Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH:19](O)[CH3:20])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28]([C:32]1[C:37]([Cl:38])=[N:36][N:35]2[N:39]=[CH:40][N:41]=[C:34]2[CH:33]=1)([CH3:31])([CH3:30])[CH3:29].[O:42]1CCCC1>>[ClH:38].[ClH:38].[C:28]([C:32]1[C:37]([O:42][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:15][CH2:14]2)=[N:36][N:35]2[N:39]=[CH:40][N:41]=[C:34]2[CH:33]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C1CCOC1
Reactant: CC(O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)c1cc2ncnn2nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cc2ncnn2nc1OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: Cl
Temperature: 0 °C

Procedure:
150 mg of 60% sodium hydride in oil was suspended in 20 ml of tetrahydrofuran; 1.05 g of [2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy]ethanol was added, followed by heating and refluxing for 1 hour. After cooling, 650 mg of 7-t-butyl-6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 2 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (10:1). The desired fraction was collected; the residue was dissolved in 5 ml of ethyl acetate; 2.1 ml of a 4N hydrogen chloride solution in ethyl acetate was added; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 1.55 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:17]=[C:10]2[C:11]([O:13]C(=O)[NH:15][C:9]2=[CH:8][CH:7]=1)=[O:12])(=[O:5])=[O:4].[Cl:18]C1C=CC(S(Cl)(=O)=O)=CC=1C(O)=O>>[Cl:18][C:9]1[CH:8]=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:17][C:10]=1[C:11]([OH:13])=[O:12].[CH3:1][NH:2][S:3]([C:6]1[CH:17]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([NH2:15])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Product: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(N)c(C(=O)O)c1

