Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:41])[CH2:3][N:4]([C:22]([C:24]1[N:28]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[N:25]=1)=[O:23])[C@@H:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C@H:7]([C:18]([O:20]C)=[O:19])[CH2:6]1.[OH-].[Na+].Cl>CO>[C:14]([O:13][C:11]([N:9]1[CH2:10][C@@H:5]([N:4]([CH2:3][CH:2]([CH3:1])[CH3:41])[C:22]([C:24]2[N:28]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:27]3[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=3[N:25]=2)=[O:23])[CH2:6][C@@H:7]([C:18]([OH:20])=[O:19])[CH2:8]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ccccc1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[(2-methylpropyl) {[1-(2-phenylethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-1,3-dicarboxylate (1.12 g) was dissolved in methanol, 2M aqueous sodium hydroxide solution (10 ml) was added dropwise at room temperature. The reaction mixture was stirred at 50° C. for 3 hr. The reaction mixture was adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.07 g).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:30])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([OH:29])=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:43][NH:44][CH3:45].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl>[NH3:9].[CH2:1]([O:8][NH:9][C:10](=[O:30])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([N:44]([CH3:45])[CH3:43])=[O:29])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)O)co1)NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Product: N
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.7 %

Procedure:
A solution of 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-1,3-oxazole-4-carboxylic acid (Preparation 65) (200 mg, 0.48 mmol) in dichloromethane (6 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (72 mg, 0.53 mmol), dimethylamine hydrochloride (79 mg, 0.96 mmol), N-methylmorpholine (160 μl, 1.45 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (111 mg, 0.58 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed sequentially with aqueous citric acid solution (10% w/v), a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was then purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the title compound as a colourless oil (200 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[CH:6]=[N:7][N:8]([CH2:11][CH3:12])[C:9]=2[CH:10]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.[NH2:48][CH2:49][C:50]1[C:51](=[O:60])[NH:52][C:53]([CH3:59])=[CH:54][C:55]=1[CH2:56][CH2:57][CH3:58]>C(Cl)Cl>[CH3:59][C:53]1[NH:52][C:51](=[O:60])[C:50]([CH2:49][NH:48][C:13]([C:4]2[C:5]3[CH:6]=[N:7][N:8]([CH2:11][CH3:12])[C:9]=3[CH:10]=[C:2]([Br:1])[CH:3]=2)=[O:15])=[C:55]([CH2:56][CH2:57][CH3:58])[CH:54]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CCn1ncc2c(C(=O)O)cc(Br)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a stirred suspension of 6-bromo-1-ethyl-1H-indazole-4-carboxylic acid, 4 (450 mg, 1.67 mmol) in DCM (50 mL) were added EDC.HCl (384 mg, 2.00 mmol), HOBt.H2O (306 mg, 2.00 mmol) and then stirred for 15 min at RT. To the resulting mixture, DIPEA (1.2 mL, 5.59 mmol) followed by 3-aminomethyl-6-methyl-4-propyl-1H-pyridin-2-one (301 mg, 1.67 mmol) were added and the contents stirred for 18 h at RT. The reaction mixture was diluted with DCM (50 mL) and washed with water (2×50 mL), 10% aq citric acid solution (2×50 mL), saturated aq NaHCO3 solution (2×30 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether (2×50 mL) to afford the title compound as a white solid (230 mg, 32%). 1H NMR (400 MHz, DMSO-d6): δ 0.83-0.79 δ (t, 3H), 1.38 (t, 3H), 1.55 (m, 2H), 2.15 (s, 3H), 2.49 (s, 2H), 4.38 (d, 2H), 4.43 (m, 2H), 5.90 (s, 1H), 7.64 (d, 1H), 8.19 (s, 1H), 8.38 (s, 1H), 8.61 (m, 1H), 11.51 (bs, 1H). LCMS (ES+): m/z=431.15.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C([Li])CCC.[Cl:21][Si:22](Cl)([Cl:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C.CCCCCC>[Cl:21][Si:22]([Cl:29])([C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cl[Si](Cl)(Cl)c1ccccc1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (106 mL) of 1-bromo-3,5-di-tert-butylbenzene (10.60 g, 39.37 mmol), a 1.65 M hexane solution of n-butyllithium (23.86 mL, 39.37 mmol) was added dropwise at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 3 hours. The resultant mixture was added dropwise to a diethyl ether solution (106 mL) of trichlorophenylsilane (24.99 g, 118.12 mmol) at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane wad added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure. Trichlorophenylsilane