Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[C:7]([C:10]1[CH:34]=[CH:33][C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([OH:32])[C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)C(O)=O)=[CH:18][CH:17]=2)=[C:12]([Cl:35])[C:11]=1[OH:36])(=[O:9])[CH3:8].[N+](=C)=[N-]>O1CCCC1.CN(C)C=O>[C:7]([C:10]1[CH:34]=[CH:33][C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]([OH:32])[C:23]3[CH:31]=[C:30]([C:2](=[O:3])[CH2:1][Cl:6])[CH:29]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[C:12]([Cl:35])[C:11]=1[OH:36])(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(Cl)c1O
Agent: C=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C(=O)CCl)c3)cc2)c(Cl)c1O
Reaction time: 2 h
Yield: 100 %

Procedure:
Add oxalyl chloride (256 mg, 2.02 mmol) to a solution of 3-{[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid (0.786 mg, 1.84 mmol) in tetrahydrofuran (0.20M). Add dimethylformamide (5 drops). Add ethereal solution of diazomethane (1.90 mmol) and stir for 2 hours. Add hydrochloric acid (4N in dioxane) to quench unreacted diazomethane and evaporate solvents to afford the title compound (0.786 mg, 1.84 mmol, 94%): MS (m/z): 457 (M−H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[O:8][N:7]=1)=O)C.[OH-].[NH4+:19]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([NH2:19])=[O:3])[CH:10]=2)=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)on1
Agent: [OH-]
Product: NC(=O)c1cc(-c2ccc(Cl)cc2)on1
Reaction time: 72 h

Procedure:
Ethyl-5-(4-chlorophenyl)-3-isoxazolecarboxylate (139 grams) and 1.5 l. of conc. aqueous ammonium hydroxide were placed in a 2 l. 3-necked flask and stirred with a mechanical stirrer for 3 days. Following this, the reaction mixture was poured into 2 l. of water, filtered, and washed with water. The resulting dry solid was swirled with 1.6 l. of chloroform for 1/2 hour, filtered, and then dried in a vacuum oven for 3 hours, m.p. 224°-225° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[O-])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][O:32][CH3:33])[N:25]=[CH:24][N:23]=[C:22]2[O:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[C:35]([O:34][C:22]3[C:21]4[C:26](=[CH:27][C:28]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:19]([O:18][CH3:17])[CH:20]=4)[N:25]=[CH:24][N:23]=3)[CH:36]=2)=[O:12])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14]
Reactant: COc1ccc(NC(=O)[O-])cc1C(F)(F)F
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(OC)c(C(F)(F)F)c4)c3)c2cc1OC
Yield: 10 %

Procedure:
According to the procedure for Example 138B, 4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A (104 mg, 0.34 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline described in Example 117B (100 mg, 0.28 mmol). To this solution was added diisopropylethyl amine (74 μL, 0.42 mmol) and DMAP (20.0 mg, 0.16 mmol). The reaction was concentrated to dryness and partitioned between water and dichloromethane, and extracted twice. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude oil was purified by silica gel chromatography (methanol/dichloromethane 0-5%) to give 1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a white solid (18.6 mg, 10% yield). 1H (DMSO-d6) 8.90 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 7.85 (s, 1H), 7.60 (m, 3FI), 7.40 (m, 2H), 7.25 (m, 2H), 6.90 (d, 1H), 4.35 (m, 2H), 3.99 (s, 3H), 3.80 (s, 3H), 3.75 (m, 2H), 3.30 (s, 3H). LCMS (ESI) m/z 559 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH:23](Br)([CH3:25])[CH3:24].Cl>C(O)C>[ClH:1].[CH:23]([N:9]1[CH2:8][CH2:7][N:6]([C:4](=[O:5])[N:3]([CH3:2])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:11][CH2:10]1)([CH3:25])[CH3:24]
Reactant: CN(C)C(=O)N(C)C(=O)N1CCNCC1
Reactant: CC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1CCN(C(=O)N(C)C(=O)N(C)C)CC1
Yield: 65.1 %

