Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: Clc1cncc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)cncc1Br
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a solution of LDA (2 M solution in THF/heptane/ethylbenzene, 2.78 g, 12.97 mL, 25.95 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere cooled to −78° C. was added a solution of the 3-bromo-5-chloropyridine (5.0 g, 25.98 mmol) in anhydrous THF (40 mL) at −78° C. The reaction mixture was allowed to stir at the same temperature for 45 minutes. Then, a solution of chloro(ethoxy)methanone (28.19 g, 259.7 mmol) was added slowly over 15 minutes. After stirring for 20 minutes, the reaction mixture was quenched with saturated NaHCO3 solution. The reaction mixture was extracted into ethyl acetate (3×100 mL), and the combined organic layer was washed with water and brine. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated, and the residue was purified through CombiFlash using 0-10% ethyl acetate in hexane to provide ethyl 3-bromo-5-chloropyridine-4-carboxylate as a pale yellow oil (5.84 g, 85% yield); 1H NMR (400 MHz, DMSO-do): δ 1.35 (t, 3H), 4.45 (q, 2H), 8.82 (s, 1H), 8.87 (s, 1H); M+ 265.5.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH2:17]>C(Cl)Cl>[N:1]1[N:2]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:12]3[C:11]([OH:17])=[C:10]([N:2]4[N:1]=[C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]5=[N:3]4)[CH:15]=[CH:14][CH:13]=3)[C:11]=2[OH:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O
Reactant: Oc1ccccc1-n1nc2ccccc2n1
Solvent: ClCCl
Product: Oc1c(-c2cccc(-n3nc4ccccc4n3)c2O)cccc1-n1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 519.6 %

Procedure:
Anhydrous ferric chloride (53.5 g, 0.33 mol) was added over a period of 180 minutes to a solution of 2-(2H-benzotriazol-2-yl)phenol, (20.0 g, 94.7 mmol), prepared by the method of Rosevear and Wilshire (Scheme I), Aust. J. Chem. 1985, 38, 1163-76, in methylene chloride (200 mL) and water (160 mg) at 0° C. After the addition was complete, the resulting mixture was removed from the cooling bath and stirred at room temperature for 36 hours. HPLC analysis of the reaction mixture (detector wavelength=290 nm) indicated 87 area % of product and 13 area % of starting material. The mixture was diluted with 2 L of methylene chloride and extracted with two 500 mL portions of 5% HCl, and two 1 L portions of water. The organic layer was rotary evaporated, leaving 19.4 g of a light grey solid which was 90% pure to HPLC. Surprisingly, very little or none of the para coupled product was found, as confirmed by NMR analysis. Recrystallization from o-dichlorobenzene gave COMPOUND 5 as off-white needles. 1H NMR (300 MHz, CD2Cl2) δ 11.62 (s, 2H), 8.41 (d, 2H), 7.88 (m, 4H), 7.42 (m, 4H), 7.39 (m, 2H), 7.10 (t, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH:6]1[CH2:9][CH:8]([S:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])=[O:11])[CH2:7]1)[CH2:4][OH:5].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>C1COCC1>[CH2:18]([O:1][CH2:2][CH:3]([CH:6]1[CH2:7][CH:8]([S:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])=[O:11])[CH2:9]1)[CH2:4][O:5][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCOS(=O)(=O)C1CC(C(CO)CO)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOS(=O)(=O)C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Yield: 32.1 %

Procedure:
Using the same reaction conditions, procedure and work up as described Intermediate I-25a (below), butyl 3-(1,3-dihydroxypropan-2-yl)cyclobutane-1-sulfonate (0.13 g, 0.489 mmol) was reacted with benzyl bromide (0.13 mL, 1.075 mmol), 60% NaH (60 mg, 1.467 mmol) and THF (5 mL) to afford the crude product. Purification by column chromatography on silica gel (8% ethyl acetate in hexane) afforded 0.07 g of the product (78% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1)=O)=[O:4].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[Cl:1][CH2:2][C:3]1[O:4][C:7]([C:9]2[C:17]3[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=2)=[N:6][N:5]=1
Reactant: COc1cccc2c(C(=O)NNC(=O)CCl)cn(CC3CCCCC3)c12
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc2c(-c3nnc(CCl)o3)cn(CC3CCCCC3)c12
