Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([CH3:14])([CH3:13])[CH3:12].CN(C)CCN(C)C.C([Li])CCC.[I:28]I>CCOCC.O1CCCC1>[CH3:10][O:9][C:6]1[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[I:28]
Reactant: COc1ccc(OC)c(C(C)(C)C)c1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C)c(OC)cc1I
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3.00 g (15.5 mmol) of 1,4-dimethoxy-2-t-butyl-benzene (obtained by methylation of t-butyl hydroqulnone with sodium hydride and methyl iodide in tetrahydrofuran) and 2.52 g (21.7 mmol) of tetramethylethylenediamine in 50 mL of anhydrous ether under nitrogen is cooled to 0° C. and 8.66 mL (21.7 mmol) of n-butyllithium (2.5M in hexane) is added over a 5 minute period. The mixture is warmed to 22° C., stirred for 18 hours and then cooled back to 0° C. The reaction is quenched with 7.86 g (30.9 mmol) of iodine in 30 mL of tetrahydrofuran and partitioned between ethyl acetate (200 mL) and 10% NaHSO3 (300 mL). The organic layer is washed with water (50 mL), brine (50 mL), dried (MgSO4) and evaporated to give a brown, partially crystalline oil which is chromatographed on silica gel (eluting with 98:2 hexane/ethyl acetate) to give crude product which is recrystallized from hexane to obtain 2,5-dimethoxy-4-t-butylphenyl iodide m p 80.5°-82.5° C.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]([CH:13]=[O:14])[CH3:12])[CH:7]=[CH:6][C:5]=1[N+:15]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]([CH:13]=[O:14])[CH3:12])[CH:7]=[CH:6][C:5]=1[NH2:15]
Reactant: [H][H]
Reactant: COC(=O)c1cc(CN(C)C=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(CN(C)C=O)ccc1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
There was dissolved, in 34 mL of methanol, 4.47 g of the crude product of 5-(N-formyl-N-methylamino-methyl)-2-nitrobenzoic acid methyl ester, prepare in the step 1, 5% Pd/C (wet product) was added to the solution in an argon gas atmosphere and then hydrogen gas was introduced into the reaction container. The reaction system was stirred at a reaction temperature of 40° C. for 8 hours, the hydrogen gas was replaced with argon gas, 14 mL of methanol was then added to the reaction system and the temperature thereof was raised up to 55° C. The Pd/C catalyst was removed through filtration under reduced pressure, the catalyst was washed with 25 mL of methanol and the resulting filtrate and the wash liquid were maintained at a temperature of 40° C. Water (31 mL) was dropwise added thereto thus separate out solid and the resulting slurry was stirred at 10° C. overnight. The resulting solid was separated from the slurry through filtration under reduced pressure, washed with 7 mL of water and then dried under reduced pressure at 70° C. for 5 hours to give 2.53 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)C>[Br:22][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 40 °C
Yield: 98.1 %

Procedure:
1-methyl-4-nitro-2-(trifluoromethyl)benzene (25 g, 122 mmol) was dissolved in dichloroethane (300 mL), followed by stirring. NBS (21.7 g, 122 mmol) and AIBN (2.0 g, 12.2 mmol) were added thereto, followed by further stirring for about 12 hours at 80° C. The resulting solid was filtered under reduced pressure, and dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (34 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[CH2:11]([N:14]=[C:15]=[S:16])[CH:12]=[CH2:13]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:13][CH:12]([CH2:11][N:14]=[C:15]=[S:16])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(F)cc1
Reactant: C=CCN=C=S
Product: Fc1ccc(C2=NOC(CN=C=S)C2)cc1

Procedure:
A 12.5 g. portion of 4-fluorobenzaldoxime was chlorinated and reacted with 50 ml. of allylisothiocyanate to prepare 3.4 g. of product, m.p. 59°-61°.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O:17][CH3:18])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[CH2:6]([O:5][C:3]([CH2:2][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([O:17][CH3:18])=[O:16])=[O:4])[CH3:7]
Reactant: COC(=O)c1ccccc1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1C(=O)OC
Yield: 110.4 %

