Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:24][O:25][CH3:26].O>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12][CH2:24][O:25][CH3:26])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1O
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(F)cc1OCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid ethyl ester (3.5 g) in dichloromethane (30 ml) were added N,N-diisopropylethylamine (5.0 g) and (chloromethyl)methyl ether (2.3 g) at 0° C., and this reaction mixture was stirred at room temperature overnight. This reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]([F:13])([F:12])[CH2:10][OH:11].C(OC(C)C)(C)C.C(N(CC)CC)C.Cl>O>[C:1]([O:11][CH2:10][C:9]([Br:8])([F:13])[F:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OCC(F)(F)Br
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CC(C)(C)C(=O)OCC(F)(F)Br
Yield: 15.6 %

Procedure:
In a glass flask with a thermometer, a condenser and a dropping funnel, 271 g (2.24 mol) of pivaloyl chloride, 360 g (2.23 mol) of 2-bromo-2,2-difluoroethanol and 1.5 L of diisopropyl ether were placed. The resulting solution was stirred, followed by dropping 318 g (3.14 mol) of triethylamine to the stirred solution while cooling the flask in an ice bath. After the dropping, the solution was kept stirred for 1 hour at room temperature. The completion of the reaction was then confirmed by gas chromatography of the solution. The reaction solution was admixed with and totally dissolved in 300 ml of water. After that, 500 ml of 2N hydrochloric acid was added to the solution. The thus-obtained solution was separated into an organic phase and an aqueous phase. The aqueous phase was extracted with 500 ml of diisopropyl ether. The extract was combined with the organic phase. The resulting organic phase was washed with 500 ml of saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then, subjected to solvent evaporation. With this, 85 g of 2-bromo-2,2-difluoroethyl pivalate was obtained as a light yellow liquid (yield: 82%, purity: 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:16]([F:29])([F:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)=[O:27]
Reactant: O=C(O)Cc1ccccc1OCC(F)(F)F
Reactant: COc1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(C(=O)Cc2ccccc2OCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-methoxyphenylpiperazine (0.062 g, 0.32 mmol) and 2-(2,2,2-trifluoroethoxy)phenylacetic acid (0.075 mg, 0.32 mmol) in DMF (1 mL) was added EDC (0.115 g, 0.40 mmol), HOBT (0.049 g, 0.32 mmol), and DIEA (0.055 mL, 0.32 mmol). The mixture was stirred at ambient temperature for 18 h. The DMF was removed under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC using 1:1 EtOAc:hexane as eluant. The title compound was obtained as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[C:6](=[O:22])[NH:5]2>O1CCCC1.CO.CN(C)C=O.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:22])[C:7](=[O:21])[N:8]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:3][C:2]=1[Cl:1].[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:22])[C:7](=[O:21])[N:8]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc2c(cc1Cl)[nH]c(=O)c(=O)n2C1CCCCC1
Product: Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Yield: 80 %
Yield: 8 %

Procedure:
28.9 g (89 mmol) of 6-Chloro-1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedione were dissolved in 300 ml of tetrahydrofuran/methanol/dimethylformamide (3:3:1) and, after addition of 3 g of palladium/carbon (10%), hydrogenated. The mixture was filtered, the carbon was washed with methanolic ammonia solution, and the combined filtrates were concentrated under reduced pressure. The residue was chromatographed on silica gel with the mobile phase toluene/acetone/glacial acetic acid (10:10:1) to yield 2.2 g (8%) of product e1 and 18.5 g (80%) of product e2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:29])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:17])=O)=[CH:11]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.[C:52]([O:57][CH2:58][CH3:59])(=[O:56])[C:53]#[C:54][CH3:55].C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]([CH3:29])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:39][CH:54]([CH2:53][C:52]([O:57][CH2:58][CH3:59])=[O:56])[CH2:55][N:17]=1)=[CH:11]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC#CC(=O)OCC
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)COC)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
To a solution of 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (874 mg) in tetrahydrofuran (20 mL) was added Lawesson's reagent (845 mg) at room temperature. The mixture was stirred at 50° C. for 45 min, and then cooled to room temperature. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=50:50 to 100:0, volume ratio) to give a yellow amorphous solid. To a solution of the solid in tetrahydrofuran (20 mL) were added ethyl 2-butynoate (0.507 mL) and tributylphosphine (0.652 mL). The whole was stirred at 50° C. for 45 min. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=50:50 to 100:0) to give the title compound (531 mg, 46%) as a brown amorphous solid. MS 547 (MH+).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[NH2:19][C:20]1[CH2:24][CH2:23][CH2:22][N:21]=1.O>CN(C)C=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC1=NCCC1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3n(c2-c2ccc(Cl)cc2)CCC3)cc1

