Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[CH:6]=O.[C:15]([N:18]1[CH2:23][C:22](=[O:24])[N:21](C(=O)C)[CH2:20][C:19]1=[O:28])(=[O:17])[CH3:16].CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(C)(C)C.C(OCC)(=O)C>[C:15]([N:18]1[CH2:23][C:22](=[O:24])[NH:21][C:20](=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:19]1=[O:28])(=[O:17])[CH3:16]
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: COc1cc(C=O)ccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: COc1cc(C=C2NC(=O)CN(C(C)=O)C2=O)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of crude 3-methoxy-4-(trifluoromethyl)-benzaldehyde and 1,4-diacetylpiperazine-2,5-dione (1.98 g) in a mixture of N,N-dimethylformamide (10 ml) and tert-butanol (10 ml) was added potassium tert-butoxide (1.12 g) at 5° C. The mixture was stirred for 18 hours at room temperature. Water (30 ml) and ethyl acetate (100 ml) were added to the mixture and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 50% of ethyl acetate in hexane as an eluent to give 1-acetyl-3-[[3-methoxy-4-(trifluoromethyl)phenyl]methylene]piperazine-2,5-dione (2.11 g) as a powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[CH:3]=1.[F:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.[Cl-].[Cl-].[Cl-].[Cl-].[Na].[Na].[Pd+4].C(P(C(C)(C)C)CCCS(O)(=O)=O)(C)(C)C>[F:23][C:24]1[N:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([CH:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cn1c(=O)n(C2CCOCC2)c2c3cc(Br)ccc3ncc21
Agent: [Pd+4]
Agent: CC(C)(C)P(CCCS(=O)(=O)O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)n(C2CCOCC2)c2c3cc(-c4ccc(F)nc4)ccc3ncc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
Monopalladium(IV) disodium tetrachloride (0.975 g, 3.31 mmol) was added to 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (60.0 g, 165.64 mmol), (6-fluoropyridin-3-yl)boronic acid (25.7 g, 182.21 mmol), K2CO3 (68.7 g, 496.93 mmol) and 3-(di-tert-butylphosphino)propane-1-sulfonic acid (0.445 g, 1.66 mmol) in 1,4-dioxane (400 mL) and water (100 mL) at r.t. under air. The resulting mixture was stirred at 80° C. for 16 h. The reaction mixture was dilated with water and the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum. The resulting solid was dissolved with DCM (18 L) and the mixture filtered through celite to remove Palladium residues. The solvent was removed under reduced pressure to afford the desired material (60.0 g, 96%) as a white solid, which was used without further purification, NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.85-2.01 (2H, m), 2.86-3.02 (2H, m), 3.57-3.68 (5H, m), 4.16-4.31 (2H, m), 5.11 (1H, t), 6.98-7.19 (1H, m), 7.83 (1H, dd), 8.16 (1H, td), 8.30 (1H, dd), 8.50 (1H, s), 8.60 (1H, s), 8.77 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=379.2.
Reaction SMILES: C([O:3]CC)C.O1CCOCC1.[O:12]=[CH:13][C:14]([Cl:17])([Cl:16])[Cl:15].CN1C=CC=C1>CCCCCC.C1(C)C=CC=CC=1.C1C=CC=CC=1.C1COCC1>[Cl:15][C:14]([Cl:17])([Cl:16])[C:13]([OH:3])=[O:12].[O:12]=[CH:13][C:14]([Cl:17])([Cl:16])[Cl:15]
Reactant: CCOCC
Agent: Cn1cccc1
Agent: O=CC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(O)C(Cl)(Cl)Cl

