Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[OH:26])(=[O:18])[CH3:17].O>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:20]1[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[C:16](=[O:18])[CH3:17]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc(C)ccc1O
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3C(C)=O)c2cc1OC
Temperature: 170 °C
Reaction time: 144 h
Yield: 3.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (220 mg) and 2-acetyl-4-methylphenol (300 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 170° C. for 6 days. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (12 mg, yield 4%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[CH2:19][C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:11]=3[N:12]=2)C(=O)C2=CC=CC=C12.CN.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[NH2:5][CH2:6][CH2:7][C:8]1[S:9][C:10]2[CH2:19][C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:11]=2[N:12]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1nc2c(s1)Cc1ccccc1-2
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: NCCc1nc2c(s1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In 20 ml of methanol, 1.79 g of 2-(2-phthalimidoethyl)-8H-indeno[1,2-d]thiazole was dissolved. Then, 40 ml of a 40% solution of methylamine in methanol was added, followed by stirring at room temperature for 14 hours. The solvent was then evaporated, and chloroform and 1N hydrochloric acid were added to the resulting residue. The aqueous layer was separated and then neutralized with a 1N aqueous solution of sodium hydroxide, followed by extraction with chloroform. The chloroform layer separated was washed successively with water and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was dissolved in methanol, and fumaric acid was added thereto. The crystals formed were collected by filtration and then washed successively with methanol and diethyl ether, followed by recrystallization from methanol, whereby 572 mg of 2-(2-aminoethyl)-8H-indeno[1,2-d]thiazole fumarate was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[N:12][CH:13]=1)=[O:19]
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Reactant: NCc1ccccn1
Product: CCc1cc(-c2ccc(C(=O)NCc3ccccn3)cn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and (pyridin-2-ylmethyl)-amine to afford the title compound. MS: m/e=349 (M+H). 1H NMR (δ ppm): 11.71 (s, 1H); 9.28 (t, 1H, J=5.8 Hz); 9.07 (s, 1H); 858 (s, 1H); 8.47 (dd, 1H, J=4.6 and 1.5 Hz); 8.24 (dd, 1H, J=8.3 and 2.5 Hz); 7.75 (m, 1H); 7.63 (d, 1H, J=8.3 Hz); 7.54 (s, 1H); 7.37 (dd, 1H, J=7.7 and 4.6 Hz); 4.53 (d, 2H, J=5.8 Hz); 2.42 (q, 2H, J=7.4 Hz); 2.35 (s, 3H); 1.11 (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]1[CH2:14][C@H:13]([S:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][N:11]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])(=[O:3])[NH2:2].SCCO>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]1[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=1)=[O:36])(=[O:3])[NH2:2]
Reactant: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: OCCS
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To a solution of (2S,4S)-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (1.76 g) in trifluoroacetic acid (10 ml) was added 2-mercaptoethanol (0.38 ml) under ice-cooling and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in toluene (10 ml) and the solution was evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (50 ml), washed successively with saturated aqueous sodium hydrogen carbonate (20 ml) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (0.58 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:12][O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:12][O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(t-butoxycarbonylamino)-3-(t-butyldiphenylsiloxy)propanol (3.03 g) in methylene chloride (100 ml), Dess-Martin periodinane (3.60 g) was added at room temperature. The resulting mixture was stirred for 30 minutes. To the reaction mixture, a saturated aqueous solution (50 ml) of sodium bicarbonate and a 10% aqueous solution (50 ml) of sodium sulfite were added to cause separation. The water layer was extracted with diethyl ether (50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (150 g of silica gel, hexane:ethyl acetate=4:1→3:1), whereby the title compound (2.97 g) was obtained as a colorless transparent oil.
Reaction SMILES: C1(C(F)(F)F)C=CC=CC=1.[F:11][C:12]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)(F)[CH:13]([F:15])[F:14]>O>[F:11][C:12]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[C:13]([F:15])[F:14]
Reactant: FC(F)C(F)(F)n1ccnc1
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: FC(F)=C(F)n1ccnc1
Yield: 7 %

