Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3](OC)=[O:4].S(C)C.[BH4-].[Na+].CO>C1COCC1>[OH:1][C@@H:2]([CH2:3][OH:4])[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C[C@@H](O)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: COC(=O)C[C@@H](O)CO
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 112.7 %

Procedure:
To a solution of (R)-dimethyl 2-hydroxysuccinate (140 g, 0.86 mol) in THF (1400 mL) was added dropwise Me2S.BH3 (86 mL, 10 M) at 20° C. over 30 min. The mixture was stirred at 20° C. for 30 min. NaBH4 (1.63 g, 42.9 mmol) was added at 10° C. and stirred at 10° C. for 30 min. The mixture was warmed to room temperature and stirred for 1 h. CH3OH (200 mL) was slowly added to the mixture while cooling in an ice-water bath. The resulting mixture was evaporated to give (R)-methyl 3,4-dihydroxybutanoate (130 g, crude).
Reaction SMILES: COC[N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][CH:6]([NH2:22])[C:5]1=[O:23].[OH-].[Na+].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>Br.C(O)(=O)C.O.O1CCCC1>[O:23]=[C:5]1[NH:4][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][CH:6]1[NH:22][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCN1C(=O)C(N)CN(c2ccccc2F)c2ccccc21
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CN(c2ccccc2F)c2ccccc2NC1=O)OCc1ccccc1
Reaction time: 1 h
Yield: 40.7 %

Procedure:
1-Methoxymethyl-2-oxo-3-amino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.94 g) was dissolved in 25% hydrobromic acid-acetic acid solution (18 ml), the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure, diethyl ether was add, the solid so precipitated was collected by filtration to give pale brown crystals. This crystals were suspended in water (5 ml), 1N aqueous sodium hydroxide (4.5 ml) and a solution of benzyl chloroformate (301 mg) in tetrahydrofuran (7 ml) were added thereto, the resultant mixture was stirred for one hour. Water was added to the reaction mixture, extracted with methylene chloride, the organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 291 mg of the titled compound as amorphous.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=O)[N:16]=1.[CH3:33][CH:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH3:35].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:33][CH:34]([S:36]([NH:39][C:26]([C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[O:23][C:17]1[N:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[N:16]=1)=[O:28])(=[O:38])=[O:37])[CH3:35]
Reactant: CC(C)S(N)(=O)=O
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)NS(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a stirred suspension of 0.33 gram (0.002 mole) of 1,1'-carbonyldiimidazole in 2 mL of tetrahydrofuran was added dropwise a solution of 0.55 gram (0.002 mole) of 2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid in 3 mL of tetrahydrofuran. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes, and then it was heated to reflux where it was stirred for an additional 30 minutes. After this time the reaction mixture was cooled, and 0.25 gram (0.002 mole) of 1-methylethylsulfonamide (prepared as in Example 1--Step H) was added. Upon completion of addition, the reaction mixture was stirred for 10 minutes, and 0.31 gram (0.002 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for five hours. The reaction mixture was then poured into aqueous dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% and 20% ethyl acetate in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.2 gram of 2-[2-(1-methylethylsulfonylaminocarbonyl)phenoxy]-4,6-dimethoxypyrimidine; m.p. 128°-130° C., Compound 9 in Table I. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [B-](F)(F)(F)F.CC[O+](CC)CC.[CH3:13][NH:14][C:15](=O)[C:16]([O:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17].[B-](F)(F)(F)F.[Br:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].Cl>C(O)C.C(Cl)Cl>[CH3:13][NH:14][C:15](=[N:34][C:33]1[CH:35]=[CH:36][C:30]([Br:29])=[C:31]([C:37]([F:40])([F:38])[F:39])[CH:32]=1)[C:16]([O:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17]
Reactant: CNC(=O)C(C)(C)OC(C)=O
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: CC[O+](CC)CC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CNC(=Nc1ccc(Br)c(C(F)(F)F)c1)C(C)(C)OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Over a five minute period, add a solution of 17.5 g. (0.10 moles) of triethyloxonium fluoborate in 50 ml. of methylene chloride to a mixture of 15.9 g. (0.10 moles) of N-methyl-2-acetoxyisobutyramide in 200 ml. of dry methylene chloride at 0°-5°C. Allow to warm to room temperature and stir for sixteen hours. Remove the solvent in vacuo and obtain the crude product of this reaction as its fluoborate salt. Dissolve the crude fluoborate salt in 150 ml. of anhydrous ethanol, add 24.0 g. (0.10 moles) of 4-bromo-3-trifluoromethylaniline and stir for three days. Remove the solvent in vacuo and partition the residue between ether and saturated aqueous sodium bicarbonate solution. Retain the ether solution, dry it over sodium sulfate and precipitate the product of this reaction as its hydrochloride salt, by adding 0.10 moles of ethereal hydrogen chloride (25 ml. of a 4.0N solution).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1Br.[C:10]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])#[CH:11].C(N(CC)CC)C.C1COCC1>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[C:11]#[C:10][Si:12]([CH:13]([CH3:15])[CH3:14])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Nc1ccc(Br)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)[Si](C#Cc1nc(N)ccc1Br)(C(C)C)C(C)C

