Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:40])[C:7]([CH2:30][CH:31]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH3:32])=[CH:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OCC2C=CC=CC=2)=O)[C@H:10]1[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[CH2:1]([NH:5][C:6](=[O:40])[CH:7]([CH2:30][CH:31]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH3:32])[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)CNC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC(C)OC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNC(=O)C(CC(C)OC1CCCCO1)C[C@H](O)[C@@H](N)CC(C)C
Reaction time: 4 h
Yield: 102.4 %

Procedure:
254 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl-2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)propyl]-2-propenoic acid isobutylamide was dissolved in 3 ml of ethanol. Then, a palladium black catalyst was added thereto, and hydrogen was continuously blown into the solution under atmospheric pressure for 4 hours. Then, the catalyst was filtered off, and a fresh palladium black catalyst was added. Then, hydrogen was continuously brown into the solution for further 4 hours. The catalyst was filtered off, and the reaction solution was concentrated and dried under reduced pressure to obtain 180 mg of (2RS,4S,5S)-5-amino-4-hydroxy-2-[2-(2-tetrahydropyranyloxy)propyl]-7-methyl-octanoic acid isobutylamide as a solid substance.
Reaction SMILES: [F:1][C:2]([F:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:3](=[O:35])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].[Cl-].[Na+]>C(#N)C.O.P(=O)(O)(O)O>[F:1][C:2]([C@:3]1([OH:35])[O:11][C@@H:10]2[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C@H:6]2[CH2:5][CH2:4]1)([F:40])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OCc1ccccc1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCC(F)(F)[C@@]1(O)CC[C@H]2[C@@H](CC(=O)[C@@H]2CCCCCCC(=O)OCc2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a solution of benzyl 7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy) cyclopentyl]heptanoate (1) (70.49 g, 124.8 mmol) in acetonitrile (705 ml), water (70.5 ml) and 85% aqueous phosphoric acid (70.5 ml) were added, and the mixture was stirred for three hours at about 20° C. 10% aqueous sodium chloride (705 ml) was added to the mixture and the mixture was extracted with ethyl acetate (276 ml) for 3 times. The organic layers were combined and washed with 10% aqueous sodium chloride (360 ml), saturated aqueous sodium bicarbonate (360 ml) and saturated aqueous sodium chloride (360 ml) successively, dried with anhydrous magnesium sulfate (51 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300 2100 g, ethyl acetate:hexane=1:4). Fractions containing impurities were purified again by silica gel column chromatography (Fuji Silysia BW-300 1000 g, ethyl acetate:hexane=1:4) to give benzyl 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanate (2) (52.64 g, 109.5 mmol, yield: 87.8%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[Br-:1].[C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH2:2][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 3-(bromomethyl)benzoic acid (16.50 g, 76.73 mmol) in acetonitrile (76.7 ml) was added triphenylphosphine (22.14 g, 84.40 mmol). After heating the mixture under reflux for 2 hr, the reaction mixture was cooled to room temperature. The precipitate was collected by filtration and dried under reduced pressure to give (3-carboxybenzyl)(triphenyl)phosphoniumbromide (30.13 g, 63.12 mmol, yield 82.3%) as a white solid.
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](SC)=[CH:12][CH:11]=1)=[O:9].[S:18]([O-:21])([O-])=[O:19].[Na+].[Na+].[C:24](O)(=O)C>O>[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([S:18]([CH3:24])(=[O:21])=[O:19])=[CH:12][CH:11]=1)=[O:9]
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: CC(=O)O
Reactant: O=S([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
A solution of 152 g (0.96 mol) of KMnO4 in 3.5 1 of water is introduced into a mixture of 117.1 g (0.7 mol) of 4-(methylthio)acetophenone, prepared in Example 2c, and 292 ml of acetic acid. 2.3 l of water are added and the reaction temperature is allowed to return to room temperature. Saturated sodium sulfite solution is added dropwise until the solution is decolorized. This is left to stand overnight at room temperature. The solid obtained is filtered off, washed copiously with water and recrystallized from 95% ethanol to give 91.5 g of 4-(methylsulfonyl)acetophenone.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12)(=[O:22])[CH3:21]
Reactant: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
0.084 g 1-amino-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of acetic anhydride and refluxed for 6 h. The reaction mixture was cooled and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to yield a solid (0.067 g). MS (m/z): 320 (M−1)+.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].C(=O)(O)[O-].[OH-].[Co+2:19]>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Co+3:19]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: [Co+2]
Agent: O=C([O-])O
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [Co+3]
Temperature: 80 °C
Yield: 129.2 %

