Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(COC)OC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1ccc(OCCCBr)cc1

Procedure:
A mixture of 11.2 g (0.1 mol) of 4-fluorophenol, 16.5 g (0.12 mol) of pulverized potassium carbonate, 20.2 g (0.1 mol) of 1,3-dibromopropane and 100 ml of anhydrous dimethoxyethane was refluxed under nitrogen for 6 hours and then cooled. The mixture was diluted with methylene chloride and washed with water. The resultant organic product solution was dried over Na2SO4 and evaporated in vacuo. The residue was chromatographed on silica gel using cyclohexane elution to give pure product.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:23]=1[NH2:24]>>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:24][C:23]3[C:25]([O:31][CH3:32])=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:22]=3[O:21][CH3:20])=[O:12])[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: COc1cc(OC)c(N)c(OC)c1
Product: COc1cc(OC)c(NC(=O)C2c3ccccc3COc3ccc(C)cc32)c(OC)c1
Yield: 40.8 %

Procedure:
The similar procedures as in Example 1 were repeated except using 2.32 g of Compound A and 1.85 g of 2,4,6-trimethoxyaniline in place of aniline to obtain 1.56 g of Compound 10 as amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:23]([C:30]1[N:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[O:33][C:34]=1[CH2:35]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([C:30]1[N:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[O:33][C:34]=1[CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)c1nc(Cc2ccccc2)c(CCl)o1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(Cc2oc(C(C)(C)C)nc2Cc2ccccc2)CC1
Yield: 64 %

Procedure:
A suspension containing 2-methoxyphenylpiperazine (1.0 mmole), potassium carbonate (2.0 mmole), potassium iodide (0.5 mmole) and 4-benzyl-5-chloromethyl-2-tertbutyl oxazole (1.0 mmole) from example 4, was stirred in acetone (10 ml) at ambient temperature for three days. The solvent was removed in vacuo, water (50 ml) added and the product extracted into ethyl acetate (3×50 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by “flash” chromatography over silica gel to afford the titled compound as a colorless oil (0.64 mmole, 64% yield). This was transformed into its mono-fumarate salt, a white crystalline powder, using the procedure outlined in example 10 above.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][O:12][CH2:11][CH:10]([OH:14])[CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][O:12][CH2:11][C:10](=[O:14])[CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(O)COC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(=O)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of 6-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-ol (53 mg, 0.22 mmol) in DCM (6 mL) was added Dess-Martin periodinane (192 mg, 0.44 mmol) and sodium bicarbonate (93 mg, 1.10 mmol). The mixture was stirred at room temperature overnight, quenched with water, and extracted with DCM (3×). Combined organic layers were concentrated to dryness and purified via silica gel chromatography (0-100% EtOAc/heptane) to afford 6-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-one (53 mg, quant.).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[F:26][C:27]1[N:32]=[C:31]([N:33]([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:29][C:28]=1[CH:48]=[O:49].O>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[C:12]([CH:48]([OH:49])[C:28]3[CH:29]=[CH:30][C:31]([N:33]([C:41]4[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=4)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:32][C:27]=3[F:26])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(Cl)ncnc21
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(Cl)c34)c(F)n2)cn1
Temperature: -5 °C

Procedure:
To a solution of 7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine (1, 0.43 g, 1.01 mmol) in Tetrahydrofuran (5 mL) at −30° C. under nitrogen was added 2.0 M Isopropylmagnesium Chloride in Tetrahydrofuran (0.5 ml) slowly. The reaction was allowed to warm to −5° C. in 75 minutes. Then, the reaction was cooled to −45° C., followed by adding tert-butyl N-(6-fluoro-5-formyl-2-pyridyl)-N-(6-methyl-3-pyridyl)carbamate (84, 0.24 g, 0.72 mmol) in THF (3.0 mL). The reaction was allowed to warm to room temperature in around 2 hours. The reaction was poured in to water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified with silica gel column chromatography eluting with 20%-100% ethyl acetate in hexane to give product (85, 0.41 g, 90.6%). MS (ESI) [M+H+]+=625.0.
Reaction SMILES: [O:1]=[C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[H][H]>C1COCC1>[OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C(=O)Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(O)Cc1ccccc1

