Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:18]=1[O:19][C:20]([C:23]1[N:27]([CH3:28])[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[N:25][N:24]=1)([CH3:22])[CH3:21]>C1(C)C(CCO)=CC=CC=1.O>[ClH:43].[ClH:43].[Cl:43][C:41]1[CH:42]=[CH:17][C:18]([O:19][C:20]([CH3:22])([C:23]2[N:27]([CH3:28])[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:36])([F:37])[F:38])=[N:25][N:24]=2)[CH3:21])=[C:39]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:40]=1
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1Br
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1ccncc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 49.6 %

Procedure:
Pyridin-4-ylboronic acid (26 mg), tetrakis triphenylphosphine palladium (10 mg) and sodium carbonate (156 mg) were added to a mixed solution of 3-[1-(2-bromo-4-chlorophenoxy)-1-methylethyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (100 mg) in toluene-ethanol-water (2 ml, 3:2:1), followed by stirring at 110° C. for 2 days. The reaction solution was concentrated under reduced pressure and diluted with chloroform. The organic layer was washed with water and saturated brine in this order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:methanol=98:2). The resulting solid was dissolved in ethyl acetate and 4M hydrogen chloride-ethyl acetate was added thereto, followed by stirring at room temperature for 2 hours. The precipitated crystal was collected by filtration and washed with ethyl acetate to obtain 4-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]pyridine dihydrochloride (19 mg) as a white crystal.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](N2CCCC2)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].[OH2:26]>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][C:8](=[O:26])[CH:9]([CH2:17][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C1CC=C(N2CCCC2)CC1
Reactant: O
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC(=O)C(CC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a 250-mL round-bottomed flask containing 3.3 mL of 1-(4-tert-butylcyclohex-1-enyl)pyrrolidine was added 100 mL anhydrous DMF, under nitrogen. The flask was fitted with an addition funnel containing 2-bromoacetophenone (4.12 gm) in 35 mL anhydrous DMF, which was dripped into the enamine solution over 60 min. This solution was stirred at ambient temperature for 10 hr, then 90 mL water was added to the solution and it was stirred for another 11 hr, under nitrogen. The solution was then extracted twice with ethyl acetate and water, the organic layers combined and further washed with water (3×), dried over sodium sulfate, filtered and rotovapped down to give a yellow oil. The oil was purified by MPLC using 10% ethyl acetate/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:29][CH:30]([CH3:32])[CH3:31])[C:26]([O-:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: OCc1ccc(C(F)(F)F)cc1F
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(C(F)(F)F)cc1F

Procedure:
Using 2-fluoro-4-(trifluoromethyl)benzyl alcohol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-[3-([2-fluoro-4-(trifluoromethyl)benzyl]oxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]2[NH:21][C:22]([C:27]3[C:28](=[O:43])[N:29]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:30]4[C:35]([C:36]=3[OH:37])=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:23][S:24](=[O:26])(=[O:25])[C:19]=2[CH:18]=1.C(N(CC)CC)C.Cl>ClCCl>[OH:37][C:36]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH2:38][CH2:39][CH:40]([CH3:41])[CH3:42])[C:28](=[O:43])[C:27]=1[C:22]1[NH:21][C:20]2[CH:44]=[CH:45][C:17]([NH:16][S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:7])=[CH:18][C:19]=2[S:24](=[O:25])(=[O:26])[N:23]=1