Procedure:
422.4 g citric acid were dissolved in 600 ml water, heated to about 80° C., and reacted at a temperature of 100° C. with a mash of 315.2 g cobalt (II) hydroxide carbonate in 1400 ml water, which was added slowly. After filtration and spray drying, 704.4 g cobalt citrate of a cobalt content of 24.8% by weight was obtained, which is about equivalent to 99% by weight of the cobalt feed.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4][NH:3][CH2:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17].CO>C(O)(=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][CH2:17][N:3]1[CH2:2][CH2:1][N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: C=Cc1ccccn1
Reactant: O=C1Nc2ccccc2N2CCNCC12
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2ccccc2N2CCN(CCc3ccccn3)CC12

Procedure:
2,3,4,4a-Tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (7 g.) and 2-vinylpyridine (12 g.) in 150 ml. of methanol containing 5 ml. glacial acetic acid were heated under reflux for 24 hours. After removing solvent under reduced pressure, the residue was slurried with water and the insoluble material filtered off and washed with water. After drying there was obtained 9.3 g. of the title compound. A portion recrystallized from ethanol gave a m.p. of 167°-69° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]=1.[F:12][C:13]([F:27])([F:26])[O:14][C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[CH:23][NH:24][CH:25]=2)[CH:18]=[CH:19][CH:20]=1.N12CCCN=C1CCCCC2>CN(C)C=O.O>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]=[C:2]([N:24]2[CH:25]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:26])[F:27])[CH:16]=3)[N:22]=[CH:23]2)[N:7]=1.[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[CH:5]=[C:6]([N:24]2[CH:25]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:26])[F:27])[CH:16]=3)[N:22]=[CH:23]2)[N:7]=1
Reactant: FC(F)(F)Oc1cccc(-c2c[nH]cn2)c1
Reactant: CCCc1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCc1cc(-n2cnc(-c3cccc(OC(F)(F)F)c3)c2)nc(Cl)n1
Product: CCCc1cc(Cl)nc(-n2cnc(-c3cccc(OC(F)(F)F)c3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 2,4-dichloro-6-propyl-pyrimidine (0.15 g) and 4-(3-trifluoromethoxy-phenyl)-1H-imidazole (0.2 g) in N,N-dimethylformamide (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL). After stirring at room temperature overnight, the solution was taken up in water and extracted three times with ethyl acetate. The ethyl acetate layers were combined washed twice with brine, dried over magnesium sulfate, and the volatiles were removed in vacuo. The resulting oil was purified on silica gel using 20% ethyl acetate/hexanes as the mobile phase to yield 4-chloro-6-propyl-2-[4-(3-trifluoromethoxyphenyl)-imidazol-1-yl]-pyrimidine (72.5 mg, first eluting regioisomer, ESI-MS (m/z) 383.3/385.2 [M+H]+, and 2-chloro-4-propyl-6-[4-(3-trifluoromethoxyphenyl)-imidazol-1-yl]-pyrimidine (88.4 mg, second eluting regioisomer).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](F)[N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[S:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([O:10][C:11]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[S:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Oc1csc(C(F)(F)F)c1
Reactant: Cc1cc(F)nc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)nc(Oc2csc(C(F)(F)F)c2)c1
Temperature: 80 °C
Yield: 65 %

Procedure:
A solution of 2-bromo-6-fluoro-4-methyipyridine (1.00 g, 5.26 mmol) and 4-hydroxy-2-(trifluoromethyl)-thiophene (0.88 g, 5.26 mmol) in dimethylformamide is treated with K2CO3 (1.09 g, 7.89 mmol), heated at 80° C. for 23 hours, cooled to room temperature, poured onto water, acidified to pH 5-6 with 6N HCl and extracted with ether. The ether extracts are combined, washed sequentially with water and brine, dried over MgSQ4 and concentrated in vacuo to give a residue. The residue is chromatographed (silica gel, ethyl acetate/hexanes, 3/97) to afford the title produce as a yellow oil, 1.16 g (65% yield), identified by 1HNMR and 19FNMR analyses.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(Cl)cc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,4-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: Cl[C:2]1(Cl)[CH2:7][O:6][CH2:5][CH2:4][O:3]1.[CH3:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH2:12]>C1COCC1>[N+:17]([C:15]1[CH:14]=[CH:13][C:11]([N:12]2[CH2:2][CH2:7][O:6][CH2:5][C:4]2=[O:3])=[C:10]([CH3:9])[CH:16]=1)([O-:19])=[O:18]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: ClC1(Cl)COCCO1
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1N1CCOCC1=O
Temperature: 80 °C

