Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C:15]1([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=2[C:32]2[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[CH:34][C:33]=2[C:41]#[C:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCOCC1>O>[C:43]1([C:42]#[C:41][C:33]2[CH:34]=[CH:35][C:36]([NH2:38])=[CH:37][C:32]=2[C:24]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:23]=2[C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=[N+]([O-])c1ccc(C#Cc2ccccc2)c(-c2cc([N+](=O)[O-])ccc2C#Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(C#Cc2ccccc2)c(-c2cc(N)ccc2C#Cc2ccccc2)c1
Yield: 46 %

Procedure:
A solution of sodium dithionite (8.00, 0.0460 mole) and sodium carbonate (7.01 g, 0.0661 mole) in water (50 ml) was stirred under a nitrogen atmosphere while 2,2'-bis(phenylethynyl)-5,5'-dinitrobiphenyl (0.500 g, 0.00112 mole) was added followed by dioxane (50 ml). The reaction mixture was stirred and refluxed for 2 hours and then the solvent was removed under vacuum. The residue was extracted with benzene and the filtered benzene extracts were freeze-dried to afford 0.198 g (46%) of 2,2'-bis(phenylethynyl)-5,5'-diaminobiphenyl, m.p. 159°-161° C. after recrystallization from chloroform-cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:58]=[CH:57][C:53]([CH:54]([OH:56])[CH3:55])=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][C:50]([F:49])=[CH:51][CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: CC(O)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 72.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-fluoro-α-methylbenzyl alcohol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (91 mg, yield 73%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:6][C:5](=[O:16])[NH:4]1.N1C=CN=C1.[CH3:22][C:23]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:24]>CN(C=O)C>[Si:26]([O:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[O:6][C:5](=[O:16])[NH:4]1)([C:23]([CH3:25])([CH3:24])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc([C@@H]2OC(=O)N[C@H]2CO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
To a solution of (4S,5S)-4-(hydroxymethyl)-5-(4-methoxyphenyl)oxazolidin-2-one [545435-91-4] (0.68 g, 3.05 mmol) and imidazole (0.249 g, 3.66 mmol) in DMF (10 mL) was added dropwise TBDPSCl (0.97 mL, 3.66 mmol) at 0-5° C. The reaction mixture was allowed to warm to RT and was stirred overnight at RT. The reaction mixture was concentrated and the residual oil was dissolved in TBME and washed with 10% aqueous KHSO4, H2O, saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 5% to 50% in order to give the title compound as a white foam (1.62 g, 55%). TLC (heptane/EtOAc 1:1) Rf=0.44; LC-MS: [M+H] 462; Rt 1.36 min; (LCMS method 2). 1H NMR (400 MHz, CDCl3): 7.65 (d, 4H), 7.35-7.60 (m, 6H), 7.24 (d, 2H), 6.92 (d, 2H), 5.24 (d, 1H), 5.20 (br s, 1H), 3.84 (m, 4H), 3.77 (m, 2H), 1.09 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13]C=[CH:11][CH:10]=1.[C:18](=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH3:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2ccccc2)cc1
Yield: 99 %

Procedure:
A mixture of the palladium catalyst formed in Example 24 (50 mg), 4-bromotoluene (1.6 mmol), phenyl boronic acid (1.6 mmol) and potassium carbonate (2.4 mmol) in xylene (10 ml) was warmed at 110° C. with stirring for 1 hour. The mixture was filtered and the solid washed with ether. The combined organic extracts were washed with water, dried and then concentrated to give 4-methyl biphenyl in 99% yield. The filtered solid was returned to the reaction flask and further 4-bromotoluene (1.6 mmol), phenyl boronic acid (1.6 mmol) and potassium carbonate (2.4 mmol) in xylene (10 ml) was added and the process repeated to give 4-methyl biphenyl in 99% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:2]1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.CN(C=O)C.CC[O-].[Na+]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[N:13]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[C:12]2=[O:17])=[CH:2]1
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccccc23)N1
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1NC(Cc2c[nH]c3ccccc23)C(=O)N1CCCN1CCC(c2ccccc2)CC1
Reaction time: 10 h