Reactant: OCc1ccccc1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A solution of chlorosulfonyl isocyanate (24.5 μL, 0.281 mmol) in dichloromethane (2 mL) was treated dropwise with benzyl alcohol (29 μL, 0.281 mmol) at 25° C., stirred at 25° C. for 30 min, treated with a solution of the product of Example 205 (100 mg, 0.234 mmol) and triethylamine (130 μL, 0.936 mmol) in dichloromethane (3 mL)and stirred for 2 hrs at 25° C. The reaction mixture was treated with dichloromethane (10 mL) and 1N aqueous hydrochloric acid (10 mL). The resulting organic layer was separated and dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (122 mg, 81%). MS (ESI−) m/z 639 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.6 Hz, 6H), 1.59 (m, 2H), 1.66 (m, 1H), 4.49 (m, 2H), 5.12 (s, 2H), 7.32 (m, 5H), 7.48 (m, 2H), 7.65 (d, J=2.2 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 8.57 (dd, J=7.7, 1.8 Hz, 1H), 8.90 (dd, J=0.8, 1.8 Hz, 1H), 11.17 (s, 1H), 12.19 (bs, 1H), 14.11 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-:19].[Na+].[C:21]1(C)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:21]=[O:19])=[CH:9][CH:8]=[C:7]2[O:12][CH3:13]
Reactant: COc1cccc2c(Cl)cccc12
Reactant: [OH-]
Reactant: Cc1ccccc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 20 %

Procedure:
To a stirred solution of 1-chloro-5-methoxynaphthalene (step-2 intermediate) (9.2 g, 47.8 mmol) in toluene (20 mL) and DMF (5.55 mL) at 0° C. was added, POCl3 (5.4 mL, 57.3 mmol) slowly. The reaction mixture was stirred at 0° C. for 45 min and then heated to reflux for 6-8 h. The dark red solution was cooled to RT and poured into a mixture of ice (50 mL) and 10% aq. NaOH (100 mL) with stirring. Aq. layer was extracted with EtOAc and the combined organic layer was washed with 2 N HCl, water, brine, dried and filtered. The solvent was evaporated and the crude product was washed with hexane, to provide the desired aldehyde intermediate as a reddish brown solid (2.1 g, 20%).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH:6]([OH:12])[C:7]#[C:8][CH2:9][CH2:10][CH3:11]>CC(=O)CC>[OH:12][CH:6]([C:7]#[C:8][CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4][I:1]
Reactant: [I-]
Reactant: CCCC#CC(O)CCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCC#CC(O)CCI
Reaction time: 18 h

Procedure:
A mixture of 15 g. of sodium iodide in 100 ml. of 2-butanone is stirred at the reflux temperature for 30 minutes. To the cooled mixture is added 12 g. of 1-chloro-3-hydroxy-4-octyne in 150 ml. of 2-butanone. The resulting mixture is stirred at the reflux temperature for 18 hours then cooled and filtered. The mother liquor is taken to dryness and the residue is triturated with benzene and filtered. The benzene is taken to dryness to give the subject product as an oil. The material is shown to be homogeneous by vapor phase chromatography and thin layer chromatography.
Reaction SMILES: ClN1C(=O)CCC1=O.[OH:9][N:10]=[CH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:13]=1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[CH:28]=1.BrC(C(F)(F)F)=C.FF.C(N(CC)CC)C>CN(C)C=O.O>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]2([C:35]([F:38])([F:36])[F:37])[O:9][N:10]=[C:11]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:13]=3)[CH2:34]2)[CH:30]=[C:29]([Cl:39])[CH:28]=1
Reactant: COC(=O)c1ccc(C=NO)c2ccccc12
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: C=C(Br)C(F)(F)F
Agent: FF
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-Chlorosuccinimide (1.16 g, 8.72 mmol) was added to a stirred solution of methyl 4-[(hydroxyimino)methyl]-1-naphthalenecarboxylate (i.e. the product of Step A, 1.0 g, 4.36 mmol) in N,N-dimethylformamide (5.0 mL). This mixture was stirred for 1.5 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (3.20 g, 13.1 mmol, prepared from commercially available 2-bromo-3,3,3-trifluoropropene by the method described in J. Fluorine Chem. 1999, 95, 167-170) and triethylamine (6.1 mL, 43.6 mmol) in N,N-dimethylformamide (4.0 mL) was added. After stirring for an additional 2 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate/hexanes to afford the title compound as a pale yellow oil (700 mg). 1H NMR (CDCl3): δ 8.88 (d, 1H), 8.80 (d, 1H), 8.10 (d, 1H), 7.68 (m, 2H), 7.55 (m, 3H), 7.46 (dd, 1H), 4.27 (d, 1H), 4.03 (s, 3H), 3.91 (d, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[OH-].[Na+].Cl>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:11][N+:8]([O-:10])=[O:9])=[CH:2]1