Procedure:
1.05 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molar ratio 1:1) are added to a solution of 1.10 g (7.24 mmol) of 2-methyl-4-nitroaniline in 20 ml of THF, and the mixture is heated to the boil. The solvent is distilled off, and the residue, a brown viscous liquid, is heated at 80° C. for 18 hours. After cooling, the residue is recrystallised from toluene/tert-butyl methyl ether: 1.50 g of 2-(2-chloroethoxy)-N-(2-methyl-4-nitrophenyl)acetamide as yellowish crystals, m.p. 113-114° C. 1H-NMR (d6-DMSO): δ=2.35 (s; 3H), 3.82 (m; 4H), 4.23 (s; 2H), 8.05 (d, J=8 Hz, 1H) 8.09 (dd, J=9 Hz, J=1 Hz, 1H), 8.16 (d, J=1 Hz, 1H), 9.33 (s, 1H).
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][N:4]([C:7](OC(Cl)(Cl)Cl)=[O:8])[CH2:3][CH2:2]1.O.[NH2:22][NH2:23].CCOC(C)=O>C1COCC1.[Cl-].[Na+]>[NH:22]([C:7]([N:4]1[CH2:5][CH2:6][N:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][CH2:3]1)=[O:8])[NH2:23]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(Cl)(Cl)Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)NN)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIPEA (105 g, 0.81 mol) was added to a solution of tert-butyl piperazine-1-carboxylate (25.0 g, 0.134 mol) in DCM (250 mL) at 0° C., followed by the addition of triphosgene (92 g, 0.27 mol) in portions over a 40 min time period. The reaction mixture was stirred for at rt for 3 hrs, filtered and concentrated to afford 1-tert-butyl 4-trichloromethyl piperazine-1,4-dicarboxylate (50 g) as an oil. A solution of 1-tert-butyl 4-trichloromethyl piperazine-1,4-dicarboxylate (50 g, 0.145 mol) in THF (50 mL) was added dropwise over a 30 minute period to a solution of hydrazine hydrate (18 mL, 0.434 mol) in THF (150 mL). The reaction mixture was stirred at rt for 2 hrs, diluted with saturated sodium chloride (50 mL) and exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried with Na2SO4, and concentrated. The residue was purified by crystallization (3:1 petroleum ether/EtOAc) to obtain of tert-butyl 4-(hydrazinecarbonyl)piperazine-1-carboxylate, (13 g, 40% for two steps). ESI-MS (EI+, m/z): 245 [M+H]+. 1H-NMR (500 MHz, CDCl3): δ5.92 (s, 1H), 3.45-3.35 (m, 8H), 1.41 (s, 9H).
Reaction SMILES: [Na].[OH:2][C:3]1[C:8]([CH2:9]N(CC)CC)=[CH:7][C:6]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])=[CH:5][C:4]=1[N:23]1[N:27]=[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]2=[N:24]1.[OH:32][C:33]1[CH:46]=[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:44]=[CH:43][C:34]=1[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C[O-].[Na+]>CO>[N:24]1[N:23]([C:4]2[CH:5]=[C:6]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH:7]=[C:8]([CH2:9][C:46]3[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:44][CH:43]=[C:34]([C:35](=[O:36])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33]=3[OH:32])[C:3]=2[OH:2])[N:27]=[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=12
Reactant: CCN(CC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reaction time: 24 h
Yield: 62 %

Procedure:
Methanol (50 ml) is placed into a 300 ml three-necked flask equipped with a stirrer, thermometer, condenser, Dean-Stark trap and nitrogen inlet. Sodium (0.3 g, 0.013 tool) is added to the methanol and the mixture stirred at room temperature till all the sodium is dissolved. Then, 2-(2-hydroxy-3-diethylaminomethyl-5-tert-octylphenyl)-2H-benzotriazole (10.2 g, 0.025 mol), 2-hydroxy-4-n-octyloxybenzophenone (8.2 g, 0.025 mol) and another 50 ml of methanol are added to the sodium methoxide solution. The reactants are heated at reflux till half the methanol is collected in the Dean-Stark trap. o-Xylene (50 ml) is added and the temperature is raised to the reflux temperature of o-xylene (143°-145° C.) and heating is continued for 24 hours. The mixture is then cooled and acetic acid is added to neutralize the sodium methoxide catalyst. The o-xylene solvent is then removed by vacuum distillation. The crude product obtained is recrystallized from heptane to afford the title compound in a yield of 10 g (62 % yield) as a white crystalline solid melting at 96°-100° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: C#CCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#CCON=C(C(=O)O)c1csc(N)n1
Yield: 77.3 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 2.8 g.), methanol (23 ml.), tetrahydrofuran (20 ml.) and 1 N aqueous solution of sodium hydroxide (22.17 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.924 g.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)Cl
Reactant: CCS(=O)(=O)Nc1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1cccc(NS(=O)(=O)CC)c1
Yield: 82.5 %

