Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N+:9]([O-])[C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.C(OC(=O)C)(=[O:29])C>>[OH:29][C:8]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:16]([N+:17]([O-:19])=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c[n+]([O-])c2ccccc12
Solvent: c1ccncc1
Product: O=[N+]([O-])c1c(N2CCOCC2)c(O)nc2ccccc12

Procedure:
The 3-morpholino-4-nitroquinoline-N-oxide obtained in Example 5-(a) was dissolved in acetic anhydride (16 ml) and pyridine (16 ml) and the solution was heated on an oil bath at 80° C. for 1 hour. Excess acetic anhydride and pyridine were distilled off under vacuum from the whole reaction mixture and the residue was dissolved in chloroform, followed by washing with 10% NaHCO3. The insoluble matter was recovered by filtration under vacuum, dissolved in acetone and treated with charcoal. The chloroform layer was dried with anhydrous Na2SO4 and CHCl3 was distilled off under vacuum. The residue was combined with the charcoal treated (insoluble) matter and washed with ethanol to obtain 2-hydroxy-3-morpholino-4-nitroquinoline in an amount of 3.5 g (yield, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.CO/N=[CH:22]/[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.Cl.[NH4+].[OH-]>O>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1[C:31]3[CH:30]=[C:26]4[O:27][CH2:28][O:29][C:25]4=[C:24]([CH2:32][N:33]4[CH:37]=[CH:36][N:35]=[CH:34]4)[C:23]=3[CH2:22][C:9]2=1
Reactant: CO/N=C/c1ccc2c(c1Cn1ccnc1)OCO2
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2cnc3c(c2cc1OC)Cc1c-3cc2c(c1Cn1ccnc1)OCO2
Temperature: 100 °C
Reaction time: 18 h
Yield: 6.5 %

Procedure:
The amine 8 (0.905 g, 3.55 mmol) and oxime ether 13c (0.41 g, 1.6 mmol) were mixed with concentrated hydrochloric acid (8 mL) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was then cooled and washed with ether (3×20 mL). It was then brought to basic pH with NH4OH. The mixture was extracted with chloroform (40 mL×3), and the solution was washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was diluted in chloroform (40 mL) and filtered. Hydrochloric acid (2 M HCl in ether, 5 mL) was added to the filtrate. The precipitate that formed was recrystallized from methanol to provide a yellow solid. The solid was dissolved in water, basified with NH4OH and extracted with chloroform. The organic layer was concentrated to dryness. The residue was purified by preparative flash chromatography (SiO2, methanol-chloroform-TEA=10:90:2) to afford the final pure product 14c as a light brown solid (0.0419 g, 6.6%): mp 250° C. (dec). IR (KBr) 2961, 1496, 1413, 1207, 1020 cm−1; 1H NMR (300 MHz, DMSO) δ 9.01 (s, 1H), 7.84 (s, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 6.90 (s, 1H), 6.15 (s, 2H), 5.33 (s, 2H), 4.08 (s, 2H), 3.99 (s, 3H), 3.92 (s, 3H); low resolution ESIMS m/z (rel intensity) 402 (MH+, 100), 334 (15). Anal. (C23H19N3O4.1.5H2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C(O)(=O)C>CO.O>[CH:17]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[S:10]([NH2:13])(=[O:11])=[O:12])[CH2:19][CH2:18]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc(NC2CC2)c(S(N)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-methoxybenzenesulphonamide (4.9 mmol) in methanol (20 mL) there are added (1-ethoxycyclopropyloxy)trimethylsilane (4 mL) and glacial acetic acid (4 mL) and then heating at reflux is carried out for 18 hours. The mixture is then evaporated to dryness under reduced pressure. The oil obtained is taken up in water (30 mL) and extracted with chloroform (3×30 mL). The organic phases are collected and dried over anhydrous MgSO4. After filtration, the filtrate is evaporated to dryness and the residual oil is dissolved in THF (50 mL). Sodium borohydride (2 g) and boron trifluoride etherate (2 mL) are added and then the mixture is heated at reflux for 18 hours. The solvent is then removed by evaporation under reduced pressure and the residue is taken up in water (30 mL), adjusted to slightly acid pH by adding 6N HCl and then extracted with chloroform (3×30 mL). The organic phases are collected and dried over anhydrous MgSO4. After filtration, the filtrate is evaporated to dryness and the expected compound is obtained in the form of an oil used directly in the next Step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:19][C:20]([O:22][CH2:23]C)=[O:21])(C(OCC)=O)[C:8]2=[O:25])=[O:4].Cl.C(O)(=O)C.C(CC1C(=O)C2C(=CC=C(C(O)=O)C=2)C1)(O)=O.S(=O)(=O)(O)O>CO>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH:9]1[C:8](=[O:25])[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[CH2:10]1
Reactant: CCOC(=O)CC1(C(=O)OCC)Cc2ccc(C(=O)OC)cc2C1=O
Agent: Cl
Agent: O=C(O)CC1Cc2ccc(C(=O)O)cc2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC1Cc2ccc(C(=O)OC)cc2C1=O
Temperature: 25 °C
Yield: 686.3 %

