Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]([O-:26])=[O:25])[NH2:23].[Na+].CO>COCCOC.Cl>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:16]=2)([C:24]([OH:26])=[O:25])[NH2:23])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: NC(C(=O)[O-])c1ccccc1F
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: NC(C(=O)O)(c1ccccc1)P(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
A solution of 3.07 g (16.5 mmol) of diphenylphosphine in 60 ml of 1,2-dimethoxyethane was admixed with 0.64 g (16.5 mmol) of potassium. After the metallation reaction was complete, 3.0 g (15.7 mmol) of sodium 2-(2-fluorophenyl)glycinate were added and the reaction mixture was heated at 80° C. for 3 hours. Subsequently, 10 ml of methanol were added and the volatile constituents were removed at 80° C. at a pressure of 10−2 bar. The residue obtained was suspended in 500 ml of dilute aqueous hydrochloric acid (pH=4) and filtered, and then dried at 20° C. and 10−2 bar. The yield was 4.7 g (89%). For the further work-up, the product was recrystallized from a 3:1 mixture of water and methanol. The 1H, 13C{1H} and 31P{1H} NMR spectra were recorded on a Bruker AC 250 spectrometer; the mass spectra were recorded on a Varian MAT 311 A instrument.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].O[CH2:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1>O>[OH:4][S:1]([O:3][CH2:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1)(=[O:2])=[O:5]
Reactant: OCC1Cc2ccccc2CN1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)OCC1Cc2ccccc2CN1

Procedure:
34 N Sulphuric acid (d=1.83; 36.8 cc) is added, over a period of a few minutes, to a suspension of (RS)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (106 g) in water (226 cc). The temperature rises to 60° C. and the solid goes into solution. The mixture is heated at 100°-110° C. whilst water is distilled off, and then at 160° C. whilst concentrating under reduced pressure (20 mm Hg). The concentration process is concluded under a pressure of 1mm Hg. The residue crystallises on cooling. Crude (RS)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (151 g) is thus obtained in the form of pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[H-].[Na+].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.O>[Br:1][C:2]1[N:6]([S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1c[nH]c(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a solution of 5-bromo-1H-pyrrole-3-carbaldehyde (3.50 g) in tetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 1.21 g) at room temperature, and the mixture was stirred for 10 min. Benzenesulfonyl chloride (4.27 g) was added, and the mixture was further stirred for 1 hr, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→7:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 5.4 g, 85%).
Reaction SMILES: Cl[C:2]([C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4].[CH3:26][O-:27].[Na+]>CO>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[N:21]=[C:16]([C:2]([O:27][CH3:26])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4])[N:17]=1
Reactant: C[O-]
Reactant: COc1cc(OC)nc(C(Cl)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)nc(C(OC)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Yield: 67.9 %

Procedure:
2-Chloro-2-(4,6-dimethoxypyrimidin-2-yl)-N-methanesulfonyl-2-phenylacetamide (0.7 g) was boiled under reflux with sodium methoxide (0.2 g) in methanol (30 ml) for 5 hours. The methanol was evaporated off under vacuum. The residue was treated with ether and the precipitated sodium salt was taken into water. The aqueous solution was washed with ether, fresh ether was added, and the whole was acidified with hydrochloric acid. A white solid crystallised from the ether layer. This was filtered off, washed with water and a little ether, and dried to give 0.47 g of the desired product, mp 155°-7° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.Cl>CN(C=O)C.C(O)(C)C>[ClH:1].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:25]([F:30])[CH:24]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCn1cncn1
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCn1cncn1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
