Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][CH:8]=2)[N:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:27][Cr](O[Cr]([O-])(=O)=O)(=O)=O.CN(C=O)C>O>[Cl:1][C:2]1[C:11]([C:12]([OH:27])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=Cc1cc2ccc(Cl)cc2nc1Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc2ccc(Cl)cc2nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
A dry reaction flask equipped with a magnetic stirring bar and a rubber septum was charged with 2,7-dichloro-3-formylquinoline 3 (1.1 g, 5 mmol), PDC (3.76 g, 10 mmol) and dry DMF (5 mL) and stirred at room temperature for 24 h. The reaction mixture was diluted with water (500 mL), filtered, the filtrate was saturated with NaCl and the resulting aqueous solution was extracted with EtOAc (3×200 mL). The EtOAc extract was dried over anhydrous Na2SO4 and solvent was removed to give 1.02 g (85%) of the desired 2,7-dichloroquinoline-3-carboxylic acid 4. TLC Rf: 0.12 (20% MeOH/EtOAc); 1H NMR (acetone d6): 8.96 (s, 1H); 8.22 (d, 1H, J=9.0 Hz), 8.04 (d, 1H, J=1.8 Hz), 7.97 (bs, 1H), 7.74 (dd, 1H, J=1.8 and 8.7 Hz); LCMS (ret. time): 25.15 min.; MS (m/z): 241 (MH+).
Reaction SMILES: CNCC1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:5]=1.C1[N:25]=[CH:24][N:23]([C:26]([N:28]2C=N[CH:30]=[CH:29]2)=[O:27])[CH:22]=1.[NH2:33]C(N)=N>C1COCC1>[CH3:20][S:17]([OH:18])(=[O:19])=[O:27].[CH3:22][N:23]([C:26]([NH:28][CH2:29][C:30]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:5]=1)=[O:27])[C:24]([NH2:25])=[NH:33]
Reactant: CNCc1ccc(Oc2ccccc2)c(S(C)(=O)=O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(N)N
Solvent: C1CCOC1
Product: CN(C(=N)N)C(=O)NCc1ccc(Oc2ccccc2)c(S(C)(=O)=O)c1
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of N-methyl-N-(3-methylsulfonyl-4-phenoxybenzyl)amine and 0.7 g of CDI dissolved in 25 ml of THF were stirred at RT for 2 h. 1.1 g of guanidine were added, the mixture was stirred overnight and the solvent was distilled off on a rotary evaporator. The residue was taken up in 100 ml of water, adjusted to pH 7.6 with 10 percent hydrochloric acid and extracted twice with ethyl acetate. After concentrating, the guanidine derivative obtained was dissolved again in ethyl acetate, and by adding the equivalent amount of methanesulfonic acid was precipitated as the methanesulfonate. 0.8 g of N-methyl-N-(3-methylsulfonyl-4-phenoxybenzyl)aminocarbonylguanidine methanesulfonate was obtained;
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCCCC1
Yield: 26.2 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) and piperidine (0.109 mL, 1.104 mmol) were reacted as described in Example 73. Isolated yield of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (57 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.20 (m, 2H), 4.00 (s, 3H), 2.50-2.25 (m, 6H), 1.95 (m, 2H), 1.60-1.30 (m, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:26]([Br:27])=[CH:25][C:10]2[C:11]([C:21]([O:23][CH3:24])=[O:22])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1.N1C=CC=CC=1>ClCCl.O>[Br:27][C:26]1[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:11]([C:21]([O:23][CH3:24])=[O:22])[C:10]=2[CH:25]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(Br)cc12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
MsCl (4.8 g, 41.2 mmol) was added to a solution of methyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (5.0 g, 13.4 mmol) and pyridine (5.4 g, 68.7 mL) in dry dichloromethane (50 mL) at 0° C. After stirred overnight at room temperature, the mixture was diluted with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography to provide methyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (5.3 g, yield: 83%). 1H-NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.99˜8.03 (m, 2H), 7.83 (s, 1H), 7.11˜7.16 (m, 2H), 6.82 (br s, 1H), 3.90 (s, 3H), 2.96 (s, 3H). MS (M+H)+: 442/444.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:21])[CH2:10][CH2:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.C(Cl)(Cl)(Cl)Cl.[Br:28]Br>Br.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:21])[CH2:10][CH:11]([C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=1)[Br:28]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CCC(=O)c1ccc(Br)cc1
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=O)CC(Br)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.52 g. of 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl ester (Example 29) in 50 ml. of carbon tetrachloride is added dropwise a solution of 0.51 ml. of bromine in 20 ml. of carbon tetrachloride. After 30 minutes 2 drops of 30% hydrobromic acid in acetic acid is added and the mixture is stirred at room temperature for 2 hours. The solvent is decanted from the resulting gum. The gum is dissolved in dichloromethane, washed twice with water, once with sodium chloride solution, dried over magnesium sulfate and clarified with charcoal. The filtrate is evaporated to dryness in vacuo giving the desired product as 3.87 g. of a gum.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:8][C:9]([C:11]1[O:12][C:13](CCl)=[CH:14][CH:15]=1)=[O:10])[CH3:7].[CH3:18]N(C)C(=O)C>>[CH2:6]([O:8][C:9]([C:11]1[O:12][C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][C:15]=1[CH3:18])=[O:10])[CH3:7]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CC(=O)N(C)C
Product: CCOC(=O)c1oc(N2CCCC2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
Pyrrolidine (0.75 g, 10.6 mmol) was added to an N,N-dimethylacetamide (15 ml) solution of 5-chloromethylfuran-2-carboxylic acid ethyl ester (1.0 g, 5.3 mmol), and stirred at room temperature for 24 hours. The solvent was evaporated, and the residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2) to afford 5-pyrrolidine-1-yl-methyl-furan-2-carboxylic acid ethyl ester (793 mg, 67%).
Reaction SMILES: CS(C)=[O:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2N=C(C(F)(F)F)N[C:32]=2[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:24][CH:23]=1)(=O)=O.C(N(CC)CC)C.[OH2:50]>C(Cl)Cl>[CH3:18][S:19][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:3])[C:32]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:50])=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)[nH]c2-c2cccnc2)cc1
Reactant: CS(C)=O
Reactant: O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CSc1ccc(C(=O)C(=O)c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A solution of dimethylsulphoxide (30 mmol, 2.13 ml) in methylene chloride (90 ml) was cooled to −65° C. Trifluoroacetic acid anhydride (20 mmol, 2.82 ml) was added over 3 minutes, then stirred 10 minutes. 2-Hydroxy-1-[4-(methylthio)phenyl]-2-(3-pyridyl)-ethanone (step 2) (10 mmol, 2.59 g) was suspended in ca 10 ml of methylene chloride and rinsed into the reaction vessel using ca 5 ml additional solvent. After 40 minutes, triethylamine (58 mmol, 8.07 ml) was added. The mixture was warmed to 0° C. over 30 minutes, with continued stirring, then-diluted with water (100 ml) and extracted with ethyl acetate (200, then 2×50 ml). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and subjected to chromatography (2:1 hexane:ethyl acetate), affording the title compound as a yellow solid (2.43 g, 94%), which was used in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.CN(C)C=O.Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[CH3:25])=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:17]=1>O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:18]2[N:17]=[C:16]([N:5]3[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]3)[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH3:25])=[CH:32][CH:31]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Temperature: 120 °C
Yield: 13.3 %

