Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([CH3:24])[C:11]=1[S:12]([NH:15][C:16]([N+:18]1[CH:23]=CC=CC=1)=[O:17])(=[O:14])=[O:13])=[O:6])[CH3:3].NC1[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=1.O>C(#N)C>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([O:34][CH3:35])[N:27]=[C:23]([NH:18][C:16]([NH:15][S:12]([C:11]2[N:10]([CH3:24])[N:9]=[CH:8][C:7]=2[C:5]([O:4][CH2:2][CH3:3])=[O:6])(=[O:13])=[O:14])=[O:17])[N:31]=1
Reactant: CCOC(=O)c1cnn(C)c1S(=O)(=O)NC(=O)[n+]1ccccc1
Reactant: COc1cc(OC)nc(N)n1
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnn(C)c1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
3.42 g (10.1 mmole) of 1-[[(4-ethoxycarbonyl-1-methylpyrazole-5-sulfonyl)amino]carbonyl]pyridinium hydroxide was dissolved in 10.00 g of dry acetonitrile. To the resulting solution was added 1.55 g (10.0 mmole) of 2-amino-4,6-dimethoxypyrimidine with stirring. The reaction mixture was stirred for one hour while maintaining the temperature of 40° to 45° C. to complete the reaction. After the reaction was completed, 25.00 g of water was added to the reaction solution. The mixture was then adjusted to pH 5 to 6, cooled to 25° C. and filtered. The resulting product was washed with water and acetonitrile and then dried to obtain 4.10 g (Yield 99%) of the title compound as the white powder.
Reaction SMILES: Cl.[OH:2][C:3]1[C:8]2=[N:9][C:10]([CH3:17])=[C:11]([CH2:14][CH2:15]O)[C:12](=[O:13])[N:7]2[CH:6]=[CH:5][CH:4]=1.[BrH:18]>>[BrH:18].[Br:18][CH2:15][CH2:14][C:11]1[C:12](=[O:13])[N:7]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[C:8]2=[N:9][C:10]=1[CH3:17]
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCO
Agent: Br
Agent: Cl
Product: Cc1nc2c(O)cccn2c(=O)c1CCBr
Yield: 34 %

Procedure:
A mixture of intermediate 9 (170 g) and hydrobromic acid (48%) (1000 ml) was stirred and refluxed overnight. The mixture was cooled and the precipitate was filtered off, yielding a first fraction of 100 g. The filtrate was evaporated, yielding a second fraction of 30 g. Both fractions were recrystallized from water, yielding 75 g (34%) of 3-(2-bromoethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydro-bromide (intermediate 15).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:12]([O:15][C:16](=O)C)(=O)[CH3:13].C(OC(OCC)OCC)C>>[CH2:12]([O:15][CH:16]=[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:13]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCCC(=O)C(=COCC)C(=O)OCC

Procedure:
A mixture of ethyl butyrylacetate (105.1 g), acetic anhydride (126 ml) and triethylorthoformate (117 ml) was stirred and boiled under reflux for 1.5 hours. The low boiling materials were distilled off under reduced pressure and the residue distilled under high vacuum to give ethyl 2-(ethoxymethylene)-3-oxohexanoate, b.p. 109°-120° C. (0.4 mmHg).
Reaction SMILES: C(S)[C@@H](O)[C@H](O)CS.[C:9]([O-:14])(=[O:13])[C:10]([CH3:12])=[O:11].[N:15]([CH2:18][C@H:19]1[O:25][CH:23]([OH:24])[C@@H:22]([NH:26][C:27](=[O:29])[CH3:28])[C@@H:21]([OH:30])[C@@H:20]1[OH:31])=[N+:16]=[N-:17].OC(C1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C1)O)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[N:15]([CH2:18][C@@H:19]([OH:25])[C@@H:20]([OH:31])[C@@H:21]1[O:30][C:10]([OH:11])([C:9](=[O:14])[OH:13])[CH2:12][C@H:23]([OH:24])[C@H:22]1[NH:26][C:27](=[O:29])[CH3:28])=[N+:16]=[N-:17]
Reactant: CC(=O)C(=O)[O-]
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CN=[N+]=[N-])[C@@H](O)[C@@H]1O
Agent: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CN=[N+]=[N-])OC(O)(C(=O)O)C[C@@H]1O
Yield: 84 %

