Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)[N:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1cc(C)nc(Sc2ccc(O)cc2)n1
Product: Cc1cc(C)nc(Sc2ccc(OC(=O)N(C)c3ccccc3)cc2)n1

Procedure:
The title product was prepared from 4-(4,6-dimethylpyrimidin-2-ylsulfanyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (59%, white solid). HPLC-MS: m/z=366.1 (M+1); Rt: 4.50 min.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][O:8][C:4]=2[C:3]=1[CH2:15][CH2:16][CH3:17].[Si:18]([O:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[Si:18]([O:25][CH2:26][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]1[O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][O:8][C:4]=2[C:3]=1[CH2:15][CH2:16][CH3:17])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCCC1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c(O[C@@H]2CCCC[C@@H]2CO[Si](C)(C)C(C)(C)C)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (730 mg, 2.98 mmol), 2-({tert-butyl(dimethyl)silyloxy}methyl)-cyclohexanol (800 mg, 3.28 mmol) from this Example step 1, and triphenylphosphine (1.02 g, 3.874 mmol) was dissolved in dry benzenes (16 mL). Diisopropylazodicarboxylate (0.78 mL, 3.874 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel using acetone and hexane (1:99) to give the title compound.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH2:30]([O:37][C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:44]=[CH:45][C:46]=2[F:50])[CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:68]([O:70][C:71](=[O:82])[CH2:72][C:73]1[CH:78]=[CH:77][C:76](Br)=[C:75]([O:80][CH3:81])[CH:74]=1)[CH3:69]>C1(C)C=CC=CC=1.O.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([O:37][C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[C:43]([C:76]3[CH:77]=[CH:78][C:73]([CH2:72][C:71]([O:70][CH2:68][CH3:69])=[O:82])=[CH:74][C:75]=3[O:80][CH3:81])[CH:44]=[CH:45][C:46]=2[F:50])[CH2:41]1)=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)OC1(C)C
Reactant: CCOC(=O)Cc1ccc(Br)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c(OC)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture under N2 of palladium(II)acetate (13 mg, 0.06 mmol, 0.02 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (48 mg, 0.12 mmol, 0.04 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.20 g, 2.92 mmol, 1.00 eq.) and potassium phosphate (1.24 g, 5.84 mmol, 2.00 eq.) in toluene (8 mL) and water (0.8 mL) was stirred at r.t. during 2 min. (4-Bromo-3-methoxy-phenyl)-acetic acid ethyl ester (797 mg, 2.92 mmol, 1.00 eq) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., diluted with Et2O (10 mL), filtered through celite, washed with Et2O and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt) to yield 8-(4-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a colorless oil.
Reaction SMILES: C[Sn](C)(C)[Sn](C)(C)C.[Cl-].[Li+].Cl[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([Cl:28])[CH:19]=2)[N:15]=[CH:14][N:13]=1.[CH3:29][O:30][C:31]([CH:33]1[CH2:37][C:36](OS(C(F)(F)F)(=O)=O)=[CH:35][N:34]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:32]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:29][O:30][C:31]([CH:33]1[CH2:37][C:36]([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([Cl:28])[CH:19]=3)[N:15]=[CH:14][N:13]=2)=[CH:35][N:34]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:32]
Reactant: CC(C)Oc1ccc(-c2cc(Cl)ncn2)cc1Cl
Reactant: COC(=O)C1CC(OS(=O)(=O)C(F)(F)F)=CN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: C[Sn](C)(C)[Sn](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)C1CC(c2cc(-c3ccc(OC(C)C)c(Cl)c3)ncn2)=CN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 16 h
Yield: 7.8 %

