Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzaldehyde (12.13 ml, 110 mmol, Aldrich) and pinacolone (12.48 ml, 100 mmol, Aldrich) in absolute ethanol (120 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 3.72 ml, 10 mmol). The clear yellow reaction mixture was stirred at room temperature under argon for 24 hours. The reaction mixture was concentrated to 1/3volume and partitioned between 50% saturated NH4Cl and EtOAc. The layers were separated and the organic layer was washed twice with H2O and brine, then dried (Na2SO4) and concentrated under reduced pressure. The oily residue was purified by flash chromatography (Merck Silica gel, 10% EtOAc/hexane), yielding the title compound as a colorless oil that slowly solidified. The white solid was recrystallized from hexane, yielding the title compound as white crystals (13.9 g, 67.5%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:39]1[CH:40]=[N:41][S:42][CH:43]=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:39]3[CH:40]=[N:41][S:42][CH:43]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cnsc1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(B2OC(C)(C)C(C)(C)O2)c1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cnsc2)c1OC
Temperature: 120 °C
Yield: 32.4 %

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Intermediate 59, 0.15 g), tri-tert-butyl-phosphinium tetrafluoroborate (0.01 g), cesium carbonate (0.34 g), tris-(dibenzylideneacetone)-dipalladium (0.016 g), and 4-bromoisothiazole (0.06 g) in dioxane (3.2 ml) and water (0.4 ml) was degassed and then heated in the microwave at 120° C. for 20 minutes. After cooling, the mixture was diluted with ether, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give crude methyl 6-(benzenesulphonylmethyl)-3-(isothiazol-4-yl)-2-methoxy-benzoate (0.044 g) as an oil. The material was used without further purification or characterisation.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].CC(O)C>[Pd].O>[S:21]1[CH:25]=[CH:24][C:23]([C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:22]1
Reactant: Ic1ccc(Oc2ccc(N3CCOCC3)cc2)cc1
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: c1cc(-c2ccc(Oc3ccc(N4CCOCC4)cc3)cc2)cs1
Yield: 35.3 %

Procedure:
The title compound (25 mg, 35%) was prepared by treating 4-[4-(4-Iodo-phenoxy)-phenyl]-morpholine (80 mg, 0.21 mmol) from Example 24 with thiophene-3-boronic acid (35 mg, 0.25 mmol) in the presence of 10% Pd/C (10 mg), potassium carbonate (87 mg, 0.68 mmol), 2-propanol (4 mL) and water (0.4 mL) by using the procedure described in step 2 of Example 16: MS (ESI) m/z 338 (M+H); 1H NMR (400 MHz, CDCl3) δ 3.13 (t, J=4.8 Hz, 4H), 3.87 (t, J=4.8 Hz, 4H), 6.91-7.01 (m, 6H), 7.34-7.38 (m, 3H), 7.51-7.53 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Li+].[Cl-]>C1(C)C=CC=CC=1.CCOC(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>[CH2:14]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)COC2=O
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-benzofuran-1(3H)-one (15.0 g, 70.4 mmol), allyl-tributyl-stannane (25.6 g, 77.5 mmol), LiCl (11.8 g, 282 mmol) and Pd(PPh3)4 (1.2 g, 1.0 mmol) in 100 mL toluene was heated under N2 at 90˜100° C. overnight. After cooling to RT, the mixture was diluted with 250 mL EtOAc and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified via column (DCM/Pet Ether=1:5) to give the title compound.
Reaction SMILES: C([NH:4][OH:5])(=O)C.CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[C:19]([O:21][CH2:22][O:23][CH3:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CN(C)C=O.CC(C)=O.C(Cl)(Cl)Cl.CCOC(C)=O>[NH2:16][C:15]1[C:14]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:13]=2[O:5][N:4]=1
Reactant: CC(=O)NO
Reactant: COCOc1ccc(C#N)c(F)c1
Agent: CC(C)(C)O[K]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc2c(N)noc2c1
Reaction time: 16 h
Yield: 125.9 %