Procedure:
In a 10 mL of 0.1M potassium phosphate buffer (pH 7.5) containing 10 mM DTT and 0.5M pyruvate were dissolved 50 mg of 6-azido-6-deoxy-N-acetylmannosamine and 1.5 mg of NeuAc aldolase. The starting material was consumed in 14 hours. The solution was lyophilized and the purification was carried out with Bio Gel P-2 gel filtration (3×90 cm) chromatography with a flow rate of 6 mL/40 minutes, at 4° C. The fractions containing the product were pooled and freezed dry to give Compound 203 in 84 percent yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[O:16][CH:15]=[N:14][CH:13]=1.[H][H]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[O:16][CH:15]=[N:14][CH:13]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnco1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1-c1cnco1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Compound 2f (50 g, 1.0 eq., Nippon Soda) and 1% Pt, 2% V on C (2.78 g, 64% wet, 2.0 wt % on a dry basis, Degussa Type CF1082) were charged to a hydrogenation vessel under nitrogen. Ethyl acetate (500 ml, 10 vol) was added and the mixture was heated to 60° C. The vessel was pressurized with hydrogen (1.00 bar overpressure) and the mixture was stirred at 60° C. The reaction was complete within 3 hours. The pressure was released and nitrogen was bubbled through the reaction mixture. The reaction mixture was filtered through Celite® and washed with EtOAc (100 ml, 2 vol). The solvent level was reduced to 4 vol by distillation at reduced pressure and toluene (500 ml, 10 vol) was charged into the vessel. The solvent level was reduced to 4 vol by distillation at reduced pressure and a second portion of toluene (500 ml, 10 vol) was charged into the vessel. The solvent level was reduced to 5 vol under reduced pressure then the mixture was heated to 90° C. at atmospheric pressure to dissolve any solids. The solution was then cooled slowly to 20° C. to induce crystallization. The resulting yellow solid was filtered and washed with toluene (100 ml, 2 vol) to give compound 2g which was dried in a vacuum oven at 50° C. with a nitrogen bleed until a constant weight of 39.4 g (91%) was achieved.
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][N:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[O:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][N:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(O)C1C2
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC2CCC(=O)C1C2
Reaction time: 66 h
Yield: 97.1 %

Procedure:
To a solution of t-butyl 4-hydroxy-6-azabicyclo[3.2.1]octane-6-carboxylate (800 mg, 3.52 mmol) in dry dichloromethane (75 ml) was added Celite (2 g), sodium acetate (0.82 g, 10 mmol) and pyridinium chlorochromate (1.1 g, 5.1 mmol). The mixture was stirred under nitrogen for 66 h. The dark suspension was diluted with ether (50 ml) and filtered through a plug of silica gel to give a light brown solution. Removal of solvent by rotary evaporation and purification by column chromatography of the residue, using a methanol/dichloromethane gradient (0-10% methanol) as eluent, gave the ketone as a pale yellow oil (770 mg, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[C:15]2[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[CH3:16][C:13]1[C:12](=[O:17])[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C:15]=2[N:14]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Cc1nc2c(Oc3cccc(N)c3)ccnc2[nH]c1=O
Product: Cc1nc2c(Oc3cccc(NC(=O)c4cccc(OC(F)(F)F)c4)c3)ccnc2[nH]c1=O

Procedure:
Method G1 was used with 8-(3-aminophenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-trifluoromethoxybenzoyl chloride to afford the title compound as a slightly yellow solid (74 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[CH:10]([CH3:14])[CH2:9][NH:8][C:7]=2[N:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[S:25])[CH:10]([CH3:14])[CH2:9][NH:8][C:7]=2[N:15]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(n1)NCC(C)C(=O)N2
Solvent: C1CCOC1
Product: COc1ccc2c(n1)NCC(C)C(=S)N2
Temperature: 80 °C
Reaction time: 12 h
Yield: 61.9 %