Procedure:
A mixture of 5,6-dibromopyridin-2-amine (60 g, 233 mmol), ethynyl-tri(propan-2-yl)silane (64 ml, 285 mmol), copper(I) iodide (1.5 g, 7.88 mmol), Dichlorobis(triphenylphosphine)-palladium(II) (4.0 g, 5.48 mmol) and triethylamine (80 ml, 577 mmol) is stirred under argon atmosphere in ACN (200 ml) with THF (100 ml) for 2 h at 50° C. The mixture is concentrated in vacuo and the product purified by NP chromatography. Yield: 76 g (92%). HPLC-MS: M+H=353/355; tR=1.79 min (*Method—1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCOCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Temperature: 110 °C
Yield: 67.8 %

Procedure:
To a stirred solution of 4-nitrobenzoyl chloride (6.23 g, 33.9 mmol) and N-phenyl piperazine (4.71 ml, 30.8 mmol) in anhydrous dioxane (250 ml) at 0° C. was added triethylamine (4.73 ml, 33.9 mmol) and the mixture was then stirred at reflux (110° C.) for 5 hours. The reaction was allowed to cool then quenched with water (100 ml) and the resulting aqueous mixture was extracted with ethyl acetate (2×75 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated to yield crude product as a yellow oil. Pure product was obtained by crystallisation from a mixture of 40% ethyl acetate in petrol to afford the title compound as a white crystalline solid (6.5 g, 62%). HPLC retention time 6.9 min. Mass spectrum (ES+) m/z 312 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH2:9]2)=[O:5])[CH3:2].[O-:28][C:29]#[N:30].[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH:23]([CH3:24])[CH3:25])[C:29]([NH2:30])=[O:28])[CH:17]=1)[C:10]([CH3:26])([CH3:27])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)C)c1)N2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C(N)=O)C(C)C)c1)N2
Temperature: 40 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 2-(3-isopropylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (310 mg, 0.85 mmol) in acetic acid (2 mL) and water (2 mL) was added a solution of sodium cyanate (110 mg, 1.7 mmol) in water (2 mL) dropwise at 40° C. The reaction mixture was stirred at 40° C. for 4 h. Then the reaction mixture was extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-isopropyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (347 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C24H31N3O3 (M+H)+: 410.53, observed: 410.1.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[NH2:25]N.O.Cl>CO>[NH:25]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccn[nH]1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (2.70 g, 8 mmol) and NH2NH2.H2O (1.94 mL, 40 mmol) in MeOH (25 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from AcOEt to give the title compound (0.969 g, 40% yield) as an off-white solid: mp 192-194° C.; 1H NMR (300 MHz, CDCl3): δ ppm 6.82 (1H, d, J=7.9 Hz), 7.03 (1H, d, J=1.9 Hz), 7.69 (1H, d, J=1.9 Hz), 7.72-7.76 (2H, m), 7.83-7.89 (1H, m), 7.91-7.93 (1H, m), 8.33 (1H, d, J=7.9 Hz), 12.85 (1H, brs). LC-MS (ESI) m/z 307 [M+H]+. Anal. Calcd for C14H9F3N4O: C, 54.91; H, 2.96; N, 18.29. Found: C, 54.92; H, 2.99; N, 18.33.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][N:25]=1.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[N:25][CH:26]=3)[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)nc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cccc3c2C(=O)OC(C)(C)O3)cn1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
8.7 g of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)benzodioxin-4-one, 23.2 g of 2-methoxy-5-tributylstannylpyridine, 3.4 g of lithium chloride, 0.6 g of tetrakistriphenylphosphinepalladium0 and 70 mg of 2,6-di-t-butyl-4-methylphenol are dissolved in 150 ml of dioxane and the mixture is stirred for 3 h at 140° C. in an autoclave. It is then concentrated under reduced pressure, the residue is stirred with 200 ml of n-pentane and filtered on a little silica gel 60, the latter is subsequently washed with n-pentane and the product is eluted using ethyl acetate. After concentration, 10.3 g of m.p. 160° C. remain.
Reaction SMILES: [CH3:1][Li].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1>C1COCC1>[OH:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10](=[O:12])[CH3:1])[CH2:8][CH2:9]1
Reactant: [Li]C
Reactant: O=C(O)C1CCC(O)CC1
Solvent: C1CCOC1
Product: CC(=O)C1CCC(O)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
Methyllithium (1M in THF) (120 mL, 3.5 eq.) was added to a solution of 4-hydroxy-cyclohexanecarboxylic acid (cis/trans mixture) (5.00 g, 1 eq.) in THF (350 mL) at −78° C. After stirring at −78° C. for 45 min, the cooling bath was removed and the resulting mixture was warmed to room temperature and stirred overnight. After total 24 h, the resulting reaction mixture was poured into ice/water (800 mL). This mixture was vigorously stirred. The separated aqueous phase was extracted with MeOH/EtOAc (˜1/20). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography (50% to 100% EtOAc/hexanes) to give 1-(4-hydroxy-cyclohexyl)-ethanone (2.08 g, 42%).
Reaction SMILES: [CH:1](=O)[CH3:2].Cl.[CH2:5]([O:12][NH2:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.CO>[CH2:5]([O:12][NH:13][CH:1]=[CH2:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC=O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: C=CNOCc1ccccc1
Reaction time: 16 h

