Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(F)c2ccccc12
Reaction time: 72 h
Yield: 48.4 %

Procedure:
21.7 g of 4-Fluoro-naphthalen-1-ol were dissolved in 250 mL acetone. 39.0 g of potassium carbonate and 14.6 mL dimethyl sulfate were added at room temperature. The reaction was placed under nitrogen and stirred for 72 h. The mixture was filtrated, the solid washed with acetone, and the filtrate was concentrated to a viscous oil, which was taken up in ethyl acetate. This was washed with water and with brine, dried over sodium sulfate, filtered through celite and concentrated. The resulting oil was distilled using a Kugelrohr-apparatus, yielding 11.4 g of 4-fluoro-1-methoxynaphthalene.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:21])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)C(C)(C)CNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Temperature: 65 °C
Yield: 87.4 %

Procedure:
To a suspension of ethyl 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (2.7 g, 9.3 mmol) in methanol (30 mL) is added 3N NaOH solution (15.5 mL, 46.5 mmol). The reaction mixture is heated at 65° C. for 16 h. The reaction mixture is diluted with water and acidified to pH 2 using 2N HCl solution at 0° C. The resulting white solid is filtered, rinsed with water and dried to afford the title compound (2.1 g, 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16](=[O:17])[N:11]3[CH2:12][CH:13]=[CH:14][CH2:15][N:10]3[CH:9]2[C:18]2[CH:23]=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=2)=[CH:4][CH:3]=1.[CH3:28][C@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16](=[O:17])[N:11]3[CH2:12][CH:13]=[CH:14][CH2:15][N:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:36][C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])[N:19]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(C2C(c3ccc(F)cc3)C(=O)N3CC=CCN23)n1
Reactant: C[C@H](N)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC=CC3)n1)c1ccccc1
Temperature: 140 °C
Yield: 80 %

Procedure:
2-(4-Fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-2,3,5,8-tetrahydro-pyrazolo[1,2-a]pyridazin-1-one, 12, (0.9 g, 2.3 mmol) is dissolved in toluene (18 mL) and (S)-(−)-α-methylbenzylamine (10.5 mL, 81.6 mmol) added. The resulting mixture is heated to 140° C. for 12 hours, cooled, and the solvent removed in vacuo. The resulting crude product is purified over silica (1:1 EtOAc/hexanes) to afford 0.8 g (80% yield) of the desired product as a red sticky solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](Cl)=[N:5][N:4]=[N:3]1.N[C:9](N)=[S:10].[CH:12]1([C:18]([CH2:20][CH2:21]CBr)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([S:10][CH2:9][CH2:21][CH2:20][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1Cl
Reactant: O=C(CCCBr)C1CCCCC1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnnc1SCCCC(=O)C1CCCCC1
Yield: 26.5 %

Procedure:
1-Methyl-5-chloro-1,2,3,4-tetrazole (2.4 g) is dissolved in ethanol (30 ml). Thiourea (1.5 g) is added to the solution and the mixture is refluxed for 2 hours. 3-Bromopropyl cyclohexyl ketone (4.7 g) and 10% aqueous sodium hydroxide (10 ml) are added to the mixture is further refluxed for 3 hours. Ethanol is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with water and then saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Wakogel C-200, eluant: chloroform) to obtain 1-methyl-5-(3-cyclohexylcarbonylpropyl)thio-1,2,3,4-tetrazole (1.4 g) as colorlss liquid, nD12 =1.5267.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH3:10])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH3:11][Li]>C1COCC1.CCOCC.O>[CH3:1][C:2]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)([CH3:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(C)=C1C=CC=C1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC(C)(C)C1=CC=CC1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 7.00 g (52.2 mmol) of 6-methyl-6-propylfulvene in 40 ml of THF, 50.3 ml (57.3 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (75° C./5-7 mmHg) to obtain 6.40 g (42.6 mmol) of a light yellow liquid (yield: 82%). The analyzed values are given below.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=O)[CH:21]([C:24](=O)[CH3:25])[CH2:20][CH2:19][CH2:18][C:8]=2[N:9](C(OC(C)(C)C)=O)[CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.[CH:31]([NH2:33])=[NH:32]>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]3[N:32]=[CH:31][N:33]=[C:24]([CH3:25])[C:21]=3[CH2:20][CH2:19][CH2:18][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: N=CN
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(C(C)=O)CCC2
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2c1-c1ncnc(C)c1CCC2
Temperature: 120 °C
Yield: 36 %

