Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:10][C:9]2([C:17](=O)[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH2:33][NH2:34]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:34][N:33]=[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[C:9]2([OH:10])[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)C2(c3ccncc3)OC2c2ccc(F)cc2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC2=NNC(c3ccc(F)cc3)C2(O)c2ccncc2)CC1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate prepared in step 4 of this Example (3.45 g, 7.8409 mmol) in ethanol (15 mL), anhydrous hydrazine (0.50 mL, 15.6818 mmol) was added. The reaction was heated to reflux overnight. The reaction solution was cooled to room temperature and ethanol was removed under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water and brine, and dried over MgSO4. After filtration the solvent was removed under reduced pressure. The crude residue was purified by chromatography (silica gel, 2:1-1:1-1:2 hexane/ethyl acetate) to give 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4,5-dihydro-4-hydroxy-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate (1.9187 g, 53.9%). This intermediate (1.8611 g, 4.0993 mmol) was dissolved in dry methylene chloride (40 mL) and treated with Martin sulfurane dehydrating reagent (4.13 g, 6.1490 mmol). The reaction solution was stirred at room temperature under N2 overnight, then diluted with ethyl acetate, washed with 1N sodium hydroxide solution, water and brine, dried over MgSO4. After filtration the solvents were removed. The resulting crude pruduct mixture was purified by flash chromatoghaphy (silica gel, 2:1-1:1-1:2 Hexane/ethyl acetate) to give 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate (0.6964 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:28]([N:31]([CH:34]([CH3:36])C)[CH2:32]C)([CH3:30])C.C(Cl)(Cl)=[O:38].N1CCCC1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:32]([N:31]2[CH2:28][CH2:30][CH2:36][CH2:34]2)=[O:38])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)N1CCCC1
Reaction time: 2 h