Procedure:
Then the entire crude reaction product was poured into water (30 ml), and subjected to extraction with ethyl acetate. After separation of an organic layer, drying with magnesium sulfate was carried out and concentration under reduced pressure was conducted. Then thereto was added 1.46 g (10 mmol) of benzotrifluoride, and it was confirmed by a 19F-NMR analysis based on benzotrifluoride that 1-(1,1,2,2-tetrafluoroethyl)imidazole had been produced at yield of 7% and 1-(1,2,2-trifluoroethenyl)imidazole had been produced at yield of 39%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[F-:12].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][F:12])=[CH:6][CH:7]=1
Reactant: [F-]
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=C(CF)c1ccc(Br)cc1
Yield: 102.1 %

Procedure:
A mixture of 2-bromo-1-(4-bromophenyl)-1-ethanone (8.54 g, 30.7 mmol), potassium fluoride (8.92 g, 153 mmol) and 18-crown-6 ether (4.06 g, 15.3 mmol) in acetonitrile (170 ml) was refluxed for 7 hr. After evaporation, the mixture was dissolved in ethyl acetate (300 ml), washed with water (100 ml×2), and dried over magnesium sulfate. Removal of solvent gave 6.8 g of brown solid, which was chromatographed on a column of silica gel (600 g) eluting with ethyl acetate/hexane (1:10) to afford 5.00 g (75%) of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(F)cc3)C2)c1

Procedure:
The compound of Example 3 was prepared according to the general preparation protocol A from 4-fluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: CN(C)CCCCCCO.O[C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:57]>O1CCCC1.CCOCC>[ClH:57].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[C:15]1[CH:24]=[CH:25][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CN(C)CCCCCCO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.5 g of N,N-dimethyl-6-amino-1-hexanol (Bull. Soc. Chim. France 1975, 2315), 3.4 g of 4-hydroxybenzophenone (Beilstein 8 (III), 1263), 4.5 g of triphenylphosphine and 140 ml of tetrahydrofuran was treated slowly at 20° with a solution of 2.7 ml of diethyl azodicarboxylate in 15 ml of tetrahydrofuran. After the dropwise addition the mixture was stirred at room temperature for a further 1 hour. The reaction mixture was evaporated in a rotary evaporator and the residue was chromatographed on 400 g of neutral aluminium oxide (activity grade III) with hexane:ethyl acetate (7:3). The yellowish oil obtained was dissolved in 25 ml of ether, whereupon the solution was treated with 25 ml of a 10 percent solution of hydrogen chloride in ether. The colorless crystals which separate were filtered off under suction, washed with ether and recrystallized from acetone. There were obtained 1.93 g (31%) of 4-[(6-dimethylamino)hexyl)oxy]benzophenone hydrochloride of m.p. 121°.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([O:20]C(C)(C)C)=[O:19])[CH:15]=[CH:14][CH:13]=3)=[N:8][C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:11]2[S:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=3)=[N:8][C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(=O)nc(-c3cccc(C(=O)OC(C)(C)C)n3)sc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c(=O)nc(-c3cccc(C(=O)O)n3)sc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
tert-Butyl 6-(8-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylate (0.50 g, 1.4 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at 0° C. for 4 hrs. The solvent was evaporated, and the residue was crystallized from diethyl ether to give the titled compound (0.39 g, 94%) as pale yellow crystals.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[NH:12][C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([O:23][CH3:24])[CH:14]=2.N.CO>O1CCCC1>[NH2:5][C:3]([NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc2c(C(N)=O)c(N)[nH]c2c1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
Trichloroacetyl isocyanate (1.7 mL, 14 mmol) was added dropwide to a solution of 2-amino-6-methoxyindole-3-carboxamide (Reference compound No.2-1, 2.9 g, 14 mmol) in anhydrous tetrahydrofuran (50 mL) at −40° C. over a period of 10 minutes and the mixture was stirred for 2.5 hours. Moreover, 2.0 M ammonia in methanol solution (40 mL, 80 mmol) was added thereto and the mixture was stirred overnight at room temperature. The reaction solution was concentrated in vacuo, and the obtained solid was filtered off and washed with a mixed solvent of chloroform-methanol (50 mL). The solid was dried at 40° C. under reduced pressure to give the title compound (3.1 g) as a gray solid (88%).
Reaction SMILES: P(C1C=CC=CC=1)(C)C.FC(F)(F)S(O[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[Cl:26])(=O)=O.[C:29](#[N:32])[CH:30]=[CH2:31].C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[Cl:26][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1/[CH:31]=[CH:30]/[C:29]#[N:32]
Reactant: C=CC#N
Reactant: O=S(=O)(Oc1ccc2ccccc2c1Cl)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CP(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#C/C=C/c1ccc2ccccc2c1Cl
Yield: 34.9 %

