Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([NH2:8])=[C:6]([CH3:9])[NH:5][N:4]=1.[S-:10][C:11]#[N:12].[NH4+]>O>[CH3:2][C:3]1[C:7]([NH:8][C:11]([NH2:12])=[S:10])=[C:6]([CH3:9])[NH:5][N:4]=1
Reactant: N#C[S-]
Reactant: Cc1n[nH]c(C)c1N
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: Cc1n[nH]c(C)c1NC(N)=S
Yield: 77.6 %

Procedure:
19.0 grams (g) of 3,5-dimethyl-4-aminopyrazole hydrochloride and 19.7 g of ammonium thiocyanate are dissolved in 100 milliliters (ml) of water, and the resulting solution is heated at boiling under reflux for 6 hours. Then the solution is concentrated to about 50 ml and cooled. Thus-formed precipitate is separated by filtration, washed with a little water and dried to yield 17.0 g of 3,5-dimethyl-4-thioureidopyrazole, mp 209° to 211°.
Reaction SMILES: [N:1]1([C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:24]([Cl:25])[C:18]=2[N:17]=1>>[Cl:25][C:24]1[C:18]2[NH:17][C:16]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:6][CH2:5]3)=[N:20][C:19]=2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Reactant: OCc1cccnc1N1CCNCC1
Product: OCc1cccnc1N1CCN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CC1

Procedure:
The piperazine from step (a) above (97 mg, 0.5 mmol) reacted with 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole (85 mg, 0.33 mmol, Example 5b) under the conditions of Example 3c to give the title compound as a white solid. M.p. 252° C. MS (ESI, pos. ion) m/z: 412 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH2:14][OH:15])[C:11]=1[NH2:12].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](ON1C(=O)CCC1=O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[NH2:12][C:11]1[N:10]([CH2:13][CH2:14][OH:15])[N:9]=[CH:8][C:7]=1[NH:6][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22]
Reactant: Nc1cnn(CCO)c1N
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To a suspension of 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (1.20 g) and N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (1.35 g) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (2.1 ml) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with water (40 ml), saturated aqueous sodium hydrogen carbonate solution (40 ml) and brine (40 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with 10% methanol/chloroform to give 5-amino-4-[2-(tert-butoxycarbonylamino)acetyl]amino-1-(2-hydroxyethyl)pyrazole (1.20 g) as a solid.
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:27]([O:29]C)=[O:28])[CH2:5][CH2:4]1)=[O:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH:24]([CH3:25])[CH3:26])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:27]([OH:29])=[O:28])[CH2:5][CH2:4]1)=[O:2]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2N(C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100.1 %

Procedure:
In a mixture of THF and ethanol (1:1, v/v, 30.0 ml) was dissolved methyl 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (445 mg). To the solution was added 1N sodium hydroxide solution (11.0 ml), and the mixture was stirred at room temperature for 13 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (430 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:29])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](O)=[O:16])=[CH:11]2.Cl.C([N:33]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH3:29])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:33])=[O:16])=[CH:11]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (1.072 g) in N,N-dimethylformamide (15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.98 g) and 1-hydroxybenzotriazole ammonium salt (0.788 g) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. Water and ethyl acetate were added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed successively with brine and water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate: methanol=100:0 to 95:5, volume ratio) to give the title compound. (910 mg, 85%) as a white amorphous solid. MS 419 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:25])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]2[CH:22]=[N:23][NH:24][C:10]1=2.[ClH:26]>ClCCl>[ClH:26].[ClH:26].[CH3:8][C:9]1([CH3:25])[CH2:14][NH:13][CH2:12][C:11]2[CH:22]=[N:23][NH:24][C:10]1=2
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C(C)(C)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCc2cn[nH]c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 mL trifluoroacetic acid were added at 0° C. to 1.6 g (6.1 mmol) tert.butyl 7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate in 15 mL dichloromethane and stirred for 2 h at RT. The reaction mixture was evaporated down. The residue was taken up in ethanol and mixed with 12 mL (15 mmol) 1.25 M ethanolic HCl and then evaporated down. The residue was triturated with ethanol and the solid was separated off by suction filtering and dried.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:19][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[F:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C.C(OCC)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:1][CH2:2][C@@H:3]2[CH2:19][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[N:13]=[CH:14][C:15]([F:18])=[CH:16][N:17]=4)[CH2:11][C@@H:6]3[CH2:5][CH2:4]2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(F)cc1
Reactant: OC[C@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Fc1ccc(OC[C@H]2CC[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.1 %

