Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)#N.[CH:8]([Mg]Br)([CH3:10])[CH3:9].S(=O)(=O)(O)[OH:14].[OH-].[Na+]>C1COCC1.O>[NH:6]1[CH:7]=[C:3]([C:1](=[O:14])[CH:8]([CH3:10])[CH3:9])[N:4]=[CH:5]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c[nH]cn1
Reactant: CC(C)[Mg]Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)c1c[nH]cn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of 4-cyanoimidazole (42.7 g , 0.458 mol) in THF (500 ml) was added dropwise over 30 min to a solution (1.4 L, 1.47 mol, 3.2 equivalents) of 1.1 M isopropyl magnesium bromide in THF at 0 to 10° C. under a nitrogen atmosphere. The mixture was stirred at 15 to 25° C. for 3 h. Water (430 ml) and 10% aqueous sulfuric acid solution (860 ml) were successively added dropwise, and the mixture was stirred at 30 min. A 30% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 8. After partitioning, the aqueous layer was extracted with ethyl acetate (300 ml×2). The organic layer was combined, and the mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, and concentrated under reduced pressure. The concentration residue was broken up with isopropyl ether (300 ml). The crystals were collected by filtration and washed with isopropyl ether. The crystals were dried in vacuo (40° C.) to give 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (51.9 g, yield 82%). 1H-NMR (CDCl3): δ 1.25 (6H, d, J=6.9 Hz), 3.36 (1H, quint, J=6.9 Hz), 7.81 (1H, s), 7.87 (1H, s)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([C:12]([C@@H:11]([NH:10][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(C)CC1)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCN(C)CC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
(S)-2-[(4-Methyl-piperazine-1-carbonyl)-amino]-4-methyl pentanoic acid (0.300 g, 1.23 mmol, Example 29, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.129 mL, 2.47 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.468 g, 1.23 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.356 g, 1.23 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (20% MeOH in EtOAc) to provide 0.53 g (78%) of the pure titled compound as a white foam: mp 65-78° C. APCI-MS m/z 528.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[C:23]1([S:29][C:12]2[CH:13]=[C:14]([O:8][C:7]3[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[C:15]([C:18]#[N:19])=[N:16][CH:17]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ncccc1O
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1cc(Sc2ccccc2)cnc1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-methylpyridin-3-ol (0.96 g, 8.8 mmol) in DMF (10 mL) cooled to 0° C. was added NaH (0.35 g, 8.8 mmol) in portions and the reaction warmed to ambient temperature. To this mixture was added 5-bromo-3-nitropicolinonitrile (2.0 g, 8.8 mmol) and the reaction stirred over night at ambient temperature. To the reaction was added thiophenol (0.96 g, 8.8 mmol) and the reaction cooled to 0° C. NaH (0.35 g, 8.8 mmol) was added and the reaction warmed to ambient temperature and the reaction stirred at ambient temperature overnight. The reaction was poured into water (1000 mL) and the aqueous layer was extracted with ether (3×100 mL). The organics were washed with 1N NaOH (100 mL), water (2×100 mL) brine (100 mL), dried over MgSO4 and concentrated in vacuo to give 5-phenylthio-3-(2-methylpyridin-3-yloxy)picolinonitrile (2.8 g, 8.8 mmol, 100%) as a solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:15]([O:14][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([Br:3])[CH:5]=2)[CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Sodium hydride (1.16 g, 29.12 mmol) was added to 6-bromo-2-naphthol (5.00 g, 22.41 mmol) in anhydrous N,N-dimethylformamide (162 mL) at 0° C. After 15 minutes, benzyl bromide (2.40 mL, 3.45 g, 20.18 mmol) was added and the reaction warmed to room temperature over 18 hours. The reaction was diluted with EtOAc (500 mL), saturated aqueous NaHCO3 (200 mL) was added, and the solution was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water (3×1 L), saturated aqueous NaCl solution (1 L), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 5:1 Hexanes:CH2Cl2) to give 36 as a colorless amorphous solid (5.71 g, 90%): 1H NMR (CDCl3, 500 MHz) δ 7.94 (d, J=1.9 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.53-7.47 (m, 3H), 7.46-7.40 (m, 2H), 7.37 (m, 1H), 7.26 (dd, J=9.0, 2.5 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 5.18 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 157.2, 136.8, 133.2, 130.3, 129.9, 129.9, 128.9 (2C), 128.8, 128.7, 128.4, 127.8 (2C), 120.3, 117.4, 107.3, 70.3; IR (film) νmax 1585, 1452, 1256, 1219, 1204, 1165, 1065, 997, 924, 852, 820, 800, 733, 698, 476 cm−1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:30])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.C(OC)(=O)C.Cl.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15](=[O:30])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CCC(C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: COC(C)=O
Product: COC(=O)CCC(C(=O)c1cccc(O)c1)c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A solution of methyl (RS)-5-(3-benzyloxyphenyl)-5-oxo-4-(2-methylphenyl)-pentanoate (46 g) in methanol (250 mL), methyl acetate (250 mL) and concentrated hydrochloric acid (25 mL) is treated with palladium on carbon catalyst (5%; 1.5 g) and shaken under hydrogen at atmospheric pressure and room temperature for 2 hours. The suspension is filtered, and evaporated. The residue is dissolved in ethyl acetate, washed with water, dried and evaporated, and the residue is recrystallised from a mixture of ethyl acetate and cyclohexane, giving methyl (RS)-5-(3-hydroxyphenyl)-5-oxo-4-(2-methylphenyl)pentanoate as colourless crystals (21.7 g), m.p. 101-103° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O:17][C:18](=O)[NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)C.CO>O=P(Cl)(Cl)Cl.C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[C:27]2[C:22]([CH2:21][CH2:20][NH:19][C:18]2=[O:17])=[CH:23][CH:24]=1
Reactant: CCOC(=O)NCCc1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 25095.9 %