Yield: 71 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N′-(2-chloroacetyl)hydrazide (250 mg, 0.662 mmol) in tetrahydrofuran (3 ml) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (315 mg, 1.32 mmol) and the resulting reaction mixture subjected to microwave irradiation at 150° C. for 15 minutes. The reaction mixture was quenched with methanol and the solvent evaporated. The resulting residue was purified by flash chromatography using 33-50% (v/v) ethyl acetate in heptane to give 3-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (169 mg, 0.47 mmol) as a yellow solid. This reaction was repeated on a 0.53 mmol scale to afford the same intermediate (a total of 276 mg, 0.77 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=2)=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:22]1[N:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([C:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[CH:7]=[C:2]([C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH:3]=2)=[O:16])=[CH:24][N:23]=1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(-c3ncccn3)c2)cc1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-4′-methyl-N-((2-methylpyrimidin-5-yl)methyl)biphenyl-3-carboxamide (100 mg, 0.0002 mol), 2-(tributylstannyl)pyrimidine (0.1 g, 0.0003 mol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.000005 mol) and toluene (1 mL, 0.009 mol) was heated in the microwave at 120° C. for 1 hour. LC/MS showed the desired product, LC/MS m/e=396.3. The mixture was cooled to room temperature and the reaction mixture filtered over celite and solvent removed under reduced pressure. The residue was purified by reverse phase prep HPLC to get the product as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]([CH3:13])/[C:9](/[NH2:12])=[N:10]/[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:11]/[N:10]=[C:9](\[NH2:12])/[C@@H:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:13])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)/C(N)=N/O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O/N=C(\N)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a mixture of tert-butyl[(1S,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (Step 3, 100 mg, 0.5 mmol) in methylene chloride (2 mL) cooled at 0° C. was added triethylamine (0.10 mL, 0.74 mmol). To the mixture was then added acetyl chloride (42 mg, 0.54 mmol) dropwise and the reaction was warmed to room temperature. After stirring at room temperature for 1 h, the reaction was concentrated. The residue was dissolved in dichloromethane (DCM), washed with water and brine, dried over MgSO4, filtered and concentrated to afford the desired crude product (100 mg, 82.8%) which was directly used in the next step reaction without further purification. 1H-NMR (300 MHz, DMSO-d6): 6.90 (d, J=9.0 Hz, 1H), 6.22 (s, 2H), 4.05 (m, 1H), 2.01 (s, 3H), 1.36 (s, 9H), 1.20 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[I:12]I>S([O-])([O-])(=O)=O.[Ag+2].C(O)C>[NH2:1][C:2]1[C:7]([I:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: II
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ncc(C(F)(F)F)cc1I
Temperature: 25 °C
Yield: 48.1 %

Procedure:
2 g (12.34 mmol) of 2-amino-5-trifluoromethylpyridine, 3.85 g (12.34 mmol) of silver sulfate and 80 mL of ethanol are introduced into a 500 mL two-necked flask equipped with a magnetic stirrer. 3.13 g (12.34 mmol) of iodine powder are then added portionwise to the reaction medium stirred at room temperature. The reaction mixture is then stirred at room temperature for 48 hours. The resulting yellow suspension is filtered, the precipitate is rinsed with ethanol and the filtrate is evaporated under reduced pressure. The residue is taken up in 100 mL of dichloromethane. This solution is washed successively with 20 mL of aqueous 5% sodium hydroxide solution, 20 mL of water and 20 mL of saturated aqueous sodium chloride solution and then dried over sodium sulfate and concentrated under reduced pressure. The resulting solid is purified by chromatography on a column of silica, eluting with a mixture of n-heptane and ethyl acetate. 1.71 g of product are obtained in the form of a pink powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:16][S:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=2)(=[O:36])=[O:35])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(O)cc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 3-benzyloxy-5-methylphenol (400 mg, 2.0 mmol), as prepared in step a of Example 3, in methylene chloride (10 mL) at 0° C. was treated with N,N-diisopropylethylamine (0.4 mL) and 3-trifluoromethylbenzenesulfonyl chloride (489 mg, 2.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (200 ml,) and water (50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (710 mg, 85%). 1H-NMR (300 MHz, CDCl3) δ 2.25 (s, 3H), 4.94 (s, 2H), 6.41 (s, 2H), 6.72 (s, 1H), 7.37 (m, 5H), 7.68 (t, 1H), 7.91 (d, 1H), 8.03 (d, 1H), 8.09 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.O>O1CCCC1>[CH3:3][O:4][C:5](=[O:6])[CH:7]=[C:24]1[CH2:23][CH2:22][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([OH:14])=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
