Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[NH:12][C:11]2=[S:21])[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:31]([S:21][C:11]1[N:10]([C@@H:9]2[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]2)[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=2[N:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(=S)[nH]c3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OC[C@@H]1C[C@H](n2c(SCc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 65 %

Procedure:
A mixture of (±)-(1R*,2S*,3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.50 g, 1.05 mmol), benzyl bromide (0.3 mL, 2.5 mmol) and anhydrous potassium carbonate (0.145 g, 1.05 mequiv as 98%) in dioxane (5 mL) was stirred vigorously at ambient temperature for 2.5 days. Volatiles were evaporated in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried(sodium sulfate) and concentrated to an oil which was stirred in ammonia-methanol (40 mL of half-saturated) for 18 hours. Volatiles were evaporated and the residue solidified from 3:1 methanol-water to give title compound as a white powder (300 mg, 65%), m.p. 160°-162° C.; 1H-NMR(DMSO-d6) δ: 8.04 and 7.89 (both s, 1 each, 2 aromatic CH), 7.5-7.2 (m, 5, C6H5), 5.06 (t, J=4.7 Hz, 1, OH), 4.98 (d, J=6.2 Hz, 1, OH), 4.75-4.55 (m overlapping d at 4.68, J=3.7 Hz, and s at 4.63, total 4, NCH, OH, and SCH2); mass spectrum(CI): 439 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[CH2:11]([O:13][C:14]([NH:16][C@@H:17]([C:21]([S:24][CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22])[C:18](O)=[O:19])=[O:15])[CH3:12].CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:18](=[O:19])[C@@H:17]([NH:16][C:14]([O:13][CH2:11][CH3:12])=[O:15])[C:21]([S:24][CH:25]([CH3:27])[CH3:26])([CH3:22])[CH3:23])=[O:10]
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC)C(C)(C)SC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
A mixture of (L)-proline methyl ester hydrochloride (0.28 g), 2-(R)-ethoxycarbonylamino-3-isopropylsulfanyl-3-methyl-butyric acid (0.44 g), N-methyl morpholine (0.73 mL) and 0.54 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethylformamide was stirred for 16 h at ambient temperature. The volatiles were pumped off and water was added followed by extraction with ethyl acetate and concentration of the organic layer. The remaining residue was purified by silica chromatography (ethyl acetate/isohexane=1/1) to give 0.45 g (72%) of the title compound as a colorless oil. (+)-APCI-MS: 375 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH3:14][S:15][C:16]1[S:20][C:19]([NH2:21])=[N:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](=[O:8])[NH:21][C:19]1[S:20][C:16]([S:15][CH3:14])=[CH:17][N:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CSc1cnc(N)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cnc(NC(=O)c2ccccc2OC(C)=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Under nitrogen a solution of acetylsalicyloyl chloride (1.237 g, 6.20 mmol, 1.3 eq) in THF (40 mL) was added to a stirred solution of 5-(methylthio)thiazol-2-amine? (700.0 mg, 4.79 mmol, 1.0 eq) in dry THF (mL). This was followed by the addition of triethylamine (0.67 mL, 4.79 mmol, 1.0 eq). The reaction mixture was stirred at room temperature and monitored by TLC. After two hours, reaction was filtered through sintered funnel and solvent removed in vacuo. The crude product was dissolved in EtOAc (150 mL) and washed twice each with 1M HCl and saturated aq. sodium hydrogen carbonate solutions. The organic fraction was dried over MgSO4 followed the removal of solvent. Flash column chromatography yielded the pure product 69 (1.450 g, 98%) as a solid.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[C:32]=1[O:41][CH3:42])=[O:30].O>C(O)(C)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[C:32]=3[O:41][CH3:42])=[O:30])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1OC
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(C(=O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
In 60 ml of isopropanol were taken up 11.9 g (47 mmol) of 1-diphenylmethylpiperazine and 5.23 g (52 mmol) of triethylamine, and the resultant mixture was added with a solution which had been prepared by dissolving 13.6 g (47 mmol) of 2-bromo-1-(2,3,4-trimethoxyphenyl)ethanone in 50 ml of isopropanol. After being stirred for 3 hours at room temperature, the reaction mixture was poured into 200 ml of water. The mixture was extracted with 150 ml of ethyl acetate. The thus obtained organic layer was washed successively with water and saturated saline and thereafter dried over anhydrous sodium sulfate. After removal of the solvent, the residue was recrystallized from ethanol to give 14.8 g of 2-(4-diphenylmethylpiperazinyl)-1-(2,3,4-trimethoxyphenyl)ethanone (yield: 68%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]O.S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:3]2[C:2]([F:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([F:13])[C:4]=2[CH2:5][Cl:27])[CH2:15][CH2:16]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CCl)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (8.5 g) in chloroform (85 ml) is added thionyl chloride (2.7 ml) at room temperature. The mixture is stirred at the same temperature for 30 minutes, and the reaction mixture is poured into ice water, and then neutralized with sodium hydrogen carbonate and extracted with diethyl ether. The extract is dried over magnesium sulfate, and then the solvent is distilled off to give 2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitrobenzyl chloride (8.1 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:6]=[C:7]([C@H:10]([CH2:19][CH:20]=C)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[O:8][CH:9]=1)=[O:4].I([O-])(=O)(=O)=[O:24].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:6]=[C:7]([C@H:10]([CH2:19][CH:20]=[O:24])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[O:8][CH:9]=1)=[O:4]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)N(C)C)co1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=O)c1coc([C@H](CC=O)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
A solution of tert-butyl (3R)-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}-5-hexenoate (Preparation 117) (1.0 g, 3.24 mmol) in acetone (20 ml) and water (20 ml) was treated with osmium tetroxide, 2.5% wt in tert-butanol (500 μl, 0.04 mmol) and stirred at room temperature for 5 minutes. Sodium periodate (2.13 g, 10.00 mmol) was added and the reaction mixture stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and aqueous sodium thiosulphate solution (20% wt). The organic layer was washed with water (×2) and brine, dried over anhydrous sodium sulphate and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (866 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[C:12]([SiH2:16][O:17][C:18]([CH3:33])([CH3:32])[C:19]1[CH:20]=[C:21]([NH2:31])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[C:19]([C:18]([CH3:33])([CH3:32])[O:17][SiH2:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:20]=2)=[N:4][CH:3]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(N)ccc1N1CCOCC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(Nc2ncc(Br)n3ccnc23)ccc1N1CCOCC1
Yield: 21.5 %

