Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]2)=[C:19]([C:33]([F:36])([F:35])[F:34])[CH:18]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]2)=[C:19]([C:33]([F:36])([F:34])[F:35])[CH:18]=1
Reactant: COC(=O)C1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C1CCN(c2ccc(Nc3c([N+](=O)[O-])cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of compound 8.0 6-bromo-4-chloro-3-nitroquinoline (0.29 g, 1.0 mmol, 1 equiv.) in dioxane (5 mL) at room temperature was added 8.1 methyl 1-(4-amino-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.3 g, 1.0 mmol, 1 equiv.). The resulting mixture was heated overnight to 85° C. under argon. Upon cooling to room temperature, the mixture was neutralized with aqueous NaHCO3, diluted with EtOAc (50 mL), and washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (Hexanes: EtOAc=4:1) to afford desired product 8.2 methyl 1-(4-(6-bromo-3-nitroquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.50 g; 90%). LC-MS (M+H): 555.10
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@@H:14]([OH:17])[CH2:15][OH:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].ClCCl.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>O>[CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@H:14]([OH:17])[CH2:15][O:16][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2c([C@@H](O)CO)cccc2cc1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c([C@H](O)CO[Si](C)(C)C(C)(C)C)cccc2cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
1.72 g (7.45 mmol) of (−)-2-ethyl-3-methyl-8-(1(R),2-dihydroxyethyl)quinoline, 25 ml of dichloromethane and 0.75 g of imidazole are introduced into a 100 ml round-bottomed flask. The mixture is cooled to 0° C., 1.12 g (7.45 mmol) of tert-butyldimethylchlorosilane are added and the resulting mixture is stirred for 2 hours at 0° C. 50 ml of water are added and this mixture is extracted with ethyl acetate (3×80 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a column of silica (elution solvent: 10% ethyl acetate in hexane). 1.85 g (yield: 72%) of (+)-2-ethyl-3-methyl-8-(1(S)-hydroxy-2-[tert-butyldimethylsilyloxy]-ethyl)quinoline are obtained in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7](O)[N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:16][C:7]1[N:8]=[C:9]([CH3:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(C)ccnc2c(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c(C)ccnc2c(Cl)n1
Temperature: 104 °C
Yield: 66.1 %

Procedure:
4,6-Dimethyl-[1,7]naphthyridin-8-ol (1.26 g, 7.23 mmol) and phosphorus oxychloride (6.7 mL, 72 mmol) in toluene (18 mL) are heated at 100° C. overnight. Phosphorus oxychloride (20 mL, 215 mmol) is added and the reaction mixture is heated at 104° C. for 1 d. The reaction mixture is cooled to RT and poured in a mixture of ice and water under stirring. After 30 min 20% NaOH is added until pH 6-7. The aqueous layer is extracted with DCM and the combined organic layers are washed with brine, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-50% EtOAc/cyclohexane) to furnish 8-chloro-4,6-dimethyl-[1,7]naphthyridine (920 mg, 66%).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15]>C(O)(=O)C>[Br:1][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:3])=[C:5]([C:14]([OH:16])=[O:15])[CH:6]=1
Reactant: BrBr
Reactant: O=C(O)c1ccc2ccccc2c1O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
Bromine (6.1 mL, 120 mmol) was added to a solution of 1-hydroxy-2-naphthoic acid (compound 66, 18.9 g, 100 mmol) in glacial acetic acid (250 mL). The mixture was stirred at room temperature overnight. The resulting solid was filtered and dried in vacuo to yield the title compound (24.6 g, 92%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:10][CH:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[CH:7]=[CH:6]1)(=O)[CH3:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC>C(OCC)C>[CH2:1]([O:4][CH:5]1[O:10][CH:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[CH:7]=[CH:6]1)[CH2:2][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CC(=O)OC1C=CC(=O)C(C(C)C)O1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOC1C=CC(=O)C(C(C)C)O1
Yield: 92.1 %

