Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, off-white solid (103 mg, 88%), MS (ISP) m/z=469.3 [(M+H)+], mp 226.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-chlorobenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:22])[NH:26][CH2:24][CH3:25])[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Solvent: ClCCl
Product: CCNC(=O)Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a sol. of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-acetic acid (4.30 g, 12.6 mmol) in CH2Cl2 (130 mL) was added 1-chloro-N,N-2-trimethylpropenyl amine (1.87 mL, 15.2 mmol), and the mixture was stirred for 60 min. Ethylamine (2M in THF, 25.0 mL, 50.0 mmol) was added, and the mixture was stirred overnight. More CH2Cl2 was added, and the mixture was washed with water and brine, was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 7:3) yielded the title compound (2.94 g, 63%). LC-MS: tR=0.97 min; ES+: 311.28.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([Br:27])[CH:21]=2)=[C:14]([Cl:28])[C:13]=1[CH2:29][CH3:30])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:31][CH:32]([CH3:36])[C:33](Cl)=[O:34]>>[C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:33](=[O:34])[CH:32]([Cl:31])[CH3:36])=[C:22]([Br:27])[CH:21]=2)=[C:14]([Cl:28])[C:13]=1[CH2:29][CH3:30])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc(N)c(Br)c2)c1Cl
Product: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc(NC(=O)C(C)Cl)c(Br)c2)c1Cl
Yield: 54.6 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) cinnamate (70 mg) was coupled with 2-chloropropionyl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 45 mg (83%) of ethyl(3,5-dichloro-4-[3-bromo-4-(2-chloropropionamido)phenoxy]phenyl) cinnamate was obtained. A part of the ethyl ester (50 mg) was hydrolysed using the method described in Example 1(i), to give 40 mg (84%) of 3,5-dichloro-4-(3-bromo-4-[2-chloropropionamido]-phenoxy)phenylcinnamic acid.
Reaction SMILES: [CH3:1][O:2][Na].[CH3:4][C:5]1([CH3:14])[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7](=O)[CH2:6]1>CC#N>[CH3:12][C:10]1([CH3:13])[CH2:9][C:7]2([CH2:1][O:2]2)[CH2:6][C:5]([CH3:14])([CH3:4])[NH:11]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: CO[Na]
Solvent: CC#N
Product: CC1(C)CC2(CO2)CC(C)(C)N1

Procedure:
44.55 g (0.825 mole) of CH3ONa were then added, under stirring, to the mixture and then, in half an hour, a solution of 77.5 g (0.5 mole) of triacetonamine dissolved in 50 cc of CH3CN was gradually added. After having stirred the mixture for 4 hours at room temperature, most of the solvent was distilled under vacuum and 500 cc of H2O were added to the mixture.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>C(O)C>[CH2:27]([O:26][C:22]([CH2:23][CH2:24][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH2:12]1)=[O:25])[CH3:28]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Reaction time: 8 h

Procedure:
To 125 ml of suspension in ethanol of 136 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride was added 98 ml of triethylamine and 83 ml of ethyl acrylate, and the solution was heated and stirred overnight under reflux. The solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with water, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure to obtain 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline. The thus obtained 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 1,000 ml of ethanol, and a catalytic amount of 10% palladium-carbon was added to the solution. The solution was stirred overnight under hydrogen atmosphere. The catalyst was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 7-amino-2-(2-(ethoxycarbonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline, which was a solid.
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=5)[C:26]([O:28]C(C)(C)C)=[O:27])[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.FC(F)(F)C(O)=O>ClCCl>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyridin-4-yl)benzoate (40. mg, 0.079 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.500 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was evaporated to dryness to yield the pure product. ESI-MS m/z calc. 452.1, found; 453.0 (M+1)+ Retention time 1.64 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400.0 MHz, DMSO-d6) d 9.01 (s, 1H), 8.22 (s, 1H), 8.03-8.00 (m, 1H), 7.89 (d, J=2.5 Hz, 2H), 7.68-7.64 (m, 2H), 7.58 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.35 (dd, J=1.7, 8.3 Hz, 1H), 2.18 (s, 3H), 1.54-1.51 (m, 2H), 1.21-1.17 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[CH:23]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)[CH2:25][CH2:24]1>>[CH2:15]([O:14][C:11]1[N:10]=[CH:9][C:8]([C:5]2[N:6]=[CH:7][C:2]([O:1][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:23]3[CH2:25][CH2:24]3)=[CH:3][N:4]=2)=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: BrCCCCCCCCC1CC1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cn1
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCCC3CC3)cn2)cn1