Procedure:
P2O5 (3.1 g, 0.0495 mmol) was added to a stirred solution of [2-(4-chloro-phenyl)-ethyl]-carbamic acid ethyl ester (2.5 g, 0.01097 mmol) in POCl3 (10 mL) The resulting mixture was heated to reflux for 3 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The concentrate was quenched with chilled water, basified with NaHCO3 solution and extracted with ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (10% methanol in CHCl3) afforded 500 mg of the product (26.3% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][C:12](=[O:17])[C:13]([Cl:16])([Cl:15])[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([NH:25][NH2:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C(OC)(C)(C)C>[CH2:1]([O:8][CH2:9][C:10]1[CH2:11][C:12]([C:13]([Cl:16])([Cl:15])[Cl:14])([OH:17])[N:25]([C:20]2[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C#CCOCc1ccccc1)C(Cl)(Cl)Cl
Reactant: NNc1ncccc1Cl
Solvent: COC(C)(C)C
Product: OC1(C(Cl)(Cl)Cl)CC(COCc2ccccc2)=NN1c1ncccc1Cl
Temperature: 30 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
5-(Benzyloxy)-1,1,1-trichloropent-3-yn-2-one (2.9 g, 0.01 mol) and 3-chloro-2-hydrazinopyridine (1.43 g, 0.01 mol) were initially charged in 20 ml of methyl tert-butyl ether (exothermic), and the mixture was stirred at 30° C. for a further 1 h. The solvent was concentrated by rotary evaporation and the resulting mixture was analysed by means of LC/MS. Only one isomer at m/e 435 was identified. The yield was 94%, the purity 92% (area percent).
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.[CH3:50][N:51]1[CH:55]=[C:54]([CH2:56][NH2:57])[CH:53]=[N:52]1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:54]4[CH:53]=[N:52][N:51]([CH3:50])[CH:55]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:48][CH:49]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 63 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with (1-methyl-1H-pyrazol-4-yl)methanamine, the title compound was obtained as a white solid in 63% yield: mp 205-206° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.45 (s, 1H), 7.41-7.32 (m, 3H), 7.07-6.98 (m, 2H), 5.88 (t, J=5.3 Hz, 1H), 4.97 (s, 2H), 4.42 (d, J=5.3 Hz, 2H), 3.88 (s, 3H), 2.62 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([CH:29]1[CH2:34][CH2:33][N:32]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:31][CH2:30]1)(=[O:27])=[O:28]
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCC(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 33 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 4-(2-naphthylsulphonyl)piperidine to give 4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidine in 33% yield;
Reaction SMILES: C[O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH2:7]([N+:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])([CH3:27])[CH3:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(=O)(=O)(O)O>C(O)(C)C.O>[S:3](=[O:4])(=[O:2])([OH:6])[O-:5].[CH2:28]([N+:25]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:27])[CH3:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: COS(=O)(=O)[O-]
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)([O-])O
Temperature: 820 °C
Reaction time: 1 h

