Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1ccc2nc(S)oc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Oc1ccc2nc(Cl)oc2c1

Procedure:
2-Sulfanyl-1,3-benzoxazol-6-ol (2.08 g) [see Preparation 33] was added to thionyl chloride (12.3 ml), followed by dimethylformamide (0.93 ml). The reaction mixture was heated to reflux for 5 minutes, after which time the mixture was allowed to cool. The solvent was removed under reduced pressure, the residue azeotroped twice with xylene, and the residue then partitioned between diethyl ether and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 0:100, by volume, hexane:ethyl acetate in 50% increments to afford 2-chloro-1,3-benzoxazol-6-ol (1.715 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3([C:20]#N)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1.C[Mg]Br.C(OCCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1CCN(C2(C#N)CCCCC2)CC1
Agent: C[Mg]Br
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1CCN(C2(C)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Intermediate 13a (0.5 mmol) from above was dissolved in anhydrous tetrahydrofuran (1.0 mL) and treated with 2.0 eq methylmagnesium bromide in butyl ether (1.0 mL 1.0 M solution, 1.0 mmol). The vial was flushed with nitrogen and stirred at room temperature for 3 h. The reaction was diluted with ethyl acetate (5.0 mL), quenched with saturated aqueous ammonium chloride (1.0 mL) and stirred overnight at room temperature. The organic layer was separated, concentrated in vacuo, then dissolved in methanol:acetonitrile (3.0 mL, 1:1 v/v) and subjected to reverse-phase HPLC purification (5-50% CH3CN/0.08% TFA) to yield 4-(5-chloro-2-methoxyphenyl)-1-(1-methylcyclo-hexyl)piperidine (compound no. 300) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 322.0 [M+H]+, retention time 2.39 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:17]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)C>[CH2:1]([O:8][C:9]([C:11]1([NH2:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1(N=C(c2ccccc2)c2ccccc2)CCOCC1
Agent: Cl
Solvent: CCOCC
Product: NC1(C(=O)OCc2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid benzyl ester (16.0 grams, 0.047 mole) in diethyl ether (120 mL) is added 1M aqueous hydrochloric acid solution (100 mL). The mixture is stirred vigorously at room temperature for 16 hours. The layers are separated and the aqueous layer washed with diethyl ether. The aqueous layer is brought to pH 10 with dilute aqueous ammonium hydroxide solution and extracted with dichloromethane. The organic extract is dried over sodium sulfate and concentrated to give 4-aminotetrahydropyran-4-carboxylic acid benzyl ester.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:3]1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH:4]2[CH2:5][N:2]([CH3:19])[CH2:3]2)=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1NC1CNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a mixture of azetidin-3-yl-(4-bromo-2-nitro-phenyl)-amine, hydrochloride (27.7 mmol, 8.54 g) in acetonitrile (100 mL) and 37% aqueous formaldehyde (83.0 mmol, 6.28 mL, 3.00 equiv.) at 0° C. add sodium triacetoxyborohydride (88.6 mmol, 18.8 g) slowly. Stir at room temperature under nitrogen overnight. Remove volatiles under reduced pressure. Dilute with ethyl acetate, wash with 10% aqueous sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 8.5 g of an orange solid. Purify on a 120 g silica column eluting with 5% methanol in dichloromethane to obtain the title compound (5.92 g, 75%). LC-MS m/z (79Br/81Br) 286.0/288.0 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5](=[NH:9])[O:6][CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOC(C)=O>C(Cl)Cl>[CH2:20]([O:19][C:17]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[CH2:4][O:3][CH3:2])=[O:18])[CH3:21]
Reactant: CCOC(=N)COC
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)N=C(COC)OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 102.6 %