Procedure:
Acetaldehyde (24.7 mL, 44.2 mmol) was added dropwise to the cooled solution (0° C.) of O-benzyl-hydroxylamine hydrochloride (7.00 g, 43.85 mmol) in water (100 mL) and MeOH (20 mL). The reaction mixture was stirred for 16 h. The volatiles were removed under reduced pressure, and the water suspension was extracted with EtOAc (2×75 mL). The combined organic extracts were washed with brine, and then dried over Na2SO4 and evaporated to yield O-benzyl-N-vinyl-hydroxylamine (LXVI) in quantitative yield. 400 MHz 1H NMR (DMSO-d6, ppm) 7.48 (0.5H, q, J=5.8 Hz), 7.39-7.26 (5H, m), 6.86 (0.5H, q, J=5.5 Hz), 5.06 (1H, s), 4.97 (1H, s), 1.78 (1.5H, d, J=5.5 Hz), 1.76 (1.5H, d, J=5.8 Hz).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1.[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl>>[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22][N:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH2:7][CH2:6][NH:5][C:4](=[O:3])[C:16]1=2
Reactant: O=C1NCCc2c1[nH]c1ccccc21
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1c2c(c3ccccc31)CCNC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous DMF (4 mL) and a 60% dispersion of sodium hydride in mineral oil (181 mg, 4.52 mmol) and the reaction mixture was cooled to 0° C. 1,2,3,4-tetrahydro-1-oxo-beta-carboline (841 mg, 4.52 mmol) was added, and the reaction was stirred at 0° C. for 15 min. After this time, 2-(trimethylsilyl)ethoxymethyl chloride (829 mg, 4.97 mmol) was added, and the reaction was stirred at 0° C. for 1 h. The reaction mixture was then partitioned between water (10 mL) and ethyl acetate (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×10 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 117a in 57% yield (818 mg) as a colorless oil: 1H NMR (500 MHz, CDCl3) d 7.67 (d, 1H, J=8.0 Hz), 7.65 (d, 1H, J=8.0 Hz), 7.46 (t, 1H, J=8.0 Hz), 7.27 (t, 1H, J=8.0 Hz), 6.14 (s, 2H), 5.72 (br s, 1H), 3.75 (t, 2H, J=7.0 Hz), 3.66 (t, 2H, J=8.0 Hz), 3.14 (t, 2H, J=7.0 Hz), 0.96 (t, 2H, J=8.0 Hz), −0.25 (s, 9H).
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10]C=2)[C:6](=O)C1=O)CC.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCCCCC>>[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:10][CH2:9][CH2:8][CH:7]([CH3:12])[CH3:6])[C:20](=[O:25])[C:19]2=[O:26]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CCCCCCBr
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCCC(C)C