Procedure:
In a 1 liter 3-necked round bottomed flask equipped with a mechanical stirrer and reflux condenser were suspended 60 grams (90.8 millimoles) of distearyl dimethyl ammonium methylsulfate in a mixture of 168.75 grams of isopropanol and 56.25 grams of deionized water. 9.57 grams of 95 percent sulfuric acid (90.8 millimoles) were then added and the reaction mixture was heated at gentle reflux, at about 820° C., for 4 hours. The resulting clear, orange-yellow solution was then cooled slowly. After about one hour, at about 30° C., crystals started to appear, followed by a massive crystallization with a noticeable exotherm of over 4° C. and the formation of white viscous slurry The crystallization was continued overnight, about 18 hours, under agitation at about 20° to 25° C. The slurry was filtered under vacuum on an 11 centimeter Whatman #4 filter paper with a Buchner funnel. The filtration time recorded was 2 minutes. The excellent filtration rate reflects the excellent crystallization characteristics of the product. A white filter cake was obtained, while a yellowish filtrate was removed. The filter cake was reslurried in 225 grams of a 75/25 mixture of isopropanol and water to remove residual acidity. The mixture of isopropanol and water was used to avoid the formation of gel experienced when water only is used to wash the highly acidic wet cake. A white slurry was obtained, which again required only 2 minutes to filter. Two more reslurry washings were accomplished as described above with filtration times of about 2 minutes each. A final reslurry wash with 200 grams of acetone was accomplished after which the product was recovered by filtration and dried overnight in vacuum at about 50° C. 42.7 grams (72.7 percent yield) of distearyl dimethyl ammonium bisulfate (IR fingerprint) were recovered. Analyticals- melting point (DSC) 94.50° C., H2O content 0.04 percent, bisulfate content (by titration) 15.24 percent.
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]2([CH2:10][C@@H:9]3[C@@H:5]([CH2:6][C@H:7]([OH:16])[C@@H:8]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]2)[O:2]1>C(Cl)Cl>[CH2:18]1[CH2:1][O:2][C:3]2([CH2:10][C@@H:9]3[C@@H:5]([CH2:6][C:7](=[O:16])[CH:8]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]2)[O:17]1
Reactant: CCOC(=O)[C@@H]1[C@@H]2CC3(C[C@@H]2C[C@@H]1O)OCCO3
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)C[C@H]2CC3(C[C@@H]12)OCCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.5 %

Procedure:
A solution of 294 mg of (1S,5R,6R,7S)-3,3-ethylenedioxy-7-hydroxy-6-ethoxycarbonylbicyclo[3.3.0]octane (III)' in methylene chloride (2 ml) as prepared in Example 1 was added to a solution of a chromic anhydride-pyridine complex in methylene chloride [prepared from chromic anhydride (688 mg), pyridine (1088 mg) and methylene chloride (18 ml)], and the mixture was stirred at room temperature for 10 minutes. The supernatant was separated, the residue was washed with ether, and the combined organic layer was extracted with 5% aqeuous sodium hydroxide solution. The aqueous layer was neutralized with dilute hydrochloric acid and extracted with ether. The organic layer was successively washed with saturated aqueous copper sulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, and concentrated to obtain 92 mg of (1R,5S)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo[3.3.0]octan-3-one. To the thus obtained (1R,5S)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo[3.3.0]octan-3-one were added 20 mg of sodium hydroxide and 0.9 ml of water-ethanol mixed solution (4:1), and the mixture was stirred at 90° C. for 4 hours. After cooling, the reaction mixture was neutralized with dilute hydrochloric acid and extracted with ether. The organic layer was then washed with saturated brine, dried over sodium sulfate, and concentrated to give 42 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH:29]3[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1CCNCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(piperidin-4-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-d6) δ ppm 9.89 (brs, 2 H), 7.875 (t, J=8.0 Hz, 2 H), 7.76 (s, 1 H), 7.625 (t, J=6.8 Hz, 1 H), 7.48 (d, J=7.6 Hz, 1 H), 7.30 (d, J=8.4 Hz, 1 H), 7.226 (d, J=1.6 Hz, 1 H), 6.73 (t, J=5.43 Hz, 1 H), 5.07 (brs, 2 H), 4.42 (brs, 2 H), 4.10 (d, J=12.63 Hz, 2 H), 3.63 (m, 2 H), 3.23-3.05 (m, 2 H), 2.50 (s, 2 H), 2.05 (s, 3 H), 1.76-1.66 (m, 3 H), 1.15-0.98 (m, 2 H).
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH2:14]=[CH:15][C@@H:16]([CH3:37])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([OH:36])[CH2:27][CH2:28]2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1.C1(=O)CCCCC1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH2:14]=[CH:15][C@@H:16]([CH3:37])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1
Reactant: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C1CCCCC1
Product: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.02 h
Yield: 73.8 %

