Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[C:11]([C:17]#[N:18])=[CH:10][CH:9]=1.[NH2:19][C@@H:20]([C:24]([OH:26])=[O:25])[C@@H:21]([CH3:23])[OH:22]>CS(C)=O>[C:17]([C:11]1[C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:8]([NH:19][C@H:20]([C@H:21]([OH:22])[CH3:23])[C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1)#[N:18]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)c2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Temperature: 80 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
K2CO3 (1.50 g, 10.9 mmol) was added to a mixture of 4-fluorobenzo[b]thiophene-7-carbonitrile (770 mg, 4.35 mmol) and D-Allo-threonine (620 mg, 5.20 mmol) in DMSO (10 mL) at room temperature. The resulting mixture was heated to 80° C. and stirred for 15 h. After cooling to room temperature, the reaction mixture was poured into ice-water (150 mL) and extracted with 10% EtOAc in hexanes (2×50 mL). The aqueous phase was acidified to pH=2˜3 with 2N HCl and extracted with EtOAc (2×100 mL). The EtOAc extracts were washed with water, brine and dried with Na2SO4. Removal of the solvent gave the crude (2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (1.20 g, ˜100%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.81 (d, J=5.7 Hz, 1H), 7.70 (d, J=5.7 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H), 6.28 (d, J=8.2 Hz, 1H), 4.33 (m, 2H), 1.39 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:19][NH2:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 103.2 %

Procedure:
1.33 g (5 mmol) of 4'-chloro-2-(4-chlorophenyl)acetophenone was dissolved in 25 ml of ethanol, and 1.25 g (25 mmol) of hydrazine monohydrate was added thereto. The mixture was refluxed under heating for 2 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, and water was added to the residue. The mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 1.44 g of [4'-chloro-2-(4-chlorophenyl)acetophenone]hydrazone as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCn1nc(I)c2ccc(Cl)cc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CC)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
To a solution of 6-chloro-1-ethyl-3-iodo-1H-indazole (150 mg, 0.47 mmol) in THF (3 mL) at 0° C. was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.28 mL, 0.56 mmol). The bright yellow heterogeneous reaction mixture was stirred at 0° C. for 20 min then tributylchlorostannane (0.15 mL, 0.56 mmol) was added dropwise. Stirring was continued at 0° C. for 20 min then at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The exact reaction was repeated once more on the same scale. The residues from the two runs were combined and purified by silica gel chromatography with 10% to 50% EtOAc/heptane (0.5% Et3N) to provide 128 mg (29%) of 6-chloro-1-ethyl-3-tributylstannanyl-1H-indazole as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6]C(=O)OC(C)(C)C)[CH2:2]1.[CH3:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[CH3:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:1]1[CH2:5][CH2:4][C@@H:3]([NH2:6])[CH2:2]1
Reactant: Cc1cccc(C=O)c1C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cccc(CN2CC[C@@H](N)C2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.6 %

Procedure:
1H-NMR (300 MHz, CDCl3) δ 0.77-0.97 (2H, m), 1.05-1.30 (3H, m), 1.36 (3H, t, J=7.1 Hz), 1.40-1.86 (10H, m), 1.97-2.25 (3H, m), 2.37-2.64 (3H, m), 3.84-4.08 (1H, m), 4.30 (2H, q, J=7.1 Hz), 5.59 (1H, br peak), 6.35 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=8.6, 2.0 Hz), 8.74 (1H, d, J=2.0 Hz). Preparation 372 1) To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (1.00 g), 2,3-dimethylbenzaldehyde (720 mg), N,N-diisopropylethylamine (1.87 mL), and ethanol (10 mL) was added sodium triacetoxyborohydride (2.28 g). After stirring for 3 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and saturated NH4Cl. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. 2) To a mixture of above product and ethyl acetate (10 mL) was added 4N hydrogen chloride in ethyl acetate (8.40 mL) at 4° C. After stirring at room temperature for 5 hours, the reaction mixture was neutrized with saturated NaHCO3. The resulting mixture was evaporated in vacuo. The residue was added chloroform, dried over Na2SO4, filtered, and evaporated in vacuo to give (3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinamine (193 mg). 1H-NMR (300 MHz, CDCl3) δ 1.41-1.53 (1H, m), 2.12-2.46 (3H, m), 2.27 (3H, s), 2.29 (3H, s), 2.64-2.77 (2H, m), 3.42-3.51 (1H, m), 3.58 (2H, s), 7.00-7.14 (3H, m), MS (ES+) m/z 205 (M+1). Preparation 373
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:24][S:25]([O:1][CH:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 5 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester (7.55 g, 33.2 mmol), triethylamine (5.1 mL, 37 mmol), and 4-dimethylaminopyridine (36 mg, 0.3 mmol) was dissolved in 100 mL of dichloromethane and cooled to 5° C. in an ice bath. Methanesulfonyl chloride (2.6 mL, 33.2 mmol) was added to the solution dropwise and the reaction warmed to room temperature and stirred at room temperature for 18 hours. The reaction washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed to afford 3-methanesulfonyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester as a clear yellow oil (10.2 g); 1H NMR (300 MHz, DMSO-d6): 5.09-5.01 (m, 1H), 4.28 (s, 1H), 4.22 (s, 1H), 3.01 (s, 3H), 2.20-1.97 (m, 6H), 1.71-1.66 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]3[C:20]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])=[CH:21][NH:22][C:17]3=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:32]C(OC(Cl)=O)C>ClCCCl>[ClH:32].[ClH:32].[C:26]1([S:23]([C:20]2[C:18]3=[N:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][CH:16]=[C:17]3[NH:22][CH:21]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)nc12
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(N3CCNCC3)nc12
Reaction time: 16 h

