Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=1[Cl:24])=O)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:65]([O:67][C:68]([CH:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)=[O:69])[CH3:66]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[CH2:65]([O:67][C:68]([CH:70]1[CH2:75][CH2:74][N:73]([C:21]2[CH:20]=[CH:19][C:18]([Cl:24])=[C:17]([C:9]3[NH:8][C:12]4[CH:13]=[N:14][CH:15]=[CH:16][C:11]=4[N:10]=3)[CH:22]=2)[CH2:72][CH2:71]1)=[O:69])[CH3:66]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(Br)ccc2Cl)nc2ccncc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ccc(Cl)c(-c3nc4ccncc4[nH]3)c2)CC1
Temperature: 80 °C
Yield: 126.7 %

Procedure:
Method C—Step d 2-(5-Bromo-2-chloro-phenyl)-imidazo[4,5-c]pyridine-3-carboxylic acid tert-butyl ester (0.50 g, 1.23 mmol), tris(dibenzylideneacetone) dipalladium(0) (Pd2 dba3) (0.13 g, 0.18 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (0.17 g, 0.37 mmol) and cesium carbonate (1.20 g, 3.68 mmol) were placed into a dried schlenk and few cycles of vacuum/nitrogen were performed. Then dry dioxane (2.00 mL) and piperidine-4-carboxylic acid ethyl ester (0.38 mL, 2.45 mmol) were added, the reaction mixture was heated at 80° C. for 4 h, left cooling to room temperature and filtered through sodium sulphate (Na2SO4). The crude was purified by flash chromatography (eluent gradient: EtOAc 100% to EtOAc:MeOH/95:5), to obtain 0.60 g of a mixture of the title compound and the starting material deprotected (7:3). The mixture was used for the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]=[CH:12][C:13]([NH:15][CH:16]([C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[O:14])=[CH:2]1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]=[CH:12][C:13]([NH:15][CH:16]([C:27]([OH:29])=[O:28])[C:17]([OH:19])=[O:18])=[O:14])=[CH:2]1
Reactant: [H][H]
Reactant: O=C(C=CCc1c[nH]c2ccccc12)NC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=CCc1c[nH]c2ccccc12)NC(C(=O)O)C(=O)O
Yield: 99.2 %

Procedure:
The diester (72) (930 mg, 1.92 mmol), palladium hydroxide on carbon (Pearlman's catalyst) (125 mg) and 95% ethanol (110 mL) were placed in a Parr hydrogenation vessel and subjected to a hydrogen pressure of 45 psi at 25° C. for 3 hours (until the uptake of hydrogen ceased). The reaction mixture was filtered through Celite to remove the catalyst, then evaporated to dryness to give the title compound (73) (576 mg, 99%) which was used without further purification. δ H (300 M Hz; D2O), 1.55 (3H, d, J 7 Hz, CH3), 1.99 (3H, S, CH3CO), 4.09 (1H, brd, J 7 Hz, CH,(CH3), 7.12-7.24 (3H, m), 7.49 (1H, d, J 8 Hz, indole 7-H), 7.71 (1H, d, J 8 Hz, indole 4-H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:19])[CH2:4][CH:5]([CH3:18])[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)(O)[CH2:7][CH3:8]>Cl>[ClH:1].[CH3:17][O:16][C:12]1[CH:11]=[C:10](/[C:6](=[CH:7]\[CH3:8])/[CH:5]([CH3:18])[CH2:4][N:3]([CH3:19])[CH3:2])[CH:15]=[CH:14][CH:13]=1
Reactant: CCC(O)(c1cccc(OC)c1)C(C)CN(C)C
Agent: Cl
Product: C/C=C(\c1cccc(OC)c1)C(C)CN(C)C
Yield: 42.4 %

Procedure:
200 g (0.69 mole) of hydrochloride (2) were dissolved in one litre of concentrated hydrochloric acid and allowed to stand at room temperature. The hydrochloric acid was removed by distillation under vacuum. The residue was dissolved in 1 l of ice-water and the pH was adjusted to 13 with 10 molar sodium hydroxide solution. After extraction with ether, drying the organic phase and removing the solvent by distillation, 162 g of crude product were obtained, and were purified by recrystallisation. 79 g (42% theoretical) of hydrochloride (1) with a melting point of 169°-170° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[SH:9].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[N+]([O-])=O.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C)C=O>[F:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[S:9]2
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccc(F)cc1S
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc2c1Nc1ccc(F)cc1S2
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
2.2 g (15 mmol) of 2-amino-5-fluorobenzenethiol was dissolved in 30 ml of dimethylformamide and 2.5 g (12 mmol) of 1-chloro-2,6-dinitrobenzene was added thereto. The resulting mixture was stirred at room temperature. After 12 hours, 2.6 ml of N,N-diisopropylethylamine was added thereto and the mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After concentrating, the residue was purified by silica gel column chromatography. Thus 1.2 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].CCN(CC)CC.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccn1Cc1cc(Cl)cc(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylamine was dissolved in CH2Cl2 and Et3N was added followed by benzoyl chloride. The reaction mixture was stirred at room temperature for 2 h and washed with 1N HCl, saturated NaHCO3 and water. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH to afford N-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-benzamide (40 mg, 56%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:22])([C:18]([F:21])([F:20])[F:19])C([O-])=O.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.[Cu]I>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:14]([F:22])([F:13])[C:18]([F:21])([F:20])[F:19]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C(F)(F)C(F)(F)F
Temperature: 150 °C

