Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].I[C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].CO.C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C.[Cu](I)I>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:19]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)O)c(I)c1
Reactant: CCCCN(CCCC)C(=O)c1cc(C)[nH]n1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(OC)ccc2C(=O)O)n1
Yield: 30.8 %

Procedure:
A mixture of 5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (0.85 g, 3.6 mmol), 2-iodo-4-methoxybenzoic acid (1.0 g, 3.6 mmol), copper iodide (0.14 g, 0.72 mmol), cesium carbonate (1.2 g, 3.6 mmol), and trans-dimethylaminecyclohexane (0.23 mL, 1.44 mmol) in dioxane (5 mL) was microwaved at 120° C. for 15 minutes. Diluted with ethyl acetate, the crude material was eluted through a silica gel column with a 0 to 100% ethyl acetate/heptane and then 0 to 20% methanol/methylene chloride gradient to afford the title compound (0.43 g, 31% yield). MS (ESI) [m/e, (M+H)+]=388.5.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=1[CH3:24])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.C(OCC)(=O)C>C(Cl)Cl.O>[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[CH:18][C:17]=1[CH3:24])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c(C)cc(OCc2ccc(C#N)cc2)cc1C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A dispersion of NaH in oil (27.3 mmol) was weighed into a 11 round bottom flask containing a magnetic stirrer. The dispersion was washed with hexane to remove the mineral oil, and the flask was immediately charged with tetrahydrofuran (THF) (200 ml). Boc-2,6-dimethyltyrosine methylester (Example 29, 8 g, 24.8 mmol) was added and a drying tube was inserted The mixture was stirred for 2 hr. α-Bromo-p-toluonitrile (5.24 g, 26.8 mmol) was then added, and the mixture stirred at room temperature overnight. A thin layer chromotogram (2:1 Skelly B: Ethyl Acetate) was then run. If starting material was still present, NaH dispersion (1/2 molar amount) and alkylating agent (1/2 molar amount) were added and the reaction run another 24 hr at room temperature. The mixture was then poured into water (1.21) and rapidly extracted thrice with CH2Cl2. The organic fractions were combined, dried (MgSO4), and stripped to give a product (O-(p-cyanobenzyl)-Boc-2,6-dimethyltyrosine methyl ester) which was directly hydrolyzed with NaOH as described in Example 1 to give the title compound. NMR: benzyl methylene ∫5.10 s; tyrosyl aromatic protons ∫6.60s; benzyl aromatic protons centered at ∫7.65.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.O.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1
Reactant: Cc1cc(O)nc(SCc2c(Cl)cccc2[N+](=O)[O-])n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(N)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
To a suspension of the 2-{[(2-chloro-6-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.0 g, 3.20 mmol) in ethanol (30 mL), a water mixture of iron powder (1.07 g, 19.24 mmol) and equivalent NH4Cl (0.741 g, 9.6 mmol) was added. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered over Celite and washed with methanol, and the solvent was evaporated. The precipitated solid was filtered off and washed with ether to provide the titled amine (0.316 g, 35% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.42 (s, 2H), 6.01 (bs, 1H), 6.60 (m, 2H), 6.95 (t, J=8.0, 16.1 Hz, 1H); M+282.06.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:9]([C:11]3[CH:12]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.Br[C:30]1[C:31]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:48])[N:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=2)=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=1>>[CH3:18][N:17]([CH3:19])[C:13]1[CH:12]=[C:11]([C:9]2[N:8]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:30]4[C:31]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:48])[N:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=5)=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=4)=[C:3]3[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)c1cccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)c1
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(N(C)C)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with {3-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}dimethylamine. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 634.6
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:39]1([OH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCOCC1.ClCCl.[Cu](I)I>[CH2:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([O:45][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:3][C:4]=3[O:24][CH2:23]2)[C:9]1=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Reactant: Oc1ccccc1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCN1C(=O)C2(COc3cc(Oc4ccccc4)ccc32)c2ccccc21
Yield: 92.2 %