Procedure:
In 50 ml of ethyl ether were dissolved 3.96 g of 6-acetoxy-2-isopropyl-2H-pyran-3(6H)-one and 4.84 g of cetyl alcohol with stirring. Into the solution was gradually added 0.1 ml of anhydrous stannic chloride at a temperature of 5° to 10° C. The reaction mixture was stirred at room temperature for 7 hours, washed twice with aqueous sodium hydrogencarbonate solution and once with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. By the distillation of solvent was obtained 7.0 g of 6-cetyloxy-2-isopropyl-2H-pyran-3(6H)-one [compound 1] in a yellow viscous oily form.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1nc2ccc(O)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc4nc(C)[nH]c4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
Sodium hydride (71 mg, 1.8 mmol) was added to 5-hydroxy-2-methylbenzimidazole (204 mg, 0.89 mmol) in anhydrous DMF (2.5 ml) under an argon atmosphere. The mixture was stirred at ambient temperature for 10 minutes. 4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) was added and the reaction mixture stirred at 95° C. for 2 hours. Upon cooling to ambient temperature the mixture was poured in water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), silica was added and the solvent evaporated off. The obtained powder was placed on the top of a disposable silica column (ISOLUTE) and the product eluted off using a gradient of methanol/dichloromethane (3/97, 5/95, 8/92). Evaporation of the solvent gave 6,7-dimethoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)quinazoline (145 mg, 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(CN)O.Cl>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:18]2[NH:12][C:13](=[O:14])[NH:15][C:16]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: O
Solvent: NCCO
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)N1

Procedure:
A mixture of p-nitrobenzaldehyde (2.510 g.) and hydantoin (1.671 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.53 g., 1.5 molar ratio) was added and the mixture was stirred magnetically and heated at 90°-92° (bath temperature) for 41/4 hours. The mixture was cooled in an ice-bath and acidified with HCl. After refrigeration overnight the mixture was filtered, washed with water and dried at 55°/10 mm. The title compound was obtained as a brown solid (3.258 g.), m.p. 252°-253° decomp.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19]C)=O)[N:5]([CH2:7][C:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=2)=O)[CH:6]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[O:19])[N:23]3[CH2:22][CH2:21][NH:24][C:8]3([C:10]3[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=3)[CH2:7][N:5]2[CH:6]=1
Reactant: COC(=O)c1cc(Br)cn1CC(=O)c1cnc(C)cn1
Reactant: NCCN
Solvent: C1COCCO1
Product: Cc1cnc(C23Cn4cc(Br)cc4C(=O)N2CCN3)cn1
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of methyl 4-bromo-1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (111 mg, 0.33 mmol) in 1,4-dioxane (2 mL) was added ethane-1,2-diamine (0.6 mL, 9.0 mmol). The solution was heated at reflux. After 2 days the reaction was complete (monitored by LCMS). The mixture was then concentrated in vacuo to give a oily solid. The material was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient CH2Cl2 1 CV, 0-10% MeOH in CH2Cl2 15 CV and hold 10% MeOH 5 CV) to give 7-bromo-10a-(5-methylpyrazin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (33 mg, yield 29%). 1H-NMR (400 MHz, CDCl3): δ 2.53 (s, 3H), 2.95 (dt, 1H, J 10.8, 7.9 Hz), 3.31 (ddd, 1H, J 11.0, 7.6, 3.8 Hz), 3.37 (ddd, 1H, J 11.3, 7.7, 3.8 Hz), 3.94 (dt, 1H, J 11.2, 7.8 Hz), 4.16 (d, 1H, J 12.0 Hz), 4.77 (d, 1H, J 12.0 Hz), 6.51 (d, 1H, J 1.6 Hz), 6.87 (d, 1H, J 1.7 Hz), 8.34 (d, 1H, J 1.4 Hz), 8.40-8.41 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Yield: 84.4 %

Procedure:
3-Methylsulfonylamino-5-nitro-1H-indazole can be obtained as described in Example 2 from 0.7 g of 3-amino-5-nitro-1H-indazole, 23 ml of pyridine and 0.455 g of methylsulfonyl chloride. 0.85 g of 3-methylsulfonylamino-5-nitro-1H-indazole is thus obtained in the form of an orange powder used as it is in the following step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)[CH:5]=[CH:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:7]=2)=[N:12][N:11]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccnc(Cl)c2)o1
Solvent: CS(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccnc(N3CCOCC3)c2)o1
Temperature: 170 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of 2-chloro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) in DMSO (2 mL) was added morpholine (257 μL, 2.95 mmol) and stirred for 18 h under an argon atmosphere at 170° C. After cooling to ambient temperature the resulting dark brown solution was extracted with ethyl acetate (20 mL) and aqueous sodium carbonate (saturated, 20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (166 mg, 72%) as a white solid. MS: m/e=390.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:14]([O-])=O)[C:5]1=[O:17].CO.[H][H]>>[NH2:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][N:4]([CH2:3][CH2:2][OH:1])[C:5]2=[O:17]
Reactant: [H][H]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1CCO
Solvent: CO
Product: Nc1cccc2c(=O)n(CCO)ccc12
Reaction time: 8 h