A solution 2 4-chloro-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline (203 mg, 0.66 mmol), (prepared as described for the starting material in Example 38), and 4-chloro-2-fluoroaniline (74 μl, 0.66 mmol) in DMF (10 ml) containing 5M hydrogen chloride in isopropanol (0.4 ml) was heated at 150° C. for 8 hours. The volatiles were removed by evaporation and the residue was partitioned between water and methylene chloride. The aqueous layer was adjusted to pH9 with I M sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride/methanol and 2M ethereal hydrogen chloride (1 ml) was added. After removal of the volatiles by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline hydrochloride (60 mg, 17%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14](=[O:32])[CH:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[O:31][CH2:30][CH2:29][O:28]1)[CH2:16][CH2:17][CH3:18])[CH3:12].I[CH2:34][CH2:35][CH3:36]>C1COCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:32])[C:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[O:31][CH2:30][CH2:29][O:28]1)([CH2:34][CH2:35][CH3:36])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: CCCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (26 mL, 26 mmol, 1 M in THF) was slowly added to a solution of 2-(4-Chloro-2-[1,3]dioxolan-2-yl-phenoxy)-pentanoic acid ethyl ester (6.6 g, 20 mmol) in 60 mL of anhydrous THF at −78° C. After the mixture was stirred for 30 min at −78° C., 1-Iodopropane (4 mL, 40 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NH4Cl, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow oil (5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@@H:13]3[CH:17]=[C:16]([CH3:18])[CH2:15][NH:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]([NH:32][C@@H:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:28][O:29][C:30](=[O:31])[NH:32][C@H:33]([C:34]([N:14]1[CH2:15][C:16]([CH3:18])=[CH:17][C@H:13]1[C:10]1[NH:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:35])[CH:37]([CH3:39])[CH3:38]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC1=C[C@@H](c2nc(-c3ccc(Br)cc3)c[nH]2)NC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC(C)=C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-bromo-phenyl)-2-((S)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole (1.10 g, 3.62 mmol) in DCM (50 mL) was added DIPEA (2.34 g, 18.1 mmol), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (761 mg, 4.34 mmol) and HATU (1.65 g, 4.34 mmol). The mixture was stirred at RT overnight, washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (10%-50% EtOAc in petroleum ether) to give the desired product, which was purified by supercritical fluid chromatography (SFC) [mobile phase A: supercritical CO2, phase B: methanol+0.05% diethylamine; flow rate: 80 mL/min] to give the title intermediate (750 mg, 45% yield). m/z): [M+H]+ calcd for C21H25BrN4O3 461.11, 463.11 found 461.1.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH:17]C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>Cl.CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH2:17])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
1-(4-Chlorobenzyl)-4-[[(N-Boc-valyl)amino]methyl]piperidine (1.1 g, 2.51 mmol) was dissolved in a 3 M HCl-methanol solution (25 mL) and stirred at 25° C. for 1 hour. The resulting reaction mixture was concentrated, and the obtained salt was dissolved in tBuOH/H2O=3:1 (25 mL). An anion (OH−) exchange resin was added until the solution became slightly basic. The obtained mixture was filtered and concentrated to provide 1-(4-chlorobenzyl)-4-[(valylamino)methyl]piperidine (819 mg, 97%). Further purification was not required for the resulting compound. ESI/MS m/e 338.1 (M++H, C18H28ClN3O).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]2[C:12]([O:14][C:15](=[O:16])[C:10]=12)=O.Cl.[NH2:21][CH:22]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:23]1=[O:24]>CN(C=O)C>[O:24]=[C:23]1[CH:22]([N:21]2[C:15](=[O:16])[C:10]3[C:11](=[CH:17][CH:18]=[CH:19][C:9]=3[OH:8])[C:12]2=[O:14])[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Triethylamine (2.70 mL, 19.4 mmol) was added to a mixture of 3-hydroxyphthalic anhydride (3.00 g, 18.3 mmol) and rac-α-aminoglutarimide hydrochloride (3.01 g, 18.3 mmol) in DMF (60 mL). The reaction mixture was heated to 90° C. overnight, then cooled to room temperature and the solvent was evaporated under vacuum. The residue was stirred in CH2Cl2 (100 mL) for 30 min and the solvent was removed under vacuum. The residue was stirred in water (120 mL) for 2 h and the resulting solid was filtered, washed with water (50 mL) and dried. 