Procedure:
To 20.0 g (0.099 mol) of N-(3-hydroxyphenyl)ethanesulfonamide, 10.06 g (0.099 mol) of triethylamine and 150 ml of methylene chloride cooled to 0° C., was added a solution of 10.39 g (0.099 mol) of methacryloyl chloride in 100 ml of methylene chloride, dropwise. Stirring was continued at reduced temperature for 4 hours, after which the solution was washed once with 2 percent hydrochloric acid, twice with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave 22.0 g (82.5 percent yield) of non-crystallizable oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[CH:16][C:15]([O:18][C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.I[CH2:48][C:49]([NH2:51])=[O:50].O>CN(C)C=O>[NH2:51][C:49](=[O:50])[CH2:48][N:17]1[C:12](=[N:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=3)[CH:22]=[CH:23][CH:24]=2)=[CH:16]1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To a solution of N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (2.7 g, 5.12 mmol) in N,N-dimethylformamide (18 mL) was added N,N-diisopropylethylamine (0.94 mL, 5.38 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (995 mg, 5.38 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100) and recrystallized from ethyl acetate and hexane to give the title compound (1.84 g, 61%) as a colorless solid.
Reaction SMILES: [C:1]([O:5]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.[CH2:16]([NH:19][C:20]1[N:21]=[C:22]([NH2:30])[C:23]2[S:28][CH:27]=[C:26]([CH3:29])[C:24]=2[N:25]=1)[CH:17]=[CH2:18].[CH2:31]([NH2:34])[CH:32]=[CH2:33].C(OCC)(=O)C.CCCCCC>C(#N)C>[CH2:16]([NH:19][C:20]1[N:21]=[C:22]([NH:30][C:1](=[O:5])[NH:34][CH2:31][CH:32]=[CH2:33])[C:23]2[S:28][CH:27]=[C:26]([CH3:29])[C:24]=2[N:25]=1)[CH:17]=[CH2:18]
Reactant: C=CCNc1nc(N)c2scc(C)c2n1
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCNC(=O)Nc1nc(NCC=C)nc2c(C)csc12
Reaction time: 0.33 h
Yield: 17.8 %

Procedure:
122 mg (1.0 mmol) of N,N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyldicarbonate in acetonitrile at room temperature, followed by stirring 20 minutes. After 220 mg (1.0 mmol) of 2-allylamino-4-amino-7-methylthieno[3,2-d]pyrimidine was added to the reaction solution, the mixture was stirred at room temperature for 2 hours. Further, 80 mg (1.4 mmol) of allylamine was added thereto, followed by heating under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=,1/2] to give 54 mg (yield: 18.8%) of the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:25])[C:15]=2[N:14]=[CH:13]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:25])[C:15]=2[N:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)NCCCn1cnc2c(Cl)nc3ccccc3c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCn1cnc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
50 mg (0.139 mg) of 1-[3-(tert-butoxycarbonylamino)-propyl]-4-chloro-1H-imidazo[4,5-c]quinoline was dissolved in 3 ml of methylene chloride. 0.11 ml (1.39 mmol) of trifluoroacetic acid was added thereto and the mixture was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure and 1 ml of a 1N sodium hydroxide aqueous solution and brine were added to the residue. The resulting solution was extracted with chloroform five times, thereafter the extract was dried (Na2SO4), and concentrated under reduced pressure. The residue was triturated with diethyl ether (containing a small amount of methylene chloride) and the precipitate thus formed was collected by filtration to obtain 14 mg (0.0536 mmol) of 1-(3-aminopropyl)-4-chloro-1H-imidazo[4,5-c]quinoline shown below as white powder. ##STR37## Its spectroscopic data are as follows: IR (KBr) cm- 1 : 340, 1590, 1510. 1H-NMR (CDCl3 +CD3OD) 5 (ppm) : 2.06 (2H, m), 2.72 (2H, t, J=6.8 Hz), 2.98 (2H, b r), 4.64 (2H, t, J=7.0 Hz), 7.57 (1H, t, J=7.6 Hz), 7.61 (1H, t, J=7.6 Hz), 8.03 (1H, s), 8.05 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=8.0 Hz).