Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:20]2[C:11]([C:12]([NH2:26])=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)=[N:10]1.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[CH2:22]([C:21]1[N:9]([CH3:8])[N:10]=[C:11]2[C:20]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]=[C:12]2[NH:26][C:27](=[O:29])[CH3:28])[CH:23]([CH3:24])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)Cc1c2c(nn1C)c(N)nc1ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2ccccc2c2c(CC(C)C)n(C)nc12
Temperature: 4 °C
Yield: 56 %

Procedure:
Triethylamine (0.49 mL, 3.53 mmol) was added to a suspension of 2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 3) (0.75 g, 2.95 mmol) in dichloromethane (30 mL) and cooled to 4° C. Acetyl chloride (0.255 g, 3.24 mmol) was added in dichloromethane (5 mL) dropwise over 5 minutes to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with dichloromethane (25 mL) and washed sequentially with water (25 mL), 4% sodium bicarbonate (2×25 mL), water (25 mL), and brine (25 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified via column chromatography on silica gel (80 g, eluting with 0-20% CMA/chloroform), concentrated under reduced pressure, and recrystallized from diethyl ether to yield 0.49 g of N-(1-isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)acetamide as white crystals, mp 130-131° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].FC(F)(F)C1C=C([C@@H](O)[C@@H](N(CC2C=C(C(F)(F)F)C=CC=2C2C=C(C(C)C)C(F)=CC=2OC)C(=O)[O:24]C(C)(C)C)C)C=C(C(F)(F)F)C=1.CN([C:59]1[C:64]2C(N(C)C)=CC=CC=2C=C[CH:60]=1)C>C(Cl)Cl.O>[C:2](=[O:24])([O:4][CH2:5][Cl:6])[O:3][CH2:60][CH2:59][CH3:64]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)OCCl
Solvent: O
Solvent: ClCCl
Product: CCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloromethyl chloroformate (0.027 mL, 0.30 mmol) was added dropwise to a stirred solution of tert-butyl {(1S,2R)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (INTERMEDIATE 7, 209 mg, 0.294 mmol) (200 mg, 0.28 mmol) and proton sponge (60 mg, 0.28 mmol) in dry CH2Cl2 (5.0 mL) at 0° C. under N2. The reaction was stirred at 25° C. for 16 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (0-20% gradient EtOAc/hexanes over 30 min) to give (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-(tert-butoxycarbonyl){[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl chloromethyl carbonate as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.81-6.82 (m, 8 H); 7.08 (dd, J=8.3 Hz, 8.7 Hz, 1 H); 5.68 (m, 2 H); 4.19-4.16 (d, J=16.7 Hz, 1 H); 4.77 (s, 3 H), 3.31-3.24 (m, 1 H); 1.76 (s, 3 H); 1.41 (s, 3 H); 1.22-1.18 (s, 9 H), 1.04 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][Mg]Br.C(OCC)C>O1CCCC1>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:12])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSc1ncc(C(C)O)c(N)n1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a suspension of 5.0 g (29 mmol) 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3) in 150 mL of tetrahydrofuran, cooled by an ice bath, is added during 20 minutes. 23.2 mL of a 3.0 M methylmagnesium bromide solution in diethyl ether (69.4 mmol). After 1 hour at 0° C. another 23.2 mL of the 3.0 M methylmagnesium bromide solution is added, and the suspension is allowed to come to room temperature and stirred overnight. The reaction is quenched with 100 mL of saturated aqueous ammonium chloride, and partitioned between water and ethyl acetate. The organic layer is dried (magnesium sulfate) and concentrated to give 5.24 g (96%) of the product, mp 140-142° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:2]1.Br[C:23]1[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=1>CC(N(C)C)=O>[F:30][C:29]([F:32])([F:31])[C:26]1[N:27]=[CH:28][C:23]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C@@H:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]3[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:2]2)=[CH:24][N:25]=1
Reactant: FC(F)(F)c1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(c2cnc(C(F)(F)F)nc2)C1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
Dimethylacetamide (5.25 mL) was added to a round bottom flask containing tert-butyl (1R,2R)-2-(piperidin-3-ylamino)cyclohexylcarbamate (0.47 gm, 1.58 mmol) and 5-bromo-2-(trifluoromethyl)pyrimidine (0.43 gm, 1.89 mmol). The reaction mixture was then heated at 100° C. After 48 h heating was stopped. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes holding at 100% EtOAc to give the diastereomeric product, tert-butyl (1R,2R)-2-(1-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-3-ylamino)cyclohexylcarbamate, (0.31 gm, 0.70 mmol, 44% yield) as light yellow solid. Anal. Calcd. for C21H32F3N5O2 m/z 443.3, found: 444.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:30]=[CH:31][CH:32]=[N:33]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:52]([O:59][C:60](=[O:73])[C:61]1[CH:66]=[CH:65][C:64]([C:67]2[N:68]=[C:69]([NH2:72])[S:70][CH:71]=2)=[N:63][CH:62]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:18])[NH:72][C:69]1[S:70][CH:71]=[C:67]([C:64]2[CH:65]=[CH:66][C:61]([C:60](=[O:73])[NH:33][CH:32]3[CH2:30][CH2:31]3)=[CH:62][N:63]=2)[N:68]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:52]([O:59][C:60](=[O:73])[C:61]1[CH:66]=[CH:65][C:64]([C:67]2[N:68]=[C:69]([NH:72][C:16]([C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[O:17])[S:70][CH:71]=2)=[N:63][CH:62]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: Nc1nc(-c2ccc(C(=O)OCc3ccccc3)cn2)cs1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Product: O=C(OCc1ccccc1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.38 g, 1.52 mmol), HATU (0.58 g, 1.52 mmol)), and DIEA (0.4 mL, 3.0 mmol) in DMF (16 mL) was stirred at room temperature for 1 h. 6-(2-Amino-thiazol-4-yl)-nicotinic acid benzyl ester (0.32 g, 1.0 mmol) was added and the reaction mixture was heated to 50° C. for 48 h. The crude product was purified by reverse phase HPLC to furnish the desired product 6-{2-[((S)-1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-nicotinic acid benzyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([O:18]CC)=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 70 °C
Yield: 67 %

