Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:45])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[CH:29]=1)(C)(C)C.[C:47](O)([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[CH2:47][O:48][C:12]1[C:11]([C:20]([F:21])([F:23])[F:22])=[CH:10][C:9]2[NH:24][C:25](=[O:45])[CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(C(F)(F)F)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M247) (0.43 g, 0.65 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (260 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[NH:7][C:6]([C:14](OCC)=[O:15])=[C:5]2[S:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)(=[O:21])=[O:20].BrC1C([N+]([O-])=O)=C2C(=CC=1)[NH:34]C(C(OCC)=O)=C2S(N1CCOCC1)(=O)=O>>[Br:1][C:2]1[C:10]([NH2:11])=[C:9]2[C:8](=[CH:4][CH:3]=1)[NH:7][C:6]([C:14]([NH2:34])=[O:15])=[C:5]2[S:19]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)(=[O:21])=[O:20]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)c([N+](=O)[O-])c2c1S(=O)(=O)N1CCOCC1
Reactant: CCOC(=O)c1[nH]c2cc([N+](=O)[O-])c(Br)cc2c1S(=O)(=O)N1CCOCC1
Product: NC(=O)c1[nH]c2ccc(Br)c(N)c2c1S(=O)(=O)N1CCOCC1

Procedure:
Using the procedures described in Example 47, replacing in Step A ethyl 5-bromo-6-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-4-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 403.2 [M+H]+.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=[N:7]1.[OH:23][C:24]([CH3:51])([CH3:50])[CH2:25][C@@:26]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C.O.NN>CN(C)C=O.O>[OH:23][C:24]([CH3:51])([CH3:50])[CH2:25][C@@:26]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH:6][NH2:7])=[O:40])=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1
Reactant: C[C@@H](c1ccc(C(=O)O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](c1ccc(C(=O)NN)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.33 g) was added to 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-benzoic acid (0.37 g) and EtNiPr2 (0.41 mL) dissolved in N,N-dimethylformamide (5 mL). After stirring the solution at room temperature for 10 min, hydrazine hydrate (0.23 mL) was added. The solution was stirred at room temperature overnight and then diluted with water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2→90:10) to afford the title compound as a colorless foam-like solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])C.[OH-].[Na+].CCCCCC>C(O)C>[C:19]1([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([OH:26])=[O:3])=[CH:18][CH:17]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: CCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Product: CCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)O

Procedure:
Analogously to the process described in Example 2, 13 g of α-[p-(1-cycloheptenyl)-phenoxy]-octanoic acid ethyl ester, on alkaline saponification with 27 ml of 2 N sodium hydroxide solution in 130 ml of ethanol, give α-[p-(1-cycloheptenyl)-phenoxy]-octanoic acid of melting point 59°-60° C (from cold hexane).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([CH:12]2[CH2:21][C:20]3[NH:19][CH:18]=[CH:17][C:16](=O)[C:15]=3[C:14](=[O:23])[CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:3][C:16]1[C:15]2[C:14](=[O:23])[CH2:13][CH:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:21][C:20]=2[N:19]=[CH:18][CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc(=O)c21
Product: O=C1CC(c2ccccc2)Cc2nccc(Cl)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Under ice-cooling, to phosphorus oxychloride (3.6 g) was added 7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4,5-dione (0.35 g), and the mixture was stirred at 100° C. for 2 hours and cooled. Under reduced pressure, phosphorus oxychloride was evaporated, and to the residue was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give colorless crystals of 4-chloro-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][OH:11])=[O:9])[CH:3]=1.B([O-])([O-])[O-].[Na+].[Na+].[Na+].FC(F)(F)C(O)=O.C(OC(=O)C)(=O)C.OO>>[CH:3]1[C:4]([C:8]([O:10][OH:11])=[O:9])=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: OO
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(OO)c1ccccc1
Reaction time: 4.5 h

Procedure:
m-Chloroperbenzoic acid (MCPBA), a mixture of sodium borate and trifluoroacetic acid or a mixture of acetic anhydride and H2O2 is preferably used for the oxidation. If desired, a commercially available wetting agent can additionally be added to the oxidizing agent. The reaction times lie in a wide range and range from about 0.5 to about 15 hours, preferably 1 to 8 hours. The reaction temperature ranges from −20 to about 100° C., preferably from 0 to about 85° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[C:11]([F:19])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.CCOCC>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:17]([CH3:18])=[C:16]([Br:22])[C:15]2[C:10](=[C:11]([F:19])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(Br)c2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Yield: 18.5 %

