Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>COCCOC.CO.CC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:16][CH:17]=1)=[O:20]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Procedure A′: A suspension of 4-(trifluoromethyl)phenylboronic acid (7.3 g, 38.4 mmol), methyl 4-bromobenzoate (7.44 g, 36.4 mmol), triphenylphosphine (1.21 g, 4.6 mmol), cesium fluoride (11.7 g, 76.8 mmol) and palladium acetate (0.26 g, 1.15 mmol) in degassed DME and methanol is heated at reflux for 24 h. The suspension is cooled to room temperature, filtered, and the resulting filtrate concentrated in vacuo to give a dark solid. This material is taken up in acetone and adsorbed on silica gel, and purified by flash filtration using 500 mL each of 2% to 20% ethyl acetate/hexanes in 2% increments. Fractions containing the product are combined to give the title compound in 92% yield. NMR (CDCl3) 8.10 (d, J=8.4 Hz, 2H), 7.99 (d, J=7.9 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.83 (d, 8.4 Hz, 2H), 3.58 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][CH2:10][N:11](CCN)CCN.O.[N+]([O-])([O-])=O.[Ga+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:8][CH2:9][CH2:10][NH2:11]
Reactant: O=Cc1ccc[nH]1
Reactant: NCCN(CCN)CCN
Agent: O=[N+]([O-])[O-]
Agent: [Ga+3]
Solvent: O
Product: NCCN=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The ligand [(((pyrrole-2-yl)methylidene)amino)ethyl]amine was prepared by adding a methanolic solution of pyrrole-2-carboxaldehyde (1.430 g, 15 mmol, 100 ml) to a methanolic solution of tris(2-aminoethyl)amine (0.720 g, 5 mmol, 10 ml). The resulting yellow solution was stirred at room temperature for 30 min. A methanolic solution of gallium(III) nitrate hydrate (1.280 g, 5 mmol, 150 ml) was added to the ligand solution and stirred at room temperature for 30 min. The solution was filtered and left to stand at ambient temperature until crystallization occurred. The crude material was then sublimed at 235° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[OH:11].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([C:12]2[O:11][C:5]3[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=3[N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc(O)c(N)c1
Agent: Cl
Solvent: O
Product: Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 180 °C
Yield: 96.9 %

Procedure:
To polyphosphoric acid at 110° C. were added simultaneously 2,4-diaminophenol dihydrochloride (7.88 g, 40 mmol) and benzoic acid (4.88 g, 40 mmol). The resulting mixture was then heated to 180° C. for 3 h. The solution was then poured into water. The resulting precipitate was collected by filtration and washed with saturated sodium bicarbonate solution. The crude product was recrystallised from ethanol/water to afford 8.15 g (97%) of the title compound (LCMS RT=5.17 min, MH+ 211.1)
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: O=O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccccc1
Yield: 801.2 %

Procedure:
A mixture containing 168 g (1 mol) of diphenylmethane, 16 g (0.1 mol) of N-hydroxyphthalimide, and 1000 mL of acetic acid was allowed to react at 100° C. for 20 hours in an atmosphere of oxygen to obtain a reaction mixture containing 146 g of benzophenone (yield 80%). From the reaction mixture, acetic acid was distilled off, and to the reaction mixture were added 1000 mL of dibutyl ether and 1000 mL of 0.4N sodium hydroxide aqueous solution. After stirring at 97° C. for 1 hour, an aqueous phase and an organic phase were separated. To the resulting organic phase was further added sodium hydroxide aqueous solution, and mixed completely at 97° C. to liquid-separate into an aqueous phase and an organic phase. The aqueous and organic phases were analyzed by gas chromatography and liquid chromatography, and, as a result, the extraction ratio of benzophenone into the organic phase was 89%, the extraction ratio of the oxidation catalyst and/or the deactivated oxidation catalyst (conversion into sodium phthalate) (on basis of the amount of N-hydroxyphthalimide used in the reaction) into the aqueous phase was 83%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]([OH:23])=[O:22])[N:18]=[C:17]([O:24][CH2:25][CH2:26][OH:27])[C:16]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1.[NH4+].[Cl-]>CC(N(C)C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:16]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[C:17]([O:24][CH2:25][CH2:26][O:27][C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[N:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncccn1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCO)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCOc2ncccn2)c1
Yield: 69.5 %

