Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:22])[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)C(OC(=O)C)CC[N:8]3[CH:7]=1)=O.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][C:33]([NH2:35])=[O:34])=[CH:24]1.CC(C)([O-])C.[K+].Cl.[O:43]1C[CH2:46][CH2:45][CH2:44]1>O>[OH:43][CH:44]1[C:16]2[C:17]3=[C:12]([C:6]([C:4]4[C:3](=[O:22])[NH:35][C:33](=[O:34])[C:32]=4[C:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[NH:23][CH:24]=4)=[CH:7][N:8]3[CH2:46][CH2:45]1)[CH:13]=[CH:14][CH:15]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)C(OC(C)=O)CC2
Reactant: C1CCOC1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)C(O)CC3)=C1c1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 36 %

Procedure:
To a solution of methyl[6-(acetyloxy)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl](oxo)acetate (632 mg, 2.09 mmol) and indole-3-acetamide (328 mg, 1.88 mmol) in anhydrous tetrahyrofuran (25 mL) at 0° C. was added a solution of potassium tert-butoxide (9.3 mL, 9.3 mmol, 1M in THF) dropwise over 30 min. The mixture was stirred at 0° C., allowed to warm to room temperature and stirred for 2 h. Concentrated hydrochloric acid (1 mL) was added and the mixture stirred for 1 hour at room temperature. The mixture was diluted with water (25 mL), and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography, eluting with a methanol/dichloromethane (1-5%) to afford 3-(6-hydroxy-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione as a bright red solid (293 mg, 36%). Mp: 165-168° C.; 1H NMR (DMSO-d6) 400 MHz δ: 11.62 (brs, 1H), 10.89 (brs, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 6.96-6.94 (m, 3H), 6.71 (t, J=7.4 Hz, 1H), 6.59 (d, J=7.4 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H), 5.41 (d, J=5.0 Hz, 1H), 4.89 (brs, 1H), 4.26 (s, 2H), 3.33 (s, 2H); LCMS [M+H]: 384.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:16].C(N(C(C)C)CC)(C)C.[F:26][C:27]1[CH:41]=[CH:40][C:30]2[C:31]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:32][O:33][C:29]=2[CH:28]=1>CO>[CH3:16][C:5]1[N:6]=[C:7]2[N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[OH:15])[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:37]1[CH2:36][CH2:35][CH:34]([C:31]2[C:30]3[CH:40]=[CH:41][C:27]([F:26])=[CH:28][C:29]=3[O:33][N:32]=2)[CH2:39][CH2:38]1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 62.5 °C
Reaction time: 16 h

Procedure:
3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-7) (5.2 grams) and diisopropyl ethyl amine (12.56 grams) was added to 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (formula-8) (5.0 grams) in methanol (75 ml) taken in autoclave and then heated to 60-65° C., 0.8 Kg pressure was applied and stirred for 16 hours. The reaction mixture cooled and then distilled under reduced pressure. Isopropyl alcohol was added to the obtained residue and stirred for 15 minutes and then distilled off under reduced pressure to get the title compound. Added methanol and heated the reaction mixture to reflux temperature and stirred for 2.0 hrs at same temperature. Cooled the reaction mixture to 20° C. and stirred for 90 minutes at the same temperature. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)=[O:4].S(Cl)(Cl)=O.CC(C)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([N:22]=[N+:23]=[N-:24])=[O:13])[CH:6]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C(=O)O)nn1C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)N=[N+]=[N-])nn1C
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
1-Methyl-1H-pyrazole-3,5-dicarboxylic acid 5-methyl ester (641, 3.2 g, 17.0 mmol) was combined with thionyl chloride (5 mL). The reaction was heated to reflux for 40 minutes and then concentrated twice from toluene. The resulting solid was dried under reduced pressure overnight. The product was dissolved into acetone (20 mL) and sodium azide (3.5 g, 54.0 mmol) was added in water (10 mL) rapidly at once. The obtained solution was stirred for one minute and then poured into ice-water (50 mL). The precipitate was filtered and dried under reduced pressure. The final compound was used without further purification (642, 2.8 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Br:27][CH:28]([CH2:32][CH3:33])[C:29](Br)=[O:30]>C(Cl)Cl>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=[C:11]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[CH:28]([Br:27])[CH2:32][CH3:33])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(N)ccc1-c1cc2ccccc2s1
Reactant: CCC(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-(1-benzothien-2-yl)benzamide (Example 8A, 886 mg) and triethylamine (650 mg) are introduced into DCM (20 ml) at 0° C., and 2-bromobutyryl bromide (1000 mg) is slowly added. The reaction mixture is warmed to RT and then stirred overnight. The reaction mixture is subsequently diluted with DCM (100 ml) and washed with 5% strength potassium bisulfate solution (twice 50 ml), dried (sodium sulfate) and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (eluent cyclohexane-ethyl acetate 10:1 to 1:1). After concentration of the relevant fraction, 607 mg (47% of theory) of product are isolated.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH2:16][CH2:17][CH2:18][C:3]1=2.[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+]>CO>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:16]1[C:4]2[O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=3[C:2](=[O:1])[C:3]=2[CH2:18][CH2:17]1
Reactant: Cc1ccccc1C=O
Reactant: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3=Cc1ccccc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester, m.p. 156°-158° C. (5.1 g) was reacted with 2-methyl-benzaldehyde (3.3 g) in methanol (80 ml) in the presence of sodium methylate (2.28 g) under stirring at room temperature for 20 hours. The precipitate was filtered and washed with methanol and then with water until neutral: crystallization from CH2Cl2 -methanol gave 5.2 g of 3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester, m.p. 203°-205° C.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)=[O:3].[Mn]([O-])(=O)(=O)=[O:25].[K+]>O>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)(=[O:25])=[O:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CS(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 8 h