Procedure:
To a suspension of ethyl 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (900 mg, 3.3 mmol) in THF:methanol (1:1, 20 mL) is added 1N NaOH (9.0 mL, 9.0 mmol). The reaction mixture is heated at 70° C. for 2 h. The reaction mixture is cooled to room temperature, diluted with water (80 mL) and is acidified with 3N HCl to pH 2-3. The resulting yellow precipitate is filtered, washed with water and dried in vacuo oven at 60° C. to afford the title compound (540 mg, 67%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:30]=[CH:31][C:32](O)=[N:33][C:34]=1[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:30]=[CH:31][C:32]([O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:33][C:34]=1[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(=O)COc1cccc(COS(C)(=O)=O)c1
Reactant: COc1ccc(F)c(-c2ccc(O)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
To a solution of, ethyl 2-(3-(((methylsulfonyl)oxy)methyl)phenoxy)acetate (100 mg) and 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-ol (100 mg) in DMF (3.0 mL) was added potassium carbonate (72 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (77 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[C:14]([O:16]C)=[O:15])[N:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+]>CO>[CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[C:14]([OH:16])=[O:15])[N:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccccc1Nc1cc(C2CCCC2)nn1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-n1nc(C2CCCC2)cc1Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 21 h
Yield: 79.3 %

Procedure:
To a solution of methyl 2-{[3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoate (0.59 mmol, 220 mg) in MeOH (1.8 mL) was added THF (5.4 mL) and 1N aqueous NaOH (1.8 mL). The reaction was stirred at rt for 21 h. The organic solvents were removed under reduced pressure, the residue was diluted with water, and the aqueous solution extracted with diethylether (2×5 mL). The aqueous layer was acidified to pH=1 to 2 with 1N aqueous HCl. The mixture was extracted with ethyl acetate (3×5 mL). After removal of the solvent under reduced pressure, the product was obtained as a white solid (169 mg, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.62 (m, 2H), 1.65-1.78 (m, 4H), 1.90-2.01 (m, 2H), 2.06 (s, 3H), 2.99-3.10 (m, 1H), 6.23 (s, 1H), 6.80 (t, 1H), 7.20-7.30 (m, 3H), 7.30-7.40 (m, 2H), 7.42-7.51 (m, 1H), 7.81 (d, 1H), 9.84 (s, 1H), 13.14 (s, 1H). ES-MS m/z 362.3 (MH+), HPLC RT (min) 3.39.
Reaction SMILES: COC1[C:4](C=O)=[CH:5][C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2C=1.[C:15]([O:18][C:19](=[O:21])[CH3:20])(=O)[CH3:16]>N1C=CC=CC=1>[C:19]([O:18][C:15]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1C=O)OCCC2
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.5 %

