Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([CH:26]=1)[C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:27]([C:5]1[CH:4]=[CH:3][C:2]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8])([O-:29])=[O:28]
Reactant: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide (2.0 g, 4.73 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL), piperidine (1.0 g, 11.74 mmol, 2.50 equiv), and potassium carbonate (2 g, 14.47 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 150 mL of ethyl acetate. The resulting mixture was washed with 1×50 mL of water and 3×50 of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.7 g (76%) of product as a yellow solid.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:23][O:24][CH2:25][CH:26]1[CH2:28][O:27]1.Cl>C1COCC1>[CH3:23][O:24][CH2:25][CH:26]([OH:27])[CH2:28][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1
Reactant: COCC1CO1
Reactant: c1ccc(-n2cccn2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC(O)Cc1ccnn1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To an THF solution (450 ml) of 1-phenylpyrazole (15 g) was added 1.6M butyllithium/hexane solution at −78° C., and the mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added 2-(methoxymethyl)oxirane (27.8 ml) at −78° C., and the mixture was allowed to be warmed to room temperature, and stirred for 1 hr. To the reaction mixture was added 1N hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]([OH:21])[CH2:8][NH:9][CH:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][CH:10]([N:9]1[CH2:8][CH:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CN(C)C=O
Reactant: CC(CO[Si](C)(C)C(C)(C)C)NCC(O)COc1cccc(F)c1
Product: CC(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(F)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 2.00 g of 1-(3-fluorophenoxymethyl)-2-(2-t-butyldimethylsilyloxy-1-methylethylamino)ethanol (prepared as described in Preparation 71), 20 ml of anhydrous dimethylformamide and 1.09 g of N,N'-carbonyldiimidazole were used, to give 0.74 g of the title compound having an Rf value of 0.29 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent) from a polar diastereomer and 1.03 g of the title compound, melting at 54° C. to 58° C. from a less polar diastereomer.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH:32]=[N:33][OH:34])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH:32]=[N:33][O:34][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:22])=[CH:36][CH:37]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCC=NO)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CON=CCOc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
To a mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-hydroxyiminoethoxy)phenyl]benzamide (255 mg) and potassium carbonate (78.5 mg) in N,N-dimethylformamide (10 ml) was added ethyl bromoacetate (94.9 mg) and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with ethyl acetate (30 ml) and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was purified by silica gel column (chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[2-(ethoxycarbonylmethoxyimino)ethoxy]phenyl]benzamide (245 mg) as a colorless amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[H-].[Na+].I[CH:15]([CH3:17])[CH3:16]>CN(C)C=O>[CH:15]([O:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[OH:11])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
A solution of 15.5 g of 4-nitrocatechol (100 mmol) in 200 ml of N,N-dimethylformamide is added dropwise at 0° C. to a 60% suspension of sodium hydride in oil (4.2 g, 105 mmol). At the end of the addition (1 hour), the dark red solution is stirred at 0° C. for 1.5 hours and 10.5 mnl of 2-iodopropane (105 mmol) are then added dropwise. The mixture is then brought to 80° C. and stirred for 16 hours. It is then cooled to room temperature, the solvent is evaporated off and the dark red oil is dissolved in dichloromethane (300 ml). The solution is washed with water and then with saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off. The expected product is isolated by chromatography on a column of silica (eluent: 80/20 cyclohexane/ethyl acetate). 10.5 g of a yellow oil which solidifies are recovered:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:14])(C)[C:10](O)=O)[CH:6]=[CH:7][CH:8]=1.C([N:17](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CC(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([NH2:17])([CH3:14])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C(=O)O)c1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: COc1cccc(C(C)(C)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(3-methoxyphenyl)-2-methylpropanoic acid (330 mg, 1.70 mmol) and triethylamine (191 mg, 1.87 mmol) in t-BuOH (15 ml), DPPA (514 mg, 1.87 mmol) was added and the resultant solution was refluxed for 2 h. Then t-BuOH was removed under vacuum. Crude residue was dissolved in THF (10 ml) and 2N HCl (10 ml) was added and stirred overnight at RT. Then solvent was removed, crude residue dissolved in water and extracted with ether. Aqueous layer was basified with 5N NaOH and extracted with ethyl acetate. Organic layer was dried and evaporated to yield 2-(3-methoxyphenyl)propan-2-amine.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C([O-])(=O)C.[K+].[S:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>CN(C)C(=O)C.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>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([C:31]2[S:27][CH:28]=[N:29][CH:30]=2)=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1cncs1
Temperature: 115 °C
Yield: 9.1 %

