Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH2:43]C)[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:45]([P:54](=[O:61])([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:59]([O:58][P:54](/[CH:45]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)([O:55][CH2:56][CH3:57])=[O:61])[CH3:60]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OCC)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)c1
Reaction time: 3 h
Yield: 77 %

Procedure:
To a mixture of ethyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-ethoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (2.0 g), tetraethyl methylenediphosphonate (1.07 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.16 g) at room temperature, and the mixture was stirred at the same temperature for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, v/v) (1.87 g, yield 77%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([C:34]([O:36]C)=[O:35])=[O:33])=[CH:22][CH:21]=2)[C:7]([C:14]([O:16]CC)=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2].O.[OH-].[Li+]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([C:34]([OH:36])=[O:35])=[O:33])=[CH:22][CH:21]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Yield: 67.8 %

Procedure:
680 mg of ethyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]imidazole-5-carboxylate [prepared as described in step (a) above] were subjected to hydrolysis using 224 mg of lithium hydroxide monohydrate in the same manner as described in Example 1(b), to give 423 mg of the title compound as a powder, melting at 138°-140° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].Cl.[CH3:51][O:52][N:53]=[C:54]1[CH2:58][CH2:57][N:56]([C:59](=[NH:62])[CH2:60][SH:61])[CH2:55]1>C(#N)C.CS(C)=O.O1CCCC1.O.P([O-])([O-])([O-])=O.[C].[Pd].CCOCC>[CH3:51][O:52][N:53]=[C:54]1[CH2:58][CH2:57][N:56]([C:59](=[NH:62])[CH2:60][S:61][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([OH:37])=[O:36])[CH2:55]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CON=C1CCN(C(=N)CS)C1
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CON=C1CCN(C(=N)CSC2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
0.21 ml of diisopropylethylamine and 0.22 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 363 mg of p-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 5 ml of anhydrous acetonitrile, and the mixture was stirred for one hour with ice-cooling. A solution of 0.18 ml of diisopropylethylamine and 307 mg of 2-(3-methoxyiminopyrrolidin-1-yl)-2-iminoethylmercaptan hydrochloride in 3 ml of dimethylsulfoxide was then added dropwise, and the mixture was stirred for a further 20 minutes with ice-cooling. The reaction mixture was poured into 100 ml of anhydrous ether, and the solvent was decanted off from the gummy material which formed. This material was dissolved in a mixture of 20 ml of tetrahydrofuran, 7 ml of water and 23 ml of 0.1M phosphate buffer (pH 7.0), and the solution was subjected to catalytic hydrogenation at room temperature for 2 hours in the presence of 0.3 g of 10% palladium-carbon. The product was worked up and purified in the same manner as in Example 2, giving 23 mg of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N:13]([CH2:18][CH3:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][N:10]2[N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]([C:23](=[O:26])[NH:24][CH3:25])=[C:9]2[CH:8]=1)(=O)=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1([NH:45][C:46](=[O:62])[C:47]2[CH:52]=[CH:51][CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)[CH2:44][CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[CH2:18]([N:13]([C:12]1[C:7]([C:51]2[CH:50]=[CH:49][CH:48]=[C:47]([C:46](=[O:62])[NH:45][C:42]3([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:43][CH2:44]3)[CH:52]=2)=[CH:8][C:9]2[N:10]([N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]=2[C:23]([NH:24][CH3:25])=[O:26])[CH:11]=1)[S:14]([CH3:17])(=[O:15])=[O:16])[CH3:19]
Reactant: CC1(C)OB(c2cccc(C(=O)NC3(c4ccccn4)CC3)c2)OC1(C)C
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OS(=O)(=O)C(F)(F)F)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)NC2(c3ccccn3)CC2)c1)S(C)(=O)=O

