Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([N:6]([CH2:30][CH3:31])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N:19]2C(=O)C3=CC=CC=C3C2=O)=[N:11]1)[CH3:5].O.NN>O>[CH2:30]([N:6]([CH2:4][CH3:5])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:19])=[N:11]1)[CH3:31]
Reactant: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)CCCn1nc(N)c2ccccc21
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To 70 ml of ethyl alcohol was added 3.30 g of 1-(3-diethylaminopropyl)-3-phthalimidoindazole. The mixture was added with 2.50 g of 85% hydrazine hydrate under cooling with ice and stirred for 3 hours under cooling with ice. The reaction mixture was filtered and the filtrate was condensed under reduced pressure. The condensed residue was added with 20 ml of water and the reaction product was extracted with chloroform. The chloroform layer was extracted with 2N-hydrochloric acid and the pH of the hydrochloric acid layer was adjusted to 10 with potassium carbonate. The alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure to give 1.78 g of 1-(3-diethylaminopropyl)-3-aminoindazole having the following analytical values in a yield of 85%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:21](O)=[O:22])[CH:5]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>>[NH:38]1[C:37]([NH:36][C:21]([C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][CH:15]=3)[N:7]=2)=[O:22])=[N:41][N:40]=[N:39]1
Reactant: Nc1nnn[nH]1
Reactant: CCOc1cc(C(=O)O)nc(-c2ccc(N(CC)CC)cc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc(N(CC)CC)cc2)c1
Yield: 76.5 %

Procedure:
In the same manner as described in Example 1-(1), 4-ethoxy-6-(4-diethylaminophenyl)-2-pyridinecarboxylic acid (0.56 g), carbonyldiimidazole (0.32 g) and 5-aminotetrazole (0.17 g) are reacted to give N-(5-tetrazolyl)-4-ethoxy-6-(4-diethylaminophenyl)-2-pyridinecarboxamide (0.52 g). M.P. 228°-230° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[CH3:38][CH:39]1[O:44][CH2:43][CH2:42][NH:41][CH2:40]1.[OH-].[Na+].Cl>C(O)(C)C>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[N:7]=[C:3]([CH2:2][N:41]5[CH2:42][CH2:43][O:44][CH:39]([CH3:38])[CH2:40]5)[S:4][CH:5]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: CC1CNCCO1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC1CN(Cc2nc(C(=O)Nc3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)cs2)CCO1
Temperature: 90 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
2-(Chloromethyl)-N-[6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.091 mmol) and 2-methylmorpholine (0.5 mL, 0.091 mmol) were put in a 0.5-2 mL vial then heated in the microwave at 90° C. for 15 min. The solvent was blown down under nitrogen. Isopropanol (2 mL) and 2M NaOH (2.000 mL) were added and the reaction mixture was stirred for 3 hr at 25° C., then neutralised with 2M HCl aqueous solution until pH=7 (checking with pH paper). The solvent was removed under nitrogen. The mixture was dissolved in 2 mL of DMSO and passed through a hydrophobic frit. Purification was carried out by MDAP to afford the title compound (10 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([CH2:9][S:10][CH3:11])=[C:7]([Cl:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:20])[CH2:14][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH2:21]([O:23][CH:24](OCC)OCC)[CH3:22]>C(OC(=O)C)(=O)C>[CH3:1][S:2][C:3]1[C:8]([CH2:9][S:10][CH3:11])=[C:7]([Cl:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:20])[C:14](=[CH:24][O:23][CH2:21][CH3:22])[C:15]([CH:17]1[CH2:18][CH2:19]1)=[O:16]
Reactant: CSCc1c(Cl)ccc(C(=O)CC(=O)C2CC2)c1SC
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Cl)c(CSC)c1SC)C(=O)C1CC1