Procedure:
Analogously to Example 2, 5-hydroxy-2-(6-octyloxypyrid-3-yl)pyrimidine is reacted with 8-cyclopropylbromooctane to give 8-cyclopropyloctyl 2-(6-octyloxypyrid-3-yl)pyrimidine-5-yl ether
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([CH2:20][CH2:21][N:22]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([Cl:36])[CH:28]=2)[S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:18][CH:17]=[CH:16]1>>[N:15]1([CH2:20][CH2:21][N:22]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH:4]=3)=[O:32])=[C:29]([Cl:36])[CH:28]=2)[S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:18][CH:17]=[CH:16]1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)N(CCn1cccc1)c1ccc(C(=O)O)c(Cl)c1
Product: CS(=O)(=O)N(CCn1cccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
64 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 529 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([O:8][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(O)cc(I)c1
Product: Ic1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 96 %

Procedure:
3,5-Dihydroxyphenyl iodide (Tex. J. Sci., 1977, 28, 253) was reacted with two equivalents of benzyl bromide using the procedure described in Example 3 to give 3,5-dibenzyloxyphenyl iodide (96%), as an oil. This was reacted with n-butyl-lithium using the procedure described in the portion of Example 24 which is concerned with the preparation of starting materials and the organometallic reagent so formed was reacted with tetrahydropyran-4-one using the procedure described in that Example. There was thus obtained 4-(3,5-dibenzyloxyphenyl)-4-hydroxytetrahydropyran (60%), as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[N:10].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>N1C=CC=CC=1>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[N:10])=[O:17]
Reactant: O=C(Cl)CCCCCl
Reactant: Cc1nn(C)c(N)c1C#N
Solvent: c1ccncc1
Product: Cc1nn(C)c(NC(=O)CCCCCl)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile (1.59 g, 11.67 mmol) in anhydrous pyridine (15 mL) was slowly added 5-chlorovaleryl chloride (1.80 mL, 14.0 mmol) at 0° C. After addition, the reaction mixture was allowed to warm up to rt and stir at rt overnight. The reaction mixture was concentrated on a rotavapor and the residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was separated by flash chromatography (silica gel, 50-80% gradient EtOAc in hexane) to provide Example 96A. Yield: 2.42 g (81%). MS (DCI): m/z 255 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([CH3:23])[C:11](OS(C(F)(F)F)(=O)=O)=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7].[Cl-].[Li+].[C:27]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:28]=1.C(C([Sn])=C(CCCC)CCCC)CCC.[F-].[K+]>CN1CCCC1=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([CH3:23])[C:11]([CH:27]=[CH2:28])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c(O)cc(OS(=O)(=O)C(F)(F)F)c(C)c1C(=O)OC
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=Cc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 867.5 %

Procedure:
To a solution of 6-hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (2.17 g, 5.85 mmol) in N-methylpyrrolidinone (15 mL) was added lithium chloride (743 mg, 17.5 mmol) and triphenylarsine (179 mg, 0.585 mmol). Tributylvinyltin (2.04 g, 6.43 mmol) was added followed by tris(tribenzylideneacetone)dipalladium(0)-chloroform adduct (90 mg, 0.087 mmol). The reaction was placed under an atmosphere of nitrogen and heated at 60° C. for 18 hrs. The reaction was cooled to room temperature and poured onto a mixture of ice (20 g), EtOAc (40 mL), and potassium fluoride (1 g). Stirring was continued for 1 hr. The aqueous layer was extracted with EtOAc and the organic extracts filtered through Celite. The combined organic layers were washed with water and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded a crude material, which was purified by silica gel chromatography to provide 1.27 g (87%) of the product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ=2.16 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 5.46 (dd, J=11.1, 1.2 Hz, 1H), 5.72 (dd, J=17.1, 0.9 Hz, 1H), 6.86 (dd, J=17.1, 11.1 Hz, 1H), 7.14 (s, 1H), 10.79 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10](Cl)=[CH:11][CH:12]=2)[N:7]([CH3:15])[C:6]=1[CH3:16])=[O:4].[CH3:17][C:18]1[CH:19]=[C:20]([OH:33])[CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:23]3[CH:22]=[CH:21][C:20]([OH:33])=[CH:19][C:18]=3[CH3:17])=[CH:11][CH:12]=2)[N:7]([CH3:15])[C:6]=1[CH3:16])=[O:4]
Reactant: COC(=O)c1c(C)n(C)c2cc(Cl)ccc12
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1c(C)n(C)c2cc(-c3ccc(O)cc3C)ccc12
Temperature: 100 °C
Yield: 87.9 %

