Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:38]([O:40][C:41](=[O:65])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[C:55](=[O:56])[CH:54]=[CH:53][C:52]([C:57]3[CH:62]=[CH:61][C:60]([CH2:63][NH2:64])=[CH:59][CH:58]=3)=[N:51]2)[CH:44]=1)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:65])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[C:55](=[O:56])[CH:54]=[CH:53][C:52]([C:57]3[CH:58]=[CH:59][C:60]([CH2:63][NH:64][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:61][CH:62]=3)=[N:51]2)[CH:44]=1)[CH3:39]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CN)cc3)ccc2=O)c1
Reactant: CC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CNC(=O)CNC(C)=O)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
61 mg (0.52 mmol) of N-acetylglycine are suspended in 2 ml of DMF, 106 μl (0.95 mmol) of 4-methylmorpholine, 66 mg (0.47 mmol) of 1-hydroxybenzotriazole and 184 mg (0.95 mmol) of N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 10 min, 180 mg (0.48 mmol) of ethyl{3-[3-(4-aminomethylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}carbamate are subsequently added, and the mixture is stirred at room temperature for 24 h.
Reaction SMILES: ClC1C(F)=CC(F)=[C:6](C=1)[C:7](NS(C)(=O)=O)=[O:8].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12(CO)[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2.C12(C(O)C)CC3CC(CC(C3)C1)C2>>[C:35]12([CH2:6][CH2:7][O:8][C:19]3[C:18]([Cl:17])=[CH:32][C:22]([C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24])=[C:21]([F:33])[CH:20]=3)[CH2:36][CH:37]3[CH2:43][CH:41]([CH2:40][CH:39]([CH2:38]3)[CH2:44]1)[CH2:42]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CC(O)C12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with adamantan-1-ylethanol, the title compound was obtained as a colorless solid (0.15 g, 33%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.28 (d, J=12.5 Hz, 1H), 4.18 (t, J=7.0 Hz, 2H), 2.87 (s, 6H), 1.93-1.88 (br s, 3H), 1.70-1.54 (m, 14H); MS (ES−) m/z 457.2, 459.2 (M−1).
Reaction SMILES: C[O:2][Si:3][O:4]C.[CH:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:12]3[N:44]=[C:43]4[N:45]=[C:36]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=54)[N:35]=[C:33]4[NH:34][C:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=54)=[N:25][C:23]4=[N:24][C:16]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=54)=[N:15][C:14]=2[NH:13]3)[CH:11]=1.O>CS(C)=O>[OH:2][Si:3][OH:4].[CH:7]1[CH:6]=[CH:11][C:10]2[C:9](=[C:14]3[N:15]=[C:16]4[N:24]=[C:23]([C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=54)[N:25]=[C:26]4[NH:34][C:33]([C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=54)=[N:35][C:36]4=[N:45][C:43]([C:42]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=54)=[N:44][C:12]=2[NH:13]3)[CH:8]=1
Reactant: CO[Si]OC
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: CS(C)=O
Solvent: O
Product: O[Si]O
Temperature: 25 °C

Procedure:
10 g of dimethoxysilicon phthalocyanine synthesized in Synthesis Example 2 was added to 10 g of water and 90 g of dimethyl sulfoxide (90% DMSO aqueous solution) and reacted at 120° C. for 3 hours. The reaction product was thermally filtrated and washed with DMF and acetone in the order named. After the product was stirred in 50 ml of acetone at room temperature, crystals were separated by filtration and dried to obtain 8.4 g of dihydroxysilicon phthalocyanine. When structural analysis was carried out by mass spectral (negative measurement) and IR (KBr method) methods, the same spectrum as that of Example 1 was obtained. Therefore, it was confirmed that the product was dihydroxysilicon phthalocyanine. According to the X-ray spectrum (FIG. 12), the obtained dihydroxysilicon phthalocyanine is a dihydroxysilicon phthalocyanine having the crystal form of the present invention and a main peak at a 2 0 of 9.20 and other peaks at 12.2, 14.0, 15.3, 19.7, 23.4 and 27.1°, respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9](=[O:11])[CH2:8][CH:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[Li+].[CH3:14]C([N-]C(C)C)C.CI>C1COCC1>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9](=[O:11])[CH:8]([CH3:14])[CH:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: CC(C)[N-]C(C)C
Reactant: CC1(C)CC(=O)CC2CCCN21
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)CC(C)(C)N2CCCC12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
Hexahydro-5,5-dimethylindolizin-7(1H)-one (racemic) (1.41 g, 8.43 mmol) was dissolved in dry THF (50 ml); the flask was flushed with nitrogen and cooled to −78° C. LDA (5.9 ml, 11.8 mmol) was added via syringe and stirred for 30 minutes. Subsequently, neat methyl iodide (1.30 ml, 21.1 mmol) was added via syringe. The clear, pale yellow solution was stirred overnight and allowed to warm to room temperature. The reaction was then quenched with a saturated NH4Cl solution and extracted with ethyl acetate (3×40 ml). The organic phases were passed through a plug of MgSO4 and solvents were evaporated in vacuo. The crude product (849 mg) was obtained in form of a yellow-brown oil and used without further purification in the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:14](O)[CH2:15][OH:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([C:10]1([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[O:16][CH2:15][CH2:14][O:13]1)[CH3:12]
Reactant: OCCO
Reactant: CCC(=O)c1ccc2occc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1(c2ccc3occc3c2)OCCO1
Yield: 87.2 %