Procedure:
Hexamethyldistannane (5.6 ml, 2.7 mmol) and lithium chloride (0.34 g, 7.8 mmol) were added sequentially in one portion to a stirred solution of, 4-chloro-6-(3-chloro-4-isopropoxy-phenyl)-pyrimidine (0.75 g, 2.7 mmol) and 4-trifluoromethanesulfonyloxy-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.0 g, 2.7 mmol) in THF (40 ml). The mixture was degassed with nitrogen for 5 minutes, after which time palladium tetrakis(triphenylphosphine) (0.31 g, 0.26 mmol) was added in one portion, the mixture was then heated to 70° C. and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (200 ml) and saturated potassium fluoride (50 ml). The organic layer was separated, washed sequentially with water (100 ml) then brine (100 ml) before being dried (MgSO4), filtered and concentrated. The resulting red gum was purified by flash column chromatography (elution: 80% EtOAc, 20% Heptane) to give the title compound (0.1 g, 9% yield) as a colourless oil. Tr=2.69 min m/z (ES+) (M+H+) 474.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6](C(=O)C)=[C:7]([CH3:9])[N:8]=1.[C:13](=O)([O:21]C1C=CC=CC=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.CN(C=O)C.C(Cl)(Cl)Cl>[CH3:9][C:7]1[N:8]=[C:4]([NH:3][C:13](=[O:21])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:5][CH:6]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)c1sc(N)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)Oc2ccccc2)n1
Yield: 100 %

Procedure:
In a round-bottom flask, NaH 60% dispersion in mineral oil (3.07 g, 77 mmol) was washed 2× with hexane and suspended in DMF. Then 2-amino-5-acetyl-4-methyl-thiazole (10.0 g, 64 mmol) was added and stirred while cooling in an ice bath. Stirring continued until the NaH was consumed. Diphenyl carbonate (34 g, 160 mmol) was added while cooling and after the addition was complete the reaction mixture was stirred for an additional 30 minutes at room temperature. The DMF was removed on a rotary evaporator (high vacuum, 40° C.) to yield a brown residue. This residue was dissolved in 1 L of CHCl3 and washed successively with 2 L of 0.5N HCl, 2×1 L of water, and finally by 1 L of brine. The aqueous portions were back extracted twice with 300 ml of CHCl3. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give a white solid. This was chromatographed on silica (15%-70% EtOAc/hexane) to give 15 g of the desired carbamate as a white solid. Mp 180-182° C. 1H NMR (300 MHz, CDCl3) δ 11.42 (bs, 1H), 7.47-7.40 (m, 2H), 7.33-7.27 (m, 1H), 7.22-7.18 (m, 2H), 2.72 (s, 3H), 2.50 (s, 3H). ESI MS: (M+H)+=277.1. Anal. Calcd for C13H12N2O3S: C, 56.51; H 4.39; N, 10.14; S, 11.60. Found: C, 56.42; H, 4.31; N, 10.11; S, 11.74. A similar procedure as described above for Example 1 was used to synthesize all the other examples listed in Table 1.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[C:5]=1[CH3:36].[OH-].[Li+]>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:21]2[C:20]([N:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11](=[O:12])[NH:10][C:6]3[C:5]([CH3:36])=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:37])=[O:2])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]3)=[N:22]2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c1C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: Cc1c(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)cccc1C(=O)O

Procedure:
In analogy to the procedure described in example 2.2, 3-{3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-3-cyclohexyl-ureido}-2-methyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as colorless solid. MS: m/e=503.4 [M+H+].
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([CH3:23])([CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])#[N:2].O.[OH-].[Li+].CC(O)=O>C1COCC1.O.CCOC(C)=O>[C:1]([C:3]1[C:4](=[O:5])[NH:6][C:7]([CH3:23])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)#[N:2]
Reactant: CCOC(=O)C(C)(CC(=O)c1ccc(C)cc1)NC(=O)CC#N
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1(C)CC(c2ccc(C)cc2)=C(C#N)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.6 %

Procedure:
Intermediate 108A (1.2837 g, 4.06 mmol) was dissolved in a mixture of THF (15 mL) and water (3.00 mL) in a 25 mL 1 neck pear shaped flask that was equipped with a magnetic stirrer. Lithium hydroxide monohydrate (0.204 g, 4.87 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was acidified to pH 4 with AcOH, diluted with EtOAc (50 mL) and the solution was washed with water (20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the desired product (1.40 g, 115%) as yellow oil. LCMS Anal. Calc'd for C17H18N2O3 298.1, found [M+H] 299.1.
Reaction SMILES: C([NH:8][C:9]1[S:10][C:11]([Cl:20])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl.CN(C=O)C>[NH2:8][C:9]1[S:10][C:11]([Cl:20])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(Cl)cc1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1sc(Cl)cc1-c1ccccc1

