Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19](CC=C)([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C[N+]1([O-])CC[O:39]CC1.CCOC(C)=O.[CH3:49][C:50]([CH3:52])=[O:51].O>>[OH:51][CH:50]([CH2:52][OH:39])[CH2:49][C@@:19]1([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:11][CH:12]=2)[N:20]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@@]1(C(=O)OC)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Reactant: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@]1(CC(O)CO)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Reaction time: 7.5 h

Procedure:
The reaction was performed on the two separated batches of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(2-propen-1-yl)-1,2-pyrrolidinedicarboxylate obtained from the previous step (D35). The first batch (119.8 g) was dissolved in a mixture of 10/1 acetone/water (1200 mL). K2OsO4.2H2O (4.7 g) was added followed by NMO (41.4 g) after a few minutes. The mixture was stirred for 7.5 hours. The reaction mixture was treated with EtOAc (1200 mL) and washed with saturated NH4Cl (1200 mL) then with saturated NaHCO3 (1200 mL). The organic layer was filtered through a celite/activated charcoal pad and concentrated to low volume. EtOAc (500 mL) was added and the solution was washed with brine (300 mL) and the organic dried over Na2SO4, and evaporated to dryness, EtOAc (300 mL) was added and filtered through CUNO filter and washed with EtOAc (50 mL). The organic was concentrated to dryness to afford the title compound (135 g). The second batch (179 g) was dissolved in a mixture of 10/1 acetone/water (1800 mL). K2OsO4.2H2O (5.5 g) was added followed by NMO (56.8 g) after a few minutes. The mixture was stirred overnight at room temperature. The reaction mixture was treated with EtOAc (900 mL) and washed with saturated NH4Cl (2×900 mL) then with saturated NaHCO3 (900 mL). The organic layer was filtered through a celite pad and concentrated to low volume to afford the title compound (250 g). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.54 (m, 1H); 7.40 (m, 3H); 7.22 (m, 2H); 6.95 (m, 2H); 5.11 (m, 2H); 4.95-4.25 (m, 3H); 3.70 (bm, 3H); 3.50-3.10 (m, 3H); 2.50-1.50 (m, 6H); 1.30-0.95 (4bs, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH2:8][C:9]([CH:13]=[O:14])=[CH:10][NH:11][CH:12]=1.[S]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=[N:11][CH:12]=1
Reactant: CN1CCC[C@H]1C1=CNC=C(C=O)C1
Agent: [S]
Solvent: Cc1ccccc1
Product: CN1CCCC1c1cncc(C=O)c1
Yield: 83.6 %

