Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20](OC)=[O:21].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2cccc(Oc3ccccc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Oc3ccccc3)cccc12
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 1e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 1e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-(4-hydroxy-1-methyl-5-phenoxyisoquinoline-3-carboxamido)acetic acid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32].[OH-].[Na+]>ClCCl.C(OCC)C>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[O:34])[CH:31]([CH3:32])[CH3:33]
Reactant: CC(C)C(O)c1ccccc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a suspension of [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (2.2 g, 5.19 mmol) in dichloromethane (18 mL) at room temperature under nitrogen was added dropwise a solution of 1-(2-bromophenyl)-2-methylpropan-1-ol of Step A (1.00 g, 4.36 mmol) in dichloromethane (18 mL) over ca. 5 minutes. After 2 hours, additional [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (0.20 g, 0.47 mmol) was added and the reaction mixture stirred at room temperature for 4 days. The reaction mixture was then diluted with diethyl ether (100 mL) and the resulting suspension added to 1.3 M aqueous sodium hydroxide solution (40 mL) with stirring. After 10 minutes the organic phase was separated, washed with 1.3 M sodium hydroxide (40 mL) and water (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (0.89 g, 90%) as a clear, pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Yield: 51.3 %

Procedure:
A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.323 mmol), tert-butyl 2-amino-2-methylpropanoate hydrochloride (82 mg, 0.42 mmol), HATU (160 mmol, 0.42 mmol) and DIPEA (66 mg, 0.51 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v) to give tert-butyl 2-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-2-methylpropanoate (75 mg, 51.8%) as a white solid. MS: (M+H)+=453; 1H NMR (300 MHz, DMSO): δ 13.93 (s, 1H), 9.13 (s, 1H), 8.57-8.52 (m, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 7.72 (dd, 1H, J=9.8, 2.1 Hz), 7.21-7.15 (m, 1H), 4.18 (s, 3H), 1.63 (s, 6H), 1.25 (s, 9H).
Reaction SMILES: [Na].[F:2][C:3]([F:14])([C:8]1[CH:12]=[C:11]([OH:13])[O:10][N:9]=1)[C:4]([F:7])([F:6])[F:5].[CH3:15][N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](=[O:20])[CH2:18]Br>C(#N)C>[CH3:15][N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](=[O:20])[CH2:18][O:13][C:11]1[O:10][N:9]=[C:8]([C:3]([F:2])([F:14])[C:4]([F:7])([F:6])[F:5])[CH:12]=1
Reactant: Oc1cc(C(F)(F)C(F)(F)F)no1
Reactant: CN(C(=O)CBr)c1ccccc1
Agent: [Na]
Solvent: CC#N
Product: CN(C(=O)COc1cc(C(F)(F)C(F)(F)F)no1)c1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
To 0.50 g (2.2 mmole) of 3-pentafluoroethyl-5-hydroxyisoxazole sodium salt were added dry acetonitrile (7 ml) and N-methyl-N-phenyl-2-bromoacetamide (0.55 g) and the resulting mixture was stirred at 60° C. for 24 hours. After completion of reaction, the reaction solution was evaporated under reduced pressure and to the residue was added water (80 ml), extracted with methylene chloride, treated with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give 0.52 g of crystals. These crystals were recrystallized from n-hexane to give 0.48 g of the titled compound as colorless plates, yield 62.3%, m.p. 88.0-89.0° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)cc1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoro-acetate salt (Intermediate 27) with 2,2,2-trichloroethyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.96-2.08 (m, 4H), 3.30 (methyl sulfonyl and water peak), 4.11-4.20 (m, 2H), 4.86-4.89 (m, 2H), 5.05-5.10 (m, 1H), 7.59-7.62 (m, 2H), 8.03-8.05 (m, 2H), 8.36 (s, 1H), 8.54 (s, 1H). Mass spectrum MH+=548.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[C:13]3[CH2:20][CH:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:22][CH:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.C([Li])CCC>C1COCC1.CCCCCC.Cl>[C:18]([C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@@H:11]3[CH2:22][C@H:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:20][C:13]=1[C:12]=23)#[N:19]
Reactant: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCC)[C@@H]1Cc2c(C#N)ccc3c2[C@H](CN3)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 113.8 %

