Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Na].[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([NH:16][NH2:17])=O>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[N:2]=[C:14]([C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([Cl:10])[CH:12]=2)[NH:16][N:17]=1
Reactant: N#Cc1ccccn1
Reactant: NNC(=O)c1cccc(Cl)c1
Agent: [Na]
Solvent: CO
Product: Clc1cccc(-c2nc(-c3ccccn3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.3 %

Procedure:
Using the procedures of Browne et al., Aust. J. Chem., (1975) 28:2543–2546, a solution of 2-cyanopyridine (0.1 mL, 1.00 mmol) in methanol (5 mL) was treated with sodium metal (6.9 mg, 0.30 mmol) and stirred for at ambient temperature for 1 hour. After this time, a solution of 3-chlorobenzhyrazide (0.17 g, 1.0 mmol) in methanol (5 mL) was added and the resulting solution heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo, and the resulting yellow solid (100 mg) dissolved in toluene (2 mL). The mixture was heated at 175° C. for 3 hours and then stirred overnight at ambient temperature. Evaporation of the solvent in vacuo and silica gel chromatography using 1% methanol in dichloromethane afforded 29 mg (11%) of 3-(2-pyridyl)-5-(3-chlorophenyl)-1,2,4-triazole as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[O:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:21]21[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: O=C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC12CCOCC2
Temperature: 100 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), tetrahydro-4H-pyran-4-one (1.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 h at 100° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate/THF (4:1, 100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then triturated with ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0715 g, 54%) as a yellow solid:
Reaction SMILES: [C:1]([C:5]1[CH:55]=[CH:54][C:8]2[NH:9][C:10]([CH2:12][CH2:13][CH:14]3[CH2:17][CH:16]([N:18]([CH2:22][C@@H:23]4[C@H:27]5[O:28]C(C)(C)[O:30][C@H:26]5[C@H:25]([N:33]5[C:37]6[N:38]=[CH:39][N:40]=[C:41]([NH:42]CC7C=CC(OC)=CC=7OC)[C:36]=6[CH:35]=[CH:34]5)[CH2:24]4)[CH:19]([CH3:21])[CH3:20])[CH2:15]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O.O.CO>[NH2:42][C:41]1[C:36]2[CH:35]=[CH:34][N:33]([C@@H:25]3[CH2:24][C@H:23]([CH2:22][N:18]([CH:16]4[CH2:15][CH:14]([CH2:13][CH2:12][C:10]5[NH:9][C:8]6[CH:54]=[CH:55][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=6[N:11]=5)[CH2:17]4)[CH:19]([CH3:20])[CH3:21])[C@@H:27]([OH:28])[C@H:26]3[OH:30])[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (390 mg, 0.52 mmol) was dissolved in a mixture of Trifluoroacetic Acid (7.2 ml) and Water (0.8 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to RT After 2.5 at RT the residue was taken up in 15 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 15 ml MeOH (gave a slurry) and was treated with 500 mg K2CO3 and 8 drops of water. The mixture was allowed to stir for 1 hr, during which time the solution was found to be basic. The mixture was filtered through a finefrit, the solids were washed with 10 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight. The crude material was purified by flash chromatography (SiO2, eluting with 8-10% 7N NH3 in CH3OH/CH2Cl2) to give a glass/stiff foam (0.22 g). 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1H), 7.48 (br. s., 1H), 7.39 (m, 1H), 7.27 (m, 1H), 7.20 (d, J=3.52 Hz, 1H), 6.60 (m, 1H), 4.32 (t, J=6.43 Hz, 1H), 3.93 (t, J=5.29 Hz, 1H), 3.54 (m, 0.2H), 3.11 (t, J=9.33 Hz, 1H), 3.02 (m, 1H), 2.82 (m, 2H), 2.66 (dd, J=13.68, 8.09 Hz, 1H), 2.46 (m, 1H), 2.36 (m, 1H), 2.23 (m, 3H), 2.05 (m, 1H), 1.91 (m, 3H), 1.59 (m, 3H), 1.36 (s, 9H), 1.02 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.C(O)(C(F)(F)F)=O>ClCCl>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3c(F)cccc3F)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 112.9 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (450 mg, 0.86 mmol, 1.00 equiv) in dichloromethane (40 mL). CF3COOH (10 mL) to added dropwise with stirring at 25° C. over 10 min and the resulting solution was stirred for 3 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum to give 410 mg of 3-[4-(2,6-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[C:16](=O)([O-])[O-].[Na+].[Na+].CI>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:16]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Yield: 91.4 %