Procedure:
2-Ethoxycarbonylmethyl-3-oxo-indan-2,5-dicarboxylic acid-2-ethyl ester-5-methyl ester (Step 2, 530 mg, 1.5 mmol) in 1.3 ml mixture of 6 N HCl: acetic acid (1:1) was heated to reflux for 3 h. The reaction mixture was evaporated to dryness, 10 ml water was added and extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulphate and then concentrated. The crude product was washed with hexane and precede next step without further purification (530 mg). To a stirred solution of 2-carboxymethyl-3-oxo-indan-5-carboxylic acid (3.5 g, 14.9 mmol) in methanol (53 ml) was added concentrated sulphuric acid (5.6 ml) at 0° C. After addition temperature of the reaction mixture was slowly raised to room temperature and then heated to reflux for 5 h. The reaction mixture was evaporated. Water was added and extracted with ethyl acetate. Ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, brine, dried and concentrated under reduced pressure. Crude was purified by column chromatography using acetone/hexane (25%) to yield a desired product (2.7 g). 1H NMR (400 MHz, CDCl3) d 8.44 (1H, s), 8.30 (1H, d), 7.57 (1H, d), 3.95 (3H, s), 3.78 (3H, s), 3.53 (1H, dd), 3.09-2.93 (3H, m), 2.71 (1H, dd) ppm.
Reaction SMILES: [C:1]([CH2:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10](O)=[O:11])(O)=[O:2]>O1CCCC1>[OH:11][CH2:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[CH2:4][CH2:1][OH:2]
Reactant: O=C(O)Cc1sccc1C(=O)O
Solvent: C1CCOC1
Product: OCCc1sccc1CO
Temperature: -20 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
0.50 g of the compound obtained in Example 4 was dissolved in 10 mL of anhydrous tetrahydrofuran, and the resulting solution was cooled to −20° C. 4 mL of 1.5M solution of borane-tetrahydrofuran complex in tetrahydrofuran was slowly added thereto, and the resulting mixture was allowed to react for at least 1 hour at −10° C. The reaction solution was warmed to room temperature and 4.5 mL of 1.5M solution of borane-tetrahydrofuran complex in tetrahydrofuran was further added thereto. The resulting mixture was kept at room temperature for 1 hour. Thereafter, the procedure of Example 5 was repeated to obtain 0.37 g (yield of 87%) of the title compound as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:37][CH2:38][CH2:39][CH2:40][OH:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][CH2:40][CH2:39][CH2:38][NH:37][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:32])([CH3:33])[CH3:31])[NH:17]1)=[O:36]
Reactant: NCCCO
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 104.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 25a (0.5 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.31 mmol) and iPr2NEt (1 g, 7.7 mmol) in CH2Cl2 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide as a white solid (0.56 g, 93%).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])(=[O:15])=[O:14].[OH-].[Li+]>O.CO>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=1[S:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][CH2:5][CH2:4][C:3]([OH:24])=[O:2])(=[O:14])=[O:15]
Reactant: COC(=O)CCCC1CCCCN1S(=O)(=O)c1c(C)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CCCC(=O)O