Procedure:
5-(N-Methylsulfamoyl)-isatoic anhydride, which is to be used as the starting material, can be obtained, for example, in a manner analogous to that described in Example 1, using 2-chloro-5-chlorosulfonyl-benzoic acid as the starting material, the product being obtained via 2-chloro-5-(N-methylsulfamoyl)-benzoic acid with a melting point of 170°-172° and 5-(N-methylsulfamoyl)-anthranilic acid with a melting point of 205°; the product melts at 260°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17](F)[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](F)[C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+].[CH3:26][OH:27]>>[CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17]([O:24][CH3:23])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:27][CH3:26])[C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1c(F)c(F)c(NCc2ccccc2)c(F)c1F
Reactant: CO
Agent: [Na+]
Product: COC(=O)c1c(OC)c(F)c(NCc2ccccc2)c(F)c1OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (24.0 g, 76.6 mmol) was cooled to 5° C.–10° C. under a nitrogen atmosphere and a 25 weight % solution of sodium methoxide in methanol (53.5 mL, 234 mmol) was added dropwise over 5 minutes with continued cooling. The resulting mixture was stirred with ice bath cooling for another 10 minutes, the ice bath was removed and the mixture allowed to warm to 35° C.–40° C. It was recooled to room temperature and held for 4.5 hours before heating to 65° C.–70° C. where it was held for 3.5 hours. The mixture was cooled to room temperature and held overnight. Acetic acid (7.5 g) was added followed by methyl tert-butyl ether (250 mL) and water (100 mL). The lower aqueous layer was separated and the organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL) followed by water (25 mL). The organic solution was concentrated under vacuum to give methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate as a yellow oil (24.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[O:28][C:27]([Si](C(C)C)(C(C)C)C(C)C)=[N:26][CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](c1ncc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)o1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cnco2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
122 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine was dissolved in 1.2 ml of tetrahydrofuran, and 0.5 ml of 1 M tetrabutylammonium fluoride tetrahydrofuran solution was added. The reaction solution was stirred at room temperature for 20 min, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 60 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-6-(oxazol-5-yl)-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine as white powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 45 mg of the objective compound as pale orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH:28][N:29]1C2C=CC=CC=2N=N1.Cl.NO.CN1CCOCC1>CN(C)C=O>[OH:28][NH:29][C:13](=[O:14])[CH:12]([CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=C(O)C(CS(=O)(=O)c1ccc(Cl)cc1)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(NO)C(CS(=O)(=O)c1ccc(Cl)cc1)CS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
A mixture of 2-(4-chlorobenzenesulfonylmethyl)-3-(4-chlorobenzenesulfonyl)-propionic acid (0.52 g, 1.1 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiinde hydrochloride (0.25 g, 1.3 mmol), and hydroxylamine hydrochloride (0.083 g, 1.2 mmol) is stirred in an ice bath for 20 minutes and 4-methylmorpholine (0.28 mL, 2.5 mmol) in dimethylformamide (10 mL) is added. After stirring overnight at ambient temperature, the mixture is partitioned between ethyl acetate and aqueous 10% hydrochloric acid. The organic phase is further extracted with aqueous acid, aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The concentrate is chromatographed over silica gel (230-400 mesh) with chloroform/acetone/acetic acid (79/20/1) and the eluate concentrated in vacuo, to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].Cl[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]=1.O>CN(C)C=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9]2[N:8]=[C:7]([O:2][CH3:1])[CH:12]=[C:11]([CH3:13])[N:10]=2)=[CH:16][CH:17]=1
Reactant: Cc1cc(Cl)nc(Nc2ccc(Cl)cc2)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)nc(Nc2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 28% methanol solution of sodium methylate (1.5 g) was added to a solution of 1.5 g of 4-chloro-2-(4-chloroanilino)-6-methylpyrimidine in 50 ml of dimethylformamide and the mixture was stirred for 2 hours at 70° C. After completion of the reaction, the reaction mixture was poured into water, extracted with 150 ml of toluene, washed with water, dried over Glauber's salt, and the toluene layer was concentrated by evaporation. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 88%) of 2-(4-chloroanilino)-4-methoxy-6-methylpyrimidine having a melting point of 101°-103° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si:25](OS(C(F)(F)F)(=O)=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>C(Cl)Cl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([O:15][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(OCc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1=CCC(OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(benzyloxy)cyclohexanone (10 g, 49 mmol) and Hunig's base (17.1 mL, 98 mmol) in DCM (50 mL) was added TBSOTf (11.8 mL, 51.4 mmol) in DCM (50 mL) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature, and left to stir until the reaction was complete. The mixture was poured into water, and the organic layer was separated, dried, and concentrated. Purification by flash chromatography afforded the title compound. 1H NMR (600 MHz, CDCl3) δ 7.20-7.36 (m, 5H); 4.72 (br s, 1H); 4.55 (s, 2H); 3.60 (m, 1H); 1.72-2.38 (series of m, 6H); 0.90 (s, 9H); 0.10 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](O)=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:23])[O:4][N:3]=1.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([Cl:26])=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)ccc2c1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)ccc2c1Cl
Yield: 95 %