Procedure:
To a solution of 7-methoxy-3-methyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-one (2.7 g, 13.03 mmol) in anhydrous tetrahydrofuran (30 mL) was added Lawesson's Reagent (8.32 g, 20.60 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated in vacuo and washed with brine (20 mL), and then the mixture was filtered through a celite pad. The filtrate was extracted with acetic ester (20 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloromethane/Methanol: 80:1→50:1→30:1) to give 7-methoxy-3-methyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepine-2(3H)-thione (1.8 g, 62%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]2[NH:5]1.I[CH3:29]>C1COCC1>[CH3:29][N:5]1[C@@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2NC(=O)c3c(cccc3C(F)(F)F)[C@@H]2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(cccc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a suspension of NaH (9 mg of 60% in mineral oil, hexane-washed, 0.22 mmol) in 2 mL of THF at ambient temperature was added (3aS,9bR)-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 13, Part A (52 mg, 0.145 mmol) as a solution in 2 mL of THF. The reaction was stirred for 20 min, at which time gas evolution had ceased and the reaction mixture was homogeneous. Then there was added iodomethane (0.023 mL, 0.36 mmol) and the reaction was allowed to stir at ambient temperature for 18 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 3:1 hexane/EtOAc) to afford 40 mg (74%) of the title compound. LRMS (ESI): 371.12 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Br[CH:21]([CH3:23])[CH3:22].Cl>CN(C)C=O.C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([CH:21]([CH3:23])[CH3:22])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: CC(C)Br
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)N(c1ccncc1)c1csc2cc(Cl)ccc12
Temperature: 50 °C
Yield: 76.1 %

Procedure:
A solution of 6-chloro-3-(4-pyridinylamino)benzo[b]thiophene (2.43 g, 9.3 mmole) in 20 mL of dimethylformamide was added to a suspension of NaH (0.48 g of 60% in oil, 12.1 mmole) in DMF. To this was added 2-bromopropane (1.26 g, 10.2 mmole) and the reaction mixture was heated to 50° C. During the next 5 hours, an additional 200 mg of NaH and 1 g of the bromo compound were added three separate times. The reaction mixture was then quenched into water and extracted with ethyl acetate (3×). The combined organics were washed with water (3×), dried (MgSO4), filtered and concentrated. Purification of the residue via flash chromatography (C6H5CH3 →5%Et3N/C6H5CH3) gave 1.57 of an oil. This was dissolved in acetonitrile, treated with ethereal HCl and the salt was crystallized out with additional ether to give 1.20 g of a yellowish powder, mp: 244°-246° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4](=[C:6]([C:8](=[CH:10][CH:11]=1)[CH3:9])[CH3:7])[CH3:5].[SH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19].[Na]>>[CH3:5][C:4]1[C:3]([CH3:2])=[CH:11][CH:10]=[C:8]([CH3:9])[C:6]=1[CH2:7][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19]
Reactant: Cc1ccc(CBr)c(C)c1C
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: Cc1ccc(C)c(CSc2cccc[n+]2[O-])c1C
Yield: 50 %

Procedure:
The intermediate 2-(2,3,6-trimethylphenylmethylthio)pyridine N-oxide is prepared from α2 -bromoprehnitene with 2-mercaptopyridine N-oxide, sodium salt by the procedure described in Example 2. Yield 50% theory. Melting point 108° - 110° C. Structure confirmed by IR and NMR.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:7][O:8]C(=O)C)(=[O:3])[NH2:2].C(OC[C@@H](C1C=CC=CC=1)COC(=O)C)(=O)N>>[C:1]([O:4][CH2:5][C@@H:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:7][OH:8])(=[O:3])[NH2:2]
Reactant: CC(=O)OC[C@@H](COC(N)=O)c1ccc(Cl)cc1Cl
Agent: CC(=O)OC[C@@H](COC(N)=O)c1ccccc1
Product: NC(=O)OC[C@H](CO)c1ccc(Cl)cc1Cl
Yield: 78.9 %

