Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]([CH2:23][CH3:24])([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=3)[CH2:13][CH3:14])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:17]([CH3:22])[CH:16]=3)([CH2:13][CH3:14])[CH2:23][CH3:24])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
2-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzooxazole-6-carboxylic acid methyl ester (1.20 g, 3.38 mmol) in acetone (40 mL) is treated with 1-bromopinacolone (0.73 g, 4.06 mmol) and K2CO3 (0.93 g, 6.76 mmol). The suspension is stirred at RT for 4 h. The mixture is filtered, and the filtrate is concentrated. The residue is purified using silica gel column chromatography (15% EtOAc/Hex) to give the title compound as a pale yellow oil (1.50 g, 98%). H-NMR (ppm, CDCl3) δ: 8.14 (1H, d, J=2.4 Hz), 8.07 (1H, dd, J=1.2, 8.4 Hz), 7.78 (1H, d, J=8.4 Hz), 7.05 (1H, d, J=1.6 Hz), 7.00 (1H, dd, J=2.4, 8.4 Hz), 6.56 (1H, d, J=8.4 Hz), 4.87 (2H, s), 3.96 (3H, s), 2.40 (2H, q, J=7.5 Hz), 2.30 (2. H, q, J=7.5 Hz), 2.28 (3H, s), 1.27 (9H, s), 0.77 (6H, t, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].CS([C:42]1[N:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][N:43]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:42]3[N:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][N:43]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: COc1cnc(S(C)(=O)=O)nc1
Product: COc1cnc(Oc2cc3c(cc2OC)CCN(CC(=O)NC2CCc4ccccc42)C3Cc2ccc(OC)c(OC)c2)nc1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-methane-sulfonyl-5-methoxy-pyrimidine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:34](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:34][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNCCCc5ccccc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNCCCc5ccccc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 83.8 %

Procedure:
[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]phenylpropylamine is prepared as described in Example 179a starting with 0.115 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]phenylpropylamine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.85 cm3 of 5N potassium hydroxide. 0.072 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-phenylpropylamine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:18][CH:19]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:18][CH:19]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Nc1ccc(CCCC(=O)O)nc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(CCCC(=O)O)nc2)cc1
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A solution of 4-methoxybenzenesulphonyl chloride (2.06 g) and 4-(5-aminopyrid-2-yl)butanoic acid (1.8 g) in pyridine (15 ml) was allowed to stand at room temperature for 18 hours. The solvent was removed and the residue was dissolved in water and treated with dilute hydrochloric acid to give a solution at pH 4.5. The resulting precipitate was collected and recrystallised from ethanol to give the title compound (1.96 g) as prisms. m.p. 129°-130° C.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][CH:22]=2)=[C:10]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:9]=1[O:38]C)(=[O:7])[CH3:6].O>C(Cl)Cl>[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][CH:22]=2)=[C:10]([CH2:32][CH2:33][C:34]([F:36])([F:35])[F:37])[C:9]=1[OH:38])(=[O:7])[CH3:6]
Reactant: COC(=O)C(=O)Nc1cccc(OCCCOc2ccc(C(C)=O)c(OC)c2CCC(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3.0 g of boron tribromide are added dropwise to a solution, cooled to -78° C., of 2.2 g of methyl N-{{3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-phenyl}}-oxamate in 20 ml of methylene chloride in the course of 5 minutes. The mixture is then stirred at room temperature for 6 hours. 5 ml of water are added, with cooling, and the organic phase is separated off and evaporated under reduced pressure. Recrystallisation from methylene chloride/ether gives methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-phenyl}}-oxamate.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][S:6][CH:7]=1)#[N:2].Cl.Cl.[C:10]1(N)[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[OH-].[Na+].C1(N)C=CC=CC=1N>O>[CH:14]1[CH:15]=[CH:10][C:11]2[N:16]=[C:1]([C:3]3[N:4]=[CH:5][S:6][CH:7]=3)[NH:2][C:12]=2[CH:13]=1
Reactant: N#Cc1cscn1
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2[nH]c(-c3cscn3)nc2c1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a 1 liter four-neck flask equipped with a mechanical stirrer, a condenser, pH probe and thermometer were added 54 grams (0.5 mole) of 4-cyanothiazole, 90.5 grams (0.5 mole) of o-phenylenediamine dihydrochloride and 250 ml of deionized water. Sodium hydroxide pellets were added in sufficient proportion to increase the pH of the reaction mixture to a value of 4.0. The mixture was heated to reflux and held at reflux (100°-102° C.) for 4 hours. The reaction was determined to be complete when the peaks corresponding to o-phenylenediamine and 4-cyanothiazole were absent from the gas chromatogram. The reaction mass was allowed to cool to room temperature before adding 0.1N NaOH to adjust the pH to a value within a range of 8-10. The product was filtered, washed three times with 300 ml portions of deionized water, and then dried overnight in a vacuum oven. A total of 78.0 grams of thiabendazole were obtained which corresponds to a 77.5% yield.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:13].[Na+].O>CO>[OH:13][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: CC(Br)C(=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)C(=O)c1ccccc1
Yield: 62.8 %