Reactant: O=Cc1ccoc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccoc1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of 3-furaldehyde (10.0 g) in ethanol (200 ml), nitromethane (6.37 g) was added at room temperature, followed by the dropwise addition of a 10N-aqueous sodium hydroxide solution (11.0 ml) at 0° C. The resulting mixture was stirred for 1 hour. The reaction mixture was poured into a 15% aqueous solution of hydrochloric acid (500 ml). The precipitate so formed was collected by filtration and dried, whereby the title compound (8.01 g) was obtained as a yellowish white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][N:34]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:35](=[O:37])[CH3:36]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:42][CH2:43][CH:38]([N:34]([CH3:33])[C:35](=[O:37])[CH3:36])[CH2:39][CH2:40]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: CC(=O)N(C)C1CCNCC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(=O)N(C)C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N-(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-N-methyl-acetamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and N-Methyl-N-piperidin-4-yl-acetamide following General Procedure B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[P:14]([O-:19])([O:17][CH3:18])[O:15][CH3:16]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:14]([O:17][CH3:18])([O:15][CH3:16])=[O:19])([OH:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: COP([O-])OC
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(C)(O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-acetyl-benzoic acid methyl ester (1.0 g, 5.61 mmol) in THF (5.6 mL) was cooled to 0° C. and dimethyl phosphite (0.7 g, 6.17 mmol) and N,N,N′N′-tetramethyl-guanidine (0.07 g, 0.56 mmol) were added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The reaction mixture was diluted with EtOAc and washed with 1N aqueous HCl (2×), brine, then dried (MgSO4) and concentrated in vacuo. The residue was purified by MPLC (Isocratic CH2Cl2 for 6 CV then 0-7.5% MeOH in CH2Cl2) to afford the title compound: MS: cal'd 289 (MH+), exp 289 (MH+)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:10](Cl)[CH:11]=[CH2:12].C1(OCC=C)C=CC=CC=1>C(O)(C)C.O>[CH2:12]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH:11]=[CH2:10]
Reactant: Oc1ccccc1
Reactant: C=CCCl
Agent: C=CCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: C=CCc1ccccc1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.6 %

Procedure:
To a reaction bottle was added 8.0 moles of phenol (753 grams) dissolved in 1,200ml of isopropanol. To this was added 8.0 moles of sodium hydroxide (320 grams) dissolved in 300ml of water. The bottle was rinsed three times by adding each time 200ml of isopropanol with reaction of the sodium hydroxide and phenol occurring immediately. Allyl chloride, in an amount of 9.6 moles, was charged. The mixture was then agitated and heated. A slight nitrogen pressure of approximately 70 kPa (10 psig) was placed on the reaction bottle. The reactor was brought up to a temperature of approximately 70° C. After approximately 5 hours at 70° C, the formation of allyl phenyl ether was judged complete and the reaction bottle was allowed to come to room temperature. The reaction mixture was then washed twice with 3 liters of water to remove sodium chloride, isopropanol, and unreacted sodium phenoxide as well as other by-products. The bottle was then charged with 3 liters of toluene, mixed, and heated to a temperature of approximately 100° C. An azeotropic distillation occured and was continued for approximately 3 hours during which time the toluene was distilled off along with traces of water, isopropanol, unreacted allyl chloride, and other by-products. The remaining allyl phenyl ether was sufficiently pure to be thermally rearranged to 2-allyl phenol. The rearrangement process occurred at 200° C and continued for approximately 5 hours. After this time, the reaction was stopped and a gas chromatographic analysis of the product was made. A 2-allyl phenol yield of 90.6 percent was achieved.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:18][N:19]1[C:23]([CH3:24])=[CH:22][C:21]([NH2:25])=[N:20]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:25][C:21]2[CH:22]=[C:23]([CH3:24])[N:19]([CH3:18])[N:20]=2)[C:3](=[O:17])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(Br)c1=O