1,4-Dioxane (200 mL) was added, and the resulting suspension was stirred for 16 h and filtered; the insoluble material was reserved. The filtrate was treated with decolorizing carbon (2 g) and heated to reflux for 1 h. After cooling to 50° C., the reaction mixture was filtered through Celite and the filter was washed with additional 1,4-dioxane (50 mL). The filtrate was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered and dried to give 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione, 4.18 g, in 56% yield; 1H NMR (DMSO-d6) δ 1.99-2.06 (m, 1H), 2.45-2.61 (m, 2H), 2.82-2.96 (m, 1H), 5.08 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.23-7.33 (m, 2H), 7.66 (dd, J=8.2 Hz, J=7.2 Hz, 1H), 1.10 (s, 1H), 1.19 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:48](O)=[O:49])[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+].Cl>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C@H:37]([C:48]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:4]([N:5]([S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:3]([O:2][CH3:1])=[O:25])=[O:49])[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Reactant: COC(=O)[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(C)cc1)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine methyl ester (369 mg, 1 mmol, example 65, step C) in THF/K2CO3 (1M) (3 mL/3 mL) was added Nα-(4-methylbenzenesulfonyl)-L-tryptophan N-hydroxysuccininide ester (547 mg, 1.2 mmol). The reaction mixture was stirred overnight, then diluted with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The crude was purified by flash chromatography using hexane/EtOAc as eluent to afford the desired product (71% yield).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccn2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccn2)ccc1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.9 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.038 g) in ethyl acetate (2 mL) and methanol (4 mL), 10% palladium-carbon (20 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 45 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-70% hexane/ethyl acetate] to obtain 0.021 g of tert-butyl 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [N:1]([CH:4]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10](=[O:18])[C:11]2[C:16]([CH3:17])=[N:15][O:14][C:12]=2[N:13]=1)[CH:5]([CH3:7])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]([C:8]1[N:9]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10](=[O:18])[C:11]2[C:16]([CH3:17])=[N:15][O:14][C:12]=2[N:13]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: Cc1noc2nc(C(N=[N+]=[N-])C(C)C)n(Cc3ccccc3)c(=O)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc2nc(C(N)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 7.2 %

Procedure:
A mixture of 6-(1-azido-2-methyl-propyl)-5-benzyl-3-methyl-5H-isoxazolo[5,4-d]pyrimidin-4-one (method 45) (40 mg, 1.118 mmol), triphenylphosphine (62 mg, 0.237 mmol) and water (4 μl) in THF was stirred at 60° C. for 5 hours. Excess amount of water (30 μl) was added to the mixture and stirred at 60° C. for another 10 hours. The volatile solvent was distilled out, the crude product was purified by ISCO (EtOAc: hexane=60%. 25 mg (68%) of 6-(1-amino-2-methyl-propyl)-5-benzyl-3-methyl-5H-isoxazolo[5,4-d]pyrimidin-4-one was obtained as colorless oil. m/z: 313 (MH+), 1H NMR (DMSO-d6): 0.55 (d, 3H), 0.95 (d, 3H), 2.02 (m, 1H), 2.15 (br, 2H), 2.55 (s, 3H), 3.59 (d, 1H), 5.38 (d, 1H), 5.65 (d, 1H), 7.25-7.42
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[C:22]([OH:29])=[C:23]([CH:25]=[CH:26][C:27]=2[Cl:28])[NH2:24])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Br:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>>[Br:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([Cl:28])=[C:21]([S:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[CH2:13][CH2:14]2)(=[O:19])=[O:20])[C:22]=1[OH:29])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Reactant: O=C=Nc1ccccc1Br
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3ccccc3Br)c2O)CC1