was removed by heating to 100° C. under reduced pressure to obtain dichloro(3,5-di-tert-butylphenyl)(phenyl)silane (11.77 g, yield 81.8%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])[NH2:24])=[C:14]([CH2:32][CH2:33][CH3:34])[C:13]=1[OH:35])(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:8])[C:5]([NH:24][C:23]1[C:25]([CH3:29])=[CH:26][C:27]([Br:28])=[C:21]([O:20][CH2:19][CH2:18][CH2:17][O:16][C:15]2[CH:30]=[CH:31][C:12]([C:9](=[O:11])[CH3:10])=[C:13]([OH:35])[C:14]=2[CH2:32][CH2:33][CH3:34])[CH:22]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCc1c(OCCCOc2cc(N)c(C)cc2Br)ccc(C(C)=O)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OCC)c(C)cc2Br)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 12.3 ml of chloro-oxalic acid ethyl ester in 30 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 43.6 g (100 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylaniline and 15.3 ml of triethylamine in 400 ml of methylene chloride and the whole is then stirred for a further 90 minutes at room temperature. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylphenyl}-oxamic acid ethyl ester having a melting point of 100°-102°.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[S:9])[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[O:5][CH:4]([CH2:14][CH2:15][NH:16][CH3:17])[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>C(O)(C)C.C(O)C>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[CH3:28][C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:16]([CH3:17])[CH2:15][CH2:14][CH:4]2[CH2:3][N:2]([CH3:1])[C:8](=[S:9])[C:7]3[CH:10]=[CH:11][CH:12]=[N:13][C:6]=3[O:5]2)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CNCCC1CN(C)C(=S)c2cccnc2O1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(CCC1CN(C)C(=S)c2cccnc2O1)Cc1ccc(C(C)(C)C)cc1

Procedure:
To 40 ml of absolute ethanol was added 6.6 g of 2,3-dihydro-4-methyl-2-[2-(methylamino)ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione and 3.35 g (0.026 mole) of diisopropylethylamine. While stirring, 4.75 g (0.026 mole) of p-(t-butyl)benzyl chloride was added at a rapid drop rate. The reaction solution was heated to reflux for 4 hr. After cooling, ethanol was removed by rotary evaporation. The residue was taken up in 100 ml of methylene chloride and the solution was washed with 2×50 ml of 1N potassium hydroxide and 50 ml of water, dried over sodium sulfate, and filtered. The methylene chloride was removed by rotary evaporation and ethylacetate was added to the residue which caused some precipitate to fall out (probably quaternary). After filtering off the precipitate, ethyl acetate was removed by rotary evaporation. The oily residue was heated with 2 equivalents of oxalic acid in isopropyl alcohol which yielded 4.3 g (31%) of yellow, analytically pure crystals, m.p. 175° -78° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[CH2:24]([CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[C:39](=[O:40])[CH2:38][C:37]([CH3:41])=[N:36]3)[CH:33]=2)[CH2:28][CH2:27]1)[CH3:25].C(=O)(O)[O-].[Na+]>Cl.C(O)C>[CH2:24]([CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[C:39](=[O:40])[C:38](=[N:20][NH:2][C:3]4[C:4]([OH:19])=[C:5]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=5)[CH:6]=[C:7]([CH3:9])[CH:8]=4)[C:37]([CH3:41])=[N:36]3)[CH:33]=2)[CH2:28][CH2:27]1)[CH3:25]
Reactant: CCC1CCc2ccc(N3N=C(C)CC3=O)cc21
Reactant: O=N[O-]
Reactant: Cc1cc(N)c(O)c(-c2cccc(C(=O)O)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCC1CCc2ccc(N3N=C(C)C(=NNc4cc(C)cc(-c5cccc(C(=O)O)c5)c4O)C3=O)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.4 %

Procedure:
3′-Amino-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid hydrochloride 11f (298 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N) upon cooling by an ice-water bath, followed by dropwise addition of 1.2 mL of aqueous sodium nitrite (70 mg, 1.01 mmol). After the mixture was stirred for 20 minutes, 2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 41d (200 mg, 0.83 mmol) was added. The mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate followed by addition of 2 mL of ethanol. The reaction mixture was warmed up to room temperature overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and 20 mL of water was added to the filter cake. The mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid. The mixture was filtered and the filter cake was dried to obtain the title compound 3′-{N′-[1-(3-ethyl-indan-5-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid 42 (290 mg, yield 70.7%) as a red solid.