60% suspension mixed with NaH mineral oil (7.6 g, 0.19 mol) was added to trimethyl phosphonoacetate (22.8 mL, 0.15 mol) solution dissolved in anhydrous tetrahydrofuran (655 mL) under 0° C. nitrogen gas. 4-(4-hydroxyphenyl)cyclohexanone (25 g, 0.13 mol) solution dissolved in tetrahydrofuran (525 mL) was slowly added thereto at 25° C. Then, the reaction mixture was stirred at room temperature for 5 hours, cooled with water, and extracted with ethyl acetate. The mixed organic phase was washed with brine and dried with Na2SO4. The solvent was reduced under reduced pressure to obtain [4-(4-hydroxyphenyl)cyclohexylidene]acetic acid methyl ester as a white solid (31.3 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])/[C:4](/C)=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].COC(=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)C1C(=CC=CC=1)O>>[CH3:1][O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]
Reactant: COC(=O)/C(C)=C/c1ccccc1O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=Cc1ccccc1O
Product: COC(=O)/C=C/c1ccccc1O

Procedure:
According to the procedure of Example 1, (E)-3-(2-hydroxy-phenyl)-2-methyl-acrylic acid methyl ester was prepared from methyl(triphenyl-phosphoranylidene)acetate and salicylaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=O)[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:27])[NH2:16])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=S)C1CCN(c2c(Cl)cncc2Cl)CC1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (40 mg, 0.15 mmol) in THF (2 mL) was added Lawesson's reagent (71 mg, 0.18 mmol) and the mixture was heated at reflux for 2.5 h. After cooling to r.t. the mixture was poured into a saturated solution of sodium hydrogen carbonate (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 99:1) to furnish the title compound as a white solid (21 mg, 40%), m/z (ESI) C11H14Cl2N2S requires 290.0280 found [M+H]+ 290.0280.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][C@@H:4]([C:14]([O:16]C)=[O:15])[NH:3]1.[OH-].[Na+].B([O-])([O-])[O-].[Na+].[Na+].[Na+]>CO.O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][C@@H:4]([C:14]([OH:16])=[O:15])[NH:3]1
Reactant: COC(=O)[C@@H]1Cc2cc(O)c(O)cc2C(=O)N1
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1N[C@H](C(=O)O)Cc2cc(O)c(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Methyl (3S)-1-oxo-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (4 g) is dissolved in methanol (100 ml), and a solution of sodium hydroxide (0.81 g) and sodium borate (7.08 g) in water (100 ml) is added thereto. The mixture is stirred at room temperature overnight. The mixture is distilled under reduced pressure to remove methanol. The residue is acidified with conc.HCl, and the solution is chromatographed on a column (2.6×35 cm) of CHP-20P resin. The column is washed with water (500 ml), and then the product is eluted with 50% methanol. The eluate is distilled under reduced pressure to remove the solvent, and water is added to the residue. The precipitated crystals are collected by filtration and recrystallized from water, whereby (3S)-1-oxo-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.81 g) is obtained.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(O)(=O)C.Br([O-])(=O)=O.[Na+]>O>[CH:3]1[C:4]([CH:7]=[O:8])=[CH:5][CH:6]=[C:1]([CH:9]=[O:10])[CH:2]=1
Reactant: OCc1ccc(CO)cc1
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(C=O)cc1

Procedure:
In the same manner as in Example 3, the operation was conducted, except that 0.55 g (4 mmols) of p-xylylene glycol was used in place of m-methoxybenzyl alcohol and 1 ml (17.4 mmols) of acetic acid was used in place of 2 ml of acetic acid, and also 1 ml of water and 0.4 g (2.7 mmols) of sodium bromate were used. With respect to the components in the reaction solution, the intended p-phthalaldehyde was produced in an area ratio, as determined by gas chromatography, of 56.0% and p-hydroxymethylbenzaldehyde as a product at the intermediate stage (compound in which only one among two hydroxymethyl groups in a molecule of the raw material was replaced by a formyl group) was produced in an area ratio of 28.6%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([NH2:15])=[CH:4][CH:3]=1.