Procedure:
This compound was prepared in a similar method as 1-propylindoline-2,3-dione by reacting commercially available 5-methyl isatin (purchase from Fisher Scientific) with commercially available 1-bromo-5-methylpentane (purchase from Fisher Scientific). 1H NMR δ 7.42 (s, 1H), 7.38 (ddd, 1H), 6.79 (d, 1H), 3.68 (t, 2H), 3.34 (s, 3H), 1.69 (m, 2H), 1.60 (m, 1H), 1.27 (m, 2H), 0.88 (d, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][N:11]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].[CH2:26]([O:33][C:34]([NH:36][CH2:37][C:38](O)=[O:39])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[Br:16][C:13]1[CH:14]=[CH:15][N:11]([NH:10][C:38](=[O:39])[CH2:37][NH:36][C:34](=[O:35])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]=1[C:17](=[O:18])[NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nn1ccc(Br)c1C(=O)Nc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)OCc1ccccc1)Nn1ccc(Br)c1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
DIEA (10.5 ml, 60 mmol) was added at 0° C. over a mixture of 1-amino-3-bromo-N-phenyl-1H-pyrrole-2-carboxamide (5.1 g, 18 mmol) and 2-(benzyloxycabonylamino)acetic acid (5.33 g, 25 mmol) in anhydrous ethyl acetate (100 ml). After 15 min T3P® solution (50% AcOEt, 15 ml) was slowly added and stirred 20 min at 0° C. and then at room temperature overnight. Further DIEA (5 ml, 30 mmol), 2-(benzyloxycabonylamino)acetic acid (2.66 g, 25 mmol) and T3P® solution (50% AcOEt, 7 ml) were added and the reaction mixture was stirred at room temperature overnight. More ethyl acetate was added and the reaction crude was washed with water and brine, dried over magnesium sulphate and the solvent was removed under vacuum. The residue was purified by flash chromatography using Isolera® Purification System (0-40%, hexane-AcOEt) to give 7.81 g (41% yield) of the final product with a purity of 45% that was used in the next step without further purification.
Reaction SMILES: C1C2C(=CC=CC=2)CC(C(O)=O)N1.O[C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][C@@H:20]([C:25]([NH:27][C@H:28]([CH2:32][N:33]3[CH2:38][CH2:37][C@:36]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=4)([CH3:39])[C@@H:35]([CH3:47])[CH2:34]3)[CH:29]([CH3:31])[CH3:30])=[O:26])[NH:21][CH2:22]2)=[CH:17][CH:16]=1.C(O)(C(F)(F)F)=O>>[OH:46][C:42]1[CH:41]=[C:40]([C@:36]2([CH3:39])[CH2:37][CH2:38][N:33]([CH2:32][C@@H:28]([NH:27][C:25]([C@H:20]3[CH2:19][C:18]4[C:23](=[CH:24][CH:15]=[CH:16][CH:17]=4)[CH2:22][NH:21]3)=[O:26])[CH:29]([CH3:31])[CH3:30])[CH2:34][C@@H:35]2[CH3:47])[CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)[C@@H](CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1)NC(=O)[C@@H]1Cc2ccc(O)cc2CN1
Agent: O=C(O)C1Cc2ccccc2CN1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1)NC(=O)[C@H]1Cc2ccccc2CN1

Procedure:
3-[1-(2S-Amino-3-methylbutyl)-3R,4R-dimethyl-4-piperidinyl]phenol (23) was coupled to 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as described for compound 15 and de-protected with TFA as previously described to give crude product which was purified by silica preparative thin layer chromatography (50% (CHCl3:MeOH:NH4OH, 80:18:2) in CHCl3, yielding 0.028 g (3R)-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (16). 1H NMR (CDCl3): 7.22 (d, J=8.8 Hz, 1H), 7.05-7.13 (m, 3H), 6.98-7.01 (m, 1H), 6.79 (s, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.65 (dd, J=7.9, 1.8 Hz, 1H), 4.05-4.14 (m, 1H), 3.99 (s, 2H), 3.56 (dd, J=10.7, 4.9 Hz, 1H), 3.18 (dd, J=16.5,4.8 Hz, 1H), 2.67-2.82 (m, 3H), 2.31-2.54 (m, 4H), 2.18-2.25 (m, 1H), 1.86-1.96 (m, 2H), 1.52 (d, J=12.9 Hz, 1H), 1.25 (s, 3H), 0.92 (t, J=7.6 Hz, 6H), 0.67 (d, J=6.9 Hz, 3H). LRMS (ES) m/z 450.3.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.Cl.CN.CC([O-])=O.[Na+].[N+:19]([CH3:22])([O-:21])=[O:20]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:22][N+:19]([O-:21])=[O:20])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 4-bromo-2-chlorobenzaldehyde (7.5 g, 34 mmol) in nitromethane was added methylamine hydrochloride (1.3 g, 22 mmol), NaOAc (1.8 g, 22 mmol). The mixture was vigorously stirred for 18 h at room temperature. The reaction mixture was diluted with water (60 mL) and extracted with CH2Cl2 (3×100 mL), organic phases dried (Na2SO4), evaporated to afford the desired product (8.5 g, 95%) as a light yellow oil: ESI MS m/z 262 [C8H5BrClNO2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:26]([N:27]1[CH2:32][CH2:31][N:30]([CH2:18][CH2:17][CH2:16][CH:14]2[O:13][N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:15]2)[CH2:29][CH2:28]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)cc1OC
Yield: 71.9 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (20.0 mg, 0.079 mmol), 1-(diphenylmethyl)piperazine (19.94 mg, 0.079 mmol), molecular sieve(5 beads) and NaBH(OAc)3 (50.2 mg, 0.237 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 28.4 mg (72.0%) of the target compound was obtained.