Reaction SMILES: [H][H].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26]>[Pd].C(OCC)(=O)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])[CH2:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
R2 is methyl, R4 is hydrogen, V is --(CH2)5 --, and W is 1-pentyl. A solution of PGE1, 15-methyl ether (100 mg.) in 10 ml. of ethyl acetate is shaken with hydrogen at about 1 atmosphere pressure at 25°C. in the presence of 5% palladium on charcoal (15 mg.). One equivalent of hydrogen is absorbed in about 90 minutes. The hydrogenation is then stopped, and the catalyst is removed by filtration. The filtrate is evaporated, and the residue is chromatographed on 25 g. of silica gel, eluting with a 50-100% ethyl acetate gradient in Skellysolve B. Those fractions shown by TLC to contain the desired product free of the starting produuct and dehydration products are combined and evaporated to give the Formula-V 13,14-dihydro-PGE1 -type title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@H:14]([OH:16])[CH3:15])[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](I)[CH3:22].C1(C)C=CC(S(O)(=O)=[O:31])=CC=1>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][C@@H:12]([CH2:13][C@H:14]([O:16][CH2:21][CH3:22])[CH3:15])[C:11]([OH:10])=[O:31])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CCI
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of (S)-4-((R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (730 mg, 2.81 mmol) in dry tetrahydrofuran (15 mL) was added sodium hydride at 0° C. (60% in mineral oil, 248 mg). The suspension was warmed to room temperature and ethyl iodide (1.2 mL) was added. The mixture was stirred overnight and extracted with diethyl ether and saturated sodium chloride solution. The organic layer was washed with saturated sodium chloride solution and dried over sodium sulfate. After the evaporation of solvents, an oily material was obtained (660 mg). This oily material was dissolved in a mixture of tetrahydrofuran (1 mL) and methanol (10 mL). To this solution was added p-toluene sulfonic acid (22 mg). The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and sodium bicarbonate solution. After the evaporation of solvents, the resulting oily compound (532 mg) was dissolved in a mixture of acetonitrile (11 mL) and phosphate buffer (8 mL, pH=7). Then 1-oxyl-2,2,6,6-tetramethylpiperidine (24 mg) and sodium chlorite (495 mg) in water (2.5 mL) were added. The solution was warmed to 35° C. and catalytic amount of diluted bleach (1 mL of 5.25% sodium hypochlorite solution diluted to 20 mL in water, 1 mL of the diluted solution was used) was added in 5 portions. The mixture was stirred for 2 h. Then second portion of sodium chlorite (495 mg) in water (2.5 mL) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and adjusted to pH=9 with dilute sodium hydroxide solution. Sodium sulfite solution (2.7 g) in water (30 mL) was added and the mixture was stirred for 20 min. The resulting solution was extracted with methyl t-butyl ether. The organic layer was discarded and the aqueous layer was acidified with 1N aqueous hydrochloric acid to pH value about 2.0. The mixture was extracted with methyl t-butyl ether three times and dried over sodium sulfate. Solvents were evaporated to afford (2S,4R)-2-t-butoxycarbonylamino-4-ethoxy-pentanoic acid (279 mg) as a thick oil: LR-ES-MS m/z calculated for C12H23NO5 [M] 261, observed 260 [M−H]; 1H NMR (300 MHz, CDCl3) δ ppm 1.18 (t, 7.2 Hz, 3H), 1.22 (d, J=6.3 Hz, 3H), 1.46 (s, 9H), 1.88-2.16 (m, 2H), 3.26-3.43 (m, 1H), 3.55-3.72 (m, 2H), 4.27-4.39 (m, 1H), 5.59 (br. s., 1H), 10.51 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[C:3]=1[S:23]([C:25]([F:28])([F:27])[F:26])=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:41]([O:44][CH2:45]C)(=O)C.[CH:47](Cl)(Cl)Cl>C(OC)(OC)OC>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[C:2]([N:1]=[CH:41][O:44][CH3:45])=[C:3]([S:23]([C:25]([F:27])([F:28])[F:26])=[O:24])[C:4]([C:19]2[N:20]=[CH:47][O:22][N:21]=2)=[N:5]1
Reactant: CCOC(C)=O
Reactant: ClC(Cl)Cl
