Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12](OC)=[O:13])=[N:10][CH:9]=[C:8]2[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:18][C:7]=12)[CH3:2].[NH2:27][OH:28].[OH-].[Na+].Cl>CO>[CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([NH:27][OH:28])=[O:13])=[N:10][CH:9]=[C:8]2[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:18][C:7]=12)[CH3:2]
Reactant: CCO/C=C/c1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCO/C=C/c1c(C(=O)NO)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To methyl 4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.1 g, 0.28 mmol) in methanol (10 mL) were added hydroxylamine (1 mL, 50% in water, 15.2 mmol) and sodium hydroxide (63.8 mg, 1.59 mmol). The mixture was stirred at room temperature for 2 h, and 4N hydrochloric acid (0.5 mL, 1.9 mmol) was added. The mixture was concentrated to provide 100 mg of the title compound that was used without further purification in the next step. 1H NMR (DMSO-d6) δ ppm 11.76 (d, 1H, J=1.9 Hz), 8.88 (d, 1H, J=1.9 Hz), 8.60 (s, 1H), 7.83 (d, 1H, J=3.0 Hz), 7.31 (t, 2H, J=8.9 Hz), 7.22 (d, 1H, J=13.2 Hz), 7.05 (t, 2H, J=8.9 Hz), 6.82 (d, 1 H, J=3.0 Hz), 6.66 (d, 1 H, J=13.2 Hz), 5.54 (s, 2H), 3.96 (q, 2H, J=7.0 Hz), 1.28 (t, 3H, J=7.0 Hz). LCMS (APCl, M+H+): 356.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][CH:7](C[Al](CC(C)C)CC(C)C)C>>[CH:2]1[CH2:7][CH2:6][CH:5]=[CH:4][CH:3]=1.[CH2:2]=[CH:3][CH:4]=[CH2:5]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: [Li]CCCC
Product: C1=CCCC=C1
Product: C=CC=C

Procedure:
Substantially the same hydrogenation reaction as conducted in Reference Example 7 is repeated, except that a hydrogenation catalyst comprised of titanocene ditolyl and n-BuLi (titanocene ditolyl/n-BuLi molar ratio: 1/1) is used instead of the catalyst comprised of CP2TiCl2 and TIBAL. As a result, a hydrogenation cyclohexadiene-butadiene triblock copolymer is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]([C:16]([CH2:18]Cl)=[O:17])([CH3:15])[CH3:14]>CC(C)=O>[CH3:12][C:13]([CH3:15])([CH3:14])[C:16](=[O:17])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)CCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Cn1cncn1
Temperature: 25 °C
Yield: 72 %

Procedure:
138 g (2 mol) of 1,2,4-triazole were added in portions to 276.4 g (2 mol) of ground potassium carbonate and 269.2 g (2 mol) of α-chloropinacolin in 500 ml of acetone at room temperature, whereupon the internal temperature rose to the boiling point. The mixture was stirred under reflux for 5 hours and then cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. After adding benzine, the oily residue crystallised. 240.8 g (72% of theory) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 62°-64° C. were obtained. ##STR103##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13]C(C)([O-])C.[K+].CI.Cl>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:13])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0° C. was added potassium tert-butoxide (4.96 g, 44.2 mmol) portionwise and the reaction mixture was stirred at 0° C. for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued over night. More MeI (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40° C. until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of 1M HCl and the aqueous phase was extracted with EtOAc (2×200 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradient to give the title compound (4.23 g, 80%) as an off white solid. MS: 240.0, 242.1 (M+H+).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([NH2:11])=[C:9](Cl)[N:8]=[C:7]([CH3:13])[N:6]=1.[CH3:14][OH:15]>>[CH3:1][O:2][C:5]1[C:10]([NH2:11])=[C:9]([O:15][CH3:14])[N:8]=[C:7]([CH3:13])[N:6]=1
Reactant: C[O-]
Reactant: CO
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Agent: [Na+]
Product: COc1nc(C)nc(OC)c1N
Temperature: 70 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Sodium methoxide (28% solution in methanol, 150 mL) was added dropwise to a stirred solution of 4,6-dichloro-2-methylpyrimidin-5-amine (15.0 g, 84.3 mmol) in methanol (150 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr, at 70° C. for 6 hr. The mixture was concentrated, diluted with aqueous saturated ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (14.2 g, 84.3 mmol, 100%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[S:20]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: ClCc1cccnc1
Agent: Cl
Product: CC(C)N1CCC(N(Cc2cccnc2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-pyridin-3-ylmethyl-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 83 mg (1 equiv.) 3-chloromethyl-pyridine hydrochloride and 200 mg (0.50 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide (reaction temperature: 60° C.). Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-pyridin-3-ylmethyl-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a light yellow amorphous material.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=1)[CH2:16][OH:17].C(N(CC)C(C)C)(C)C>C(O)CCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:14]([C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH:20]=1)[CH2:16][OH:17])[CH2:12]2
Reactant: C[Si](C)(C)C#Cc1cccc(C[C@H](N)CO)c1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(C[C@@H](CO)N2Cc3cc(Br)ccc3C2=O)c1