Procedure:
To a stirred solution of 4.8 g (0.0124 mol) of 1-benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole prepared as in Example 1 in 200 mL of THF cooled to -78° C. under N2 atmosphere, was added 16 mL (0.025 mol) of 1.6M solution of n-butyllithium in hexane. The reaction mixture was stirred at -78° C. for 30 minutes and then allowed to warm to -20° C. To the reaction mixture was added 100 mL in 1N HCl. The mixture was extracted once with ethyl ether. The acidic solution was made alkaline with the addition of cold 5N NaOH. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed with saturated aqueous NaCl solution. The CH2Cl2 solution was dried over MgSO4 and evaporated to give 4 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 3 g (85%) of product as an oil, which upon standing solidified.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:10]([CH2:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1
Reactant: ClCc1cnccn1
Reactant: CN1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Nc2nc3ccccc3n2Cc2cnccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a stirred mixture of 11.5 parts of N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine and 144 parts of N,N-dimethylformamide were added 5 parts of a sodium hydride dispersion 50%. After stirring for 1 hour at room temperature, a solution of 12.8 parts of 2-(chloromethyl)pyrazine in N,N-dimethylformamide was added dropwise to the thus obtained mixture. Upon complete addition, stirring was continued for 2 hours at 50° C. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.5 parts (9.3%) of N-(1-methyl-4-piperidinyl)-1-(2-pyrazinylmethyl)-1H-benzimidazol-2-amine; mp. 169.3° C. (compound 69).
Reaction SMILES: C[O-].[Na+].Cl[CH2:5][C:6]1([CH2:9][Cl:10])[CH2:8][O:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>C(#N)C>[Cl:10][CH2:9][C:6]1([CH2:5][S:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH2:8][O:7]1
Reactant: ClCC1(CCl)CO1
Reactant: Sc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: ClCC1(CSc2ccc(Cl)cc2)CO1
Reaction time: 4 h
Yield: 73 %

Procedure:
5.4 g (0.1 mole) of sodium methylate are introduced in portions into a mixture of 16.9 g (0.12 mole) of 2,2-di(chloromethyl)-oxirane and 14.5 g (0.1 mole) of 4-chlorothiophenol in 200 ml of acetonitrile. The reaction mixture is subsequently stirred for 4 hours and filtered and the filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride and the solution is washed with water, dried over sodium sulphate and concentrated. The oil which remains is distilled. 18.2 g (73% of theory) of 2-chloromethyl-2-(4-chlorophenylthiomethyl)-oxirane of refractive index nD20 1.5895 are obtained.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:14](N)=[N:13][C:12]=2[N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=[O:21].[Na+]>O.C(O)(=O)C>[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:14](=[O:21])[NH:13][C:12]=2[N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
35.9 g (0.13 mol) of 7-benzylguanine hydrochloride from stage a) were dissolved in a mixture of 90 ml of water and 807 ml of glacial acetic acid and heated to 100° C. After cooling to 50° C., a solution of 35.88 g (0.52 mol) of sodium nitrite in 90 ml of water was added in one portion. After 16 hours at room temperature, the resulting precipitate was filtered off with suction, washed with water on the suction filter and dried.
Reaction SMILES: C([O:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7])(=O)C.[F:11][C:12]1[CH:18]=[C:17]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].N1C=CC=CC=1>C(Cl)Cl>[F:11][C:12]1[CH:18]=[C:17]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH:14][C:6](=[O:7])[C:5]([OH:4])([CH3:9])[CH3:10]
Reactant: Nc1ccc(Sc2ccccc2)cc1F
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(O)C(=O)Nc1ccc(Sc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Acetoxy-2-methylpropanoyl chloride (0.47 ml) was added to a solution of 2-fluoro-4-phenylsulphanylaniline (Method 7) (0.64 g) and pyridine (0.28 ml) in DCM (10 ml). The solution was stirred at ambient temperature for 90 minutes then volatile material was removed by evaporation. The residue was dissolved in methanol (20 ml and a solution of lithium hydroxide monohydrate (0.378 g) in water (2.5 ml) was added. Stirring was continued for another 1 hour then the mixture was acidified to pH 1 with 2M hydrochloric acid and concentrated by evaporation to about 5 ml. Water (10 ml) was added and the product was extracted with ethyl acetate. Organic layers were washed with brine then combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-20% ethyl acetate/hexane to yield the title compound (0.784 g) as a solid. Mp 91-92.5° C.; NMR: 1.34 (s, 6H), 5.96 (s, 1H), 7.15 (d, 1H), 7.23 (dd, 1H), 7.27-7.4 (m, 5H), 8.02 (t, 1H), 9.3 (s, 1H); MS (ESP−): 304; EA: found: C, 62.8; H, 5.3; N, 4.5; S, 10.5%; C16H16FNO2S requires: C, 62.9; H, 5.3; N, 4.6; S, 10.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:20]
Reactant: NC1CCCCC1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: O=C(Nc1cc(OC2CCCC2)c(Cl)cc1F)C1=C(C(=O)NC2CCCCC2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), cyclohexylamine (0.360 g, 3.63 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-cyclohexyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.579 g, 45.5% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[N:3]=1.[CH2:21]([O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:21]([O:28][C:29]1[CH:34]=[C:33]([C:17]2[CH:18]=[C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:4]4[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([CH3:8])[CH:5]=4)[NH:20][C:14]3=[N:15][CH:16]=2)[CH:32]=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4cccc(OCc5ccccc5)c4)cnc3[nH]2)c1
Yield: 61 %