Procedure:
To a solution of 6-methoxy-3,4-dihydrobenzopyran-7-carboxaldehyde (5.00 g, 28.1 mmol) in pyridine (15.0 mL) was added acetic anhydride (3.5 mL, 31.1 mmol) and the mixture allowed to stir at room temperature for 4 hours then poured into ice water (300 mL). The product which precipitated was collected by filtration, washed with water (75 mL) and air dried to afford 6-acetoxy-3,4-dihydrobenzopyran, (5.86 gm, 94.5%), m.p. 76°-77°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[CH:12]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13]1.C1(C2C3C(=C(Cl)C=CC=3)CCN=2)C=CC=CC=1>>[CH:12]1([C:16]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][OH:11])=[O:17])[CH2:15][CH2:14][CH2:13]1
Reactant: NCCc1ccccc1CO
Reactant: O=C(Cl)C1CCC1
Agent: Clc1cccc2c1CCN=C2c1ccccc1
Product: O=C(NCCc1ccccc1CO)C1CCC1

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and cyclobutanecarbonyl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-cyclobutylcarbonylamino-2-(2-hydroxymethylphenyl)ethane as in oil. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-cyclobutylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-cyclobutylisoquinoline-5-acetic acid having a decomposition point of 202.8° to 209.8° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13](OC)[CH:12]=[CH:11]2.[Cl:20][CH2:21][CH2:22][CH2:23]Br>C(#N)C.O>[Cl:20][CH2:21][CH2:22][CH2:23][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:13])[C:1](=[O:4])[CH:12]=[CH:11]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2cc(O)ccc2n1
Reactant: ClCCCBr
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCCCl)ccc21

Procedure:
Potassium carbonate (0.829 g) was dissolved in acetonitrile (10 ml) and water (10 ml), and 6-hydroxy-2-methoxyquinoline (0.875 g) and 1-chloro-3-bromopropane (1.48 ml) was added thereto, and the mixture was stirred while heating under reflux for 4 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (1.107 g) as a white powder.
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][CH:11]1[O:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:26][CH:25]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][CH2:12]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[CH3:19][CH:18]([CH3:20])[CH2:17][CH:16]([C:14]1[O:15][CH:11]([CH2:10][C:9]([OH:42])=[O:8])[CH2:12][N:13]=1)[NH:21][C:22](=[O:41])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[O:32])=[CH:26][CH:25]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C2=NCC(CC(=O)OCc3ccccc3)O2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C2=NCC(CC(=O)O)O2)cc1
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of [2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-oxazol-5-yl]-acetic acid benzyl ester (120 mg) and palladium hydroxide (40 mg) in 10 ml of THF and 10 ml of MeOH was shaken on a Parr Apparatus under 30 p.s.i. H2 for 2 h. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was suspended in EtOAc and concentrated under reduced pressure. Trituration with hot EtOAc gave 93 mg of the title compound as a light pink solid. MS [M+1]+481.3; 1H nmr (400 MHz, DMSO-d6) δ0.77-0.87 (m, 6H), 1.39-1.59 (m, 3H), 2.10-2.33 (m, 4H, including s at 2.21, 3H), 2.40-5.08 (m, 7H, including q at 3.36, J=14.2 Hz, 2H), 6.90 (t, J=7.4 Hz, 1H), 7.08-7.14 (m, 4H), 7.35 (d, J=6.8 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.95-8.45 (m, 2H), 9.13-9.23 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[CH:17]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:22]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:23]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[CH:17]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:34])[CH3:35])=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:23]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1cc(C(NS(C)(=O)=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)COc1ccc(C(NS(C)(=O)=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
In 7 ml of ethanol is dissolved 1.26 g of ethyl 3-(5-{(2,4-diisobutoxyphenyl)[(methylsulfonyl)-amino]methyl}-2-isobutoxyphenyl)propanoate, to which is added 1.3 ml of 5 mol/L solution of sodium hydroxide. The mixture is stirred at ambient temperature for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) to obtain 0.92 g of 3-(5-{(2,4-diisobutoxyphenyl)[(methylsulfonyl)amino]methyl}-2-isobutoxyphenyl)propanoic acid as a light yellow oily product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[C:4]([CH2:13][CH3:14])[CH:3]=1.C1C=C([O:21]O)C(C(O)=O)=C(C(O)=O)C=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[C:6](=[O:12])[O:11][C:7](=[O:21])[NH:8][C:9]=2[CH:10]=1
Reactant: CCc1cc(Br)cc2c1C(=O)C(=O)N2
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(Br)cc2[nH]c(=O)oc(=O)c12