Procedure:
8020 g (65.44 mol) of ethyl chloroacetate are added to a mixture of 62 l of acetonitrile, 9490 g (62.38 mol) of methyl salicylate, 8610 g (62.38 mol) of potassium carbonate and 620 g of potassium iodide at 20° C., and the mixture is stirred and heated under reflux for 9 hours and stirred overnight without further heat being supplied. The mixture is filtered over Celite and the filtrate is concentrated under reduced pressure. 16.4 kg of methyl 2-ethoxycarbonylmethoxybenzoate are obtained (HPLC: logP=2.1)
Reaction SMILES: Cl[C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@@:7]31[CH2:23][C@H:8]3[CH2:9][C@@H:10]2[OH:22].[BrH:24]>>[Br:24][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@@:7]31[CH2:23][C@H:8]3[CH2:9][C@@H:10]2[OH:22]
Reactant: Br
Reactant: C[C@]12CCC(=O)C(Cl)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Product: C[C@]12CCC(=O)C(Br)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312

Procedure:
The target compound is synthesized in a manner similar to the synthesis of 4-Chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one, 48% hydrobromic acid being used instead of hydrochloric acid.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[N:9][N:8]=1>CO>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([S:5][CH2:2][CH:3]=[CH2:4])=[N:8][N:9]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(Cl)c2ccccc12

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml (0.01 mol) of allylmercaptan. To this mixture was added 1.99 g(0.01 mol) of 1,4-dichlorophthalazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale white needle crystal.
Reaction SMILES: C1(B2O[C:7]([CH3:10])([CH3:9])[C:6]([CH3:12])([CH3:11])O2)CC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].BrC1C=[CH:26][C:25]([N:28]([CH3:35])[CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[C:24]([N+:36]([O-:38])=[O:37])C=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.O>[CH:6]1([C:7]2[CH:9]=[CH:26][C:25]([N:28]([CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH3:35])=[C:24]([N+:36]([O-:38])=[O:37])[CH:10]=2)[CH2:11][CH2:12]1
Reactant: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCN(C)c1ccc(C2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a pressure vessel was added 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 5.36 mmol), potassium phosphate (3.0 g, 14 mmol), and 0.82 mL water. After stirring at RT for 15 minutes, N-(4-Bromo-2-nitro-phenyl) -N,N′,N′-trimethyl-propane-1,3-diamine (Step 1, 1.30 g, 4.12 mmol), palladium acetate (92 mg, 0.412 mmol), tricyclohexylphosphine (231 mg 0.824 mmol), and 21 ml toluene were added. The reaction was sealed and stirred at 80° C. for 19 h. The reaction was then cooled to RT, quenched with EtOAc and extracted into water, washed once with brine, and then dried over Mg2SO4. The crude mixture was then purified by reverse phase chromatography to yield the title compound as a dark red-brown oil. MS (M+H+)=278; Calc'd for C15H23N3O2=277.36.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].P([O-])([O-])([O-])=[O:13].[K+].[K+].[K+]>C(O)C>[OH:13][C@@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)Cc1ccccc1
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)[C@@H](O)c1ccccc1
Reaction time: 0.03 h

Procedure:
Experimental description: 90 mg methyl 2-phenyl acetate were dissolved in 500 μL ethanol and added to 240 mL potassium phosphate buffer pH 8.0. P450BM3 was added to the mixture at a final concentration of 2 μM. The mixture was split in 4 mL aliquots into 15 mL scintillation vials equipped with a stir bar. 500 μL of a 5 mM NADPH solution were added to each vial and stirred for 2 minutes. 500 μL of a cofactor regeneration solution containing 300 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 4 hours, the reaction mixtures were joined together and extracted with chloroform (3×100 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5% ethyl acetate:95% hexane) afforded the activated product ((S)-methyl 2-hydroxy-2-phenylacetate, 40.5 mg). 40 mg (0.24 mmol) of activated product were dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and added with 41 μL DAST (0.29 mmol). The reaction was stirred in dry ice for 12 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5% ethyl acetate: 95% hexane) afforded the fluorinated product ((R)-methyl 2-fluoro-2-phenylacetate) (30 mg, 75% yield, pale yellow oil) in 74% ee, as determined by chiral GC analysis. 1H-NMR (300 MHz, CDCl3): δ 3.75 (s, 3H, —OCH3), δ 5.77 (d, J=48 Hz, 1H, —CHF), δ 7.37-7.46 (m, 5H); 13C-NMR (75 MHz, CDCl3): δ2.8, 89.5 (d, J=184.5 Hz), 126.8, 126.9, 129.0, δ 129.9, δ 134.4 (d, J=34.5 Hz), δ 169.0. 19F-NMR (282 MHz, CDCl3): δ −180.29 (d, J=48.7 Hz). HRMS (EI+): exact mass calculated for C9H9FO2 requires m/z 168.0587, found 168.0594.
Reaction SMILES: [F:1][C:2]1(C(OC)=O)[CH:7](O)[N:6]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:5](=[O:14])[NH:4][C:3]1=[O:15].FC(F)(F)C(O)=O>O>[F:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1
Reactant: COC(=O)C1(F)C(=O)NC(=O)N(C2CCCO2)C1O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F