Procedure:
The title compound is synthesized according to General Procedure A. 150 mg of 2-[2-(2-amino4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine in 7.5 ml dioxane, 1.36 ml Na2CO3 solution, 116 mg of 3-benzyloxyphenylboronic acid, 20 mg of PdCl2(PCy3)2, 120° C. for 48 h, 20 ml of CH2Cl2/H2O, 220 mg of crude title compound is purified by re-crystallization from 6.0 ml isopropyl alcohol to yield 120 mg of the title compound. M.p. 181° C. ESI-MS: 436.3 (MH+). TLC: Rf=0.30 (dichloromethane/methanol 10:1).
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][N:12]3[CH:18]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>[Pt](=O)=O.CO>[ClH:1].[C:3]1([C:9]2[N:10]=[C:11]3[CH2:16][CH:15]([NH2:17])[CH2:14][CH2:13][N:12]3[CH:18]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2c1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: NC1CCn2cc(-c3ccccc3)nc2C1

Procedure:
Concentrated hydrochloric acid (0.11 ml) and platinum(IV) dioxide (83 mg) were added to a methanol (183 ml) solution of 2-phenylimidazo[1,2-a]pyridin-7-amine hydrochloride (900 mg), and the obtained mixture was then stirred in a hydrogen atmosphere for 4 hours. Thereafter, platinum(IV) dioxide (83 mg) was added to the reaction solution, and the obtained mixture was further stirred in a hydrogen atmosphere for 14 hours 30 minutes. Thereafter, the reaction solution was filtered with Celite, and was then washed with methanol (15 ml). The filtrate was concentrated under reduced pressure, and diethyl ether (3.6 ml) was then added to the obtained residue to solidify it, so as to obtain the title compound (733 mg) in the form of a gray solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:7]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCc1ccc(O)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C
Yield: 70.8 %

Procedure:
A mixture of 4-butyl-3-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenol (0.313 mmol), ethyl bromoisobutyrate (0.18 mL, 1.25 mmol) and cesium carbonate (0.41 g, 1.25 mmol) in anhydrous DMF (2 mL) was heated for 18 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 5-15% ethyl acetate/hexanes to give a yellow oil (0.12 g, 68%). 1H NMR (400 MHz, CDCl3) δ8.04 (dd, J=6.9, 1.7 Hz, 2H), 7.65 (q, J=7.8 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.29 (dd, J=8.1, 2.2 Hz, 1H), 4.25-4.18 (m, 4H), 2.98 (t, J=6.4 Hz, 2H), 2.48 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 1.57 (s, 6H), 1.44 (penta, J=7.6 Hz, 2H), 1.33-1.24 (m, 5H), 0.86 (t, J=7.1 Hz, 3H), MS (ES) m/e 542 (M+1).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(N(C(C)C)C(C)C)C>[OH:11][CH2:10][CH2:9][CH2:8][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: OCCCNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(CCCO)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A mixture of 3-(phenylamino)propan-1-ol (Huang, Yande; Arif, Atta M.; Bentrude, Weseley G. J. Org. Chem.; 58; 23; 1993; 6235-6246) (65.6 g, 0.43 mol), ethyl 4-bromobutyrate (104.5 g, 0.54 mol) and 100 mL of ethyldiisopropylamine is stirred at 100° C. for 1 h. The reaction is cooled to room temperature and partitioned between water 400 mL and ethyl acetate (500 mL). The organic layer is washed with saturated NaHCO3, brine and dried over Na2SO4. The oil obtained after concentration is chromatographed on silica eluting with 10% EtOH/CHCl3. Concentration of the appropriate fractions affords 115 g (100%) of the desired product as a colorless, viscous oil. 1H NMR (CDCl3) δ: 7.23 (m, 2H), 6.72 (m, 3H), 4.14 (q, J=7 Hz, 2H), 3.72 (t, J=6 Hz, 2H), 3.43 (t, 7 Hz, 2H), 3.34 (t, 7 Hz, 2H), 2.35 (t, 7 Hz), 1.88 (m, 4H), 1.26 (t, 7 Hz, 3H).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1cccc2cc(C(Cl)C3CCCCC3)oc12
Product: COc1cccc2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)oc12
Yield: 7.3 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-7-methoxy-1-benzofuran (401 mg) synthesized in Example A20(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (360 mg) synthesized in Example 2(2) and in the same manner as in Example A7(3), the title object compound (48.7 mg, 7%) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Br:16])=[CH:11][C:10]=1[C:17](=[O:28])[N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[CH3:19])C(OC)=O.O[Li].O.Cl>C1COCC1.O>[Br:16][C:12]1[C:13]([Cl:15])=[CH:14][C:9]([CH2:4][C:3]([OH:29])=[O:2])=[C:10]([C:17](=[O:28])[N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH3:19])[CH:11]=1
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)c(Br)cc1C(=O)N(C)c1ccccc1OC
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1CC(=O)O
Yield: 37 %

Procedure:
A mixture of 2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-malonic acid dimethyl ester (1.4 g, 2.8 mmol) and LiOH.H2O (0.7 g, 16.7 mmol) was stirred at 60° C. in a mixture of THF (20 mL) and water (2 mL) for 24 hrs, then acidified by 1N HCl to pH 4. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and brine, and was dried over MgSO4. The filtrate was then concentrated and purified by silica gel flash column chromatography eluting with 10% MeOH in DCM to yield 2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic acid (427 mg). MS: [M+H]+413.9/412.0; tR=2.60 min (method 1)