Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C(O)=O)C1C=CC(CC2C(=O)CCC2)=CC=1.[OH-].[K+].[C:21]([OH:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[OH-].[Ca+2:42].[OH-]>O>[C:21]([O-:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[Ca+2:42].[C:21]([O-:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(C(=O)O)c1ccc(CC2CCCC2=O)cc1
Agent: [Ca+2]
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
A lubricant composition was formed by first adding 40.00 gms of oxidized CS-600 low viscosity byproduct wax (viscosity: 11 cps; acid number: 14.7 mg KOH/gram; Mettler drop point: 109.5° C.), 29.46 gms of hydrocarbon wax and 98.30 gms of stearic acid to a reactor vessel. The combination was melted and held at 140° C. with slight agitation. Approximately 6.00 gms of calcium hydroxide was then added with agitation. The calcium hydroxide reacted with the stearic acid, forming a calcium stearate product and water as a byproduct. The high temperatures converted the water to steam, generating foam. Approximately 20.24 gms of glycerol monostearate was then added to dissipate the foam. Next, another 6.00 gms of calcium hydroxide was added to the vessel with agitation. The mixture was mixed until water formation stopped, and it was slowly stirred to remove any entrapped air. The mixture was then held for a finishing step such as prilling or pastiliating. The resulting lubricant composition contained 20.65% of an oxidized, low viscosity byproduct wax, 15.21% of a hydrocarbon wax, 6.91% residual stearic acid, 10.45% residual glycerol monostearate, and 46.77% calcium stearate. At 140° C., this lubricant composition had a viscosity of 300 centipoise and an acid number of 15.1 mg KOH/gram.
Reaction SMILES: Cl[CH2:2][C:3]([O-:5])=[O:4].[Na+].[I-].[K+].[NH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+].N.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([NH:9][CH2:2][C:3]([OH:5])=[O:4])=[CH:11][CH:12]=1)#[N:15]
Reactant: O=C([O-])CCl
Reactant: N#Cc1ccc(N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: N
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 87.5 °C
Reaction time: 24 h

Procedure:
Sodium mono chloroacetate (197.42 g), followed by potassium iodide (5 g) and tetrabutyl ammonium bromide (2.5 g) were added to a mixture of 4-aminobenzonitrile (100 g), water (1000 ml) and sodium bicarbonate (42.71 g). The reaction mixture was heated to 85-90° C. and stirred for 24 hours. The reaction mixture was cooled to 25-30° C. and treated with ammonia followed by hydrochloric acid. Filtered the solid, washed with water and then dried to get title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10]O)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.O>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:8]=[C:4]2[CH:3]=1
Reactant: ON=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Agent: Cl[Fe]Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Product: Fc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.0 g, 30 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was added trifluoroacetic anhydride (6.3 g, 30 mmol), keeping the temperature below 10° C. during the addition. After the addition was complete, the reaction was warmed to room temperature. The solution was then cooled to 4° C. and a solution of triethylamine (8.4 mL, 60 mmol) in 1,2-dimethoxyethane (20 mL) was added over a period of 0.5 hours. The mixture was allowed to warm to room temperature and was stirred for 1.5 hours. To this mixture was added iron(II) chloride (40 mg) and the reaction was heated at 75° C. for 15 hours. The reaction mixture was poured into water (300 mL). The resulting suspension was extracted with ethyl acetate. The combined organics were dried (magnesium sulfate), filtered and concentrated to a solid residue. This residue was purified by flash chromatography (1:1 ethyl acetate-hexane) to give 5-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine (4.2 g, 57%) as a white solid. 1H-NMR (CDCl3): δ 8.36 (d, 1H), 7.93 (q, 2H), 7.49 (d, 1H), 7.15 (t, 2H), 6.70 (dd, 1H), 6.69 (s, 1H); 19F-NMR (CDCl3): δ −113.30; MS m/z 247 (M+1).
Reaction SMILES: [CH:1]1([C:10]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH3:12])[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.C1(C(C2C3C(=CC=CC=3)C=C2)(C)C)C2C(=CC=CC=2)C=C1.[Li].[Li].[Si:50](Cl)([CH3:53])([CH3:52])[CH3:51]>CCOCC.CCCCC>[CH3:51][Si:50]([CH3:53])([CH3:52])[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:2]2)([CH3:11])[CH3:12])[CH:14]=1
Reactant: CC(C)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C1C=C([Si](C)(C)C)c2ccccc21)C1C=C([Si](C)(C)C)c2ccccc21