Procedure:
Methyl 2-oxo-3-phenylpropionate (16d, R18=Ph, R19=methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig) hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand (R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 30% conversion to methyl 2-hydroxy-3-phenylpropionate (17d, R18=Ph, R19methyl) with 85.4% ee as determined by chiral GC analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:28])[C:10]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[CH3:26])[C:5]([OH:7])=[O:6].[BH4-].[Na+]>CO>[OH:25][CH:22]1[CH2:21][CH2:20][N:19]([C:17]2[CH:16]=[CH:15][C:14]([CH3:26])=[C:13]([CH:18]=2)[C:12]([NH:11][C:10]2[C:9]([CH3:28])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[CH3:1])=[O:27])[CH2:24][CH2:23]1
Reactant: Cc1ccc(N2CCC(=O)CC2)cc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N2CCC(O)CC2)cc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
To a solution of 3,5-dimethyl-4-[[2-methyl-5-(4-oxo-1-piperidyl)benzoyl]amino]benzoic acid (69.5 mg, 182.68 moles) in methanol (1.83 ml) is added sodium tetrahydroborate (13.82 mg, 365.36 moles) and the resulting mixture is stirred at ambient temperature. After 1 hour, the mixture is quenched with saturated solution of NH4Cl (0.2 ml) and extracted with CHCl3 (3 ml):IPA (1 ml). The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid is triturated with H2O (5 ml), filtered, and washed with H2O (5 ml). The residue is purified by reverse phase chromatography (C18) using 20% acetonitrile in H2O with 0.1% formic acid to afford the title compound as a white powder (0.01 g, 15.7%). Mass spectrum (m/z): 383.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:16]([CH3:17])[C:11]2=[CH:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.BrN1C(=[O:37])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:16]([CH:17]=[O:37])[C:11]2=[CH:10][C:9]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(=O)C(C)(C)C)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1C=O
Temperature: 25 °C

Procedure:
A 10 mL rb flask equipped with a magnetic stir bar was charged with 0.227 g (0.52 mmol) of the product of Example 89, 0.101 g (0.57 mmol) of N-bromosuccinimide, 3 mL CCl4 and ca. 5 mg of 2,2′-azobisisobutyronitrile (AIBN). The reaction mixture was heated to reflux under a nitrogen atmosphere for 2 h then cooled to room temperature and filtered. The filtrate was evaporated in vacuo, and the residue was then redissolved in 2 mL of DMSO. The solution containing the crude bromination product was transferred to a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor and 73 mg (0.62 mmol) of N-methylmorpholine-N-oxide was added. The reaction vessel was sealed, placed in the microwave reactor and heated at 150° C. for 2–3 min. After the reaction mixture had cooled to room temperature, it was partitioned between EtOAc and 10% aq. NaHSO4 and extracted. The organic layer was washed with 10% aq. NaHSO4, water, brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 452.1 (M+1), 454.0 (M+3); Rt=4.63 min.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1])([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C)s1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Temperature: 0 °C
Yield: 44 %

Procedure:
To a solution of methyl 5-methylthiophene-2-carboxylate (109 g, 700 mmol) in conc. sulfuric acid (850 ml) was added dropwise a solution of fuming nitric acid (31 ml, 738 mmol) in conc. sulfuric acid (150 ml) under ice-cooling in such a manner that an inside temperature did not exceed 5° C. After the completion of the dropwise addition, the mixture was stirred under ice-cooling for 30 min, and slowly poured into ice (2 kg). The precipitated solid was collected by filtration, washed with water (500 ml×6) and dried under reduced pressure to give methyl 4-nitro-5-methylthiophene-2-carboxylate (62 g, yield 44%).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+]=[N-])[O:24][CH2:23]2)[CH:17]([CH:32]([OH:34])[CH3:33])[C:16]3=[O:35])=[O:13])=CC=1)([O-])=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[Pd].O1CCOCC1>[NH2:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:31])[CH:18]3[N:15]([C:16](=[O:35])[CH:17]3[CH:32]([OH:34])[CH3:33])[C:14]=2[C:12]([OH:13])=[O:11])[CH2:26]1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 18 using 2.8 g of product from Example 45, 0.60 g of 10% palladium/carbon, 27 ml of sodium phosphate buffer (pH 7) and 82 ml of dioxane to give 0.562 g of thedesired product.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH2:11][N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([CH3:31])([CH3:32])[CH2:11][N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)(C)CNC(=O)OC(C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)(C)CN)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
To a solution of diethyl 1-{3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropyl}-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (4.20 g, 9.39 mmol) in CH2Cl2 (20 mL) is added TFA (10 mL). The mixture is stirred at room temperature for 4 hr. The solvent is evaporated and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The layers are separated and the aqueous layer is further extracted with ethyl acetate. The combined organic phases are washed with brine, and are dried (Na2SO4) and concentrated in vacuo to afford the title compound (3.30 g, quantitative). LCMS: 348.79 (M+H+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([NH:8][C:16](=[O:17])[C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][C:12]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(Br)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)ccc1C(=O)NCc1ccccc1
Reaction time: 3 h
Yield: 86 %