Procedure:
0.2 g of 6-(4-tert-butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid in 5 ml of dimethylacetamide was stirred at 20° C. for 3 hours with 0.04 g of sodium hydride and 0.07 g of 2-chloropyrimidine and the mixture was neutralized with saturated NH4Cl solution. The reaction mixture was washed with ethyl acetate. The aqueous phase was adjusted to pH 2 with 1N HCl and extracted with chloroform. The organic phase was dried, the solvent was evaporated and the residue was purified over silica gel with chloroform-methanol-water 60:35:5. There was obtained 0.16 g of 4-(4-tert-butyl-phenylsulphonylamino)-5-(3-methoxy-phenoxy)-6-(2-pyrimidin-2-yloxy-ethoxy)-pyrimidine-2-carboxylic acid, MS: (M+H)+ 596.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:31])[CH3:32])[C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(N)c1=O)C(=O)C(F)(F)F
Reaction time: 0.25 h

Procedure:
To a solution of 2-[5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide in dichloromethane (35 mL) and anisole (1.2 mL) at 0° C. was added trifluoromethanesulfonic acid, and the resulting suspension was stirred for 15 minutes. The reaction was quenched by addition of sodium bicarbonate and the product extracted into ethyl acetate. The organic layer was washed (brine) and dried. The solvent was removed and the residue was purified by chromatography, with methanol:dichloromethane (gradient, 5:95, 7:93) as the eluent, to provide 2-[5-amino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a yellow solid; 300 MHz NMR (DMSO/D2O): 7.94 (d,1), 7.65 (d,1), 7.30 (s,1), 7.22 (d,1), 7.02 (m,1), 4.84 (d,1), 4.69 (d,1), 4.07 (d,1), 2.24 (m,1), 0.89(d, 3), 0.76 (d,3).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.[O:26]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:36]1[CH:37]=[CH:38][C:33]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:34][CH:35]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 37 °C
Yield: 44 %