Procedure:
A stirred mixture of 5-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (0.865 g, 2.00 mmol) and 1-chloroethylchloroformate (0.65 mL, 6.00 mmol) in 1,2-dichloroethane is heated at reflux temperature for 2.5 h under nitrogen, cooled and concentrated in vacuo, and reconcentrated from CH2Cl2 to a solid. This solid is heated with ethanol at reflux temperature under nitrogen for 2 h, cooled and concentrated in vacuo. The resultant residue is stirred in ethanol for 16 h and filtered. The filtercake is heated with methanol and two drops of concentrated hydrochloric acid for 30 h and concentrated in vacuo to a solid. This solid is chromatographed (silica gel, 5:95 concentrated ammonium hydroxide:ethanol as eluent) to afford the free amine of the title compound as a white solid. The free amine is dissolved in methanol, treated with 2.0 M aqueous hydrochloric acid (1.1 mL, 2.2 mmol) and concentrated to an off-white solid residue. This residue is recystallized from methanol to afford the title compound as an off-white solid, 165 mg (24% yield), mp 198-203° C. (foams), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]#[N:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][OH:22]>>[CH3:21][O:22][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[NH:20]
Reactant: COc1cccc2c(C#N)cn(CC3CCCCC3)c12
Reactant: CO
Product: COC(=N)c1cn(CC2CCCCC2)c2c(OC)cccc12
Reaction time: 72 h

Procedure:
Hydrochloride gas was bubbled, for 30 mins, through a cooled (0° C.) solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbonitrile (prepared as described in Example 1; 3.15 g, 11.0 mmol) in methanol (200 ml). The resulting mixture was left to stand for 72 h before being concentrated, by two thirds, in vacuo. Crystallisation of the product was achieved on addition of diethyl ether, and the resultant solid was collected via filtration to give 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboximidic acid methyl ester as the hydrochloride salt (3.82 g). 1-(Cyclohexyl)methyl-7-methoxy-1H-indole-3-carboximidic acid methyl ester hydrochloride salt (0.10 g, 0.297 mmol), hydrazine hydrate (0.289 ml, 5.94 mmol), aluminium chloride (39.6 mg, 0.297 mmol) and toluene (18 ml) were combined and the mixture was subjected to microwave irradiation for 60 min at 120° C. The resultant mixture was concentrated in vacuo, re-dissolved in toluene and concentrated in vacuo twice more. The obtained residue was suspended in a toluene/acetonitrile mixture (12/1) (19.5 ml) and chloroacetylchloride (0.118 ml, 1.49 mmol) added, before the mixture was subjected to microwave irradiation for 12 min at 120° C. The resultant mixture was concentrated in vacuo and re-dissolved in acetonitrile (3 ml). N-(2-methoxyethyl)isopropylamine (0.068 ml, 0.446 mmol), potassium carbonate (45.2 mg, 0.327 mmol) and sodium iodide (44 mg, 0.297 mmol) was added and the mixture was subjected to microwave irradiation for 5 min at 160° C. before being left to stand for 72 hours and then concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 2.5%-5% (v/v) methanol in dichloromethane to afford the title compound as a 1:1 hydrochloride salt (46 mg). 1H NMR (400 MHz, CD3OD): 0.95-1.12 (2H, m), 1.13-1.24 (3H, m), 1.50 (6H, s (br)), 1.55-1.73 (5H, m), 1.79-1.93 (1H, m), 3.34-3.50 (5H, m), 3.70-3.99 (6H, m), 4.24 (2H, d, J 6.4), 4.67 (2H, s (br)), 6.70 (1H, d, J 7.7), 7.16 (1H, t, J 7.7), 7.95 (1H, d, J 7.7), 8.02 (1H, s (br)); EsIMS: m/z 440.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16]CC)=[O:15])=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(C)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Yield: 90.6 %