Procedure:
A solution of (8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (501.9 mg, 1.717 mmol) and N-bromosuccinimide (366.0 mg, 2.056 mmol) in N,N-dimethylformamide (5 mL) was stirred at r.t. for 60 min. It was poured into 50 ml ether, washed with 5% aq. NaHCO3 two times, then with water 3 times, white precipitate formed, which was filtered and washed with ether to give 118 mg of the pure title product. Supernatant gave 490 mg more of the title product as a colourless solid; total yield 95.4%. LC-MS (m/z) 271.5 and 273.3 (major fragment, M-Boc), tR=1.39. 1H NMR (500 MHz, CDCl3) 1.51 (br. s, 9H, tBu), 2.64 (s, 3H, Me), 7.11 (dd, J=8.2 Hz, J=10.6 Hz, 1H, C7H), 3.67 (br. s, 1H, NH), 7.63 (dt, J (d)=4.95 Hz, J (t)=8.1 Hz, 1H, C6H), 7.68 (d, J=8.1 Hz, 1H, C5H). 19F NMR (470.59 MHz, CFCl3=0 ppm), 4:96 mixture of rotamers, −108.9 (br. s, 0.04F), −109.98 (br. s, 0.96F). 13C APT NMR (CDCl3=77.43 ppm): 20.15 (Me), 28.47 (tBu), 83.47 (C of tBu), 113.44 (C), 114.24 (d, J=21.4 Hz, C7H), 122.57 (d, J=4 Hz, C5H), 134.68 (d, J=10.3 Hz, C6H), 138.31 (s, C), 142.69 (s, C), 155.91 (C), 158.42 (C), 161.63 (s, C), 163.74 (s, C).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C-:6]1[CH2:10][CH:9]=[CH:8][S:7]1.O.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>>[CH2:12]([O:14][P:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: BrCCCC[C-]1CC=CS1
Reactant: CCOP(OCC)OCC
Solvent: O
Product: CCOP(=O)(CCCCc1cccs1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A solution of 1d (4.58 g, 0.02 mol) in 20 mL of triethylphosphite was heated at 160° C. for 20 hours, with nitrogen bubbling directly into the solution. The solution was cooled to room temperature and 50 mL of water was added; the resulting mixture was stirred for 4 hours. The product was extracted with methylene chloride, the organic layer was separated and washed with brine, then dried over anhydrous magnesium sulfate. Evaporation of the solvent yielded an oily residue, which was distilled under vacuum (0.12 mm Hg, 135° C.) to give 1e as a colorless oil (6.0 g, 82%). 1H NMR (250 MHz, 25° C., CDCl3): δ 7.06 (m, 1H, Ar—H), 6.85 (m, 1H, Ar—H), 6.72 (m, 1H, Ar—H), 4.03 (m, 4H, POCH2CH3), 2.79 (t, 2H, Ar—CH2), 1.72 (m, 6H, CH2CH2CH2P), 1.26 (t, 6H, POCH2CH3).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][C:2]1=[O:12].[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[O:12]=[C:2]1[NH:3][C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=2)[NH:1]1
Reactant: O=S(=O)(O)O
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Product: O=c1[nH]c(=O)c2cc(S(=O)(=O)O)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
2,4(1H, 3H)-Quinazolinedione (10 g) was added portionwise to a stirred mixture of 65% fuming sulphuric acid (10 ml) and concentrated sulphuric acid (40 ml) at room temperature. After the addition was complete, the mixture was stirred at 55°-60° for 30 minutes, cooled, poured onto ice (100 g) and stood in a refrigerator for 1 hour. The colourless crystals were filtered, washed with a little ice-cold 6 N hydrochloric acid and finally dried in a vacuum oven to give the hydrated title compound, (14.7 g, m.p. >300°).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[O:20][C@@H:19]5[C@@H:21]([C:22]([O:24]CC)=[O:23])[C@@H:18]5[C:17]=4[CH:27]=3)[C:5]=2[CH2:4][CH2:3]1.[OH-].[Na+]>C1COCC1.CO>[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[O:20][C@@H:19]5[C@@H:21]([C:22]([OH:24])=[O:23])[C@@H:18]5[C:17]=4[CH:27]=3)[C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(Oc4ccnc5c4CCC(=O)N5)cc3[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCc2c(Oc3ccc4c(c3)[C@@H]3[C@H](O4)[C@H]3C(=O)O)ccnc2N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a stirred solution of ester product of Step A (360 mg, 0.98 mmol) in THF (3 mL) and methanol (3 mL) was added sodium hydroxide aqueous solution (1 mL, 2 M, 2 mmol) at room temperature. The mixture was stirred at 60° C. for 2 hrs. The solvent was removed under reduced pressure and the residue was dissolved into water (5 mL). The solution was neutralized with HCl (2 mol/L) to pH=7 and white solid precipitated out of solution. The white solid was collected by filtration and dried in air to give the title compound (230 mg, 69.3%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)=[O:13])=[N:8][N:7]=1.O1C=CC=C1C1OC(NC(C2C=CC=C(I)C=2)=O)=NN=1.[S:41]([C:45]1[CH:50]=[CH:49][C:48](B2OC(C)(C)C(C)(C)O2)=[CH:47][CH:46]=1)(=[O:44])(=[O:43])[NH2:42]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:48]3[CH:49]=[CH:50][C:45]([S:41](=[O:44])(=[O:43])[NH2:42])=[CH:46][CH:47]=3)=[CH:16][CH:15]=2)=[O:13])=[N:8][N:7]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1ccc(I)cc1
Agent: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(I)c1