Procedure:
In the first process of this invention, it is essential to react the pyrrole reactant with trihaloacetaldehyde to produce the adduct (II). 1-Methyl-2-(2',2',2'-trihalo-1'-hydroxyethyl)pyrrole (Formula (II); R=methyl) obtained using 1-methylpyrrole in this process is a known compound, and as to its synthetic method, it has been reported that 1-methylpyrrole is reacted with freshly distilled chloral in the presence of molecular quantities of zinc chloride, a Lewis acid [R. C. Blinn et al., J. Amer. Chem. Soc., 76, 37 (1954)]. However, it is difficult to use this process in industrial scale because the yield is very low such as only 26.5%. As a result of further studies on this process, the present inventors have found that it is possible to obtain the compound of the formula (II) in almost quantitative yield, by treating the reactants at from -10° C. to room temperature, without using added catalysts such as Lewis acid and the like. It was discovered that the rate of this reaction--which is preferably conducted in the presence of solvents which do not directly affect on the reaction, for example, ethereal solvents such as diethyl ether, dioxane, THF, and the like, and hydrocarbons such as benzene, toluene, hexane, and the like--is dependent on the origin (or the purity) of chloral used. Chloral from a freshly opened bottle did not react with N-methylpyrrole at room temperature and only after prolonged reflux (sometimes several days) was the adduct formed. In contrast, chloral from an old bottle reacted instantly at room temperature. Acting on the hypothesis that trichloroacetic acid, which is formed easily by the oxidation of chloral, does catalyze this reaction, the present inventors have found that the addition of organic acid such as trichloroacetic acid, acetic acid or p-toluenesulfonic acid to the reaction mixture accelerates this reaction. Among these three acids, p-toluene-sulfonic acid presently appears even more effective than the others. By conducting the process in the presence of a protonic acid added preferably in the form of either an organic acid or a cation exchange resin (e.g., Amberlyst), the adduct has been readily formed in almost quantitative yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:21]([N:23]=[C:24]=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CNC.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([N:23]([CH3:24])[CH3:21])=[O:15])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccccc1Nc1ccc2[nH]ncc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccccc1Nc1ccc2[nH]ncc2c1
Yield: 66.6 %

Procedure:
To a solution of 2-(1H-indazol-5-ylamino)benzoic acid (80 mg, 0.316 mmol) in N,N-dimethylformamide (0.5 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (73 mg, 0.379 mmol), hydroxybenzotriazole (58 mg, 0.379 mmol) and a 40%-aqueous dimethylamine solution (107 mg, 0.948 mmol), and the resulting mixture was stirred at room temperature for 4 hours. Then, a 5%-aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with a mixed solvent of ethyl acetate and toluene. The organic layer was washed with a 5%-aqueous sodium hydrogencarbonate solution and then a 5%-aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate/methanol=1/1/0.05) to obtain 2-(1H-indazol-5-ylamino)-N,N-dimethylbenzamide (59 mg, 67%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCn1c(=O)c(Cn2cncn2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 1,2,4-triazole (0.033 g) in dimethylformamide (0.7 ml) was stirred at ice-bath temperature with 60% sodium hydride (0.02 g) for 10 mins under nitrogen and then a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.14 g) in dimethylformamide (1.7 ml) was added to it. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and then washed several times with water. The organic layer was dried and evaporated under reduced pressure. The resulting crude reaction product was chromatographed on silica-gel (4 g). Elution with 2.5% methanol-ethyl acetate gave 1-hexyl-3-(1,2,4-triazol-1-ylmethyl)-4-methoxy-6-methyl-2(1 H)-quinolinone as white crystals (80%). That the expected product was obtained was confirmed by the spectral data: MS: m/e 354 (M+); NMR (CDCl3): δ4.15 (s, H, OCH3), 5.42 (s, 2H, CH2), 7.86, 8.5 (s, 2H, CH=).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>ClCCl>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Step A To a solution of 3-methanesulfonyl-propan-1-ol (Cambridge) (0.5 g, 3.6 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (0.5 g, 5 mmol), and methanesulfonyl chloride (0.3 mL, 4 mmol, Aldrich). The reaction mixture was stirred at 0° C. for 2 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude methanesulfonic acid 3-methanesulfonyl-propyl ester as a yellow oil (Yield 0.7 g, 90%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:38][CH2:39][CH2:40][OH:41]>[Cu]I>[OH:41][CH2:40][CH2:39][NH:38][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(Nc1cc2ccc(NCCO)cc2cn1)C1CC1
Temperature: 130 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.51 mmol), copper(I) iodide (96 mg, 0.51 mmol), 1,10-phenanthroline (100 mg, 0.51 mmol) and cesium carbonate (216 mg, 0.66 mmol) were combined in a stainless steel container with 2-aminoethanol (3.0 mL). The resulting mixture was stirred at 120-140° C. for 12 hours under nitrogen. The reaction mixture was concentrated and purified via TLC to afford the desired product (23.4 mg, 17%). LCMS (ESI): RT (Min)=0.959, M+H+=271.8, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.75 (s, 1H), 8.19 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.77 (s, 1H), 6.00 (s, 1H), 4.74 (s, 1H), 3.61 (d, J=5.6 Hz, 2H), 3.17 (d, J=4.8 Hz, 2H), 1.99-1.95 (m, 1H), 0.79-0.75 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](C3C=CC([N+]([O-])=O)=CN=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].CC(C)[C@H](N1CC2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C1=O)C(OC)=O.Br[C:56]1[CH:57]=[N:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=1>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(Cl)Cl>[CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:56]3[CH:57]=[N:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cn3)cc2C1=O
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1=O
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])nc3)cc2C1=O
Yield: 33 %