Procedure:
To a solution of 2-bromo-1-phenylpropan-1-one (6.0 g, 28.2 mmol) in methanol (50 mL) was added sodium formate (7.66 g, 113 mmol) and the mixture was heated under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (2.66 g, yield 63%) as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:20]([CH3:33])[CH:19]=1>C1(C)C=CC=CC=1>[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[C:20]([CH3:33])[CH:19]=1
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (150 mg, 1.34 mmol), 1,2,3,4-tetrahydroisoquinoline (107 mg, 0.8 mmol) and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (200 mg, 0.67 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. (113.20 mg, 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Cl.[NH2:25][C@H:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([NH2:29])=[O:28]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:25]([C@H:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([NH2:29])=[O:28])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NC(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)[C@@H](c1ccccc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2 g, 0.01 mol), methanol (20 mL, 0.5 mol), triethylamine (3 mL, 0.02 mol) and (R)-2-amino-2-phenylacetamide hydrochloride (2.3 g, 0.012 mol) and the reaction heated at 50° C. for 3 hours. The starting material disappeared and the solvent was removed under reduced pressure and the residue purified by flash chromatography (40 g silica gel, 0-10% MeOH/DCM) to obtain the product as a brown solid. MS m/z=324.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:6]([C@H:9]([C@H:12]([CH3:14])[OH:13])[O:10][CH3:11])[O:7][CH3:8])[CH:4]=[O:5].N1C=CN=C1.Cl[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[C:24]([Si:21]([CH3:23])([CH3:22])[O:5][C@H:4]1[C@H:3]([O:2][CH3:1])[C@H:6]([O:7][CH3:8])[C@@H:9]([O:10][CH3:11])[C@H:12]([CH3:14])[O:13]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CO[C@H]([C@@H](OC)[C@H](C=O)OC)[C@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1OC
Reaction time: 72 h
Yield: 41.2 %

Procedure:
Tri-O-methylrhamnose (20.0 g, 97.0 mmol) was dissolved in CH2Cl2 (400 mL) and treated with imidazole (10.0 g, 147 mmol) and chloro-tert-butyldimethyl silane (TBSCl; 20.0 g, 132 mmol). After 3 days (d), the reaction mixture was partitioned between water (H2O) and CH2Cl2, and the organic layer was washed with brine, dried over sodium sulfate (Na2SO4) and concentrated. The crude residue was further purified by chromatography on silica gel (10-20% ethyl acetate (EtOAc) in petroleum ether as eluant) to give the title compound (12.8 g, 82%) as a clear syrup in a 20:80 α:β ratio. The physical properties of the major β-epimer are: 1H NMR (CDCl3) δ 4.55 (s, 1H), 3.58 (s, 3H), 3.48 (m, 1H), 3.45 (s, 3H), 3.40 (s, 3H), 3.00 (m, 3H), 1.24 (d, J=6.2 Hz, 3H), 0.80 (s, 9H), 0.05 (s, 6H); EIMS m/z 263 ([M-tBu]+, 1), 88 (100).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:6](=[O:18])[N:5]=[C:4](SC)[N:3]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:6](=[O:18])[N:5]=[C:4]([N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[N:3]=1
Reactant: CSc1nc(C)n(Cc2ccc(C(F)(F)F)s2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 97.1 %