Procedure:
8.6 g (34.6 mmol) of ethyl 4-(4-fluorophenyl)-1-methyl-3-pyrazolecarboxylate were heated to 70° for 60 minutes with 90 ml of 2N sodium hydroxide solution and 50 ml of water. Conversion into the acid form and recrystallization of the crude product from ethyl acetate/hexane yielded 6.9 g (90.4%) of 4-(4-fluorophenyl)-1-methyl-3-pyrazolecarboxylic acid as white crystals, melting point 146°-147°.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][O:14][C:13](=[O:17])[NH:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C(#N)C.Cl.C(=O)(O)[O-].[NH4+]>O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][O:14][C:13](=[O:17])[NH:12]2)[CH2:7][CH2:6]1
Reactant: O=C1NC(C2CCC3(CC2)OCCO3)CCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1CCC(C2CCOC(=O)N2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 250 mL round bottom flask was charge with 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3-oxazinan-2-one (1.39 g, 5.76 mmol) and acetonitrile (96 mL). A solution of concentrated HCl (6.4 mL) in water (19 mL) was added to the mixture. The mixture was stirred at room temperature for 20 h. Saturated aqueous ammonium bicarbonate was added until the pH was >7. The mixture was extracted with ethyl acetate. Dry organic layer with MgSO4, filter, and concentrate in vacuo to give the target material as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)[N:13]=[C:12]2[CH3:26])[CH:5]=1.[Cl:28]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:28])=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)[N:13]=[C:12]2[CH3:26])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)cc2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
To a solution of 4-methyl-3-[2-methyl-4-(2-methyl-thiazol-4-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-benzoic acid methyl ester from Step A, of Example 11 (120 mg, 0.31 mmol) in isopropanol (1.5 mL) was added N-chlorosuccinimide (46 mg, 0.34 mmol) and 2 drops of dichloroacetic acid. The solution was heated at 60° C. for three hours. The solution was allowed to cool and concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as colorless oil (125 mg, 96%). MS (M+H): 420
Reaction SMILES: [NH2:1][CH:2]([CH3:10])[CH:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[OH:4].C(N(C(C)C)CC)(C)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:10][C@H:2]1[C@H:3]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)[O:4][C:21](=[O:23])[NH:1]1
Reactant: CC(N)C(O)c1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1NC(=O)O[C@H]1c1nccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of diastereoisomers of 2-amino-1-thiazol-2-yl-propan-1-ol (4.20 g, 18.2 mmol) was dissolved in 160 mL of CH2Cl2. Diisopropylethylamine (11.1 mL, 63.6 mmol) was added at 0° C., followed by triphosgene (2.70 g, 9.09 mmol) dissolved in 40 mL of CH2Cl2. The reaction mixture was stirred at room temperature for 2 hours and then diluted with CH2Cl2. The organic solvents were separated, washed with aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (80 g SiO2) using EtOAc in hexane from 0% to 100 in order to give the title compound as a single enantiomer (2.16 g, 64%). LC-MS: [M+H] 185.3; Rt 0.45 min; (LCMS method 1). 1H NMR (400 MHz, CHCl3-d): 7.75 (d, 1H), 7.35 (d, 1H), 5.60 (br s, 1H), 5.32 (d, 1H), 4.18-4.09 (m, 1H), 1.45 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[C:12]([N+:20]([O-])=O)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]>C(O)(=O)C.[Fe]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:13]([CH2:16][C:17](=[O:18])[NH:20]3)=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Yield: 90.5 %

Procedure:
Iron powder (2.4 g) was added in one portion to 4.6 g of 3′-ethoxy-3-nitrobiphenyl-4-acetic acid in 40 mL of glacial acetic acid and refluxed for 2 hours. The reaction mixture was concentrated to dryness, treated repeatedly with ethyl acetate and filtered to remove the insolubles. The filtrate was washed twice with 1N hydrochloric acid and brine and then dried over anhydrous sodium sulfate and concentrated to give 3.5 g (91% yield) of 6-(3-ethoxyphenyl)-2-oxindole as a light brown solid.
Reaction SMILES: ClC1N=C2C(C=[CH:7][C:8]([N:12]3[CH:20](OC(OC4C=CC=CC=4)=O)[C:19]4[C:14](=CC=[CH:17][CH:18]=4)[C:13]3=O)=N2)=CC=1.C(#[N:34])C>>[CH2:20]([N:12]1[CH2:8][CH2:7][NH:34][CH2:14][CH2:13]1)[CH2:19][CH2:18][CH3:17]
Reactant: CC#N
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Product: CCCCN1CCNCC1

