Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@H:15]([CH3:16])[C@H:23]([C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)[OH:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Product: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](O)c1ccc(Cl)cc1
Yield: 80 %

Procedure:
The title compound (1.32 g, 80%) was prepared from 4-(S)-benzyl-3-propionyl-oxazolidin-2-one and 4-chlorobenzaldehyde as in Example 55, Part B. 1H NMR (400 MHz, CDCl3): 7.37-7.26 (m, 7H), 7.23-7.17 (m, 2H), 5.12-5.08 (m, 1H), 4.69-4.62 (m, 1H), 4.22-4.13 (m, 2H), 4.03 (dq, J=7.0, 3.6, 1H), 3.25 (dd, J=13.4, 3.3, 1H), 3.20 (d, J=2.5, 1H), 2.79 (dd, J=13.4, 9.4, 1H), 1.18 (d, J=7.0, 3H).
Reaction SMILES: I.[CH3:2][N:3](C)[C:4](=[NH:6])S.[NH2:8][CH2:9][C:10]([OH:12])=[O:11]>[OH-].[NH4+]>[CH3:2][N:3]=[C:4]([NH2:6])[NH:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: NCC(=O)O
Reactant: CN(C)C(=N)S
Agent: I
Agent: [NH4+]
Agent: [OH-]
Product: CN=C(N)NCC(=O)O
Reaction time: 8 h

Procedure:
N,N-dimethylisothiourea hydroiodide (9.5 g., 0.041 mole) was added portionwise to a stirred solution of glycine (4.45 g., 0.0595 mole) in concentrated ammonium hydroxide (40 ml.) at room temperature. The reaction was stirred overnight and the product recovered by filtration as white crystals: 3.0 g., m.p. 230° C. (dec.).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]([CH3:25])[NH2:24].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH3:25])[NH:24][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:13][CH:14]=1
Reactant: CN(C)N
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NN(C)C)cn1
Yield: 33.6 %

Procedure:
To a stirred solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) in DMF (5 mL) at room temperature under argon was added N,N-dimethylhydrazine (23 mg, 0.38 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (122 mg, 0.38 mmol) and N,N-diisopropylethylamine (223 mg, 1.7 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (38 mg, 33%) as a colourless gum. MS: m/e=333.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([S:26](Cl)(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1>>[Cl:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([S:26]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: Cc1cc(S(=O)(=O)Nc2cccc(COCc3ccc(F)cc3)n2)c(C)cc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 4-chloro-2,5-dimethyl-benzenesulfonyl chloride (0.066 g) as a light yellow gum (0.089 g). MS (ESI−): 433.2. ([M−H]−)
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])=[CH:31][CH:30]=2)=[CH:6][C:7]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20]C(=O)OC(C)(C)C)[CH2:15]2)=[N:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:7]2[CH:6]=[C:5]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:36])=[CH:31][CH:30]=3)[C:4]([C:1]([NH2:2])=[O:3])=[C:9]([O:10][CH2:11][CH2:12][CH3:13])[N:8]=2)[CH2:15]1
Reactant: CCCOc1nc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1nc(N2CCC[C@@H](N)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of (R)-tert-butyl 1-(5-carbamoyl-4-(4-(morpholine-4-carbonyl)phenylamino)-6-propoxypyridin-2-yl)piperidin-3-ylcarbamate (530 mg, 0.910 mmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL, 64.9 mmol) and stirred at rt for 1 hr. Solvent was removed by evaporation on a rotary evaporator. The residue was dissolved in CH2Cl2 and washed with NaHCO3 and concentrated to give 380 mg of (R)-6-(3-aminopiperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)-2-propoxynicotinamide as a white solid. LCMS: (M+H)+=483.36. 1H NMR (400 MHz, CDCl3) δ ppm 11.60 (1H, s), 7.94 (1H, br. s.), 7.41 (2H, d, J=8.35 Hz), 7.27 (2H, d, J=8.35 Hz), 6.03 (1H, s), 5.69 (1H, br. s.), 4.36 (2H, t, J=6.48 Hz), 4.06 (1 H, d, J=10.77 Hz), 3.86 (1H, d, J=12.96 Hz), 3.71 (8H, br. s.), 2.81-2.97 (2H, m), 2.75 (1H, dd, J=12.30, 9.23 Hz), 1.89-2.05 (1H, m), 1.80-1.88 (2H, m), 1.70-1.80 (1H, m), 1.53 (1H, ddd, J=10.44, 3.41, 3.30 Hz), 1.25-1.38 (1H, m), 1.05 (3H, t, J=7.36 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1.[Cl:23]N1C(=O)CCC1=O>C(#N)C>[Cl:23][C:20]1[N:21]=[C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:22])[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]2[CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1ccc(Cl)cc1F
Solvent: CC#N
Product: O=c1cc(C(F)(F)F)n2cc(Cl)nc2n1-c1ccc(Cl)cc1F