Procedure:
Sodium hydride (60% in mineral oil, 160 mg, 4.1 mmol) was added to 3,5-dimethylpyrazole (320 mg, 3.4 mmol) dissolved N,N-dimethylformamide (10 mL) and the mixture was stirred for 30 min. (2-Chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)amine (1.0 g 3.40 mmol) was added and the reaction mixture was heated at 120° C. for 4 days, cooled down and poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol/ammonia) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-amine (160 mg, 13%) as a yellow crystalline compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:23][F:24])[CH:13]([CH3:14])[CH2:12][N:11]([C@@H](C2C=CC=CC=2)C)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd].[H][H]>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:23][F:24])[CH:13]([CH3:14])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CC1CN([C@H](C)c2ccccc2)C[C@@]1(CF)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC1CNC[C@@]1(CF)NC(=O)OC(C)(C)C

Procedure:
To a solution of (3S)-3-(tert-butoxycarbonylamino)-3-fluoromethyl-4-methyl-1-[(1R)-1-phenylethyl]pyrrolidine (200 mg, 0.594 mmol) in ethanol (12 mL) was added 10% palladium-carbon catalyst (containing 52.8% water, 200 mg), and the suspension was stirred in an oil bath at 40° C. for 2 hours in hydrogen gas atmosphere. After removing the catalyst by filtration, the solvent was removed by distillation under reduced pressure to obtain 150 mg (quantitative) of the crude title compound as a white solid.
Reaction SMILES: C(O[C:4](=[O:8])[O:5][CH2:6][CH3:7])C.[H-].[Na+].[Si:11]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH2:33][C:34]2=[O:39])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Si:11]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH:33]([C:4]([O:5][CH2:6][CH3:7])=[O:8])[C:34]2=[O:39])([C:24]([CH3:26])([CH3:27])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1=O
Reaction time: 4 h

Procedure:
To a solution of diethylcarbonate (10.3 ml) and sodium hydride (4.2 g, 60%, in oil) in toluene (300 ml) was added 5-t-butyidiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (17 g) at 100° C. The mixture was stirred for 4 hours at the same temperature and then the cooled solution was washed with sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 5-t-butyldiphenylsilyloxy-2-ethoxycarbonyl-1-oxo-1,2,3,4-tetrahydronaphthalene (20 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18]N)[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.F[C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.CO.C[N:38](C=O)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:30]4[CH:31]=[CH:21][CH:22]=[C:23]5[C:28]([NH:38][C:25](=[O:26])[C:24]=45)=[O:27])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Solvent: CO
Solvent: ClCCl
Product: O=C1NC(=O)c2c(CCN3CCC(c4n[nH]c5cc(F)ccc45)CC3)cccc21
Temperature: 80 °C