Procedure:
A stirred solution of 0.64 g (1.98 mmoles) of 2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]pyrrolo[1,2-a]imidazole of Example 4 in water was treated dropwise over 45 minutes with an aqueous solution of 0.209 g (1.32 mmoles) of potassium permanganate. After stirring overnight, the suspension was extracted with methylene chloride. The organic phase was dried over anhydrous potassium carbonate and stripped in vacuo. The residue flash chromatographed in silica eluting with 2 to 4% methanol in chloroform. The solvent was removed in vacuo and the residue recrystallized from ethyl acetate to afford the desired titled compound, mp 222.5°-224° C. 1H NMR (250 MHz, CDCl3) δ 8.62 (2H,d), 7.85 (2H,d), 7.72 (2H,d), 7.26 (2H,d), 4.05 (2H,t), 3.05(s) superimposed upon 3.03(t) (5H total), 2.70 (2H,q).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: OCc1cccc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Br)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
2-Bromo-4-nitrophenol (4.86 g, 0.0223 mol), triphenylphosphine (7.6 g, 0.0290 mol), 3-fluorobenzylalcohol (3.65 g, 0.0290 mol) were combined and dissolved in THF (89 mL). The reaction temperature was cooled to 0° C. and DIAD (4.50 g, 0.0290 mol) was added. The reaction was allowed to warm slowly to rt and stirred for 3 h before it was diluted with water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (200 mL×2). The organic extracts were combined and washed with brine, followed by drying over sodium sulfate. The volatiles were removed in vacuo and the residual semi-solid was treated with diethyl ether. The solids were removed by filtration. The volatiles from the resulting filtrate were removed in vacuo and the material was purified using EtOAc:Hexanes (90/10) in a biotage LC system to afford the title compound as a yellow solid (3.73 g, 68% yield). 1H NMR (DMSO-d6) □ 8.43 (d, 1H); 8.26 (m, 1H); 7.45 (m, 1H); 7.38 (d, 1H); 7.30 (m, 2H); 7.17 (m, 1H); 5.39 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C.O>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:30][CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3
Reactant: NCCCc1ccccn1
Reactant: N#Cc1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cn2c3c(c(NCCCc4ccccn4)c(F)c(N)c3c1=O)OCC21CC1
Yield: 17.2 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopropane]-6-carbonitrile (320 mg, 1.1 mmol) and 3-(pyridine-2-yl)propan-1-amine (270 mg, 2 mmol) and triethylamine (221 μL, 2.7 mmol) in DMSO (8 mL) was stirred at 120° C. for 15 hr. The reaction mixture was added portion wise to water and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The dry residue was purified by column chromatograph (ethylacetate, to ethylacetate-MeOH 10:1) to yield the title compound (76.9 mg) as a yellow solid. MS (EP) m/z: 406.2 (M++1). (Calcd for C22H20FN5O2, 405.42). 1H NMR (400 MHz, CD3OD) δ 1.15 (2H, t), 1.59 (2H, t), 2.03 (2H, t), 2.88 (2H, t), 3.54 (2H, m), 4.15 (2H, s), 7.23 (1H, m), 7.33 (1H, m), 7.74 (1H, m), 8.04 (1H, s), 8.42 (1H, m)
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6]O.[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BrH:28]>C1C=CC=CC=1>[Br-:28].[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)CCCCO
Solvent: c1ccccc1
Product: CN(C)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 155 °C
Yield: 51 %