Procedure:
Ethyl 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-3-quinolinecarboxylate (for a preparation see Intermediate 7, 20 g, 64.04 mmol) was reacted with thionyl chloride (326 ml) and heated to reflux overnight. Excess thionyl chloride was co-evaporated with toluene. The crude product was triturated with iPr2O and filtered to give the title compound as a brown powder (20.15 g, 95%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.Cl.C([N:16]=C=NCCCN(C)C)C.[Cl:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[Cl:32].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[NH:3][C:4]4[CH:9]=[C:8]([C:10]([NH2:16])=[O:12])[CH:7]=[CH:6][C:5]=4[N:1]=3)[CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2nc(N3CCN(c4ccc(Cl)c(Cl)c4)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
Benzimidazole-5-carboxylic acid (1 mMol, 162 mg) was dissolved in 5 mL dry DMF and reacted with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride for 15 minutes. 1-(3,4-dichlorophenyl )-piperazine, 1 mMol (231 mg) was added followed by 10 mg DMAP. The mixture was stirred for 20 h at room temperature. The reaction mixture was poured into water and extracted with methylene chloride (3×50 mL). The extracts were combined, washed with brine, water and dried over MgSO4. After evaporation of the solvent, the residue was chromatographed on silica gel with chloroform-methanol (0-5% methanol, gradient). Evaporation of the desired fractions gave 150 mg (40%) of the title compound; MS (ESI) m/e 375 (M+).
Reaction SMILES: C(O[C:6](=[O:25])[CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH:9]=1)(C)(C)C.C(C1NC=CN=1)(C1[NH:29]C=CN=1)=O.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:10]2[CH:9]=[C:8]([CH2:7][C:6]([NH2:29])=[O:25])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=2)[CH2:23][CH2:22]1
Reactant: CN1CCN(c2cc(CC(=O)OC(C)(C)C)c(C(F)(F)F)cn2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc(CC(N)=O)c(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
[2-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-pyridin-4-yl]-acetic acid tert-butyl ester (475 mg, 1.32 mmol) is dissolved in a mixture of TFA and CH2Cl2 (10 ml/10 ml) and stirred at RT. After 1.5 h at RT, TLC analysis indicated complete conversion of starting material. The solvent is removed by rotary evaporation, and replaced by dry DMF (5 ml). Under an atmosphere of argon, carbonyl diimidazole (236 mg, 1.46 mmol) is added. After 3 h at RT, TLC analysis indicated complete conversion of the carboxylic acid. An aqueous solution of ammonia (25%, 20 ml) is added at RT. After 15 minutes at RT, solvents are removed under high vacuum. The residue is dissolved in CH2Cl2/MeOH (9:1) and purified by FCC (CH2Cl2/MeOH, slow gradient from 90:10 to 40:60) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.69 (s, 3H), 2.93-3.18 (m, broad, 4H), 3.54 (s, 2H), 3.59-3.98 (m, broad, 4H), 6.95 (s, 1H), 7.02 (s, broad, 1H), 7.47 (s, broad, 1H), 8.45 (s, 1H). ES+−MS: 303.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[N:8][CH:7]=[CH:6]2.B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[N:16]1([CH2:15][CH2:14][O:13][C:9]2[C:10]3[C:5](=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc2c(OCCN3CCCCC3)nccc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c(OCCN3CCCCC3)nccc2c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
6-Methoxy-1-(2-(piperidin-1-yl)ethoxy)isoquinoline (0.60 g, 2.10 mmol) was dissolved in 30 mL of dry CH2Cl2 at room temperature. BBr3 (10.50 mmol, 10.50 mL of 1.0 M CH2Cl2 solution) was added dropwise with stirring via a syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. in an ice bath and hydrolyzed by adding water. EtOAc was added to partition the solution. The organic layer was separated; the aqueous layer was extracted with EtOAc twice. The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica-gel with CH3OH/CH2Cl2 (1/9 v/v) to give a white solid product, 40 g, 70.2% yield. MS: 273.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz) δ 10.29 (s, 1H), 8.05 (d, 1H, J=8.7 Hz), 7.32 (d, 1H, J=7.2 Hz), 6.93 (d, 1H, J=8.4 Hz), 6.87 (s, 1H), 6.43 (d, 1H, J=7.2 Hz), 4.03 (s, br, 2H), 2.62 (s, br, 2H), 2.50 (s, br, 2H), 1.49-1.39 (m, 6H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:9][CH:8]=1.O[Li].O>C(Cl)Cl.O1CCOCC1.O>[CH3:30][C:27]1[N:26]=[CH:25][C:24]([C:14]2[N:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=3)[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cn1
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(NS(C)(=O)=O)cc2)cn1
Reaction time: 2 h
Yield: 55.9 %

Procedure:
Methanesulfonyl chloride (0.026 mL, 0.33 mmol) was added to a mixture of 3-(4-aminophenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one (0.11 g, 0.33 mmol) and TEA (0.093 mL, 0.67 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 2 hours and concentrated in vacuo. The residue was redissolved in 1:1 dioxane and H2O (5 mL) and LiOH.H2O (0.050 g, 1.2 mmol) was added. The mixture was stirred at room temperature for 20 minutes, then extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was conducted by flash chromatography on silica gel, eluting with 10% to 80% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, followed by further purification by reverse-phase chromatography, eluting with 10% to 50% CH3CN in H2O with 0.1% TFA. The desired fractions were basified and extracted to afford the title compound as a white solid (0.075 g, 56%). 1H-NMR (300 MHz, DMSO-d6): δ9.91 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.85-7.98 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.54-7.69 (m, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.05-7.22 (m, 3H), 2.97 (s, 3H), 2.39 (s, 3H). MS (APCI) m/z: 407 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]#[C:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(Cl)cc2)C3=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(CCCc2cc(Cl)c3c(c2)CN(Cc2ccc(Cl)cc2)C3=O)CC1
Yield: 83.5 %