Procedure:
Following the procedure of Example 15 but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (5.1 g.) and 1-t.-butylpiperazine (5 g.) in acetonitrile (31 cc.), 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-t.-butylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (3.3 g.), melting at 240° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(N)cc2)cc1
Yield: 100.7 %

Procedure:
Combine {2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.3 g), 5% Pd/C (100 mg), and methanol (50 mL) then hydrogenated at 40 PSIG at room temperature for 2 hours. Filter off catalyst then concentrate on a rotary evaporator to yield {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.2 g): 1H NMR (CDCl3, 300.00 MHz): 7.12 (d, 2H, J=8.4 Hz), 6.89 (d, 4H, J=8.8 Hz), 6.72 (d, 2H, J=8.8 Hz), 4.61 (s, 1H), 3.42-3.32 (m, 2H), 2.77 (t, 2H, J=7.0 Hz), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH3:14].[C:15]12([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[C:15]12([CH2:25][C:26]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH3:14])=[O:27])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: Cc1nc2cc(Cl)ccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1nc2cc(Cl)ccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-7-chloro-2-methylquinazolin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59-1.74 (m, 12H), 1.93-1.98 (m, 3H), 2.08-2.18 (m, 2H), 2.40 (s, 3H), 7.57 (dd, J=8.5, 2.0 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 10.90 (s, 1H); MS (DCI/NH3) m/z 386 (M+H)+; Elemental Analysis: Calculated for C21H24ClN3O2.H2O: C, 62.45; H, 6.49; N, 10.40. Found: C, 62.63; H, 6.27; N, 10.36.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=O)[CH3:5].[C:13]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:25]([O:24][C:22]([C:21]1[C:4]([CH3:5])=[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:2][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CC(=O)C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccncc2)[nH]c(-c2ccccc2)c1C
Temperature: 0 °C
Yield: 16.3 %

Procedure:
A mixture of 1-amino-1-phenyl-propan-2-on hydrochloride (10.5 g, 50.5 mmol), ethyl isonicotinoylacetate (8.1 g, 42.1 mmol), and ammonium acetate (6.5 g, 84.2 mmol) in acetic acid (50 mL) was heated under reflux temperature for 6 hours. After cooling, the mixture was diluted with ice-water (50 mL). The whole was extracted with CH2Cl2 (30 mL×3), and the combined organic layers were dried over MgSO4, and concentrated in vaciio. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (2 : 1) to afford the title product (2.1 g, 16% yield) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[CH3:18][N:19]=[C:20]=[O:21]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[CH3:18][NH:19][C:20](=[O:21])[O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[OH:1])=[C:7]([CH3:13])[CH:8]=1
Reactant: CN=C=O
Reactant: Cc1cc(O)ccc1N=Cc1ccccc1O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1ccc(N=Cc2ccccc2O)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 4.54 grams (0.020 moles) of 4-(2-hydroxybenzylideneamino)-3-methylphenol prepared in Part A, 2.57 grams (0.045 moles) of methyl isocyanate, 100 milliliters of ethyl acetate and 5 drops of dibutyltin diacetate. The resulting reaction mixture was stirred for 24 hours at room temperature forming a precipitate. The precipitate was removed from the reaction mixture by filtration, washed with cold hexane and air dried to give 5.69 grams (0.020 moles) of 4-(2-hydroxybenzylideneamino)-3-methylphenyl methylcarbamate in the form of a yellow solid having a melting point of 156.5°-157° C. and the following structural formula: ##STR7##
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:22]([Cu])#[N:23]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:9]2[C:8]3[N:7]=[CH:6][CH:5]=[N:4][C:3]=3[C:2]([C:22]#[N:23])=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: N#C[Cu]
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3nccnc23)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2ccc(C#N)c3nccnc23)c1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 1.4) (4.54 g, 13.2 mmol) and CuCN (1.54 g, 17.1 mmol, 1.3 equiv) in NMP (50 mL) was stirred for 2 h at 180° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with EtOAc (10% aqueous solution of ethylenediamine) (150 mL), and filtered to afford 1.19 g (batch 1) of the title compound as a yellow solid. The filtrate was extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in EtOAc to provide 2.31 g (batch 2) of the title compound: ESI-MS: 292.1 [M+H]+; tR=4.53 min (System 1).