Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)[N:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:19][C:16]1[CH:15]=[CH:14][C:13]([CH:9]2[C:10]3[C:5](=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=3)[CH2:6][CH2:7][N:8]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C2c3ccc(OC)cc3CCN2c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C2c3ccc(O)cc3CCN2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred solution of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.075 g, 0.217 mmol, 1.0 eq.) in CH2Cl2 (3 ml) cooled to −78° C. under an atmosphere of N2 was added BBr3 as a 1.0 M solution in CH2Cl2 (0.65 ml, 0.65 mmol, 3.0 eq.). The reaction was stirred overnight, slowly allowing the reaction mixture to warm to rt. The reaction was quenched with MeOH (2 ml) and stirring was continued for 1 hour. The mixture was diluted with EtOAc (20 ml), water (2 ml), and sat. NaHCO3 (2 ml, until the pH of the aqueous layer was approximately 8). The layers were separated and the aqueous layer diluted with water (10 ml), then extracted with EtOAc (2×20 ml) and CH2Cl2 (2×20 ml). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, hexanes:EtOAc 3:2) to give the desired compound (0.053 g, 0.167 mmol, 77% yield).
Reaction SMILES: [CH3:1][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.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:4]2[C:5]3[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)[C:2]([CH3:1])=[N:3]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3cc([N+](=O)[O-])ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-methyl-5-nitro-1H-indazole (1.0 g, 5.6 mmol) was dissolved in DMF (11.2 mmol) and cesium carbonate (2.0 g, 6.2 mmol) added. The slurry was cooled to 0° C. and p-methoxy benzyl chloride (0.97 g, 6.2 mmol) added to vigorously stirred slurry drop wise. The slurry was stirred at 0° C. for 1 hour, the cooling bath removed and the mixture stirred at RT for 3 h. The mixture was diluted with 4:1 water:saturated sodium bicarbonate (200 ml), extracted with EtOAc (3×50 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 30% acetone:hexanes to give the titled compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([S:19][C:20]4[CH:36]=[CH:35][C:23]5[N:24]=[C:25]([NH:27]C(=O)OC(C)(C)C)[S:26][C:22]=5[CH:21]=4)=[N:17][N:18]=3)[N:15]=2)=[CH:6][CH:5]=1.[CH3:37][O:38][CH2:39][CH2:40]Cl.C1(C)C=CC=CC=1>CN(C)C=O.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([S:19][C:20]4[CH:36]=[CH:35][C:23]5[N:24]=[C:25]([NH:27][CH2:40][CH2:39][O:38][CH3:37])[S:26][C:22]=5[CH:21]=4)=[N:17][N:18]=3)[N:15]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: COCCNc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
45 mg of sodium hydride at 60% in oil are added to a mixture of 263 mg of 1,1-dimethylethyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate and 0.10 cm3 of 2-chloroethyl methyl ether in 3 cm3 of N,N-dimethylformamide at 20° C. The suspension is heated in a bath at 90° C. overnight. The cooled reaction mixture is coevaporated to dryness several times with toluene. The residue obtained is taken up in methanol. After paste formation for 15 min, the brownish-yellow suspension is spin-filter-dried. The insoluble material is washed several times with methanol. This solid is treated with 0.4 cm3 of trifluoroacetic acid in 3 cm3 of dichloromethane at 20° C. for 2 h. The resulting reaction mixture is concentrated to dryness under vacuum, to give 116 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-N-(2-methoxyethyl)-1,3-benzothiazol-2-amine in the form of a yellowy-beige powder, the characteristics of which are as follows:
Reaction SMILES: Cl.[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:3].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: CCN(CC1CCNCC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC1CCN(c2ccc(C(F)(F)F)cn2)CC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Temperature: 165 °C
Yield: 51.4 %