Procedure:
To 5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (600 mg, 1.5 mmol, from Example 14, Step 1) dissolved in N,N-dimethylacetamide (4.8 mL) was added potassium acetate (221 mg, 2.24 mmol), thiazole (0.53 mL, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol). After heating at 115° C. overnight. The cooled reaction was extracted with dichloromethane (100 mL) and water (2×100 mL). The dichloromethane layer was dried using anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 95/5/0.1 dichloromethane/methanol/ammonium hydroxide to yield 5-(2-isopropyl-4-methoxy-5-thiazol-5-yl-phenoxy)-pyrimidine-2,4-diamine (49 mg, 9%) as pale yellow solid, MS (M+H)=358.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13](Cl)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([NH2:37])[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.Cl>C(O)(C)C.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([NH:37][C:25]4[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[C:23]([Cl:22])[CH:24]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a 4-Chloro-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (3.08 g, 9.40 mmol, 1.05 equiv) in 40 mL of isopropyl alcohol solution was added 3-Chloro-4-(pyridin-2-ylmethoxy)phenylamine (2.10 g, 9.0 mmol, 1 equiv) at rt. 4 N HCl in dioxane (0.1 mL) was added to the reaction mixture to accelerate the reaction. The reaction mixture was heated at 80° C. for 16 h. The mixture was allowed to cool to rt then filtered and washed with IPA (50 mL). DCM (100 mL) and sat. sodium bicarbonate (100 mL) were added to the solid. The mixture was stirred at rt for 1 h before separated the layers. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.50 g of crude material. The crude material was purified by flash chromatography (50% THF/DCM) to yield a light yellow (3.60 g, 6.87 mmol, 76%) as product. 1H-NMR (DMSO-d6) δ 9.32 (broad s, 1H), 8.67 (d, J=4.0 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 8.05 (t, 1H), 7.79 (d, J=2.7 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.53 (t, 1H), 7.24 (d, J=8.9 Hz, 1H), 5.35 (s, 2H), 4.66 (s, 2H), 3.66 (t, 2H), 3.19 (t, 2H), 1.43 (s, 9H); LCMS RT=3.39 min, [M+H]+=524.0.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>C(#N)C.CO>[CH2:1]([O:8][C:9]([C@H:10]([NH:11][CH2:18][CH2:17][CH2:23][S:20]([OH:22])(=[O:21])=[O:19])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](N)C(=O)OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CO
Solvent: CC#N
Product: CC(C)C[C@@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of D-Leucine benzylester (6.3 mmol) in acetonitrile (9 mL) and MeOH (3 mL) was added 1,3-propane sultone (691 mg, 5.7 mmol). The solution was stirred at reflux for 2.5 hours. The reaction mixture was cooled to room temperature. The solid material was filtered and washed with aconitrile (2×20 mL). The solid was dissolved in 20% water/EtOH (75 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure and dried in vacuo, affording the title compound (960 mg, 49%). 1H NMR (D2O, 500 MHz) δ ppm 7.52 (m, 5H), 5.41 (d, 1H, J=12.2 Hz), 5.35 (d, 1H, J=12.2 Hz), 4.16 (m, 1H), 3.22 (m, 2H), 2.97 (t, 2H, J=6.8 Hz), 2.16 (m, 2H), 1.88 (m, 1H), 1.79 (m, 1H), 1.76 (m, 1H), 0.94 (d, 6H, J=3.9 Hz). 13C (DMSO, 125 MHz) δ ppm 169.60, 135.62, 129.24, 129.21, 129.11, 68.08, 58.09, 49.87, 46.48, 24.77, 23.50, 22.50, 22.04. [α]D=−2.1° (c=0.00095 in water), ES-MS 344 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3F)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5]1)(=[O:3])[CH3:2].Cl.Cl.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][C:35]([CH2:36][NH2:37])=[C:30]2[CH:29]=[CH:28]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:37][CH2:36][C:35]3[CH:34]=[CH:33][N:32]=[C:31]4[NH:27][CH:28]=[CH:29][C:30]=34)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3F)cc21
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Product: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)cc21

Procedure:
The titled compound was prepared from N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 455 (M+H). Calc'd. for C26H26N6O2—454.53.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[C:32]([F:33])=[CH:31][C:21]5[N:22](C6CCCCO6)[CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[C:32]([F:33])=[CH:31][C:21]5[NH:22][CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc2c(cc1CNc1nccc(Nc3cc(C4CC4)[nH]n3)n1)ncn2C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Fc1cc2[nH]cnc2cc1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
A mixture of 108 (170 mg, 0.38 mmol) and TsOH.H2O (72 mg, 0.38 mmol) in MeOH (5 mL) and water (1 mL) was heated at reflux for 2 h. After solvent was removed in vacuo, the residue was purified by preparative HPLC to give 60 mg (43%) of I-28 as white solid.
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:12]=[C:11]1[C:23]([OH:25])=O>C(Cl)(Cl)Cl>[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:12]=[C:11]1[C:23]([Cl:1])=[O:25]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)O
Solvent: ClC(Cl)Cl
Product: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)Cl