Procedure:
In the same way as described in the general procedure for amine displacement using 5,8-dibromo-imidazo[1,2-a]pyrazine (0.534 g, 1.94 mmol), 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-morpholin-4-yl-phenylamine (0.751 g, 2.33 mmol), N,N-diisopropyethylamine (0.31 mL, 1.8 mmol) and iso-propanol (10 mL). Purification by silica gel column chromatography eluting with 7:3 petroleum ether:ethyl acetate followed by trituration with diethyl ether affords the title compound (0.216 g, 17%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]O)[CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:24]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:81]/[O:82][CH3:83])/[C:50]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[S:64])=[C:57](C(=O)C)[CH2:58][S:59][C@H:54]23)=[O:51])[N:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1CCOCC1.[F:90][C:91]([F:104])([F:103])[S:92]([O:95][CH2:96][CH:97]1[CH2:102][CH2:101][O:100][CH2:99][CH2:98]1)(=[O:94])=[O:93]>C(N(CC)CC)C.N1C=CC=CC=1>[F:103][C:91]([F:90])([F:104])[S:92]([O:95][CH2:96][CH:97]1[CH2:98][CH2:99][O:100][CH2:101][CH2:102]1)(=[O:93])=[O:94].[C:24]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:81]/[O:82][CH3:83])/[C:50]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[S:64])=[C:57]([CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:58][S:59][C@H:54]23)=[O:51])[N:48]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OCC1CCOCC1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=S(=O)(OCC1CCOCC1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1COCCN1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCOCC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 98 %

Procedure:
Tetrahydropyran-4-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27(a) from tetrahydropyran-4-yl-methanol (348 mg), pyridine (0.27 ml) and trifluoromethanesulfonic acid anhydride (931 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (866 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27(b), followed by reacting the resulting reaction product with the tetrahydropyran-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27(b). The reaction solution so obtained was post-treated in the same manner as in Example 27(b) and the produced compound was recovered and purified similarly to Example 27 (b) to afford the titled compound (904 mg; 98%).
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].C(N(CC)CC)C.[CH2:19]([N:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])[CH3:20].O>ClCCl>[CH2:19]([N:21]([CH2:25][CH3:26])[C:22](=[O:23])[O:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11])[CH3:20]
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: CCN(CC)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC1CC(=O)N(COC(=O)N(CC)CC)C1