Procedure:
4-(1-(2-Chloro-6-methylphenylsulfonyl)piperidin-2-yl)butanoic acid methyl ester (2.7 g, 7.3 mmol, 1 eq.) was dissolved in water (20 ml) and methanol (30 ml). Lithium hydroxide (0.87 g, 36.5 mmol, 5 eq.) was added, while stirring. The mixture was stirred at room temperature for 24 h.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([N:16]=[C:17]=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:17]2=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: CC(C)(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)N1C(=O)CN(c2ccccc2)C1=O
Yield: 60 %

Procedure:
A mixture of N-phenyl glycine (0.1 mole), t-butyl isocyanate (0.12 mole) and toluene (30 ml) was refluxed for 5 hours and then cooled. The product was collected by filtration and crystallized from ethanol to produce 0.06 mole of the aforedescribed product having a melting point of 116° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:25]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][C:29]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:22]([Cl:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCOCC2)c(Cl)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(N5CCOCC5)c(Cl)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 77 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.29568 mmol), 3-Chloro-4-morpholin-4-yl-benzaldehyde (73.4 mg, 0.325 mmol), and Ammonium acetate (45.6 mg, 0.591 mmol) were reacted to produce 123.8 mg (77%) of the title compound. (300 MHz, DMSO-d6) 13.27 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=8 Hz, 1H), 8.02 (s, 1H), 7.74 (s, 1H), 7.33 (s, 1H), 7.22 (s, 1H), 7.17 (d, J=9 Hz, 1H), 6.30 (s, 2H), 5.20 (t, J=17 Hz, 8.5 Hz, 1H), 3.77 (m, 4H), 3.07 (m, 4H), 2.90 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=9 Hz, 1H), 2.24 (d, J=9 Hz, 1H), 1.39 (d, J=9 Hz, 1H). MS=545 (M+H), HPLC: 2.67 min. (G Method)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:30]>CO>[ClH:30].[ClH:30].[N:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:20][CH2:21][CH:16]([NH:15][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)=[O:28])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)NC2CCN(c3ccccn3)CC2)CC1
Agent: Cl
Solvent: CO
Product: NC1CCN(C(=O)NC2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[1-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-ylcarbamoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.45 g, 1.12 mmol) is treated with 4 M HCl (in dioxane)(2.5 ml) and methanol (1 ml, co-solvent) and the reaction mixture is allowed to stir at room temperature for 1 hour. The solvent is removed in vacuo and the resulting solid is dried in a vacuum oven to yield the title product.
Reaction SMILES: [C:1]([CH2:5][C:6]1(C(OC)=O)[C@@H:10]([CH:11]=[CH:12][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][C@H:8](C(OC)=O)[C:7]1=[O:24])([O:3]C)=[O:2].[OH-].[Na+].Cl>O.CO>[OH:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C@@H:10]1[CH2:9][CH2:8][C:7](=[O:24])[C@H:6]1[CH2:5][C:1]([OH:3])=[O:2]
Reactant: CCCCCC(O)C=C[C@H]1C[C@H](C(=O)OC)C(=O)C1(CC(=O)OC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=C[C@@H]1CCC(=O)[C@H]1CC(=O)O