Procedure:
To a stirred solution of acetohydroxamic acid (3.88 g) in N,N-dimethylformamide (DMF) (120 ml) was added potassium tertiarybutoxide (tBuOK) (5.80 g) under N2. After one hour of stirring 2-fluoro-4-(methoxymethoxy)-benzonitrile (6.0 g) was added. Stirring continued for 16 hours. TLC (silica gel) in 10% acetone/CHCl3 showed the presence of starting material. An additional 1 equivalent of acetohydroxamic acid and tBuOK were added in DMF (120 ml). After one hour the reaction was diluted with EtOAc (2 l), filtered, washed filtrate with brine (4×11), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) was performed eluting with 2.5% acetone/CH2Cl2 solution affording 8.1 g of the product, m.p. 88°-89° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:26][C@H:27]1[CH2:32][O:31][CH2:30][CH2:29][NH:28]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][C@@H:27]2[CH3:26])[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccccc1
Reactant: C[C@H]1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(Cl)n1
Temperature: -5 °C
Yield: 76.5 %

Procedure:
2,4-dichloro-6-[(phenylsulfonyl)methyl]pyrimidine (2.8 g, 9.24 mmol) was dissolved in DCM (20 mL) and stirred (under nitrogen) at −5° C. Triethylamine (1.42 mL, 10.17 mmol) was added to give a clear brown solution. (3S)-3-methylmorpholine (935 mg, 9.24 mmol) was dissolved in DCM and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give the desired material as a white solid (2.6 g).
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:31]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=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.O.C(O)C>[C:31]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][C:34]([C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)=[CH:18][CH:17]=3)=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:33][CH:32]=1
Reactant: Brc1c2ccccc2c(-c2ccc(-c3nc4ccccc4o3)cc2)c2ccccc12
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(-c3c4ccccc4c(-c4ccc(-c5nc6ccccc6o5)cc4)c4ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
In a 100 mL three-neck flask, 0.91 g (2.0 mmol) of 2-[4-(10-bromo-9-anthryl)phenyl]benzoxazole, 0.44 g (2.2 mmol) of 4-biphenylboronic acid, 0.47 g (4.4 mmol) of sodium carbonate, 10 mL of toluene, 3 mL of ethanol, and 3 mL of water were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 29 mg (0.025 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 80° C. for 13 hours. After a certain period, the mixture was cooled to room temperature, and the precipitated solid was obtained by suction filtration and washed with water. A toluene solution of the obtained solid was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855) and alumina, and the filtrate was condensed to give a solid. The solid was recrystallized with toluene/hexane, giving 0.52 g of the target white powder. Further, an aqueous layer of the filtrate which was obtained through suction filtration after stirring was extracted with toluene. The obtained extracted solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the filtrate was condensed to give a solid. A toluene solution of the solid was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855) and alumina, and the filtrate was condensed to give a solid. The solid was recrystallized with toluene/hexane, giving 0.47 g of the target white powder. In this manner, a total of 0.99 g of the target white solid was obtained in a yield of 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7]([CH:9]=O)=[CH:8][C:4]=2[CH:3]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1C=CC=CC=1.N1CCCCC1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7](/[CH:9]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:8][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2cc(Cl)ccc2s1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc2cc(Cl)ccc2s1
Temperature: 110 °C