Procedure:
The compound of example 489 was prepared analogous to the compound of example 391 by reaction of the compound of example 390, 3-bromo-6-nitro pyridine and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])[NH2:25].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]([C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([C:24](=[O:26])[NH2:25])[CH:32]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)N1C2C=C(c3cccc(C(N)=O)c3)CC1CC2
Temperature: 70 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a 250 mL flask was added 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (20 g, 56 mmol), 3-carbamoylphenyl boronic acid (10.2 g, 61 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2 dba3) (2 g, 2.2 mmol), tricyclohexylphosphine tetrafluoroborate (PCy3HBF4) (1.65 g, 4.4 mmol) and KF (9.8 g, 168 mmol). The reagents were purged with nitrogen for 5 min, and then THF (120 mL) and DMF (30 mL) was added. The suspension was stirred and purged with nitrogen for another 5 min, then heated to 70° C. After 2 h at 70° C., the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was partitioned between EtOAc (350 mL) and 0.5 N NaOH (400 mL)/brine (50 mL). The organic layer was separated and dried with Na2SO4. A quarter of the solution was removed. The remainder of the solution was concentrated to ˜100 mL to which hexanes (50 mL) was added. Solid precipitates were observed. The solution volume was reduced by 10 mL, hexanes (10 mL) was added, and the slurry was stirred at 0° C. for 1 h. The solids were filtered and dried to give the title intermediate (8.4 g) as light yellow solids. The mother liquor was further concentrated to give more solid precipitate, which was filtered to provide additional product (0.5 g). (Combined 66% yield).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][S:3]1.C(OCC)C.Cl[C:19]([O:21][C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[O:20].O>N1C=CC=CC=1.C(Cl)Cl>[C:22]([O:21][C:19]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:20])([CH2:25][CH3:26])([CH3:24])[CH3:23]
Reactant: CCOC(=O)Cc1csc(=N)[nH]1
Reactant: CCC(C)(C)OC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1

Procedure:
To a solution of ethyl 2-(2-amino-1,3-thiazol-4-yl) acetate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (14 g.) in a mixture of pyridine (40 g.) and methylene chloride (300 ml.) was gradually added diethyl ether solution of tert-pentyl chloroformate (70 ml.) containing 0.35 mole of tert-pentyl chloroformate over 10 minutes at -20° C. with stirring, and the mixture was stirred for 2 hours at the same temperature and further stirred for 0.5 hour at 0° C. After the reaction, the reaction mixture was poured into water (200 ml.), and then the organic layer was separated. The organic layer was washed with 2 N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water in turn and then dried over magnesium sulfate. The solvent was distilled off from the organic layer to give dark brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2 -(2-tertpentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (12 g.).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH:23]=O.[Cl-].[NH4+]>ClCCl>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH:23]=[N:2][OH:3]
Reactant: NO
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CC=NO
Yield: 85.1 %