Procedure:
A suspension of dimethyl trans-1-(carbomethoxymethyl)-5-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate (26.24 g), described in Example 42, in a solution of sodium hydroxide (12 g) in 70 ml of water and 80 ml of methanol is heated at reflux for 2 hr. The reaction mixture is cooled, acidified to pH 6 with 2N HCl. The resulting oil is extracted with ether. The ether extract is washed with water, dried (MgSO4) and the solvent removed. The residue is subjected to chromatography on silica gel (850 g). Elution with methanol-chloroform (1:9) yields the title compound, νmaxfilm 3350, 1727 cm-1. The corresponding methyl ester of the title compound, prepared by treatment with diazomethane, has νmaxfilm 3412, 1737 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH:40]=O)=[CH:33][CH:32]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][N:24]3[CH2:40][CH2:39][CH2:38][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=3)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCCC=O)cc1
Reactant: Cc1cc(C)cc(-c2c(OCC3CCCCN3)c3ccc(Cl)cc3[nH]c2=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CCCCN2CCCCC2COc2c(-c3cc(C)cc(C)c3)c(=O)[nH]c3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-4-(piperidin-2-yl-methoxy)-1H-quinolin-2-one (prepared essentially as described in Example 10, 34 mg in 3.0 mL dry methanol) was added 18 mg of 4-(4-methoxyphenyl)-butyraldehyde, 150 mg powdered 4 Å molecular sieves and one drop of acetic acid. After 30 minutes, 0.13 mL of a 1M solution of sodium cyanoborohydride in tetrahydrofuran was added and the mixture stirred at room temperature for 18 hours. At this time the reaction mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo. Purification by flash chromatography on silica gel (chloroform:methanolic ammonium hydroxide, 97:3) gave the title compound, 39 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.C([Si](C)(C)[O:30][CH2:31]/[CH:32]=[CH:33]/B1OC(C)(C)C(C)(C)O1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.O.C(O)C>[OH:30][CH2:31]/[CH:32]=[CH:33]/[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(Br)cc3)n2)cc1
Reactant: CC1(C)OB(/C=C/CO[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(/C=C/CO)cc3)n2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
A flask is charged with 4-{[4-(4-bromophenyl)pyrimidin-2-yl]amino}benzenesulfonamide (0.681 g, 1.68 mmol), tert-butyl(dimethyl){[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy}silane (1.00 g, 3.35 mmol), (Ph3)4Pd (0.194 g, 0.168 mmol), potassium carbonate (0.695 g, 5.03 mmol), ethanol (3.0 ml), water (3.0 ml), and toluene (25 ml). The reaction mixture is stirred at 85° C. for 4 h. The reaction mixture is cooled to room temperature, and trifluoroacetic acid (1.0 ml) is added. The reaction mixture is then stirred for 16 h at room temperature. The reaction mixture is concentrated and purified on preparative HPLC to yield 0.196 g of a yellow solid. MS (ESI) m/z 383.2; HRMS: calcd for C19H18N4O3S+H+, 383.11724; found (ESI-FTMS, [M+H]1+), 383.11752.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH2:19][C@H:18]3[N:15]([C:16](=[O:30])[C@@H:17]3[C@H:20]([O:22][Si](CC)(CC)CC)[CH3:21])[C:14]=2[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH:10]=[CH:11][CH:12]=1)=[O:4].FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C1COCC1.O>[OH:22][C@@H:20]([C@H:17]1[C:16](=[O:30])[N:15]2[C@@H:18]1[CH2:19][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][O:5][C:3]([NH:2][CH3:1])=[O:4])[CH:8]=1)=[C:14]2[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH3:21]
Reactant: C=CCOC(=O)C1=C(c2cccc(COC(=O)NC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C1=C(c2cccc(COC(=O)NC)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.42 h
Yield: 62.9 %

Procedure:
To a solution of allyl (5R,6S)-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (284 mg) in THF (4 ml) was added a solution of anhydrous trifluoromethanesulfonic acid (0.6 ml) in water (2 ml) at 0° C., and the solution was stirred for 25 minutes. Thereto was added a cold aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (139 mg).
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].II.[Cl-].[CH2:9]([O:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH3:10].S(=O)(=O)(O)O>[Cu].[Zn].O.C1(C)C=CC=CC=1.C(OCCCC)(=O)C>[O:19]=[C:17]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:20]
Reactant: CCOC(=O)CCCCC(=O)O
Reactant: CCCCI
Agent: [Cu]
Agent: II
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCCCOC(C)=O
Solvent: O
Product: CCCCC(=O)CCCCC(=O)OCC
Temperature: 115 °C