Procedure:
A solution of (S)-5-(1-methylpyrrolidin-2-yl)-1,4-dihydropyridine-3-carbaldehyde IV (0.011 g, 0.044 mmol) and elemental sulfur (0.0015 g, 0.044 mmol) in 2 mL of toluene was refluxed for 1 day. After filtration through a pad of Celite, and evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (silica gel, 5% EtOAc/hexanes then EtOAc) to afford 0.007 g (83%) of 5-(1-methylpyrrolidin-2-yl)pyridine-3-carbaldehyde V as a clear oil. IR (thin film, neat, NaCl): 2950, 1586, 1370, 1120 cm−1. 1H NMR (CDCl3, 300 MHz) δ 10.13-10.12 (m, 1 H), 8.97-8.96 (m, 1 H), 8.79 (s, 1 H), 8.18 (s, 1 H), 3.30-3.20 (m, 2 H), 2.38-1.67 (m, 4 H); 13C NMR (CDCl3, 100 MHz) δ 191.26, 154.81, 150.91, 135.13, 131.69, 68.53, 57.19, 40.64, 40.64, 35.66, 23.02. HRMS Calcd for C11H14N2O: 191.1184 [M+H]+. Found: 191.1182 [M+H]+. [α]23D −92 (c=0.2, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[N:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Si:13]([O:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([CH3:1])=[N:3][C:4]=2[CH:10]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nc2cc(CO)ccc2[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a DMF solution (10 mL) of (2-methyl-1H-benzimidazol-5-yl)methanol (811 mg) were added tert-butyldimethylsilyl chloride (904 mg) and imidazole (680 mg), followed by 2 hours of stirring at room temperature. The reaction solution was concentrated, water was added thereto, the mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain 5-(tert-butyldimethylsilyloxymethyl)-2-methyl-1H-benzimidazole (1305 mg, 94%).
Reaction SMILES: [NH3:1].[Na].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[O:11][CH3:12]>CCCCCC.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:1])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: N
Reactant: COc1cc(Cl)ccc1Cl
Agent: [Fe+3]
Agent: O=[N+]([O-])[O-]
Agent: [Na]
Solvent: O
Solvent: CCCCCC
Product: COc1cc(N)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
900 mL of ammonia was condensed at −78° C. 1 g of thinly shaven strips of sodium was added followed by 1.0 g of iron (III) nitrate nonahydrate. Upon disappearance of the deep blue color 25 g of thinly shaven strips of sodium was added. After 30 mins of stirring at −78° C., 50 g of 2,5-dichloroanisole was added as a solution in hexane (70 mL) dropwise and the reaction warmed to −45° C. for 2 hrs. Upon completion the ammonia was allowed to evaporate. The crude pot was then diluted in chloroform and 100 g of NH4Cl was added slowly. The combines were taken up in a separatory funnel and washed with water (3×) followed by brine (1×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid can be used without further purification. Yield: 99%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:16])[CH:6]=1)=[O:4].CO.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[N:20]1[CH:21]=[CH:22][C:17]([C:15]([NH:14][CH2:13][CH2:12][N:7]2[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]2)=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(=O)n(CCNC(=O)c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(=O)n(CCNC(=O)c2ccncc2)c1

Procedure:
1,6-dihydro-1-[2-(4-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.600 g, 2.0 mmol) was hydrolysed in a mixture consisting of methanol (4.0 ml), water (0.7 ml), and 15% aqueous sodium carbonate (6.0 ml) at 75°-80° C. for 1.25 hours. The solution was acidified (to pH 5.5 with acetic acid). The precipitated product was recovered by filtration, washed with water, and dried, MP: >300° C.
Reaction SMILES: [N+]([O-])(O)=O.[O:5]1[CH:10]=[CH:9][CH:8]=[C:7](O)[BH:6]1.C(#N)C.[C:15](=[O:17])=O.[N+:18]([C:21]1[CH:26]=CC=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[CH3:10][CH:9]1[CH2:15][O:17][B:6]([OH:5])[C:7]2[CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=[CH:23][C:8]1=2
Reactant: O=C=O
Reactant: O=[N+]([O-])c1ccccc1
Reactant: OC1=CC=COB1
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: CC1COB(O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a 100 ml round bottom flask, the fuming nitric acid was cooled to −45° C. using a dry ice/acetonitrile bath. 3.2054 g (10.2330 mmol, 1.0 eq) of the oxaborininol was dissolved in 2.5 mL of nitrobenzene. This solution was then added dropwise to the stirred and cooled nitric acid over a period of approximately 15 minutes. The reaction was allowed to stir for 45 minutes, recharging the acetonitrile and dry ice as needed. After 45 minutes, the reaction solution was poured over approximately 250 mL of wet ice. The mixture/suspension was allowed to warm to room temperature, stirring as it warmed (approximately 90 minutes). The aqueous mixture was then extracted with DCM (2×50 mL). The layers were separated and the organic layers were combined and washed with water to remove excess nitric acid (2×100 mL) until pH paper showed the water retained a neutral pH. The organic solution was then dried over MgSO4, filtered under vacuum, and then the solvent was removed under reduced pressure. The resultant yellow oil was then treated slowly with heptane, swirling as the solvent was added, until a yellow-white solid crashed out. The solid was then collected by filtration and washed with additional ice-cooled heptane. A yellow powder was isolated. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.47 (m, 4H) 3.14 (dd, J=10.98, 5.86 Hz, 1H) 3.88 (dt, J=11.21, 5.79 Hz, 1H) 4.13 (dd, J=11.03, 4.00 Hz, 1H) 7.57 (d, J=8.44 Hz, 1H) 8.27 (dd, J=8.42, 2.56 Hz, 1H) 8.48 (d, J=2.49 Hz, 1H) 8.95 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[Cl-].[NH4+]>CO.[Fe]>[C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC1(c2ccc([N+](=O)[O-])cc2)CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC1(c2ccc(N)cc2)CCCC1
Yield: 69.9 %