Procedure:
6-Methyl-4-(methylthio)-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (309 mg, 0.962 mmol) synthesized in Reference Synthesis Example 292 and tert-butyl piperazine-1-carboxylate (269 mg, 1.44 mmol) were used to obtain the title compound (429 mg, yield 97%) by synthesis in a similar manner to Reference Synthesis Example 348.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2>CO>[Cl:3][C:4]1[CH:13]=[C:12]([I:1])[C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2
Reactant: Cc1ccc2c(Cl)ccc(O)c2n1
Reactant: ClI
Solvent: CO
Product: Cc1ccc2c(Cl)cc(I)c(O)c2n1
Reaction time: 3 h
Yield: 88 %

Procedure:
Iodine monochloride (19.0 g) is added to a solution of 5-chloro-8-hydroxy-2-methylquinoline (21.5 g) in 250 mL of MeOH, and the resulting mixture is stirred for 3 h. Additional iodine monochloride (4.5 g) is then added, and the mixture is stirred for another 18 h. The reaction mixture is quenched with sat'd Na2SO3 (aq), then neutralized with sat'd NaHCO3 (aq). The solid precipitate is collected by filtration and dried under vacuum to give 31.22 g of the title compound as a pale green solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH2:13][C:14]#[N:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:17][CH2:18][O:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:7]1([CH:13]([CH2:17][CH2:18][O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]#[N:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCc1ccccc1
Reactant: C[Si](C)(C)OCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)OCCC(C#N)c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of potassium tert-butoxide (12.3 g) in toluene (200 mL) was treated dropwise with a mixture of phenylacetonitrile (12.9 g) and (2-bromoethoxy)trimethyl-silane (23.8 g) at room temperature. Upon completion of the addition, the reaction mixture was refluxed for 5 h, then cooled to room temperature and quenched by pouring onto a mixture of ice and water. The formed organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give 2-phenyl-4-trimethylsilanyloxy-butyronitrile. The obtained butyronitrile derivative was redissolved in a mixture of ethanol (40 mL) and 70% aqueous sulfuric acid (40 mL), stirred at 50° C. for 3 h and, after cooling to room temperature, diluted with water (150 mL). The resulted organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, then with saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.0 g (62%) of the title compound.
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)CCC>O1CCOCC1.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>[CH3:14][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[C:5]1[CH:17]=[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:2]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:3][C:4]2=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(-c3ccccn3)cc21
Temperature: 120 °C
Yield: 62.2 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.193 mmol) in 1,4-dioxane (2 mL) was added 2-(tributylstannyl)pyridine (85 mg, 0.231 mmol) and Pd(PPh3)4 (11.14 mg, 9.64 μmol). The reaction mixture was degassed for 30 min and heated to 120° C. for 1 h in a microwave. The reaction mixture was cooled and diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (3% methanol in chloroform) to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-9-(pyridin-2-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.120 mmol, 62% yield) as a pale yellow solid which was carried on without further purification LC/MS (ESI) m/e 517.7 [(M+H)+, calcd for C30H37N4O4 517.3]; LC/MS retention time (method E): tR=1.19 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 106.6 %

Procedure:
According to the general procedure A described above, 4-chloroanisole (130 mg, 0.92 mmol) reacted with diphenylamine (169 mg, 1.00 mmol) at 80° C. for 12 h using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 catalyst and sodium tert-butoxide to give the title compound (270 mg, 99%) as a solid: 1H-NMR (300 MHz, CDCl3): δ 7.30 (app.t, 4H, J=7.5 and 8.1 Hz), 7.17 (app.t, 6H, J=8.4 and 9.0 Hz), 7.04 (app.t, 2H, J=7.2 and 6.9 Hz), 6.94 (d, 2H, J=9.0 Hz), 3.88 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 156.11, 148.13, 140.74, 129.04, 127.26, 122.84, 121.78, 114.71, 55.44. GC/MS(EI): m/z 275 (M+).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][CH2:6][CH2:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.O>C(O)(=O)C>[OH:5][CH2:6][CH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1
Reactant: OCCc1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: OCCC1Cc2ccccc2N1
Reaction time: 24 h
Yield: 98.8 %