Procedure:
A solution of 1-(benzofuran-5-yl)propan-1-one (650 mg, 1.0 eq), ethane-1,2-diol (3.5 g, 15.0 eq) and 4-methylbenzenesulfonic acid (65 mg, 0.1 eq) in 20 mL toluene was refluxed for 72 h, cooled, quenched with sat. NaHCO3 (aq) and extracted with EtOAc. The extract was washed with brine, dried, concentrated, and purified by column chromatography to give the desired product (710 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.0 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.39 (dd, J=8.4 Hz, 1.6 Hz, 1H), 6.76 (dd, J=2.4 Hz, 0.4 Hz, 1H), 4.02-4.05 (m, 2H), 3.78-3.81 (m, 2H), 1.96 (q, J=7.2 Hz, 2H), 0.89 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)=[CH2:2].I[C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1.C1(C)C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)/[CH:2]=[CH:1]/[C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: C=Cc1cnc(Nc2ccc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cn1
Reactant: Oc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Nc3cnc(/C=C/c4cccc(O)c4)cn3)cc2)CC1
Temperature: 120 °C
Yield: 78.5 %

Procedure:
A mixture of tert-butyl 4-(4-(5-vinylpyrazin-2-ylamino)phenylsulfonyl)piperazine-1-carboxylate (40 mg, 0.09 mmol), 3-iodophenol (19 mg, 0.09 mmol), Pd(OAc)2 (1.2 mg, 0.005 mmol), tri-p-tolylphosphine (2.5 mg, 0.008 mmol), and DIEA (31 μL, 0.18 mmol) in DMF (3 ml) was heated at 120° C. for 18 h after which, it was filtered with a pad of celite and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (20% to 40% Ethyl acetate/Hexane) as a solvent to afford title compound (38 mg, 78% yield). MS m/z: 538 [M+1].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C[Si](C)(C)[NH:10][Si](C)(C)C.[Li].[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:22][Mg]Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH3:18][C:19]1[CH:20]=[C:21]([CH2:22][CH:6]([NH2:10])[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: O=Cc1cccs1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cc1cc(C)cc(C[Mg]Cl)c1
Agent: [Li]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(CC(N)c2cccs2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A solution of thiophene-2-carbaldehyde (2.24 g) in anhydrous toluene was cooled to 0° C. under nitrogen inert-gas atmosphere and a solution of lithium hexamethyldisilazane (LiHMDS, 22 ml, 1.1 equiv.) was added via cannula over a 30 min period. The reaction mixture was allowed to warm up to room temperature for 2 h. After cooling to 0° C. again a solution of 3,5-dimethylbenzylmagnesium chloride (50 ml, ca. 1.5 equiv.) in tetrahydrofuran (THF) was added within 10 min and the reaction mixture allowed to warm up to room temperature and stirring continued for 3 h. This solution was quenched with aqueous potassium carbonate solution (5%) and extracted with diethyl ether. The dried and concentrated ether extracts were purified by column chromatography to give the product (1.4 g) as a yellowish oil in 30% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([O:13][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CCN(c2ccc(Br)cc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
(S)-1-(4-Bromo-phenyl)-pyrrolidin-3-ol (14.0 g, 57.7 mmol) was dissolved in DMF (100 mL), and TBDMS-Cl (10.4 g, 69.2 mmol) and imidazole (9.81 g, 144 mmol) were added. The mixture was stirred at rt overnight. Aq. sat. NH4Cl (100 mL) was added, and the mixture was extracted with heptane (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:15→1:4) yielded the title compound (17.3 g, 84%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=2[F:17])=[C:6]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)[N:5]2[N:25]=[CH:26][N:27]=[C:4]2[N:3]=1.O.C(OC)(C)(C)C.[CH3:35][N:36](C)C=O>[C-]#N.C([N+](CC)(CC)CC)C>[C:35]([C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=2[F:17])=[C:6]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)[N:5]2[N:25]=[CH:26][N:27]=[C:4]2[N:3]=1)#[N:36]
Reactant: CN(C)C=O
Reactant: CC1CCN(c2c(-c3c(F)cc(C#N)cc3F)c(Cl)nc3ncnn23)CC1
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: COC(C)(C)C
Solvent: O
Product: CC1CCN(c2c(-c3c(F)cc(C#N)cc3F)c(C#N)nc3ncnn23)CC1