Procedure:
A mixture of 1-[2-(methylsulphenyl)-3-(methylsulphenylmethyl)-4-chlorophenyl]-3-cyclopropylpropan-1,3-dione (1.5 g) and triethylorthoformate (8 ml) in acetic anhydride (25 ml) was heated at reflux temperature for 4 hours. The excess reagent and solvent were evaporated under reduced pressure, yielding 1-[2-(methylsulphenyl)-3-(methylsulphenylmethyl)-4-chlorophenyl]-2-ethoxymethylene-3-cyclopropylpropan-1,3-dione as a brown oil (2.3 g).
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13](I)=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([Zn]C#N)#[N:26]>CN(C=O)C>[C:1]([O:9][C:10]1[C:11]([C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]([C:25]#[N:26])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Zn]C#N
Reactant: COC(=O)c1nc(I)c2cccnc2c1OC(=O)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cccnc2c1OC(=O)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 8-(benzoyloxy)-5-iodo-1,6-naphthyridine-7-carboxylate (750 mg, 1.727 mmol) in anhydrous DMF (10 ml) was added dicyanozinc (142 mg, 1.21 mmol) and tetrakis(triphenylphospine)palladium(0) (299 mg, 0.26 mmol) and the solution was stirred at 85° C. overnight. The reaction was quenched with water and extracted with chloroform three times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (17-55% EtOAc/Hexanes gradient elution) to provide a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]([C:7]1[C:11](=[O:12])[C@@H:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C@:9]([OH:25])([C:18]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[O:19])[C:8]=1[OH:26])=[O:6])[CH3:3].[H][H].S(=O)(=O)(O)O>CO.[Pd]>[CH3:17][CH:15]([CH2:14][CH2:13][C@@H:10]1[C@@:9]([OH:25])([C:18]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:19])[C:8]([OH:26])=[C:7]([C:5]([CH2:4][CH:2]([CH3:3])[CH3:1])=[O:6])[C:11]1=[O:12])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)=CCC(=O)[C@]1(O)C(O)=C(C(=O)CC(C)C)C(=O)[C@H]1CC=C(C)C
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(C)CCC(=O)[C@@]1(O)C(O)=C(C(=O)CC(C)C)C(=O)[C@@H]1CCC(C)C
Reaction time: 0.08 h

Procedure:
96.3 mg of the dry Mg salt of (+)-cis isohumulone ((+)-VIII) was dissolved in 1 mL of methanol. 3.1 mg (0.3 eq) of MgO was added, and the reaction mixture was stirred for five minutes. 30 mg of 10% Pd/C was added to the solution, and stirring was resumed. A hydrogen atmosphere was introduced by bubbling hydrogen gas into the solution. After 45 minutes the reaction was judged to be complete by HPLC, the stirring was stopped, and the hydrogen atmosphere was removed by opening the vial. 1 equivalent of sulfuric acid was added to the reaction mixture (pH˜1), and the reaction was filtered through a 0.2 mm syringe filter. The reaction vessel and filter were washed 2 times successively with ethyl acetate. The filtrate was concentrated in vacuo, redissolved in hexanes, dried over Na2SO4, filtered via a cotton pipette, and concentrated in vacuo and dried overnight at 0.070 mbar. 58.1 mg of (+)-KDT-500 was produced. Further purification was carried out via chromatography and crystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(Cl)(Cl)(Cl)[Cl:12]>>[Cl:12][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Clc1ccc2nccn2n1
Product: Clc1ccc2ncc(Cl)n2n1