Procedure:
In 15 ml. of water is dissolved 30 mg. of methyl 5-fluoro-1-(2-tetrahydrofuryl)-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and the solution is cooled in an ice-water bath. To this solution is added 1 ml. of trifluoroacetic acid and the mixture is left standing in a refrigerator. 5-Fluoro-1-(2-tetrahydrofuryl)uracil formed can be quantitatively determined spectrophotometrically (λmaxpH 1.0 272 mm, (ε 9000)).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:26]=[CH:25][C:24]2[N:23]3[CH2:27][CH2:28][CH2:29][C:22]3=[CH:21][C:20]=2[C:19]=1[C:30]([O:32]C)=[O:31])(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O.C(O)C>O1CCOCC1.O.C1(C)C=CC=CC=1>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:26]=[CH:25][C:24]2[N:23]3[CH2:27][CH2:28][CH2:29][C:22]3=[CH:21][C:20]=2[C:19]=1[C:30]([OH:32])=[O:31])(=[O:15])=[O:16])[CH3:35]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(cc3n2CCC3)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=CO
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(cc3n2CCC3)c1C(=O)O
Yield: 43.6 %

Procedure:
A suspension of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 16, 0.092 g) and lithium hydroxide monohydrate (0.077 g) in dioxane (2 mL) and water (0.5 mL) was irradiated in the microwave at 135° C. for 45 minutes. After cooling, the mixture was acidified to pH4 with formic acid. Ethanol and toluene were added and the resultant mixture was concentrated in vacuo. The residue was triturated with methanol in DCM (10% solution) and the solid was filtered off and washed with DCM. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-8%. The resultant solid was triturated with ethyl acetate and dried in vacuo, at 60° C. overnight to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylic acid (0.039 g) as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7.2 %

Procedure:
A solution of 19.9 g (124 mmol) of indole-2-carboxylic acid, 16 ml (155 mmol) of benzyl alcohol, and 3.0 g (25 mmol) of 4-dimethylaminopyridine in 800 ml of dichloromethane was treated with 25.6 g (124 mmol) of N,N'-dicyclohexylcarbodiimide and stirred at ambient temperature for 2.5 h. The resulting mixture was filtered, concentrated in vacuo, taken up in 1 l of ethyl acetate, and filtered. The solution was subsequently washed sequentially with 1N NCl, H2O, saturated NaHCO3, and saturated brine, dried over MgSO4, and concentrated. Recrystallization of the residue from ethyl acetate/hexane gave three crops of crystalline material containing 15.79 g, 11.13 g, and 2.25 g of the desired compound (94%). 1H NMR (CDCl3) δ 5.40 (s,2H), 7.26 (br t,1H), 7.3-7.5 (m,8H), 7.69 (br d,1H), 8.9 (br s,1H). Mass spectrum: (M+H)+ =252.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.CN([C:16]([O:20][N:21]1N=NC2C=CC=N[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.O>[CH3:16][O:20][N:21]([CH3:22])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2=[N:1][O:2][N:3]=[C:4]2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a stirred solution of benzo[c][1,2,5]oxadiazole-5-carboxylic acid (0.49 g, 2.987 mmol) in DCM (50 mL) were added HATU (1.7 g, 4.481 mmol), N-methoxy, N-methylamine (0.44 g, 4.481 mmol) and TEA (914 mg, 8.963 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3×50 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford N-methoxy-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide (0.49 g, 79%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[C:4]([F:13])[CH:3]=1.C([Li])CCC.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[C:4]([F:13])[C:3]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COCCOc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-difluoro-5-(2-methoxyethoxy)benzene (1.0 eq) in dry THF (0.2 M) under an atmosphere of N2 at −78° C. was added n-butyllithium (1 eq, 1.6 M in hexanes) slowly keeping the internal temperature below −65° C. The reaction was stirred for 1 hr at −78° C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield 2-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, <cdcl3>) ppm 6.42 (d, 2H), 4.10 (m, 2H), 3.74 (m, 2H), 3.44 (s, 3H), 1.37 (s, 12H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:35])=[CH:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=1)([CH3:25])[CH3:24])(=O)C>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([CH3:24])([CH3:25])[CH:22]=[C:21]([F:35])[CH2:20][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[CH:27][CH:28]=1)[CH3:34]
Reactant: CCOc1ccc(C(C)(C)C=C(F)COC(C)=O)cc1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(C(C)(C)C=C(F)Cc2cccc(Oc3ccccc3)c2)cc1
Yield: 45.1 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.31 g), tetrahydrofuran (2 ml) and magnesium (24 mg), and 4-(4-ethoxyphenyl)-2-fluoro-methylpent-2-enyl acetate (Example 14) (70 mg). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) to give the title compound (44 mg, 45%/).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[I:14].[OH-].[Li+].Cl>CO.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[I:14]
Reactant: COC(=O)c1cc(I)c(N)nc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(N)c(I)cc1C(=O)O
Temperature: 70 °C
Yield: 97.4 %