Procedure:
A stirred solution of [1-(4-nitro-phenyl)-cyclopentyl]-acetic acid tert-butyl ester [1.0 g, Reference Example 6(a)] in methanol (40 mL) was treated with water (40 mL), ammonium chloride (0.87 g) and iron powder (325 mesh, 0.55 g). The mixture was stirred at gentle reflux for 2.5 hours and then the hot mixture was filtered through hyflo. The filter pad was washed well with methanol. The combined filtrate and washings was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and then evaporated to give the title compound (0.63 g) as a golden oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C@H:12]([OH:15])[CH2:13][OH:14].N1C=CC=CC=1.[C:22](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:22]([O:14][CH2:13][C@H:12]([C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[OH:15])(=[O:23])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
To a suspension of (S)-1-(2-Bromo-6-methyl-4-nitrophenyl)ethane-1,2-diol (17.0 g, 61.6 mmol) in DCM (435 mL) at 0° C. was added pyridine (18.6 g, 235.4 mmol) and PivCl (13.4 g, 110.8 mmol) slowly. After stirring at 0° C. for 5 min, the system was raised to room temperature and stirred at this temperature for 5 h. TLC showed the reaction was complete. The reaction mixture was treated with saturated aqueous NaHCO3 (500 mL), and the resulting system was extracted with DCM (2×200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated in vacuum, and purified by silica gel column (Petroleum Ether:EtOAc (30:1)) to afford (S)-2-(2-Bromo-6-methyl-4-nitrophenyl)-2-hydroxyethyl pivalate (17 g, 77%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.28 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 5.70-5.66 (m, 1H), 4.58-4.53 (m, 1H), 4.31-4.26 (m, 1H), 2.84 (d, J=5.6 Hz), 2.68 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:33]2[C:28]([Cl:27])=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: OB(O)c1cccnc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cccnc2Cl)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-chloro-3-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=43%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:16][O:17][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: C[O-]
Reactant: Cc1nc2ccc(Cl)nn2c1S(N)(=O)=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(C)c(S(N)(=O)=O)n2n1
Yield: 99.7 %

Procedure:
To a solution of 4.9 g of 6-chloro-2-methylimidazo [1,2-b]pyridazine-3-sulfonamide in 50 ml of methanol is added 2.2 g of sodium methylate, followed by refluxing for 4 hours. Methanol is distilled off and the residue after addition of water is neutralized with hydrochloric acid. The precipitated crystals are collected by filtration and dried to give 4.8 g of the title compound. mp. 251° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH:25]C(=O)CCl)[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31].CSC(=S)N.[Na]>O>[C:1]([O:4][C@@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1OC(C)=O)c1csc(N)n1
Yield: 56 %