Procedure:
To a solution of (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.207 g, 0.54 mmol) and diisopropylethylamine (0.38 mL, 2.16 mmol) in CH2Cl2 (2 mL) at 0° C. was added phosgene (20% in toluene; 0.43 mL, 0.81 mmol), and the reaction was stirred for 2 hours. Pyrrolidine (0.13 mL, 1.62 mmol) was added, and the reaction was stirred at 0° C. for 30 minutes. The mixture was concentrated, and the residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([NH:18][C@@H:19]([C:24]([OH:26])=O)[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:35]>ClCCl>[C:1]([NH:18][C@@H:19]([C:24]([F:35])=[O:26])[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CSCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
FMOC-D-Methionine (5.00 g, 13.46 mmol) (Bachem) was dissolved in dichloromethane (70 mL). Pyridine (1.09 mL, 13.46 mmol) (Aldrich) and cyanuric fluoride (1.82 g, 13.46 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 4 hours. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford FMOC-D-methionyl fluoride as a white powder. (Yield 3.7 g., 74%).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]([NH:11][C@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[CH:27][CH:26]=1)[CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:10])[CH2:2][CH2:3][CH3:4]>CCOC(C)=O.[Pd]>[CH2:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]([NH:11][C@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[CH:27][CH:26]=1)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CCC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CCC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
A suspension of (R)-benzyl 3-(4-butoxy-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoate (Example 3-3: 178.9 mg, 0.334 mmol) and Pd/C (71.0 mg, 0.033 mmol) in EtOAc (3 ml) is allowed to stir under hydrogen at room temperature for 1.5 hours. The reaction mixture is filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-3-(4-butoxy-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (90.7 mg) as a white solid; HPLC retention time=1.27 minutes (condition B); MS (m+1)=446.24; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.91 (t, J=7.5 Hz, 3 H) 1.31-1.40 (m, 2 H) 1.55-1.62 (m, 2 H) 2.43-2.47 (m, 2 H) 2.52-2.69 (m, 4 H) 2.93 (A of ABX, Jab=13.7 Hz, Jax=7.7 Hz, 1 H) 3.00 (B of ABX, Jab=13.7 Hz, Jbx=6.8 Hz, 1 H) 4.07 (t, J=6.7 Hz, 2 H) 4.49-4.57 (m, 1 H) 6.31 (br d, J=8.6 Hz, 1 H) 7.26-7.37 (m, 4 H) 7.43-7.46 (m, 1 H) 7.49-7.52 (m, 2 H) 7.55 (br t, J=1.8 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[C:9]([N+:13]([O-:15])=[O:14])[C:10]([OH:12])=[O:11].[Cl:16][C:17]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:18]=1[O:19][CH2:20][C:21](Cl)=[O:22].[CH3:29]N(C)C=O>>[CH3:29][O:11][C:10](=[O:12])[C:9](=[C:5]1[N:4]([CH3:3])[CH2:8][CH2:7][N:6]1[C:21](=[O:22])[CH2:20][O:19][C:18]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:17]=1[Cl:16])[N+:13]([O-:15])=[O:14]
Reactant: CN(C)C=O
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: CN1CCNC1=C(C(=O)O)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(=C1N(C)CCN1C(=O)COc1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.3 g of sodium hydride was slurried in 75 ml of dimethylformamide at 5°. To that slurry, at 5°, was added 19.5 g of 1B over a 30-minute period. The stirred mixture was allowed to warm to room temperature and stirred at that temperature for one hour. The mixture then was cooled to 5° and there was added thereto a solution of 25.5 g of 2,4-dichlorophenoxyacetyl chloride in 25 ml of dimethylformamide, over a 20-minute period, the stirred mixture being held at 5°-12°. The stirred mixture was allowed to warm to room temperature and stirred at that temperature overnight. The mixture then was poured into ice water. The solid was filtered, washed with water and dried by air aspiration and ether washing to give a tan-colored solid, which on recrystallization from acetonitrile gave 1, as an off-white solid, m.p.; 191°-192° (with decomposition).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:8])[NH:6][N:7]=1)[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=O>C(O)(=O)C>[CH2:1]([C:3]1[C:4]2[C:20]([C:19]([OH:24])=[O:23])=[CH:22][C:13]([C:12]3[CH:15]=[CH:16][C:17]([OH:18])=[C:10]([F:9])[CH:11]=3)=[N:8][C:5]=2[NH:6][N:7]=1)[CH3:2]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CCc1cc(N)[nH]n1
Reactant: CC(=O)C(=O)O
Solvent: CC(=O)O
Product: CCc1n[nH]c2nc(-c3ccc(O)c(F)c3)cc(C(=O)O)c12
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A mixture of 5-ethyl-2H-pyrazol-3-ylamine (1 g, 9 mmol), 3-fluoro-4-hydroxybenzaldehyde (1.26 g, 9 mmol), pyruvic acid (0.63 ml, 9 mmol) and glacial acetic acid (14 ml) was heated to reflux under nitrogen for 2 h and then cooled to room temperature. The precipitate was filtered and washed with absolute ethanol to afford the title compound (0.614 g, 23%) as beige solid.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([N:31]([CH2:36][CH2:37][O:38][CH3:39])[CH2:32][C:33](O)=[O:34])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2.C(OCC)C.S(Cl)([Cl:47])=O>>[N:1]#[N:2].[ClH:47].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([N:31]([CH2:36][CH2:37][O:38][CH3:39])[CH2:32][C:33]([Cl:47])=[O:34])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2
Reactant: COCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reactant: O=S(Cl)Cl
Agent: N#N
Solvent: CCOCC
Product: COCCN(CC(=O)Cl)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.00 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry ethyl ether to give N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl chloride hydrochloride.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.Cl.[CH3:20][O:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27](C)[CH2:26][CH2:25]1)=[O:23].[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:20][O:21][C:22]([C:24]1([CH3:31])[CH2:25][CH2:26][N:27]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([C@@H:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)=[CH:12][CH:13]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: COC(=O)C1CCN(C)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccc([C@H]2COc3ccccc3O2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Reaction time: 4 h