Procedure:
6-Chloroimidazo[1,2-b]pyridazine (7.68 g) was added to 150 ml of carbon tetrachloride, to which 7.0 g of N-chlorossuccinimide were added and refluxed for 2 hours. After cooling, the precipitated crystals were filtered off. The filtrate was washed in turn with 1N-sodium hydroxide aqueous solution, 1N-hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was washed with diethyl ether to obtain 7.13 g of 3.6-dichloroimidazo[1,2-b]pyridazine.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[CH3:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9].CC(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1.O>[CH:10]1([C:8](=[O:9])[CH2:7][C:1]([O:4][CH3:5])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of dimethyl carbonate (361 g) in toluene (1250 ml) added cyclopropyl methyl ketone (125 g) and stirred for 15 min at 25° C. Cooled the reaction mixture to 10° C., added potassium tert.butoxide (100 g) to it under nitrogen atmosphere. Heated the reaction mixture to 75° C. and stirred for 14 hrs. Cooled the reaction mixture to 25° C. and slowly poured it into chilled water (750 ml). Cooled the reaction mixture to 0° C. and adjusted the pH to 2.5 by using 50% HCl solution. Raised the temperature to 25° C. and stirred for 45 minutes. Separated the both organic and aqueous layers. Extracted the aqueous layer with toluene (500 ml). Washed the organic layer with water (500 ml). Distilled off the toluene completely from organic layer under reduced pressure to get the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([C:18]([O:20]CC)=[O:19])[C:12]3=[O:23])[CH2:4][CH2:3]1.[OH-].[Na+].[ClH:26]>C1COCC1>[ClH:26].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=[O:19])[C:12]3=[O:23])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc(N3CCN(C)CC3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(c2ccn3c(=O)c(C(=O)O)ccc3c2)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 0.865 g (2.75 mmol) of ethyl 8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 12 mL of THF and 16.5 mL of a 0.5N aqueous solution of sodium hydroxide was heated, with stirring, at 75° C. for 8 hours. The THF was removed from the reaction mixture by distillation during the reaction. The concentrated reaction mixture was cooled to ambient temperature and adjusted to pH 2.0 with 10.5 mL of 1N aqueous hydrochloric acid solution. The aqueous solution was concentrated in vacuo to remove ~80% of the water and the concentrate was diluted with 50 mL of 95% ethyl alcohol. The solid was collected by filtration, washed with 2×5 mL of ethyl alcohol and dried in vacuo to afford the desired product. The product was recrystallized from ethyl alcohol/water (3:1 v/v) to afford 0.332 g (37% yield) of the title compound, m.p. 257°-258° C.; MS DCI-NH3 : 288 (M-Cl)+ 90%, 244 ((M-Cl)--CO2H)+ base, 270 (M-Cl--H2O)+ ; IR (KBr): 3420 (OH), 1645 (C=O) cm-1 ; 1H NMR (TFA) d 3.20 (m, 3H), 3.52 (dd, 2H, J=10 Hz), 4.02 (m, 4H), 4.63 (d, 2H, J=12 Hz), 7.41 (m, 2H), 7.65 (d, 1H, J=7.5 Hz), 8.26 (d, 1H, J=9 Hz), 9.18 (d, 1H, J=7.5 Hz). Analysis calculated for C15H18ClN3O3 +0.5H2O: C, 54.14; H, 5.75; N, 12.62. Found: C, 54.23; H, 5.54; N, 12.64.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1OS(C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1OS(=O)(=O)C(F)(F)F
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccccc2)nc1N1CCCCC1
Temperature: 80 °C
Yield: 96 %

Procedure:
To a solution of the above-prepared 2-phenyl-4-trifluoromethanesulfonyloxy-thiazole-5-carboxylic acid ethyl ester (0.75 mmol) in toluene (5 mL) was added piperidine (4.5 mmol). The reaction mixture was heated to 80° C. for 2 hours. The mixture was then diluted in ethyl acetate, washed successively with water and brine, and dried over MgSO4. Silica gel chromatography of the crude mixture provided title compound (96%) as a yellowish oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.O>[CH2:11]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (283 mg, 2.5 mmol) in dry DMF (5 ml) under an argon atmosphere was added NaH (120 mg, 2.75 mmol) in small portions at 0° C. The reaction mixture was stirred at rt for 1 hour, cooled again to 0° C. before benzyl bromide (300 μl, 2.5 mmol) was added and stirred at rt for 12 h. The mixture was diluted with water, extracted with ethyl acetate and the product was purified by chromatography on silica gel using heptane/ethyl acetate as eluent. The title compound was obtained as light yellow oil (484 mg, 95%). MS ISP (m/e): 226.3 (100) [(M+Na)+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH2:21][CH3:22])=[C:13]([CH3:26])[N:12]=1)[CH3:2]>CO.[Pd]>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[C:13]([CH3:26])[N:12]=1)[CH3:10]
Reactant: CCC=C(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC

Procedure:
A solution of 2-(2,6-diethylphenyl)-4-methoxy-6-methyl-5-(1-propylbutenyl)pyrimidine (100 mg) in MeOH is hydrogenated over Pd-C at 50 psi for 18 h. The catalyst is removed by filtration and the filtrate is concentrated to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 7.24-7.29 (m, 1H), 7.13 (d, J=8 Hz, 2H), 3.91 (s, 3H), 2.51 (s, 3H), 2.41 (q, J=7.5 Hz, 4H), 2.38-2.45 (m, 8H), 1.58-1.82 (m, 3H), 1.14-1.44 (m, 2H), 1.08 (q, J=7.5, 6.6 Hz, 6H) 0.89 (t, J=7.5 Hz, 6H); LC-MS found 355 (MH+).
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a solution of ethyl (1RS)-1-hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (150 mg, 0.35 rmnol) in CH2Cl2 was added triethylsilane (67 μl, 0.42 mmol), followed by boron trifluoride etherate (213 μl, 1.73 mmol). The reaction mixture was allowed to stir for 30 min, at which time was added slowly 5% aqueous HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to provide the title compound (45 mg, 31%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:31])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH2:2][CH3:3].Br[C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[C:33]([O:31][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1)([CH3:40])[CH3:39])[CH3:38]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCc1cc(O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-propyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/Dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-propylphenoxy}-2-methylpropionic acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J=8.3 Hz, 2H) 7.67 (d, J=3.4 Hz, 1H), 7.65 (dd, J=6.8, 2.0 Hz, 7.62 (d, J=2.9 Hz, 1H), 7.45 (t, J=6.6 Hz, 2H), 7.37 (t, J=7.8 Hz, 2H), 6.72-6.61 (m, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.20 (t, J=6.6 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.48, (t, J=7 Hz, 1H), 2.38 (s, 3H), 1.53-1.48 (m, 8H), 1.25 (t, J=7 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H); MS (FIA) m/e 528 (M+1).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH2:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH2:25][CH2:26][CH3:27].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:24]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)=[CH:30][CH:29]=1)[CH2:25][CH2:26][CH3:27]
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: CCCCc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(-c2nc(C)ccc2Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-n-butylphenylboronic acid (178 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (55 mg, yield 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:4]2[CH:5]=[C:6]([Cl:32])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C@H:14]4[CH2:15][CH2:16][C@H:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:29])[CH3:30])[CH2:18][CH2:19]4)[C:10]3=[O:31])=[C:2]([Cl:1])[CH:3]=2)=[CH:47][CH:46]=1)=[O:44]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Mix Trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 19) (1.70 g, 2.64 mmol), (4-methoxycarbonylphenyl)boronic acid (0.576 g, 3.17 mmol), tetrakis(triphenylphosphine)palladium(0) (0.305 g, 0.26 mmol) and 1.32 ml of 2M solution of K2CO3 in DME (10 mL). Stir for 12 hours at 80° C. Quench the reaction with water and extract with ethyl acetate. Wash the extract with brine and dry over magnesium sulfate. Flash chromatography affords 1.32 g (80%) of the title compound: Mass spectrum (apci) m/z=632 (M+H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)CCBr
Reactant: CCCCCCOc1c(O)c2ccc(O)cc2oc1=O
Product: CCCCCCOc1c(O)c2ccc(OCCC(=O)OCC)cc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-hexyloxy-4,7-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-hexyloxy-4-hydroxy-7-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[K].O.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(NC1C=CC=CC=1)=O>C1(C)C(C)=CC=CC=1>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:5][CH:6]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Yield: 92 %

Procedure:
The highest yields at minimum reaction temperature are attained from essentially anhydrous potassium formanilide, but small amounts of water have little effect. From a reaction mixture of 31.8 parts by weight (0.2 mole) of dry potassium formanilide, 24.2 parts by weight (0.154 mole) of para-nitrochlorobenzene, 9.3 parts by weight (0.077 mole) of formanilide and 25 parts by weight of xylene there is obtained after heating at 137°-149° C. for about 125 minutes a 92% yield of 4-nitrodiphenylamine and 97% conversion. The addition of 0.5% weight and 1.0% by weight of water respectively based on the potassium formanilide results in little or no reduction in yield and conversion. Addition of 1.0% by weight 45% potassium hydroxide improves the yield slightly. The innocuous effect of a little free water is to be contrasted with the adverse effect of bound water. Potassium formanilide forms a monohydrate which hydrolyzes rapidly when heated above temperatures of 85°-90° C. Replacing about half the formanilide with aniline in the foregoing procedure gives comparable result. The presence of aniline reduces the by-product carbon monoxide about 40% with formation of formanilide by mechanism imperfectly understood.