Procedure:
To 20 ml of ethanol, were added 5.0 g of 1-(2,4,4-trimethylallophanoyl)piperazine hydrochloride and 3.7 g of sodium carbonate. To the resulting mixture, was added dropwise with stirring 2.5 g of isopropyl bromide. The mixture was allowed to react under reflux for 8 hours and the precipitate was removed by filtration. The filtrate was concentrated and the residue was purified with a silica gel column to obtain an oil. This oil was converted to hydrochloride in the customary way and recrystallized from ethanol to obtain 3.8 g (65% yield) of 1-(isopropyl)-4-(2,4,4-trimethylallophanoyl)piperazine hydrochloride having a melting point of 213°-215° C.
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:10])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:10])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCC1(c2cccc(O)c2)CCCCNC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC1(c2cccc(OCc3ccccc3)c2)CCCCNC1=O

Procedure:
To a solution of 3-ethyl-3-(3-hydroxy-phenyl)-azepan-2-one (Example 8, Step B) (1.28 g, 0.0055 mol) in DMF (50 mL) was added Cs2CO3 (1.79 g, 0.055 mmol) and benzyl bromide (0.653 mL, 0.0055 mmol) at ambient temperature. After 1.5 h the reaction was concentrated to remove most of the DMF and the residue was partitioned between EtOAc and H2O. The aqueous layer was washed with EtOAc, the organics combined, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].Br[CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([O:8][CH3:9])=[O:7]>C(#N)C>[N:1]([CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:16]([O:18][CH3:19])=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Solvent: CC#N
Product: COC(=O)CCCCCCC(N=[N+]=[N-])C(=O)OC
Yield: 99.1 %

Procedure:
Soldium azide (4.87 g, 75 mmol) was added to a solution of dimethyl 2-bromoazelate (5.9 g, 20 mmol) prepared according to Auguston, M, et al; Acta Chim. Acad. Sci. Hung; 46: 85 (1965) in acetonitrile, and the mixture was heated at reflux temperature for 4 h. The solvent was removed in vacuo, dichloromethane (80 ml) was added to the residue, and the mixture was washed with water. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo to give the title compound as an oil (5.1 g, 98% yield).
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[C:15]([C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[S:13][C:12]=2[CH:11]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Reaction time: 2 h

Procedure:
Phenoxathiin (22.9 g.) and acetyl chloride (8.8 ml) were dissolved in carbon disulphide (120 ml) and mechanically stirred while aluminium chloride (15.5 g) was added in small portions. The red mixture was stirred for 2 hr. at room temperature, then boiled under reflux on the water bath for a further 21/4 hr. The mixture was cooled and poured on to ice and hydrochloric acid, and the precipitated product filtered off, washed with water, and recrystallised once from ethanol and twice from petroleum ether (b.p. 80°-100° C.) to give the product m.p. 112° C.
Reaction SMILES: C[Si](C)(C)[C:3](=[O:16])[C:4]([F:15])([F:14])[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=[CH2:7].[N+](=[CH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N-].C(N(N=O)C(N[N+]([O-])=O)=N)CCCC.[OH-].[K+]>C(OCC)C>[F:14][C:4]([F:15])([C:3](=[O:16])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=[CH2:7]
Reactant: C=CC(c1ccccc1)C(F)(F)C(=O)[Si](C)(C)C
Reactant: CCCCC=[N+]=[N-]
Agent: CCCCCN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: C=CC(c1ccccc1)C(F)(F)C(=O)CCCCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
Trimethyl-(2,2-difluoro-3-phenyl-4-pentenoyl)silane (400 mg, 1.5 mmol) was dissolved in diethyl ether (10 ml). The resulting solution was cooled to 0° C. and etheral 1-diazopentane [prepared from 1-pentyl-3-nitro-1-nitrosoguanidine (0.6 g) added slowly to a two-phase mixture of aqueous KOH (0.67 g in 2 ml of water) and ethyl ether (10 ml)] was added dropwise. The mixture was then stirred at room temperature for 12 hours, refluxed for 0.5 hours and allowed to cool to room temperature. Excess diazopentane was destroyed and the enol ether hydrolyzed by the addition of excess aqueous acetic acid. The mixture was concentrated in vacuo to give 731 mg of crude product. This material was purified by flash chromatography using 1:4 chloroform:hexane as eluant. Pure fractions were combined and concentrated to provide 99 mg (24% yield) of title product as a viscous yellow oil. 1H-NMR(CDCl3)delta(ppm): 7.32 (m, 5H), 6.16 (ddd, 10 12 and 20 Hz, 1H), 5.32 (d, 12 Hz, 1H), 5.24 (d, 20 Hz, 1H), 4.06 (dt, 10 and 16 Hz, 1H), 2.50 (dt, 7 and 17 Hz, 1H), 2.28 (dt, 5 and 17 Hz, 1H), 1.45 (m, 2H), 1.16 (m, 4H), 0.84 (t, 6 Hz, 3H). 13C-NMR(CDCl3)delta(ppm): 134.87, 132.03, 129.51, 128.70, 127.93, 120,62, 120.40, 117.25, 114.00, 53.27, 52.98, 52.67, 37.86, 30.85, 22.24, 21.93, 13.79. IR (CDCl3) cm-1 : 2925, 1739. Mass spectrum m/e (relative intensity): M+ 276.1 (1).
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:25][CH:24]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=c1ccc(-c2ccc(CCNCC(O)COc3ccc(CCOCC4CCC4)cc3)cc2)n[nH]1