Procedure:
Ethyl 2-methoxyacetimidate hydrochloride (0.95 g, 6.18 mmol) was suspended in DCM (12.4 mL) and the mixture was cooled to 0° C. Pyridine (2.5 mL, 30.9 mmol) and ethyl chloroformate (1.2 mL, 12.4 mmol) were added sequentially and the solution was allowed to warm to RT and stirred for 12 h. EtOAc (100 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-methoxyacetimidate (1.2 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 4.08-4.03 (m, 2H), 3.90 (q, J=7.0 Hz, 4H), 3.20 (s, 3H), 1.11 (t, J=6.9 Hz, 6H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:23][C:24]1[C:25]([O:33][CH3:34])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[C:25]=4[O:33][CH3:34])=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Reactant: COc1c(F)cccc1B(O)O
Product: COc1c(F)cccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Yield: 33.8 %

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester (389.9 mg, 1.1 mmol) and 3-fluoro-2-methoxyphenylboronic acid [762287-59-2] (216.2 mg, 1.3 mmol) to afford 153.8 mg of light yellow powder as a free base, mp. 52-53° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.32 Hz, 6 H) 3.49-3.56 (m, 4 H) 3.75 (dd, J=6.44, 4.17 Hz, 4 H) 3.83 (d, J=1.01 Hz, 3H) 4.82 (spt, J=6.23 Hz, 1 H) 6.81 (d, J=8.08 Hz, 1 H) 7.06 (ddd, J=11.37, 8.08, 1.52 Hz, 1 H) 7.16 (td, J=8.08, 5.81 Hz, 1 H) 8.23 (dt, J=7.89, 1.36 Hz, 1 H) 8.42 (s, 1 H). 19F NMR (377 MHz, DMSO-d6) δ ppm −131.42. 13C NMR (100 MHz, DMSO-d6) δ ppm 21.95, 42.83, 44.05, 60.38, 68.16, 97.24, 99.94, 99.98, 112.72, 112.90, 123.22, 124.06, 127.98, 136.39, 143.40, 143.51, 144.25, 144.49, 154.28, 154.63, 155.53, 157.04. LRMS (ESI) m/z 414.1 [(M+H)]+, calc'd for C21H24FN5O3: 413.46.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)=[CH:8]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]2=[O:13])=[CH:33][CH:34]=1
Reactant: CN(C)CCN(C(=O)OC(C)(C)C)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.8 %

Procedure:
According to Scheme 19 Step 5: tert-Butyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl(2-(dimethylamino)ethyl)carbamate (0.16 mmol, 79.0 mg) was dissolved in dry CH2Cl2 (30 mL). Then TFA (7 mL) was added dropwise and the resulting solution was stirred at room temperature for 3 hours. Then the solvent was evaporated under reduced pressure and the resulting residue thus obtained was resulting suspension was taken up in CH2Cl2, washed with a saturated aqueous NaHCO3 solution. The organic solvent was separated, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge CH2Cl2/MeOH(NH3)sat. 95/5. The product fractions were collected and the solvent was evaporated to yield 1-(4-chlorobenzyl)-5-(4-(2-(dimethylamino)ethylamino)phenyl)pyridin-2(1H)-one (16.4 mg, 26%)
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=C(CCN)[CH:36]=[CH:37][CH:38]=1>>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:36]=[CH:37][CH:38]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCc1cccc(C(F)(F)F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(3-trifluoromethylphenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 431 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.28 (1H, s) 8.20 (1H, t, J=5.56 Hz) 8.02 (1H, d, J=5.27 Hz) 7.77 (1H, d, J=5.47 Hz) 7.60 (1H, s) 7.44-7.56 (4H, m) 7.31 (1H, dd, J=3.32, 2.54 Hz) 6.82 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.42, 1.85 Hz) 3.47-3.56 (2H, m) 2.94 (2H, t, J=7.03 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[CH3:9].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:17])[F:18])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([N:32]1[C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]2[C:28]1=[O:38])[CH3:9]
Reactant: CC(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
In a solution of 0.88 g of 3-[3-chloro-4-(1-chloroethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 5 mL of N,N-dimethylformamide, 0.36 g of potassium phthalimide was added, and stirred at 100° C. for 1.5 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and diluted with 20 mL of ethyl acetate, washed with water (10 mL×3), and then dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with medium pressure preparative liquid chromatography (medium pressure collection apparatus: YFLC-Wprep manufactured by Yamazen Corporation) that was eluted with ethyl acetate-hexane (gradient of 1:10 to 1:3) to obtain 0.45 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1)#[N:2].NN>[Pd].C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: N#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Yield: 98.1 %

