Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:21]([C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]([C:52](Cl)=[O:53])[C:33]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)([CH3:44])[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)([CH3:36])[N:35]=2)=[C:27]([O:55][CH2:56][CH3:57])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[C:21]([C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]([C:52]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:9][CH2:10]3)=[O:53])[C@@:33]([C:45]3[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=3)([CH3:44])[C@@:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)([CH3:36])[N:35]=2)=[C:27]([O:55][CH2:56][CH3:57])[CH:26]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3-Methanesulfonyl-propyl)-piperazine (30 mg, 0.11 mmol, prepared as described in Fotouhi, N. et al. WO 2005110996) was suspended in 5 mL of methylene chloride and cooled to 0° C. Triethylamine was added followed by drop wise addition of rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride in 2 mL of methylene chloride. The mixture was stirred at room temperature for 30 min and then taken up in methylene chloride and washed successively with 10% sodium hydrogen carbonate and water. The methylene chloride phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel eluting with methylene chloride/methanol (95:5) gave rac-[(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone as a white solid (16 mg). HR-MS (ES, m/z) calculated for C37H48N5O4SCl2 [(M+H)+] 728.2799, observed 728.2793.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>O>[O:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]1[O:9][CH2:8][CH2:7][OH:10]
Reactant: OCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: OCCOC1C=CC=CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,4-Dihydro-2H-pyran (30.0 g, 0.36 mol), ethylene glycol (310.0 cm3, 5.36 mol) and p-toluene sulphonic acid (ca. 1 mol %, catalyst) were added to dichloromethane (100 cm3) and the mixture stirred at ambient temperature for 18 hours under an inert gas atmosphere. Water (ca. 150 cm3) was then added, resulting in a biphasic mixture. The organic phase (containing the desired product) was collected and the aqueous phase (containing excess ethylene glycol) extracted with further portions of dichloromethane (3×50 cm3). The combined organic phase and washings were dried over anhydrous magnesium sulphate, filtered and solvent removed in vacuo to yield the crude product containing, almost exclusively, the mono-protected alcohol. The desired product was isolated via flash column chromatography (using silica gel 60 and a 3:1 ratio of hexane:ethyl acetate as eluant). Yield=9.10 g (17.3%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=O)[N:22]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=[O:10].C([O-])(=O)C.[Na+].Cl.[NH2:38][OH:39]>C(O)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21](/[CH:23]=[N:38]/[OH:39])[N:22]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=[O:10]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1/C=N/O

Procedure:
A solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole -5-carboxylate (0.10 g, 0.2 mmol, Example 252), sodium acetate (0.041 g, 0.5 mmol) and hydroxylamine hydrochloride (0.028 g, 0.4 mmol) were heated to reflux in absolute ethanol for 3 hours. After cooling to room temperature the ethanol was removed under reduced pressure followed by EtOAc/H2O partitioning, drying with MgSO4 and concentrating to a yellow solid (0.081 g) MS (ES): 504 NMR: 1.25 (t, 3H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.31 (s, 3 H) 3.36 (s, 3 H) 3.55 (s, 1 H) 3.95 (s, 1 H) 4.18-4.26 (m, 2 H) 4.26 (d, 2 H) 7.16 (d, 1 H) 8.61 (s, 1 H) 11.72 (s, 1 H) 12.16 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[C:17]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][CH2:2][OH:1])(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCCC1CCCCN1
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1CCCCC1CCO
Temperature: 20 °C

