Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:31][C@H:30]([C:32]([O:34]CC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:38])[CH:10]=1)#[N:2].[OH-].[Na+].Cl.[CH3:42][Mg]Br>O1CCCC1.C(O)C>[C:32]([C@H:30]1[CH2:29][C@H:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:38])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:31]1)(=[O:34])[CH3:42]
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(=O)OCC)C2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(C)=O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate (0.86 g), tetrahydrofuran (10 mL), ethanol (10 mL) and 1 M aqueous sodium hydroxide solution (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was mixed with N,O-dimethylhydroxyamine hydrochloride (0.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.48 g), 1-hydroxybenzotriazole (0.33 g), triethylamine (0.69 mL) and N,N-dimethylformaldehyde (10 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in tetrahydrofuran (10 mL), methylmagnesium bromide (6.6 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 60%).
Reaction SMILES: [CH2:1]1[O:14][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=CC=2)=[C:3]([C:4](O)=O)[O:2]1.[Br:15]Br.[Na].[C:18]([OH:21])(=[O:20])[CH3:19]>O>[CH2:1]1[O:14][C:7]2[CH:8]=[CH:13][C:12]([CH2:11][CH:19]([Br:15])[C:18]([OH:21])=[O:20])=[CH:4][C:3]=2[O:2]1
Reactant: BrBr
Reactant: CC(=O)O
Reactant: O=C(O)C1=C(c2ccccc2)OCO1
Agent: [Na]
Solvent: O
Product: O=C(O)C(Br)Cc1ccc2c(c1)OCO2
Reaction time: 0.25 h

Procedure:
Stir powdered methylenedioxy cinnamic acid (19.2 g, 210 mmol) in glacial acetic acid (200 mL) at room temperature while adding a solution of bromine (16 g, 100 mmol) in acetic acid (50 mL) over 30 minutes. Stir the homogeneous yellow solution for 15 minutes and add a solution of sodium cyabiborohydride (20 g) in water (50 mL) over 30 minutes. Stir for 48 hours at room temperature. Add water (70 mL) and stir for an additional 2 hours. Filter and wash the filtercake with acetic acid/water. Evaporate the solvent in vacuo and partition the residue between chloroform and water. Dry the organic phase (MgSO4) and evaporate the solvent in vacuo. Redissolve the residue in chloroform, filter and evaporate the solvent in vacuo to give 3-(3,4-methylenedioxyphenyl)-2-bromopropionic acid as a crystalline solid (15.1 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][CH2:24][CH2:25][OH:26].C(N(C(C)C)CC)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].Cl>C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][CH2:24][CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(C#CCCCO)c(F)cc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCc3cc(C#CCCCOS(C)(=O)=O)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of 50 mg (0.141 mmol) of 5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-yn-1-ol and 0.072 ml (0.42 mmol) diisopropyl ethylamine in 2 ml CH2Cl2 was treated at 0° C. with 0.033 ml (0.42 mmol) methanesulfonylchloride and stirred at room temperature for one hour. Addition of aqueous 0.1M HCl, extraction with Et2O, drying of the organic layer with MgSO4, and evaporation of the solvent gave 60 mg of Methanesulfonic acid 5-[6-fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl ester as brown oil of which 12 mg were dissolved in 0.5 ml DMF, treated with 0.043 ml (0.053 mmol) 2-(methylamino)ethanol and stirred at 80° C. during 2 hours. Evaporation of the solvent and excess 2-(methylamino)ethanol and chromatography on silica gel with EtOAc/MeOH/NEt3 10:1:0.1 gave 10 mg (82%) of 2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanol as a light yellow oil, MS: 431 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[Si]([CH:14]=[N+:15]=[N-:16])(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[NH:16]1[CH:2]([C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:3][CH:14]=[N:15]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CC=NN1
Yield: 41.1 %

Procedure:
To a solution of t-butyl acrylate (17 g, 133 mmol) dissolved in toluene (200 mL) and n-hexanes (200 mL) was added TMS-diazomethane (99 mL, 199 mmol) over 10 minutes. After 1 h the reaction mixture was concentrated and the residue diluted with DCM (300 mL) and TFA (20.44 mL, 265 mmol) was added slowly over 15 minutes. After 30 minutes the reaction mixture was concentrated, basified with 1N NaOH and extracted into DCM (400 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by filtration through a pad of silica gel eluting the product with 50% ethyl acetate/hexanes to afford 10 g (54.6 mmol) of 1,1-dimethylethyl 4,5-dihydro-1H-pyrazole-5-carboxylate as a yellow oil. LC-MS (ES) m/e 170.91 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].[CH:5]1[N:9]=[C:8](N)[S:7][CH:6]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O.[BrH:20].[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>O>[Br:20][C:8]1[S:7][C:22]([C:21]([O:24][CH2:25][CH3:26])=[O:23])=[C:5]([CH3:6])[N:9]=1
Reactant: CCOC(C)=O
Reactant: Nc1nccs1
Reactant: Br
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1sc(Br)nc1C
Temperature: -10 °C
Yield: 19 %