Procedure:
6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.1 g, 0.17 mmol, 1 eq), N-(1-(pyridin-2-yl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.0.65 g, 0.18 mmol, 1.1 eq), tetrakistriphenylphosphine palladium (0.0058 g, 0.0051 mmol, 0.03 eq) and cesium carbonate (0.165 g, 0.51 mmol, 3 eq) were dissolved in 1,4-dioxane (10 ml) and water (2 ml) and the reaction was heated at 90° C. for 14 hours. The solution was filtered through celiete. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield: 22 mg (26%) 1HNMR (400 MHz, CD3OD): δ 1.05 (t, J=8 Hz, 3H), 1.65-1.66 (m, 2H), 1.78-1.82 (m, 2H), 2.89 (s, 3H), 3.20 (s, 3H), 3.62 (br s, 2H), 7.28-7.30 (t, J=7.76 Hz, 2H), 7.57 (br s, 1H), 7.67 (t, J=7.72 Hz, 1H), 7.75 (d, J=8.20 Hz, 1H), 7.86-7.88 (m, 3H), 7.96 (s, 1H), 8.02 (d, J=2.09 Hz, 1H), 8.18 (br, 1H), 8.23 (s, 1H), 8.55 (d, J=5.32 Hz, 1H), 8.98 (s, 1H). LCMS: (ES+) m/z=627.2 (M+H); Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH; Flow: 1 mL/Min; RT min: 1.768;
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]1[C:53]2[C:54]([O:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=3)=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][O:50]1>CN(C)C=O>[CH3:48][CH:49]1[C:53]2[C:54]([O:58][C:59]3[N:64]=[CH:63][C:62]([NH:65][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:61][CH:60]=3)=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][O:50]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1OCc2cccc(Oc3ccc(N)cn3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2C(C)OC3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 8 ml vial (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (32.2 mg, 0.158 mmol) was dissolved in N,N-dimethylformamide (0.5 ml) to give a colourless solution. DIPEA (0.035 ml, 0.198 mmol) and HATU (60.3 mg, 0.158 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. 6-[(3-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinamine (Intermediate 100, 32 mg) was dissolved in 1.5 ml of DMF and the obtained solution was added to the reaction mixture. It was shaken at 60° C. After 2 hours, no reaction occurred. Additional 0.5 ml of a solution [obtained dissolving in 0.5 ml of DMF (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (32.2 mg, 0.158 mmol), DIPEA (0.035 mL, 0.198 mmol) and HATU (60.3 mg, 0.158 mmol)] was added to the reaction mixture. It was shaken at 60° C. over weekend. After that time, only traces of the title compound along with the Intermediate 100 was detected. The reaction mixture was evaporated under vacuum using the Vaportec V10 to give the crude product which was purified by silica gel chromatography (Biotage SP1 system, 10 g-SNAP Silica column) with Cyclohexane/EtOAc as eluents (from 3/1 to 1/1 in 10 CV; then 1/1 for 10 CV). The collected fractions afforded 4.9 mg of the title compound mixed with the amino acid and 61 mg of a mixture of starting material (Intermediate 100) and the amino acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].CN(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].[CH2:35]([N:37]([CH2:42][CH3:43])[C:38](=[O:41])[CH2:39]Cl)[CH3:36]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:39][C:38](=[O:41])[N:37]([CH2:42][CH3:43])[CH2:35][CH3:36])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CC(=O)N(CC)CC
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 15.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 250 ml. of hexamethylphosphoric acid triamide is treated under nitrogen at 5° C. with 0.055 mol of sodium hydride (2.5 g. of a 55% dispersion in mineral oil) and then stirred at the same temperature for 15 minutes. At 5°-10° C. a solution of 15 g. of N,N-diethylchloroacetamide in 40 ml. of ethanol is added thereto and the mixture stirred for 30 minutes at room temperature and subsequently heated for 4 hours at 80° C. The mixture is cooled and poured into 2.5 liters of ice-water. After the addition of 150 g. of sodium chloride, the separated product is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulfate, filtered and evaporated to dryness. The residue is triturated with 100 ml. of ether, the unreacted starting material crystallizes out. The latter is removed by filtration under vacuum and washed with ether. The ethereal filtrate is evaporated to dryness. The oily residue is cooled and triturated with ether, crystals being obtained. Recrystallization from ethanol yields 5-chloro-2-[(diethylcarbamoyl)methyl]-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 118°-120° C.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[C:7]([C:8](O)=[O:9])=[CH:6][NH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:24]1([C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH:24]1([C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[NH:32][C:8]([C:7]2[C:3]([CH:2]([F:11])[F:1])=[N:4][NH:5][CH:6]=2)=[O:9])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Nc1ccccc1C1CCCCC1
Reactant: O=C(O)c1c[nH]nc1C(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1C1CCCCC1)c1c[nH]nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (2.0 g) and 1,1'-carbonyldiimidazole (2.0 g) were mixed in THF (20mL, anhydrous) and stirred for 1 h. 2-Cyclohexylaniline (2.2 g) was added, and the contents were heated at reflux for 2 h. After cooling to RT, the contents were concentrated in vacuo leaving a foam (3.7 g). The foam was chromatographed on silica gel (Waters Prep 500) eluting with EtOAc and hexanes to give the desired amide as a white foam (750 mg). The foam was crystallized from EtOAc /pentane to give the product as a white solid (510 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(OCC)(=O)C>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc(NC(C)=O)cc1
Yield: 84.7 %

