue was dissolved in ethyl acetate (200 ml.) under warming and filtered. The filtrate was cooled, and the precipitating crystals were collected by filtration, washed with ethyl acetate and then recrystallized from a mixture of ethanol and ethyl acetate to give the captioned compound (3.4 g.). mp 206° to 209° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>CS(C)=O.CCOCC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
260 mg (1 mmol) Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine in 2 ml DMSO were treated with 175 mg (1 mmol) 1-bromo-4-fluorobenzene and 26.4 mg (0.1 mmol) 18-crown-6 and 182 mg (1 mmol) KF on alox. The suspension was stirred at 120° C. for 2 h, additional 175 mg (1 mmol) 1-bromo-4-fluorobenzene, 26.4 mg (0.1 mmol) 18-crown-6 and 182 mg (1 mmol) KF on alox were added. The suspension was stirred for 1 h, cooled to RT and diluted with ether and filtered. The solution was washed with 1M NaOH and water, and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 4:1 yielded 205 mg (48%) {4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow oil, MS: 415 (MH+, 1Br). (analogously to William J. Smith III, J. Scott Sawyer, Tetrahedron Letters 1999, Vol.37, No.3, 299-302.)
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@@H:12]([O:22][CH2:23][P:24]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])=[O:25])[CH2:13][O:14]CC2C=CC=CC=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@@H:12]([O:22][CH2:23][P:24]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:27])[CH3:28])=[O:25])[CH2:13][OH:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](COCc2ccccc2)OCP(=O)(C(C)C)C(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H](CO)OCP(=O)(C(C)C)C(C)C)cc1
Reaction time: 24 h
Yield: 87.6 %

Procedure:
10% Palladium on carbon (1.05 g) was added to a solution of 7 (11.5 g, 22.4 mmol) in methanol (150 ml) and the mixture was hydrogenated at room temperature under atmospheric pressure for 24 h. The solid was filtered off through Celite, washed with methanol (2×100 ml) and combined filtrates were concentrated in vacuo. The syrupy residue was chromatographed on a column of silica gel (400 ml) in ethyl acetate. Product containing fractions were evaporated to give 7.7 g (81%) of compound 8 as a colorless syrup,
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
22.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-chloroaniline are dissolved in 170 ml of acetic acid, and 20 g of boron trifluoride etherate are added thereto. The mixture is stirred at 95° to 100° C. for 30 minutes. The mixture is cooled and concentrated under reduced pressure to remove acetic acid. Water is added to the residue and the mixture is neutralized with sodium bicarbonate. The mixture is extracted with chloroform, and the extract is washed with water, dried and then concentrated to dryness under reduced pressure. Isopropanol is added to the crystalline residue and the crystals are collected therefrom. The thus-obtained crystals are recrystallized from a mixture of dimethylformamide and ethanol (1:2). 18.5 g of 2-fluoromethyl-3-(2-methyl-4-chlorophenyl)-6-nitro-4(3H)-quinazolinone are obtained as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)=[O:6]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC3CCCCC3)c(OC3CCCCC3)c2)cc1
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC(=O)c2cc(Cl)c(OC3CCCCC3)c(OC3CCCCC3)c2)cc1
Yield: 18.7 %

Procedure:
4-(3-Chloro-4,5-bis(cyclohexyloxy)benzamido)benzoic acid (AAA-047) (15 mg, 19%) was prepared from methyl 4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8) (80 mg, 0.17 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (6 mL) was used instead of THF: m/z 470 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.72 (1H, br s), 10.44 (1H, s), 7.94 (2H, d), 7.87 (2H, d), 7.67 (1H, d), 7.53 (1H, d), 4.53 (1H, m), 4.36 (1H, m), 1.98-1.82 (4H, m), 1.80-1.65 (4H, m), 1.58-1.20 (12H, m).