Procedure:
The title compound was synthesized in a similar manner to that of Example XXII, except that (S)-3-acetoxy-2-(2,4-dichlorophenyl)propanol carbamate, instead of (S)-3-acetoxy-2-phenylpropanol carbamate, was used as a starting material. Yield 78.9%. Purity 99.7%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][NH2:23])[CH:17]=1.C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:23][N:22]([C:18]2[CH:17]=[C:16]([C:15]([F:14])([F:25])[F:24])[CH:21]=[CH:20][CH:19]=2)[C:7]=1[CH3:8])[CH3:2]
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn(-c2cccc(C(F)(F)F)c2)c1C
Yield: 85.4 %

Procedure:
14.9 grams 3,3-diacetyl-propionic acid-ethyl ester, 14.1 grams (α,α,α-trifluoro-m-tolyl)-hydrazine, 4.8 grams glacial acetic acid and 100 milliliters ethanol were mixed, and the mixture heated to boiling temperature under reflux for 1 hour. The reaction mixture was evaporated and the residue distilled to produce 22.3 grams of crude 3,5-dimethyl-1-(α,α,α-trifluoro-m-tolyl)-pyrazol-4-acetic acid ethyl ester. This ester was saponified aas and worked up in accordance with the method described in Example (1b), using 4.0 grams sodium hydroxide as the base. The free acid was precipitated from the alkaline solution obtained in this manner by the addition of 2% acetic acid and of sufficient aqueous hydrochloric acid to complete the precipitation.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Cl)([O-:11])=[O:10].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>COCCOC.CCOCC.CCCCCCCCCCCC.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].CC([O-])(C)C.[Na+]>[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)([O-:11])=[O:10]
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
Pd2(dba)3 (4.6 mg, 0.005 mmol, 1 mol % Pd), ligand 1 (see FIG. 1) (8.4 mg, 0.02 mmol) and NaOt-Bu (2 mg, 0.02 mmol) were stirred in 1 mL DME (anhy). After 10 minutes, the solution was added to a test tube containing (under an Argon atmosphere) K3PO4 (297 mg, 1.4 mmol), 2-nitrochlorobenzene (158 mg, 1.0 mmol), and p-anisidine (148 mg, 1.2 mmol). The test tube was capped and heated at 100° C. for 35 hours. The reaction mixture was cooled to r.t., diluted with ether and dodecane was added as an internal standard. The reaction mixture was purified by column chromatography (10% EtOAc/hexanes) to yield 238 mg (98% yield) of the product.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][CH:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].CI.CN(P(N(C)C)(N(C)C)=O)C.[Cl-].[NH4+]>C1COCC1>[CH3:13][C:14]([CH3:1])([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: [Li]CCCC
Reactant: COC(=O)C(C)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
n-Butyl lithium (1.49N, 28.3 ml, 42.2 mmol) was added dropwise to a solution of diisopropylamine (5.9 ml, 42.2 mmol) in 50 ml of anhydrous THF at -78° C. under argon atmosphere. After the mixture was stirred at -78° C. for 20 minutes, methyl 2-methyl-3-phenylpropionate (5.00 g, 28.1 mmol) was added dropwise. After the mixture was stirred at -78° C. for 30 minutes, a solution of methyl iodide (2.6 ml, 42.2 mmol) in HMPA (1.5 ml, 8.43 mmol) was added dropwise. The reaction mixture was further stirred at -78° C. for 2 hours, and 10 ml of an aqueous saturated solution of ammonium chloride was added. The mixture was extracted with ether (50 ml×4), and then, the combined ether layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. This residue was distilled to give a colorless oil of methyl 2,2-dimethyl-3-phenylpropionate (1.8909 g, yield 51.7%, b.p. 127.5°-131° C./18 mmHg), which was assigned the structure by the following data:
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[CH3:15][C:10]([CH3:16])([CH2:9][NH:8][CH3:6])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)(C)CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNCC(C)(C)C(=O)OC
Temperature: -10 °C
Reaction time: 3 h
Yield: 125 %

