Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCN(C(=O)OC(C)(C)C)CC1
Yield: 68.4 %

Procedure:
To a microwave reaction vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (500 mg, 3.10 mmol), tert-butyl 1,4-diazepane-1-carboxylate (744 mg, 3.72 mmol). Ethanol (15 mL) and diisopropylethylamine (3.23 mL, 18.57 mmol) were added and the mixture was irradiated with a microwave for 60 min at 130° C. The mixture was cooled, concentrated and purified via flash chromatography, ethyl acetate/heptane 0% to 100% to afford yellow oil tert-butyl 4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane-1-carboxylate (690 mg, 69%).
Reaction SMILES: Cl.Cl.[C:3]([C:6]1[CH:10]=[C:9]([C:11]2[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][NH2:18])=[CH:13][CH:12]=2)[N:8]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:7]=1)([CH3:5])=[CH2:4].CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:3]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][NH:18][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:19][CH:20]=2)[N:8]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:7]=1)([CH3:5])=[CH2:4]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)c1cc(-c2ccc(OCCN)cc2)n(-c2ccc(OC)nc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1cc(-c2ccc(OCCNS(C)(=O)=O)cc2)n(-c2ccc(OC)nc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine dihydrochloride (126.4 mg) and Et3N (125 μl) in CH2Cl2 (2 ml) was added methanesulfonyl chloride (34.7 μl ) under ice bath cooling. The mixture was stirred at ambient temperature for 1 hour. Additional methanesulfonyl chloride (6.9 μl ) and Et3N (41.6 μl) were added and the reaction mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 1M HCl. The aqueous layer was reextracted with AcOEt. The combined organic layers were washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=70%. The seaparated silica gel was extracted with 10% MeOH/CDCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide (48.0 mg) as white powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:15](S(Cl)(=O)=O)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>CCCCCC.O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:15]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(S(=O)(=O)S(=O)(=O)Cl)c1
Reactant: O=C1CCCN1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(S(=O)(=O)N2CCCC2=O)c1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
15.75 cm3 of a 1.6M solution of M-butyllithium in hexane is added to 2.22 g of 2-pyrrolidinone in solution in 80 cm3 of tetrahydrofuran and cooled to -25° C., the temperature being maintained between -25° C. and -20° C. After agitation for 30 minutes at -25° C., a solution of 5.40 g of 3-methoxybenzenesulphonyl sulphonyl chloride [J. Chem. Soc. P.T.2., 579 (1982)] in 40 cm3 of tetrahydrofuran is poured drop by drop into the mixture, operating between -25° C. and -20° C. After agitation for 30 minutes at -25° C., the whole is allowed to return to ambient temperature. The solvent is evaporated under reduced pressure; the residue is taken up in water, filtered and crystallized from isopropanol. 3.5 g of expected product is obtained.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.OC[C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:5][CH2:1][C:12]1[CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)[CH:9]=[CH:8][CH:13]=1
Reactant: CCOC(=O)c1cccc(-c2cccc(CO)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-c2cccc(CBr)c2)c1
Temperature: 25 °C

Procedure:
A mixture of ethyl-3-bromobenzoate (3.0 g, 13 mmol), [3-(hydroxymethyl)-phenyl]boronic acid (3.0 g, 20 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol), K2CO3 (3.6 g, 26 mmol), methanol (4 mL), and toluene (36 mL) was heated at 80° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was filtered through Celite and then poured into a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give ethyl 3′-(hydroxymethyl)biphenyl-3-carboxylate as an orange oil. A solution of CBr4 (5.8 g, 17 mmol) and CH2Cl2 (20 mL) was added dropwise to a solution of the above alcohol, PPh3 (4.6 g, 18 mmol), and CH2Cl2 (50 mL) at 0° C. under N2. The reaction was allowed to warm to rt, maintained for 2 h, concentrated, and purified by silica gel chromatography to give ethyl 3′-(bromomethyl)biphenyl-3-carboxylate as a clear oil. Ethyl 3′-(bromomethyl)biphenyl-3-carboxylate was used to alkylate 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (0.66 g, 1.4 mmol), 1 N LiOH (8 mL), and THF (8 mL) was heated at 40° C. for 2 d and then cooled to 0° C.—acetone can used in place of THF if faster reaction rates are desired. The reaction was acidified to pH=1 with conc. HCl and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 8.39 (s, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.76 (s, 1H), 7.59-7.48 (m, 4H), 7.12 (d, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 5.16 (s, 2H), 3.84 (s, 2H), 2.95 (t, 2H), 1.76 (m, 2H), 1.01 (t, 3H), 0.99 (s, 9H). MS (ESI): 456 (M+H).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:25]([O:27][CH3:28])=[O:26])[C@@H:3]([CH3:24])[O:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(NCC)C>C(#N)C>[NH2:1][C@H:2]([C:25]([O:27][CH3:28])=[O:26])[C@@H:3]([CH3:24])[O:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: CC#N
Product: COC(=O)[C@@H](N)[C@@H](C)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of Fmoc-L-Thr(Trt)-OMe (2.40 g, 4.00 mmol) in acetonitrile (20.0 mL) was added diethylamine (20.0 mL). After 30 minutes, the mixture was concentrated in vacuo and the residue was diluted with acetonitrile (3×10 mL) and azeotroped in vacuo to afford L-Thr(Trt)-OMe which was used without further purification.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH:2]=[CH2:3].[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCCC1>[CH2:1]([N:4]([C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCNC(=O)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
4.6 g (0.02 mole) of N-allyl-2,4-dichlorobenzamide was added to 1.2 g (0.024 mole) of 50% sodium hydride in 20 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 30 minutes to react them. Then, 4.2 g (0.024 mole) of p-toluenesulfonyl chloride was added, and reacted at room temperature for 1 hour. The tetrahydrofuran was distilled off under reduced pressure. After adding cold water to the residual oil, it was extracted with benzene, dried over anhydrous magnesium sulfate, and concentrated to afford an oily substance. It was purified by silica gel chromatography to afford compound No. 42 shown in Table 2 in a yield of 68%. Its refractive index and elemental analysis values are also shown in Table 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH:7]([N:16]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-])=O)[CH:23]=3)[N:18]=[C:17]2[CH2:30][CH2:31][CH3:32])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>CCOC(C)=O.[Pd]>[NH2:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH2:30][CH2:31][CH3:32])[N:16]([CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:25]2=[O:26]
Reactant: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1nc2ccc(N)cc2c(=O)n1C(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 69.8 %

