Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=1)[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:33]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=1)[S:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:33]
Reactant: OO
Reactant: COc1ccccc1OCCNCC(Sc1ccccc1)c1ccc(C)c(S(N)(=O)=O)c1
Solvent: CC(=O)O
Product: COc1ccccc1OCCNCC(c1ccc(C)c(S(N)(=O)=O)c1)S(=O)c1ccccc1

Procedure:
In 20 ml of acetic acid was dissolved 2 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamide and after adding thereto 0.5 ml of 30% H2O2, the mixture was heated to 50°-60° C. for 3 hours. After adding thereto 100 ml of water, the reaction mixture was extracted with 200 ml of ethyl acetate. The ethyl acetate extract was washed with an aqueous 1% sodium carbonate solution and then ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, the product was eluted with a mixed solvent of chloroform and methanol (9:1 by volume ratio), and the colorless viscous oily product thus obtained was crystallized by the addition of ethyl acetate. The crystals formed were recovered by filtration to provide 1.3 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylsulfinylethyl}-2-methylbenzenesulfonamide.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4C)c3O2)cc1
Agent: [Na+]
Product: Cc1ccccc1-c1c(Cl)ccc2c1OC(CN=[N+]=[N-])C2
Yield: 99 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 m]L) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.
Reaction SMILES: [O:1]1[C:11]2[CH:10]=[C:9]([CH2:12][OH:13])[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[O:1]1[C:11]2[CH:10]=[C:9]([CH:12]=[O:13])[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCCCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2c(cn1)OCCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
To a solution of 13 g of (3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-yl)methanol in 250 mL of chloroform, 13 g of manganese dioxide was added, and the mixture was stirred at room temperature for 30 minutes. Thereto was further added 20 g of manganese dioxide dividedly, the mixture was then stirred at room temperature for 20 minutes and at 60 to 70° C. for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, the insoluble substance was then filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 2.2 g of 3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridine-8-carbaldehyde as a light yellowish white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>ClCCl>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1S(C)(=O)=O
Temperature: 25 °C

Procedure:
10-Methoxyharmalan (646 mg, 3 mmol) is dissolved in dry dichloromethane (40 ml). Triethylamine (1 ml, 7.2 mmol) and then, dropwise, mesyl chloride (0.25 ml, 3.2 mmol) are successively added with stirring at room temperature under a nitrogen atmosphere. The mixture is stirred for 4 hours at room temperature. Subsequently, after removal of the dichloromethane, the residue is subjected to flash chromatography on a silica column (AcOEt/PE, 50/50). 1-Methylene-2-mesyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline is thus obtained (350 mg, Y=40%).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[C:29]([CH3:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:27][CH2:26][C:25]4[C:21](=[CH:22][NH:23][N:24]=4)[CH2:20]3)[C:15]2=[O:28])=[C:11]([CH3:32])[CH:10]=1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:30]=[C:29]([CH3:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:27][CH2:26][C:25]4[C:21](=[CH:22][NH:23][N:24]=4)[CH2:20]3)[C:15]2=[O:28])=[C:11]([CH3:32])[CH:10]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C[C@@H]1CCN(C2CCc3n[nH]cc3C2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(O)cc(C)c1C[C@@H]1CCN(C2CCc3n[nH]cc3C2)C1=O
Reaction time: 48 h
Yield: 65.9 %

Procedure:
Treat a solution of (R)-3-(4-Benzyloxy-2,6-dimethyl-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (Preparation 64) (1.65 g, 3.8 mmol) in EtOH (20 mL) with Palladium Hydroxide on carbon (1.7 g). Purge the solution with Hydrogen and pressurize to 35 psi. The reaction stirs 2 days at 35 psi of hydrogen. Filter the reaction through celite to remove catalyst. Purify the crude by silica gel column chromatography using CH2Cl2 and 2M Ammonia in MeOH to elute the pure product. Remove the solvent to afford 0.85 g (65%) of desired product. MS (m/e): 340 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[F:18][C:19]([F:27])([F:26])[C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH3:23])[C:21]([C:20](=[O:25])[C:19]([F:27])([F:26])[F:18])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 80 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-(4-fluoro-phenyl)-methanone [example A2] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 80%; MS: m/z=411/413 (M).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([NH2:9])(=[O:8])=[O:7])=[CH:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>CC(C)=O.Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccsc1
Yield: 73.5 %