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)benzoate (0.75 g, 2.4 mmol), (2S)-2-amino-3-{3-[(trimethylsilyl)ethynyl]phenyl}propan-1-ol (0.60 g, 2.4 mmol) and N,N-diisopropylethylamine (2.1 mL, 12 mmol) in 1-butanol (2 mL) in a sealed tube was stirred at 140° C. for 2 h. The solvent was removed under vacuum and the residue was eluted with 0-100% EtOAc in hexanes giving 0.78 g (73% yield) of the pure desired product as off white solid. LC/MS found: 442.0 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]([OH:48])[CH3:47])[CH:41]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]([OH:48])[CH3:47])[CH:41]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A mixture of hydroxylammonium chloride (1.36 g), sodium hydrogen carbonate (1.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[3-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile (0.97 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.35 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then 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 colorless crystals (0.89 g, 60%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:12][CH3:13])[C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][O:12][CH3:13])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCOC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
2,5-Dibromopyridine (16.582 g) was dissolved in triethylamine (200 ml), followed by the addition of methyl propargyl ether (5.9 ml), copper iodide (267 mg) and bis(triphenylphosphine)palladium (II) chloride (46 mg). The resulting mixture was stirred in nitrogen atmosphere at room temperature for 1 hr. Subsequently, it was stirred at room temperature for further 3 hr. After the resulting insoluble matters were filtered off, the resulting solution was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a brown solid (12.411 g, yield; 79%).
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([C:15](=[O:17])[CH3:16])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:20]([O:19][CH3:18])=[O:29])=[CH:22][CH:23]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(=O)Cc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(C)=O)c2cccc(Cl)c2)cc1
Temperature: -78 °C