Procedure:
A mixture of activated zinc-copper catalyst (11.5 g), butyl acetate (4 g), toluene (5 g), butyl iodide (15 g) and iodine (3 mg) was heated at 110-120° C. for 2 hours. The mixture was then added dropwise with adipic acid monoethyl ester chloride(15.7 g) at 0° C., and then was allowed to react. After the reaction was completed, ice-cooled water was added to the reaction solution, and then decomposed with dilute sulfuric acid. The oily layer was extracted with ether, washed with aqueous sodium hydrogencarbonate, washed with water, and then dried. The residue was evaporated to remove the solvent, and then distilled, thereby giving ethyl 6-oxodecanoate (8.1 g).
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:28]([F:39])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[F:39][C:28]1[CH:27]=[C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)[CH:31]=[C:30]([F:32])[C:29]=1[O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Reactant: CC(C)(C)COc1c(F)cc(-c2csc(NC(=O)CBr)n2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2cc(F)c(OCC(C)(C)C)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (130 mg, 0.310 mmol) in the presence of NaH (15 mg, 0.625 mmol) in dry DMF (5.0 mL) to give 55 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 1.01 (s, 9H), 2.26 (s, 3H), 3.17 (s, 3H), 3.34 (s, 3H), 3.80 (s, 2H), 5.33 (s, 2H), 6.07 (s, 1H), 7.63 (s, 1H), 7.66 (s, 1H), 7.77 (s, 1H), 12.74 (br s, 1H); ESI-MS (m/z) 532.24 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Br:14])[CH:8]=1)(=O)=O.N1C(C)=CC=C[C:16]=1C>CO.CCOCC>[Br:14][C:9]1[CH:8]=[C:7]([CH2:6][O:5][CH3:16])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)OCc1ccc(F)c(Br)c1
Solvent: CO
Solvent: CCOCC
Product: COCc1ccc(F)c(Br)c1

Procedure:
A solution of 3-bromo-4-fluorobenzyl methanesulfonate (Intermediate 14, 330 mg; 1.17 mmol) and 2,6-lutidine (176 μL; 1.52 mmol) in methanol (4 mL) was stirred for 16 hours at RT. Additional aliquots of 2,6-lutidine (176 μL; 1.52 mmol each) were added once a day for a total of three days, during which stirring was continued at RT. The mixture was taken up in Et2O, washed with water, HCl (0.1N in water) and brine. The organic phase was dried over MgSO4, filtered and concentrated with moderate vacuum and without heating affording the title compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH:12]=1)[C:8](OC)=[O:9].[NH2:18][OH:19].O.[OH-].[K+]>C1COCC1.C(Cl)Cl.CO>[OH:19][NH:18][C:8](=[O:9])[C:7]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: NO
Reactant: COC(=O)c1cc(OC)ccc1-c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cccs2)c(C(=O)NO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a stirring solution of methyl 5-methoxy-2-(thiophen-2-yl)benzoate 10 (0.13 g, 0.524 mmol) and a solution of 50% hydroxylamine in water (0.53 mL, 0.524 mmol) in THF (1 mL) and MeOH (1 mL) was added KOH (0.117 g, 2.094 mmol) and the reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was solvent evaporated, diluted with DCM, washed with 5% KHSO4, brine, dried over MgSO4, filtered and solvent evaporated to provide title compound 11 (50 mg, 38% yield) as a white solid after trituration (overnight, DCM). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.87 (s, 1H), 9.06 (s, 1H), 7.49 (d, J=1.2 Hz, 1H), 7.45 (dd, J=15.5, 1.2 Hz, 1H), 7.14 (dd, J=3.5, 1.2 Hz, 1H), 7.05 to 7.02 (m, 2H), 6.84 (d, J=2.7 Hz, 1H), 3.78 (s, 3H). LRMS (ESI): (calc.) 249.05 (found) 250.1 (MH)+