Procedure:
A mixture of ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-4-ylmethyl-amine hydrochloride salt (30 mg, 0.064 mmol), 2-bromo-5-trifluoromethylpyridine (188 mg, 0.83 mmol), and triethylamine (27 μL, 0.19 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 20 minutes at 165° C. The crude mixture was purified by HPLC to provide compound A127 as a white solid (19 mg, 51%). Exact mass calculated for C26H27F4N7O2S 557.19, found 578.3 (MH+).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].N1C2N=C[CH:21]=[CH:22][C:17]=2[C:16](=O)OC1=O>>[CH2:16]([N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12])[CH2:17][CH2:22][CH3:21]
Reactant: O=c1[nH]c2cccnc2c(=O)o1
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Product: CCCCn1c(=O)oc(=O)c2ncccc21

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting the product of Example 159A for the product of Example 1A (0.12 g, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J=7.35 Hz, 3 H) 1.40 (m, J=15.26, 7.17 Hz, 2 H) 1.60 (m, 2 H) 3.98 (m, 2 H) 7.81 (dd, J=8.82, 4.41 Hz, 1 H) 7.97 (dd, J=8.64, 1.29 Hz, 1 H) 8.55 (dd, J=4.23, 1.29 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]=1[C:3]1[O:4][C:5]2[C:10]([C:11](=[S:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: S=c1c(Br)coc2ccccc12
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: S=c1cc(-c2nc3ccccc3[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 95.2 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, bezimidazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography and recrystallized from benzene/hexane to give the titled compound (133 mg; yield=95.3%) as white needle crystals. Melting point: 160°-161° C. 1H-NMR(CDCl3, δ ppm): 7.22 (s, H3), 8.59 (d, H5), 7.64 (t, H6), 7.73 (t, H7), 7.70 (m, H8), 8.25 (s, H2'), 7.78-7.93 (m, H4'), 7.40-7.48 (m, H5'), 7.40-7.48 (m, H6'), 7.78-7.93 (m, H7').
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.C(N(CC)CC)C.[N:25]1([C:31]2[N:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39](O)=[O:40])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[C:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][NH:2][C:39](=[O:40])[CH:38]=[CH:37][C:34]1[CH:35]=[N:36][C:31]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:32][CH:33]=1)#[CH:17]
Reactant: O=C(O)C=Cc1ccc(N2CCOCC2)nc1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(N3CCOCC3)nc2)cc(F)c1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (20 mg, 0.072 mmol) was suspended in THF and treated with triethylamine (11 mg, 0.108 mmol) and then the resulting mixture was stirred for 10 mins. 3-(6-morpholin-4-yl-pyridin-3-yl)-acrylic acid (17 mg, 0.072 mmol) was added to the reaction mixture followed by DMTMM (22 mg, 0.08 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×2), brine, and then dried over anh. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl) to yield the title compound (8 mg, 24%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl.[Zn]>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Agent: Cl
Agent: [Zn]
Product: c1ccc(C2CNc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
1.3 G of 3-phenylindole was suspended in 100 ml of 20% aqueous hydrochloric acid. The mixture was heated to 60° C while stirring vigorously and 20 g of zinc dust was added thereto in small portions over a period of 45 minutes. On completing the addition of zinc dust, the reaction mixture was heated to 100° C and maintained at this temperature for one hour, filtered hot, and the filtrate cooled to room temperature and washed with ether. The aqueous layer was basified with 50% aqueous sodium hydroxide and the desired product was extracted with ether and then purified by column chromatography using silica gel. The 3-phenylindoline was obtained in a yield of 0.8 g as a yellow viscous oil.
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)=O>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)c(Br)cnc32)cc1
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)ccnc32)cc1
Yield: 91.9 %