Procedure:
In a sealed tube are 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.1 mmol) and formamidine acetate (5.5 mmol) and 10 mL EtOH. The mixture is heated at 120° C. for 48 hours. The solvent is evaporated in vacuo and the residue is taken up in CH2Cl2 and washed two times with NaHCO3 (aq). The organic layer is dried over Na2SO4 and evaporated in vacuo and the residue chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 7-Methyl-3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester (36%). LRMS 271.1 found (M+1) 272
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[Br:7][N:8]1[C:12](=O)CC[C:9]1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.N1CCOCC1>C(N(CC)CC)C.CN(C)C=O>[Br:7][CH2:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[CH3:9][N:8]([CH2:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1)[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cncs1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCN(CC)CC
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: BrCc1cncs1
Product: CN(C)Cc1cncs1
Yield: 49.1 %

Procedure:
An N,N-dimethylformamide solution of 5-(bromo-methyl)thiazole was prepared by using 5-methylthiazole (5.00 g), N-bromosuccinimide (8.97 g) and α,α′-azobisisobutyronitrile (414 mg) in a similar manner to Referential Example 86, and morpholine (2.20 ml) and triethylamine (7.02 ml) were reacted with this solution to obtain the title compound (1.76 g) as a yellow oil.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][NH:13][C:14]([C:16]2[CH:20]=[CH:19][O:18][N:17]=2)=O)=[N:4][NH:3]1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][N:13]=[C:14]([C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[N:4]2[N:3]=1
Reactant: O=C(NCc1n[nH]c(=O)c2ccccc12)c1ccon1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nn2c(-c3ccon3)ncc2c2ccccc12

Procedure:
The title compound was prepared from isoxazol-3-carboxylic acid (4-oxo-3,4-dihydrophthalazin-1-ylmethyl)amide (Part a) and phosphorus oxychloride according the procedure described in Example 1, Part b. 1H NMR (360 MHz, CDCl3) δ 7.25 (s, 1H), 7.66 (t, J=8 Hz, 1H), 7.86 (t, J=8 Hz, 1H), 7.97 (brs, 1H), 8.09 (d, J=8 Hz, 1H), 8.21 (d, J=8 Hz, 1H), 8.57 (d, J=2 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:8]1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])=[O:6].[I-].[Na+].[NH:39]1[CH:43]=[CH:42][CH:41]=[N:40]1.C(OCC)(=O)C>CN(C=O)C.O>[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[CH:8]1[CH:7]([C:5]([NH:4][CH2:3][CH2:2][N:39]2[CH:43]=[CH:42][CH:41]=[N:40]2)=[O:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: c1cn[nH]c1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCCl)C1c1ccc(Cl)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCn2cccn2)C1c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 29.1 %

Procedure:
To a solution of 573 mg of (3RS,4RS)—N-(2-chloroethyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of DMF were added 150 mg of sodium iodide and 340 mg of 1H-pyrazole, followed by stirring at 100° C. for 24 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain a colorless crystal. The crystal was recrystallized from ethanol to obtain 176 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[2-(1H-pyrazol-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.C1COCC1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][CH2:7]1
Reactant: Sc1ccccc1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21
Reaction time: 5 h

Procedure:
To a stirred solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G, 1.48 g, 5.9 mmol), titanium tetrachloride (1.09 g, 5.7 mmol) and THF (10 mL) was added a mixture of thiophenol (660 mg, 6 mmol), triethylamine (1.16 g, 11.5 mmol) and THF (20 mL) via an addition funnel at ambient temperature. The mixture was stirred for 5 h, and water (10 mL) was added, extracted with ether (3×50 mL). The combined organic layer was washed successively with water (10 mL), 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4) and the solvent distilled off at reduced pressure. After silicagel chromatography the title compound was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:5])[OH:4].[CH2:8](O)[CH:9](O)[CH3:10].S(=O)(=O)(O)O>>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]1[O:5][CH2:10][CH2:9][CH2:8][O:4]1
Reactant: CC(O)CO
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: ClC(Cl)(Cl)C1OCCCO1