Procedure:
N-(1-chloro-2-methylprop-1-enyl)-N,N-dimethylamine (660 μL, 4.99 mmol) was added to a mixture of 1-methyl-4-(BOC amino)imidazole-2-carboxylic acid (1.00 g, 4.17 mmol) in CHCl3 (8.00 mL). After a few minutes, the 1H-NMR of the reaction mixture showed complete conversion of the acid to the acid chloride. 1H NMR (CDCl3): δ 7.48 (br s, 1H), 3.95 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([CH3:19])[CH:17]=[CH:18][C:11]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1.Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:33])[N:22]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([CH3:19])[CH:17]=[CH:18][C:11]=12
Reactant: Cn1ccc2c(Nc3ccc(N)cc3F)ccnc21
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1ccc2c(Nc3ccc(Nc4cc(-c5ccncc5)nc(N)n4)cc3F)ccnc21

Procedure:
200 mg (0.78 mmol) of 2-fluoro-N1-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 169 mg (0.82 mmol) of 4-chloro-6-pyridin-4-ylpyrimidine-2-amine are suspended in 5 ml of water. 84 μl (1.01 mmol) of a 37% strength hydrochloric acid solution are then added, and the mixture is heated under reflux overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off, washed with a little water and then dissolved in DMSO and purified by preparative RP-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:35][C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH2:38][S:39][CH3:40].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:35][C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH2:38][S:39][CH3:40])=[O:24])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@@H](CCSC)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (237 mg, 0.5 mmol) and L-methionine (149 mg, 1 mmol) in N,N-dimethylformamide (1 ml) was added triethylamine (0.21 ml, 1.5 mmol). The mixture was stirred at room temperature for 16 hours. After removal of the solvent, the residue was dissolved in ethyl acetate (10 ml) and the solution was washed with 1N hydrochloric acid (5 ml×3) and saturated aqueous sodium chloride (5 ml×3) in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was chromatographed on a column of silica gel (7 g). Elution was carried out with chloroform-methanol (4:1, v/v) and with chloroform-methanol-acetic acid (32:8:1, v/v) in the order mentioned. The fractions containing the desired compound were combined and the solvent was distilled off under reduced pressure to give 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-L-methionine (150 mg), melting at 83°-85° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)#[N:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:15]([S:36]([C:33]1[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:35][CH:34]=1)(=[O:38])=[O:37])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CN[C@H](CO)CCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN([C@H](CO)CCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 8 h
Yield: 36 %

Procedure:
(S)-(6-Hydroxy-5-isobutylamino-hexyl)-carbamic acid tert-butyl ester (4) (1.85 g) was dissolved in 50 mL CH2Cl2. Triethylamine (1.05 eq) and 4-cyano benzene sulfonylchloride (1 eq) were added and the mixture was stirred overnight. Saturated NaHCO3 (50 mL) was added, the mixture was well shaken. Organic layer was separated, dried on MgSO4, filtrated and evaporated. The crude compound was purified by column chromatography using EtOAc-heptane (1-3) as the eluent. Fractions containing the product were evaporated yielding (1.06 g, 36%) of a solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][CH2:20][CH2:21][CH2:22][O-:23].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([O:23][CH2:22][CH2:21][CH2:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC[O-]
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reaction time: 2 h
Yield: 57.2 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and sodium butylate (370 mg, 3.85 mmol) were dissolved in 1-butanol (20 ml) and then the solution was refluxed on heating under stirring for 2 hours. The reaction mixture was evaporated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to of give the subject compound (131 mg, yield 54%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:14][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:2]=1[Br:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Br)c(O)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
Add 1-bromo-6-methoxy-naphthalen-2-ol (66.7 g, 264 mmol), potassium carbonate (K2CO3, 40.0 g, 290 mmol) and benzyl bromide (49.6 g, 290 mmol) to DMF (800 mL). Stir the mixture at ambient temperature for 1 hour. Add water (400 mL) to precipitate the product. Collect the precipitate and wash the filter cake with heptane (3×125 mL) then dry to provide 2-benzyloxy-1-bromo-6-methoxy-naphthalene (83.7 g, 98.9 mmol).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH3:5])=[N:24][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Thionyl chloride (5.39 g) was added to a mixture of 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethanol (12.2 g) and toluene (200 ml), which was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, which was neutralized with saturated aqueous sodium bicarbonate solution, and was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (11.7 g, yield 90%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane to obtain colorless prism crystals. Melting point: 86–87° C.