Procedure:
Into a solution of 4-dimethylaminobutan-1-ol (2.95g, 25 mmol) and triphenylphosphine (6.55 g, 25 mmol) in benzene (20 ml) was bubbled anhydrous HBr at a moderate rate for about 10 minutes with ice bath cooling. The nearly solid white mass was removed from the cooling bath and heated to about 155° C. for about five hours (benzene distilled off at about 80° C.). After cooling to ambient temperature, water was added to the solid mass and the mixture was filtered to remove insoluble material. The acidic filtrate was extracted three times with chloroform and the aqueous layer was made basic (pH 9) with aqueous saturated NaHCO3, and then concentrated to a white solid. The solids were slurried with chloroform and removed by filtration. The filtrate was dried over magnesium sulfate, filtered, concentrated, and recrystallized from ethanol/ether (1/4). White clusters of needles were obtained and dried under vacuum to afford 5.6 g (51%) of title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5].Br[C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C([NH2+]CCC1C=CC=CC=1)C1C=CC=CC=1>C(O)C>[C:17]([O:16][C:14]([C:13]([O:1][N:2]=[C:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])([CH3:22])[CH3:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(O)C(=NO)c1cccs1
Agent: c1ccc(CC[NH2+]Cc2ccccc2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)O)c1cccs1
Yield: 78 %

Procedure:
The title compound was prepared from 2-hydroxyimino-2-(thien-2-yl)acetic acid (syn isomer) and t-butyl 2-bromo-2-methylpropionate, in a similar manner to that described for Preparation 5, in 78% yield as a colourless oil, and was characterised as the N-benzyl-2-phenylethylammonium salt, m.p. 201.3°-201.9° (from ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N1C2C=C(Cl)C=CC=2N=N1)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@H:20]([C:25]([OH:27])=[O:26])[C@H:21]([CH2:23][CH3:24])[CH3:22].C(N(CC)CC)C>O.C(O)(C)(C)C>[C:1]([O:5][C:6]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[C@H:21]([CH2:23][CH3:24])[CH3:22])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)On1nnc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Yield: 104.7 %

Procedure:
A suspension of 1-tert-butoxycarbonyloxy-6-chloro-1H-benzotriazole (2.7 g.), L-isoleucine (1.3 g) and triethylamine (3.5 ml.) in a mixture of water (8 ml.) and tert-butyl alcohol (12 ml.) was stirred for 2 hours at 60° to 62° C. tert-Butyl alcohol was distilled off from the reaction mixture under reduced pressure and water (15 ml.) was added to the residue. The mixture was adjusted to pH 3 with a citric acid aqueous solution under ice-cooling and extracted with ethyl acetate. The extract was in turn washed with water and a saturated sodium chloride aqueous solution, and then precipitates were filtered off, after which the filtrate was dried over magnesium sulfate. The solution was concentrated and to the residue was added a mixture of ether and petroleum ether (1:1). An insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give N-tert-butoxycarbonyl-L-isoleucine (2.4 g.), oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:20]=[C:21]=[O:22])(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:21]([NH2:20])=[O:22])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 68 h
Yield: 84.7 %

Procedure:
3(R/S)-(tert-Butoxycarbonylaminomethyl)piperidine (3 g, 14.0 mmoles) was dissolved in anhydrous dichloromethane (50 mL) and trimethylsilylisocyanate (9.68 g, 11.4 mL, 84.0 mmoles) was added. The mixture was stirred under argon at 25° C. for 68 h. Additional trimethylsilylisocyanate (4.84 g, 5.7 mL, 42.0 mmoles) was added and the mixture was stirred at 25° C. for a total of 90 h. The mixture was evaporated to dryness and chromatographed on a silica gel column (30×5 cm) using 2% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(tert-butoxycarbonylaminomethyl)piperidine-1-carboxamide (3.05 g, 85%): FABMS: m/z 258.1 (MH+); HRFABMS: m/z 258.1816 (MH+). Calcd. for C12H24O3N3: m/z 258.1818; δH (CDCl3) 1.22 91H, m, CH2), 1.42 (9H, s, —COOC(CH3)3), 1.48 (1H, m, CH2), 1.67 (2H, m, CH2), 1.78 (1H, m, CH), 2.80 (1H, m, CH2), 2.99, 3H, m, CH2), 3.59 (1H, m, CH2O 3.69 (1H, m, CH2), 4.76 (2H, bm, CONH2) and 4.98 ppm (1H, bm, NH); δC (CDCl3) CH3, 28.5, 28.5, 28.5; CH2, 24.0, 28.3, 43.2, 45.1, 47.8; CH, 36.5; C, 79.4, 156.3, 158.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N+:8]1([O-])[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C[Si]([C:24]#[N:25])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O.C(Cl)(Cl)Cl>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:7][C:2]1[N:1]=[C:6]([C:24]#[N:25])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)[N+]1([O-])Cc1ccccn1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
2-(2-Pyridylmethyl)-1H-isoindole-1,3(2H)-dione N-oxide (8.0 g, 31 mmol) was dissolved in mixed solvent of nitroethane (80 ml) and chloroform (150 ml), and trimethylsilyl cyanide (9.3 g, 94 mmol) and N,N-dimethylcarbamoyl chloride (6.8 g, 63 mmol) were added thereto. The mixture was stirred at room temperature for 4 hrs and at 60° C. for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.8 g, 22%) as white crystals.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+:9].CN(C=O)C.[Cl:15][C:16]1[C:17]([NH2:25])=[N:18][CH:19]=[C:20]([Cl:24])[C:21]=1[CH2:22]Cl>C1COCC1.O>[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:9].[Cl:15][C:16]1[C:17]([NH2:25])=[N:18][CH:19]=[C:20]([Cl:24])[C:21]=1[CH2:22][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncc(Cl)c(CCl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(Cl)c(COc2ccccc2)c1Cl
Product: [O-]c1ccccc1
Temperature: 60 °C
Yield: 83.3 %