Procedure:
Procedure of Example 4B was followed with 3-thiophenesulfonamide (1.1 g, 6.81 mmole), acetone (10 ml), 1N NaOH (6.8 ml), 4-chlorophenyl isocyanate (1.05 g, 6.8 mmole) in acetone (10 ml), 1N HCl (8 ml) to give the N-[[(4-chlorophenyl)amino]carbonyl]-3-thiophenesulfonamide (1.44 g, 4 5 mmole).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[N:33]=1.O>C(#N)C>[Br:30][CH2:31][C:32]1[N:33]=[C:34]([CH2:38][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]3[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:12]([NH:14][CH:15]3[CH2:16][CH2:17]3)=[O:13])=[O:7])=[CH:22][CH:23]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: BrCc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CBr)n2)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To 3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (1.50 g, 4.84 mmol) and potassium carbonate (3.34 g, 24.2 mmol) in refluxing acetonitrile (20 mL) was added a solution of 2,6-bis(bromomethyl)pyridine (5.13 g, 19.4 mmol) in acetonitrile (10 mL) over 25 mins. The reaction was cooled to room temperature and water (20 mL) was added. The mixture was extracted with DCM (3×30 mL) and the organic layers were combine and evaporated to leave a solid which was triturated with hot ethyl acetate to give 3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamide as a white solid (1.449 g, 61%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.70 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 4.73 (s, 2H), 5.30 (s, 2H), 7.19 (d, 2H), 7.32 (d, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.65 (d, 1H), 7.81 (s, 1H), 7.90 (t, 1H)7.98 (d, 2H), 8.38 (d, 1H), 9.85 (s, 1H); Mass Spectrum: M+H+ 494, 496 Br pattern.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH3:23])[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:24][CH3:25])(=[O:9])=[O:10])=[C:15]([CH3:23])[CH:16]=2)=[O:21])=[CH:37][CH:36]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(C)cc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carboxylic acid (150 mg, 0.393 mmol), ethyl 4-aminobenzoate (130 mg, 0.786 mmol), 4-methylmorpholine (199 mg, 1.96 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (224 mg, 0.589 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (49 mg, 0.39 mmol) was added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester (190 mg, 91%). White solid, MS (ISP): m/e 529.2 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)[N:18]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[CH:17]=2)=[O:15])=[N:10][CH:9]=1)C.C1(CN2C3C(=CC=C(F)C=3)C(C(NC3SC=C(SCC(O)=O)N=3)=O)=C2)CC1>>[CH:30]1([CH2:29][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:16]([C:14]([NH:13][C:11]3[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:9][N:10]=3)=[O:15])=[CH:17]2)[CH2:31][CH2:32]1
Reactant: CCOC(=O)CCSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(C(F)(F)F)ccc23)s1
Agent: O=C(O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Product: O=C(O)CCSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(C(F)(F)F)ccc23)s1

Procedure:
3-{2-[(1-Cyclopropylmethyl-6-trifluoromethyl-1H-indole-3-carbonyl)-amino]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester was hydrolysed according to the procedure given in the procedure for the synthesis of {2-[(1-cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol4-ylsulfanyl}-acetic acid
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[C:11](=[N:24][NH2:25])([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.C([O-])(=O)C.[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:10][C:4]1[CH:3]=[C:2]([NH:25][N:24]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([F:8])[C:5]=1[F:9]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: Fc1cc(NN=C(c2ccccc2)c2ccccc2)cc(F)c1F
Temperature: 86 °C
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
1-Bromo-3,4,5 trifluorobenzene (5 g, 24 mmol) was added to a slurry of Pd(OAc)2 (0.269 g, 5 mol %), bisdiphenylphosphino-ferrocene (1.0 g, 7 mol %) in anhydrous toluene (50 mL) at rt. Benzophenone hydrazone (4.9 g) was added, stirred for 5 min following by addition of dried cesium acetate (9.33 g) and toluene (40 mL). The flask was removed from a glove box and heated to 86° C. for 72 hours. The reaction was monitored by disappearance of bromotrifluourobenzene by LC (210 nm) or 19F NMR. The reaction mixture was cooled down to room temperature and filtered through a sintered glass funnel. The solvent was removed under the vacuum. The orange solid residue was re-dispersed in ether (15 mL) and hexane (150 mL) and heated up to 58° C., stirred for 20 min. The hot solution was quickly filtered, solid discarded and the solution was allowed to cool to room temperature, stirred for 30 min, then 1 hour at 4° C. The formed slurry was filtered, washed with cold hexane (2×25 mL). Crystals were dried in air then in the vacuum at 80° C. for 1 hour to give 5 g of diphenylmethanone (3,4,5-trifluorophenyl)hydrazone (64% yield) as a yellowish solid.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:24][CH:25]([CH3:60])[C:26]([NH:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[NH:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[C:47]([Cl:59])[CH:46]=1)=[O:27]>C1COCC1>[Cl:59][C:47]1[CH:46]=[C:45]([NH:44][C:32]2[C:31]3[C:36](=[CH:37][C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[C:29]([NH:28][C:26]([C@H:25]([NH:24][C:1](=[O:5])[CH:2]=[CH2:3])[CH3:60])=[O:27])[CH:30]=3)[N:35]=[CH:34][N:33]=2)[CH:50]=[CH:49][C:48]=1[O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)C(C)N
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)N[C@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
75 μl of acrylic acid was dissolved in 4 ml of THF, and cooled to 0° C. 180 μl of pyridine and 520 ml of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added thereto, the resulting solution was reacted with 284 mg of 2-amino-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxy-ethoxy)-quinazolin-6-yl]-propionamide dissolved in 4 ml of THF as a starting material for 30 mins, and then stirred for 3 hours while heating to room temperature. The reacted solution was washed with saturated sodium bicarbonate solution, extracted with a mixture of chloroform and methanol, dried over sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (87 mg, 28%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>ClCCl>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:23])[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(O)ccn1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=c1c(Br)c(O)ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of N-benzyl-4-hydroxy-2-pyridone ((0.75 g, 3.7 mmol), NBS (0.7 g, 1.05 mmol) in dichloromethane was stirred at room temperature for 1.5 h under argon atmosphere. It was diluted with dichloromethane (25 mL), cooled and filtered. The solids were washed with dichloromethane and dried in vacuo. The filtrate and the washings were combined and washed with water, dried (Na2SO4), filtered, and concentrated to dryness. The resulting residue was washed with EtOAc, and dried in vacuo to give a combined mass of 0.65 g of the title compound as a white powder: 1H NMR (CD3OD) δ: 7.54 (d, 1H, J=7.6 Hz), 7.27 (m, 5H), 6.12 (d, 1H, J=7-6 Hz), 5.15 (s, 2H); ES-MS: m/z=280 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][O:8][CH2:9]Cl)=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[N:16][C:17](=[O:20])[NH:18][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][O:8][CH2:9][N:18]2[CH:19]=[C:14]([Cl:13])[CH:15]=[N:16][C:17]2=[O:20])=[CH:5][CH:4]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COc1ccc(COCCl)cc1
Product: COc1ccc(COCn2cc(Cl)cnc2=O)cc1
Yield: 52 %