Procedure:
Benzylamine (0.69 mL, 6.31 mmol) was added slowly to a mixture of 4-Bromo-2-methoxy-1-benzenecarbonyl chloride (1.5 g, 6.01 mmol) and triethylamine (1.3 mL, 9.02 mmol) in dichloromethane (60 mL). After 3 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was re-crystallized from ethyl acetate/heptane to give N1-benzyl-4-bromo-2-methoxybenzamide (1.654 g, 86%). 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 4.67 (d, J=5.67 Hz, 32H), 7.31 (m, 7H), 8.03 (bs, 1H), 8.13 (d, J=8.41, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH2:2][CH3:3].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:2][CH3:3]
Reactant: CCCc1c(O)cccc1O
Reactant: CCOC(=O)C(C)Br
Solvent: C1CCOC1
Product: CCCc1c(O)cccc1OC(C)C(=O)OCC
Temperature: 25 °C

Procedure:
Sodium hydride (1.08 g of a 60% oil dispersion, 27 mmoles) under an argon atmosphere was washed with 15 ml of dry hexane. The hexane supernatant was removed via syringe. Dry tetrahydrofuran (60 ml) was added to the sodium hydride and, with stirring at room temperature, the 2-propyl-1,3-dihydroxybenzene (4.08 g, 27 mmoles) was added as a 40 ml tetrahydrofuran solution. After stirring at room temperature for 25 minutes, the ethyl 2-bromopropionate (4.64 g, 26 mmoles) was added rapidly. After stirring at room temperature for 17 hours, the reaction was quenched with a saturated aqueous ammonium chloride solution and the tetrahydrofuran was removed under vacuum. The resulting aqueous mixture was extracted several times with ethyl acetate. The organic extract was dried over magnesium sulfate. Filtration and solvent removal gave an orange oil. This oil was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane. The desired title ester was obtained as a white solid (2.43 g, 36%).
Reaction SMILES: N#N.C[O:4][C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([O:13]C)[C:6]=1[CH2:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:17].B(Br)(Br)Br>C(Cl)Cl>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:13])[C:6]=1[CH2:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:17]
Reactant: COc1cc(OC)c(CC(=O)Nc2cccc(C(=O)O)c2)c(OC)c1
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: O=C(Cc1c(O)cc(O)cc1O)Nc1cccc(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
Step 3 (The following reaction is done in an anhydrous N2 atmosphere.) Dissolve 3-[2-(2,4,6-Trimethoxy-phenyl)-acetylamino]-benzoic acid (17) (134 mg, 0.39 mmol) in anhydrous DCM (5.3 mL), cool the solution to −78° C. and add dropwise BBr3 (240 μL, 2.55 mmol). Stir the reaction mixture for 30 min at −78° C. and after slowly warming up for additional 2 h at rt. Add dropwise ice water, separate layers and extract aqu. layer with EtOAc (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain 3-[2-(2,4,6-Trihydroxy-phenyl)-acetylamino]-benzoic acid (18) (29 mg, 22%) as a yellowish solid. 1H NMR (400 MHz, CD3OD): 3.69 (s, 2 H); 5.97 (s, 2 H); 7.43 (t, 1 H, J=8.0 Hz); 7.76 (br.dd, 1 H, J1=7.6 Hz); 7.84 (br.dd, 1 H, J1=8.1 Hz); 8.17 (t, 1 H, J=1.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:26]([N:28]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]1)=[O:27])[C@H:9]([CH:11]1[CH2:16][CH2:15][C:14]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)=[CH:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO.C(O)(=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:26]([N:28]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]1)=[O:27])[C@H:9]([CH:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C[C@@H](C1CC=C(c2cccc3ncnn23)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](C1CCC(c2cccc3ncnn23)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
The material from Step B (0.13 g, 0.27 mmol) was hydrogenated at 50 psi hydrogen in the presence of 10% palladium on carbon (0.13 g) in methanol (5 mL) containing 30 drops of acetic acid using a Parr shaker. After 1 h, the reaction mixture was filtered by passage through a syringe filter. The filtrate was concentrated and the residue was dissolved in chloroform and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (anhydrous sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% methanol in dichloromethane) gradient to afford the title compound. LC/MS 492.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl-].[CH3:15]O>>[CH3:15][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Cl-]
Product: COC(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a mixture of 4-amino-3-nitro-benzoic acid (10.0 g, 54.9 mmol) suspended in methanol (150 mL) was added thiony chloride (3.99 mL, 54.9 mmol). The mixture was heated to reflux overnight, then cooled to room temperature and filtered. The solid recovered by filtration was rinsed with cold methanol and dried to give 8.68 g (81%) of 4-amino-3-nitro-benzoic acid methyl ester.
Reaction SMILES: CC(C[CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=C.Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>>[CH3:19][C:18](=[CH:17][CH2:16][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:20]
Reactant: C=C(C)CCc1cc2ccccc2[nH]1
Reactant: CC(C)=CCBr
Product: CC(C)=CCCc1cc2ccccc2[nH]1

