Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=1)[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:33]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=1)[S:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:33]
Reactant: COc1ccccc1OCCNCC(Sc1ccccc1)c1ccc(C)c(S(N)(=O)=O)c1
Reactant: OO
Solvent: CC(=O)O
Product: COc1ccccc1OCCNCC(c1ccc(C)c(S(N)(=O)=O)c1)S(=O)c1ccccc1

Procedure:
In 20 ml of acetic acid was dissolved 2 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamide and after adding thereto 0.5 ml of 30% H2O2, the mixture was heated to 50°-60° C. for 3 hours. After adding thereto 100 ml of water, the reaction mixture was extracted with 200 ml of ethyl acetate. The ethyl acetate extract was washed with an aqueous 1% sodium carbonate solution and then ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, the product was eluted with a mixed solvent of chloroform and methanol (9:1 by volume ratio), and the colorless viscous oily product thus obtained was crystallized by the addition of ethyl acetate. The crystals formed were recovered by filtration to provide 1.3 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylsulfinylethyl}-2-methylbenzenesulfonamide.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C(N(S(F)(F)[F:23])CC)C>C(Cl)Cl>[F:23][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1cc(CO)cc(C(=O)OC)c1
Solvent: ClCCl
Product: COC(=O)c1cc(CF)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
Under Ar atmosphere, with ice-cooled, to a solution of dimethyl 5-hydroxymethylisophthalate (32) (3.36 g, 15.0 mmol) in CH2Cl2 (150 mL, 0.1 M solution) was slowly added dropwise (diethylamino)sulfur trifluoride (4.00 mL, 30.5 mmol), and stirred for 2 hours at a room temperature. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with MeOH (150 mL). The solvent was removed under reduced pressure. The residue was subjected to extraction with EtOAc and a saturated sodium hydrogen carbonate aqueous solution (three times). The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=10:1) to isolate dimethyl 5-fluoromethylisophthalate (33) (2.57 g, 78%) as white crystals.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:14]=[CH:13][C:12]=1[C:23]([OH:25])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]([CH2:58][N:59]([CH2:67][CH3:68])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([OH:57])[C:53]([F:56])([F:55])[F:54]>CN(C)C=O>[NH2:10][C:11]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[N:14]=[CH:13][C:12]=1[C:23]([NH:50][CH2:51][C:52]([CH2:58][N:59]([CH2:67][CH3:68])[CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)([OH:57])[C:53]([F:56])([F:55])[F:54])=[O:25]
Reactant: CCN(Cc1ccccc1)CC(O)(CN)C(F)(F)F
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1)CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 150.6 %

Procedure:
Diisopropylethylamine (0.175 ml, 1 mmol) was added to a mixture of 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (0.119 g, 0.54 mmol) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.205 g, 0.54 mmol) in dimethylformamide (1 ml). The resultant mixture was stirred at room temperature for 20 minutes, then a solution of 3-amino-2-{[ethyl(phenylmethyl)amino]methyl}-1,1,1-trifluoro-2-propanol (0.296 g, 1.07 mmol) in dimethylformamide (1 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml) and the separated organic phase washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica (10 g) using 0-100% ethyl acetate in cyclohexane gradient over 15 minutes to give the title compound (0.39 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]([C:9](O)([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[OH-:20].[Na+].[C:22](#[N:24])[CH3:23]>>[CH3:10][C:9]([NH:24][C:22](=[O:20])[CH3:23])([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[N:8]=1)[CH3:11]
Reactant: [OH-]
Reactant: CC(C)(O)c1cccc(C(F)(F)F)n1
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC(C)(C)c1cccc(C(F)(F)F)n1
Temperature: 0 °C
Yield: 82 %

Procedure:
Add 2-(6-trifluoromethyl-pyridin-2-yl)-propan-2-ol (44.4 g, 216 mmol) to acetonitrile (450 mL) and cool the mixture to 0° C. Add concentrated sulfuric acid (35 mL, 657 mmol) and maintain 10° C. or lower during the addition. Warm the mixture to 45° C. for 16.5 hours, then cool the mixture to 4° C. Add 1 N NaOH (1.3 L). Add t-butylmethyl ether (900 mL) and separate the layers. Extract the aqueous layer with t-butylmethyl ether (450 mL) and separate the layers. Combine the organic layers and extract with brine (450 mL), then separate the phases and add anhydrous sodium sulfate. Filter the suspension and concentrate the filtrate to dryness under reduced pressure to afford N-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-acetamide (43.9 g, 219 mmol, 82%). 1H NMR (400 MHz, DMSO d6) δ 8.26 (s, 1H), 7.95 (t, J=7.9 Hz, 1H), 7.63 (dd, J=7.7, 17.4 Hz, 2H), 1.82 (s, 3H), 1.51 (s, 6H). HRMS (ESI) m/z (M+H)1 calcd for C11H14F3N2O (M+H)+: 247.1053, found 247.1051.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH2:33]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:33][CH:32]([O:35][CH3:36])[O:31][CH3:30])[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(CBr)OC
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21)OC
Temperature: 50 °C
Yield: 136.2 %