Procedure:
was prepared as described in Example 3 from chloromethyl 4-methoxybenzyl ether (see Preparation 4a and 4b) (10 mmol) and 5-chloropyrimidin-2-one (10 mmol) in 52% yield (1.45 g), m.p. 118° C. 1H NMR (CDCl3): δ3.77 (OMe), 4.57 (CH2Ph), 5.27 (CH2O), 6.6-7.3 (Ph), 7.63 and 8.35 (H-4, H-6, J 4 Hz). IR(KBr): 1670 cm1 (CO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH3:26][O:27][CH2:28][O:29][C:30]1[CH:47]=[CH:46][C:33]([CH:34](O)[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:44][O:43][CH2:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH:34]([C:33]2[CH:46]=[CH:47][C:30]([O:29][CH2:28][O:27][CH3:26])=[CH:31][CH:32]=2)[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[S:14]([N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:13][CH2:12]2)(=[O:16])=[O:15])=[CH:40][CH:39]=1
Reactant: O=S(=O)(c1cc2ccccc2[nH]1)N1CCN(c2ccccc2Cl)CC1
Reactant: COCOc1ccc(C(O)c2ccc(OCOC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.9 %

Procedure:
Boron trifluoride-ether complex (0.04 ml, 0.32 mmol) was added to a solution of 2-[4-(2-chlorophenyl)piperazinylsulfonyl]indole (1.2 g, 3.19 mmol) in 15 ml of methylene chloride, and a solution of 4,4'-bis(methoxymethoxy)benzhydrol (991 mg, 3.26 mmol) in 10 ml of methylene chloride was added thereto, followed by stirring at room temperature for 20 hours. Then, a solution of 4,4'-bis(methoxymethoxy)benzhydrol (490 mg, 1.60 mmol) in 10 ml of methylene chloride was further added to the reaction mixture to complete the reaction. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization followed by extraction with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was crystallized from diisopropyl ether/hexane to give 1.9 g (yield: 90%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C=O.ClC1C=CC=C(C(OO)=[O:27])C=1.C(=O)(O)[O-].[Na+].S(=O)(O)[O-].[Na+].[OH-].[K+]>ClCCl.CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:27])[CH:7]=[C:8]([CH3:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)cc(C)c1OCc1ccccc1
Yield: 47.3 %

Procedure:
A solution of 18.0 g (75 mmol) of 3,5-dimethyl-4-(phenylmethoxy)benzaldehyde (Example F) and 17.1 g of 85% meta-chloroperbenzoic acid (14.5 g contained; 1.2×75 mmol) in 600 mL of dichloromethane is stirred at reflux for 16 hours. The cooled solution is stirred with 2×150 mL saturated sodium bicarbonate solution, 150 mL of 10% sodium bisulfite solution, then dried (magnesium sulfate) and evaporated leaving 15.2 g of a turbid oil. A solution of the latter in 225 mL of methanol is stirred at ambient temperature with a solution of 12.6 g (3×75 mmol) of potassium hydroxide in 75 mL of water. After 18 hours the methanol is removed on a rotary evaporator and the residual aqueous solution is diluted with 200 mL of water, and back-extracted with 150 mL of diethyl ether. The aqueous solution is acidified with 50 mL of 6N hydrochloric acid solution and the product is isolated with diethyl ether. The diethyl ether solution is washed with brine, dried (magnesium sulfate) and evaporated leaving 8.1 g of a brown solid. The original diethyl ether extract is dried (magnesium sulfate) and evaporated leaving 10.7 g of a light yellow viscous oil. The two fractions are combined and the crude precipitate is chromatographed on a 4.5 cm column containing 250 g of silica gel prepared in toluene. Elution with 98% toluene:2% ethyl acetate affords 16.6 g of the product. Recrystallization from cyclohexane affords the title compound as off-white leaflets; mp 89°-91° C.