Procedure:
To a stirred mixture of tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (600 mg, 1.8 mmol) and 400 mg 4 Å MS in 16 mL dry DMF were added 4-phenoxyphenylboronic acid (1.05 g, 4.9 mmol), Cu(OAc)2 (320 mg, 1.8 mmol) and pyridine (1 mL, 12.7 mmol). The reaction mixture was heated at 37° C. for 5 hrs under an O2 atmosphere. After cooling down to rt, the reaction mixture was filtered through a Celite pad. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL×1), dried over Na2SO4, then concentrated to dryness. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in DCM) to give tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenylcarbamate (6) (404 mg, 45%) as a brown solid. LC-MS (ESI): m/z (M+1) 511.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.C([Li])(C)(C)C.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>C1COCC1>[CH3:17][C:13]1[N:12]=[C:11]([C:3]2[C:2]([B:23]([OH:28])[OH:24])=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccc(-c2nn3ccccc3c2Br)n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3ccccc3c2B(O)O)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine (PREP. 17, 0.2 g, 0.69 mmol) in THF (10 mL) is cooled to −78° C. and treated with tert-butyllithium (1.7 M in pentane, 1.6 mL, 2.8 mmol). This solution is stirred for 30 minutes at −78° C., treated with triisopropyl borate (0.39 g, 2.08 mmol), and stirred for 2 hr at −78° C. The reaction is then quenched with 1N HCl and stirred for 30 minutes at room temp. Evaporation leads to the solid crude product that is used without further purification. MS ES+ m/e 253.9 (M+1).
Reaction SMILES: Cl[C:2]1([CH:8]=[N:9][OH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[CH2:11]([N:18]1[CH2:22][CH2:21][C:20](=[CH2:23])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C(N(CC)CC)C>O>[CH2:11]([N:18]1[CH2:22][CH2:21][C:20]2([O:10][N:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:23]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ON=CC1(Cl)C=CC=CC1
Reactant: C=C1CCN(Cc2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(CN2CCC3(CC(c4ccccc4)=NO3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound C (3.9 g, 25.2 mmol, dissolved in abs. DCM (25 ml)) was added dropwise to a solution of 1-benzyl-3-methylenepyrrolidine (P) (2.18 g, 12.6 mmol) in abs. DCM (25 ml) at 0° C. within 10 min. A solution of triethylamine (14 ml, 10.2 g, 100.1 mmol) in abs. DCM (25 ml) was added to this mixture at 0° C. within 10 min. As the reaction was highly exothermic, cooling was carried out in an ice/sodium chloride mixture. The reaction mixture was stirred for 16 h at RT. For working up the mixture, DCM (50 ml) and water (70 ml) were added. The phases were separated. The aqueous solution was extracted with DCM (2×20 ml). The combined organic phases were washed successively with water (50 ml) and sat. NaCl solution (50 ml) and then dried and concentrated (5.3 g, yellow oil). The residue was purified by column chromatography [silica gel 60 (500 g); EtOAc/cyclohexane 1:2 (3 l)]. The desired compound Q was obtained as a solid in a yield of (2.4 g, 65%) having a melting point of 31-40° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:20])=O>>[CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCc1ccc(C(=O)Cl)cc1

Procedure:
20 g. of p-n-octylbenzoic acid and 100 ml. of thionyl chloride are boiled at reflux for 1 hour. The excess thionyl chloride is removed by distillation at normal pressure. The residue is mixed with absolute toluene and concentrated under vacuum. The obtained crude p-n-octylbenzoic acid chloride can be used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]([F:58])([F:57])[S:35]([O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[C:44]2OS(C(F)(F)F)(=O)=O)(=[O:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:44]3[C:45]4[C:40](=[C:39]([O:38][S:35]([C:34]([F:58])([F:33])[F:57])(=[O:36])=[O:37])[CH:48]=[CH:47][CH:46]=4)[CH:41]=[CH:42][CH:43]=3)=[CH:22][CH:23]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Oc1cccc2c(OS(=O)(=O)C(F)(F)F)cccc12)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3cccc4c(OS(=O)(=O)C(F)(F)F)cccc34)cc2)[nH]1
Temperature: 100 °C
Yield: 80.3 %