Procedure:
To 10 g (0.0517 mole) of ethyl 2-(4-aminophenyl)propionate was added 50 ml of ethyl acetate with stirring, and to this solution, a mixed solution of 5.81 g of acetic anhydride and 10 ml of ethyl acetate was added dropwise and was stirred for 3 hours. After completion of the reaction, the reaction mixture was washed with a saturated solution of sodium bicarbonate and with a saturated solution of sodium chloride. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the ethyl acetate was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 10.3 g of ethyl 2-(4-acetylaminophenyl)propionate (Yield: 85%). M.P. 94.5°-95.5° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.[F:23][C:24]1[C:25](B(O)O)=[CH:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.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>[F:23][C:24]1[C:25]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Reactant: COc1cc(B(O)O)c(F)cn1
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: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 92.9 %

Procedure:
To a stirred solution of 66.13B (1.00 g, 2.9 mmol) in DMF (12 mL) at 23° C. was added 5-fluoro-2-methoxypyridin-4-ylboronic acid (0.75 g, 4.4 mmol) (commercially available from Asymchem), potassium carbonate (1.2 g, 8.8 mmol), followed by tetrakis(triphenylphosphine)palladium (0.24 g, 0.20 mmol). The mixture was heated to 90° C. The reaction mixture was then stirred for 17 hours and then cooled to room temperature. The reaction was diluted with brine and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-30% EtOAc in hexanes) to yield 83.21A as a colorless solid (0.860 g, 92% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([N:15]=[C:16]([NH2:26])[NH:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([O:24]C)=[O:23])[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+:34]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([N:15]=[C:16]([NH2:26])[NH:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([O-:24])=[O:23])[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+:34]
Reactant: COC(=O)COCCNC(N)=Nc1cc(C(C)c2ccc(-c3ccccc3)c(F)c2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(N=C(N)NCCOCC(=O)[O-])on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (4.32 g) obtained in Example 48 was dissolved in tetrahydrofuran (80 ml) and a 5% aqueous sodium hydroxide solution (80 ml) was added, after which the solution was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and then filtered, after which the solid materials were washed with ethyl acetate and water. The filtrate was concentrated and thereafter the solid materials were again separated by filtration and then washed with ethyl acetate and water. The combined crude crystals were purified by a recrystallization method from water to obtain the desired compound (3.08 g).
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1>>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([O:7][CH:17]([F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)c(Cl)c1
Product: CC(C)C(C(=O)OC(F)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared from α-isopropyl-(3,4-dichlorophenyl)acetic acid and α-fluoro-3-phenoxybenzyl bromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δ ppm (solvent CDCl3): 0.76(3H, d, J=6Hz, CH3); 1.07(3H, d of d, J=6Hz and J=2Hz, CH3); 2.33(1H, m, --CH(CH3)2); 3.28(1H, d, J=10Hz, CH); 7.24(1H, d of d, J=56Hz and J=2Hz, CHF) and about 7.33(12H, m, aromatic protons).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:34])=[O:3])=[CH:10][C:11]=1[O:19][CH2:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(OC(C)(C)C(=O)O)cc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 55 °C
Yield: 88.6 %

