Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([F:41])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36]([O:38]CC)=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([F:41])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36]([OH:38])=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2F)c2c1[nH]c1cc(OCCOC)ccc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3F)c12
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
To a light orange, homogeneous solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate (0.8002 g, 1.435 mmol) in THF (30.8 mL) and MeOH (10.25 mL) was added a solution of LiOH hydrate (0.241 g, 5.74 mmol) in water (2 mL). After 1.5 hr. the reaction was concentrated in vacuo. Water (10 mL) was added followed by 1 N aqueous HCl to pH 4-5 by litmus paper. The precipitate was filtered and washed with water, dried over Drierite under vacuum to give the desired product (0.705 g, 1.331 mmol, 93% yield) as a tan solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].O.[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15]C=1C(O)=O>C(Cl)Cl.CN(C)C=O>[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.81 ml) in methylene chloride (10 ml) was added dropwise to a solution of 2-methoxy-4-nitrobenzoic acid monohydrate (1 g) in methylene chloride (40 ml) and dimethylformamide (1 drop) and the reaction mixture was stirred at room temperature for 1 hour after gas evolution ceased. The solvent was then evaporated in vacuo to give an oil which was crystallised from cold ethyl acetate/hexane to give the title compound, yield 0.7 g.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S(=O)(=O)(O)O>Cl[Pd]Cl.O.C(O)CO>[CH2:17]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(-c2ccc(I)cc2)cc1
Reactant: CCCCCOc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: OCCO
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1
Temperature: 95 °C

Procedure:
32.4 g of 4′-iodobiphenyl-4-carboxylic acid are introduced together with 25.8 g of glycol ester of 4-n-pentoxyphenylboronic acid and 15.9 g of sodium carbonate into 300 ml of ethylene glycol and, while stirring vigorously, 18 mg of PdCl2 and 26.6 mg of PPh3 are added, and the mixture is stirred at 80° C. for 6 hours. The hot reaction mixture is cautiously poured into a mixture of 30 g of 37% strength sulfuric acid and 200 g of water, and the mixture is heated at 90-100° C. for 30 minutes. After filtration and washing with water, the crude product is dried at 80° C./100 mbar and then recrystallized from dimethylacetamide. This affords after drying 24.1 g (67%) of 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylic acid with a purity of <99%.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:26])[CH:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10].[Cl-].[Na+]>O.O1CCCC1.CO>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][O:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:26])=[O:5])=[CH:15][CH:16]=1
Reactant: COC(=O)C(CC(C)C)OCc1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(OCc1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
A solution of lithium hydroxide monohydrate (0.0443 g, 1.056 mmol) in water (3 ml) was added drop-wise over 1 minute to a solution of 2-(biphenyl-4-ylmethoxy)-4-methyl-pentanoic acid methyl ester (0.11 g, 0.3521 mmol) in tetrahydrofuran:methanol 2:1 (15 ml) at 0° C. The mixture was stirred at ambient temperature for 16 hours then poured into saturated aqueous sodium chloride solution (10 ml). The aqueous layer was extracted with diethyl ether (2×10 ml) which was discarded. The aqueous layer was acidified with 1M hydrochloric acid to pH (1˜2), then the product was extracted into dichloromethane (3×10 ml). The combined dichloromethane layers were washed with water (2×10 ml), saturated aqueous sodium chloride solution (2×10 ml) then dried (Na2SO4) and the solvents removed in vacuo to leave 2-(biphenyl-4-ylmethoxy)-4-methyl-pentanoic acid as a colourless oil (0.048 g, 45.69%). TLC (single UV spot, Rf=0.2, methanol:dichloromethane 0.5:9.5), HPLC-MS (297.1 [M−1)+, 321.1 [M+Na]+, 619.3 [2M+Na]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]2)[C:5]([Cl:15])=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([C@H:44]([NH2:47])[CH2:45][OH:46])[CH:38]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:43][C:41]1[CH:40]=[C:39]([CH:44]([NH:47][C:12]([CH:10]2[CH2:9][N:8]([C:6]3[C:5]([Cl:15])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:11]2)=[O:14])[CH2:45][OH:46])[CH:38]=[CH:37][CH:42]=1
Reactant: O=C(O)C1CN(c2nc(Cl)ncc2Cl)C1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC(CO)c1cccc(Cl)c1)C1CN(c2nc(Cl)ncc2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
1-(2,5-Dichloropyrimidin-4-yl)-azetidine-3-carboxylic acid (66 mg, 0.27 mmol, 1 equivalent) was dissolved in DMF (1 mL) together with EDCI (103 mg, 0.53 mmol, 2 equivalents), HOBt (18 mg, 0.13 mmol, 0.5 equivalent) and (S)-(+)-3-chlorophenylglycinol (67.4 mg, 0.32 mmol, 1.2 equivalents). Triethylamine (121 mg, 0.32 mmol, 1.2 equivalents) was then added and the resulting mixture was stirred at room temperature for 1 hour then warmed to 90° C. for 10 minutes. The crude reaction mixture was diluted with ethyl acetate, washed with water, and the organic fraction dried over sodium sulfate. The resulting crude oil was purified by HPLC Gilson (acetonitrile/water/0.1% TFA), yielding the title compound as a white solid (44 mg, 41%). HPLC Rt=5.528 minutes.