Procedure:
A mixture of 0.1 mol of 5-chloro-6-(2,6-difluoro-4-cyanophenyl)-7-(4-methylpiperidin-1-yl)-[1,2,4]-triazolo-[1,5-a]-pyrimidine (No. I-5) and 0.25 mol of tetraethylammonium cyanide in 750 ml of dimethylformamide (DMF) was stirred at 20–25° C. for 16 hours. After addition of water and methyl tert-butyl ether (MTBE), the organic phase was separated, washed with water, dried and freed from the solvent. After chromatography on silica gel, 6.33 g of the title compound were obtained from the residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([CH:30]1[CH2:35][CH2:34][C:33](B(O)O)=[CH:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O>[C:1]([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:18]2[CH:23]=[CH:22][C:21]([C:33]3[CH2:34][CH2:35][CH:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:31][CH:32]=3)=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)C1CC=C(B(O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(C3=CCC(C(C)(C)C)CC3)cc2)cc1

Procedure:
A mixture of 3.1 g of 4-[(R)-2-(4-Bromo-phenyl)-2-carboxy-ethyl-]-benzoic acid tert-butyl ester (3.Step 2, above), 1.5 g of 4-t-butyl-cyclohex-1-enyl boronic acid, 644 mg of PdCl2(P(o-tolyl)3)2, and 2.21 g of sodium carbonate in 12 mL of DME and 6 mL of ethanol and 3 mL of water was heated to reflux for a 16 h period. The reaction mixture was quenched with an excess of aqueous ammonium chloride, added ethyl acetate and the heterogeneous mixture was filtered through a celite pad. The organic phase was washed (water, saturated sodium chloride), dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using a methanol-dichloromethane gradient to yield the carboxylic acid. HNMR (300 MHz, CDCl3, partial): 6.14 (1H, m), 1.58 (9H, s), 0.92 (9H, s). LCMS m/z=407.9 [(C30H38O4+H)—C4H9]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][C:31]3[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=3)[C:24]=2[CH3:39])=[C:19]([CH3:40])[CH:18]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][C:31]3[CH:32]=[CH:33][C:34]([CH:35]=[O:36])=[CH:37][CH:38]=3)[C:24]=2[CH3:39])=[C:19]([CH3:40])[CH:18]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(O)ccc1-c1cccc(COc2ccc(C=O)cc2)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1cccc(COc2ccc(C=O)cc2)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride was dropwise added under ice-cooling to a mixture of 4-[(4′-hydroxy-2,2′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, pyridine and dichloromethane; followed by stirring at 0° C. for 1 hour to obtain 3′-[(4-formylphenoxy)methyl]-2,2′-dimethylbiphenyl-4-yl trifluoromethanesulfonate.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][C:28](=[O:30])[O:27][N:26]=2)=[C:21]([F:31])[CH:20]=1)C1C=CC=CC=1.B(Br)(Br)Br.ClCCl.CC(C)=O.C([O-])(O)=O.[Na+]>ClCCl.CO>[F:31][C:21]1[CH:20]=[C:19]([O:18][CH2:17][C:16]2[S:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:34][CH:33]=3)=[N:13][C:12]=2[CH2:11][CH2:10][CH2:9][OH:8])[CH:24]=[CH:23][C:22]=1[C:25]1[NH:29][C:28](=[O:30])[O:27][N:26]=1
Reactant: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCOCc3ccccc3)cc2F)no1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CO
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCO)cc2F)no1
Reaction time: 1 h