Procedure:
A mixture of 5-(indol-3-ylmethyl)hydantoin (6.4 g, 0.028 mole), 1-(3-chloropropyl)-4-phenylpiperidine (6.6 g, 0.028 mole) and 200 ml of DMF in 200 ml of anhydrous C2H5OH and 0.028 mole of NaOC2H5 was heated under reflux with stirring for 10 hours. The mixture was filtered and the filtrate was diluted with H2O. The solid was collected and twice recrystallized from aqueous C2H5OH, yield 2.0 g, mp 179°-80°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[N:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12]([C:13]#[N:14])=[C:8]2[NH:7][CH2:6][CH2:5]1.CS(C)=[O:30].[OH-].[Na+].OO>CCO>[CH3:1][NH:2][CH2:3][CH:4]1[N:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12]([C:13]([NH2:14])=[O:30])=[C:8]2[NH:7][CH2:6][CH2:5]1
Reactant: CS(C)=O
Reactant: CNCC1CCNc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn21
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCC1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Temperature: 60 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 7-((methylamino)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (20 mg, 0.0557 mmol) in 2 mL of EtOH was added 1 mL of DMSO, 0.5 mL of NaOH (5N) and 0.5 mL of H2O2 (30% solution). The reaction mixture was stirred at 60° C. for 1 hr. Then the mixture was concentrated to remove EtOH. The residue was partitioned between water (20 mL) and EA (20 mL). The EA layer was concentrated to give the product as a white solid (10 mg, yield: 48%). 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J=8 Hz, 2H), 7.47-7.40 (m, 2H), 7.19 (t, J=7.6 Hz, 1H), 7.11-7.04 (m, 4H), 6.61 (s, 1H), 4.26-4.16 (m, 1H), 3.34-3.27 (m, 2H), 2.97-2.95 (m, 1H), 2.83-2.77 (m, 1H), 2.33 (s, 3H), 2.08-2.02 (m, 2H). MS (ESI) m/e [M+1]+378.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:12]3=[C:11]([CH3:28])[C:10]=2[CH:9]=1)#[N:2].C(S)[C@H](N)C(O)=O.C(O)(C(F)(F)F)=O>CCOCC.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[C:11]([CH3:28])[C:10]=2[CH:9]=1)#[N:2]
Reactant: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C#N)c4)cc13)CCC2CC(=O)OC(C)(C)C
Agent: N[C@@H](CS)C(=O)O
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C#N)c4)cc13)CCC2CC(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 110.1 %

Procedure:
To a pre-cooled flask containing tert-butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.308 g, 0.649 mmol) was added a pre-cooled solution of D/L-2-Amino-3-mercaptopropanoic acid (0.079 g, 0.649 mmol) in TFA (6.49 mL, 0.649 mmol) at 0° C. After stirring for 3 h at 0° C., ice-cold water (65 mL) was added. The resulting suspension was diluted with Et2O (130 mL). The organic layer was separated, washed with water (2×30 mL), brine (30 mL), and dried over MgSO4. The solvent was coevaporated with toluene (25 mL) in vacuo at 25° C. The residue was coevaporated with toluene (20 mL) again to give an oil. The oil was dissolved in DCM (5 mL) and coevaporated with hexanes (25 mL) to give the title compound as a grey solid (0.299 g). LCMS m/z=419.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (d, J=6.06 Hz, 6H), 2.16 (s, 3H), 2.19-2.29 (m, 1H), 2.47 (d, J=6.69 Hz, 1H), 2.70-2.82 (m, 2H), 3.54-3.65 (m, 1H), 3.92 (m, 1H), 4.03 (dt, J=8.05, 1.91 Hz, 1H), 4.79 (dt, J=12.13, 6.06 Hz, 1H), 5.04 (s, 2H), 6.74 (dd, J=8.72, 2.40 Hz, 1H), 7.00 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.28 (d, J=8.84 Hz, 1H), 7.72 (dd, J=8.78, 2.21 Hz, 1H), 7.78 (d, J=2.15 Hz, 1H), 12.27 (bs, 1H).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][N:5]=[CH:4][CH2:3]1.C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Na+]>CCOCC.O>[C:14]([N:6]1[CH:2]([CH3:1])[CH2:3][CH:4]=[N:5]1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC1CC=NN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1N=CCC1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a stirred solution of 6.5 g (0.0773 mole) of 5-methyl-2-pyrazoline and 8.08 g (0.08 mole) of triethylamine in 350 mls of ether was added in a rapid dropwise manner, a solution of 6.06 g (0.0773 mole) of acetylchloride in 100 mls of ether. After the addition was complete, the mixture was stirred at room temperature for 30 minutes then 50 mls of water was added. This mixture was stirred for 10 minutes. Sufficient sodium chloride was added to saturate the water present and the aqueous and ether phases were allowed to separate. The ether phase was removed and dried. The ether was evaporated off to yield 7 g of the crude product. This material was distilled at 68°-70° C. at 2 millimeters of mercury to give 4.5 g of the desired product as a colorless liquid. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 56.76, 7.79 and 22.26 percent, respectively, as compared with the theoretical contents of 57.12, 7.99 and 22.21 percent, respectively, calculated for the above-named compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[CH3:19])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[CH3:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2Cc3ccccc3CN2C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: CN1Cc2ccccc2CC1c1ccc(O)cc1