Procedure:
Under an nitrogen atmosphere, methyl 3-(tert-butoxycarbonyl(methyl)amino)-2,2-dimethylpropanoate (250 mg, 1.019 mmol) was suspended in dry THF (5 mL) and cooled to −10° C. 4.0 M HCl in dioxane (5.10 mL, 20.38 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue co-evaporated with DCM (5 mL) to give 185 mg of crude product as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH:2]=1.[Cl:18]N1C(=O)CCC1=O>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(-c3cccnc3)ccc2N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(-c3cccnc3)cc(Cl)c2N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one (560 mg, 2.50 mmol) in 5 ml dry DMF was added N-chlorosuccinimide (368 mg, 2.75 mmol) in 5 ml dry DMF over a period 2 h at 65° C. After additional 3 h at 65° C., the mixture was poured into 75 ml ice water and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water and brine, dried over MgSO4 and the solvent was evaporated in vacuo. 8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one was obtained after flash chromatography on silica gel (hexanes/ethyl acetate, 3/7, Rf=0.15) and crystallization from acetone/diethylether as colorless needles (225 mg, 0.87 mmol, 35%), mp (acetone/diethylether) 178° C. 1H-NMR (500 MHz, DMSO-d6): δ=2.54 (m, 2H), 3.01 (m, 2H), 7.45 (ddd, 3J=8.0 Hz, 3J=4.8 Hz, 5J=0.8 Hz, 1H), 7.60 (d, 4J=2.0 Hz, 1H), 7.69 (d, 4J=2.0 Hz, 1H), 8.06 (ddd, 3J=8.0 Hz, 4J=2.5 Hz, 4J=1.5 Hz, 1H), 8.53 (dd, 3J=4.8 Hz, 4J=1.5 Hz, 1H), 8.88 (dd, 4J=2.5 Hz, 5J=0.8 Hz, 1H), 9.64 (s, 1H). 13C-NMR (125 MHz, DMSO-d6): δ=25.3, 30.3, 119.7, 123.8, 125.0, 125.6, 127.4, 131.7, 133.7, 133.8, 134.8, 147.3, 152.4, 170.3. MS m/z 258.95 (M+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Yield: 37 %

Procedure:
A solution of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (170 mg, 0.37 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously at room temperature for 120 hours. The mixture was diluted with ethyl acetate and acidified to pH 2 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 61 mg (37%) of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.6-7.4 (m, 4H), 7.3 (t, 1H, J=8 Hz), 7.1-6.9 (m, 3H), 6.6 (d, 1H, J=8 Hz), and 5 7 (s, 2H). IR (CHCl3, cm−1) 3423, 3201 (br), 1630, 1600, 1579, 1564, 1445, 1330, 1261, and 775. MS (ES) m/e 441, 443.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:9]([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:27]([O:26][C:24]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([CH2:17][CH2:18][CH:19]=[O:20])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCOC(=O)CC[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CCC=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
A solution of (S)-1-tert-butyl 5-ethyl 2-(bis(tert-butoxycarbonyl)amino)pentanedioate (1.7 g, 3.93 mmol) in dry tetrahydrofuran (30 mL) was cooled to −78° C. with acetone/dry ice bath and added diisobutylaluminum hydride (1.0 M in hexanes 5.9 mL, 5.90 mmol) dropwise over the period of 5 minutes. The reaction was complete after stirring for four hours, then quenched with water (1.5 mL) and allowed to warm to room temperature by removing the external cold bath. The resulting white thick solution was filtered through celite powder and washed with diethyl ether (200 mL). The filtrate was concentrated under reduced pressure and purified on 40 g silica gel column (eluent hexanes to 20% ethyl acetate in hexanes) to afford (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (0.90 g, 59.1% yield) as a thick oil. 1H NMR (CDCl3) δ ppm: 9.79 (s, 1H), 4.77 (dd, J=9.3, 5.2 Hz, 1H), 2.52 (m, 3H), 2.16 (m, 1H), 1.52 (s, 18H), 1.47 (s, 9H). 13C NMR (CDCl3) δ ppm: 201.2, 169.2, 152.4, 83.1, 81.5, 58.11, 40.7, 28.0, 27.9 and 21.9. MS (ESI+): 410 (M+Na)+.