Product: NS(=O)(=O)c1ccc(-c2ccc(C(=O)Nc3nnc(-c4ccco4)o3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50 described below, using N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-4-iodobenzenecarboxamide prepared in Reference Example 1 instead of N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-3-iodobenzenecarboxamide and using commercially available 4-sulfamoylphenylboronic acid pinacol ester instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].C(OC([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=O)[CH2:31][CH2:30]1)=O)(C)(C)C.[B-][N+](C)(C)C>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:2]=2[NH:1][CH2:35][CH:32]2[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]2)=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [B-][N+](C)(C)C
Product: COC(=O)c1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using a similar procedure to that described in Example 47-C&D, 2-amino-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide (3.23 g, 10.6 mmol), 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (2.50 g, 11.7 mmol), and borane trimethylamine complex (2.31 g, 31.7 mmol) afforded, after purification by column chromatography (SiO2: 10 to 25% methanol:methylene chloride), 3.10 g (73%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][C:11]1[N:12]=[C:13]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:21])[S:14][C:15]=1[C:16](O)=[O:17]>>[CH3:10][C:11]1[N:12]=[C:13]([NH:19][C:20](=[O:21])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:14][C:15]=1[C:16](=[O:17])[NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCCc1ccccc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use phenethylamine in place of benzylamine to react with 4-methyl-2-[(pyridine-4-carbonyl)amino]thiazole-5-carboxylic acid, the title compound was obtained as a white solid in 34% yield; 1H NMR (DMSO-d6, 300 MHz) δ 13.2 (s, br, 1H), 8.89-8.66 (m, 2H), 8.16-7.88 (m, 3H), 7.29-7.14 (m, 5H), 3.47-3.32 (m, 2H), 2.81-2.65 (m, 2H), 2.46 (s, 3H); MS (ES+) m/z 367.2 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:47])[CH2:10][N:11]([S:40]([CH2:43][CH2:44][CH2:45][CH3:46])(=[O:42])=[O:41])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C@H:26]([OH:39])[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].CO>[CH2:43]([S:40]([N:11]([CH2:10][C:9]([OH:47])=[O:8])[C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:24][CH2:25][C@H:26]([OH:39])[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=3)[CH2:22][CH2:23]2)=[CH:16][CH:17]=1)(=[O:42])=[O:41])[CH2:44][CH2:45][CH3:46]
Reactant: CCCCS(=O)(=O)N(CC(=O)OCc1ccccc1)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCS(=O)(=O)N(CC(=O)O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 0.18 g of [(butane-1-sulfonyl)-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-amino]-acetic acid benzyl ester (which was obtained in Example 342) and 0.05 g of 10% palladium on carbon in 15 mL of methanol was shaken on a Parr hydrogenator at 25 psi overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo, which afforded a beige solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=7.23 Hz, 3H), 1.29–1.41 (m, 2H), 1.48–1.51 (m, 2H), 1.54–1.73 (m, 2H), 1.92–2.09 (m, 2H), 2.57–2.64 (m, 2H), 2.79–2.87 (m, 2H), 2.94 (s, 3H), 3.00–3.07 (m, 4H), 3.16 (s, 2H), 3.20–3.26 (m, 2H), 3.64–3.75 (m, 2H), 4.02–4.04 (m, 2H), 4.77–4.81 (m, 1H), 6.84–6.91 (m, 3H), 7.06 (dd, J=2.1 Hz, 8.4 Hz, 2H), 7.23 (d, J=1.8 Hz, 1H), 7.34 (d, J=9.00 Hz, 2H); MS (ES) m/z:599.0 (MH+); HRMS found for C26H38N4O8S2: 599.2202.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][C:12](=[O:20])SC1C=CC=CN=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23].C(Br)C(C)C.[Mg].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][C:12](=[O:20])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCC(=O)Sc1ccccn1)C(=O)OC(C)(C)C
Reactant: CC(C)C[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)CBr
Product: CC(C)CC(=O)CCN(C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of S-2-pyridyl 3-(N-t-butoxycarbonyl-N-methylamino)propanethioate (490 mg) in dry tetrahydrofuran (20 ml) which was cooled to 0° C., was added dropwise a solution of isobutylmagnesium bromide prepared from isobutyl bromide (1.13 g) and magnesium (200 mg) in dry tetrahydrofuran (30 ml), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride (50 ml). The resulting slurry was extracted with diethyl ether (50 ml×2), and the combined extract was dried over magnesium sulfate and concentrated to give 1-(N-t-butoxycarbonyl-N-methylamino)-3-oxo-5-methyl-hexane (400 mg) as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]2[C:54]=1[NH:53][C:52]([C:55](O)=[O:56])=[CH:51]2.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:55]([C:52]2[NH:53][C:54]3[C:50]([CH:51]=2)=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:45])=[O:56])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1cccc2cc(C(=O)O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c12
Reaction time: 1 h
Yield: 57.5 %