Procedure:
2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.30 g, 2.96 mmol), Trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy-naphthalen-1-yl ester (982 mg, 2.31 mmol), Pd(PPh3)4 (134 mg, 0.116 mmol) and potassium carbonate (639 mg, 4.62 mmol) were suspended in toluene. After degassing with nitrogen for 28 min, the stirred suspension was heated to 100° C. for 18 hours. The reaction mixture was then cooled to RT, diluted with ethyl acetate (250 mL), washed with water, brine, dried over magnesium sulfate and concentrated. The resulting residue was purified by silica column chromatography (0% to 60% EtOAc/hexanes) to provide 2-{5-[4-(5-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.09 g, 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13]O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[C:26](=[O:34])[NH:27][C:28]3=[O:33])=[O:22])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[C:26](=[O:34])[N:27]([CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:12][CH2:11]2)[C:28]3=[O:33])=[O:22])=[CH:18][CH:17]=1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Reactant: OCC1CCN(c2ccncc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c1C(=O)N(CC1CCN(c3ccncc3)CC1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Pyridyl)-4-piperidinemethanol (U.S. Pat. No. 4,968,704) (211.5 mg, 1.1 mmol), 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide (306.7 mg, 1 mmol), triphenylphosphine (1049 mg, 4 mmol) are initially charged in 40 ml of THF, and diethylazodicarboxylate (DEAD) (696.6 mg, 4 mmol, 0.63 ml) is added. The mixture is stirred at room temperature overnight and then concentrated by evaporation, the residue is dissolved in ethanol, silica gel is added, the mixture is re-concentrated by evaporation and the residue is applied to a silica gel column. Elution with toluene/ethyl acetate and toluene/ethanol (25:1) mixtures gives a main fraction of Rf (SiO2, toluene/ethanol=4:1)=0.19. This fraction is evaporated and treated with ethanol, and the resulting crystals (112 mg, 23.3% of theory) are filtered off with suction. M.p.: 123° C. (decomp.).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:51])=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][C:5]([CH3:51])=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(CC)sc4C)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)c(C)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.30 g), tetrahydrofuran (6 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hrs. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give {4-[4-({4-[({4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as crystals (0.19 g, yield 66%). Recrystallization from tetrahydrofuran-hexane gave pale-yellow prism crystals. melting point: 198-199° C.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[C:9]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=O.[C:26](OCC)(=[O:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30].Cl>C(O)(C)(C)C.O>[OH:34][C:26]1[N:7]=[C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=3[C:9]2=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:27]=1[CH2:28][C:29]([OH:31])=[O:30]
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(-c2c(CC(=O)O)c(O)nc3sc4c(c23)CCCC4)cc1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of potassium tert-butoxide (0.269 g; 2.4 mmol) in dry tert-butanol (10 mL) under a nitrogen atmosphere at 50° C. were added (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone (0.542 g; 2 mmol) and diethyl succinate (0.464 mL; 2.8 mmol). The mixture was heated at reflux for 24 h and then cooled down to room temperature. Water (8 ml) was added and then the reaction mixture was acidified with a solution of hydrochloric acid 1N until pH 1. The aqueous layer was extracted with diisopropylether (3×10 ml) and ethyl acetate (3×10 mL). The organics were combined and the volatiles were removed under reduced pressure. The remaining crude was crystallized from acetic acid to furnish 0.101 g (14%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si](C)(C)C)#[CH:17].[OH-].[K+]>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.C(NCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:16]#[CH:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCNCC
Product: C#Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-benzyloxy iodobenzene (193 g, 0.625 mol), ethynyl-trimethyl-silane (75 g, 0.76 mol), Cul (2 g, 10.5 mmol) and Pd(PPh3)2Cl2 (1 g, 1.0 mmol) were added to diethylamine (880 mL) at 0° C. The reaction mixture was warmed to 25° C. and then stirred for 6 h. The reaction mixture was concentrated and partitioned in H2O/ethyl acetate (100 mL/100 mL). The reaction mixture was further extracted with ethyl acetate (300 mL×2). The combined organic layers were washed by water (300 mL), dried over MgSO4 and concentrated in vacuo. The crude product was dissolved in methanol (400 mL) and was stirred with KOH (28 g, 0.5 mol) for 1 h at 25° C. Concentration and purification by silica gel column chromatograph (5% ethyl acetate/Hexane) yielded 4-benzyloxy phenyl acetylene as liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[S-:24][C:25]#[N:26].[K+].BrBr>C(O)(=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:17]=[C:18]3[S:24][C:25]([NH2:26])=[N:22][C:19]3=[CH:20][CH:21]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc(N)cn2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc3nc(N)sc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of tert-butyl{3-[(5-aminopyridin-2-yl)oxy]-4-fluorophenyl}carbamate (2.50 g, 7.8 mmol) and potassium thiocyanate (2.92 g, 30 mmol) in acetic acid (30 mL) was added dropwise bromine (1.93 g, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. The yellow insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (1.92 g, 65%) as a pale-yellow amorphous.