Procedure:
Pd(OAc)2 (3 mol %, 11 mg), PMe2Ph (5 mol %, 11 mg), 1-chloronaphthalen-2-yl trifluoromethanesulfonate (500 mg, 1.61 mmol), acrylonitrile (103 mg, 1.93 mmoli), triethylamine (242 mg, 2.4 mmol) and 15 mL of acetonitrile were added to a microvawe vial and the mixture was irradiated by MW at 120° C. for 1 h. At the conclusion of the reaction, the solvent was evaporated under reduced pressure and the residue was treated with dichloromethane and washed with water; the organic layer was filtered through a pad of silica gel with copious washings, concentrated, and purified by flash chromatography on silica gel eluted with petroleum ether/ethyl acetate (93:7) to give (2E)-3-(1-chloronaphthalen-2-yl)prop-2-enenitrile as colourless oil (120 mg, 35% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]Cl)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClCCCC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCCCC2CCN(c3ccc(Cl)nn3)CC2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A mixture of 4.1 parts of 3-choro-6-[4-(3-chloropropyl)-1-piperidinyl]pyridazine, 2.5 parts of ethyl 3-hydroxybenzoate, 14 parts of potassium carbonate and 94 parts of N,N-dimethylformamide was stirred overnight at 110° C. The reaction mixture was evaporated and the residue was taken up in water and dichloromethane. The separated organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried at 50° C., yielding 4.6 parts (75.9%) of ethyl 3-[3-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]propoxy]benzoate; mp. 105.3° C. (comp. 99).
Reaction SMILES: O=C1OCC(C([O-])=O)C1.[C:10]([O:14][C:15]([C:17](=[C:22]([OH:62])[C:23](=[O:61])[N:24]([C@H:34]([CH3:60])[C@@H:35]([C:51]1[CH:56]=[CH:55][C:54]2[O:57][CH2:58][O:59][C:53]=2[CH:52]=1)[CH2:36][C:37]1[O:38][C:39]([C:42](=[O:50])[NH:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:40][CH:41]=1)[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]([OH:21])=[O:20])=[O:16])(C)([CH3:12])[CH3:11]>>[CH:10]([O:14][C:15]([C:17](=[C:22]([OH:62])[C:23](=[O:61])[N:24]([CH:34]([CH3:60])[CH:35]([C:51]1[CH:56]=[CH:55][C:54]2[O:57][CH2:58][O:59][C:53]=2[CH:52]=1)[CH2:36][C:37]1[O:38][C:39]([C:42](=[O:50])[NH:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:40][CH:41]=1)[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:18][C:19]([OH:21])=[O:20])=[O:16])([CH3:12])[CH3:11]
Reactant: C[C@H]([C@H](Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2)N(C/C=C/c1ccccc1)C(=O)C(O)=C(CC(=O)O)C(=O)OC(C)(C)C
Agent: O=C1CC(C(=O)[O-])CO1
Product: CC(C)OC(=O)C(CC(=O)O)=C(O)C(=O)N(C/C=C/c1ccccc1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Yield: 17 %

Procedure:
56 mg of isopropyl (2RS,3RS)-2-[N-(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-{(E)-3-phenyl-2-propenyl}carbamoyl]-5-oxotetrahydrofuran-3-carboxylate was subjected to the same reactions as in Example 1(2) to (4) to give 10 mg (yield: 17%) of the title compound.
Reaction SMILES: [NH2:1][C:2](=[N:36][N+:37]([O-:39])=[O:38])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+]([NH:43][C:44]([NH:46][C:47](N)=[O:48])=[O:45])([O-])=O.C(N(C(C)C)CC)(C)C>CO>[NH2:43][C:44]([NH:46][C:47]([NH:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:24](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:36][N+:37]([O-:39])=[O:38])[NH:8][C:9](=[O:23])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:33][CH:32]=1)=[O:48])=[O:45]
Reactant: NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reactant: NC(=O)NC(=O)N[N+](=O)[O-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reaction time: 14 h