Procedure:
Intermediate A (100 mg, 0.42 mmol), methyl-piperidine-4-carboxylic acid methyl ester hydrochloride (105 mg, 0.54 mmol), and TEA (75 uL, 0.54 mmol) are stirred in dry THF (3 mL) for 10 minutes. Sodium triacetoxyborohydride (176 mg) is added and stirred for 4 h. The mixture is diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-3% MeOH in DCM to give [(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-4-methyl-piperidine-4-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)(=[O:32])=[O:31].C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH:36]3[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Reaction time: 2 h
Yield: 8 %

Procedure:
To a stirred solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (122 mg, 0.50 mmol) in methanol (8 mL) at rt, was added 1-(methylsulfonyl)piperidin-4-one (89 mg, 0.50 mmol). The mixture was stirred for 2 hrs, after which, sodium cyanoborohydride (94.2 mg, 1.5 mmol) and three drops of acetic acid were added. The reaction mixture was stirred at rt for 6 hrs, then diluted with water (25 mL) and extracted with EtOAc (3×10 mL). The extracts were dried with sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column to give 16 mg (8%) of desired product as a white solid. MS +m/z: 404.9 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:30]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])[CH3:31])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CNCC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Yield: 52.7 %

Procedure:
A solution of 0.57 g (1.67 mmol) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonyl chloride and 0.61 g (3.34 mmol, 2 eq) of sarcosine t-butyl ester hydrochloride in 0.51 mL of pyridine and 15 mL of chloroform was allowed to react overnight at room temperature. The reaction was concentrated in vacuo, diluted with water/ethyl acetate, neutralized with NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to afford a yellow oil which was purified via flash chormatography using 6:1 hexane:ethyl acetate to afford 0.396 g (53%) of tert-butyl [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetate as a white solid. Electrospray Mass Spec 450.4 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:9].CO.[CH3:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:4][C:3]=1[NH2:9]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
35.8 g of 4-chloro-1,3-diaminobenzene are stirred thoroughly into 250 ml of water and 50 ml of methanol. 23 ml of methanesulphonyl chloride are added dropwise at 0° C. in the course of about 2 hours; the pH is kept at 4 by dropwise addition of concentrated sodium hydroxide solution. The mixture is subsequently stirred at room temperature for about 2 hours and, if appropriate after diluting with water, the 1-chloro-2-amino-4-methanesulphonamido-benzene which has separated out is then filtered off. It is sufficiently pure for further reactions according to Example 59.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.Cl[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[O:19])(=[O:16])=[O:15]
Reactant: CCN(CC)C(=O)CCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 6, piretanide can be reacted with 2-chloro-N,N-diethylacetamide, triethylamine and sodium iodide in dimethylformamide (DMF) to yield N,N-diethylaminocarbonylmethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1([CH3:34])[S:26][C@@H:25]2[C@H:27]([NH2:30])[C:28](=[O:29])[N:24]2[C@H:23]1[C:31](O)=O.C([N:37](CC)CC)C>C(Cl)(Cl)Cl>[C:2]1([C:1]([NH:30][CH:27]2[C:28](=[O:29])[N:24]3[CH:23]([C:31]#[N:37])[C:22]([CH3:34])([CH3:21])[S:26][C@H:25]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N