Procedure:
To 30 ml of 3-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (Compound No. 19) in benzene, 0.85 g of aluminum chloride was added and the resulting mixture was heated to reflux for 5 hours. After completion of the reaction, the reaction mixture was allowed to cool and water was added thereto. The generated precipitates were removed by filtration through Celite. The filtrate was made alkaline with saturated aqueous sodium hydrogen carbonate solution, and the resultant was extracted with ethyl acetate. After drying the combined organic layers over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate (1/1)] to obtain 0.28 g of 3-(4-hydroxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [N:1]([CH:4]([CH3:20])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:20]
Reactant: COC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: COC1=C2C=c3c(cnn3CC(C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.3 %

Procedure:
0.85 g (3.2 mmol) of (RS)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol was hydrogenated on 85 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 70 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 371 mg (3.2 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.9 g (78%) of (RS)-2-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 182° was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]3[O:36][CH:35]=[C:34]([CH3:37])[C:33]=3[CH:38]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:32]3[O:36][CH:35]=[C:34]([CH3:37])[C:33]=3[CH:38]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1coc2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4occ(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.36 mmol) in 1,4-dioxane (6 mL) was added 4,4,5,5-tetramethyl-2-(3-methyl-1-benzofuran-5-yl)-1,3,2-dioxaborolane (350 mg, 1.36 mmol), Pd(PPh3)4 (40 mg, 0.034 mmol), K3PO4 (430 mg, 2.04 mmol) and water (5 drops) with stirring for 5 h at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(3-methyl-1-benzofuran-5-yl)quinoxaline-6-carboxylate as a yellow solid (110 mg, 63%).
Reaction SMILES: Cl.Cl.N[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]([NH:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:10][CH:9]=1.C([N:27](C(C)C)CC)(C)C.I.[NH2:34][C:35]1[C:36]([C:43]([NH:45][C:46](=[NH:49])SC)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1>C(O)C.CO>[NH2:34][C:35]1[C:36]([C:43]([N:45]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]([NH:16][C:17]3[NH:21][CH:20]=[CH:19][N:18]=3)=[O:15])=[CH:10][CH:9]=2)[C:46]([NH2:49])=[NH:27])=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: I
Solvent: CO
Solvent: CCO
Product: N=C(N)N(CCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1)C(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N-(1H-imidazol-2-yl)acetamide dihydrochloride 35 (99 mg, 0.27 mmol) and diisopropylethylamine (0.27 mL, 1.53 mmol) in absolute ethanol (4 mL) and anhydrous methanol (3 mL) was stirred at 70° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (130 mg, 0.34 mmol) was added in one portion. The reaction mixture was stirred for 3 h and then cooled to room temperature. The yellow insolubles were removed by suction filtration and the liquid filtrate was concentrated by rotary evaporation. The crude residue was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, 150:10:1, and 100:10:1, v/v) to give 2-(4-{4-[N-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-(1H-imidazol-2-yl)-acetamide as a yellow solid (44 mg, 29% yield). The free base thus obtained was dissolved in methanol and treated with 4 drops of 4 N aqueous HCl. The solution was concentrated under reduced pressure and further dried under vacuum to give the final compound 36. mp 172-174° C. 1H NMR (300 MHz, CD3OD) δ 1.61-1.77 (m, 4H), 2.58-2.70 (m, 2H), 3.32-3.40 (m, 2H), 4.80 (s, 2H), 7.00 (d, 2H), 7.18 (d, 2H), 7.20 (s, 2H). m/z (ESI): 501 [C21H25ClN10O3+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:16]([O:25][CH3:26])=[N:17][C:18]([O:23][CH3:24])=[N:19][C:20]=2[O:21][CH3:22])[CH2:12][C:11](=[O:27])[C:10]=1[C:28](=O)[CH2:29][CH3:30]>C(O)C.O>[CH2:2]([O:4][N:5]=[C:28]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[C:16]([O:25][CH3:26])=[N:17][C:18]([O:23][CH3:24])=[N:19][C:20]=2[O:21][CH3:22])[CH2:12][C:11]=1[OH:27])[CH2:29][CH3:30])[CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2c(OC)nc(OC)nc2OC)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2c(OC)nc(OC)nc2OC)CC1=O
Yield: 88.6 %