Procedure:
A stirred solution of 6-bromo-4-ethyl-1H-indole-2,3-dione (2.64 g, 10.4 mM) and the hexahydrate magnesium salt of monoperoxyphthalic acid (80% pure, 3.54 g, 5.73 mM) in glacial acetic acid (30 mL) was stirred at 60° C. for 1 hr during which time a precipitate formed. The cooled reaction mixture was then poured into cold water and the resulting mixture was filtered to separate (2.04 g, 73%) the title compound as a tan solid. Recrystallization of a portion of this material from ethyl acetate/hexane provided an analytical sample of the title compound as off white crystals, mp 208.5°-210.5° C.; MS(CI): 270 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22]1([CH:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C(c3ccccc3)c3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and diphenylchloromethane as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from methanol. M.p. 133°-135° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH:39]=[O:40])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[BH4-].[Na+].O>CO.ClCCl>[OH:40][CH2:39][CH2:38][CH2:37][CH:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:27]=[CH:26][C:25]([C:24]([NH:23][S:20]([C:6]3[CH:7]=[CH:8][C:9]([NH:10][CH2:11][CH2:12][S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)(=[O:21])=[O:22])=[O:41])=[CH:30][CH:29]=2)[CH2:36][CH2:35]1
Reactant: O=CCCC1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCC(CCCO)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 226 (15 mg, 0.025 mmol) in methanol (0.5 mL) and dichloromethane (2 drops) at 0° C. was treated with NaBH4 (24 mg, 0.6 mmol), stirred for 1 hour, warmed to room temperature, and stirred for 90 minutes. The mixture was treated with water and filtered. The filter cake was treated with dichloromethane (5 mL) and methanol (1 drop), stirred for 2 hours, and filtered. The filter cake was washed with diethyl ether, and dried under vacuum to provide the desired product. MS(ESI(−)) m/e 597 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.49 (d, 1H), 8.45 (d, 1H), 7.85 (dd, 1H), 7.71 (d, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 7.20 (m, 2H), 6.95 (d, 1H), 6.90 (d, 2H), 4.34 (t, 1H), 3.75 (m, 2H), 3.60 (m, 2H), 3.39 (m, 2H), 3.25 (m, 2H), 2.65 (m, 2H), 1.71 (m, 2H), 1.45 (m, 2H), 1.25-1.11 (m, 4H).
Reaction SMILES: CN1CCOCC1.Cl[C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([S:15]([O:18][C:19]2[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=2)(=[O:17])=[O:16])[CH:14]=1>[Pd].CO>[CH3:28][O:27][C:12]1[CH:11]=[CH:10][CH:9]=[CH:14][C:13]=1[S:15]([O:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=1)(=[O:16])=[O:17]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: [Pd]
Solvent: CN1CCOCC1
Solvent: CO
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
4-Methylmorpholine (3.2 mL, 29.1 mmol) was added to a mixture of 3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenol (8.82 g, 26.8 mmol, prepared in the preceding step) and 10% palladium on carbon(2.23 g) in deoxygenated methanol (15 mL). The mixture was stirred at ambient temperature under hydrogen (balloon) for 3 h, then filtered through Celite (drafomaceous earth) with methanol. Solvent was removed in vacuo and crude product was purified by flash column chromatography (CH2Cl2 to 5% ethyl acetate in dichloromethane) to give the title compound (4.97 g, 63%) as a colorless syrup. 1H-NMR (300 MHz, DMSO-d6) (9.71 (s, 1H), 7.76 (ddd, 1H, J=8.4, 7.4, 1.7 Hz), 7.69 (dd, 1H, J=7.9, 1.7 Hz), 7.38 (d, 1H, J=8.4 Hz), 7.09 (dt, 1H, J=7.9, 1.0 Hz), 6.48 (br s, 1H), 6.33 (br s, 1H), 6.26 (t, 1H, J=2.2 Hz), 4.00 (s, 3H), 2.15 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C14H14O5S: 317.0 (M+Na). Found: 316.9.