Procedure:
65 g (0.5 mol) of 2-(2-hydroxyethyl)-piperidine and 90 ml of triethylamine (0.64 mol) are dissolved in 1 liter of tetrahydrofuran, and 80 ml (0.67 mol) of valeryl chloride are added at -20° C. The mixture is warmed at 20° C. for one day and the solvent is then largely removed on a rotary evaporator; the residue is taken up in methylene chloride, the mixture is washed with 1N NaOH solution, the organic phase is dried and the solvent is removed by distillation on a rotary evaporator. In order to remove impurities of the bis-acylated compound, the product is taken up in 200 ml of ethanol and the mixture is warmed at 50° C. with 200 ml of 1N sodium hydroxide solution for one hour. It is evaporated on a rotary evaporator again, the residue is extracted with CH2Cl2 /H2O, the organic phase is dried and evaporated on a rotary evaporator and the residue is distilled in a bulb tube oven (boiling point0.2 =165° C.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][Mg+].[Br-].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]=1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=O)[CH2:20][CH2:19]2>C1COCC1>[CH3:1][C:21]1[C:22]2[C:18](=[CH:17][C:16]([C:5]3[C:6]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)=[CH:7][CH:8]=[CH:9][N:4]=3)=[CH:24][CH:23]=2)[CH2:19][CH:20]=1
Reactant: O=C1CCc2cc(-c3ncccc3-c3ccncc3)ccc21
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1=CCc2cc(-c3ncccc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
MeMgBr [2 mL, 1.4 M solution in toluene/THF (75:25)] was added to a stirring solution of 5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one (175 mg) in THF (4 mL) at −78° C. under argon. The reaction was stirred for 30 min and warmed to room temperature after complete addition of MeMgBr and. After 1 h, the complete consumption of 5-([3,4′-bipyridin]-2-yl)-2,3-dihydro-1H-inden-1-one to 5-([3,4′-bipyridin]-2-yl)-1-methyl-2,3-dihydro-1H-inden-1-ol was observed. Subsequently, the reaction was cooled in ice-bath, quenched with conc. HCl (5 mL) over a period of 30 min. The cooling was removed and allowed the reaction to warm to temperature. After 4 h, the reaction mixture was concentrated, diluted with EtOAc (50 mL) and aq. NaHCO3 solution (15 mL). Aqueous layer was discarded, washed the organic layer with brine, dried over MgSO4, filtered, concentrated and purified by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 12 g, 30-50-70% EtOAc/hexanes as an eluting solvent) to obtain 2-(3-Methyl-1H-inden-6-yl)-3,4′-bipyridine as an oil. LCMS: rt 4.47 min (A), purity 95%, MS (m/e) 285 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:25]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:25]=1
Reactant: COc1ccc2nc(-c3cccc4c3-c3ccccc3C4=O)[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.2 %

Procedure:
In a 50-ml three-necked flask under an argon atmosphere, dissolve 700 mg of 4-(6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one, obtained in stage 2 of Example 106, in 10 ml of dichloromethane, then add dropwise 5.35 ml of a 1M solution of boron tribromide in dichloromethane and stir for 20 hours at room temperature. Pour the reaction mixture into 50 ml of water. The precipitate that forms is drained and washed with water then with toluene and finally dried. After purification by silica gel flash chromatography, eluting with a mixture of dichloromethane and methanol (90-10 by volume), we obtain 363 mg of 4-(6-hydroxy-1H-benzimidazol-2-yl)-fluoren-9-one, in the form of a brown powder, with the following characteristics:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[C:14](Br)[S:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I>[CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[C:14]([N:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:26][C:27]2=[O:31])[S:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(NCc1ccccc1)c1csc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1csc(-n2ccc(OCc3ccccc3)cc2=O)c1
Temperature: 130 °C
Reaction time: 17 h
Yield: 17.6 %

Procedure:
A mixture of N-benzyl-5-bromothiophene-3-carboxamide (0.57 g, 1.91 mmol), 4-(benzyloxy)pyridin-2(1H)-one (0.42 g, 2.10 mmol), copper(I) iodide (0.055 g, 0.29 mmol), 8-hydroxyquinoline (0.042 g, 0.29 mmol) and potassium carbonate (0.40 g, 2.87 mmol) in N,N-dimethylformamide (15 mL) was stirred at 130° C. for 17 h under nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature, and then diluted with ethyl acetate (50 mL). The organic layer was washed with water (2×25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with 10-80% ethyl acetate in hexanes to afford the title compound as a white solid (0.14 g, 18%): mp 162-163° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=6.0 Hz, 1H), 8.07 (d, J=7.9 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.49-7.20 (m, 10H), 6.26 (dd, J=7.8, 2.7 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.46 (d, J=6.0 Hz, 2H); MS (ES+) m/z 417.2 (M+1).
Reaction SMILES: C1CO[CH:4]([CH2:5][CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH:3]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[O:2]1.Cl>CN(C=O)C>[N:7]1([CH2:6][CH2:5][CH2:4][C:3]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:2])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: O=C1CCc2cc(C3OCCOC3CCn3cncn3)ccc2N1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)CCCn3cncn3)ccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.5 Grams (35.5 mM) of 6-(1-ethylenedioxy-4-chlorobutyl)-3,4-dihydrocarbostyril was dissolved in 10.6 g (71 mM) of dimethylformamide, to this solution was added 10.6 g (71 mM) of sodium iodide, 5.4 g (78.1 mM) of 1H-1,2,4-triazol and 6.5 ml (46.2 mM) of DBU, and the whole mixture was heated at 80° C. for 7 hours with stirring. The reaction mixture was concentrated by removing the solvent by evaporation under reduced pressure, the residue was extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous magnesium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=40:1), and recrystallized from ethanol-n-hexane to yield 8.0 g of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1-yl)butyl]-3,4-dihydrocarbostyril. Next, to a solution of 1 g (3.0 mM) of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1-yl)butyl] -3,4-dihydrocarbostyril with 10 ml of DMF was added 3 ml of 5%-hydrochloric acid and stirred for 2 hours at room temperature. After concentration by removal of the solvent, the residue was extracted with chloroform: methanol=3:1. The extract was washed with water, dried with an anhydrous magnesium sulfate, then concentrated by removal of the solvent. The resulting residue was recrystallized from chloroform-ethanol to yield 6-[4-(1H-1,2,4-triazol-1-yl)butyryl]-3,4-dihydrocarbostyril.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:12]=[C:11]([NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:15]([O-])([O-])OCC>>[Cl:1][CH2:2][C:3]1[N:12]2[CH:15]=[N:14][N:13]=[C:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCOC([O-])[O-]
Reactant: NNc1nc(CCl)nc2ccccc12
Product: ClCc1nc2ccccc2c2nncn12
Temperature: 125 °C
Reaction time: 1 h