Reaction SMILES: [C-:1]1([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:25](Cl)Cl>C1C=CC=CC=1>[C:12]([C:11]1[CH2:10][CH2:9][CH2:8][C:6]=1[C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:15][CH:25]=1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:20]
Reactant: ClCCl
Reactant: O=C(Cl)CCCCC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(C1=C([c-]2cccc2)CCC1)c1ccccc1
Reaction time: 0.5 h
Yield: 9 %

Procedure:
Ferrocenoylvaleryl chloride (prepared as above and assumed to be 0.01 mole) was diluted with methylene chloride (10 mls.) and benzene (20 mls.) and the solution was cooled to 0°-5°. Aluminium chloride (2.6g; 0.02 mole) was then added with stirring over 30 minutes. After further stirring at room temperature for 2 hours, ice was added to the reaction mixture. The organic layer was then separated and washed successively with water, aqueous sodium bicarbonate solution, and water, before being dried over sodium sulphate. Evaporation under reduced pressure produced a brown oil from which chromatography on silica gel with toluene/ethyl acetate provided a pure sample of the required compound (0.32 g; 9% yield) mp 135°-7°.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:33][CH2:34]N(C(C)C)C(C)C.C(I)C>ClCCCl>[CH2:33]([N:14]1[CH:15]=[C:16]([CH2:20][C:21]2[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=2)[C:17](=[O:19])[N:18]=[C:13]1[S:12][CH2:11][C:10]1[CH:29]=[CH:30][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=2)=[CH:8][CH:9]=1)[CH3:34]
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCI
Product: CCn1cc(Cc2cnc(OC)nc2)c(=O)nc1SCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 55 °C
Yield: 5.6 %

Procedure:
To a solution of 2-((4-(4-fluorophenoxy)benzyl)thio)-5-((2-methoxypyrimidin-5-yl)methyl)pyrimidin-4(1H)-one (167 mg, 0.371 mmol) in DCE (5 mL) was added Hunig's base (0.194 mL, 1.112 mmol) and EtI (0.045 mL, 0.556 mmol). The mixture was heated at 55° C. for 2 days. Purification via reverse phase flash chromatography then afforded the title compound (10 mg, 5.64% yield). LCMS: rt=3.24 min, [M+H+]=479
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C[O:12][C:13]([C:15]1[NH:16][N:17]=[C:18]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])[CH:19]=1)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCOCC1>[CH3:27][C:26]1[O:25][N:24]=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]=1[CH2:21][O:20][C:18]1[CH:19]=[C:15]([C:13]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:12])[NH:16][N:17]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: C1COCCN1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)N2CCOCC2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 0.92 mL, 1.3 mmol) was added dropwise (exothermic) to a solution of morpholine (111 μL, 1.3 mmol) in dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) in dioxane (2 mL) was added. The resulting mixture was heated at 90° C. overnight and then cooled to room temperature and then poured into Seignette's salt solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane:methanol=9:1) afforded the title compound (47 mg, 40%), which was obtained as a colorless oil. MS: m/e=369.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH2:3][CH2:2]1.CN([CH2:19][C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)C>>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([C:4]3[CH2:3][CH2:2][N:1]([CH2:19][C:20]4[C:28]5[C:23](=[N:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)[CH2:6][CH:5]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: C1=C(c2ccc3[nH]ccc3c2)CCNC1
Product: C1=C(c2ccc3[nH]ccc3c2)CCN(Cc2c[nH]c3ncccc23)C1
Yield: 35 %

Procedure:
5-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole (200 mg, 1.0 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (177 mg, 1.01 mmol) were coupled as described in Example 4 to give a solid which was purified by flash chromatography, eluting with 10% methanol in dichloromethane containing 1% ammonia. Recrystallisation from methanol gave the title compound (115 mg, 35%) as a tan solid, m.p. 187°-189° C.; (Found: C, 73.78; H, 6.34; N, 16.13. C21H20N4.0.75 H2O requires C, 73.77; H, 6.34; N, 16.39%); δH (DMSO-d6) 2.68 (2H, m, tetrahydropyridinyl H), 3.10 (2H, s, tetrahydropyridinyl H), 3.18 (1H, d, J 4.4 Hz, tetrahydropyridinyl H), (other tetrahydropyridinyl H obscured by solvent at 3.30), 3.74 (2H, s, ArCH2N), 6.02 (1H, m, CH=CR), 6.40 (1H, s, ArH), 7.04 (1H, dd, J 7.5, 3.2 Hz, 5-H), 7.20 (1H, d, J 8.2 Hz, ArH), 7.32 (2H, m, ArH), 7.40 (1H, s, ArH), 7.52 (1H, s, ArH), 8.04 (1H, d, J 7.5 Hz, 4-H), 8.18 (1H, d, J 3.2 Hz, 6-H), 11.00 (1H, br s, NH), and 11.48 (1H, br s, NH); m/z (CI+, NH3) 329 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6]Cl.C(O)C.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+].C(OCC)C>O>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]
Reactant: O=S([O-])[O-]
Reactant: ClCCOCCCl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCOCCCl
Reaction time: 2 h

Procedure:
Bis(2-chloroethyl)ether (94.4 g), ethanol (250 ml) and water (90 ml) were stirred together under reflux, and a solution of sodium sulphite (25.0 g) in distilled water (90 ml) was added to the stirred, refluxing reaction mixture over a period of 2 hours. After the addition, refluxing was continued for two hours after which time the excess alcohol and bis(2-chloro-ethyl) ether were removed by distillation. The remaining aqueous solution was evaporated to dryness on a water bath to give a white crystalline solid, which was stirred with diethyl ether and filtered to yield sodium 2-chloroethoxyethyl sulphonate.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:18]([CH:19]=1)=[C:17](Br)[CH:16]=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:18]([CH:19]=1)=[C:17]([N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1)[CH:16]=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(OCc1ccccc1)c1cc2c(Br)cccc2n1Cc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCN(c2cccc3c2cc(C(=O)OCc2ccccc2)n3Cc2ccccc2)CC1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
A solution of 1-Benzyl-4-bromo-1H-indole-2-carboxylic acid benzyl ester (235 mg, 0.56 mmol) and 1-methyl-piperazine (80 ul, 0.72 mmol) in 5 ml Dioxane was added to a mixture of Pd2(dba)3 (10 mg, 0.01 mmol), BINAP (18 mg, 0.03 mmol), Cs2CO3 (547 mg, 1.68 mmol). With stirring, the solution was heated at 100° C. overnight and was allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and the resulting brown residue was purified by preparative TLC (7% MeOH in CH2Cl2 containing 0.7% NH4OH) to give 174 mg of 1-benzyl-4-(4-methyl-piperazin-1-yl)-1H-indole-2-carboxylic acid benzyl ester as a yellow solid (71%). MS: (M+H)+ 440.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:13]3[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=3[CH:22]([CH3:24])[CH3:23])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[C:31]1([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClCCl>C1(C)C(C)=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:22]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:13]=1[N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[N:37]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:39]=1)([CH3:24])[CH3:23]
Reactant: c1ccc(Nc2cccc(-c3ccccn3)c2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(N(c2ccccc2)c2cccc(-c3ccccn3)c2)c1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
2-(3-bromophenyl)-1-(2,6-diisopropylphenyl)-1H-imidazole (2.8 g, 7.30 mmol), Pd2(dba)3 (0.067 g, 0.073 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (S-Phos) (0.120 g, 0.292 mmol), and sodium t-butoxide (1.053 g, 10.96 mmol) were mixed in 100 mL of xylene. The solution was bubbled with nitrogen for 20 min. N-phenyl-3-(pyridin-2-yl)aniline (1.979 g, 8.03 mmol) was added. The reaction was heated up to reflux for 6 h. After cooled to rt, dichloromethane was added. The mixture was filtered through Celite®. The solvent was then evaporated. The residue was coated on Celite® and columned with hexanes/ethyl acetate (3:1) to give 3-(1-(2,6-diisopropylphenyl)-1H-imidazol-2-yl)-N-phenyl-N-(3-(pyridin-2-yl)phenyl)aniline (3.66 g, 6.67 mmol, 91% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:51]=[CH:50][CH:49]=[CH:48][C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40](C)(C)C)=[O:38])[CH2:33][CH2:32]4)=[CH:27][C:26]=3[C:44]([F:47])([F:46])[F:45])[CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].CCN(C(C)C)C(C)C.ClC(OC)=O.C(=O)([O-])N.[OH-].[Li+].Cl>C(Cl)Cl.O1CCOCC1.C(#N)C>[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].[CH3:40][O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:22]3[CH:48]=[CH:49][CH:50]=[CH:51][C:21]=3[C:19]3[N:20]=[C:15]([N:9]4[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)[CH:16]=[CH:17][CH:18]=3)=[C:26]([C:44]([F:47])([F:45])[F:46])[CH:27]=2)[CH2:36][CH2:35]1)=[O:38]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3C(F)(F)F)n2)c1C(F)(F)F