Procedure:
A mixture of 7-chloro-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.078 g, 0.18 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2,3-dihydro-isoindol-1-one (0.065 g, 83%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.31-2.72 (m, 15H), 4.18 (s, 2H), 4.74 (s, 2H), 7.08 (s, 1H), 7.28 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]=[C:21]([CH3:23])[CH3:22])[CH:18]=3)[N:13]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:12]=2)[N:10]=1)=[O:5])[CH3:2].C(Cl)Cl>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:18]=3)[N:13]([S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:12]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(C=C(C)C)cc23)cs1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CC(C)C)cc23)cs1
Reaction time: 72 h
Yield: 75 %

Procedure:
To a solution of 80 (548 mg, 1.32 mmol) in MeOH:CH2Cl2=3:1 (v/v; 20 mL) was added 20% Pd(OH)2 on carbon (100 mg, cat.), and the reaction mixture was stirred vigorously under H2 for 72 h. The mixture was then filtered through Celite, which was then washed with MeOH:CH2Cl2=1:1 (v/v; 100 mL). The solutions were combined and concentrated to afford 81 as a foam (412 mg, 0.99 mmol, 75%). 1H NMR (400 MHz, CDCl3) δ 0.84 (d, J=6.6 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.82 (nonet, J=6.7 Hz, 1H), 2.51 (d, J=7.2 Hz, 2H), 4.45 (q, J=7.1 Hz, 2H), 7.41 (t, J=7.8 Hz, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.66 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 8.15 (d, J=7.5 Hz, 1H), 8.20 (s, 1H), 8.22 (d, J=1.9 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>C(Cl)Cl>[F:79][C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([F:80])[CH:76]=1)[CH2:72][C@H:58]([NH:57][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:21][CH2:22][CH3:23])=[O:6])[CH:8]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncc[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-[(dipropylamino)carbonyl]-5-(1H-imidazol-2-yl)benzoic acid (250 mg, 0.79 mmol), diisopropylethylamine (103 mg, 0.8 mmol), and HBTU (330 mg, 0.87 mmol) in methylene chloride (5 mL) is added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of EXAMPLE SP-272 (322 mg, 0.79 mmol) and diisopropylethylamine (206 mg, 1.6 mmol) in methylene chloride (5 mL). The reaction mixture is stirred at room temperature for 4 h and concentrated under reduced pressure. The residue is diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 methanol/methylene chloride) provides the title compound in pure form. APCI MS m/z 632.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[C:7]([OH:11])[C:8](=[O:10])[CH:9]=1)([OH:3])=O.[C:12]([O:15]C(=O)C)(=O)[CH3:13].S(=O)(=O)(O)O.C(Cl)(=O)C([Cl:27])=O>ClCCl.CN(C)C=O>[C:12]([O:11][C:7]1[C:8](=[O:10])[CH:9]=[C:4]([C:1]([Cl:27])=[O:3])[O:5][CH:6]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(=O)c(O)co1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1coc(C(=O)Cl)cc1=O
Temperature: 0 °C

Procedure:
2-Carboxy-5-hydroxypyran-4-one (20 mmole) (Chem.Abs., 1948,42,567; J. Gen. Chem., 1946,16, 2025), acetic anhydride (10 ml) and concentrated sulphuric acid (0.5 ml) were heated to reflux temperature. On cooling to 0° C., the 5-acetoxy compound crystallised (recrystallised from ethanol); δ(DMSO-d6); 2.27(s,3H); 7.05(s,1H); 8.10(s,1H). This compound (5 mmole) was treated with oxalyl chloride (10 mmole) in dichloromethane (5 ml) containing dimethylformamide (15 μl). After 30 minutes the solvent was evaporated, the residue dissolved in toluene (evaporated several times to remove oxalyl chloride) and on final evaporation crystallised to give 5-acetoxypyran-4-one-2-carbonyl chloride which was used directly.