Procedure:
Into a 500 ml round bottom flask was combined 2-(2-hydroxyethyl)-5-nitroisoquinolin-1(2H)-one (2.0 g, 0.0085 mol) palladium on C (0.09 g, 0.0008 mol), and methanol (100 mL, 2 mol). The vessel was charged with hydrogen and evacuated three times and stirred under hydrogen at 1 atm. overnight. The mixture was filtered over Celite and the filtrate was removed under reduced pressure to yield the title compound as a light brown solid. It was taken onto the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:2]1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23](OB(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20]>>[NH:1]1[CH2:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][C:8]2([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:26]=3)[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]2)=[O:5])[CH2:2]1
Reactant: O=C(OCc1ccccc1)C1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(C2(COC(=O)C3CCCNC3)C=CC=CC2)c1
Yield: 32.9 %

Procedure:
Using benzyl nipecotate (4.39 g, 20.0 mmol) and 3-methoxycarbonylphenylboric acid (7.20 g, 40.0 mmol), the same procedure was followed as in Example 2 to give 2.34 g (33%) of the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].Br[CH2:15][CH:16]1[O:20][CH:19]([CH3:21])[CH:18]([CH3:22])[O:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][NH:8][CH2:15][CH:16]1[O:20][CH:19]([CH3:21])[CH:18]([CH3:22])[O:17]1)[CH2:11][CH2:12][CH3:13]
Reactant: CC1OC(CBr)OC1C
Reactant: CCCCOC(CN)OCCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOC(CNCC1OC(C)C(C)O1)OCCCC
Temperature: 25 °C

Procedure:
2,2-Dibutoxyethylamine (0.11 mole), 2-bromomethyl-4,5-dimethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CCc1cnoc1-c1cc(Cl)cc(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1cc(Cl)cc(Cl)c1
Yield: 99 %

Procedure:
A mixture of 3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionic acid (3.50 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionate (3.49 g, yield 99%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.62–2.72 (2H, m), 2.92–3.02 (2H, m), 3.70 (3H, s), 7.45 (1H, t, J=1.8 Hz), 7.60 (1H, d, J=1.8 Hz), 8.24 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.C1C2C=CC3C(=CC([CH:38]=[O:39])=C4C=3C=CC=C4)C=2C=CC=1.C(Cl)Cl>CCOC(C)=O>[Cl:1][C:2]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:4](=[C:5]3[C:10](=[C:11]([CH:38]=[O:39])[CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:3]=1
Reactant: Clc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cc2c3ccccc3c(Cl)cc2c2ccccc12

Procedure:
6-Chlorochrysene (Cambridge Chemical, Inc., 70 g, 0.266 mol) was formylated according to the proceudre outlined in 1A, except that CH2Cl2 (2.5 L) was used as the reaction solvent. Chromatography on a plug of SiO2 (1 kg) using EtOAc as the eluting solvent afforded after removal of solvent and drying 19.1 g (25%) of 12-chloro-6-chrysenecarbaldehyde mp 255°-257°, (EtOAc).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[C:8]([CH3:27])=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[N:14]=2)[S:10][C:11]=1Br.IC.[Cl-].[NH4+]>C1COCC1>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:15]1[N:14]=[C:13]([C:9]2[S:10][C:11]([CH3:1])=[C:7]([Br:6])[C:8]=2[CH3:27])[N:17]([CH3:18])[N:16]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1sc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(C)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
n-Butyllithium (0.7 g, 10.8 mmol) was added dropwise to a solution of 5-(4,5-dibromo-3-methylthien-2-yl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (5 g, 10.8 mmol) in THF (70 mL) at −70° C. and stirred for 1 hour. Iodomethane (1.6 g, 11.29 mmol) was added to the reaction mixture and allowed to warm to 25° C. After adding saturated aq ammonium chloride (10 mL), the organic layer was separated, washed with water, followed by saturated aq sodium chloride (20 mL) and dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed to give the product as a yellow oil (2.0 g, 47%): 1H NMR (CDCl3) δ 2.32 (s, 3H), 2.48 (s, 3H), 3.99 (s, 3H), 7.07-7.13 (m, 1H), 7.28-7.38 (m, 2H); EI/MS 400 m/e (M+); Calcd. for C15H12ClBrFN3S: C, 44.96; H, 3.02; N, 10.49; Found: C, 44.94; H, 3.01; N, 10.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:26][C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][N:18]=3)[S:28][C:29]=2[CH:35]=1)=[O:6]
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(Cl)c(Cl)c5)cc4s3)c2cc1OC