Procedure:
Added 100 mg of 10% palladium on carbon to a round bottom flask under N2 and covered with 50 ml ethanol. Added 1.00 g (3.17 mmol) 4-[(3-cyanophenyl)amino]-6-nitro-quinoline-3-carbonitrile and 250 μl (7.39 mmol) anhydrous hydrazine and heated to reflux. Removed heat at 2 hours and filtered hot through celite. Stripped solvent and dried in vacuo, giving 887 mg of yellow solid: mass spectrum (electrospray m/e): M+H=286.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(O)c1cc2cccc(F)c2nc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cccc(F)c2nc1Cl
Temperature: 25 °C
Yield: 72 %

Procedure:
To a round-bottomed flask containing toluene (183 mL) was added 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (6.20 g, 27.5 mmol) and manganese dioxide (19.1 g, 220 mmol, 8 eq). The reaction was heated to reflux for 2 h, cooled to rt, filtered and concentrated. The product was diluted with hexanes and filtered to give as a white solid 1-(2-chloro-8-fluoroquinolin-3-yl)ethanone (4.43 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.40 (d, J=1.6 Hz, 1H), 7.71 (br d, J=8.2 Hz, 1H), 7.56 (td, J=7.8, 5.1 Hz, 1H), 7.54 (ddd, J=9.8, 7.8, 1.6 Hz, 1H). Mass Spectrum (ESI) m/e=223.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](F)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:16][NH2:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:17][CH3:16])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: Fc1cc(-c2cccnc2Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-c2cccnc2Cl)ccn1
Temperature: 80 °C

Procedure:
2-chloro-2′-fluoro-[3,4′]bipyridinyl (5.30 g, 25.4 mmol), methylamine hydrochloride (9.00 g, 133 mmol) and K2CO3 (28.1 g, 203 mmol) was added DMSO (70 mL). The mixture was heated overnight at 80° C. in a sealed tube. The cooled mixture was diluted with water (300 mL) and the resulting solid was filtered, washed with water and dried to yield (2-chloro-[3,4′]bipyridinyl-2′-yl)-methyl-amine. MS m/z=220 [M+1]+. Calc'd for C11H10ClN3: 219.68.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([NH2:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].CN(C)C=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([NH2:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])=[O:28]
Reactant: CN(C)C=O
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1Cl
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1Cl
Yield: 84 %