Procedure:
Prepared analoqously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethyl)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: N[C:2]1C=CC=C2[C:3]=1C(=O)N(C1CCC(=O)NC1=O)C(C)=N2.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:24]=1[C:25]([OH:27])=[O:26]>C(O)(=O)C>[CH3:2][C:3]1[O:26][C:25](=[O:27])[C:24]2[C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CC(=O)O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1

Procedure:
In one particular embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-amino-6-nitrobenzoic acid with an activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) reacting 2-methyl-5-nitro-4H-benzo [d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent in the presence of a coupling reagent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; and (c) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione via transfer hydrogenation in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; and wherein steps (a), (b), and (c) are each as described herein elsewhere.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[S:22][C:23]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:19][C:18]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:17]1.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[S:22][C:23]([C:26]3[CH2:27][CH2:28][N:29]([S:41](=[O:43])(=[O:42])[N:40]([CH3:45])[CH3:39])[CH2:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:19][C:18]([C:32]([F:37])([F:38])[C:33]([F:35])([F:36])[F:34])=[N:17]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(C3=CCNCC3)s2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Step 2 of Example 200, except for using 1-(2,4-difluoro-phenyl)-5-[5-(1,2,3,6-tetrahydropyridin-4-yl)-thiophen-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate Prepared in Step 1 of Example 200; and using dimethylsulfamoyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([O:28]C)=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:31][CH:32]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
Into a solution of methyl 7-[[4-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.54 g) in THF-methanol (10-5 ml) was added at room temperature 2.4 ml of a 1 M aqueous solution of potassium carbonate (2.6 mmol), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[4-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (321 mg) as light yellow crystals.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:19]C1C=C(Br)C=CC=1N.FC1C=C(Br)C=CC=1N>>[Br:19][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(Br)cc1Br
Reactant: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: Nc1ccc(Br)cc1F
Product: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1Br

Procedure:
This compound was prepared by the method described for 2-fluoro-4-(2 -aminosulfonylphenyl)aniline described in EXAMPLE 8 by starting with 2,4-dibromoaniline rather than 2-fluoro-4-bromoaniline.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].CI.[C:32](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:32][N:5]([C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 36 from (Z)-3-[1-(3-methylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone, methyliodide and potassium carbonate in acetone.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[N+:18]([C:21]1[N:25]=[CH:24][NH:23][N:22]=1)([O-:20])=[O:19]>CN(C=O)C.O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([N:23]2[CH:24]=[N:25][C:21]([N+:18]([O-:20])=[O:19])=[N:22]2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(C=O)ccc1-n1cnc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.9 %