Procedure:
A flask containing a mixture of 6-chloro-1,2-dimethyl-1H-indole-3-carboxylic acid methyl ester (1.60 g, 6.73 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (3.15 g, 13.5 mmol), aqueous tribasic potassium phosphate (1.27 M, 9.0 mL, 11 mmol), tricyclohexylphosphine (53 mg, 0.19 mmol) and tris(dibenzylideneacetone)dipalladium (0) (73 mg, 0.080 mmol) and dioxane (22 mL) is evacuated and filled with nitrogen several times. The reaction mixture is heated to 100° C. for 18 h. The mixture is allowed to cool and is filtered thru celite, washing with ethyl acetate. The filtrate is concentrated and partitioned with 1 N HCl and ethyl acetate. The ethyl acetate layer is washed with brine, dried over MgSO4 and concentrated. The residue is triturated in THF-heptane to provide 1.83 g (88%) of the title compound as a white solid. MS m/e 310.0 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23](Br)[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C(OCC)(=O)C.Cl>[Pd].C(N(CC)CC)C.CN(C=O)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: N#Cc1ncc2c(c1O)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A mixture of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (9.91 g, 23.1 mmol), palladium on carbon hydrogenation catalyst (10 wt %, 1.0 g, 0.94 mmol), ethanol (250 mL), ethyl acetate (50 mL), DMF (50 mL) and triethylamine (50 mL) was stirred at room temperature under an atmosphere of hydrogen for 16 hours. The catalyst was removed by filtration through Celite© and the filtrate evaporated to dryness to give a gum, that was mixed with hydrochloric acid (1M, 100 mL) and sonicated in a laboratory ultrasonic cleaning bath for 30 minutes. The resultant solid was collected by filtration, washed with water then dried under vacuum to afford the title compound as a tan coloured solid (7.19 g, 89%). 1H NMR (400 MHz, DMSO-d6): 9.27 (s, 1H), 8.71 (dd, J=4.9, 1.7 Hz, 1H), 8.68 (dd, J=7.9, 1.7 Hz, 1H), 8.20-8.20 (m, 2H), 7.74-7.73 (m, 1H), 7.60-7.59 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([C:20]4[CH:36]=[CH:35][C:23]5[C:24]([C:26]6[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=6)=[CH:25][C:22]=5[CH:21]=4)=[O:19])=[CH:17][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.[BH4-].[Na+].[OH-].[Na+]>C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([C:20]4[CH:36]=[CH:35][C:23]5[C:24]([C:26]6[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=6)=[CH:25][C:22]=5[CH:21]=4)=[O:19])=[CH:17][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(c1ccc2c(c1)C=C2c1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)C=C2c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2=Cc3cc(C(=O)c4ccc5c(c4)C=C5c4ccc(N)cc4)ccc32)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
Into a 250 ml three neck round bottom flask equipped with a magnetic stirring bar, a reflux condensor with a nitrogen inlet and a thermometer and an equilibrating addition funnel is charged 1.0 g (3.95 mmol) of 4-nitrophenyl-4-benzocyclobutenyl ketone, 4.46 g (19.75 mmol) of (SnCl2 9.2H2O) and 100 ml of ethanol. Under a nitrogen atmosphere, the mixture is heated to 60° C. To the mixture, in a slow dropwise manner is added sodium borohydride, 75 mg (1.975 mmol) in 20 ml of ethanol, over a period of 20 minutes. After the addition, the temperature of the mixture is maintained at 60° C. for 30 minutes. The mixture is cooled to 10° C. and 80 ml of water previously chilled is added. Concentrated sodium hydroxide is added until the pH is 7 (4M, NaOH, about 6 ml). The mixture is transferred to a 500 ml round-bottom flask and the ethanol is removed on a rotovap. Thereafter, 100 ml of water is added to the off-while slurry and the aqueous phase is extracted with diethyl ether four times with 100 ml aliquots. The ether extracts are dried over sodium sulfate overnight. The sodium sulfate is filtered from the diethyl ether extracts and the diethyl ether is removed on a rotovap. A bright orange solid (0.87 g) is obtained. The solid is recrystallized using carbon tetrachloride (200 ml) and decolorizing charcoal. The first crop of crystals is a pale yellow solid 0.54 g (61.3%). The carbon tetrachloride is concentrated to 50 ml and left standing overnight. NMR and IR indicate the product is 4-aminophenyl-4-benzocyclobutenyl ketone.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:4]([N+:21]([O-:23])=O)[CH:3]=1.[K+].[Br-]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:10](=[O:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[N+:21]2[O-:23]
Reactant: COc1cccc(CC(=O)Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])c1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(-c2c(=O)[nH]c3cc(Cl)c(Cl)cc3[n+]2[O-])c1
Yield: 91 %