Procedure:
26.3 g (0.1 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 6.4 g (0.06 M) of sodium carbonate, 8 ml (0.123 M) of methyliodide and 200 ml of ethanol are mixed and heated for 4 hours in a water bath at 70°-75°. The ethanol is distilled off. The residue is washed with water and filtered. The sediment, after drying, is boiled with 180 ml of iso-propanol and then is filtered. From the filtrate 15.3 g (55.2% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-acetyl-S-methylisothiourea with a melting point of 137°-141° are isolated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH2:36]([N:43]=[C:44]=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([NH:43][C:44]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:22]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C=NCc1ccccc1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)NCc6ccccc6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and benzyl isocyanate (Aldrich, Cat. No. 227269). LCMS (M+H)+: m/z=618.2.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5])C.[OH-].[K+]>C(O)C>[C:16]([O:15][C:13]([C:12]([CH3:21])([O:11][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][C:4]([OH:5])=[O:3])[CH:24]=[CH:23][CH:22]=1)[CH3:20])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CCc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[3-[2-(ethoxycarbonyl)ethyl]phenoxy]-2-methylpropionate (37.1 g, 0.11 mmol) was dissolved in ethanol. Subsequently, aqueous 10% potassium hydroxide solution was added dropwise, and the mixture was stirred overnight at room temperature. The resultant mixture was concentrated under reduced pressure, and then an aqueous 5% potassium hydrogensulfate solution was added thereto. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=3/2), whereby the target compound was obtained (32.0 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[N:17][N:16]=[CH:15]2>C1COCC1.CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH:22]([CH3:27])[C:23]([F:26])([F:24])[F:25])=[N:17][N:16]=[CH:15]2
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(C(C)C(F)(F)F)nncc3c2)c1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(C(C)C(F)(F)F)nncc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of methyl 4-methyl-3-(1-(1,1,1-trifluoropropan-2-yl)phthalazin-6-yl)benzoate (91 mg, 243 μmol) in THF (1200 μl) and methanol (600 μl) was added NAOH (1N aqueous solution; 1215 μl, 1215 μmol) and stirred at 50° C. for 2 h, during which LC-MS indicated completion of reaction. After concentrating in vacuo, the slurry was diluted with water and the pH was adjusted with 10% aqueous HCl solution to ˜7, resulting in the precipitation of 4-methyl-3-(1-(1,1,1-trifluoropropan-2-yl)phthalazin-6-yl)benzoic acid (86 mg, 98% yield) as a yellow solid. MS (ES+): 361.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[C:4]([O:22]CC2C=CC=CC=2)=[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:8][CH2:7][N:6]2[CH:21]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[CH2:12][N:9]1[CH2:8][CH2:7][N:6]2[CH:21]=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:3](=[O:30])[C:4]([OH:22])=[C:5]2[C:10]1=[O:11]
Reactant: Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cn2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
By subjecting 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (29 mg) obtained in Example 349, Step 2 to a reaction operation similar to that in Example 349, Steps 3 and 4 except that methanesulfonyl chloride was used instead of isobutyryl chloride, N-[2-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanesulfonamide (4.7 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(S([O-])(=O)=O)=CC=2C(C)C)CCCCC1.[Na+].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[C:13]([C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6])#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCCCCCC
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCC#Cc1c(F)ccc(C(=O)O)c1F
Yield: 69.3 %

Procedure:
The general procedure described in Example 27 was used with 3-chloro-2,4-difluoro-benzoic acid (97 mg, 0.50 mmol), 1-decyne (0.136 mL, 0.75 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.0 mL), 12 h, 100° C. The product was isolated as a white solid (102 mg, 70%). Mp=117° C. 1H NMR (400 MHz, d6-DMSO) δ: 10.1 (br-s, 1H), 7.88 (q, 1H, J=8.8 Hz), 7.26 (t, 1H, J=8.4 Hz), 2.51 (t, 2H, J=6.8 Hz), 1.57 (p, 2H, J=6.8 Hz), 0.80-1.43 (m, 13H). 13C NMR (125 MHz, CDCl3) δ: 168.7, 167.9, 165.3, 162.6, 132.3, 132.2, 114.1, 111.7, 111.5, 104.8, 103.1, 66.7, 32.0, 29.4, 29.3, 28.9, 28.5, 22.9, 20.0, 14.3. IR (neat, cm−1): 3428 (br), 2922, 2848, 2235, 1689, 1611, 1406, 1268, 1242, 1051, 1036. Anal. Calcd for C17H20F2O2: C, 69.37; H, 6.85. Found: C, 69.13; H, 6.80.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>ClCCl>[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:14])([F:15])[F:16])=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:41][CH2:40]1
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol) were dissolved in dichloromethane (30 mL), and stirred at room temperature for 8 hours. The resultant solution was washed with saturated sodium carbonate aqueous solution (30 mL), purified water (30 mL) and saturated sodium chloride aqueous solution (30 mL), respectively. Then, the organic layer was dried with anhydrous sodium sulfate, concentrated, and purified with column chromatography so as to provide a white solid required compound (528 mg, 1.34 mmol, 73%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([CH:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(O)c1
Yield: 62 %