Procedure:
To a solution of 1-(hydroxymethyl)-4-propyl-pyrrolidin-2-one a24 (4 g, 25.44 mmol) and triethylamine (1.2 eq, 30.53 mmol, 3.089 g; 4.26 ml) in 25 ml of dichloromethane was added dropwise a solution of diethylcarbamyl choride (1.1 eq, 27.99 mmol, 3.795 g, 3.55 ml) in dichloromethane (5 ml) at room temperature. The crude mixture was allowed to react under agitation and inert atmosphere overnight. Hydrolysis (15 ml of water), extraction (CH2Cl2), drying of the combinated organic layers (MgSO4), filtration and solvent evaporation under reduced pressure gave (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate a26 (100%) which was used without any further purification.
Reaction SMILES: [C:1]1(=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=N)[NH:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=N)[NH:2]1.[CH3:21][N:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[N:25]([CH3:31])[C:23]1=[O:24]>CN1C(=O)CCC1.C(O)(=O)C>[CH3:31][N:25]1[C:26](=[O:27])[C:28](=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[C:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3](=[C:28]4[C:29](=[O:30])[N:22]([CH3:21])[C:23](=[O:24])[N:25]([CH3:31])[C:26]4=[O:27])[NH:2]3)[NH:12]2)[C:29](=[O:30])[N:22]([CH3:21])[C:23]1=[O:24]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: N=C1NC(=C2NC(=N)c3ccccc32)c2ccccc21
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CN1C(=O)C(=c2[nH]c(=c3[nH]c(=C4C(=O)N(C)C(=O)N(C)C4=O)c4ccccc34)c3ccccc23)C(=O)N(C)C1=O
Temperature: 25 °C

Procedure:
10 g of [1,1′]biisoindolylidene-3,3′-diimine and 18.1 g of 1,3-dimethyl-barbituric acid are stirred in a mixture of 160 ml of NMP and 40 ml of glacial acetic acid at reflux for 5 hours. After cooling to room temperature the suspension is filtered and the filter product is washed with ethanol and then water and dried at 60° C. This gives 14.5 g (70%) of a virtually black powder of a compound of the following formula
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]([Cl:23])[N:8]=1)C.O.[OH-].[K+].Cl>C(O)CO>[Cl:23][C:9]1[N:8]=[C:7]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:13][C:12]2=[CH:11][CH:10]=1
Reactant: CCOC(=O)CNc1nc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A solution of N-[6-chloro-3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (1.7 g. 0.00462 mole) in ethylene glycol (25 ml) was refluxed under nitrogen for two hours. To one-half of the solution (0.0023 mole) was added water (2 ml) and solid potassium hydroxide (0.20 g, 0.003515 mole) and the mixture was refluxed for an additional 15 minutes, poured into ice water (100 ml) and acidified with 3N hydrochloric acid solution. The resulting solid was collected by filtration, rinsed with water, dissolved in hot methanol and filtered hot. Addition of water to the cloud point and cooling to room temperature gave a solid which was collected by filtration, washed with water, and dried at 60° C. under high vacuum to give 0.4 g (54% yield) of title compound, mp >250° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH4+].[OH-]>C(O)C.[Ni].O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH2:29])[CH2:20][CH2:21]2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Yield: 105.7 %

Procedure:
4-(2-Cyanophenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (˜5.3 mmol) was dissolved in 50 mL of ethanol. 5 mL of aqueous NH4OH was added along with 500 mg of 50% Raney nickel in water. The reaction mixture was hydrogenated in a Parr shaker at 45 psi overnight. The reaction mixture was filtered through a plug of Celite and concentrated under vacuum. 2.5 g of crude product was obtained, and used without further purification.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]=1[N:19]([C:28]([C:30]([F:33])([F:32])[F:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)=O.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[F:32][C:30]([F:31])([F:33])[C:28]([N:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:7]1[CH:8]=[C:9]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([F:12])=[CH:11][C:6]=1[NH2:5])=[O:29]
Reactant: CCOC(=O)Nc1cc(N(Cc2cccc(Cl)c2)C(=O)C(F)(F)F)c(NC(=O)C(F)(F)F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=O)Nc1cc(N(Cc2cccc(Cl)c2)C(=O)C(F)(F)F)c(N)cc1F
Yield: 105.4 %

Procedure:
A solution of 3.7 grams (0.007 mole) of N-trifluoromethylcarbonyl-2-[(trifluoromethylcarbonyl)(3-chlorophenylmethyl)amino]-4-ethoxycarbonylamino-5-fluoroaniline in 50 mL of methanol was stirred, and a solution of 1.0 gram (0.007 mole) of potassium carbonate in a minimum amount of water was added. The reaction mixture was then heated at reflux for about three hours, after which the reaction mixture was cooled, poured into cold water, and acidified to a pH of 6 with aqueous 3N hydrochloric acid. The resultant solid was collected by filtration and dried, yielding 3.2 grams of 2-[(trifluoromethylcarbonyl)(3-chlorophenylmethyl)amino]-4-ethoxycarbonylamino-5-fluoroaniline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=4)=[N:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[C:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1>CC(C)=O>[F:55][C:52]1[CH:53]=[CH:54][C:49]([C:48]#[C:47][CH2:46][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]4[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=5)=[N:11][C:10]=4[N:9]=3)=[CH:6][CH:7]=2)=[CH:50][CH:51]=1
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCC#Cc4ccc(F)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Yield: 42.9 %