Procedure:
To a 250 mL round-bottom flask was added 2-bromo-1-methoxy-4-nitrobenzene (3.5 g, 15.08 mmol), copper(I) iodide (5.75 g, 30.2 mmol), and sodium 2,2,3,3,3-pentafluoropropanoate (5.25 g, 28.2 mmol) in DMF (75 ml) and toluene (25 ml) to give a tan suspension. The mixture was heated at 150° C. and toluene was removed by a Dean-Stark trap. The mixture was heated at 155° C. for 6 h under nitrogen, cooled and poured into 100 mL of water and 100 mL of ether, filtered through a 1-inch plug of Celite and the plug was rinsed with ether. The filtrate layers were separated. The organic layer was washed with brine, dried (Na2SO4) filtered and concentrated. The dark oil was flash chromatographed on an Isco 40 g silica cartridge eluting with 4:1 hexane/EtOAc to give a yellow oil that was a (3:1) mix of desired material and starting material (1.5 g, 37%).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8](C3C(F)=CC=CC=3F)[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4](COCC[Si](C)(C)C)[N:3]=1>O1CCOCC1>[N:4]1[NH:3][CH:2]=[C:6]2[C:5]=1[C:14]1[CH:13]=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=1[CH:8]=[N:7]2
Reactant: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Solvent: C1COCCO1
Product: N#Cc1ccc2c(cnc3c[nH]nc32)c1

Procedure:
707 mg of 3-bromo-5-(2,6-difluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile are introduced into 17 ml of 1,4-dioxane. After argon has been bubbled through the mixture for 10 min, 846 mg of 4-aminopiperidine-1-sulphonamide, 2.15 g of caesium carbonate, 95 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 30 mg of palladium(II) acetate are added. The mixture is heated at reflux for 20 h. After cooling, the mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (40-63 μm), eluting with a DCM/EtOH/NH3 (7N solution in MeOH) mixture (90/10/1 by vol.), to give 407 mg of 5-(2,6-difluorophenyl)-3-(piperidin-4-ylamino)-2-[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (yellow oil). 1H NMR: −0.05 (broad s, 9 H) 0.88 (t, J=7.9 Hz, 2 H) 1.39 (m, 2 H) 1.93 (m, 2 H) 2.08 (broad m, 1 H) 2.39 (m, 2 H) 2.93 (m, 2 H) 3.71 (t, J=7.9 Hz, 2 H) 4.42 (m, 1H) 5.66 (s, 2 H) 6.58 (d, J=8.1 Hz, 1 H) 7.33 (t, J=7.9 Hz, 2 H) 7.66 (m, 1 H) 7.95 (broad s, 1 H) 8.12 (broad d, J=8.3 Hz, 1 H) 8.46 (d, J=8.3 Hz, 1 H).
Reaction SMILES: C([C:5]1[N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)=[CH:16][C:15]=2[CH3:27])[N:8]=[CH:7][N:6]=1)(OC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(OCC)(=O)C>C1COCC1>[CH3:26][N:24]1[N:23]=[N:22][C:21]([C:17]2[CH:16]=[C:15]([CH3:27])[C:14]([O:13][CH2:12][CH2:11][CH2:10][N:9]3[CH:5]=[N:6][CH:7]=[N:8]3)=[C:19]([CH3:20])[CH:18]=2)=[N:25]1
Reactant: COC(=O)c1ncnn1CCCOc1c(C)cc(-c2nnn(C)n2)cc1C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1cncn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
To a solution of 5-carbomethoxy-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole (868 mg, 2.34 mmol) in 23 ml of THF was added dropwise at 0° C. a solution of 1M LAH in THF (1.52 ml, 1.52 mmol). The mixture was stirred for 20 min at 0° C. and then stirred at 20° C. for 24 h. Rochelle salt solution was added to the mixture and the solution was stirred at 20° C. for 10 min. Ethyl acetate was added to the above mixture and the aqueous layer was extracted with methylene chloride (3×). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (16 cm column, methylene chloride/acetone, 8/1-0/1) to afford 132 mg (18%) of 2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]propyl]-1,2,4-triazole, m.p. 76°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[C:19]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=O)[CH2:29]Br)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:29]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([C:19](=[O:21])[CH3:20])[CH2:23][CH2:24]3)[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)CBr)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Temperature: 60 °C
Yield: 95 %