Procedure:
To a solution of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.08 g, 0.19 mmol) in anhydrous dioxane (4.00 mL) was added copper iodide (0.01 g, 0.01 mmol), N,N-dimethyl glycine hydrochloride (0.01 g, 0.01 mmol), cesium carbonate (0.17 g, 0.52 mmol) and phenol (0.03 g, 0.32 mmol). The resulted mixture was refluxed for 16 h under nitrogen, diluted with dichloromethane (50.0 mL) and filtered through a celite bed. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/6) to give the title compound (0.07 g, 87%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.36-7.28 (m, 3H), 7.20-7.00 (m, 4H), 6.92 (d, 1H), 6.62 (dd, 1H), 6.58 (br, 1H), 6.44 (dd, 1H), 4.95 (d, 1H), 4.71 (d, 1H), 3.92-3.64 (m, 2H), 1.70-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H); MS (ES+) m/z 400.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:14][CH3:15])[CH2:12][CH3:13].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O.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>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCC1(CC)C(=O)Nc2ccc(Br)cc21
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: COCCOC
Product: CCC1(CC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Temperature: 25 °C
Yield: 26.7 %

Procedure:
A solution of 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one (2.7 g, 10 mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassium carbonate (4 g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:3) to afford 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (0.8 g, 27%), tmp. 195-197° C.; 1H-NMR (DMSO-d6) δ 7.70 (t, 1H, J=2 Hz), 7.62-7.60 (m, 1H), 7.58 (d, 1H, J=1.7 Hz), 7.52 (dd, 1H, J=8.1, 2 Hz), 7.43 (t, 1H, J=7.9 Hz), 7.36-7.33 (m, 1H), 6.90 (d, 1H, J=8.1 Hz), 1.87-1.70 (m, 4H) and 0.52 (t, 6H, J=7.4 Hz); MS (+APCI) m/z 300/302 (M−H).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[N:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:12]=2[CH2:11][CH:10]([NH:24]C(=O)OCC2C=CC=CC=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.I[Si](C)(C)C.[C:43]1([S:49](Cl)(=[O:51])=[O:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.O.Cl>[CH2:1]([N:8]1[C:13]2[N:14]=[N:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:12]=2[CH2:11][CH:10]([NH:24][S:49]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)(=[O:51])=[O:50])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NC1Cc2cc(-c3ccccc3)nnc2N(Cc2ccccc2)C1)OCc1ccccc1
Agent: C[Si](C)(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: O=S(=O)(NC1Cc2cc(-c3ccccc3)nnc2N(Cc2ccccc2)C1)c1ccccc1
Reaction time: 0.33 h
Yield: 70.9 %

Procedure:
To a stirred solution of 5G (0.023 g, 0.051 mmol) in 0.3 ML of acetonitrile at room temperature under argon was added iodotrimethylsilane (0.020 mL, 0.144 mmol). The yellow solution was stirred 20 min and then quenched with methanol (2 mL). After stirring for 30 min, the reaction mixture was evaporated and then re-evaporated from dichloromethane/hexanes. The solid residue was slurried twice with ether, decanting each time. The remaining solid was slurried in 10% sodium carbonate solution (1.0 mL) at room temperature while a solution of benzenesulfonyl chloride (0.020 mL, 0.157 mmol) in 1.0 mL of THF was added. After rapid stirring for 15 h, the reaction mixture was diluted with water. The solution was adjusted to pH 8 with a few drops of hydrochloric acid and then extracted twice with EtOAc. The organic extracts were dried (MgSO4), filtered, evaporated and purified by chromatography on silica gel (1:5 Ether/CH2Cl2) to give the title compound as a yellow solid (16.5 mg, 71% yield). MS [M+H]+: found 457. HPLC (Method C): retention time, 7.33 min; 98.3% purity. 1H NMR (CDCl3, 400 MHz) δ7.90 (m, 2H), 7.77 (m, 2H), 7.54 (m, 1H), 7.49-7.37 (m, 5H), 7.32-7.21 (m, 6H), 5.61 (d, 1H, J=8.0 Hz), 5.09 (d, 2H, J=14.9 Hz), 4.59 (d, 2H, J=14.9 Hz), 3.84 (m, 1H), 3.33 (dd, 1H, J=2.6, 11.3 Hz), 3.09 (m, 1H), 2.90 (dd, 2H, J=4.4, 17.1 Hz), 2.77 (dd, 2H, J=3.1, 17.1 Hz); 13C NMR (CDCl3, 101 MHz) δ155.5, 151.2, 140.7, 137.3, 136.3, 132.7, 129.2, 128.8, 128.7, 128.3, 127.6, 126.9, 125.9, 125.9, 124.9, 51.3, 51.0, 44.8, 33.6.
Reaction SMILES: [OH:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([O:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCCCCC1C(=O)C=CC1(C)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCC1C(=O)C=CC1(C)OC(C)=O
Reaction time: 2 h
Yield: 96 %