Procedure:
To a stirred solution of 100 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 3 mL of dichloromethane at −70° C. was added 0.34 mL of a 1M solution of boron tribromide in dichloromethane. After 1 h at −60° C., TLC monitoring (dichloromethane/acetone 8/2) showed remaining starting material so 1 mL of a 1M solution of boron tribromide in dichloromethane was added. After 10 min, the reaction mixture was poured into 30 mL of methanol and was neutralised with 5 mL of a saturated aqueous solution of NaHCO3. The suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up into dichloromethane then water added. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 60 mg of crude product. Purification by column chromatography on silica gel (dichloromethane 1/acetone 1) gave 13 mg of a first batch of the title compound (purity >95%) and 50 mg of a second batch of the title compound (purity >90%). The second batch was repurified by column chromatography on silica gel (dichloromethane 90/methanol 10). A total of 48 mg of 3-{2-fluoro-4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[C:19]([Cl:20])=[C:18]2[C:14]([CH2:15][CH2:16][NH:17]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[C:19]([Cl:20])=[C:18]2[C:14]([CH2:15][CH2:16][N:17]2[C:8](=[O:9])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: O=C=Nc1cccnc1
Reactant: Clc1ccc2c(c1Cl)NCC2
Product: O=C(Nc1cccnc1)N1CCc2ccc(Cl)c(Cl)c21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 6,7-dichloroindoline (D34) to give (E17) (0.84 g, 46%) m.p. 178°-180° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O1CCCC1>C(O)(=O)C>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1ccc(C#Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Oc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.2 %

Procedure:
4-(Phenylethynyl)phenyl acetate (60.6 g, 0.256 moles), 20 percent aqueous sodium hydroxide (400 mL), and tetrahydrofuran (400 mL) are added to a 2-L Erlenmeyer flask and stirred at room temperature for 5 hours. The mixture is acidified with glacial acetic acid (120 mL) until a pH of 7 is reached. The aqueous layer is removed and extracted with tetrahydrofuran. The organic layers are combined and concentrated on a rotovap to give a tan solid. The solid is heated with hexanes (700 mL) on a steam bath and the hot solution decanted from the solid. This is repeated with a second volume of hexanes (700 mL). A white solid crystallizes from the hexane solution upon cooling and is isolated by filtration and dried in vacuo to give 18 g of a white solid, mp 126° C. to 127° C. NMR analysis is consistent with the structure of the desired material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].CO.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(CC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1cccc(CC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]propionate (1.378 g, 3.309 mmol), sodium hydroxide (0.26 g, 6.62 mmol), methanol (10 ml), water (5 ml) and tetrahydrofuran (10 ml) was stirred overnight at room, temperature. The reaction solution was concentrated and diluted with water, acidified with 1N hydrochloric acid and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]propionic acid as a liquid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:41])(=[O:40])[NH:35]C(C)(C)C)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:41])(=[O:40])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step B) according to the procedure of Example 8, Step B, and was obtained as a pale yellow solid, mp >90° C. (gradual), homogeneous by TLC (19:1 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 542 (M+1)+.
Reaction SMILES: C([O:8][C:9]1[C:18]([Br:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][C:13]([O:20][CH:21]([CH3:23])[CH3:22])=[N:14]2)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(O)(=O)=O.C(O)(=O)C.O>[Br:19][C:18]1[C:9]([OH:8])=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([O:20][CH:21]([CH3:23])[CH3:22])[CH:12]=[C:11]2[C:24]([F:27])([F:26])[F:25]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c(OCc3ccccc3)c(Br)ccc2n1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(C(F)(F)F)c2c(O)c(Br)ccc2n1
Yield: 91.8 %

Procedure:
A solution of 5-benzyloxy-6-bromo-2-isopropoxy-4-(trifluoromethyl)quinoline (13.5 g, 30.8 mmol) in 31 mL methanesulfonic acid and 31 mL acetic acid was stirred at rt for 10 h, whereupon it was poured in water (500 mL), neutralized with K2CO3 (ca. 75 g) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (2%–5% EtOAc:hexanes, gradient elution) afforded 9.9 g (92%) of 6-bromo-5-hydroxy-2-isopropoxy-4-(trifluoromethyl)quinoline, a yellow-brown oil. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, 1H, J=9.1), 7.38 (d, 1H, J=9.1), 6.23 (s, 1H), 5.53 (sept, 1H, J=6.2), 1.41 (d, 6H, J=6.2).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(N(CC)CC)C>C(O)C>[OH:16][C:9]1[CH:10]=[CH:11][C:12]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)CC1
Reactant: CNc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(c1ccccc1)c1ccc(O)cc1
Yield: 32.2 %

Procedure:
1.07 g of N-methylaniline, 2.24 g of 1,4-cyclohexanedione and 1.4 ml of triethylamine were heated with stirring in 15 ml of ethanol at 50° C. to 60° C. and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and 0.64 g of N-(4-hydroxyphenyl)-N-methylaniline was obtained (yield 32.1%).