Procedure:
HATU (0.072 g, 0.19 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.040 g, 0.13 mmol), 7-methyl-1H-indole-2-carboxylic acid (0.033 g, 0.19 mmol) and DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL). After 1 h, the reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (hexane/EtOAc) to give a sticky solid, which was triturated with methanol and dried under vacuum to give the title compound (0.035 g, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.38 (s, 1H), 8.99 (t, 1H), 7.81 (s, 1H), 7.26-7.63 (m, 5H), 7.15 (d, 1H), 6.68-7.06 (m, 2H), 4.57 (d, 2H), 2.21-2.69 (s, 3H). MS: m/z 468 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(O)ccc21
Yield: 89.2 %

Procedure:
23 g (68.6 mmol) 5-Benzyloxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 250 ml methanol with 2.5 g 10% Pd/C were hydrogenated for 2 h, the suspension was filtered. The filtrate was concentrated and purified by column chromatography on silica gel with MeOH/EtOAc 1:1, yielding 14.4 g (90%) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless solid, MS: 235 (M).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:7]2[OH:26].C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cccc(F)c21
Reaction time: 1 h

Procedure:
To a flask containing 1,1-dimethylethyl N-((8-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (1.5 g, 4.1 mmol) was added TFA (20 mL). The reaction was stirred under nitrogen for 1 hours and then concentrated in vacuo to afford an oil. Addition of water caused a white precipitate to form. The solid was collected by filtration, washed with water, washed with ether, and then dried in vacuo (0.68 g). MS (m/z)=308 (M+H)+. Calculated for C15H14FNO5 307.08.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=O)C.[CH:26](=O)[CH2:27][CH2:28][CH3:29].C([BH3-])#N.[Na+].Cl>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 1.52 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 600 ml ofdimethylformamide, 40 g of butyraldehyde and 1.60 g of molecular sieves [Na12 (AlSiO4)12. 27 H2O], 36 g of sodium cyanoborohydride are added while stirring under nitrogen and keeping the temperature between about 20 and 30° for one hour. After stirring the mixture for 68 hours at room temperature, 6 lt of water are added, followed by 110 ml of concentrated hydrochloric acid and stirring is continued for one hour. The precipitate formed is filtered off, washed with water, dissolved in 1.2 lt of 2N aqueous sodium hydroxide and the solution refluxed for 2 hours under nitrogen. After cooling to room temperature it is filtered and the filtrate combined with 250 ml of glacial acetic acid. The precipitate formed is collected, 333 g thereof are dissolved in 2.8 lt of hot, 80% aqueous acetonitrile, the solution filtered, the filter washed with 500 ml more of said acetonitrile and the filtrate diluted with 3.3 lt of hot water. The precipitate formed at 14° is filtered off, taken up in 2.15 lt of hot, 90% aqueous ethanol and the solution diluted with 2.5 lt of hot water. The solids separated after cooling are collected and washed with water, to yield the 4-(4-aminophenylmercapto)-3-n-butylamino-5-sulfamoylbenzoic acid melting at 232°-234°it is identical with that obtained according to Example 3.