Procedure:
Ethoxyamine hydrochloride (0.30 g) and then aqueous sodium hydroxide (0.15 g in 2 ml of water) were added to a solution of 3-hydroxy-5-(2,4,6-trimethoxy-5-pyrimidyl)-2-propionylcyclohex-2-en-1-one (0.90 g) in absolute ethanol (30 ml) at 20° C. with stirring. After 20 hours at 20° C. the mixture was diluted with water (150 ml) and extracted with chloroform (2×75 ml). The chloroform layer was dried over anhydrous magnesium sulphate and the solvent was removed by evaporation under reduced pressure to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethoxy-5-pyrimidyl)cyclohex-2-en-1-one (900 mg) as a pale yellow oil. The product was characterized by nuclear magnetic resonance spectroscopy.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[C:14]1([CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][CH2:21][CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:24])[CH2:11]2
Reactant: CC(CCN)c1ccccc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(CCN1Cc2cccc(I)c2C1=O)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.178 g, 0.5 mmol), 3-phenyl-butylamine (0.090 g, 0.6 mmol), and K2CO3 (0.166 g, 1.2 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(3-phenyl-butyl)-2,3-dihydro-isoindol-1-one (0.046 g, 23%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.32 (d, 3H), 1.96 (m, 2H), 2.78 (m, 1H), 3.54 (m, 2H) 4.16 (s, 2H), 7.14-7.38 (m, 7H), 7.88 (d, 1H). GC-MS: m/z 391 (M)+.
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C(OC(C)C)(C)C>CCCCCC>[C:9]([N:2]([C:3]1[CH:8]=[CH:7][C:6]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:5][CH:4]=1)[CH3:1])(=[O:11])[CH3:10]
Reactant: CC(=O)N(C)c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
N-Methylacetanilide (25.0 g, 188.0 mmol) was added to chlorosulfonic acid (62.8 ml) under cooling with ice in portions at such a rate as not to raise the temperature of the resulting mixture to 50° C. or above, which took about 10 minutes. The obtained mixture was stirred at 80° C. for 2.5 hours and poured into a mixture comprising ice (200 ml), hexane (30 ml) and isopropyl ether (30 ml) under cooling with ice at 20° C. or below in portions to decompose excess chlorosulfonic acid. The precipitated crystal was recovered by filtration, washed with water and dissolved in ethyl acetate. The obtained solution was washed with water and a saturated aqueous solution of common salt. The organic layer was dried over magnesium sulfate and concentrated to give the title compound as a white crystal (19.4 g, yield: 42%). m.p. (°C.): 139 to 140
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH:10]([CH3:13])[C:11]#N>O>[Cl:9][CH:10]([C:13]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH3:11]
Reactant: CC(Cl)C#N
Reactant: Nc1cccnc1N
Solvent: O
Product: CC(Cl)c1nc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
5.2 g of 2,3-diaminopyridine in 209 g of polyphosphoric acid are heated at 120° C. for 0.5 h. The solution is cooled to 80° C. and 4.6 ml of 2-chloropropionitrile are added. Thereafter, the reaction mixture is heated to 180° C. for 2.5 h. After cooling, the polyphosphoric acid is hydrolyzed with water, the mixture is filtered using charcoal and celite and the pH value of the filtrate is adjusted to pH 4 using 9 M aqueous sodium hydroxide solution. The mixture is extracted twice each with 250 ml of ethyl acetate, the combined organic phases are dried using sodium sulfate, concentrated and lyophilized from ethanol/water to give 3.56 g of the title compound as a light brown, amorpheous solid. M.p. 132° C. TLC: Rf=0.60 (dichloromethane/methanol 8:1).