Procedure:
To a solution of 0.101 g of sodium (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate (anti-isomer) in 4 ml of water is added 29 mg of sodium monomethyldithiocarbamate under ice-cooling with stirring, and the mixture is stirred at room temperature for one hour. The insolubles are filtered off and the filtrate is purified on a column of XAD-II (Rohm and Haas Co.). The above procedure yields 48 mg of sodium (3S,4S)-4-acetoxy-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate (anti-isomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]1[C:17]([OH:18])=[C:16]([C:19](OCC)=[O:20])[C:15](=[O:24])[N:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]1=[O:32].C1(CNC([CH:43](C(OCC)=O)[C:44]([O:46]CC)=[O:45])=O)C=CC=CC=1.[H-].[Na+].COC1C=C(OC)C=CC=1C[N:61]=C=O.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]1[C:17]([OH:18])=[C:16]([C:19]([NH:61][CH2:43][C:44]([OH:46])=[O:45])=[O:20])[C:15](=[O:24])[N:14]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:13]1=[O:32]
Reactant: CCOC(=O)c1c(O)n(Cc2ccc(OC)cc2OC)c(=O)n(Cc2ccccc2)c1=O
Reactant: COc1ccc(CN=C=O)c(OC)c1
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc3ccccc3)c2=O)c(OC)c1
Reaction time: 0.17 h
Yield: 39 %

Procedure:
Ethyl 1-{[2,4-bis(methyloxy)phenyl]methyl}-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate. Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (820 mg, 2.8 mmoles) was added to a suspension of sodium hydride (60% suspension in mineral oil, 280 mg, 7.0 mmoles) in dry tetrahydrofuran (50 mL) and stirred for 10 minutes under argon. 2,4-dimethoxybenzyl isocyanate (1.0 mL, 6.0 mmoles) was added and the mixture heated under reflux for 3 hours, cooled, acidified with 1 molar hydrochloric acid and extracted with ethyl acetate. Flash chromatography (30% methanol in dichloromethane) afforded the title compound (480 mg, 39%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=6.69 Hz, 3 H) 3.71 (s, 3 H) 3.78 (s, 3 H) 4.09 (q, J=5.05 Hz, 1 H) 4.81 (s, 2 H) 4.92 (s, 2 H) 6.40-6.59 (m, 3 H) 6.62-7.26 (m, 5 H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1>O.C(O)C.C(N(CC)CC)C>[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: O=C(O)CCS
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(CSCCC(=O)O)cc1

Procedure:
A solution of betamercaptopropionic acid (5.3 g, 50 mMol) in water (95 ml) was diluted with absolute ethanol (80 ml) and triethylamine (15 ml). While this solution was mechanically stirred and cooled with an ice bath, a solution of 4-methylbenzyl bromide (9.4 g) in ethanol (80 ml) was added over a period of 15 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. The mixture was then concentrated in vacuo and the residue was suspended in water (100 ml). As the pH of the suspension was adjusted to 10, the residue dissolved. The resulting solution was extracted three times with di-ethyl ether and the aqueous phase was acidified to pH 1 with concentrated HCl. An oily residue separated. The mixture was then exhaustively extracted with di-ethyl ether, the ether extracted was dried over MgSO4 and concentrated to an oil. The latter solidified on standing and the solid residue was recrystallized from ethyl acetate-liquid petroleum. The yield was 7.9 g (75%), m.p. 75.8° C., NMR (CDCl3) 11.5 (s, 1H), 7.09 (q, 4H), 3.67 (s, 2H), 2.60 (m, 4H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3](=[O:27])[CH2:4][O:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[NH:8][N:7]=1.F[C:31]1C=CC(C2C(OCC(=O)C(C)(C)C)=NNC=2C)=C[CH:32]=1>O>[CH2:31]([N:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([O:5][CH2:4][C:3](=[O:27])[C:2]([CH3:29])([CH3:28])[CH3:1])=[N:7]1)[CH3:32]
Reactant: CC(C)(C)C(=O)COc1n[nH]c(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccccc1
Reactant: Cc1[nH]nc(OCC(=O)C(C)(C)C)c1-c1ccc(F)cc1
Solvent: O
Product: CCn1nc(OCC(=O)C(C)(C)C)c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1