Procedure:
A solution of sodium nitrite (8.56 g, 124 mmol) in 20 mL of H2O was added over a 30 minute period to a mixture of the aminothiazole (7.44 g, 40 mmol), 85% phosphoric acid (50 mL) and 70% nitric acid (25 mL) at −10° C. The mixture began to bubble immediately and an exotherm was observed. A CO2/acetone bath was used to maintain the temperature at −10° C. throughout the addition. An orange precipitate formed and the mixture became very difficult to stir. Once the addition was complete, the mixture was allowed to warm to room temperature and stirred for ˜20 minutes. The reaction mixture was then poured into a mixture of hydrobromic acid (20 mL) and cuprous bromide (5.74 g, 40 mmol). After vigorous gas evolution, the mixture was diluted with H2O (650 mL) and filtered to yield a brown solid. The solid was dissolved in ethyl acetate and concentrated onto ˜100 g of silica gel and chromatographed over silica gel, eluting with a serial dilution of hexane to 90% hexane/10% ethyl acetate. Isolation of the major product gave 1.92 g (19% yield) of the desired product as a yellow solid: mp 63-65° C.; 1H NMR (CDCl3) δ4.35 (q, 2H), 2.7 (t, 3H), 1.35 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: OCCO
Reactant: O=Cc1sccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccsc1C1OCCO1
Yield: 74.1 %

Procedure:
3-Bromothiophen-2-aldehyde (2) (7.44 g, 39 mmol), ethylene glycol (2.7 ml, 48 mmol), anhydrous benzene (130 ml) and a few crystals of p-toluenesulphonic acid were refluxed in a Dean-Stark apparatus until no more water separated. The benzene layer was washed with a solution of bicarbonate, dried (Na2SO4), and evaporated under reduced pressure to give the derivative 3 (6.8 g, 28.9 mmol, 74% yield) as an oil.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)[C@@H]([C@@H](CO)S)S.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: ClCCN1CCCC1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: OC[C@@H](S)[C@@H](S)CO
Product: O=C(Nc1ncc(SCCN2CCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithio-erythritol and 1-(2-chloroethyl)-pyrrolidine
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:11]([C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=4[N:17]=3)=[CH:10][C:9]([N+:26]([O-])=O)=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.[C:29](O)(=[O:31])[CH3:30]>[Pd]>[NH2:26][C:9]1[CH:10]=[C:11]([C:12]2[NH:13][C:14](=[O:25])[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)[C:6]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:7][CH:8]=1.[CH:1]1([O:5][C:6]2[N:7]=[CH:8][C:9]([NH:26][C:29](=[O:31])[CH3:30])=[CH:10][C:11]=2[C:12]2[NH:13][C:14](=[O:25])[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc([N+](=O)[O-])cnc3OC3CCC3)nc12
Reactant: CC(=O)O
Agent: [Pd]
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)cnc3OC3CCC3)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NC(C)=O)cnc3OC3CCC3)nc12
Reaction time: 14 h

Procedure:
The title compound from example 88 (266 mg, 0.69 mmol) was dissolved in glacial acetic acid (10 ml) and the vessel charged with 5% Pd on carbon (20 mg) and stirred under hydrogen (60 psi) for 14 h. The catalyst was removed by filtration (Arbocel*) and the residue concentrated in vacuo. The residue was taken up in water (5 ml), basified to pH 8 (5% NaHCO3 solution) and extracted with methylene chloride (3×20 ml). Combined organic extracts were washed with brine (20 ml), dried over MgSO4, reduced in vacuo and purified by column chromatography (first with 98:2 methylene chloride:methanol as eluant, then 30:70:1 ethyl acetate:pentane:0.88 ammonia). 5-[5-amino-2-(cyclobutyloxy)-3-pyridinyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one was obtained (70 mg, 0.19 mmol) together with N-[6-(cyclobutyloxy)-5-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3-pyridinyl]acetamide (34 mg, 0.09 mmol).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH:13]1([NH:16][C:17]2[C:18]([NH2:25])=[CH:19][C:20]([F:24])=[C:21]([F:23])[CH:22]=2)[CH2:15][CH2:14]1>C1COCC1.C(OCC)(=O)C>[CH:13]1([N:16]2[C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[NH:25][C:1]2=[O:2])[CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)c(F)cc1NC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(F)c(F)cc2n1C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.5 %