Procedure:
1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (Example 1, Step E; 30.0 g, 92.5 mmol) and 1-(1-acetylpiperidin-4-yl)-2-bromoethanone (Example 2, Step C, 32.1 g, 130 mmol) were suspended in ethanol (400 mL) and DIEA (48.3 mL, 278 mmol) was added. The resulting mixture was heated to 60° C. for 4 hours and then at ambient temperature overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water, dried over Na2SO4, filtered and concentrated. The resulting material was purified on silica eluting with 3% MeOH/EtOAc to give 1-(4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone (41.6 g, 95.0% yield) as a tan solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14]([CH:17]=O)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1.C(O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14]([CH:17]=[N:21][OH:22])=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=CC1=Cc2cc(Oc3ccccc3)ccc2OC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=CC1=Cc2cc(Oc3ccccc3)ccc2OC1
Reaction time: 1 h

Procedure:
6-Phenoxy-2H-1-benzopyran-3-carboxaldehyde (5.00 g, 19.9 mmol) is dissolved in 175 ml of pyridine/ethanol (1:1) and treated with hydroxylamine hydrochloride (2.07 g, 29.7 mmol). The mixture is stirred for 1 hour and partitioned between ether and water. The aqueous layer is extracted with ether, and the ether layer is washed with 2N HCl, dried (MgSO4) and evaporated to give 6-phenoxy-2H-1-benzopyran-3-carboxaldehyde oxime as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22]([CH:23]=CC)=[CH:21][C:20]([F:26])=[CH:19][C:18]=2[Br:27])[CH:14]=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[Br:27][C:18]1[CH:19]=[C:20]([F:26])[CH:21]=[C:22]2[C:17]=1[O:16][C@@H:13]([CH2:12][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:14]=[CH:23]2
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(Br)cc(F)cc1C=CC
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(Br)c3O2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.3 %