Procedure:
Refer to 28a) using 4-bromo-2-methyl-2-butene as the alkylating reagent.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([CH3:23])[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([CH3:23])[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:1]2[CH2:6][CH2:5][N:4]([C:14](=[N:13][C:10]3[CH:11]=[CH:12][C:7]([CH3:23])=[CH:8][CH:9]=3)[NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[CH2:3][CH2:2]2)=[N:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(N=C=Nc2ccc(C)cc2)cc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: Cc1ccc(N=C(Nc2ccc(C)cc2)N2CCN(C(=Nc3ccc(C)cc3)Nc3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
0.5 mmol of piperazine was dissolved in 10 ml of DMF and 1.05 mmol of 1,3 di-p-tolylcarbodiimide was added. After 0.5 h. of stirring at room temperature, a small precipitation was filtered off and washed twice with 1 ml of DMF. The filtrates were collected and kept at room temperature overnight. To the DMF solution, 50 ml of water was added. The precipitated solid was filtered and washed with water. The solid was dissolved in ethyl acetate (20 ml) and 0.2 ml of conc. HCl conc. was added. The product began to precipitate within 15 min. After 1 hour, the precipitate was filtered and washed with ethyl ether. Yield=76%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][N:12]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][N:12]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: Cn1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)nc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1c(CN(CCCCN)C2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a solution of 2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (0.1030 g, 0.21 mmol) in ethanol (1 mL) was added hydrazine monohydrate (0.51 mL, 10.5 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified first via column chromatography on silica gel (91:12:1 CH2Cl2—MeOH—NH4OH) and then by radial chromatography on silica (18:1:1 CH2Cl2—MeOH—NH4OH) to yield 0.0246 g (32%) of N1-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine. 1H NMR (CDCl3) δ 1.32-1.42 (m, 5H), 1.91-2.02 (m, 2H), 2.05-2.11 (m, 1H), 2.55 (t, 2H, J=6.9 Hz), 2.60-2.64 (m, 3H), 2.76-2.86 (m, 1H), 3.98 (s, 3H), 4.04-4.17 (m, 3H), 7.00-7.04 (m, 1H), 7.21-7.27 (m, 2H), 7.30-7.33 (m, 2H), 7.68-7.72 (m, 1H), 8.47 (d, 1H, J=3.3 Hz).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@H:8]1[CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)=O.[C-]#N.[K+].[CH3:32][N:33](C=O)C>O>[Si:12]([O:11][CH2:10][C@@H:8]1[CH2:9][C@H:7]1[CH2:6][C:32]#[N:33])([C:25]([CH3:26])([CH3:27])[CH3:28])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1C[C@H]1COS(C)(=O)=O)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H]1CC#N)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of trans-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl methanesulfonate (1.23 g, 2.94 mmol), potassium cyanide (0.383 g, 5.88 mmol) and DMF (10 mL) was stirred overnight at 60° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→60% ethyl acetate/hexane) to give trans-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)acetonitrile (0.970 g, 2.78 mmol, 94%) as a colorless oil.