Procedure:
Carbonyldiimidazole (4.3 g) was added to the solution of N1-cyclopropyl-4,5-difluorobenzene-1,2-diamine (3.2 g) in THF (30 ml). The mixture was stirred at rt for 20 hours, then diluted with ethyl acetate (200 ml) and washed with hydrochloric acid (1M, 200 ml). Organic layer dried over sodium sulphate, solvent removed to give expected product as a black solid (2.5 g). 1H NMR (CD3OD)δ: 7.20 (dd, 1H), 6.95 (dd, 1H), 2.86 (m, 1H), 1.11 (m, 2H), 0.94 (m, 2H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH3:23])[CH2:21][OH:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=C[CH:25]=1>>[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH3:23])[CH2:21][O:22][S:7]([C:4]1[C:5]([CH3:25])=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:8])=[O:9])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: c1ccncc1
Product: Cc1ccccc1S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
p-Toluenesulphonyl chloride (4.2 g.) was added to a solution of (S)-2-t-butoxycarbonylamino-1-propanol (3.5 g.) in pyridine (10 ml.) at 0°. The mixture was kept at 0°-5° for 20 hr. and then poured into ice-water (200 ml.) and extracted with diethyl ether (3×50 ml.). The diethyl ether extract was washed successively with 1 M-hydrochloric acid (50 ml.), saturated sodium carbonate solution (50 ml.) and brine (50 ml.), and then dried (MgSO4). The solvent was evaporated and the residue was crystallised from ethyl acetate-petroleum ether to give (S)-2-t-butoxycarbonylamino-1-toluenesulphonyloxypropane, m.p. 73°-4°.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[CH2:2].[NH+]1C=CNC=1.[Br:13][CH2:14][CH2:15][OH:16]>C1(C)C=CC=CC=1>[Br-:13].[OH:16][CH2:15][CH2:14][N+:5]1[CH:6]=[CH:7][N:3]([CH:1]=[CH2:2])[CH:4]=1
Reactant: C=Cn1ccnc1
Reactant: OCCBr
Agent: c1c[nH+]c[nH]1
Solvent: Cc1ccccc1
Product: C=Cn1cc[n+](CCO)c1
Product: [Br-]

Procedure:
With reference to FIG. 4, 0.14 mmloe of 1-vinylimidazole, being the imidazolium liquid monomer, and 50 ml of toluene are mixed to obtain a mixture, followed by sequentially dropping 0.16 mmole of 2-bromoethanol into the mixture to trigger off an alkylation of the 1-vinylimidazole and the 2-bromoethanol. Then, a solution with two phase of layering is obtained after three days of reaction, wherein the lower layer of the solution is further isolated and repeatedly washed by toluene and ether, followed by being condensed and dried in vacuo for 1 hour, to obtain 1-(2-hydroxyl-ethyl)-3-vinylimidazolium bromide (also known as HEVIMB).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]#[N:17])=[CH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCCl>[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][N:1]1[CH2:2][CH2:3][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]#[N:17])=[CH:8][CH2:7]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)CC=O
Reactant: N#CC1=CCC2(CCNCC2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)CCN1CCC2(CC=C(C#N)c3ccccc32)CC1
Reaction time: 8 h