Procedure:
3.1. 88 g of 2-(chloromethyl)-4-hydrazinoquinazoline are suspended in 1.2 l of ethyl orthoformate. The suspension is heated (bath temp. 125° C.) while stirring and the resulting ethanol is distilled off. After 1 h., the mixture is cooled to 15° C., the precipitate is filtered off and washed with 100 ml of diethyl ether. The product is dried in a vacuum. 80 g of crude 5-(chloromethyl)-1,2,4-triazolo [4,3-c]quinazoline are obtained. The filtrate is concentrated in a vacuum and the residue is boiled in 20 ml of ethanol. The mixture is cooled to 0° C., filtered, the filter cake is washed with diethyl ether and the crystals are dried in a vacuum. A second portion of 5.3 g of crude 5-(chloromethyl)-1,2,4-triazolo[4,3-c]quinazoline is obtained. The two crude crystallizates (together 85.3 g) are stirred in 8.5 ml of dioxan at 85° C. for 1 h. The insoluble constituent is filtered off and the filtrate is concentrated to about 300 ml in a vacuum. The suspension is cooled, filtered and the filter cake is washed with 100 ml of diethyl ether. 66 g of 5-(chloromethyl)-1,2,4-triazolo [4,3-c]quinazoline of m.p. 189° C. (dec.) are obtained. A second portion of 2.5 g of 5-(chloromethyl)-1,2,4-triazolo[4,3-c]quinazoline is obtained after concentration of the filtrate.
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=2)=[C:5]([F:24])[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:9][C:8]1[C:3]([Cl:2])=[CH:4][C:5]([F:24])=[C:6]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=2)[CH:7]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 44.8 %

Procedure:
Then, 0.37 g of iron powder was added to a mixture of 5.3 ml of acetic acid and 2.0 ml of water, to which a solution of 0.39 g of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-17) in 1.0 ml of acetic acid was slowly added dropwise, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed twice with water and further with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated, which afforded 0.16 g (yield, 46%) of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-23).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:7])([OH:3])=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH2:4][CH2:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:7])([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(OCCCN(C(=O)CCC(=O)O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(=O)N(CCCOc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 100.4 %

Procedure:
Methyl 4-[3-[N-(3-carboxypropionyl) -N-(4-chlorophenyl)amino]propoxy]benzoate (1.0 g) was dissolved in methanol (20 ml), and 1N aqueous sodium hydroxide solution (5.25 ml) was added thereto, and the mixture was heated with stirring at 60° C. for 24 hours. After the reaction mixture was cooled, the mixture was adjusted to pH 4-5 by adding conc. hydrochloric acid thereto. The mixture was concentrated under reduced pressure, and thereto was added water, then, the precipitate was crushed, collected by filtration, and washed with water to give the desired product (0.97 g). mp. 155°-158° C.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:35]>CN(C=O)C.O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[N:13]([CH3:35])[C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(S(=O)(=O)c4ccccc4)cc3c2CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(C(=O)c1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
A 0° mixture of 3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Step II, 1.61 g, 3.74 mmol) in dry DMF (18 mL) is treated with sodium hydride (60% in oil, 165 mg, 4.11 mmol). After 30 min, the mixture is treated with iodomethane (256 μL, 4.11 mmol) and allowed to slowly warm to 20-25° under nitrogen over 16 hr. The resultant mixture is diluted with H2O and filtered. The residual solid is triturated with refluxing methanol, isolated, and dried in the vacuum oven at 50° to give the desired indole, mp=254-255°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][NH2:6].[Cl:30][CH2:31][CH2:32][CH2:33][S:34](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:36])=[O:35]>>[Cl:30][CH2:31][CH2:32][CH2:33][S:34]([NH:6][CH2:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:36])=[O:35]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)COC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)COC