Procedure:
5.45 g (20 mmol) of 2,2-bis(indenyl)propane was dissolved in 100 ml of ether. The solution thus obtained was taken to -20° C., and 22 ml of a 2.0 M solution of n-butyl-lithium in pentane was added, thus giving a suspension of dilithium-2,2-(indenyl)propane. 8.77 g (30.85 mmol) of dilithium 2,2-bis(indenyl)propane was dissolved in 100 ml of ether, and 10 ml of Me3SiCl (excess) was added at a temperature of -40° C. The resulting mixture was allowed to return to room temperature. The organic phase was then separated off, the solvent removed and the product dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].C(S)CCCCCCC>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCc1ccc(OC)cc1F
Agent: CCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-methoxyphenyl)propanoate (57.4 g, 254 mmol) and aluminum chloride (101 g, 761 mmol) in dichloromethane (250 mL) was added dropwise 1-octanethiol (74.3 g, 508 mmol) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into ice water and the mixture was stirred for 30 min. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (44.6 g, yield 83%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)[C:19]([C:33](O)=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN.O1CCCC1.C[CH2:44][N:45](CC)CC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:29]([CH3:30])[CH3:31])=[O:32])=[CH:24][CH:23]=5)[C:19]([C:33]([NH:45][CH3:44])=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C(=O)O)cc1
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Reaction time: 3 h
Yield: 10.3 %

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl) biphenyl-2-carboxylic acid (47 mg, 0.10 mmol) and 75 μL of a 2.0 M solution of methylamine in tetrahydrofuran (0.15 mmol) were dissolved in DMF (1.0 mL) containing Et3N (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide (5.0 mg, 10%). ESI-MS m/z calc. 485.5, found 486.5 (M+1)+; retention time 2.54 minutes.
Reaction SMILES: Cl.[F:2][C:3]1([F:19])[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]1=[O:13].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[C:23]([CH2:22][CH2:21][C:20]([O:10][CH2:9][C@H:6]1[O:5][C@@H:4]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[C:3]([F:2])([F:19])[C@@H:7]1[OH:8])=[O:26])([OH:25])=[O:24]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ccn([C@@H]2O[C@H](COC(=O)CCC(=O)O)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 600 mg portion of dry 2'-deoxy-2',2'-difluorocytidine, hydrochloride, was added to 6 ml of dry pyridine, and 804 mg of succinic anhydride was added. The reaction mixture was stirred at ambient temperature for 1.5 hours. The mixture was then concentrated to an oil under vacuum, and the oil was stored overnight in the freezer. It was then allowed to stand at ambient temperature for 4 hours, and was chromatographed over a 500 ml Q-Sepharose column (Pharmacia Inc.). The oil was dissolved in 6 ml of 0.lM ammonium acetate buffer, and was passed over the column, eluting with a gradient buffer which changed from 0.lM to 1.0M ammonium acetate, at pH 8.0 at all times. Analytical chromatography of the mixture on a small mono-Q column showed that bisacylated and tris-acylated products were present, as well as mono-acylated product and a small amount of starting material. The product-containing fractions, amounting to about 200 ml, were placed in a 37° C. bath, for 68 hours. At the end of that time, the tris-acylated product had been decomposed and both mono- and bisacylated products were still present.
Reaction SMILES: [CH2:1]([N:5]1[CH2:21][C:20](=[O:22])[N:19]2[C@H:7]([CH2:8][C:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[C@@H:18]2[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:18]2[C:10]3[NH:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:9]=3[CH2:8][C@@H:7]3[C:6](=[O:32])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:21][C:20](=[O:22])[N:19]23)=[CH:24][CH:25]=1
Reactant: CCCCN1CC(=O)N2[C@@H](c3ccc([N+](=O)[O-])cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CC(=O)N2[C@@H](c3ccc(N)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Temperature: 25 °C
Yield: 39.4 %