Procedure:
To a solution of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (135 mg, 1 mmol) in DMF (1 mL) was added KHMDS (0.5 M in THF, 1.1 mL) was dropwise at room temperature. The mixture was stirred for half an hour before adding bromoacetaldehyde dimethyl acetal (95 mg, 0.55 mmol). The mixture was warmed to 50° C. and stirred at that temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate (3×15 mL), dried and concentrated under reduced pressure. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) gave the desire product as colorless oil (268 mg, 75%). LC/MS m/e calcd. for C20H20ClNO3: 3570, observed (M+H)+: 358.7.
Reaction SMILES: [OH:1][C:2]1[C:11]([S:12](=[O:21])(=[O:20])[N:13](C(C)C)[CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]([N:22]=[N:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[S:33]([CH3:36])(=[O:35])=[O:34])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:37][S:38]([C:41]1[CH:42]=[C:43]([S:47]([O-:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)(=[O:40])=[O:39].[Na+:51].[C:52]([Cl:65])(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63].C(Cl)(=O)CCCCCCCCCCCCC>>[OH:1][C:2]1[C:11]([S:12](=[O:20])(=[O:21])[NH:13][CH:14]([CH3:15])[CH3:16])=[CH:10][C:9]([N:22]=[N:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[S:33]([CH3:36])(=[O:35])=[O:34])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:37][S:38]([C:41]1[CH:42]=[C:43]([S:47]([O-:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)(=[O:39])=[O:40].[Na+:51].[C:52]([Cl:65])(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CC(C)N(C(C)C)S(=O)(=O)c1cc(N=Nc2ccc([N+](=O)[O-])cc2S(C)(=O)=O)c2c(NS(=O)(=O)c3cccc(S(=O)(=O)[O-])c3)cccc2c1O
Agent: CCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Product: CC(C)NS(=O)(=O)c1cc(N=Nc2ccc([N+](=O)[O-])cc2S(C)(=O)=O)c2c(NS(=O)(=O)c3cccc(S(=O)(=O)[O-])c3)cccc2c1O

Procedure:
In this case, sodium 3-{N-[5-hydroxy-8-(2-methylsulfonyl-4-nitrophenylazo)-6-(N,N-diisopropylsulfamoyl)naphthyl]sulfamoyl}benzenesulfonate and lauroyl chloride or myristoyl chloride were used as the raw materials for producing Compound 35 or 36, and sodium 3-{N-[5-hydroxy-8-(2-methylsulfonyl-4-nitrophenylazo)-6-(N-isopropylsulfamoyl)naphthyl]sulfamoyl}benzenesulfonate and lauroyl chloride were used for producing Compound 41.
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6].N[NH:12][C:13]([NH2:15])=[S:14].C(Cl)Cl.CO>CN(C=O)C>[C:2](=[N:10][NH:12][C:13]([NH2:15])=[S:14])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=N)OCC
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCC(=NNC(N)=S)OCC
Reaction time: 2.5 h

Procedure:
A solution of 10.79 g (65 mmol) of ethyl valerimidate hydrochloride [prepared by method of A. J. Hill and I. Rabinowitz, J. Am. Chem. Soc., 48, 734 (1926)] in 130 ml of dry DMF was stirred at room temperature as 5.91 g (65 mmol) of thiosemicarbazide was added. Stirring was continuted under N2. After 2.5 hours, by which time TLC (19:1 CH2Cl2 -MeOH) indicated complete conversion of thiosemicarbazide to a higher Rf product, the mixture was partitioned between 1 L of H2O, then dried over MgSO4, filtered, and concentrated in vacuo. The residual oil, upon drying in vacuo (<1 mm) overnight, solidified to yield 11.05 g (84%) of nearly white solid, mp 73°-74.5° C.; homogeneous by TLC in 97:3 CH2Cl2 -MeOH. NMR indicated a mixture of syn and anti isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:7]2.C1(P(C2C=CC=CC=2)CC(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C=CC=CC=1.C(N(CC)CC)C.[CH3:65][OH:66].CN([CH:70]=[O:71])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:65]([O:71][CH3:70])=[O:66])=[C:6]2[C:11]=1[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:7]2
Reactant: CO
Reactant: CN(C)C=O
Reactant: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(CP(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(C(=O)OC)c2C1
Reaction time: 18 h