Procedure:
Hydroxylamine hydrochloride (5.74 g, 82.6 mmol) and triethylamine (31.4 mL, 225 mmol) were sequentially added to a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde (14.2 g, 75.1 mmol) in dichloromethane. The resultant suspension was stirred at room temperature for several hours and adjusted to pH 6 with the addition of saturated aqueous ammonium chloride. The aqueous layer was then separated and extracted with several portions of dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on a vacuum filter funnel (silica gel, eluting with 3% to 5% methanol in dichloromethane). The product was then dissolved in dichloromethane, and the solution was washed with 1 N hydrochloric acid. The aqueous layer was extracted a few times with dichloromethane, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated to provide 13.05 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanal oxime as a white solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]([C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>C(O)C>[C:3]([O:7][C:8]([NH:10][CH:11]([CH:17]([OH:18])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)C(O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
461 mg (0.7 mmol) of sodium borohydride are carefully added to a solution of 4.1 mg (12.2 mmol) of ethyl 2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-3-oxo-propanoate in 40 ml of ethanol cooled to −78° C. After stirring for 15 minutes, the reaction medium is hydrolysed with a saturated aqueous solution of ammonium chloride. The ethanol is evaporated off and the aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by silica gel chromatography, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 3 g of ethyl 2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoate are obtained in the form of a yellow oil with a yield of 72%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH2:40]([N:47]=[C:48]=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:40]([NH:47][C:48](=[O:49])[O:31][CH2:30][N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)[CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 35 °C
Reaction time: 24 h

Procedure:
To a solution of hemi-aminal A1 from Example 1 (4 g, 8.4 mmol), 4-dimethylaminopyridine (0.15 g, 1.3 mmol) and triethylamine (1.1 mL, 7.5 mmol) in dichloromethane (30 mL) was added benzylisocyanate (1.03 mL, 8.3 mmol) and the reaction mixture stirred for 24 hours. The reaction mixture was then heated at 35° C. for 20 hours, cooled and washed with water/brine (1:1, 50 mL). The organic phase was dried over MgSO4, filtered and evaporated under vacuum. The residue was further purified by chromatography on silica eluting with ethyl acetate/dichloromethane/methanol (1:1:0.1) to give the desired product as an off white foam (530 mg, 14% yield). 1H NMR (CDCl3, 300 MHz) δ 1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H), 300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H), 6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16 (m, 1H), 7.23-7.35 (m, 6H); m/z (M+H) 611.12 and 613.10.
Reaction SMILES: O=[C:2]([CH2:7][C:8](=O)[CH3:9])[C:3]([O:5][CH3:6])=[O:4].O1CCCC1.[Cl:16][C:17]1[C:18]([NH:24][NH2:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>C(O)(=O)C>[Cl:16][C:17]1[C:18]([N:24]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[CH:7][C:8]([CH3:9])=[N:25]2)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: COC(=O)C(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)nn1-c1ncc(Cl)cc1Cl
Yield: 50.7 %

Procedure:
To a 100 mL flask, methyl 2,4-dioxopentanoate (2.88 g, 0.020 mol), tetrahydrofuran (15 mL), acetic acid (30 mL), and 3,5-dichloro-2-hydrazinylpyridine (3.56 g, 0.020 mol) were added sequentially. The reaction mixture was heated to reflux for 2 hours and then the mixture was concentrated by rotary evaporator. Then ethyl acetate (150 mL) and water (100 mL) was added, the organic layer was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/5) to give the product (2.9 g) as a white solid in 50% yield. Melting point: 97-98° C. 1H NMR (300 MHz, CDCl3): 8.432 (d, 1H), 7.888 (d, 1H), 6.802 (s, 1H), 3.760 (s, 3H), 2.370 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:12]Br>S([O-])([O-])(=O)=O.[Ag+2].OS(O)(=O)=O>[Br:12][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: Cc1cccc2cccnc12
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1ccc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
To a solution of 8-Metyl quinoline (30 g, 0.209 mol) in Conc.H2SO4 (300 ml) was added Silver sulphate (97.98 g, 0.314 mol) in lots at 0° C. and followed by Bromine (10.74 ml, 0.209 mol) drop wise for 10 min. After addition of Bromine, the reaction mixture was stirred at RT for 4 h and the reaction completion was confirmed by TLC. After completion of reaction the reaction mixture was quenched with ice and basified with NH4OH solution and extracted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous sodium sulphate and concentrated to afford (43 g, 92.4% yield) as dark brown liquid. The crude product was as such taken for next step without further purification. 1H NMR (DMSO-d6 400 MHz): δ 8.97-8.96 (dd, J=4.16, 5.8 Hz, 1H), 8.45-8.42 (dd, J=8.56, 10.2 Hz, 1H), 7.81-7.79 (d, J=7.68 Hz, 1H), 7.67-7.64 (dd, J˜8.52, 12.64 Hz, 1H), 7.53-7.51 (dd, J=7.64, 8.52 Hz, 1H), 2.66 (s, 3H).