Procedure:
To a solution of Example 75 (1.5 g) in methanol (100 mL) was added SnCl2 ·H2O (3.06) and the resulting mixture was heated at reflux for 8 hours. The mixture was cooled to ambient temperature, poured into ice and was adjusted to pH5 with 1N NaOH. The methanol was evaporated off and the residue was basified to pH11 with 1N NaOH and extracted with EtOAc (2×150 mL). After drying over Na2SO4 and evaporation of EtOAc, the resulting yellow powder was purified by radial chromatography eluting with CH2Cl2 to give the title compound as a white powder (550 mg) m.p.: 192° C.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOCC>C1COCC1.ClCl>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9]1
Reactant: N#CCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl
Agent: ClCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(4,4-diphenylpiperidin-1-yl)butyronitrile (4.65 g, 15.3 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 54 mL, 54 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature and concentrated to a volume of about 40 mL. Aqueous HCl (6N, 55 mL) was added cautiously at 0° C. and stirring was continued for 2 hours at 55°-65° C. The mixture was cooled to 0° C., basified to pH 10 by addition of 6N aq. NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2 Cl2 (50 mL) was added HCl in ether (1.0M, 30 mL, 2.0 equiv). After removal of the solvents, the residue was dissolved in CH2Cl2 (10 mL) and this solution was added dropwise into ether (150 mL) with swirling. The resulting solid was filtered and washed with ether (100 mL). This solid was taken up in water (30 mL), which was basified to pH 10 by addition of 1M aqueous NaOH, and extracted with CH2Cl2 (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 4.51 g (95%) of light brown oil, which was characterized spectroscopically.
Reaction SMILES: [CH:1]12BC(C[CH2:7][CH2:8]1)CCC2.C(Br)C#C.[OH-].[Na+].Cl[C:17]1[N:22]=[N:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[C:19]([O:31][CH3:32])[CH:18]=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.O.O1CCCC1>[CH:7]1([C:17]2[N:22]=[N:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([O:31][CH3:32])[CH:18]=2)[CH2:8][CH2:1]1
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Reactant: B1C2CCCC1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCBr
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C2CC2)nnc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 70.7 %

Procedure:
To a tetrahydrofuran solution (2.94 mL) containing of 9-borabicyclo[3.3.1]nonane (0.5 mol/l, 1.47 mmol) was added 87.5 mg (0.735 mmol) of propargyl bromide, and the resulting mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, 0.74 mL (2.2 mmol) of 3 mol/L aqueous sodium hydroxide solution was added to the mixture, and the resulting mixture was stirred at room temperature for 70 minutes. To the mixture were successively added 168 mg (0.669 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1) and 38.7 mg (0.00334 mmol) of tetrakis(triphenylphosphine)palladium, and the resulting mixture was refluxed overnight. The reaction mixture was allowed to stand for cooling, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography to obtain 121 mg (0.473 mmol, Yield: 70.1%) of 6-cyclopropyl-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].[I-:15].C(N)CN.S1(CCCC1)(=O)=O>[Cu]I.CCCCCC>[I:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CCCCCC
Solvent: NCCN
Product: Ic1ccc(-c2ccccc2)cc1
Temperature: 130 °C
Reaction time: 23 h
Yield: 93.5 %