Procedure:
(R)-8-Fluoro-3-(N-3-pentyl-N-n-propylamino)-5-trifluoromethanesulfonyloxychroman (1.04 g, 2.43 mmol), palladium(II)acetate (55 mg), 1,2-bis(diphenylphosphino)propane (100 mg) was dissolved in 10 ml DMF. Triethylamine (0.75 ml, 5.38 mmol) and MeOH (1.0 ml, 24.6 mmol) was added under CO atm. via septa. The solution was stirred at +70° C. for 18 hours, and thereafter evaporated to dryness. 100 ml 2M NH3 and 100 ml EtOAc was added and the aqueous phase was extracted with 100 ml EtOAc. The combined organic layers was dried (MgSO4) and evaporated. Flash chromatography on silica with a gradient of Hexane-Hexane:EtOAc, 50:1 gave 0.76 g of (R)-8-fluoro-5-methyloxycarbonyl-3-(N-3-pentyl-N-n-propylamino)chroman as an uncoloured oil. Purity: 94% according to GC.
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH2:20]([N:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[N:25]([CH2:31][CH3:32])[C:23]1=[S:24])[CH3:21].C(N(CC)CC)C>C(O)C>[CH2:31]([N:25]1[C:26](=[O:27])[C:28](=[C:7]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:8]2)[C:29](=[O:30])[N:22]([CH2:20][CH3:21])[C:23]1=[S:24])[CH3:32]
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Reactant: CCN1C(=O)CC(=O)N(CC)C1=S
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1C(=O)C(=C2C=C(N3CCCC3)CC(C)(C)C2)C(=O)N(CC)C1=S

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (3.1 g., 0.01 mol.), 1,3-diethyl-2-thiobarbituric acid (2.0 g., 0.091 mol.) and triethylamine (3.1 ml.) are dissolved in ethanol (15 ml.) and heated at reflux for 10 minutes. After chilling, the crude dye is collected on a filter, rinsed with ethanol and dried. After one recrystallization from methanol, the yield of purified dye is 2.3 g. (64%), m.p. 226°-227°C. This dye is an excellent spectral sensitizer for photographic silver halide emulsions as shown in Table 2 hereinafter.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
In a solution of 1-fluoro-4-nitro benzene (3.00 g, 21.3 mmol) in DMSO (30 mL) was added ethyl piperidine-4-carboxylate (5.01 g, 31.9 mmol) and K2CO3 (5.87 g, 42.5 mmol). The resulting mixture was stirred at 100° C. for 8 h. After cooling to rt, the reaction was quenched with H2O (70 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:2 v/v) to obtain compound 18a as a yellow solid (5.00 g, 80% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H18N2O4: 279.1 (M+H). Found 279.1.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH:15]=[C:16]2[C@H:17]([CH3:20])[CH2:18][OH:19])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]>[C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:20])[CH2:18][OH:19])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@@H]3[C@H](CC[C@]4(C)C([C@H](C)CO)=CC[C@@H]34)[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: [Pt]
Solvent: CCO
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 86.2 %

Procedure:
To a solution of 860 mg (2.0 mmol) of (20S)-20-methylpregna-5,16-diene-1α,3β,21-triol 1,3-diacetate in 50 ml of absolute ethanol was added 89 mg of 5% platinum on charcoal. The suspension was stirred under a hydrogen atmosphere at 23° until (2 hr.) the hydrogen uptake was 48 ml (theory 48.8 ml). The catalyst was removed by filtration (several filtrations were necessary to remove colloidal charcoal) through diatomaceous earth and was washed several times with methylene chloride. The filtrate was evaporated under reduced pressure, and the residue, 835 mg (97%), was recrystallized from 20 ml of hexane (cooled to -5°) to yield 746 mg (86%) of (20S)-20-methylpregn-5-ene-1α,3β,21-triol 1,3-diacetate as white crystals, mp 133.5°-134.5°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)(C)C>[CH3:9][O:8][C:6]([CH:5]1[CH2:10][CH2:11][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: COC(=O)C1CCC(=O)CC1