Procedure:
To a solution of methyl 6-amino-5-iodo-2-(methyloxy)-3-pyridinecarboxylate (1.4 g, 4.54 mmol) in methanol (30 ml), 1M aqueous lithium hydroxide (9 ml, 9 mmol) was added and the mixture was heated at 70° C. for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo to give a solid. The residual solid was dissolved in water (50 ml) and acidified (pH=5) by addition of 2N aqueous hydrochloric acid. The resultant solid was collected by filtration, washed with water and dried in vacuo under 60° C. to give 1.3 g (92%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([OH:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[CH2:22](I)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl.[Ag-]=O>[CH3:1][O:2][C:3](=[O:21])[CH:4]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1
Reactant: CCCCCCI
Reactant: COC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: O=[Ag-]
Solvent: ClCCl
Product: CCCCCCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
3-(4-Benzyloxyphenyl)-2-hydroxypropanoic acid methyl ester (0.4243 g; 1.482 mmole) was dissolved in dry dichloromethane (10 ml). Silver (I) oxide (1.717 g; 7.41 mmole) was added, followed by slow addition of hexyl iodide (0.943 g; 4.45 mmole). The reaction mixture was stirred at room temperature for 3 hours then molecular sieves (3 Å) was added and the reaction mixture was stirred for 4 more days and then filtered. The solvent was evaporated and evacuation at 60° C. for 5 hours gave 0.48 g (87% yield) of 3-(4-benzyloxyphenyl)-2-hexyloxypropanoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH:29]1([C:35]#[CH:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:36]#[C:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:16]=2)=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(I)c1
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(C#CC2CCCCC2)c1
Yield: 35.6 %

Procedure:
0.5 g (1.2 mmol) of methyl 5-chloro-2-{[(3-iodophenyl)carbonyl]amino}benzoate obtained in Example 63-(i), 146 mg (1.4 mmol) of triethylamine, 11.5 mg (0.06 mmol) of copper iodide, 25 mg (0.036 mmol) of bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), and 208 mg (1.92 mmol) of cyclohexylacetylene were stirred in DMF (10 mL) at room temperature for 21 hours. The reaction mixture was diluted with ethyl acetate, and washed with H2O, diluted hydrochloric acid, aqueous saturated sodium hydrogen carbonate solution, and saturated saline in this order. Thereafter, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 169 mg of methyl 5-chloro-2-({[3-(cyclohexylethynyl)phenyl]carbonyl}amino)benzoate (yield: 36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl.[CH3:11][C:12](=O)CC(=O)C.C([O-])(O)=O.[Na+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([CH3:12])=[N:9][C:4]=2[CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(F)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2cc(F)ccc2[nH]1
Temperature: 50 °C

Procedure:
Under an N2 atmosphere, 4-fluorobenzene-1,2-diamine (5.00 g, 39.6 mmol) was suspended in EtOH (220 mL) and 5M HCl (160 mL) was added. The reaction was warmed to 50° C. and 2,4-pentandione (8.14 mL, 7.93 mmol) was added and the reaction was heated to reflux for 30 min. Upon cooling to room temperature, the reaction was neutralized with a saturated solution of NaHCO3(aq) and extracted with dichloromethane. The layers were separated and the aqueous layer was washed with additional dichloromethane (2×). The organics were then combined, dried (Na2SO4), filtered and concentrated in vacuo. The resulting solid was triturated with dichloromethane to afford the title compound. 1H NMR (400 MHz) (DMSO-d6) δ 7.43-7.19 (bm, 2H); 6.92 (bs, 1H); 2.44 (s, 3H).