Procedure:
A mixture containing 5-chlorobenzo[b]thiophene-2-carboxaldehyde (Matsunaga Bioorg. Med. Chem. 2004, 12, 2251), malonic acid (1.4 equiv), pyridine (2.5 equiv) and piperidine (0.1 equiv) was heated at 110° C. for a period of 4 h. The reaction mixture was cooled, poured into H2O and filtered to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[O:18]C.[I-].[Na+].[Si](Cl)(Cl)(Cl)Cl>C(#N)C.C1(C)C=CC=CC=1>[OH:18][C:3]1[CH:4]=[C:5]([C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: CCOC(=O)C(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A suspension of 17.2 g of ethyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate in 100 ml of dry acetonitrile and 100 ml of dry toluene is treated with 10.53 g of sodium iodide and 11.9 g of silicon tetrachloride and heated under reflux for 47 hours. The reaction mixture is then evaporated and the residue is distilled six times with 200 ml of toluene each time. The residue obtained is partitioned between water and ether and filtered through a filter aid of diatomaceous earth. The ethereal phase is washed four times with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The oily residue is treated three times with ether and active carbon. There is obtained ethyl 3,4-dihydroxy-5-nitrophenylglyoxylate of m.p. 77°-79° (from ether/n-hexane).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].Cl[C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>CN(C)C=O>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][C:15]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:14]2[SH:10])=[O:34]
Reactant: [S-2]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a mixture of sodium sulfide nonahydrate (202 mg) in dimethylformamide (5 ml) was dropwise added 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (297 mg), and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added ice-water, and the mixture was adjusted to pH 3 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water to give 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonyl-4-mercaptoquinoline (260 mg).
Reaction SMILES: Cl[CH2:2][CH2:3]Cl.[Cl:5][SiH:6]([Cl:8])[Cl:7]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:5][Si:6]([Cl:8])([Cl:7])[CH2:2][CH2:3][Si:6]([Cl:8])([Cl:7])[Cl:5]
Reactant: ClCCCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl
Yield: 48.9 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.44 g (1.50 mmol) of tetrabutylphosphonium chloride, 0.74 g (7.5 mmol) of 1,2-dichloroethane, and 10.16 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 10 hrs. The resulting mixture was distilled to give 1.09 g of 1,2-bis(trichlorosilyl)ethane (yield; 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([C:14](=[O:16])[CH3:15])[C:8]([CH3:18])([CH3:17])[CH2:7]1.[C:20]([N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27]C(O)[CH2:25][C:24]1([CH3:33])[CH3:32])(=[O:22])[CH3:21].[NH2-].[Li+].CO>CCCCCCC.O>[C:20]([N:23]1[C:24]([CH3:33])([CH3:32])[CH2:25][CH:1]([O:2][C:3](=[O:19])[CH2:4][NH:5][CH:6]2[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([C:14](=[O:16])[CH3:15])[C:8]([CH3:18])([CH3:17])[CH2:7]2)[CH2:27][C:28]1([CH3:30])[CH3:29])(=[O:22])[CH3:21]
Reactant: COC(=O)CNC1CC(C)(C)N(C(C)=O)C(C)(C)C1
Reactant: CC(=O)N1C(C)(C)CC(O)CC1(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: O
Solvent: CO
Solvent: CCCCCCC
Product: CC(=O)N1C(C)(C)CC(NCC(=O)OC2CC(C)(C)N(C(C)=O)C(C)(C)C2)CC1(C)C
Yield: 73.1 %

Procedure:
To a four-necked flask equipped with a thermometer, a stirrer and a Deanstark trap were added 27 g (0.1 mole) of N-(1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl)glycine methyl ester, 21.9 g (0.11 mole) of 1-acetyl-2,2,6,6-tetramethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, the reaction solution was cooled, and water was added thereto to dissolve the product in the heptane layer. The heptane layer was separated and concentrated by removing heptane by distillation. The residue was purified by column chromatographic separation to obtain 32 g of N-(1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl)glycine(1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl)ester as a pale yellow liquid. Yield, 73% based on N-(1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl)-glycine methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC(C)=CCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCn1ccc([N+](=O)[O-])n1
Yield: 78.5 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 270 mg, 2.39 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL) and a 60% dispersion of sodium hydride in mineral oil (116 mg, 2.90 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, the 1-bromo-3-methyl-but-2-ene (390 mg, 2.60 mmol) was added. The reaction continued to stir under nitrogen for 2 h. The solution was diluted with ethyl acetate (75 mL), washed with water (2×25 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes) afforded 1-(3-methyl-but-2-enyl)-3-nitro-1H-pyrazole (340 mg, 79%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 1.79 (3H, s), 1.83 (3H, s), 4.80 (2H, d, J=7.2 Hz), 5.45 (1H, t, J=7.2 Hz), 6.88 (1H, s), 7.43 (1H, s).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.F[P-](F)(F)(F)(F)F.[N:23]1([O:32][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.NO.C(N(CC)CC)C>N1C=CC=CC=1.C(Cl)Cl>[OH:32][NH:23][C:7]([C:2]1[C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(NO)c1ccccc1-c1ccccc1
Yield: 3.3 %