Procedure:
A solution of 0.82 g (3.08 mmol) of (7S,9aS)-7-hydroxymethyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 13), 0.52 g (4.62 mmol) of 4-fluorophenol, 0.97 g (3.70 mmol) of triphenylphosphine in dry THF was treated with 0.64 g (3.70 mmol) of diethyl azodicarboxylate and stirred at room temperature for 72 h. The solvent was evaportated, the residue dissolved in 50:50 ethyl acetate:ethyl ether, and treated with HCl(g) in ethyl ether until precipitation ceased. The solid was collected by filtration, dissolved in chloroform, 1M sodium hydroxide was added, and the layers were separated. The organic layer was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 hexane:ethyl acetate gave 0.49 g (44%) of the title compound. mp (.HCl) 225–228° C. 13C NMR (base, CDCl3): δ 24.8, 25.2, 33.8, 44.3, 49.7, 54.8, 56.6, 61.0, 69.5, 115.48, 115.53, 115.59, 115.83, 144.97, 145.26, 149.85, 153.15, 155.42, 155.54, 158.69, 158.74. HRMS calcd for C19H22F2N4O: 360.1762, found: 360.1752.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:17]=2)[CH2:10][C:11](=[O:15])[CH:12]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][OH:31]>>[C:1]1([C:7]#[C:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:17]=2)[CH2:10][C:11](=[O:15])[CH2:12][O:31][CH3:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)C=[N+]=[N-])cc1OC1CCCC1
Reactant: CO
Product: COCC(=O)CC(C#Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.08 h
Yield: 4 %

Procedure:
(+/-)-1 -Phenyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-5-oxo-6-diazohexyne (120 mg, 0.35 mmol) was added portionwise to a refluxing solution of BF3 ·Et2O (0.5 ml) in MeOH (20 ml). After 5 min, the solvent was concentrated, the reaction diluted with H2O, basified with NaHCO3, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent removed. Purification by flash chromatography (silica gel, 30% Et2O in hexane) gave the titled product (4.8 mg, 4%). 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.30 (m, 3 H), 6.98 (m, 2 H), 6.84 (d, 1 H), 4.80 (m, 1 H), 4.40 (t, 1 H), 4.06 (d, 1 H), 3.92 (d, 1 H), 3.84 (s, 3 H), 3.38 (s, 3 H), 3.04 (d of d, 1 H), 2.88 (d of d, 1 H), 1.68-2.00 (m, 6 H), 1.58 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21][CH2:22]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:11][CH2:22][CH2:21][O:20][CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cc(C(=O)OC)ccc1N
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The reaction was repeated in two batches as follows. To a solution of Methyl3-hydroxy-4-aminobenzoate (135 mg, 0.81 mmol) in acetone (4 ml), in a microwave tube. Was added Potassium Carbonate (185 mg, 1.34 mmol) and Methoxyethyl bromide (115 μl, 1.22 mmol) The reaction was heated to 120° C. in a microwave and held for 1 hour. The reactions was cooled, treated with a further aliquot of methoxyethyl bromide (58 μl, 0.62 mmol) and re-heated to 120° C. holding for a further hour.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1C(=O)O[N:8]([C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:13])[CH:7]=1)=[O:5])[CH3:2]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[S:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=S)Oc2ccccc2)oc1=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc(Oc2ccccc2)s1
Yield: 90 %

Procedure:
5-Oxo-2-phenoxythiocarbonyl-2,5-dihydro-isoxazole-4-carboxylic acid ethyl ester described in Preparation Example 113 (500 mg, 2.01 mmol) was dissolved in acetone (500 mL), and the solution was irradiated with light (300 nm) for 30 minutes at room temperature. The reaction solution was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (384 mg, 1.54 mmol, 90%) was obtained as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:15]=1[C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH3:13]>>[CH2:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:15]=1[C:26]1[N:27]=[CH:28][N:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:30]=1)[CH3:13]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CCc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: CCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 33 %

Procedure:
As described for 1f, 1-fluoro-4-trifluoromethyl-benzene was converted, using 5-ethyl-3-(4-fluoro-phenyl)-4-(1H-imidazole-4-yl)-isoxazole (100 mg, 0.39 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-isoxazole was converted to the title compound (52 mg, 33%) which was obtained as an off-white solid. MS: m/e=402.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:19].S(O)(O)(=O)=O.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>CO>[CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[C:4]([CH:5]=[N:25][OH:26])[C:3]=1[OH:19]
Reactant: NO
Reactant: CCCCCCCCCc1cc(C)c(O)c(C=O)c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCc1cc(C)c(O)c(C=NO)c1
Yield: 178.9 %