Procedure:
Aluminum isopropoxide (0.39 g, 1.9 mmol) in 3.6 ml of hot toluene was added to a solution of 21-methylene-20(R)-methylpregn-5-en-3β-ol (208.2 mg, 0.6337 mmol) in cyclohexanone (3.6 ml, 35 mmol) and 18 ml of toluene, and the mixture was refluxed with exclusion of moisture for 2 h. After cooling in ice, 0.92 ml of water and 2.2 ml of 3.6 N sulfuric acid were added and the mixture was shaken 1 min. Further water (4.6 ml) was added, the mixture was shaken 5 min., and the aqueous phase was discarded. Volatile components were removed by azeotropic/steam distillation and the resulting aqueous suspension was extracted three times with 5 ml portions of methylene chloride. The combined organic extracts were filtered through a small column of sodium sulfate resting on a bed of diatomaceous earth, all of which was contained in a Pasteur pipette. The residue was washed with 5 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Recrystallization of the residual film gave white needles (152.7 mg, 0.4677 mmol, 74%), m.p. 138-139° C. TLC (25% ethyl acetate/hexanes on silica gel) showed a major product at Rf 0.54 with a trace contaminant at Rf 0.71 (starting material Rf 0.36).
Reaction SMILES: C(O[CH2:6][C:7]([CH3:28])([CH3:27])[CH:8](N=C=O)[O:9][C:10]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(C)(C)C.C(C1C=C(O)C(=CC=1)C(OC)=O)(C)(C)C.[C:44]([O:48][C:49]([NH:51]CC(C)(C)CO)=[O:50])([CH3:47])([CH3:46])[CH3:45]>>[C:44]([O:48][C:49]([NH:51][CH2:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10]1[CH:19]=[C:18]([C:20]([CH3:22])([CH3:23])[CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:50])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1OC(N=C=O)C(C)(C)COC(C)(C)C
Agent: COC(=O)c1ccc(C(C)(C)C)cc1O
Product: COC(=O)c1ccc(C(C)(C)C)cc1OCC(C)(C)CNC(=O)OC(C)(C)C
Reaction time: 204 h

Procedure:
Using methods substantially equivalent to Example 21-C, except that the Mitsonobu reaction was allowed to proceed for 7 to 10 days, methyl 2-(3-tert-butoxy-carbonylamino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoate (10.85 g, 39%) as a pale yellow brittle foam was prepared from methyl 4-(tert-butyl)salicylate (14.72 g, 70.8 mmol) and 3-(tert-butoxycarbonylamino)-2,2-dimethylpropanol (14.37 g, 70.8 mmol).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:17][N:18]([CH3:22])[C:19]([N:7]1[C:8]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:20]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)CSc1nc(C(C)(C)C)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)CSc1nc(C(C)(C)C)nn1C(=O)N(C)C
Yield: 85.2 %

Procedure:
To 100 g (0.411 mole) of 3-t-butyl-5-carboethoxymethylthio-1H-1,2,4-triazole, 6 g (0.05 mole) of 4-dimethylaminopyridine, and 200 ml of pyridine was added 54 g (0.50 mole) of dimethylcarbamoyl chloride. The resulting solution was refluxed for eight hours and allowed to cool overnight. The reaction mixture was concentrated under vacuum, partitioned between ether and dilute hydrochloric acid. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated under vacuum. Distillation yielded a fraction boiling at 148°-160° C at 0.1 torr 100 g (0.35 mole) of 1-dimethylcarbamoyl-3-t-butyl-5-carboethoxymethylthio-1,2,4-triazole. m.p. 55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[Cr](Cl)([O-])(=O)=[O:13].[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9](=[O:11])[CH3:10]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(=O)Cc1ccccc1Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)C(=O)c1ccccc1Cl
Reaction time: 22 h

Procedure:
To a solution of 2-chlorophenylacetone (10.800 g, 64.049 mmol) in 279 mL of CH2Cl2, pyridinium chlorochromate (41.418 g, 192.15 mmol), and pyidine (16 mL) in three portions were added over 2.5 hours and the mixture was refluxed under vigorous stirring. After 22 h, he mixture was removed from heat. The mixture was concentrated in vacuo to give a dark red syrup. The crude mixture was purified by column chromatography on a 120 g of Redi-Sep™ column using 0-10% gradient of EtOAc in hexane over 28 min as eluent to give 1-(2-chlorophenyl)propane-1,2-dione as yellow liquid: 1H NMR (400 MHz, choroform-d) δ ppm 7.66 (1 H, dd, J=7.6, 1.8 Hz), 7.49-7.54 (1 H, m), 7.38-7.45 (2 H, m), 2.58 (3 H, s); LC-MS: m/z 182.9 [M+H]+.