Procedure:
To a solution consisting of 2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to 80° C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure (<0.5 mmHg, 55° C.) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186°-188° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.CCN(CC)CC.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:8])[O:7]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (2.0 g, 17.2 mmol) in DCM (20 mL) was added Et3N (4.8 mL, 34.44 mmol) followed by p-toluenesulfonyl chloride (3.61 g, 18.94 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred at the same temperature for 15 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 50% EtOAc/hexane as eluent) to provide compound A94-1 (4.06 g, 87%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Oc2ncnc3cc(OC)c(OC)cc23)c1
Yield: 66 %

Procedure:
In the manner described in Example 159B, ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate from the previous step (0.138 g, 0.4 mmol) was reacted with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]ureido}-1H-pyrazol-1-yl)acetate as solid (0.145 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.59 (s, 1H), 8.56 (s, 1H), 7.59 (m, 1H), 7.56 (s, 1H), 7.39 (m, 2H), 7.22 (d, 1H), 6.94 (d, 1H), 6.11 (s, 1H), 4.85 (s, 2H), 4.16 (q, 2H), 3.99 (s, 6H), 1.19 (t and s, 12H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][CH:24]1[CH2:29][N:28]([CH2:21][CH2:20][CH2:19][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4)C(C)C3)nn2-c2ccccc2)cc1

Procedure:
112 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 2-methyl-1-m-tolylpiperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=2)=[CH:5][CH:6]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[K+]>C(O)(=O)C.O>[C:15]([O:18][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[O:3][C:2]([Br:1])=[CH:6][CH:5]=2)[CH:8]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: BrCc1cccc(-c2ccc(Br)o2)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCc1cccc(-c2ccc(Br)o2)c1
Reaction time: 19 h
Yield: 56 %

Procedure:
A stirred solution of 7.3 g (0.023 mol) of 2-bromo-5-(3-bromomethylphenyl)furan in 50 mL of acetic acid was cooled in an ice-water bath, and 3.4 g (0.035 mol) of potassium acetate was added. Upon complete addition, the reaction mixture was heated to reflux temperature and stirred for 19 hours. The reaction mixture was transferred to a separatory funnel, diluted with 100 mL of water, then extracted with two portions of 150 mL each of chloroform. The combined extracts were washed with one portion of 150 mL of a saturated aqueous solution of sodium chloride, two portions of 150 mL each of a saturated aqueous solution of sodium bicarbonate, and finally with one portion of 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel, eluting with hexane: chloroform (2:1). The appropriate fractions were combined to give 3.8 g of 3-(2-bromo-5-furanyl)phenylmethyl acetate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=[O:32].O>CCCCCC.O1CCCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:31]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[OH:32])[CH:33]=1
Reactant: CC(C)[Si](C#Cc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C#Cc1ccc(C(O)c2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
33.8 ml of a 1.6 M solution of n-butyllithium in hexane are added dropwise under argon to a solution of 17.4 g 1-bromo-4-triisopropylsilylethynyl-benzene in 120 ml dry tetrahydrofuran chilled to −78° C. The solution is stirred for 1 h at −70° C. Then 10.8 g 5-bromo-2-fluoro-benzaldehyde dissolved in 30 ml of tetrahydrofuran are added dropwise over 15 min. The resulting solution is left in the cooling bath to warm up overnight to ambient temperature. Then water is added and the mixture is extracted with ethyl acetate. The combined organic phase are dried over sodium sulphate, and the solvent is removed. The residue is purified through silica gel (cyclohexane/ethyl acetate 4:1).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:13]2[CH:25]=1.O>CS(C)=O>[CH3:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:13]2[CH:25]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nc(C)cn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nc(C)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of 60% sodium hydride (1.10 g, 25.3 mmol) in dimethyl sulfoxide (50 mL) was added trimethylsulfoxonium iodide (5.56 g, 25.3 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methylimidazo[1,2-a]pyridin-5-yl)acrylate (4.85 g, 21.1 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=33/67) to give the title compound (3.40 g, yield 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:16]=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][C:11](SC)=[CH:10][CH:9]=2)[CH:7]=1.O[O:19][S:20]([O-:22])=O.[K+].[CH2:24]1COCC1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:16]=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:20]([CH3:24])(=[O:22])=[O:19])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2cc(F)ccc2C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(F)ccc2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5'-Fluoro-2'-formyl-4-methylthiobiphenyl (10 mmol) (Example 1E) in THF (20 ml) is charged dropwise with oxone® (6 mmol) and tetrabutylammonium hydrogensulfate (1 mmol) in water (15 ml). The mixture is stirred at room temperature for 1 hour. The suspension is poured into water (300 ml), the precipitate is filtered off, is washed with water and is dried in vacuo to give the title product.