Procedure:
2-(N-Boc-amino)-5-chloro-3-phenyl-thiophene (66 mg, 0.21 mmol) was treated with trifluoroacetic acid (1 ml) in dichloromethane (3 ml) at ambient temperature for 1 hr. The mixture was diluted with DMF (1 ml) and the more volatile materials removed under reduced pressure. The resulting DMF solution of 2-amino-5-chloro-3-phenylthiophene was used in the subsequent coupling step without purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCCc2ccccc21
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCCc2ccccc21
Yield: 119.4 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (720 mg, 2.26 mmol), piperazine (583 mg, 6.77 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.77 mmol) in acetonitrile (10 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 257 mg (30%) of 1,2,3,4-tetrahydro-N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)naphthalen-1-amine: 1H NMR (400 MHz, CD3OD): δ 7.60 (d, 1H), 7.30 (d, 1H), 7.20-7.10 (m, 2H), 6.32-6.26 (m, 2H), 6.23 (br s, 1H), 4.67 (dd, 1H), 3.26 (br t, 4H), 2.98 (br t, 4H), 2.92 (s, 3H), 2.90-2.72 (m, 2H), 2.02-1.80 (m, 4H). MS (ESI) m/z: Calculated: 385.52; Observed: 386.2 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(OCCc1ccccc1)c2CN1CCNCC1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-phenethoxy-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0730 g, 0.126 mmol) in methylene chloride (3 mL) was added with trifluoroacetic acid (3 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, added with methanol (8 mL) and a 5% solution of hydrogen chloride in methanol (2 mL), and thereby made basic, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then the residue was suspended in acetonitrile and thereby washed to obtain an orange solid. This solid was suspended in water (4 mL) and saturated aqueous sodium hydrogencarbonate (4 mL), and the suspension was stirred for 1 hour. The reaction mixture was filtered, and then the resulting solid was washed with water to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-phenethoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0211 g, 34%).
Reaction SMILES: [CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[C:12](/[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH:18]=[C:17]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:16]=2[CH:15]=1)\[CH3:13])=[CH:3]\[C:4]([O:6]CC)=[O:5].CO.[Li+].[OH-].Cl>C1COCC1.CCOCC>[CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[C:12](/[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:24])([CH3:25])[CH2:19][CH:18]=[C:17]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:16]=2[CH:15]=1)\[CH3:13])=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CC(/C=C/C=C(\C)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C)=C\C(=O)O
Reaction time: 6 h

Procedure:
To a solution of ethyl (E,E,E)-3-methyl-7-(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)-2,4,6-octatrienoate (Compound 51) 85.0 mg, 0.20 mmol) in THF (1 ml) and methanol (1 ml) was added 12.0 mg (0.50 mmol) of LiOH (0.5 ml, 1M solution). The mixture was stirred for 6 hours, diluted with ether (60 ml), acidified with 10% HCl (1 ml). The solution was washed with water, and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure afforded the title compound as a solid, which was purified by recrystallization from acetone. 1H NMR (acetone-d6): δ 7.35-7.45 (2H, m), 7.19-7.28 (4H, m), 7.17 (1H, d, J=1.8 Hz), 7.09 (1H, dd, J=11.5, 15.1 Hz), 6.48 (1H, d, J=11.5 Hz), 6.42 (1H, d, J=15.1 Hz),5.99 (1H, t, J=4.7 Hz),5.82 (1H, s), 2.36 (3H, s), 2.33 (2H, d, J=4.7 Hz), 2.32 (3H, s), 2.13 (3H, s), 1.32 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](B4OC(C)(C)C(C)(C)O4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:41]([O:45][C:46]([N:48]1[CH:53]([C:54]2[NH:55][C:56]([C:59]3[CH:64]=[CH:63][C:62](Br)=[CH:61][CH:60]=3)=[CH:57][N:58]=2)[CH:52]2[CH2:66][CH:49]1[CH2:50][CH2:51]2)=[O:47])([CH3:44])([CH3:43])[CH3:42].C([O-])([O-])=O.[K+].[K+].N#N>COCCOC.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>[C:41]([O:45][C:46]([N:48]1[CH:53]([C:54]2[NH:55][C:56]([C:59]3[CH:64]=[CH:63][C:62]([C:26]4[CH:25]=[CH:24][C:23]5[C:28](=[CH:29][CH:30]=[C:21]([C:18]6[NH:17][C:16]([CH:12]7[CH2:13][CH2:14][CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:40])[CH:6]([CH3:7])[CH3:8])=[N:20][CH:19]=6)[CH:22]=5)[CH:27]=4)=[CH:61][CH:60]=3)=[CH:57][N:58]=2)[CH:52]2[CH2:66][CH:49]1[CH2:50][CH2:51]2)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 16.3 %