Procedure:
21.6 g of chloral hydrate are admixed with 9.6 g of propylene-glycol, then 16.8 ml of concentrated sulphuric acid are added. It is heated at 60°-70° C. for two hours and after dilution with 60 ml of water it is extracted two times with 60 ml of chloroform. The chloroformic phase is washed with water and sodium hydrogen carbonate, dried on magnesium sulfate, then the product is vacuum distilled after distilling off the chloroform.
Reaction SMILES: [CH2:1]([N:9]([CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:19][CH2:20][CH2:21][CH2:22][Cl:23].CO.C(C(C)=O)C>CCCCCC>[Br-:19].[Cl:23][CH2:22][CH2:21][CH2:20][N+:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:18]
Reactant: ClCCCBr
Reactant: CCCCCCCCN(C)CCCCCCCC
Solvent: CO
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: CCCCCCCC[N+](C)(CCCCl)CCCCCCCC
Product: [Br-]
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A one-liter, 3-necked, round-bottomed flask equipped with air condensers and a magnetic stirring plate was charged with N,N-dioctylmethylamine (202.48 grams, 0.79 moles), 1-bromo-3-chloropropane (124.8 grams, 0.79 moles) and methanol (250 mL). Reaction was maintained at 65° C. for two days. Methanol was removed by rotary evaporation under reduced pressure to yield an oil. To the oil was added ethylmethylketone (50 mL) and hexane (200 mL) causing a white solid to slowly form. The solvent was decanted from the mixture. The remaining solid was washed with hexane (50 mL) two times. The solid was placed in a vacuum oven at 35° C. for 24 hours. Yield 259 grams of a waxy solid (0.625 moles, 79%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C(O)C>[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25.0 mg, 0.0464 mM), then 4-hydroxy-benzaldehyde (6.2 mg, 0.051 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (19.2 mg, yield: quantitative).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.[S]>C1C2C(CCCC2)CCC1>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cc1ncc2n1CCC=C2c1ccccc1
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Product: Cc1ncc2c(-c3ccccc3)cccn12
Temperature: 185 °C

Procedure:
Add 250 g (1.2 mol) of the product from Example XVIII to a solution of 75 g (2.3 mol) of sulfur in 1.5 liters of decalin and heat to 180-190° C. under nitrogen for 6 hr. Cool to room temperature and extract with 2-1.5 liters of 2N sulfuric acid. Combine the acid extracts and make basic with potassium hydroxide, then wash with 2×1 liter of methylene chloride. Combine the methylene chloride extracts, dry over sodium sulfate, treat with charcoal, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1C=CC=C[CH:27]=1.NC1C=CC(CN/C=C2\C(=O)N[C:44](=[O:52])[C:45]3C\2=CC(I)=[CH:47][CH:46]=3)=CC=1O[Si](C(C)C)(C(C)C)C(C)C.[C:67](OC(=O)/C=C/C)(=O)/C=C/C>>[C:44]([O:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:32])/[CH:26]=[CH:27]/[CH3:67])(=[O:52])/[CH:45]=[CH:46]/[CH3:47]
Reactant: C/C=C/C(=O)OC(=O)/C=C/C
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Product: C/C=C/C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1OC(=O)/C=C/C

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) is reacted with crotonic anhydride (49 μL, 0.33 mmol). Following desilylation and precipitation, 2-[(2E)-but-2-enoylamino]-5-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl (2E)-but-2-enoate is obtained (17 mg, 27%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH2:16][OH:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH2:16][O:17][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2NC(=O)OC(C)(C)C)cc1