Procedure:
One mole of methyl 4-hydroxybenzoate was reacted with two moles of hydrogen in the presence of 5% palladium-carbon catalyst. This reaction was carried out in isoproyl alcohol at a temperature of 170°-180° C. and a hydrogen pressure of 20-40 kg/cm2. After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to obtain cyclohexanone-4-carboxylic acid methyl ester as the distillate at 140° C./20 mmHg.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(COC)OC>C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.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>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:4]3[S:3][C:2]([Br:1])=[CH:6][CH:5]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: Brc1ccc(Br)s1
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(Br)s3)cc2)[nH]1
Temperature: 90 °C
Yield: 98.7 %

Procedure:
A mixture of 2,5-Dibromo-thiophene (4.93 g), 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.896 g, prepared according to WO2008021927 A2), and Pd(PPh3)4 (0.118 g) in 2M K2CO3 (3.06 mL)/dimethoxyethane (6.12 mL) was heated at 90° C. for 8 hours. Reaction mixture was cooled, diluted with ethyl acetate and washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give 2-{5-[4-(5-Bromo-thiophen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.955 g): LCMS-ESI+: calc'd for C22H25BrN3O2S: 475.42 (M+H+); Found: 473.8, 475.9 (M+H+).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH2:19][C:20]1[C:24]([C:25]([OH:27])=[O:26])=[CH:23][NH:22][N:21]=1>O1CCCC1>[O:18]=[C:10]1[C:9](=[CH:8][NH:19][C:20]2[C:24]([C:25]([OH:27])=[O:26])=[CH:23][NH:22][N:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11]1
Reactant: Nc1n[nH]cc1C(=O)O
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1n[nH]cc1C(=O)O

Procedure:
The named compound is prepared by substituting 3-amino-1H-pyrazole-4-carboxylic acid for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1601 gms. of 3-amino-1H-pyrazole-4-carboxylic acid by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:13]([N:10]1[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCC(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(N)C1
Yield: 86.6 %

Procedure:
t-Butyl-1-isopropylpyrrolidin-3-ylcarbamate (0.90 g, 3.9 mmol) obtained in Preparation Example (2-vii-1) was dissolved in dichloromethane (10 ml) in a 50 ml vessel, and trifluoroacetic acid (1.45 ml, 1.95 mmol, 5 eq.) was slowly added dropwise thereto while stirring. The resulting mixture was reacted for 18 hrs. After the completion of reaction, the reaction mixture was distilled and concentrated under reduced pressure, and then subjected to azeotropic distillation with CHCl3 3 times. The resultant was basified with aqueous 2N potassium hydroxide solution (20 ml) and extracted with CHCl3 3 times. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain 433 mg of the title compound as yellow oil (yield 86%).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:35]([C:34]1[CH:37]=[CH:38][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=1)[OH:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 5.65 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (3.3 g, 12.5 mmol) in THF (126 mL) at −78° C. and the mixture solution was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-tert-butylbenzaldehyde (1.68 g, 10.4 mmol) in THF (42 mL) was added at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.17 g, 60%).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc2c(cc1Br)C(C)CNCC2
Temperature: 20 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.18 g, 3.00 mmol) in methanol (35 mL) was treated with 15% aqueous NaOH (35 mL), and stirred overnight at 20° C. The product mixture was diluted with water (200 mL), extracted twice with EtOAc (200 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.880 g of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 6.63 (s, 1H), 6.04 (m, 1H), 5.47 (d, J=17 Hz, 1H), 5.29 (d, J=11 Hz, 1H), 4.58 (s, 2H), 3.01 (m, 3H), 2.89 (m, 3H), 2.75 (m, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated for C14H18BrNO+H: 296, observed: 296.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.N[N:12]=[CH:13]S(O)(=O)=O.C(#[N:20])C>>[CH:7]1[CH:8]=[CH:9][C:10]2[CH2:1][N:2]([C:13]([NH2:12])=[NH:20])[CH2:3][CH2:4][C:5]=2[CH:6]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: NN=CS(=O)(=O)O
Reactant: CC#N
Product: N=C(N)N1CCc2ccccc2C1

Procedure:
Tetrahydroisoquinoline (0.013 m) is treated with aminoiminomethanesulfonic acid (0.01 m) at ambient temperature. After completion of the reaction, it is diluted with acetonitrile, cooled and the solid product is collected by filtration.