Procedure:
Sodium t-butoxide (0.60 g, 6.34 mmol) was added all at once to a THF solution (10 mL) of 1-(3-chloro-phenyl)-propan-2-one (1.08 g, 6.40 mmol) stirred at −78° C. After 3 minutes 4-bromomethyl-benzoic acid methyl ester (1.54 g, 6.72 mmol) was added all at once and the reaction solution was allowed to warm to room temperature. After stirring for 1 hour the reaction solution was partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with brine and dried over MgSO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.2 Hz, 2H); 7.29-7.25 (m, 2H); 7.20 (s, 1H); 7.13 (d, J=8.2 Hz, 2H); 7.07-7.03 (m, 1H); 3.91 (broad s, 4H); 3.47 (dd, J=7.2, 13.8 Hz, 1H); 2.96 (dd, J=7.6, 13.8 Hz, 1H); 2.07 (s, 3H). LCMS1 3.66 min. (M+H)=317.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C(Cl)Cl>[C:1]12([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)[C:27]3=[O:28])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1cc(CCCNCCCNCCC23CC4CC(CC(C4)C2)C3)ccn1
Solvent: ClCCl
Product: O=C1N(CCCc2ccncc2)CCCN1CCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To anhydrous methylene chloride (50 ml) were added a solution of the obtained N-[2-(1-adamantyl)ethyl]-N′-[3-(4-pyridyl)propyl]-1,3-propanediamine (80 mg, 0.23 mmol) in anhydrous methylene chloride (10 ml) and a solution of 1,1′-carbonyldiimidazole (40 mg, 0.26 mmol) in anhydrous methylene chloride (10 ml) dropwise simultaneously with stirring at room temperature over 20 minutes. The mixture was stirred overnight, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 8.0 mg (9.4%) of the titled compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.[CH2:24]([N:29]=[C:30]=[O:31])[CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)(Cl)Cl>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][C:30]([NH:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31]
Reactant: CCCCCN=C=O
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in chloroform (5 mL) were sequentially added triethylamine (0.26 mL) and pentyl isocyanate (0.09 mL), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 1-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]-3-pentylurea (117 mg).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[N:23]=[C:22]([C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[CH2:43][OH:44])[CH:20]=2)[N:15]=1.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.Cl.C(=O)(O)[O-]>N1C=CC=CC=1>[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:1]([O:44][CH2:43][C:36]2[CH:37]=[C:38]([F:42])[C:39]([F:41])=[CH:40][C:35]=2[C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([NH2:13])[N:23]=[C:22]3[C:24]([N:26]2[CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:34]2)=[O:25])=[O:2])[CH2:48][CH2:47]1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: CN1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CN1CCN(C(=O)OCc2cc(F)c(F)cc2-c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
400 mg of 1,1′-carbonyldiimidazole are dissolved in 10 ml of pyridine and cooled to 0° C. A solution of 1.0 g of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone dissolved in 10 ml of pyridine is added. The mixture is subsequently stirred at 0° C. for 2 h and at 25° C. for 2 h. 300 μl of N-methylpiperazine are then added, and the mixture is stirred at 25° C. for a further 18 h. The mixture is added to 250 ml of 1 N HCl, neutralised using bicarbonate solution and washed 3 times with 150 ml of dichloromethane each time. The organic phases are washed twice with 50 ml of water each time, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15]N(CC(NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1.CCN(C(C)C)C(C)C.[CH2:48]([CH:55]1CCNCC1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(C)C>[CH2:48]([CH:55]1[CH2:13][CH2:12][N:11]([C:6]2[C:5]([Br:26])=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCC(Cc3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 72 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (1.00 g, 3.96 mmol), DIPEA (3.5 eq, 13.86 mmol, 2.41 mL), isopropanol (20 mL) and 4-benzylpiperidine (1.1 eq, 4.36 mmol, 0.77 mL). Concentration in vacuo to half volume after 18 h gave a bright yellow solid, which was filtered and washed with cold water (2×5 mL) to give the product (1.12 g, 72%) as a yellow solid; δH (500 MHz, DMSO-d6) 1.38 (qd, br, J=12.2, 3.5 Hz, 2H, 2× piperidine CHAHB), 1.60 (d, br, J=10.9 Hz, 2H, 2× piperidine CHAHB), 1.69-1.76 (m, 1H, piperidine CH), 2.55 (d, J=7.1 Hz, 2H, 2× piperidine NCHAHA), 2.74 (t, br, J=11.9 Hz, 2H, 2× piperidine NCHAHA), 3.22 (d, br, J=12.5 Hz, 2H, PhCH2), 6.93 (s, br, 2H, NH2), 7.16-7.18 (1H, m, phenyl H-4), 7.19 (d, J=7.4 Hz, 2H, phenyl H-2 & H-6), 7.28 (t, J=7.1 Hz, 2H, phenyl H-3 & H-5), 8.13 (s, 1H, pyridine H-6);
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Li]C(C)(C)C.[OH2:28].C1[CH2:33][O:32]CC1>>[CH3:16][N:15]([CH3:17])[CH:12]([CH2:13][CH3:14])[CH:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:33]([OH:32])=[O:28])[S:3][C:4]=2[CH:10]=1)[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Reactant: C1CCOC1
Reactant: O
Agent: [Li]C(C)(C)C
Product: CCC(C(c1ccc2nc(C(=O)O)sc2c1)n1ccnc1)N(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine (76 mg, 0.2 mmol) in THF (10 mL) at −78° C. was added t-BuLi (0.24 mL, 1.7 M solution) and the reaction was stirred for 15 min. Dry CO2 was bubbled for 1 h while allowing the reaction to warm to 0° C. Water was added and extracted with DCM. The water layer was neutralized and evaporated. The residue was extracted with methanol to afford 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole-2-carboxylic acid. MS ESI: m/z 345.26 [M+H+].
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=O)C=1.[CH2:12]([N:15]([CH:30]([CH3:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:29])N(C)C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:13]=[CH2:14]>C(Cl)(Cl)Cl>[CH3:12][NH:15][CH3:30].[CH2:12]([N:15]([CH:30]([CH3:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([Cl:1])=[O:29])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:13]=[CH2:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN(C(C)c1ccccc1)S(=O)(=O)c1ccc(C(=O)N(C)C)cc1
Solvent: ClC(Cl)Cl
Product: C=CCN(C(C)c1ccccc1)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Product: CNC