Procedure:
The title compound was prepared according to the general procedure described in Example 6 by substituting 8 mmol of 129 for 125. Yield: 91%; mp 238°-240° C. (from EtOH); IR (KBr) 3436, 3046, 2926, 2855, 1652, 1618, 1597, 1374, 1363 and 1263 cm-1 ; 1H NMR (in DMSO-d6) δ3.73 (s, 3H), 7.00 (m, 1H), 7.18 (m, 2H), 7.20 (s, 1H), 7.36 (m, 1H), 7.52 (s, 1H), 8.28 (s, 1H), 12.57 (br.s, 1H, N--H); HPLC: 100%; HRMS Calcd for C15H10N2O3Cl2 : 336.0068. Found: 336.0075.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:10]([C:9]([O:16][CH3:17])=[O:15])[C:11]([O:13][CH3:14])=[O:12])=[N:3][CH:4]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Fc1ccc(Br)nc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(F)cn1
Temperature: 25 °C
Yield: 31 %

Procedure:
The solution of 2-bromo-5-fluoropyridine (1.0 g, 5.68 mmol), dimethyl malonate (3.0 g, 22.7 mmol) picolinic acid (559.6 mg, 4.54 mmol), CuI (431.8 mg, 2.27 mmol) and Cs2CO3 (5.6 g, 17.05 mmol) in DMF (30 mL) was stirred at 100 degree for 12 h. After cooling to room temperature, the reaction mixture was filtered, diluted with H2O and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound (400 mg). LC-MS: m/z (M+H)=228.2
Reaction SMILES: C[O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:5][CH:4]=1.C([O-])(=O)CC[C@H](NC(C1C=CC(NCC2CNC3N=C(NC(C=3N=2)=O)N)=CC=1)=O)C(O)=O>>[NH2:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:14][CH:13]=1
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1
Agent: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1)CN2
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
To further demonstrate that the observed phenotype is due to the site-specific incorporation of O-methyl-L-tyrosine by the orthogonal mtRNACUATyr/mutant TyrRS (LWJ16) pair in response to an amber stop codon, an O-methyl-L-tyrosine mutant of dihydrofolate reductase (DHFR) was generated and characterized. The third codon of the E. coli DHFR gene (a permissive site) was mutated to TAG and a C-terminal His6 tag was added in order to separate the mutant protein from endogenous E. coli DHFR. As a control, the mtRNACUATyr was coexpressed with the wild type M. jannaschii TyrRS, resulting in efficient suppression of the nonsense codon in DHFR with tyrosine. See FIG. 2. When the mutant TyrRS (LWJ16) was expressed in the presence of mtRNACUATyr and 1 mM O-methyl-L-tyrosine in liquid GMML growth media, full length DHFR was also produced and could be purified by Ni affinity chromatography with an isolated yield of 2 mg/liter.
Reaction SMILES: CO.[NH2:3][CH:4]1[C:15](=[O:16])[N:6]2[CH:7]([C:12]([OH:14])=[O:13])[CH:8]([OH:11])[CH2:9][S:10][C@H:5]12.C(=O)(O)[O-].[Na+].[CH3:22][O:23][N:24]=[C:25]([C:29]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])[CH2:30][Cl:31])[C:26](Cl)=[O:27]>O.O1CCCC1>[CH3:22][O:23][N:24]=[C:25]([C:29]([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])[CH2:30][Cl:31])[C:26]([NH:3][CH:4]1[C:15](=[O:16])[N:6]2[CH:7]([C:12]([OH:14])=[O:13])[CH:8]([OH:11])[CH2:9][S:10][C@H:5]12)=[O:27]
Reactant: CCOC(CCl)(OCC)C(=NOC)C(=O)Cl
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CCl)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 132.9 %

Procedure:
Methanol (40 ml) was added to a solution of 7-amino-3-hydroxycepham-4-carboxylic acid (2 g) and sodium bicarbonate (0.57 g) in water (13.4 g) under ice-cooling. A solution of 2-methoxyimino-3,3-diethoxy-4-chlorobutyryl chloride (syn isomer, 1.34 g) in dry tetrahydrofuran (2 ml) was added to a solution while adjusting pH 6.5 to 7.8, then and stirred under ice-cooling for three hours. After adjusting the resultant mixture to pH 7.5, the solvent was removed in vacuo. The aqueous residue was adjusted to pH 7.5 under ice-cooling, and diisopropyl ether (10 ml) was added to the solution. After the aqueous solution was separated, ethyl acetate (20 ml) was added to the aqueous solution, and adjusted to pH 2.0 with 20% sulfuric acid. The ethyl acetate layer was separated and the aqueous solution was extracted with ethyl acetate (10 ml) twice. The ethyl acetate layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give 7-(2-methoxyimino-3,3-diethoxy-4-chlorobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 2.97 g).