Procedure:
A solution of 12.1 g (26.0 mmol) of the product of Step B dissolved in 250 mL of EtOAc was hydrogenated under atmospheric pressure over three days in the presence of three portions of 1.2 g of 10% Pd/C added daily. The mixture was filtered through celite and concentrated in vacuo to give an oil. The product was purified by flash chromatography over silica gel eluted with 50% EtOAc/hexanes to give 7.8 g (72%) of the amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(CCc2cccc(Cl)c2)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(CCc3cccc(Cl)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of 4-[2-(3-chloro-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as an off-white solid; MS: m/e=342 (M−H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:14][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1CBr
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a slight suspension of (2-methyl-5-nitrophenyl)methanol (2.0 g, 12 mmol) in DCM (20 ml) in an ice-water bath under nitrogen was a added a solution of phosphorus tribromide (1.13 mL, 12 mmol, Aldrich) in DCM (20 ml). The resulting solution was allowed to warm to ambient temperature and stirred for 45 min. The solution was poured onto a mixture of ice-water (50 ml) and saturated sodium hydrogen carbonate (50 ml). The biphasic mixture was diluted with dichloromethane (50 ml) and the phases separated. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give 2-(bromomethyl)-1-methyl-4-nitrobenzene as a pale yellow solid (1.81 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=O)[O:4]C1=O.[NH3:13]>O1CCCC1>[CH3:1][NH:2][C:7]1[CH:8]=[CH:9][S:10][C:6]=1[C:5]([NH2:13])=[O:4]
Reactant: Cn1c(=O)oc(=O)c2sccc21
Reactant: N
Solvent: C1CCOC1
Product: CNc1ccsc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.60 g (14.2 mmol) 1-Methyl-1H-thieno(3,2-d)(1,3)oxazine-2,4-dione were dissolved in 30 ml tetrahydrofuran and 15.0 ml ammonia (25%) were added at 0° C. The solution was stirred for 30 min at 0° C. and for 30 min at room temperature. THF was distilled under vacuum and the remaining suspension was neutralized with diluted hydrogen chloride acid. The product was isolated by filtration.
Reaction SMILES: [C:1]1(=[O:44])[N:5]([CH:6]2[C:37](=[O:38])[N:8]3[C:9]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:10]([CH2:13][S:14][C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:11][S:12][C@H:7]23)[C:4](=[O:39])[C:3]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:2]12.C1C[O:48]CC1.O.S(=O)(=O)(O)O>C(OCC)(=O)C>[C:1]([C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([NH:5][CH:6]1[C:37](=[O:38])[N:8]2[C:9]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[O:39])([OH:48])=[O:44]
Reactant: C1CCOC1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC2)s1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 7-phthalimido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 25 ml. of THF and 8 ml. of water is cooled in an ice-water bath, and 660 mg. of Na2S. 9H2O are then added. The mixture is stirred for 15 minutes, and 10 ml. of water and 40 ml. of ethyl acetate are added. The layers are separated, and a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and is extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried, and evaporated to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1.C(=O)([O-])[OH:13].[Na+].O>CC(C)=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([CH2:2][OH:13])[CH:8]=[C:7]([CH3:9])[CH:6]=1
Reactant: O=C([O-])O
Reactant: COc1cc(C)cc(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C)cc(CO)c1
Yield: 80.6 %