Procedure:
3,4-Dichloro-N-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzo-thiazol-6-yl]benzamide was prepared from 3,4-dichlorobenzoyl chloride (24 mg, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 49 mg, 92 μmol, 82%). LC/ESI-MS: m/z=526 [M(35Cl2)+H]+; m/z=524 [M(35Cl2)−H]−; Rt=3.82 min.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[O-2].[Mg+2].[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>O.C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:16]([C:14]1[S:15][C:11]([Cl:10])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1)(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: OCCNCCO
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)N(CCO)CCO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
To a stirred solution of diethanolamine (1.16 g, 11 mmol) in water (4 ml) was added at room temperature magnesium oxide (2.22 g, 55 mmol) and THF (16 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (3.46 g, 13.2 mmol) in THF (4 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (0.48 g, 13%) as a yellow solid. MS (ISP) 331.2 [(M+H)+], mp 113° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][C:6]([N:16]([CH3:18])[CH3:17])=[C:7]([Cl:15])[N:8]=2)[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:15][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:16]([CH3:18])[CH3:17])[N:3]=[C:2]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[N:11]=[C:10]2[N:12]([CH3:14])[CH3:13]
Reactant: CN(C)c1nc2nc(Cl)nc(N(C)C)c2nc1Cl
Reactant: C1CNCCN1
Product: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1Cl

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4,7-bis(dimethylamino)pteridine and piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (9.20 g, 40.1 mmol), N,O-dimethylhydroxylamine hydrochloride (5.87 g, 60.2 mmol) and CH2Cl2 (120 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.54 g, 60.2 mmol), N,N-diisopropylethylamine (10.51 mL, 60.2 mmol) and 4-(dimethylamino)pyridine (250 mg, 2.046 mmol) before being stirred at RT overnight. After this time, the mixture was diluted with DCM (100 mL) and washed sequentially with 1 M hydrochloric acid (2×75 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The organic phase was dried (MgSO4) and then concentrated in vacuo to give tert-butyl 4-(methoxy(methyl)carbamoyl)-piperidine-1-carboxylate as a colorless oil (9.9 g), which was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([N:17](C)[C:18](=O)OC(C)(C)C)[CH2:13]2)[C:9]2[CH2:8][CH2:7][CH2:6][C:5]3([CH2:29][CH2:28][CH2:27][CH2:26]3)[C:4]=2[N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:18][NH:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5]4([CH2:29][CH2:28][CH2:27][CH2:26]4)[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2nc(N)nc3c2CCCC32CCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCN(c2nc(N)nc3c2CCCC32CCCC2)C1
Reaction time: 16 h

Procedure:
A solution of Example 1G (38 mg, 0.09 mmol) in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.1 mL) at ambient temperature, and the reaction was stirred for 16 hours. The mixture was diluted with CH2Cl2 (20 mL) and washed with 1N NaOH and water. The organic layer was dried (MgSO4) and concentrated under reduced pressure, and the resulting residue was chromatographed on silica gel (0.8:7.2:92 NH4OH/MeOH/CH2Cl2, eluant) to provide the title product. 1H NMR (300 MHz, CD3OD) δ 3.55-3.78 (m, 3 H), 3.37-3.44 (m, 1 H), 3.22 (t, 1 H), 2.57-2.65 (m, 2 H), 2.38-2.41 (m, 3 H), 2.02-2.17 (m, 3 H), 1.51-1.91 (m, 11 H). MS (DCI+) m/z 302 (M+H).