Procedure:
A solution of 2H-spiro[naphthalene-1,4′-piperidine]-4-carbonitrile (A4) (66 mg, 0.3 mmol), 3,3-dimethylbutanal (46 mg, 0.46 mmol) in 1,2-dichloroethane (5 ml) was stirred at 40° C. for 2 h. To the solution was added sodium triactoxyborohydride and the resulting mixture was stirred overnight, followed by treatment of MeOH (1 ml). Evaporation and the residue was dissolved in MeOH (2 ml) and purified by reverse phase C-18 HPLC to give 1′-(3,3-dimethylbutyl)-2H-spiro[naphthalene-1,4′-piperidine]-4-carbonitrile (Compound No. 51). LC-MS: m/e=309.1 (M+H). Rt=1.92 min. 1H-NMR (500 MHz, DMSO-d6): 9.03 (br. s, 1H), 7.49-7.40 (m, 4H), 7.12 (t, 1H), 3.45 (d, 2H), 3.22-3.11 (m, 4H), 2.78 (d, 2H), 2.03 (td, 2H), 1.88 (d, 2H), 1.58-1.54 (m, 2H), 0.92 (s, 9H).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][C:6](=O)[N:5]=[C-:4]1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]1[CH2:29][CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)C=[O:45]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]1[CH2:29][CH2:30][N:5]1[CH2:6][CH2:7][O:3][C:4]1=[O:45])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CO[C-]=N1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCN2CCOC2=O)C1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60%, 57 mg) in N,N-dimethylformamide (20 ml), 2-oxazolidone (0.122 g) was added, followed by stirring at 90° C. for 1 hour. A solution of 1,4-di(tert-butoxycarbonyl)-2-(2-tosyloxyethyl)piperazine (0.686 g) in N,N-dimethylformamide (15 ml) was added to the reaction mixture. The resulting mixture was stirred at 90° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated aqueous NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure, whereby the title compound (0.515 g) was obtained as a colorless solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18]Br>CS(C)=O.O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:18][CH2:17]1)#[N:2]
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol) produced in Example A3(i) in dimethyl sulfoxide (30 mL) was added sodium hydride (60% in oil, 1.0 g, 26 mmol) while cooling the solution to a temperature of 25° C. or below at which the solution did not solidify. The reaction mixture was stirred at room temperature for 30 min, 1,2-dibromoethane (2.4 g, 12.8 mmol) was added, and the mixture was further stirred at room temperature for 10 hr. The reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and fractions containing the object product was concentrated under reduced pressure to give the title compound (1.3 g, 76%) as a colorless oil.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:58][O:59][C:60](=[O:75])[CH2:61][CH:62]([N:64]1[CH2:69][CH2:68][NH:67][CH:66]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:65]1=[O:74])[CH3:63]>CN(C=O)C.O>[CH3:58][O:59][C:60](=[O:75])[CH2:61][CH:62]([N:64]1[CH2:69][CH2:68][N:67]([C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH:66]([CH2:70][CH:71]([CH3:72])[CH3:73])[C:65]1=[O:74])[CH3:63]
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: COC(=O)CC(C)N1CCNC(CC(C)C)C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(C)N1CCN(C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)C(CC(C)C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
To a stirred mixture of [4-(3-o-tolyl-ureido)-phenyl]-acetic acid (55 mg, 0.19 mmol), diisopropyl ethyl amine (0.17 ml), BOP (86 mg, 0.19 mmol) in DMF (1 ml) was added 3-(3-isobutyl-2-oxo-piperazin-1-yl)-butyric acid methyl ester (50 mg, 0.19 mmol). After stirring 16 h at room temperature the solution was diluted with water and extracted into ethyl acetate. The combined organics were washed with 5% citric acid, saturated NaHCO3, and brine; dried over MgSO4, filtered, and concentrated under reduced pressure. Column chromatography on silica gel eluting with 2% MeOH/CH2Cl2 gave 20 mg of the title compound as a yellow amorphous solid. MS [M+1]+523.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]1>>[C:44]([N:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][NH:35][C:31](=[O:33])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:39][CH2:40]1)(=[O:46])[CH3:45]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: CC(=O)N1CCN(CCN)CC1
Product: CC(=O)N1CCN(CCNC(=O)Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1

Procedure:
{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid was coupled with 1-[4-(2-amino-ethyl)-piperazin-1-yl]-ethanone to give the titled compound.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)=[O:9].[ClH:23]>CC(O)C>[ClH:23].[O:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:15][CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)N
Reactant: O=C(CBr)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)NCC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Tert-butylamine (15 ml) was added with stirring to a solution of 2-bromo-4'-phenoxyacetophenone (12.7 g, prepared by bromination of 4'-phenoxyacetophenone according to Tetrahedron Letters, 1993, 34, 3177) in propan-2-ol and the mixture heated at 80° C. for 3 hours. The mixture was cooled to 0° C. and concentrated hydrochloric acid (10 ml) added. The suspension was stirred at ambient temperature for 18 hours and the solid collected by filtration to give 4'-phenoxy-2-(tert-butylamino)acetophenone hydrochloride (3.75 g), m.p. 210-212° C.