Procedure:
A solution of [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (500 mg, 0.92 mmol), 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (383 mg, 0.92 mmol) and aq K2CO3 (920 μl of a 2M solution, 1.84 mmol) in DME (9 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (106 mg, 0.092 mmol) and PdCl2dppf (75 mg, 0.092 mmol) and then the reaction was heated to 80° C. overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The crude product was purified by reverse phase preparative HPLC (5-50% MeCN—H2O; 0.1% formic acid modifier) to afford 3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (112 mg, 0.15 mmol, 16% yield). LCMS-ESI+: calc'd for C44H52N7O5: 758.4 (M+H+). Found: 758.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[I-:12].[K+].ClCCl.C(OCC)C>CN(C)C=O.[Cu]I>[I:12][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: [I-]
Reactant: Brc1ccc2cnccc2c1
Agent: [Cu]I
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Ic1ccc2cnccc2c1
Yield: 101.8 %

Procedure:
Heat a mixture of 6-bromoisoquinoline (Aldrich; 0.320 g, 1.54 mmol), copper (I) iodide (0.155 g, 0.815 mmol), and potassium iodide (1.27 g, 7.96 mmol) in N,N-dimethylformamide (5.0 mL) to 130° C. at 3 h under microwave irradiation. Pour the cooled reaction mixture into 4:1 dichloromethane/diethyl ether (100 mL) and filter. Wash the filtrate with 5% aqueous sodium bisulfite solution (2×50 mL). Dry the organic layer over sodium chloride, decant the organic layer, and remove the solvents under reduced pressure. Dry the residue under vacuum for 18 h to give 0.4 g (100%) of the title compound as a dark red-brown solid. This material is carried on directly to the next step without further purification. MS (electrospray, m/z) 256.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[C:17]([F:23])=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:6]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:20][C:18]1[C:17]([F:23])=[CH:16][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:6]=2)=[C:2]([F:1])[CH:19]=1
Reactant: CCC(=O)Nc1cc(Oc2cc(F)c([N+](=O)[O-])cc2F)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 80 °C
Yield: 70.5 %

Procedure:
To a suspension of N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)propionamide (27.2 g, 84.2 mmol) in EtOH (750 mL) was added a solution of NH4Cl (18 g, 337 mmol) in water (188 mL) and Fe powder (97%, 325 mesh, 18.8 g, 337 mmol) in one portion at RT. The mixture was then heated at 80° C. for 1 h, cooled to ambient temp, filtered through a bed of diatomaceous earth, and washed with MeOH (1 L). The combined filtrates were concentrated to dryness and purified by silica gel chromatography (EtOAc/hexanes) to give N-(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)propionamide (17.4 g, 70.5% yield). 1H-NMR (400 MHz, CDCl3): δ 8.07 (d, J=5.6 Hz, 1 H), 8.00 (br s, 1 H), 7.77 (d, J=2 Hz, 1 H), 6.85 (dd, J=10.4, 7.2 Hz, 1 H), 6.63-6.58 (m, 2 H), 3.79 (s, 2 H), 2.38 (q, J=7.6 Hz, 2 H), 1.20 (t, J=7.6 Hz, 3H); MS (ESI): m/z 294.1 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.[C:15]1(B(O)O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>O.C(O)C.C1C=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>[C:23]1([C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=2)[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Nc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: Nc1ccc(-c2cccc3ccccc23)cn1

Procedure:
Potassium carbonate (5.19 mmol, 717 mg) in water (2.5 mL) and tetrakis(triphenylphosphine)palladium(0) (0.04 mol %, 80 mg) in ethyl alcohol (2.5 mL) were added to 2-amino-5-bromopyridine (1.73 mmol, 299 mg) and 1-naphthaleneboronic acid (2.60 mmol, 446 mg) in benzene (10.0 mL). After 2 hours at 90° C. the reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3×30 mL). The organic phases were concentrated in vacuo and the residue chromatographed on silica gel (eluted with 50% ethyl acetate in hexanes) to give 260 mg (Y: 68%) of the title compound 11a. MS (E+) m/z: 381 (MH+).