Procedure:
A Schlenk tube was charged with CuI (19.5 mg, 0.102 mmol, 10 mol %), 4-bromobiphenyl (234 mg, 1.00 mmol), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. Ethylenediamine (13.5 μL, 0.202 mmol, 20 mol %) and sulfolane (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 23 h. The resulting suspension was allowed to reach room temperature, poured into hexane (20 mL) and washed with water (3×20 mL). The combined organic phases were dried (MgSO4), concentrated, and the residue was purified by flash chromatography on silica gel (hexane) to provide 262 mg (94% yield) of 4-iodobiphenyl as white crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O.O1CCCC1>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[CH2:25][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: ClCc1ccco1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (1.5 g, 5.2 mmol) and tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice bath. Add sodium hydride (0.25 g, 60% in oil, 6.24 mmol). Warm to ambient temperature. After about 90 minutes, when the gas evolution ceases, add 2-(chloromethyl)furan (1.04 g, 8.5 mmol). After 56 hours, add ice and then a saturated aqueous solution of ammonium chloride. Evaporate the reaction mixture to remove most of the tetrahydrofuran, dilute with ethyl acetate and extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine: Rf =0.29 (silica gel, ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[C:21]([Si:18]([CH3:20])([CH3:19])[O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(CO)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a well stirred solution of 2-hydroxyacetophenone (1.0 g, 7.34 mmol) in dichloromethane (15 mL) is added triethylamine (1.23 mL, 8.81 mmol), 4-dimethylaminopyridine (45 mg, 0.367 mmol) and tert-butyldimethylsilyl chloride (1.16 g, 7.71 mmol) dissolved in dichloromethane (2 mL). The reaction mixture is stirred at room temperature for 1 h, then diluted with dichloromethane (50 mL), washed with 10% citric acid, saturate sodium carbonate, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified via silica gel chromatography (20% ethyl acetate in hexanes) to yield the title compound as a yellow oil (1.3 g, 5.19 mmol).
Reaction SMILES: [Tl+].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:20][C:19]3[C:14](=[C:15]([O:23]C)[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=3)[C:12](=[O:13])[CH:11]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:20][C:19]3[C:14](=[C:15]([OH:23])[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=3)[C:12](=[O:13])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OC)cc3o2)cc1
Agent: BrB(Br)Br
Agent: [Tl+]
Product: COc1ccc(-c2cc(=O)c3c(O)cc(OC)cc3o2)cc1

Procedure:
The desired 6-iodinated species was prepared in excellent yield with almost exclusive regioselectivity by exploiting the ortho-directing capabilities of thallium(I) salts in the iodination of phenols14 (Scheme 2). Selective demethylation of apigenin trimethyl ether (5b) in the 5-position may be accomplished with boron tribromide in an amount generally ranging between about 0.9 equiv and about 3.0 equiv, preferably about 1.1 equiv boron tribromide, to afford apigenin 7,4′-dimethyl ether (6). The reaction is generally carried out a temperature ranging between about −40° C. and about 50° C., preferably about 25° C., for a time period ranging between about 0.5 h and about 24 h, preferably about 5 h, in the presence of a suitable solvent such as methylene chloride, chloroform, benzene and toluene, preferably methylene chloride, until a thick precipitate is formed. The precipitate is then collected and recrystallized in a suitable solvent such as ethanol, methanol, ethyl acetate/hexane, preferably ethanol. If desired, other boron compounds such as boron trichloride may be used in place of boron tribromide29.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[C:40]([C:41]2[N:42]=[C:43]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([Cl:52])[N:47]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[NH2:59].[O:60]1[CH:64]=[CH:63][CH:62]=[C:61]1[S:65](Cl)(=[O:67])=[O:66]>>[Cl:34][C:35]1[C:40]([C:41]2[N:42]=[C:43]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([Cl:52])[N:47]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[NH:59][S:65]([C:61]1[O:60][CH:64]=[CH:63][CH:62]=1)(=[O:67])=[O:66]
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccco1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}amine (1.03 g, 2.52 mmol) and 2-furansulfonyl chloride (0.588 g, 3.53 mmol) the title compound of Step E was obtained as an off-white solid (430 mg, 0.735 mmol, 29.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.43-7.58 (m, 2H), 7.31-7.43 (m, 1H), 7.08 (d, J=3.5 Hz, 1H), 6.55 (dd, J=3.5, 1.8 Hz, 1H), 6.18 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.55 (t, J=4.7 Hz, 4H). MS (ESI): 537.96 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].Br[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:6][C:2]([CH3:5])([CH3:1])[C:3]#[C:4][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: C#CC(C)(C)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(C)O)c21

Procedure:
Using Method D above, 3-methyl-1-butyn-3-ol (150 mg, 1.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (101 mg, 0.32 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (16 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 43 mg, 38%).