Procedure:
3-Methyl-5-nonylsalicylaldehyde (1b) (570.8 g, 2.18 mol) was treated with hydroxylamine sulfate (197 g, 1.2 mol) and anhydrous sodium acetate (197 g, 2.40 mol) in methanol (1.5 L) at reflux for 16.5 h. Crude product in the solvent was filtered and concentrated to obtain 3-methyl-5-nonylsalicylaldoxime (595.45 g) in 98.6% yield.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[N:24]2[CH2:25][CH2:26][N:27]([C:9](=[O:11])[C@@H:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:28][CH2:29]2)=[CH:35][CH:34]=1
Reactant: CC(C)C[C@H](NC1CCCCC1)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC1CCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (0.556 g, 2.62 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.378 g, 1.31 mmol) in dry DMF (7 mL) was treated with Triton® B (2.40 mL, 5.28 mmol, 40 weight percent solution in methanol), a clear solution was obtained. The resulting reaction solution was cooled to 0° C. in an ice-water bath. To this solution was added solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.993 g, 2.62 mmol). After stirring at 0° C. for 30 minutes, the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether and 60 mL of saturated aqueous NaHCO3 solution. White solid which forms was removed by filtration. The two layers of the filtrate were separated; the organic layer was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (30% EtOAc in hexanes) affording 0.48 g (76%) of the pure titled compound as a white foam: mp 45-54° C. APCI-MS m/z 484.4 (MH+).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][CH:32]=[CH2:33])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si](C(C)(C)C)(C)C)[CH2:38]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][CH:32]=[CH2:33])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([OH:44])[CH2:38]2)=[CH:10]1
Reactant: C=CCc1ccccc1OC(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1ccccc1OC(CC)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 34.6 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.12 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-allylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 24, above] and 22.3 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.27 g of the title compound as white crystals, melting at between 143° and 145° C.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:48])[CH2:18][N:19]2[C:24](=[O:25])[CH:23]=[C:22]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:35][CH:34]=3)[C:20]2=[O:47])=[CH:13][CH:12]=1.[N:49]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:48])[CH2:18][N:19]2[C:24](=[O:25])[CH:23]=[C:22]([O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[NH:49][C:4](=[O:7])[O:5][N:46]=4)=[CH:35][CH:34]=3)[C:20]2=[O:47])=[CH:13][CH:12]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Reactant: COc1ccc(C(=O)Cn2c(=O)cc(OCC(F)(F)F)n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: COc1ccc(C(=O)Cn2c(=O)cc(OCC(F)(F)F)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2=O)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
A mixture of hydroxylammonium chloride (0.74 g), sodium hydrogencarbonate (1.08 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-6-(2,2,2-trifluoroethoxy)-3,4-dihydropyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.022 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.019 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.04 g, 6%).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 66.2 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (121.0 mg, 0.41 mmol), benzotriazol-1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (218.1 mg, 0.49 mmol), triethylamine (172 μL, 1.23 mmol), and 2-aminothiazole (45.3 mg, 0.45 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25° C. under nitrogen for 24 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution (1×100 mL), water (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 to 3/1 hexanes/ethyl acetate gradient elution) afforded 2-biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide (102.2 mg, 66%) as a white solid: mp 194-195° C.; EI-HRMS m/e calcd for C23H24N2OS (M+) 376.1609, found 376.1612.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=2)=[O:14])=[CH:6][C:5]=1[C:23]([F:26])([F:25])[F:24].CO.O.[OH-].[Li+]>O>[CH3:11][O:10][C:8]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=2)=[O:14])=[CH:6][C:5]([C:23]([F:26])([F:24])[F:25])=[C:4]([CH:9]=1)[C:3]([OH:27])=[O:2]
Reactant: COC(=O)c1cc(OC)c(NC(=O)Nc2cnc(C)cn2)cc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)c(C(F)(F)F)cc1NC(=O)Nc1cnc(C)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a stirred suspension of 5-methoxy-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-2-trifluoromethyl-benzoic acid methyl ester (257 mg, 0.67 mmol) in 6.7 mL 3:1 MeOH:H2O at room temperature under nitrogen was added lithium hydroxide monohydrate (281 mg, 6.7 mmol) and the mixture was heated to 85° C. After stirring overnight the reaction was cooled to room temperature, MeOH was removed by rotovap and the residual suspension was neutralized with concentrated HCl to pH of approximately 5. The suspension was filtered and rinsed with H2O and the filter cake dried under high vacuum to give the acid as a white solid (161 mg, 61%). 1H-NMR (400 MHz, d6-DMSO) δ 8.90 (br s, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.38 (s, 1H), 4.00 (s, 3H), 2.42 (s, 3H). LRMS (esi, negative) m/e 369.0 (M−1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([C:20]3[C:21]([C:27]([F:30])([F:29])[F:28])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)[N:17]=[N:18][CH:19]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([C:20]3[C:21]([C:27]([F:28])([F:30])[F:29])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)[N:17]=[N:18][CH:19]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(-c2cnnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2cnnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc(O)c1O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
3-(5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine 1-oxide (1.27 g, 3 mmol) was taken up in dichloromethane (25 mL). The yellowish solution was cooled to −78° C. under argon and boron tribromide (2.55 mL, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then carefully poured into ice-water (100 mL) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. The solid was recrystallised from dichloromethane-ethanol to give 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine 1-oxide as a yellow solid, 0.84 g (71%).