Reactant: Cc1cc(N)nn1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Cl)nn(COCC[Si](C)(C)C)c2=O)nn1C
Temperature: 25 °C
Yield: 71.7 %

Procedure:
To a mixture of 4-bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one 110a (1.19 g, 3.50 mmol), 1,5-dimethyl-1H-pyrazol-3-amine (409 mg, 3.68 mmol), in 1,4-dioxane (20 mL) in a 100 mL single-neck round-bottomed flask was added desium darbonate (3.42 g, 10.5 mmol). The mixture was purged with ditrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) (321 mg, 0.350 mmol) and 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (344 mg, 0.596 mmol) were then added. The flask was connected to a nitrogen-purged condenser and the mixture was refluxed under nitrogen for 18 h. The mixture was cooled to room temperature, and filtered. The filter cake was suspended in ethyl acetate (30 mL) and water (10 mL) and filtered through Celite®. The layers were separated. The combined organic layers were dried with anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified on silica eluted with a gradient 0 to 50% ethyl acetate in eeptane to afford 6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one 110b as a yellow solid (928 mg, 72%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:20]([O:19][C:15](=[O:18])[CH2:16][O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:12][CH3:13])[CH3:21]
Reactant: CCOC(=O)CO
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of 5-nitrovanillin (2.00 g, 10.11 mmol) in tetrahydrofuran (100 mL) was added ethyl glycolate (0.960 mL, 10.11 mmol), triphenylphosphine (3.84 g, 14.65 mmol), and dropwise addition of diethyl azodicarboxylate (2.70 mL, 17.10 mmol). The reaction was stirred overnight at room temperature. The solution was then concentrated in under reduced pressure to yield a crude oil. Purification of the residue by silica gel flash chromatography (20% ethyl acetate/hexane to 40% ethyl acetate/hexane) afforded the title compound. 1H NMR (d6-DMSO) δ 1.15 (t, 3H), 3.94 (s, 3H), 4.10 (q, 2H), 4.93 (s, 2H), 7.79 (d, 1H), 8.02 (d, 1H), 9.94 (s, 1H). MS: M++1=284.2 Da.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.P([N:50]=[N+:51]=[N-:52])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:50]=[N+:51]=[N-:52])=[O:5]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To 2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoic acid (0.412 g, 1.134 mmol) in a 100 mL round-bottomed flask equipped with a stir bar under N2 was added isopropyl alcohol (11 mL), triethylamine (0.205 ml, 1.474 mmol) and diphenyl phosphorazidate (0.319 ml, 1.474 mmol). The reaction was stirred at room temperature overnight. The resultant solid was filtered, washed with isopropyl alcohol followed by hexanes and dried under vacuum providing the title compound as a white solid (0.294 g, 0.757 mmol, 67%): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.13 (s, 1H), 8.11-8.02 (m, 2H), 7.84-7.77 (m, 2H), 7.40 (d, J=8.6 Hz, 2H), 2.74 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 389 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)#[N:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:13]#[N:14])[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: N#Cc1ccccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4. Step 1; 0.3373 g) and 1-(2-cyanophenyl)piperazine (Emka-Chemie; 0.347 g) give, after crystallization from dichloromethane/ethyl acetate, 0.309 g of the title compound; mp 167-169° C.; MS m/z 351, 353; IR (mineral oil) 1326, 1448, 809, 1484, 1073 cm-1 ; 1H NMR (CDCl3) δ2.79, 3.27, 3.79, 6.99, 7.12, 7.52, 8.14.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-trifluoromethylphenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH:33]([CH3:35])[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:39]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31]([OH:39])=[O:32])[CH:20]=[C:19]1[CH:33]([CH3:35])[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-4-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 38, 0.727 g, 1.42 mmol) following the procedure described for Intermediate 19. The desired product was obtained as an off-white foam (0.65 g, 87%).