Procedure:
(3S,4S)-1-Benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine (5.00 g, 14.3 mmol) was dissolved in pyridine (50 mL). p-Toluenesulfonyl chloride (4.08 g, 21.4 mmol) and 4-(N,N-dimethyl)aminopyridine (174 mg, 1.43 mmol) were added thereto at room temperature, and the resultant mixture was stirred under a nitrogen atmosphere for 24 hours. Under cooling, ethyl acetate (200 mL) and 1 mol/L hydrochloric acid (200 mL) were added thereto, followed by extraction with ethyl acetate (200 mL×2). The organic layer was washed sequentially by 1 mol/L hydrochloric acid (100 mL), saturated sodium hydrogencarbonate (100 mL), and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:1), to thereby yield the title compound as a colorless amorphous substance (6.27 g, 87%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].BrC[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=O.[Na].[CH2:29]([OH:31])C>[O-]CC>[C:1]([NH:4][C:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[C:29]=[O:31])[O:25][CH2:26][CH3:27])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)CCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na]
Product: CCOC(=O)C(CCCCCC(=C=O)OCC)(NC(C)=O)C(=O)OCC
Temperature: 0 °C

Procedure:
Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml) and the mixture was refluxed for 27 h. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxy-carbonylhexyl)malonate as a pale yellow oil, 2.2(3H, singlet, -COCH3), 4.17(6H, multiplet, 3×--OCH2 --CH3). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 51/2 h., the cooled solution was washed with ether, and the aqueous layer was decolourised with activated charcoal and evaporated to dryness in vacuo. The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 h., refluxed for 11/2 h., cooled, and poured into ice-water, adjusting the pH to 9 with aqueous hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminononanedioate (55% yield) as a colourless oil, b.p. 114°-115°/0.02-0.03 mm.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C1COCC1>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:20]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=2)=[N:1]1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: CC(C)(N)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To an ice-cold solution of 2-amino-2-methyl-1-propanol (21.4 g, 240 mmol) and triethylamine (16.8 mL, 120 mmol) in THF was added dropwise 4-trifluoromethyl benzyl chloride (25.0 g, 120 mmol). After the addition, the reaction mixture was stirred at 0° C. for 30 mins and then stirred at ambient temperature for 8 hrs. The precipitate was removed by filtration and the filtrate was concentrated by evaporating the solvent under reduced pressure. The resulting residue was treated dropwise with thionyl chloride with vigorous stirring at 0° C. After complete addition, the reaction mixture was further stirred at ambient temperature for 1 hr. Ether was poured into the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in water and the aqueous solution was hydrolyzed with 10% (w/v) NaOH. The aqueous phase was extracted three times with ether, and the combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex/EtOAc=5/1) to yield the title compound (25.4 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[O:29][C:7]1([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]4[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:33].CC[N:36]([CH2:39]C)CC.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:43]>C1COCC1>[CH3:26][O:25][C:23]1[C:22]2[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:13]([N:10]2[CH2:11][CH2:12][C:7]3([CH2:6][C:5](=[O:33])[C:4]4[C:30](=[CH:31][CH:32]=[C:2]([NH:1][C:39]([NH2:36])=[O:43])[CH:3]=4)[O:29]3)[CH2:8][CH2:9]2)=[O:14])[CH:24]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N)ccc2O3)nc2c(OC)cccc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(NC(N)=O)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C

Procedure:
The compound of Example 5 (1.35 g) was dissolved in 15 mL of THF; and 0.505 mL of NEt3 and 669 mg of 4-nitrophenyl chloroformate were added thereto in order, and stirred at room temperature. The reaction mixture was filtered, and 0.226 mL of 25% aqueous ammonia was added to the filtrate, and stirred overnight at room temperature. The reaction solution was diluted with chloroform, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified through silica gel thin-layer chromatography (CHCl3/MeOH=7/1) to obtain the intended compound as a yellow amorphous solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (1H, s), 7.80 (1H, d, J=2.9 Hz), 7.66 (1H, dd, J=8.5, 1.5 Hz), 7.53 (1H, dd, J=8.6, 3.0 Hz), 7.50 (1H, t, J=8.4 Hz), 7.22 (1H, dd, J=8.0, 2.0 Hz), 7.16 (1H, s), 6.99 (1H, d, J=8.8 Hz), 5.83 (2H, s), 4.21-4.36 (1H, m), 4.05 (3H, s), 3.93 (3H, s), 3.64-3.55 (1H, m), 3.46-3.32 (1H, m), 3.31-3.20 (1H, m), 2.84 (2H, s), 2.08-1.99 (1H, m), 1.91-1.84 (1H, m), 1.83-1.70 (2H, m). MS [M+H]+=491.