Procedure:
Sodium cyanoborohydride (63 g) is added in portions to a stirred solution of 2-(2-hydroxyethyl)indole (43 g) in acetic acid (750 cc), whilst cooling the reaction mixture with a bath of cold water so as not to exceed 20° C. The mixture is stirred for 24 hours at this temperature. It is then concentrated to about 100 cc at 50° C. under reduced pressure (20 mm Hg). The residue is taken up in a mixture of water and ice (500 cc), the resulting mixture is rendered alkaline to pH 10 with an aqueous solution of sodium hydroxide and extraction is carried out with diethyl ether (3×300 cc). The organic extracts are combined, washed with water (50 cc), dried over magnesium sulphate and filtered and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). 2-(2-Hydroxyethyl)indoline (43 g) is obtained in the form of a yellow oil (mass spectrum m/e=163).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[O:35][C:34]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:31])=[O:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1>C(Cl)(Cl)Cl>[CH2:12]1[O:35][C:34]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:31])(=[O:9])=[O:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1
Reactant: CS(=O)c1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of 0.65 g (3.8 mmol) of m-chloroperbenzoic acid in 20 ml of chloroform was dropped into a solution of 1.00 g (2.93 mmol) of the 4-(3,4-methylenedioxybenzyl)amino-6-methylsulfinylquinazoline prepared in Example 137 under stirring at room temperature. The obtained mixture was stirred at room temperature for several hours, washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was purified by silica gel column chromatography (ethyl acetate) and recrystallized from chloroform/n-hexane to give 0.85 g of the title compound as a yellow crystal.
Reaction SMILES: O[CH2:2][C:3]1[NH:7][N:6]=[C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=1.[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=O>C(Cl)(Cl)Cl.C1(C)C(C)=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]1[N:7]2[N:6]=[C:5]([O:8][S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:4]=[C:3]2[CH:2]=[N:25][N:24]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(CO)[nH]n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Oc2cc3cnnc(-c4ccccc4F)n3n2)cc1
Temperature: 70 °C
Yield: 92.4 %

Procedure:
To a solution of toluene-4-sulfonic acid 5-hydroxymethyl-1H-pyrazol-3-yl ester (25 g, 93 mmol) in chloroform (800 ml) was added manganese dioxide (40.3 g, 465 mmol) and the suspension was heated at 70° C. for 14 h. The reaction mixture was filtered through sand/silica and the plug of silica was then washed several times with 10% methanol/dichloromethane. The combined filtrates were concentrated under vacuum to give crude aldehyde (25 g). Some of the crude aldehyde (2 g, 7.6 mmol) and 2-fluorobenzoic hydrazide (1.16 g, 7.6 mmol) were suspended in xylene (60 ml) and heated together at reflux for 3 h. After cooling, the solid formed was collected by filtration and dried under vacuum at 80° C. to afford 2.7 g (94%) of the condensation product as a light brown solid. Some of this condensation product, which existed in nmr solution as a mixture of isomers (1 g, 2.5 mmol), was dissolved in Dowtherm A (100 ml) and heated at 180° C. for 72 h. The whole reaction solution was cooled and eluted through a silica gel column using 0 to 15% ethyl acetate/dichloromethane to give the title compound as a light tan solid (0.614 g, 64%); 1H NMR (360 MHz, CDCl3) δ 2.46 (3H, s), 6.73 (1H, s), 7.18-7.35 (4H, m), 7.61 (1H, m), 7.71 (1H, m), 7.82 (2H, d, J 8.3 Hz), 9.33 (1H, s).