Procedure:
A mixture of 6.2 g (0.018 mol) of 2-bromo-1,2-di-(4-chlorophenyl)ethanone and 4.6 g (0.054 mol) of 2-amino-4,5-dihydro-3H-pyrrole in 60 ml of dry N,N-dimethylformamide was stirred at 25° with exclusion of water for five days. The mixture was then poured into water and the aqueous solution was extracted three times with methylene chloride. The extracts were combined and washed eight times with water, dried (K2CO3) and evaporated. The residue was chromatographed on silica gel (dry column) with 1% tetrahydrofuran in chloroform and 5% tetrahydrofuran in chloroform as eluants. The product-containing section was washed with methanol to remove the product which was, after evaporation of the methanol, recrystallized from methanol-water to give the title compound, m.p. 189°-192°.
Reaction SMILES: O=[C:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=1[O:19][CH3:20])[CH2:3][CH2:4][C:5]([O:7]C)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.C(O)(=O)C.[BH3-]C#N.[Na+].[OH-].[Na+]>C1COCC1.CO>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=3[O:19][CH3:20])[CH2:3][CH2:4][C:5]2=[O:7])=[CH:26][CH:25]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CCC(=O)c1c(OC)cc(OC)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(OC)c(C2CCC(=O)N2Cc2ccc(OC(F)(F)F)cc2)c(OC)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 4-oxo-4-(2,4,6-trimethoxyphenyl)butanoate (200 mg; 0.70 mmol; 1.0 equiv.), (4-(trifluoromethoxy)phenyl)methanamine (677 mg; 3.54 mmol; 5.0 equiv.), acetic acid (472 mg; 7.86 mmol; 11.1 equiv.), and NaBH3CN (93 mg; 1.41 mmol; 2.0 equiv.) in anh. THF (1.5 ml), and anh. MeOH (1.5 ml) was refluxed, under nitrogen, for 24 h. After cooling to rt, 15% aq. NaOH was added, and the organic solvents were removed under reduced pressure. The residue was extracted with DCM, and the mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) afforded 1-(4-(trifluoromethoxy)benzyl)-5-(2,4,6-trimethoxyphenyl)pyrrolidin-2-one as a colorless oil. LC-MS (conditions D): tR=1.08 min.; [M+H]+: 425.72 g/mol.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: O=[N+]([O-])c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 50 °C
Yield: 46.4 %

Procedure:
A mixture of 3-bromo-2-(2,4-difluorophenoxy)-5-nitropyridine (1.9 g, 5.9 mmol), ammonium chloride (637 mg, 11.8 mmol), and iron powder (1.65 g, 30 mmol) suspended in THF (10 mL), water (3 mL) and ethanol (10 mL) was heated to 90° C. using microwave irradiation (normal) for 5 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with warm (50° C.) MeOH (˜50 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (100 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (824 mg, 46%). LCMS (M+H)+=302.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH3:36][C:37]([CH3:39])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH:37]([CH3:39])[CH3:36])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Reaction time: 0.17 h
Yield: 7.9 %

Procedure:
A suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoro acetate (250 mg, 0.51 mmol) in DCE (5 mL) was added acetone (0.06 mL, 0.77 mmol) and 4 Å molecular sieves was stirred under an atmosphere of argon for 10 min before adding sodium triacetoxy borohydride (216 mg, 1.02 mmol) and stirring for 18 h at RT. Further acetone (0.06 mL) and sodium triacetoxyborohydride (216 mg) were added and stirring continued for a further 24 h. The reaction mixture was diluted with DCM and saturated aqueous sodium hydrogen carbonate and the organic layer washed with water followed by brine and then dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was subjected to RPHPLC (gradient 20 to 70% methanol in water+0.1% HCO2H) to give 357 as a yellow solid (17 mg, 8%). LCMS: RT=2.81 min, [M+H]+=421. 1H NMR 400 MHz (DMSO-d) δ: 8.37-8.26 (1H, m), 7.90-7.89 (2H, m), 7.05 (1H, dd, J=8.33, 1.81 Hz), 6.89 (1H, d, J=1.73 Hz), 5.89-5.88 (1H, m), 4.49-4.48 (4H, m), 2.91 (2H, d, J=10.95 Hz), 2.76-2.75 (1H, m), 2.46 (1H, s), 2.26 (2H, t, J=11.38 Hz), 1.78 (2H, d, J=12.43 Hz), 1.64 (2H, td, J=12.20, 3.68 Hz), 1.48 (6H, d, J=6.60 Hz), 1.01 (6H, d, J=6.57 Hz)
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N:12]([CH:15]([CH2:21][CH2:22]Br)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14].C(N(CC)CC)C>C(#N)C>[N:12]([CH:15]([CH2:21][CH2:22][NH:1][CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[CH2:10][CH3:11])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]
Reactant: CCOC(=O)C(CCBr)N=[N+]=[N-]
Reactant: CCC(N)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCNC(CC)C(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 50 °C
Yield: 52.5 %