Procedure:
To a stiffing solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the resultant reaction mixture was stirred at ambient temperature for 14 h. After completion of reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J=9.3 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H); ESIMS m/z 242.3 ([M−H]−); IR (thin film) 2238, 1705, 1551, 1314 cm−1.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>C(Cl)Cl>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:38])[CH:30]=2)=[O:37])=[CH:15][CH:14]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and N,N-diisopropylethylamine (0.109 mL, 0.63 mmol) in 3.0 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.047 mL, 0.377 mmol) and the reaction stirred at rt for 2 hours. The reaction was quenched with 1.0 mL MeOH, stirred for 15 min and then evaporated. The sample was partitioned between EtOAc and H2O/brine mixture, the EtOAc layer washed with aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4, and evaporated to a tan solid. The solid was chromatographed eluting with CH2Cl2, EtOAc, then 3% MeOH/EtOAc to give the title compound as a white solid (79 mg, 88%). 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.29-7.35 (m, 2H), 7.28 (s, 1H), 7.16-7.23 (m, 2H), 7.10-7.16 (m, 1H), 6.96-7.02 (m, 2H), 6.76 (d, J=7.0 Hz, 1H), 4.33 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.7 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].Cl[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][Cl:40])=[CH:35][N:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][Cl:40])=[CH:35][N:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(CCl)cn3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 21 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (106 mg, 0.25 mmol, see step (b) Example 12) and 2-chloro-5-chloromethylpyridine (41 mg, 0.25 mmol). Yield 90 mg (66%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([O:14][C:15](=[O:21])[CH:16]=[CH:17][N:18]([CH3:20])[CH3:19])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([C:16](=[CH:17][N:18]([CH3:20])[CH3:19])[C:15]([O:14][CH2:12][CH3:13])=[O:21])=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)ccc1F
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 11.3 %

Procedure:
A solution of 2,5-difluorobenzoyl chloride (5.26 g, 29.8 mmol) in toluene (100 mL) was treated with ethyl-3-(dimethylamino)-2-propenoate (5.27 g, 36.8 mmol), followed by triethylamine (5.9 mL, 42.5 mmol). The mixture was stirred at 90° C. for 6.5 h then allowed to cool, and the precipitate removed by filtration. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography (silica gel, 50-100% diethyl ether in petroleum ether [b.p. 40-60° C.]) to give the title compound as a yellow oil (0.95 g); ESMS m/z 284.4 [M+H]+.
Reaction SMILES: [C:1]12([CH2:11][C:12](O)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[NH2:20]>>[CH3:25][O:24][C:22]1[CH:21]=[C:19]([NH:20][C:12](=[O:13])[CH2:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)[CH:18]=[C:17]([O:16][CH3:15])[CH:23]=1
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(NC(=O)CC23CC4CC(CC(C4)C2)C3)cc(OC)c1
Yield: 82.6 %

Procedure:
Prepared according to the method of Example 39 from 1-adamantaneacetic acid (3.0 g) and 3,5-dimethoxyaniline (3.0 g) to give the title compound as a white solid (4.2 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[C:11]=1[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:13])=[CH:8][CH:7]=[CH:6][N:5]=2.[Cl:27]C1C2C(=NC=CC=2)N=C(C)C=1C(OCC)=O>>[Cl:27][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:13]
Reactant: Cc1[nH]c2ncccc2c(=O)c1C(=O)NCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1c(C)nc2ncccc2c1Cl
Product: Cc1nc2ncccc2c(Cl)c1C(=O)NCc1cccc(C(F)(F)F)c1
Yield: 59 %

Procedure:
This substance was synthesized from 2-Methyl-4-oxo-N-(3-(trifluoromethyl)benzyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (130.0 mg, 0.36 mmol) following the same procedure used for ethyl 4-chloro-2-methyl-1,8-naphthyridine-3-carboxylate. Purification was done by flash chromatography (EtOAc/MeOH 100:0→96:4) giving 80.0 mg (59%) of the title compound.