Procedure:
The desired compound was prepared according to the method of Example 27, substituting 3,3-dimethyl-1-[(5-(4-(methylsulphonyl)phenyl)-4-phenyl-1H-pyrazol-3-yl)oxy]butan-2-one, prepared according to the method of Example 32B, in place of 1-[(4-(4-fluorophenyl)-5-methyl-1H-pyrazol-3-yl)oxy]-3,3-dimethylbutan-2-one (yield: 145 mg, 94%). MP 158-161° C.; MS (APCI+) m/z 441 (M+H)+; (APCI−) m/z 475 (M+Cl)−; 1H NMR (300 MHz, DMSO-d6) δ1.20 (m, 12H), 3.30 (s, 3H), 3.80 (q, J=7 Hz, 2H), 5.25 (s, 2H), 7.19 (m, 5H), 7.62 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H); Anal. calc. for C24H28N2O4S.0.25 H2O: C, 64.76; H, 6.45; N, 6.29. Found: C, 64.72; H, 6.60; N, 6.13.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(OCC)(=O)C>[C:13]1([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1N
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Nc1ccccc1
Temperature: 180 °C
Yield: 90 %

Procedure:
A mixture of methyl 2-aminobenzoate (7 g), iodobenzene (3.9 ml), potassium carbonate (6.4 g), and copper powder (0.46 g) was heated at 180° C. for 17 hours. The reaction solution was allowed to cool to room temperature, and ethyl acetate was added thereto. The resulting mixture was stirred and filtered with celite. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The thus-obtained residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: hexane=1:30) to obtain methyl 2-phenylaminobenzoate (7.13 g; yield, 90%) as a pale yellow solid.
Reaction SMILES: C[Si](C)(C)Cl.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].Cl>C(OC(C)C)(=O)C.[Zn]>[OH:13][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: COC(=O)CC(O)c1ccccc1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 5.7 g of zinc powder (87 mmol) in 35 ml of isopropyl acetate. After 1.65 ml of trimethylchlorosilane (13 mmol) had been added, the mixture was heated at 65° C. for 30 min. Following cooling to 60° C., 6.2 g of benzaldehyde (58 mmol) were added and, over the course of 4 min, 10.6 g of methyl bromoacetate (70 mmol) were added dropwise at 55° C., the temperature being maintained at 55° C. by external cooling. The mixture was then stirred at 55° C. for 5 min and, after cooling to 0° C., acidified with 40 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration and the organic phase separated. The organic phase was then stirred at 0° C. with 40 ml of 0.5 N hydrochloric acid and finally washed with 20 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was distilled off under reduced pressure. Methyl 3-hydroxy-3-phenylpropionate was obtained in a yield of 8.9 g (85% of theory) with a boiling point of 76° C. (0.07 mbar).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][N:8]([CH3:11])C=O.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([CH3:27])=[C:25]([C:28]([OH:30])=O)[CH:24]=[N:23]2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([CH3:27])=[C:25]([C:28]([NH:22][C:26]3[CH:7]=[N:8][C:11]([CH:16]4[CH2:21][CH2:20][C:19]5([O:5][CH2:1][CH2:2][O:3]5)[CH2:18][CH2:17]4)=[CH:24][CH:25]=3)=[O:30])[CH:24]=[N:23]2)=[CH:18][CH:17]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(C)(C)C)cc1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(C3CCC4(CC3)OCCO4)nc2)cnn1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.25 ml) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to a solution of 1-(4-tert-butylphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (222 mg) described in Reference Example 17 in dichloromethane (5 ml) and stirred at room temperature for two hours. The solvent and an excess amount of oxalyl chloride were evaporated. Toluene (5 ml) was added to the resulting reaction mixture, a solution of 6-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine-3-amine (185 mg) described in Reference Example 102 in pyridine (4 ml) was added under ice-cooling, and stirred at room temperature overnight. After the reaction, 1N aqueous solution of sodium hydroxide was added under ice-cooling and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified with a silica gel column chromatography (n-hexane/ethyl acetate) and ethanol was added to give 1-(4-tert-butylphenyl)-N-[6-(1,4-dioxaspiro[4.5]decan-8-yl)pyridin-3-yl]-5-methyl-1H-pyrazole-4-carboxamide (242 mg) as a white solid.