Procedure:
Toluene (30 ml) was mixed with 3.0 g (6.3 mmol) of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 10% Pd--C (100 mg) and 9.6 g (95 mmol) of triethylamine, followed by the dropwise addition of 2.9 g (63 mmol) of formic acid under stirring. The obtained mixture was heated under reflux for 10 hours. The reaction liquid was brought to room temperature, and filtered to remove the catalyst, and then the filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 2.3 g of the title compound (yield 92%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][CH3:20]>>[CH:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([N:19]([CH3:20])[CH3:18])=[O:11])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)[C@H](CC1CC1)NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7) and dimethylamine hydrochloride as starting materials. MS (EI): m/e=256.3 [M]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[N:13]=[C:12]([C:15](=[O:26])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[NH:11][C:10]=2[CH:9]=[CH:8][C:7]=1[F:27])=[O:5])C.[Cl:28][C:29]1[S:33][C:32]([C:34]2[O:38][N:37]=[C:36]([CH2:39]OS(C)(=O)=O)[CH:35]=2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[S:33][C:32]([C:34]2[O:38][N:37]=[C:36]([CH2:39][N:11]3[C:10]4[CH:9]=[CH:8][C:7]([F:27])=[C:6]([C:4]([OH:3])=[O:5])[C:14]=4[N:13]=[C:12]3[C:15](=[O:26])[NH:16][CH:17]3[CH2:18][CH2:19][N:20]([CH:23]([CH3:24])[CH3:25])[CH2:21][CH2:22]3)[CH:35]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1c(F)ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(Cl)s2)on1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)c(F)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-fluoro-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid was prepared by a procedure according to example 81 starting from 230 mg (0.60 mmol) 5-Fluoro-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid ethyl ester and 179.5 mg (0.60 mmol) methanesulfonic acid 5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl ester. Hydrolysis of the resulting ethyl ester by treatment with LiOH and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compound as its formiate in form of a white amorphous solid.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=2[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:16](O)(=[O:18])[CH3:17]>>[C:16]([C:11]1[CH:10]=[C:8]([OH:9])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][C:12]=1[OH:14])(=[O:18])[CH3:17]
Reactant: CC(=O)O
Reactant: Oc1ccc(O)c(-c2ccccc2)c1
Solvent: O
Product: CC(=O)c1cc(O)c(-c2ccccc2)cc1O
Temperature: 80 °C

Procedure:
A suspension of 32.4 g of phenylhydroquinone in 30 ml of acetic acid was made. It was heated to 80° C. and boron trifluoride gas was bubbled through. After a reaction period of 4 h the reaction mixture was poured into water. The precipitation formed was suction-filtered and stirred in water whereto some sodium carbonate was added up to pH 8. The precipitate was suction-filtered again, washed with water, dried and recrystallized from toluene. Yield: 23 g of purified product. Melting point: 169° C.
Reaction SMILES: F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=O.[CH3:45][NH:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>CN(C=O)C>[F:32][C:33]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:34]=1[C:35]([N:46]([CH3:45])[NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:37]
Reactant: CNNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)OC(C)(C)C)C(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under argon and at RT, 17.1 g (53.4 mmol, 1.3 eq.) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate and 21.4 ml (123.1 mol, 3.0 eq.) of N,N-diisopropylethylamine were added to a solution of 9.1 g (49.3 mmol, 1.2 eq.) of 2-fluoro-4-nitrobenzoic acid in 200 ml of DMF, and the mixture was stirred at RT for 20 min. A solution of 12.5 g (purity 48%, 41 mmol) of tert-butyl 2-methylhydrazinecarboxylate in 50 ml of DMF was added, and the reaction mixture was stirred at RT for 6 h. After removal of the DMF under reduced pressure and addition of water/ethyl acetate and phase separation, the organic phase was washed with 10% aqueous citric acid and with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 8.35 g (65% of theory)
Reaction SMILES: ClC1C(Cl)=CC=C2C=1C(O)=CC(O)=N2.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]=[C:21]([OH:27])[CH:20]=[C:19]2[OH:28].[N+:29]([O-])([OH:31])=[O:30]>C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[NH:22][C:21](=[O:27])[C:20]([N+:29]([O-:31])=[O:30])=[C:19]2[OH:28]
Reactant: Oc1cc(O)c2cc(Cl)c(Cl)cc2n1
Reactant: O=[N+]([O-])O
Agent: Oc1cc(O)c2c(Cl)c(Cl)ccc2n1
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2c(O)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 19 %