Procedure:
To a solution of 1-(bromomethyl)-3-methoxy-5-methylbenzene (2.14 g) in acetone (80 mL) were added sodium hydrogen carbonate (1.05 g) and water (50 mL), and the mixture was heated under reflux for 18 hr. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.22 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 91 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 2.46 (s, 3H), 3.21-3.28 (m, 4H), 3.72-3.86 (m, 4H), 4.13 (s, 3H), 6.74-638 (m, 4H), 7.00-8.01 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1.[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:9]1[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7](=[O:21])[C:8]1=2)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Product: CCCCn1cc(C(=O)OCC)c(=O)c2oc3ccc(Cl)cc3c(=O)c21
Yield: 95.1 %

Procedure:
Prepared from ethyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate (3.195 g, 0.01 mole) and butyl iodide (7.36 g, 0.04 mole) by the method described for Example 9. Recrystallization from methanol gave white crystals (3.575 g, 95%), m.p. 226°-228°.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:9]=3[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([O:35]C)=[O:34])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:17][C:15]3[CH:14]=[CH:13][C:10]4[C:11](=[O:12])[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[O:8][C:9]=4[CH:16]=3)[CH:21]=2)=[CH:27][C:28]=1[C:33]([OH:35])=[O:34]
Reactant: COC(=O)c1cc(-c2cccc(CBr)c2)ccc1Cl
Reactant: O=c1c2ccc(O)cc2on1C1CCCCC1
Product: O=C(O)c1cc(-c2cccc(COc3ccc4c(=O)n(C5CCCCC5)oc4c3)c2)ccc1Cl
Yield: 31 %

Procedure:
2-Cyclohexyl-6-hydroxybenzo[d]isoxazol-3(2H)-one (0.100 g, 0.43 mmol) and methyl 3′-(bromomethyl)-4-chlorobiphenyl-3-carboxylate (0.174 g, 0.51 mmol) were processed according to the general procedure for Example 23 to provide 4-chloro-3′-((2-cyclohexyl-3-oxo-2,3-dihydrobenzo[d]isoxazol-6-yloxy)methyl)biphenyl-3-carboxylic acid in 31% yield over 2 steps (0.034 g) as a colorless solid. 1H NMR (DMSO-d6): δ 8.01 (s, 1H), 7.81 (d, 1H, J=8.6 Hz), 7.79 (d, 1H, J=8.5 Hz), 7.63-7.58 (m, 3H), 7.49-7.48 (m, 2H), 7.15 (s, 1H), 6.95 (d, 1H, J=8.6 Hz), 5.23 (s, 2H), 4.19-4.18 (m, 1H), 1.76-1.69 (m, 7H), 1.66-1.64 (m, 3H). HRMS (ESI)Calcd for C267H24ClNO5 [M+H]+: 478.1416. Found: 478.1418.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N+:9]([O-])=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[CH:12]=2.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:28]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=[O:28])[C:11]2[CH:12]=[C:13]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[N:14]=[CH:15][C:16]=2[CH:17]=1
Reactant: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2c(=O)[nH]c(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a slurry of 3-(2-chlorophenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (50 mg, 0.1 mmol) in tetrahydrofuran (0.5 mL) at 0° C. was added trifluoroacetic anhydride (0.04 mL, 0.29 mmol) dropwise over 2 minutes. The mixture was allowed to warm to room temperature and stir for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as a yellow solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 10.33 (s, 1H), 9.51 (s, 1H), 8.86 (s, 1H), 8.54 (s, 1H), 7.62-7.52 (m, 1H), 7.53-7.38 (m, 3H), 2.08 (m, 1H), 0.88 (m, 4H). LCMS (Method E): RT=3.759 min, M+H+=340.0.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([C:20]1[CH:32]=[CH:31][C:23]([CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)[CH2:16][CH2:17][O:18][CH3:19])=O)(C)(C)C>>[CH3:19][O:18][CH2:17][CH2:16][NH:15][C:20]1[CH:32]=[CH:31][C:23]([CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C=Cc1ccc(N(CCOC)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=Cc1ccc(NCCOC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
Trifluoroacetic acid (3 ml) was added to ethyl 4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl)amino]cinnamate (932 mg) in ice water bath and stirred for 15 minutes at same temperature. The solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting to a mixture of n-hexane and ethyl acetate (3:1) and recrystallized from a mixture of n-hexane and ethyl acetate to give ethyl 4-(2-methoxyethylamino)cinnamate (470 mg) as crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([S:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Clc1ccnc2ncccc12
Reactant: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(OCc3cccc(F)c3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with 4-[2-amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 22 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (75 mg, 43%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.16 (s, 2H) 6.31 (d, J=7.36 Hz, 1H) 6.64 (d, J=8.82 Hz, 2H) 7.09-7.28 (m, 6H) 7.29 (2, 1H) 7.44 (m, J=6.61 Hz, 1H) 7.93 (dd, J=4.41 Hz, 1H) 8.47 (d, J=6.98 Hz, 1H) 9.14 (dd, J=1.47 Hz, J=8.46 Hz, 1H) 9.18 (dd, J=1.47 Hz, J=4.41 Hz, 1H) 9.79 (s, 1H) 11.16 (br s, 1H) 14.52 (br s, 1H); MS (ESI+) m/z, 470 (M+H−TFA)+; (ESI−) m/z, 468 (M−H−TFA)−.