Yield: 36.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl-4-chloro-2-hydroxyaniline (110 mg, 0.28 mmol) and 2-bromophenylisocyanate (67 mg, 0.34 mmol) were coupled to form the desired urea (60 mg, 36%). Element Analysis Theory: C 44.80%, H 4.44%, N 9.50%, Found: C 44.65%, H 4.15%, N 9.20%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C@@H:10]1[CH2:19][N:20]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[S:36]1(=[O:46])=[O:45])[C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCCl>[C:5]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[O:9][C@@H:10]([CH2:19][N:20]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[S:36]1(=[O:46])=[O:45])[C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:11][CH2:12]2)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: O=C(OCc1ccccc1)N(CCCCN1C(=O)c2ccccc2S1(=O)=O)C[C@H]1CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC[C@H](CN(CCCCN1C(=O)c3ccccc3S1(=O)=O)C(=O)OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.7 g (95 mmol) of anhydrous aluminum chloride are suspended in 10 ml of 1,2-dichloroethane. At 0° C., initially 5.9 ml (82 mmol) of acetyl chloride are added. At 0° C., a solution of 34 g (63 mmol) of benzyl (2R)-3,4-dihydro-2H-chromen-2-ylmethyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamate in 100 ml of 1,2-dichloroethane is slowly added dropwise to this mixture. The reaction is stirred at room temperature overnight. The mixture is poured into ice-water and the organic phase is then separated off and the aqueous phase is repeatedly extracted with dichloromethane. The combined organic extracts are dried over magnesium sulfate and concentrated. The resulting crude product is purified by chromatography (silica gel, mobile phase toluene/ethyl acetate 3:1). This gives 9.6 g (26.5% of theory) of benzyl [(2R)-6-acetyl-3,4-dihydro-2H-chromen-2-yl]methyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamate.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: Cc1cccc(CC(=O)O)c1
Product: Cc1cccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)c1

Procedure:
The product of Example 86A and 2-(3-methylphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.74 (m, 1H), 7.60-7.66 (m, 4H), 7.24 (t, J=7.5 Hz, 1H), 7.19-7.21 (m, 1H), 7.16-7.19 (m, 1H), 7.08-7.12 (m, 1H), 3.65 (s, 2H), 2.31 (s, 3H); MS (ESI−) M/Z 402 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[C:27]([CH:36]=O)[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:36][C:27]3[CH:26]=[C:25]([CH3:24])[N:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:28]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: Cc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1-c1ccccc1
Yield: 58 %

Procedure:
Compound 92 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:23]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][CH2:7][C:6]2[CH:21]=[CH:22][CH:3]=[CH:4][CH:5]=2)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 14.7 %

Procedure:
4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (Example 5-1b) (450, mg, 1.4 mmol), benzyl bromide (770 mg, 4.5 mmol), and cesium carbonate (1.5 g, 4.5 mmol) in DMF (10 mL) were stirred at 80° C. for 2 hours. The solution was cooled to room temperature, diluted with H2O (200 mL) and extract with ethyl acetate (3×, 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromotography (10% ethyl acetate in hexanes) to afford benzyl 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoate (51.7 mg, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 4.28 (s, 2H), 4.32 (s, 2H0, 5.40 (s, 2H), 6.79 (d, J=8 Hz, 2H), 6.96 (d, J=8 Hz, 2H), 7.04-7.07 (m, 2H), 7.21-7.23 (m, 3H), 7.35-7.47 (m, 5H), 7.85 (d, J=8 Hz, 2H), 8.17 (d, J=8.4 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.C(N(CC)CC)C>C(O)(C)C>[NH2:17][C:13]1[CH:12]=[C:11]([NH:18][C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1cccc(N)c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(Br)nc(Nc2cccc(N)c2)c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 3,5-dibromo-1-methylpyrazin-2(1H)-one (536 mg, 2.0 mmol) and benzene-1,3-diamine (324 mg, 3.0 mmol) in isopropanol (18 mL) was added triethylamine (2.8 mL). The reaction mixture was stirred at 80° C. overnight. Then the mixture was evaporated under reduced pressure to afford 219a (480 mg, 81%) as a white solid. MS-ESI: [M+H]+ 295.0