Procedure:
A mixture of 19.5 g. (0.0468 mol.) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanone, 12.3 g. of sodium bicarbonate, 3.00 g. of 10% palladium-on-carbon and 250 ml. of ethanol was stirred under one atmosphere of hydrogen pressure for 1.5 hours. The reaction mixture was then filtered through diatomaceous earth with ethyl acetate and the filtrate evaporated to a solid. The crude solid was purified via column chromatography on 280 g. of silica gel eluted with 20% ethercyclohexane to yield a solid. Recrystallization of this sold from aqueous methanol gave 9.1 g. (62%) of the title product, m.p. 87° C., principally in the hemiketal form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH2:11][C@@H:10]([C:17]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](OC(=O)C)(=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][C@H:12]([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)C[C@H](C(=O)O)C1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: -40 °C
Reaction time: 7 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)piperidine-3,5-dicarboxylic acid (222 g) was suspended in acetic anhydride (2 L), and the suspension was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure. Toluene (200 ml) was added and the mixture was concentrated under reduced pressure. This operation was repeated twice. The obtained residue and quinidine (142 g) were dissolved in THF (900 ml), and the mixture was cooled to −40° C. A solution of methanol (161 ml) in THF (100 ml) was added dropwise over 30 min, and the mixture was stirred at the same temperature for 7 hr. THF (about 700 ml) was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, the organic layer was combined and the mixture was washed successively with 2 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue (106 g) was suspended in ethanol (410 ml). (R)-(+)-1-Phenylethylamine (45 g) was added, and the mixture was dissolved by heating to 75° C. The hot ethanol solution was rapidly filtered, and the filtrate was allowed to stand at room temperature for 12 hr. The resulting colorless crystals were collected by filtration, washed with ethyl acetate-hexane, and then with hexane and air-dried. The obtained solid was suspended in water (490 ml). Saturated aqueous potassium hydrogen sulfate solution (490 ml) was added and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to dryness to give the object compound (148 g) as a solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:27]1[N:28]([CH2:35][C:36]2([CH3:39])[CH2:38][O:37]2)[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=1>CN(C=O)C>[CH3:38][C:36]1([CH2:39][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=2)[O:37][C:27]2=[N:31][C:30]([N+:32]([O-:34])=[O:33])=[CH:29][N:28]2[CH2:35]1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
4-[4-(4-Trifluoromethylphenyl)piperazin-1-yl]phenol (296 mg, 0.92 mmol) was dissolved in DMF (10 ml). To the solution, sodium hydride (44 mg, 1.1 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (200 mg, 0.92 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and then crystallized from methylene chloride/ethyl acetate to afford 2-methyl-6-nitro-2-{4-[4-(4-trifluoromethylphenyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (178 mg, yield 38%) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([CH3:17])[C:10]2=[O:18])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[N+](=[CH2:25])=[N-].[Na+].[Cl-]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([C:14]([O:16][CH3:25])=[O:15])[CH2:12][N:11]([CH3:17])[C:10]2=[O:18])=[CH:5][C:4]=1[C:19]([F:21])([F:22])[F:20])#[N:2]
Reactant: C=[N+]=[N-]
Reactant: CN1C[C@H](C(=O)O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CN(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a solution of (R)-3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylic acid (25e) (0.280 g, 0.894 mmol) in THF (10 mL), cooled to 0° C., Diazomethane [prepared from N-Nitrosomethyl urea (0.276 g, 2.68 mmol) and 40% KOH solution (15 mL) in ether (10 mL)] was added under nitrogen atmosphere. The resulting reaction mixture was warmed up to room temperature and stirred for 1 h. After completion (by TLC), the reaction mixture was poured into saturated NaCl solution and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to provide the crude residue which was purified by column chromatography to afford the methyl ester 25f (0.210 g, 72%) as a colorless syrup.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:13])=[O:12].[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([C:18]([CH2:17][CH2:16][CH2:15][NH:14][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:12])=[O:13])=[O:20])[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: O=C(O)CCCNS(=O)(=O)c1ccc2ccccc2c1
Reactant: c1cc(N2CCNCC2)ccn1
Product: O=C(CCCNS(=O)(=O)c1ccc2ccccc2c1)N1CCN(c2ccncc2)CC1
Yield: 15 %

Procedure:
Using an analogous procedure to that described in Example 36, 4-(2-naphthalenesulphonamido)butyric acid was reacted with 1-(4-pyridyl)piperazine to give N-{3-[4-(4-pyridyl)piperazin-1-ylcarbonyl]propyl}naphthalene-2-sulphonamide in 15% yield as a foam;