Procedure:
A mixture of 8-(4-Hydroxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.115 g, 0.21 mmol), potassium carbonate (0.067 g, 0.48 mmol), 1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.67 g, 0.27 mmol) and acetone (10 ml) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. Solvent was evaporated and the residue was purified by preparative TLC to obtain pure 8-{4-[3-(4-Fluoro-Phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.061 g, 43%) as pale yellow oil.
Reaction SMILES: COC1C=CC=CC=1CC(C1[CH:20]2[C:15](CO)(CC3C=CC=CC=3[CH:19]2[C:21]2C=CC=CC=2)[CH2:14][NH:13]1)=O.[F:33][C:34]([F:47])([F:46])[S:35]([O:38]S(C(F)(F)F)(=O)=O)(=[O:37])=[O:36].O>N1C=CC=CC=1>[F:33][C:34]([F:47])([F:46])[S:35]([O-:38])(=[O:37])=[O:36].[NH+:13]1[CH:14]=[CH:15][CH:20]=[CH:19][CH:21]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccccc1CC(=O)C1NCC2(CO)Cc3ccccc3C(c3ccccc3)C12
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)([O-])C(F)(F)F
Product: c1cc[nH+]cc1

Procedure:
500 mg (1.1 mmol) of (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano-2-(2-methoxyphenyl)acetyl-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-methanol are dissolved, at a temperature in the region of 20° C. under a nitrogen atmosphere, in 10 cm3 of pyridine which has been dried over potassium hydroxide and then 336 mg (1.2 mmol) of trifluoromethanesulphonic anhydride are added. After stirring for 3 hours at a temperature in the region of 20° C., 25 cm3 of water are added and extraction is carried out with 3 times 25 cm3 dichloromethane. The combined organic phases are washed with 0.1N hydrochloric acid and then with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by recrystallizing from a methanol/isopropyl ether (60/40 by volume) mixture. 310 mg (42%) of N-[(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano-2-(2-methoxyphenyl)acetyl-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindolyl-3a-methyl]pyridinium trifluoromethanesulphonate are thus obtained in the form of pale-yellow crystals, the characteristics of which are as follows: melting point=244° C., 1H N.M.R. spectrum (250 MHz, d6-(CD3)2SO, at a temperature of 393 K, δ in ppm): 1.37, 1.67, 1.98 and 2.12 (4 mts, each 1H, CH2CH2), 2.80 (mt, 1H, H at 9a), 3.20 (mt, 1H, H at 4), 3.38 (limit AB, 2H, CH2 at 1), 3.52 (broad s, 2H, COCH2Ar), 3.56 at 4.02 (2 d, J=12.5 Hz, each 1H, CH2 at 3), 3.68 (unresolved peak, 3H, OCH3), 4.38 and 4.50 (2 d, J=12.5 Hz, each 1H, CH2N+), 6.51 (broad d, J=7.5 Hz, 1H, H at 8), 6.88 (broad t, J=7.5 Hz, 1H, aromatic H para to the OCH3), 6.95 (broad d, J=7.5 Hz, 1H, aromatic H ortho to OCH3), 7.15 (dt, J=7.5 and 2 Hz, 1H, H at 7), from 7.20 to 7.45 (mt, 4H, H at 5, H at 6 and aromatic H meta to the OCH3), from 7.35 to 7.60 (mt, 5H, aromatic H of the phenyl at 9), 8.15 (broad t, J=7 Hz, 2H, H at 3 and H at 5 of the pyridyl), 8.65 (broad t, J=7 Hz, 1H, H at 4 of the pyridyl), 8.91 (broad t, J=7 Hz, 2H, H at 2 and H at 6 of the pyridyl).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[H][H]>[Ni].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: [H][H]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1N
Reaction time: 3.5 h

Procedure:
70 g of 3-nitro-4-methylphenol, prepared according to German Offenalegungschrift No. 2,213,568, 200 ml of tetrahydrofuran and 2 g of activated Raney nickel catalyst were placed in a Parr bomb. The mixture was shaken for 3.5 hours under 60 p.s.i. hydrogen pressure. The mixture then was filtered and the solvent was evaporated from the filtrate. The residue was recrystallized from ether to give 3-amino-4-methylphenol (3A), as a grey solid, mp: 145°-148° C.