Procedure:
Sodium phenoxide was prepared by the reaction of phenol (250 mg, 2.7 mmol) and sodium hydride (60% in oil, 106 mg, 2.7 mmol) in dry THF (15 ml) at RT. The solvent was removed in vacuo and replaced with dry DMF (10 ml), 3,5-dichloro-4-(chloromethyl)-2-pyridinamine (300 mg, 1.2 mmol) was added and the mixture heated to 60° C. for 2.5 h. After cooling to RT, the reaction mixture was diluted with water (15 ml) and extracted with diethyl ether (4×15 ml)). The combined ethereal extracts were washed with water and saturated brine, dried over MgSO4, then concentrated to a solid. This was crystallised from methylene chloride and hexane to give the title compound as a white solid (219 mg+2nd crop of 45 mg, 1.0 mmol):
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>ClCCl>[C:27]([N:15]1[CH2:16][CH2:17][CH:12]([CH:3]([O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])[C:2]([F:18])([F:1])[F:19])[CH2:13][CH2:14]1)(=[O:30])[CH2:28][CH3:29]
Reactant: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCC(C(O[Si](CC)(CC)CC)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
4-[2,2,2-Trifluoro-1-(triethylsiloxy)ethyl]piperidine (250 mg, 0.841 mmol) was dissolved in dichloromethane (5.0 mL). To this, triethylamine (0.176 mL, 1.26 mmol) and propionyl chloride (0.110 mL, 1.26 mmol) were added at 0° C. and the mixture was stirred at room temperature for 2 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 1-propionyl-4-[2,2,2-trifluoro-1-(triethylsiloxy)ethyl]-piperidine (231 mg, yield: 78%).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([CH2:12][NH:13][C:14](=[O:17])[CH:15]=[CH2:16])[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>O>[C:19]1([N:25]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([CH2:12][NH:13][C:14](=[O:17])[CH:15]=[CH2:16])[C:9]([CH3:10])=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: C=CC(=O)NCC(C(C)=O)C(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: C=CC(=O)NCc1c(C)nn(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 29.4 g of the 1-phenyl-2-(acrylamidomethyl)-butane-1,3-dione prepared according to Synthesis Example I, 12.9 g of phenylhydrazine, 180 ml of acetic acid and 180 ml of water was refluxed for 5 minutes, cooled to room temperature and then diluted with 600 ml of water. The crystals precipitated in this procedure were filtered off under suction and washed with diethyl ether. This gave 37.4 g of 1,5-diphenyl-3-methyl-4-acrylamidomethylpyrazole having a melting point of 157°-159° C. The 1H-NMR spectroscopic measurement confirmed the presence of this product:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([O:3][CH3:4])=[O:2].IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:18])([O:3][CH3:4])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(CC(C)=O)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(CC(C)=O)ccc1OC
Yield: 99.9 %

Procedure:
A mixture of 1-(3-carbomethoxy-4-hydroxyphenyl)propan-2-one (3.0 g), iodomethane (5.0 g), potassium carbonate (7.0 g) was refluxed in acetone until tlc showed no starting material (~6 hours). The mixture was cooled, filtered and evaporated. The residue was partitioned between ether and water and the layers separated. The ether layer was dried (MgSO4) and evaporated to give the title compound (3.2 g). τ (CDCl3) 7.84 (3H, s), 6.35 (2H, s), 6.1 (3H, s), 3.05 (1H, d, J=8 Hz), 2.68 (1H, dd, J=8 Hz, J=2 Hz), 2.36 (1H, d, J=2 Hz).