Procedure:
To a mixture of 1.25 g (5.43 mmol) of 5,6-dichloro-2,4-dihydroxyquinoline and 6,7-dichloro-2,4-dihydroxyquinoline in 8 mL of glacial acetic acid was added 1.5 mL of HNO3 (69-71%) and the mixture was heated at 90° C. for 2 h. The mixture was cooled to room temperature, filtered and washed with water, and dried to leave 280 mg (19%) of the title compound as a yellow solid, mp 235°-236° C. (decomposed). 1H NMR (CDCl3 +DMSO-d6), 7.362 (s, 1), 8.039 (s, 1), 11.369 (s, 1). MS, 274 (50, M+), 214 (100), 187 (18), 160 (20). High resolution MS, Calcd for C9H435Cl2N2O4 273.9544, found 273.9548.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl.[F:13][C:14]1[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>COCCOC>[F:13][C:14]1[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[CH:19][C:15]=1[C:16]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)c(F)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(C(C)=O)C(=O)OCC)c(F)c1

Procedure:
A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 2-fluoro-4-(hexadecylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Recrystallization from ether affords ethyl 2-[2-fluoro-4-(hexadecylamino)benzoyl]-acetoacetate as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])[CH2:7][CH2:6]1.Cl[C:21]1[C:22]2[C:29]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:31])=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:21]2[C:22]3[C:29]([C:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:7][CH2:6]1
Reactant: COCCN1CCN(CCc2ccccc2N)CC1
Reactant: O=C(c1ccccc1)c1c[nH]c2ncnc(Cl)c12
Product: COCCN1CCN(CCc2ccccc2Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)CC1

Procedure:
(4-((2-(2-(4-(2-Methoxyethyl)piperazin-1-yl)ethyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was synthesized using 2-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethyl)aniline and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone according to the general procedure A. A white solid was obtained. M.p.=192-193° C.; 400 MHz 1HNMR (DMSO-d6) δ 10.66 (s, 1H), 8.31 (s, 1H), 7.98-7.94 (m, 2H), 7.84-7.82 (m, 2H), 7.70-7.66 (m, 1H), 7.60-7.57 (m, 2H), 7.30-7.25 (m, 2H), 7.13-7.09 (m, 1H), 3.33 (t, J=6.0 Hz, 4H), 3.32 (s, 3H), 2.90 (d, J=8.0 Hz, 2H), 2.51-2.46 (m, 4H), 2.36-2.33 (m, 4H), 2.24 (bs, 2H); LCMS [M+H] 463.
Reaction SMILES: CC([C:5]1([C:20]([O-:22])=[O:21])[CH2:9][N:8]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7](=[O:18])[N:6]1[CH3:19])(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24].C(Cl)Cl>>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[CH3:19][N:6]1[CH:5]([C:20]([OH:22])=[O:21])[CH2:9][N:8]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:7]1=[O:18]
Reactant: CN1C(=O)N(CCN2CCOCC2)CC1(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(CCN2CCOCC2)CC1C(=O)O

Procedure:
To a stirred solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (1.0 g, 5 mmol) (prepared as described in step (iii) of Example 13) in N,N-dimethylformamide (20 ml) at 0° C. was added sodium hydride (60% dispersion in oil) (220 mg, 5.5 mmol). After 10 minutes a solution of 4-(2-chloroethyl)morpholine (898 mg, 6 mmol) in N,N-dimethylformamide (2 ml) and potassium iodide (166 mg, 1 mmol) was added and the mixture was heated at 70° C. for 2 hours. After cooling to room temperature water was added and the mixture was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic extracts were separated, washed with water and brine, dried and evaporated. The residue was purified by silcia gel chromatography eluting with 5-10% 2M ammonia in methanol and dichloromethane to give 1,1-dimethylethyl-3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxylate (740 mg, 47%) as an oil. LC/MS [M+H]+=314. (ii) A solution of 1,1-dimethylethyl-3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxylate (740 mg, 2.361 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 5 hours. The solution was evaporated and the residue was co-evaporated with DCM and dried to give crude 3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.3 mmol) which was used in the next step. LC/MS [M+H]+=258.