Procedure:
A solution of 2-{4-butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (0.12 g, 0.258 mmol) in ethanol (3 mL) was treated with 2 N aqueous NaOH (0.64 mL), and heated at 55° C. for 8 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with EtOAc (25 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give a white solid (0.10 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.99-7.97 (m, 2H), 7.00 (d, J=7.8 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 6.49 (dd, J=8.3, 2.0 Hz, 1H), 4.23 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.59 (s, 6H), 1.50 (quintet, J=7.8 Hz, 2H), 1.32 (sextet, J=7.5 Hz, 2H), 0.90 (t, J=7.3 Hz, 3H), MS (ES) m/e 438 (M+1).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]3([F:26])[F:25])[CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>C(Cl)Cl.S(=O)(=O)(O)O>[F:26][C:19]1([F:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:18]1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: FC1(F)CCCCCC1n1cnc2ccc(OCc3ccccc3)nc21
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Oc1ccc2ncn(C3CCCCCC3(F)F)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(Benzyloxy)-3-(2,2-difluorocycloheptyl)-3H-imidazo[4,5-b]pyridine was dissolved in DCM and diluted with excess sulfuric acid. The resulting solution was stirred overnight at room temperature then acidified with the addition of 1 M aqueous hydrochloric acid. The solvent was removed from the organic layer and the residue was purified via preparative HPLC to give the title compound. LCMS m/z=267.9 [M+H]+.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])[CH:12]=2)[C:3]([O:5]C)=O.[NH2:30][C:31]([NH2:33])=[S:32].C([O-])(=O)C.[Na+]>C(O)C>[NH:30]=[C:31]1[NH:33][C:3](=[O:5])[CH:2]([CH2:7][C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:27])([F:28])[F:29])[CH:12]=3)[S:32]1
Reactant: COC(=O)C(Br)Cc1cnc2cc(OCc3ccccc3C(F)(F)F)ccc2c1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C1NC(=O)C(Cc2cnc3cc(OCc4ccccc4C(F)(F)F)ccc3c2)S1

Procedure:
In ethanol (10 mL) was dissolved the crude residue (720 mg) of methyl 2-bromo-3-[7-(2-trifluoromethylbenzyloxy)-3-quinolyl]propionate. The solution was heated under reflux for 5 hours after addition of thiourea (117 mg, 1.53 mmol.) and sodium acetate (126 mg, 1.53 mmol.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
Oxalyl chloride (1.72 ml) and dry dimethylformamide (2 drops) were added to a stirred suspension of 4'-benzyloxy-4-biphenylcarboxylic acid (3.04 g) in dry dichloromethane (100 ml). The reaction mixture was stirred for 12 hours at ambient temperature. The mixture was evaporated to dryness. Triphenylphosphine (5.2 g) and bis(triphenylphosphine) copper [I] tetrahydroborate (6.0 g) was added to a solution of the crude product in acetone (150 ml). The mixture was stirred at ambient temperature for 2 hours. The mixture was filtered and the filtrate evaporated. The residue was purified by medium pressure chromatography on silica gel using a mixture of 20% dichloromethane/hexane to remove less polar impurities, followed by ethyl acetate as eluant to give 4'-benzyloxy-4-biphenylcarboxaldehyde as a colourless solid (41% yield), m.p. 122°-123° C., NMR (CDCl3): 5.1 (2H, s), 7.1 (2H, d), 7.4-7.6 (7H, m), 7.7-7.9 (4H, d of d), and 10.0 (1H, s); m/z 289 (M+H).