Procedure:
2-Methoxymethyl-3-octadecylcarbamoyloxypropylamine IVk2 is allowed to react and worked up by the same procedure as described in (4). m.p. 72°-73° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1.[N+:14]([C:17]1[CH:21]=[N:20][NH:19][N:18]=1)([O-:16])=[O:15].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[N+:14]([C:17]1[CH:21]=[N:20][N:19]([CH2:4][C:5]2[S:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=2)[N:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: COC(=O)c1csc(CCl)n1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methyl 2-(chloromethyl)thiazole-4-carboxylate (S. A. Hermitage et al. Organic Process Research & Development, 5, 37-44, 2001) (2.05 g, 10.7 mmol) in DMF (20.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (11.53 g of a 8% solution in DMF, 9.70 mmol) in DMF (20.0 mL) pre-treated for 30 min with DIPEA (3.21 mL, 19.4 mmol) and the reaction mixture was stirred overnight at 50° C. Water (50 mL), followed by EA (50 mL) was added. The layers were separated and the aq. layer was extracted with EA (2×50 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (gradient from 60:40 hept-EA to 50:50 hept-EA)) gave the title compound as a yellow solid. TLC: rf (6:4 hept-EA)=0.31. LC-MS-conditions 07: tR=0.67 min, [M+H]+=270.21.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][C:12](=[O:22])[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:24][NH2:25].CO.[ClH:28]>C(O)(C)(C)C.O1CCOCC1>[ClH:28].[ClH:28].[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:12](=[O:22])[N:11]=3)[CH:6]=2)[NH:25][N:24]=1
Reactant: NN
Reactant: N#Cc1cc(-c2cc(-c3ccccc3)[nH]c(=O)n2)ccc1F
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1n[nH]c2ccc(-c3cc(-c4ccccc4)[nH]c(=O)n3)cc12
Yield: 11 %

Procedure:
A solution of 4-(3-bromo-4-fluorophenyl)-6-phenylpyrimidin-2(1H)-one (0.3 g, 0.9 mmol) and copper(I) cyanide (0.16 g, 1.7 mmol) in N,N-dimethylformamide (3 mL) was heated to 155° C. for 24 hours. The crude reaction mixture was concentrated in vacuo then partitioned between saturated sodium bicarbonate (aqueous) and ethyl acetate/methanol (10:1). The layers were separated and the aqueous layer was extracted once with 10:1 ethyl acetate/methanol. The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo to give 0.30 g (quantitative yield) of crude 2-fluoro-5-(2-oxo-6-phenyl-1,2-dihydropyrimidin-4-yl)benzonitrile that was used without further purification for the next step. A solution of 2-fluoro-5-(2-oxo-6-phenyl-1,2-dihydropyrimidin-4-yl)benzonitrile (0.30 g, 1.0 mmol) and hydrazine monohydrate (1.7 mL, 36 mmol) in t-butanol (34 mL) was heated at 120° C. for 12 hours. The solution was concentrated in vacuo to give a solid, which was taken into hot methyl alcohol and treated with an excess of 4.0M hydrogen chloride in dioxane. After concentration in vacuo, the resultant solid was triturated in hot ethyl acetate, collected by vacuum filtration then lyophilized from aqueous solution to give 4-(3-amino-1H-indazol-5-yl)-6-phenylpyrimidin-2(1H)-one dihydrochloride (0.034 g, 11% yield). 1H NMR (400 MHz, DMSO): 8.93 (broad s, 1H), 8.20 (d, 1H), 8.11 (d, 1H), 7.70 (t, 1H), 7.65 (t, 2H), 7.57 (broad s, 1H), 7.47 (d, 1H). MS (EI) for C17H13N5O: 304 (MH+).