Procedure:
Into the same flask as in Example 1, 3-hydroxy-2-n-pentyl-3-methyl-4-cyclopentenone (18.2 g), triethylamine (20.3 g) and chloroform (150 g) were charged, and acetyl chloride (15.8 g) was dropwise added thereto at a temperature of 10° to 15° C. in 2 hours. Then, stirring was continued at room temperature for 20 hours. The reaction mixture was treated as in Example 1. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate (10:1) as an eluent to give dl-3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone (21.5 g). Yield, 96%.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C@@H:7]([C:27]([OH:29])=[O:28])[CH2:6]1)=[O:4]>O1CCCC1.C(O)C.[Pd]>[CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C@@H:7]([C:27]([OH:29])=[O:28])[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCN(S(=O)(=O)N2CC=C(c3ccc(F)cc3)CC2)[C@@H](C(=O)O)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3ccc(F)cc3)CC2)[C@@H](C(=O)O)C1
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (1.39 g, 3.16 mmol) [prepared as described in Example 28, Steps 1-4] and 10% Pd/C (0.7g) in 10% tetrahydrofuran/ethanol (45 ml) was stirred under an atmosphere of hydrogen (1 atm) overnight. The reaction mixture was filtered through Celite with excess ethanol and the filtrate was concentrated in vacuo to give 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (88%) as a white solid. This material was converted to N-hydroxy-4-dimethylaminocarbonyl-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide by following the procedure described in Example 28, Step 5 above.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]([C:21]1[CH:25]=[C:24]([NH2:26])[N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[N:22]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:17]([C:21]1[CH:25]=[C:24]([NH:26][C:2]2[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[N:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: O=C(O)c1ncccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Temperature: 150 °C
Yield: 2.3 %

Procedure:
A mixture of 3-bromopyridine-2-carboxylic acid (71 mg, 0.35 mmol), potassium carbonate (53 mg, 0.39 mmol), 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (80 mg, 0.35 mmol) (Intermediate F), and copper (II) acetate (1.3 mg, 0.007 mmol) in DMF (1 mL) was heated (150° C.) in a sealed tube for 16 h. The mixture was cooled to rt, filtered through with a silica gel plug using ethyl acetate as eluent. The mixture was concentrated to dryness and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 2.8 mg (2.3%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 8.11 (dd, 2H), 7.79 (dd, 1H), 7.32-7.45 (m, 4H), 6.45 (s, 1H), 2.11 (s, 3H), 1.40 (s, 9H); ES-MS m/z 351.0 (MH+), HPLC RT (min) 2.46.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[CH2:9][CH2:10][O:11]C1CCCCO1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>C1COCC1>[C:34]([O:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[CH2:9][CH2:10][OH:11])(=[O:36])[CH3:35]
Reactant: COC(=O)COc1cccc2c(CCOC3CCCCO3)c(CCO)oc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1cccc2c(CCO)c(CCOC(C)=O)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Methyl (2-(2-hydroxyethyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (403 mg), pyridine (0.13 ml) and acetic anhydride (0.3 ml) were dissolved in THF (5 ml) and the solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 ml) and the organic layer was separated, followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was dissolved in methanol (4 ml). To this solution, 1N hydrochloric acid (1 ml) was added and the solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/2) using silica gel to obtain the desired compound (412 mg, yield: 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1-c1ccccc1