Procedure:
To a solution of (R)-2-[2-bromo-4-fluoro-6-(prop-1-enyl)phenoxy]but-3-enyl 4-methylbenzenesulfonate (7.26 g, 0.016 mol) in dry dichloromethane (300 mL) at room temperature under nitrogen was added benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (2.6 g, 3.2 mmol) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure to a small volume and directly pre-adsorbed onto silica gel. Purification by flash chromatography using a solvent gradient of 5 to 30% ethyl acetate in hexane gave 6.7 g (100%) of (R)-(8-bromo-6-fluoro-2H-chromen-2-yl)methyl-4-methylbenzenesulfonate as a grey solid. [α]D25=+206.6° (c 1% solution in MeOH); MS (ES) m/z 430.0 ([M+NH4]+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[Br-].[Mg+2].[Br-].C(N(CC)CC)C.[CH3:26][S:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>C1COCC1.O.CCCCCC>[CH3:7][C:6](=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([S:27][CH3:26])=[CH:29][CH:30]=1)[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CSc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(SC)cc1
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To a solution of triethyl 2-phosphonopropionate (47 g, 0.19 mol) in THF (200 mL) was added solid magnesium bromide etherate (59 g, 0.23 mol) under nitrogen. Triethylamine (26.5 mL, 0.19 mol) was added after 5 min. The mixture was stirred for 10 min and 4-(methylthio)benzaldehyde (27.1 mL, 0.19 mol) was added. After 15 h at room temperature the mixture was diluted with water (400 mL) and hexane (400 mL). The two layers were separated. The organic layer was washed with water (400 mL), dried over 4 Å molecular sieves, filtered, and concentrated to give 42.5 g (95%) of ester 6a as a light yellow oil: IR (neat) 2980, 1705, and 1240 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 7.63 (1 H), 7.33 (2 H), 7.25 (2 H), 4.26 (2 H), 2.50 (3 H), 2.12 (3 H), and 1.34 (3 H); 13C NMR (CDCl3, 75.5 MHz) δ 168.71, 139.37, 138.08, 132.55, 130.19, 127.98, 125.89, 60.87, 15.38, 14.37 and 14.17.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH3:12])[CH3:11].N1C=CC=CC=1.[Cl:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C(OCC)(=O)C>[Cl:19][C:20]1[C:21]([C:22]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3([CH3:12])[CH3:11])=[O:23])=[CH:25][CH:26]=[CH:27][N:28]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CC1(C)CCc2c(N)cccc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1(C)CCc2c(NC(=O)c3cccnc3Cl)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 200 mg (1.2 mmol) of 4-amino-1,1-dimethylindane and 0.15 g (1.9 mmol) of pyridine in 15 ml of ethyl acetate was added 0.24 g (1.4 mmol) of 2-chloronicotinic acid chloride under ice cooling, and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over Glauber's salt and then concentrated under reduced pressure. The white residue was recrystallized with hexane to obtain 300 mg of white crystals (Compound No. 1 shown in Table 2). The yield was 80.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)C>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: C[C@@H]1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 g (0.3 mol) of (S)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 700 ml of dry acetone. The solution is treated with 79 ml of ground potassium carbonate and with 31.4 ml of methyl iodide and the mixture is stirred at room temperature for 4 hours. The mixture is treated with 30 ml of glacial acetic acid and evaporated. The residue is treated with an ice/water mixture and extracted several times with methylene chloride. The organic phase is washed with water, dried over sodium sulphate, concentrated and treated with methanol. After filtering off the separated crystals, there is obtained (S)-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 159°; [α]25D =+381.2° (1 percent solution in methylene chloride).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([CH3:20])=[N:18][N:17]([CH3:21])[C:14]3=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([CH3:20])=[N:18][N:17]([CH3:21])[C:14]3=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: Cc1nn(C)c2cnc(Nc3cc(Br)cn(C)c3=O)cc12
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4c(C)nn(C)c4cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 325f (120 mg, 0.35 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (417 mg, 1.05 mmol), Pd(dppf)Cl2 (29 mg, 0.035 mmol), K3PO4 (148.0 mg, 0.70 mmol), sodium acetate (57.4 mg, 0.70 mmol), water (0.5 mL), and acetonitrile (15 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at reflux for 1 hr. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 325g as a yellow solid (70 mg, 33%). MS-ESI: [M+H]+ 620.8.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12]CC=C)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[O:7]2.CCOC(C)=O.CCN([C:28]1[CH:29]=CC=C[CH:33]=1)CC>>[CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH2:29][CH:28]=[CH2:33])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[O:7]2
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc(C)c2ccc(=O)oc2c1
Solvent: CCOC(C)=O
Product: C=CCc1c(O)cc(C)c2ccc(=O)oc12

Procedure:
A solution of 5-methyl-7-allyloxycoumarin (IV; 13.8 g) in diethylaniline (60 ml) was refluxed for 5 hours. After cooling, EtOAc (250 ml) was added and the mixture was washed several times with dil. HCl and then with water; the solvent was evaporated from the dried (Na2SO4) organic phase and the residue by crystallization from EtOAc gave 5-methyl-7-hydroxy-8-allylcoumarin (VIII; 4.5 g; m.p. 177° C.). ##STR11##
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:14]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:23])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: O=S(CCCCBr)c1ccccc1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)cc21
Product: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCS(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenylsulfinyl-butylbromide.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)[C:16](=[O:35])[CH:15]=1)C1C=CC=CC=1>[H][H].[Pd]>[OH:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:24][CH:25]=2)[C:16](=[O:35])[CH:15]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OCCN2CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1cc(O)ccn1-c1ccc(OCCN2CCCCC2)cc1
Yield: 74.6 %

Procedure:
Into a THF (10 mL) solution of 4-benzyloxy-1-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1H-pyridin-2-one (Example 2, 130 mg, 0.32 mmol), 10% palladium-on-carbon (165 mg) was added and stirred at room temperature for 10 hours in hydrogen atmosphere. The reaction liquid was filtered, washed thoroughly with methanol, and the filtrate was concentrated under reduced pressure. THF was added to the resulting residue and the formed precipitate was recovered by filtration and dried to provide the title compound (75 mg, 74%).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].C([Mg]Br)C.[CH:10](=[O:17])[CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH3:16]>O1CCCC1>[CH3:1][CH:2]([OH:5])[C:3]#[C:4][CH:10]([OH:17])[CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH3:16]
Reactant: C#CC(C)O
Reactant: CCC=CCCC=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC=CCCC(O)C#CC(C)O

Procedure:
But-3-yn-2-ol was added into a solution of ethyl magnesium bromide (EtMgBr) in tetrahydrofuran (THF). Hept-4-enal was then dropped into the mixture at room temperature and aged for 2 hours. The rush over process provided the product undec-8-en-3-yne-2,5-diol.