Procedure:
Tritylchloride (61.2g., 0.22 mole) is added to a mixture of 6-aminopenicillanic acid (43.3g., 0.20 mole) and triethylamine (5.56 ml.) in chloroform (300 ml.) at about 5° C. The somewhat exothermic reaction is stirred and allowed to rise gradually to room temperature. It is stirred at room temperature for three days. Evaporation of the reaction mixture affords the title product which is used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:27]=[C:26]([C:28](=[O:39])[NH:29][C:30]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31]3)[CH:25]=[CH:24][C:23]=2[F:40])=[CH:20][C:5]2[C:6]([C:16]([NH:18]C)=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].[CH3:46]S(NS(C)(=O)=O)(=O)=O>>[F:40][C:23]1[CH:24]=[CH:25][C:26]([C:28](=[O:39])[NH:29][C:30]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)=[CH:27][C:22]=1[C:21]1[C:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)=[C:6]([C:16]([NH2:18])=[O:17])[C:5]=2[C:20]=1[CH3:46]
Reactant: CS(=O)(=O)NS(C)(=O)=O
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3F)cc12
Product: Cc1c(-c2cc(C(=O)NC3(c4ccccc4)CC3)ccc2F)c(NS(C)(=O)=O)cc2oc(-c3ccc(F)cc3)c(C(N)=O)c12

Procedure:
Prepared from the coupling between 6-Amino-5-(2-fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide and methanesulfonyl chloride (N,N-diisopropylethylamine, ClCH2CH2Cl, r.t.), followed by hydrolysis of the intermediate N-(methylsulfonyl)methanesulfonamide (Cs2CO3, 1:5 H2O/1,4-dioxane, 90° C.). Purification by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.70-7.25 min. (UV detection at 220 nm). 1H NMR (500 MHz, CD3OD) δ 8.00-7.95 (overlapping m, 4H), 7.83 (s, 1H), 7.66 (s, 1H), 7.35 (t, J=9.00, 1H), 7.30-7.27 (overlapping m, 6H), 7.18 (m, 1H), 2.94 (s, 3H), 2.88 (s, 3H), 1.37-1.35 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=616.48, HPLC Rt=1.563 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.57 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.80 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3Cl)ccn2)cn1
Temperature: 90 °C
Yield: 77.3 %

Procedure:
5-Chloro-4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (1.177 g, 4.31 mmol) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.166 g, 5.60 mmol) were dissolved in DMF (16.16 ml), cesium carbonate (4.21 g, 12.93 mmol) was added, followed by water (5.39 ml). Argon was bubbled through the mixture for 5 minutes, and then palladium tetrakistriphenylphosphine (0.249 g, 0.215 mmol) was added. The flask was fitted with a reflux condenser, flushed with argon, and heated in a 90° C. oil bath under a balloon of argon for 4 hours. The reaction mixture was then cooled to RT and diluted with a 4:1 mixture of ethyl acetate and THF. The solution was extracted with 10% aqueous LiCl (2×150 mL) and brine (100 mL), dried (MgSO4), evaporated under reduced pressure and purified via silica gel chromatography (ethyl acetate/hexanes) to yield 5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine as a tan solid (1.062 g, 77% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 6.92 (d, 1H), 6.52 (dd, 1H), 5.49 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 319.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[C:41](=O)[O:40][C:39]3([CH3:47])[CH3:46])[CH2:30][CH2:29]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:41]1[C:42]2[C:38](=[CH:37][C:36]([CH2:35][CH2:34][N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)=[CH:44][CH:43]=2)[C:39]([CH3:47])([CH3:46])[O:40]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC1(C)OC(=O)c2ccc(CCN3CCC(O)CC3)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OC(=C2C(=O)Nc3ccc(F)cc32)c2ccc(CCN3CCC(O)CC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a stirred solution of 5-fluorooxindole (7.86 g, 52 mmol) in anhydrous THF (60 ml) under nitrogen was added 1.0M LiHMDS/THF solution (104 ml, 104 mmol). The mixture was stirred at room temperature for 15 minutes, and then 5-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-3,3-dimethyl-3H-isobenzofuran-1-one (5.0 g, 17.3 mmol) was added. After stirring at room temperature for 2 hours, the mixture was quenched with 50 ml of 2.5M H2SO4, heated at 65° C. for 30 minutes and poured into 500 ml of water. The mixture was basified with 5M NaOH to about pH=9 and continuously stirred at room temperature for 16 hours. The resulting solids were filtered, rinsed with water, dried under vacuum to give the title compound as a yellow solid (4.74 g, 65%).