Procedure:
10.1 g (34 mmol) of 2-(4-fluorophenyl)-5-methyl-1-phenyl-hexane-1,4-dione (Example 2) and 9.3 mmol (102 mmol) of aniline in 150 ml of toluene are heated under reflux in a water separator for 24 hours with the addition of 500 mg of p-toluenesulphonic acid. After cooling and diluting with ethyl acetate, the reaction mixture is washed with 1 N hydrochloric acid and then with sodium bicarbonate solution, dried over magnesium sulphate and concentrated in vacuo. The residue is then chromatographed on silica gel.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29]Cl)=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C-:31]#[N:32].[Na+].O>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29][C:31]#[N:32])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCCc1nc2cccc(CCl)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(CC#N)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-chloromethylbenzimidazole (0.83 g) and sodium cyanide (0.12 g) in DMF (10 ml) was stirred for 22 hours at room temperature. To the reaction mixture was added water and this mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was crystallized from ethyl acetate to givecolorless prisms (0.76 g, 94%), m.p. 180°-181° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:23])[NH:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[CH:7]=[CH:6][C:5]=12.[OH-].[Li+]>O1CCCC1.CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:23])[NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)[CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc3nccn3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 4-(3-imidazo[1,2-a]pyridin-6-ylureido)benzoate (2.1 g, 6.77 mmol) in tetrahydrofuran (18.05 ml) and methanol (9.02 ml) was treated with 2N lithium hydroxide (13.53 ml, 27.1 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The mixture was concentrated, redissolved in 225 mL water and acidified to pH 4 with 3N hydrochloric acid. The suspension was filtered with water washes to give the title compound after vacuum drying.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[CH:23][C:22]=2[CH:31]([F:33])[F:32])=[N:8][C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:14]=1.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:36].[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>C1COCC1.CO.C(OC(=O)C)C>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([N:35]([CH3:36])[CH3:34])=[O:27])=[CH:23][C:22]=2[CH:31]([F:32])[F:33])=[N:8][C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:14]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)c(C(F)F)c1
Agent: CNC
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)c(C(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
LiOH (495.9 μL of 1 M aq solution, 0.4959 mmol) was added to a suspension of methyl 4-[5-amino-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-3-(difluoromethyl)benzoate (70 mg, 0.1653 mmol) in THF (5 mL) and methanol (2 mL). The reaction mixture was stirred for 4 h at room temperature and then concentrated in vacuo. The residue was acidified to pH2 by the addition of 1M HCl. A precipitate formed which was then filtered and washed with water, ethylacetate and ether. The solid was taken up in DMF (2 mL) and TBTU (79.63 mg, 0.2480 mmol) and DIPEA (64.09 mg, 86.37 μL, 0.4959 mmol) added followed by N-methylmethanamine (495.9 μL of 1 M, 0.4959 mmol) in THF. The resulting mixture was stirred at room temperature for 2 h, diluted with ethylacetate (5 mL), washed with water (2×5 mL) and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were freeze dried to leave the product as a solid (29.6 mg, 40% yield); 1H NMR (400.0 MHz, DMSO) d 3.0 (d, 6H), 7.6-7.7 (m, 4H), 7.82 (s, 1H), 7.9 (d, 2H), 8.15-8.18 (m, 2H) and 8.7 (s, 1H) ppm; MS (ES+) 437.2