Procedure:
In the same manner as in Example 140 and using 5-[3-[3-chloro-4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-amine instead of 2-methyl-5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole and using N,N-dimethylformamide instead of dichloromethane, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)([OH:3])=[O:2].[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]O)([O-:29])=[O:28]>>[Cl:24][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:25])[C:18]=1[CH2:17][C:16]([C:10]1[C:9]2[C:5]([CH2:4][C:1]([O:3][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[N+:27]([O-:29])=[O:28])=[O:2])=[CH:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:26]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Reactant: O=[N+]([O-])c1ccccc1CO
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)OCc3ccccc3[N+](=O)[O-])coc12
Yield: 37.2 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 151 (0.30 g) obtained in Example 151 and 2-nitrobenzyl alcohol (0.12 g) to give Compound 154 (0.15 g, 38%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:21])[C:15]#[C:16][Si](C)(C)C)[CH3:2].CCOCC.Cl>CO>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:21])[C:15]#[CH:16])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)C#C[Si](C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C#CC(=O)c1cc(Br)ccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a solution of [4-bromo-2-(3-trimethylsilanylpropynoyl)phenoxy]acetic acid ethyl ester (0.83 g, 2.16 mmol) in methanol (20 mL) was added a 0.1M aqueous solution of Na2B4O7 (10 mL). After stirring for 2-3 minutes at room temperature, Et2O and 1N aq. HCl were added. The phases were separated, and the organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as yellow oil which crystallized upon standing (0.65 g, 2.09 mmol, 96%). LC/MS (an 10p8) Rt 3.58 min, m/z 311 [M+H]+; 1H NMR (CDCl3): δ1.31 (t, 3H), 3.45 (s, 1H), 4.27 (q, 2H), 4.74 (s, 2H), 6.83 (d, 1H), 7.61 (dd, 1H), 8.14 (d, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[CH:15]([CH3:34])[C:16]([C:22]1[CH:33]=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:24]=2[CH:23]=1)([OH:21])[C:17]([F:20])([F:19])[F:18].Cl[C:36]1[N:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:37]=1[C:38]([O:40][CH3:41])=[O:39].C(O)=O>CN(C=O)C>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[C:43]([Cl:46])[CH:44]=[N:45][C:36]=1[O:14][C:12]1[CH:11]=[CH:10][C:9]([CH:15]([CH3:34])[C:16]([C:22]2[CH:33]=[CH:32][C:25]3[N:26]([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:24]=3[CH:23]=2)([OH:21])[C:17]([F:18])([F:19])[F:20])=[C:8]([Cl:7])[CH:13]=1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: COC(=O)c1cc(Cl)cnc1Oc1ccc(C(C)C(O)(c2ccc3c(c2)n(C)c(=O)n3C)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (6 mg) was added to a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 20 mg) in DMF (3.6 ml). The solution was added to methyl 2,5-dichloronicotinate (CAS Reg. No. 67754-03-4, 20 mg). The resulting mixture was stirred overnight at room temperature. The mixture was acidified with HCOOH and purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (10 mg). MS (m/e)=584.3 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH2:26](O)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)[CH3:27]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.697 g, 2.00 mmol), ethanol (0.140 mL, 2.40 mmol) and triphenylphosphine (0.787 g, 3.00 mmol) in toluene (8 mL) was added with a 40% solution of diethyl azodicarboxylate in toluene (1.31 g, 3.00 mmol), and the mixture was stirred at 110° C. for 5 hours in a sealed tube. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.138 g, 18%).
Reaction SMILES: [F:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([C:17]([F:20])([F:19])[F:18])[S:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([CH3:35])[C:23]=1[CH3:36]>>[F:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][O:16][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([CH3:35])[C:23]=3[CH3:36])=[C:13]([C:17]([F:20])([F:19])[F:18])[S:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(F)c1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(C(C)F)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling [3-[4-(1-fluoroethyl)phenyl]-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1HNMR (300 MHz, CD3OD) δ 7.67 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 6.92 (d, J=8.1 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 5.53-5.75 (m, 1H), 5.06 (s, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.47 (t, J=7.5 Hz, 2H), 2.18 (s, 3H), 2.00 (s, 3H), 1.53-1.65 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H23F4NO3S, 480.1 (M−H). found 480.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH2:14]([C:16]([CH2:20][OH:21])([CH2:18][OH:19])[CH3:17])[OH:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:15])=[O:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:15])=[O:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:15])=[O:7].[CH2:14]([C:16]([CH2:20][OH:21])([CH2:18][OH:19])[CH3:17])[OH:15]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: CC(CO)(CO)CO
Product: COc1ccc(C(=O)O)cc1OC
Yield: 90 %

Procedure:
Following the procedure of Example I, 3,4-dimethoxybenzoyl chloride was allowed to react with 1,1,1-trimethylolethane in the molar ratio of 3:1. The product was obtained in 90% yield as a glassy substance which slowly crystallized after being precipitated from methanol at dry-ice temperature. The triester is a white crystalline material, mp 105°-106° C., with an ester carbonyl band at 5.85μ. The proton magnetic resonance spectrum was consistent with the title compound.