Agent: COC(=O)Cl
Agent: Cl
Agent: NC(=O)[O-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(c2ccc(COc3ccccc3-c3cccc(-n4ncc(C(=O)O)c4C(F)(F)F)n3)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the title compound from Example 11 Step C (200 mg, 0.278 mmol) in DCM (3 mL) was added TFA (1 mL). After 10 min, the reaction mixture was concentrated in vacuo, and the crude TFA salt was used without further purification: LCMS m/z 618.8 [M+H]+. To a portion of the crude TFA salt in DCM (1.5 mL) were added DIEA (486 μL, 2.78 mmol) and methyl chloroformate (65 μL, 0.84 mmol), and the resulting mixture was allowed to stir at room temperature. After 90 min, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the crude carbamate, which was used without further purification: LCMS m/z 676.8 [M+H]+. To a solution of the carbamate in dioxane (3 mL) was added lithium hydroxide (1.5 mL, 2N aqueous, 3 mmol), and the mixture was stirred at 50° C. After 1 h, the reaction mixture was rendered acidic by addition of HCl (2N aqueous), then was diluted with acetonitrile and purified by reverse phase HPLC (30 to 100% acetonitrile/water, both 0.1% v/v TFA) to provide the title compound: LCMS m/z 648.8 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.07 (t, J=8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.72-7.69 (m, 2H), 7.62-7.61 (m, 2H), 7.54-7.52 (m, 1H), 7.47-7.43 (m, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.13 (t, J=8.5 Hz, 1H), 5.32 (s, 2H), 4.14-4.08 (m, 2H), 3.60 (s, 3H), 2.88-2.80 (m, 3H), 1.78-1.75 (m, 2 H), 1.58-1.49 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[SH:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[S:18][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(S)n1-c1ccc(F)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (3) (4.09 g, 15.34 mmol) in THF (70 mL) was added triethyl amine (4.50 mL, 32.29) and triphenylmethyl chloride (4.67 g, 16.76 mmol) and the solution was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10%-40% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate. A solution of ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate (6.34 g, 12.47 mmol), sodium hydroxide (0.74 g, 18.39 mmol), methanol (10 mL), THF (20 mL), and water (10 mL) was stirred at room temperature for 16 hour and was then concentrated in vacuo. The aqueous was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to yield 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylic acid (6).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[NH2:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1O.[OH-].[Na+].C1COCC1>CO.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:14]3[CH:15]=[C:16]([OH:17])[CH:18]=[CH:19][C:13]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Oc1ccc2nc(-c3ccc(Cl)cc3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
25 g (142.8 mmol) of 4-chlorobenzoyl chloride and 3.0 g (18.6 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 170° to 200° C. for 1 hour, then the excessive acid chloride was removed by distillation. To the residue, 8.4 g (210 mmol) of NaOH, 60 ml of THF, 60 ml of water and 30 ml of methanol were added, and the mixture was stirred at room temperature for about 2 hours. The reaction solution was extracted with ethyl acetate, the extract was washed with saturated sodium chloride water solution, and ethyl acetate was distilled off. Recrystallizing the residue with water/methanol/THF and drying the crystal, there was obtained 1.24 g (5.05 mmol) of 2-(4-chlorophenyl)-6-hydroxybenzoxazole. The yield was 27.2%.