Procedure:
A mixture of 0.53 g (0.997 mMol) of (R)-N5 -[amino(nitroimino)-methyl]-N-[[4-(aminomethyl)phenyl]methyl]-N2 -(diphenylacetyl)-ornithinamide, 0.16 g (1.08 mMol) of nitrobiuret, 50 ml of methanol and 0.2 ml of diisopropylethylamine was refluxed for 5 hours with stirring. The same amount of nitrobiuret and diisopropylethylamine was added again and the mixture was refluxed for a further 3 hours. The crystals obtained after leaving the mixture to stand for 14 hours at ambient temperature were suction filtered, washed thoroughly with methanol and diethylether and dried in vacuo. 0.51 g (83% of theory) of colourless crystals were obtained, Mp. 214-218° C.
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]3[N:23]=[CH:24][N:25]=[C:26](Cl)[C:21]=3[CH:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][C:41]=1[Cl:47]>O>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:22]3[N:23]=[CH:24][N:25]=[C:26]([O:46][C:43]4[CH:44]=[CH:45][C:40]([NH2:39])=[C:41]([Cl:47])[CH:42]=4)[C:21]=3[CH:20]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Reaction time: 0.17 h

Procedure:
After adding 12 ml of dimethylsulfoxide to the 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine synthesized in Production Example 153-4, 141 mg (1.5 equivalents) of sodium hydride (60% dispersion, Aldrich) and 507 mg (1.5 equivalents) of 4-amino-3-chlorophenol were added while stirring, and stirring was then continued at room temperature for 10 minutes and then at 135–140° C. for 4 hours. The mixture was returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 1.20 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4]>[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])=[CH:8][C:9]=1[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CN(c1ccc([N+](=O)[O-])c(N2CCCCC2)c1)S(C)(=O)=O
Agent: [Pd]
Product: CN(c1ccc(N)c(N2CCCCC2)c1)S(C)(=O)=O
Yield: 90.7 %

Procedure:
Using a procedure similar to Example 23, step (a), N-methyl-N-(4-nitro-3-piperidin-1-yl-phenyl)-methanesulfonamide (89 mg, 0.28 mmol) was stirred with 5% Pd—C (55 mg) under H2 to afford 72 mg (91%) of N-(4-Amino-3-piperidin-1-yl-phenyl)-N-methyl-methanesulfonamide as an oil. Using a procedure similar to Example 4, step (c), N-(4-amino-3-piperidin-1-yl-phenyl)-N-methyl-methanesulfonamide was coupled to 5-cyano-furan-2-carbonyl chloride (77 mg, 0.49 mmol) in the presence of DIEA (107 μL, 0.55 mmol) to afford 26.2 mg (23%) of the title compound as a yellow powder. 1H-NMR (DMSO-d6, 400 MHz): δ 9.66 (s, 1H), 8.10 (d, 1H, J=8.7 Hz), 7.81 (d, 1H, J=3.8 Hz), 7.52 (d, 1H, J=3.7 Hz),), 7.26 (d, 1H, J=2.8 Hz), 7.21-7.19 (m, 1H), 3.23 (s, 3H), 2.95 (s, 3H), 2.84-2.82 (m, 4H), 1.72 (br s, 4H), 1.57 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C19H22N4O4S, 403.1 (M+H), found 403.1.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]1=[O:24])(C(C)(C)C)(C)C.Cl>O1CCOCC1>[OH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CNCCN1CCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
A mixture of tert-butyl 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-oxopiperazine-1-carboxylate (3.4 g, 9.50 mmol) and hydrogen chloride (15 ml of a 4M solution in 1,4-dioxane) in 1,4-dioxane (10 ml) was stirred at room temperature for 4 hour and then the mixture was evaporated. The residue was dissolved in a mixture of 5% methanol in dichloromethane (30 ml), basified with a 7N solution of ammonia in methanol and then filtered. The filtrate was evaporated and the residue was purified by silica gel chromatography eluting with 10% methanol in dichloromethane containing 0-5% 7M ammonia in methanol to give 1-(2-hydroxyethyl)piperazin-2-one (0.708 g, 57% yield) as a pale yellow oil.