Procedure:
To a solution of tert-butyl 2-amino-butanoate (0.397 g) and ethyl 2-azido-4-bromo-butanoate (0.286 g) in acetonitrile (5 ml) was added triethylamine (0.347 ml). The mixture was heated at 50° C. for 18 h, cooled and evaporated onto silica gel (Merck.7734). The pre-absorbed material was purified by flash column chromatography (Merck. 9385, eluting with cyclohexane:ethyl acetate 6:1) to give the title compound (0.200 g) as a mixture of four diastereomers.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@H:7]([CH3:35])[NH:8][C@@H:9]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1)(C)(C)C.C(OCC)C.C(OCC)(=O)C.[ClH:48]>>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([NH:8][C@H:7]([C:6]([OH:36])=[O:5])[CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:15][CH2:16]1)=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[ClH:48]
Reactant: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)O
Reaction time: 4 h

Procedure:
In 20 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 1.7 g of N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine tert-butyl ester, and the solution is allowed to stand at room temperature for 4 hours. 100 ml of ethyl ether is added to the reaction solution, and the colorless powder, which separates out, is collected by filtration to give 1.2 g of N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine·hydrochloride.
Reaction SMILES: C([Li])CCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[O:32].[Cl-].[NH4+]>C1COCC1>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:25]1([OH:32])[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=2)[NH:27][C:26]1=[O:31]
Reactant: c1ccc2scnc2c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (35 ml, 56 mmol) was added dropwise to a solution of benzothiazole (6.2 ml, 56 mmol) in THF (100 ml) at −78° C. After stirring at −78° C. for 1.5 h, the solution of the lithiated benzothiazole was transferred via a needle into an ice-cold suspension of 5-chloroisatin (3.63 g, 20 mmol) in THF (70 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure, during which the intermediate starts to crystallize. Filtration and drying yielded 4.47 g of the intermediate as yellow crystalline solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][Si:9]([CH3:12])([CH3:11])Cl.C[Si](C)(C)NCCN[Si](C)(C)C>ClCCl>[CH2:1]([O:7][Si:9]([CH3:12])([CH3:11])[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCO
Agent: C[Si](C)(C)NCCN[Si](C)(C)C
Solvent: ClCCl
Product: CCCCCCO[Si](C)(C)C
Yield: 59 %

Procedure:
To hexan-1-ol (5.1 g, 0.05 mole) in dichloromethane (50 ml) were added trimethylchlorosilane (1.81 g, 0.0166 mole) and N,N'-bis(trimethylsilyl)ethlenediamine (3.44 g, 0.0166 mole). The mixture was stirred under reflux for 30 minutes, filtered and the solvent removed. The residue, hexanoxytrimethylsilane, was obtained in 59% yield (5.15 g).
Reaction SMILES: CO.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[OH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=CC=CC=2)[C:13]=1[CH:22]=O>C(O)C.ClCCl>[CH:22](=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[C:13]1[C:12](=[CH:21][CH:20]=[CH:19][CH:14]=1)[OH:11]
Reactant: Nc1ccccc1O
Reactant: O=Cc1c(O)ccc2ccccc12
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Oc1ccccc1C=Nc1ccccc1O

Procedure:
The preparations of compounds used in this invention are shown in detail below. In general [nBu4N][OsVI(N)Cl4] is reacted with the ligand in a suitable organic solvent, such as methanol, ethanol or dichloromethane. The Schiff base ligands 5-X—H2salpa (salpa=N-salicylidene-2-aminophenol dianions) are synthesized by condensation of the appropriate 2-hydroxybenzyaldehyde with the 2-aminophenol in refluxing ethanol. The Schiff base ligand nalph is synthesized by condensation of the 2-hydroxy-1-naphthaldehyde with the 2-aminophenol in refluxing ethanol. [NnBu4][OsVI(N)Cl4] were prepared by a literature procedure (Griffith, W. P. and Pawson, D. J. J. Chem. Soc., Dalton Trans. 1973, 1315.).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[N:5]=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][C@@H:22]2[CH2:24][C@@H:20]([C:21]2([CH3:26])[CH3:25])[C@H:19]1[CH3:27].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[N:5]=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][C@@H:22]2[CH2:24][C@@H:20]([C:21]2([CH3:26])[CH3:25])[C@H:19]1[CH3:27]
Reactant: CCOC(=O)CCCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCCC(=O)O)c(=O)c1Br)C2(C)C
Yield: 45 %