Reactant: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: COC=Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 51 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinyl-3-pyrazolecarboxamide oxime (1.81 g, 3.85 mmol) was dissolved in 25 ml of trimethyl orthoformate and p-toluenesulfonic acid monohydrate (0.08 g) was added, and then the mixture was heated under reflux for 6 hours. After heating, trimethyl orthoformate was distilled off and 80 ml of ethyl acetate was added to the residue. The ethyl acetate layer was washed three times with 50 ml of an aqueous saturated sodium hydrogencarbonate solution, and then washed with 50 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a colorless oil. The oil was subjected to silica gel column chromatography [eluent: mixed solvent of ethyl acetate and chloroform (volume ratio=1:20)] and the resulting crystal was washed with hexane to obtain 1.03 g (1.97 mmol) of the title compound as a colorless crystal. Yield 51%.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:10].[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.CCCCCCC>CO>[ClH:10].[NH2:9][C:8]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=2)[N:18]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
A solution of pivaloylacetonitrile (750 g, 6.0 mol) and p-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L) was refluxed for 3 h. Heptane was added, and methanol was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 1.05 kg, 94%. 1H NMR δ (CDCl3) 7.50 (d, 2H), 7.30 (d, 2H), 5.60 (s, 1H), 2.45 (s, 3H), 1.40 (s, 9H). MS (CI) m/z 229 (M++H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][S:8](CCC(OC)=O)(=[O:10])=[O:9])=[N:4][CH:3]=1.C[O-].[Na+].CC([O-])=O.[Na+].[NH2:25]OS(O)(=O)=O>C1COCC1.O>[Br:1][C:2]1[S:6][C:5]([CH2:7][S:8]([NH2:25])(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)CCS(=O)(=O)Cc1ncc(Br)s1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)Cc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
The product of Step 3 (1.244 g, 3.79 mmol) was taken up in THF (50 mL) at room temperature, and NaOMe (25% in MeOH, 0.819 g, 3.79 mmol) was added. After 30 min at room temperature, the suspension was evaporated to dryness, providing a yellow solid. The solid was taken up in water (25 mL), and a solution of NaOAc (1.710 g, 20.85 mmol) and hydroxylamine-O-sulfonic acid (2.143 g, 18.95 mmol) in water (12.5 mL) was added while cooling the reaction (0° C.). The reaction was vigorously stirred at room temperature overnight. The reaction was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (dry load, 10-100% EtOAc/hexanes) afforded 1-(5-bromo-1,3-thiazol-2-yl)methanesulfonamide (470 mg, 48%) as a colorless solid. MS ESI: [M+H]+ m/z 256.9/258.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH:16]([CH3:15])[C:17]#[CH:18])[N:3]=[CH:4][N:5]=1
Reactant: C#CC(C)O
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)Oc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95.1 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 458 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 231 mg of 3-butyn-2-ol, to which 132 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 10 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 506 mg of 4-(2-fluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (150)).
Reaction SMILES: C([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])([CH2:9][CH3:10])[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:26][O:25][C:12]1[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:3]([CH2:9][CH3:10])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C#N)(CC)c1cccc(Oc2ccccc2Cl)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1OC
Yield: 82 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]butyrate (5.9 g) and potassium hydroxide (4.5 g) in ethanol (80 ml) and water (40 ml) was treated in a similar manner to that of Example 14-(7). The resultant residue was washed with n-hexane and dried to give 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]butyric acid (4.15 g).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][O:8][C:31](=[O:33])[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A solution of 1.0 g of 17-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione in 10 ml of pyridine is stirred with 5 ml of acetic anhydride for one hour at 0° C. Then the mixture is poured on an ice water-sodium chloride solution; the precipitate is filtered off and purified by crystallization from acetone/hexane, thus isolating 810 mg of 17,21-diacetoxy-11β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 216° C.