Procedure:
5.4 g of metachlorperbenzoic acid was added to a chloroform solution of 3.7 g of N-allyl-N-(α-methylbenzyl)-4-(N,N-dimethylcarbamoyl)benzenesulfonamide obtained by reaction between dimethylamine and N-allyl-N-(α-methylbenzyl)-4-chlorocarbonylbenzenesulfonamide. The mixture was reacted under reflux for 2 hours. Thereafter, an aqueous sodium sulfite solution was added to decompose the excess of the peroxide. After washing with an aqueous sodium bicarbonate solution and water, the chloroform solution was dried over anhydrous magnesium sulfate, concentrated and purified by the silica gel chromatography to obtain 3.0 g (77%) of the intended product (Compound No. 163), m.p. 98.0°~100.0° C. The elemental analysis of the product was effected with the results shown below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[Cl:8][C:3]1[C:2]([NH:1][C:42](=[O:43])[C:41]2[CH:45]=[C:37]([CH2:36][C:30]3[C:31](=[O:35])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[C:28](=[O:51])[C:29]=3[CH3:50])[CH:38]=[CH:39][C:40]=2[O:46][C:47](=[O:49])[CH3:48])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 54 %

Procedure:
3-Amino-2-chloropyridine (0.206 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:1) to obtain the titled compound (0.140 g, 0.289 mmol, 54%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:30]2[CH:29]=[CH:28][C:16]3[C:17](=[O:27])[N:18]([CH2:24][CH2:25][Br:26])[C:19](=[O:23])[C:20]4=[CH:21][CH:22]=[C:13]([C:14]=2[C:15]=34)[C:12]1=[O:31])([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>C(#N)C>[Br-:26].[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:30]2[CH:29]=[CH:28][C:16]3[C:17](=[O:27])[N:18]([CH2:24][CH2:25][N+:35]4[CH:36]=[CH:37][N:33]([CH3:32])[CH:34]=4)[C:19](=[O:23])[C:20]4=[CH:21][CH:22]=[C:13]([C:14]=2[C:15]=34)[C:12]1=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccnc1
Reactant: CC(C)(C)c1ccccc1N1C(=O)c2ccc3c4c(ccc1c24)C(=O)N(CCBr)C3=O
Solvent: CC#N
Product: Cn1cc[n+](CCN2C(=O)c3ccc4c5c(ccc(c35)C2=O)N(c2ccccc2C(C)(C)C)C4=O)c1
Product: [Br-]

Procedure:
0.40 g (0.84 mmol) of 1-(2-tert. butylphenyl)-6-(2-bromoethyl)-1H-indolo[5,4,3-def]isoquinoline-2,5,7(6H)-trione from Step 1 was dissolved in 40 mL of acetonitrile. After adding 0.35 g (4.20 mmol) of N-methylimidazole, the mixture was stirred at reflux for 2 hours. After removing the solvent, the precipitate was filtered off, washed with ethyl acetate and dried.