Procedure:
A solution of 2-biphenylcarboxylic acid 1 (0.25 g, 1.261 mmol), BOP (0.558 g, 1.261 mmol), hydroxylamine hydrochloride (0.088 g, 1.261 mmol) and triethylamine (0.527 mL, 3.78 mmol) was stirred in pyridine (5 mL) at room temperature overnight then diluted with DCM, washed with water (2×), dried over MgSO4, filtered and solvent evaporated to provide title compound 2 (8.8 mg, 3% yield) as a white solid after purification by Biotage (50 to 100% EtOAc in Hexane) followed by trituration (Et2O). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.77 (s, 1H), 8.97 (s, 1H), 7.52 to 7.42 (m, 1H), 7.40 to 7.33 (m, 8H). LRMS (ESI): (calc.) 213.23 (found) 214.2 (MH)+
Reaction SMILES: C([O:8][C:9]1[C:10]([C:41]2[NH:42][N:43]=[CH:44][CH:45]=2)=[CH:11][C:12]([CH2:39][CH3:40])=[C:13]([CH:38]=1)[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:20]([CH2:35][CH2:36][CH3:37])=[C:21]([CH:32]=[CH:33][CH:34]=1)[O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26])C1C=CC=CC=1.B(F)(F)F.CCOCC>C(S)C.C(OCC)C.O>[CH2:39]([C:12]1[CH:11]=[C:10]([C:41]2[NH:42][N:43]=[CH:44][CH:45]=2)[C:9]([OH:8])=[CH:38][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:20]([CH2:35][CH2:36][CH3:37])=[C:21]([CH:32]=[CH:33][CH:34]=1)[O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26])[CH3:40]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccn[nH]3)cc2CC)cccc1Oc1ccccc1C(=O)O
Agent: FB(F)F
Solvent: O
Solvent: CCS
Solvent: CCOCC
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccn[nH]3)cc2CC)cccc1Oc1ccccc1C(=O)O
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2H-pyrazol-3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid (300 mg, 0.490 mmol) in ethanethiol (2.5 mL) was treated with boron trifluoride etherate (2 mL) at room temperature for 3 h, at which time an additional portion of boron trifluoride etherate (1 mL) was added and stirring resumed for an additional 1 h. The mixture was diluted with diethyl ether and water. The organic layer was separated, washed with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane to 60% ethyl acetate/40% hexane) of the residue provided 60 mg (24%) of the title compound as a white solid. 1H NM (CDCl3) δ 8.23 (d, J=8Hz, 1H), 7.61 (s, 1H), 7.42 (t, J=7 Hz, 1H), 7.30 (s, 1H), 7.19 (d, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 6.61 (s, 1H), 6.60 (d, J=8 Hz, 1H), 6.54 (s, 1H), 4.20 (m, 4H), 2.58 (m, 4H), 2.33 (quintet, J=6 Hz, 2H), 1.48 (hextet, J=8 Hz, 2H), 1.17 (t, J=8 Hz, 3H), 0.86 (t, J=7 Hz, 3H); TOF MS ES+ exact mass calculated for C30H33N2O6 (p+1): m/z=517.2339. Found: 517.2334. IR (CHCl3, cm−1) 2965, 1738, 1454. Anal. Calcd for C30H32N2O6: C, 69.75; H, 6.24; N, 5.42. Found: C, 69.73; H, 6.33; N, 5.25.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-]>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.C1(C)C=CC=CC=1.CCO>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12]([C:31]3[CH:32]=[CH:33][O:29][CH:30]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccoc1
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)c1ccc(-c2cnc3c(c2)c(-c2ccoc2)cn3S(=O)(=O)c2ccccc2)cc1
Yield: 77.6 %

Procedure:
A mixture of 3 (300 mg, 0.596 mmol), EtOH (3.6 mL), toluene (3.6 mL), furan-3-boronic acid (100 mg, 0.894 mmol), 1M aq. Na2CO3 (1.49 mL, 1.49 mmol), LiCl (75.8 mg, 1.79 mmol) and PdCl2(PPh3)2 (41.8 mg, 59.6 μmol) was refluxed for 15 min. The organic layer was separated, brine was added, and the aqueous layer was extracted with AcOEt. The combined organic solutions were concentrated and separated by means of silicagel chromatography using hexane:AcOEt as eluent (in gradient up to 15% AcOEt) to give 4 as an orange foam (205 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 3.03 (s, 6H), 6.73 (m, 1H), 6.84 (d, J=8.8 Hz, 2H), 7.45-7.65 (m, 6H), 7.84 (s, 2H), 8.05 (d, J=2.1 Hz, 1H), 8.26 (m, 2H), 8.68 (d, J=2.2 Hz, 1H).