Procedure:
Ethyl 4-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}butanoate (454 mg, 0.981 mmol) in 1,4-dioxane (4.5 mL) was stirred with 1 M aqueous sodium hydroxide (2.06 mL, 2.06 mmol) at room temperature for 6.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (182 mg, 64% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][OH:13])=[CH:9][CH:8]=[CH:7]2>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cccc2cccc(CO)c12
Solvent: ClCCl
Product: Cc1cccc2cccc(C=O)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1-L 4-neck equipped with an overhead stirrer, a condenser and a thermocouple was charged with 8-methyl-1-napthalenemethanol (18.5 g, 0.107 mol) in CH2Cl2 (500 mL) and stirred at room temperature under N2. Solid Mn(IV)O2 (61 g, 0.7 mol) was carefully added and the reaction was stirred at room temperature for 3 h, then at 40° C. for 6 h and then at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (500 mL), filtered and the filtrate was washed with 1N HCl and then dried over MgSO4. The resulting crude material was purified using silica gel chromatography (8/2 hexane/ethyl acetate) to yield 8-methyl-naphthalene-1-carbaldehyde as a solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=3)[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C:31]1([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClC1C=C2C(=CC=1)C(=O)NCC2>>[C:31]1([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[N:39]([CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]4[O:24][N:23]=[C:22]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:21]=4)[CH2:17][CH2:18]3)[CH2:38]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc1
Reactant: O=C1NCC(c2ccccc2)c2ccccc21
Agent: O=C1NCCc2cc(Cl)ccc21
Product: O=C1c2ccccc2C(c2ccccc2)CN1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1

Procedure:
According to the same procedure described in Example 61, using the compound prepared in Example 65 instead of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate and 4-phenyl-3,4-dihydroisoquinolin-1(2H)-one (prepared according to the reported preparation in Davies, R. V.; et al. J. Chem. Soc. Perkin Trans. 1 1978, 180) instead of 6-chloro-3,4-dihydroisoquinolin-1(2H)-one, the title compound having the following physical data was obtained.
Reaction SMILES: CN(C)C1C=CC(CN[C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=CC=1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>>[OH:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][NH:10][C:9]([NH:22][CH2:23][CH:24]([OH:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:18]
Reactant: NCC(O)c1ccccc1
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Product: O=C(CCCNC(=O)NCC(O)c1ccccc1)NO

Procedure:
Compound 15 was prepared using the methodology described for the preparation of compound 2, by substituting 4-dimethylaminobenzylamine dihydrochloride with 2-amino-1-phenyl-ethanol. 1H NMR (CD3OD) δ 7.42-7.24 (m, 5H), 4.73 (dd, J=7.8, 4.2 Hz, 1H), 3.43 (dd, J=13.8, 4.2 Hz, 1H), 3.26 (dd, J=13.8, 7.8 Hz, 1H), 3.14 (t, J=6.9 Hz, 2H), 2.12 (t, J=7.2 Hz, 2H), 1.76 (m, 2H). 13C NMR (CD3OD) δ 172.7, 161.5, 144.2, 129.5, 128.7, 127.3, 74.6, 48.1, 39.4, 30.6, 27.0.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][C:10]([CH2:12]O)=O>C(O)C.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:12][C:10]1[C:2]2[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[O:7][CH:9]=1
Reactant: CC(=O)CO
Reactant: O=C1CCCC(=O)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1coc2c1C(=O)CCC2
Yield: 37.5 %

Procedure:
A mixture of 1,3-cyclohexanedione (3.36 g, 30 mmol), acetol (hydroxyacetone; 2.22 g, 30 mmol), and zinc chloride (4.09 g, 30 mmol) in ethanol (10 mL) was heated at reflux temperature for 3 hours. After cooling, the mixture was dissolved in ethyl acetate (100 mL). The whole was washed with water (100 mL), brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chlomatography eluting with ethyl acetate-hexane (1:10) to give the subtitle compound (1.69 g, 38% yield).