[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]=[CH:16][N:8]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1NC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: Brc1ccc2ncn(C3CCOCC3)c2c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of compound 5-bromo-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (500 mg, 1.852 mmol) in HC(OMe)3 (2 mL) was added TsOH (15 mg, 0.0789 mmol). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was extracted with DCM washed with water and the organic layer dried over sodium sulfate which was removed by filtration. After concentration of the filtrate, the crude product was purified by column (201 mg, 38.53%). LCMS (m/z): 281.0, 283.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2)([O-:3])=[O:2].[C:15]([O-])([O-])=O.[Cs+].[Cs+].IC.O>CN(C=O)C>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc2cccc([N+](=O)[O-])c2[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cccc([N+](=O)[O-])c2n1
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1,2-dihydro-8-nitroquinolin-2-one, as described above in Step C, (2.55 g, 13.41 mmol) in DMF (80 mL) were added Cs2CO3 (13.11 g, 40.23 mmol) and iodomethane (1.37 mL, 14.75 mmol) and the mixture was stirred vigorously for 2.5 hours. The reaction mixture was poured into water at 0° C. and the solid was isolated by filtration. The resulting solid was dried in vacuo, to yield the above-titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH3:31].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH2:28][N:29]([CH2:30][CH3:31])[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCNCCN
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CCN)C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, N-(2-aminoethyl)ethylamine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.82 minutes; C21H23Cl2N5O2 (448.35); mass spectrum: (M−H)−=447/449/451 (chlorine isotope).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[O:10]N.O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>>[Cl:2][C:3]1[C:4]2[O:10][C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]=3[C:5]=2[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NOc1ccc(Br)cc1Cl
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Yield: 20 %

Procedure:
The product of step A was reacted with tert-butyl 4-oxopiperidine-1-carboxylate then Boc protected following the procedure of Example 29, step B. Purification by flash column chromatography (SiO2, 95:5 hexanes/ethyl acetate) provided tert-butyl 6-chloro-8-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (3.9 g, 20%) as a pink solid: 1H NMR (CDCl3, 300 MHz) δ 7.44 (d, J=1.5 Hz, 1H), 7.38 (d, J=1.5 Hz, 1H), 4.50 (s, 2H), 3.88 (t, J=5.4 Hz, 2H), 2.89 (t, J=5.4 Hz, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[H-].[Na+].[Br:7][C:8]1[CH:13]=[C:12]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1F.[NH4+].[Cl-]>C1COCC1.CC(=O)OCC>[Br:7][C:8]1[CH:13]=[C:12]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCO
Reactant: CCS(=O)(=O)c1ccc(F)c(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCOc1ccc(S(=O)(=O)CC)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of n-propanol (224 mg, 3.74 mmol) in THF (10 mL) was added NaH (112 mg, 2.80 mmol, 60% in mineral oil) at 0° C. After stirring at 0° C. for 30 min, 2-bromo-4-(ethanesulfonyl)-1-fluorobenzene (500 mg, 1.87 mmol) was added and the mixture was stirred at room temperature for 4 h. Addition of saturated NH4Cl (10 mL) followed by EA extractive work up gave the title compound (300 mg, yield: 52.3%) which was carried on directly.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([C:14]2[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:29])[C:3]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[Li+].[OH-].Cl>O.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([C:14]2[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:29])[C:3]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cn2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
Methyl 3-(6-(1-(2,6-dimethyl-4′-(trifluoromethyl) biphenyl-4-yl amino)-3-methylbutyl)nicotinamido)propanoate (400 mg, 0.74 mmol) was dissolved in H2O (3 mL) and tetrahydrofuran (3 mL). Then 1N LiOH (93.0 mg, 2.2 mmol) was added. The mixture was stirred at ambient temperature for 5 hours. The mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 10 to 80% MeCN in water) gave (+/−)-3-(6-(1-(2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinamido)propanoic acid (50.7 mg, 13%) as a yellow solid. 1H NMR (400 MHz, CD3CN, 6): 8.85 (s, 1H), 8.02 (m, 1H), 7.64 (d, 2H), 7.46 (d, 1H), 7.22 (d, 3H), 6.32 (s, 2H), 4.59 (m, 1H), 3.54 (m, 2H), 2.55 (m, 2H), 1.93 (m, 6H), 1.78 (s, 2H), 1.72 (m, 2H), 1.60 (m, 1H), 0.96 (d, 3H), 0.91 (d, 3H). MS (M+1): 528.2.