Procedure:
A mixture of 8-(4-chloro-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (1.0 g), N-chlorosuccinimide (0.4 g) and acetonitrile (30 ml) was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure and the residue was purified by a preparative thin-layer plate of silica gel (developing solvent: ethyl acetate/hexane=2/8) to give the compound of interest (0.3 g).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>O>[C:28]([O:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1)(=[O:30])[CH3:29]
Reactant: OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
4-(N,N-Diphenylamino)benzyl alcohol (5.94 g, 0.0216 mol), pyridine (16 mL) and acetic anhydride (11.4 mL) were mixed in a three-neck flask equipped with a condenser and addition funnel. The resulting mixture was stirred overnight at room temperature. Deionized water (50 mL) was then added and the resulting mixture stirred for 2 hours. The product was obtained by filtration, and recrystallized from hexane to yield the desired product (6.52 g, 95%). m.p. 105-6° C.; 1H NMR δ: 2.10 (s, 3H, CH3), 5.04 (s, 2H, CH2), 7.0-7.4 (m, 14H, phenyl). Analysis: Calculated for C19H17NO2: C, 79.46%; H, 6.03%; N, 4.41%. Found: C, 79.37 %; H, 5.72 %; N, 4.41%.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cc1ccccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Agent: Cl
Product: Cc1ccccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-methylbenzenesulfonamide (19 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH2:14][CH3:15])=[O:8]
Reactant: Cc1ccsc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sccc1C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 3-methylthiophene-2-carboxylic acid (5.00 g, 35.17 mmol) in ethanol (50 mL) was added thionyl chloride (2.60 mL, 35.62 mmol). The resulting reaction mixture was stirred at reflux for 16 h, and allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate solution (3×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 3-methylthiophene-2-carboxylate as light yellow liquid (5.96 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=5.0 Hz, 1H), 6.91 (d, J=5.0 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:21])=[C:5]2[C:12](I)=[C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:10][C:6]2=[N:7][C:8]=1[CH3:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[C:4]([CH3:21])=[C:5]2[C:12]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:10][C:6]2=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCc1c(C)nc2sc(C(=O)OC(C)(C)C)c(I)c2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCc1c(C)nc2sc(C(=O)OC(C)(C)C)c(-c3ccc(OC)cc3)c2c1C
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a solution of compound tert-butyl 5-ethyl-3-iodo-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate (42 mg, 0.1 mmol) in 0.5 mL of DME/H2O (1/1) was added K2CO3 (41 mg, 0.3 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), p-methoxyphenyl boronic acid (18 mg, 0.12 mmol). The mixture was then heated to reflux for 16 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved with ethyl acetate (2 mL), washed with water (2 mL×3), brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude solid was purified by preparative HPLC to provide t-butyl 5-ethyl-3-(4-methoxy-phenyl)-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate (12 mg, 30%).
Reaction SMILES: C([Cl:6])(=O)OCC.[CH2:7]([O:9][CH:10](OCC)[CH:11]1[CH2:15][CH2:14][O:13][CH:12]1OCC)[CH3:8]>>[Cl:6][CH2:14][CH2:15][C:11](=[CH:10][O:9][CH2:7][CH3:8])[CH:12]=[O:13]
Reactant: CCOC(OCC)C1CCOC1OCC
Reactant: CCOC(=O)Cl
Product: CCOC=C(C=O)CCCl
Yield: 95.8 %

Procedure:
3-(Diethoxymethyl)-2-ethoxytetrahydrofuran (20.03 g, 91.8 mmol) obtained by the method of Reference Example 1, toluene (46.0 g) and pyridine (0.22 g, 2.8 mmol) were added to a 100 ml three-necked flask equipped with a thermometer, a stirrer and a dimroth condenser, and the mixture was heated to 100° C. to 106° C. under a nitrogen atmosphere. Ethyl chlorocarbonate (19.92 g, 183.5 mmol, 2-fold mol relative to 3-(diethoxymethyl)-2-ethoxytetrahydrofuran) was added dropwise to the mixture over 1 hr. After completion of the dropwise addition, the mixture was reacted at the same temperature for 6 hr, and the reaction solution was analyzed by gas chromatography. As a result, the conversion ratio of 3-(diethoxymethyl)-2-ethoxytetrahydrofuran was 100%, and 4-chloro-2-ethoxymethylidenebutanal (14.3 g, 87.9 mmol, yield 95.8%) was produced.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](/B(O)O)=[CH:27]\[CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH3:30])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCC/C=C/B(O)O
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCC/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 60.7 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (200 mg, 0.45 mmol) and trans-1-penten-1-ylboronic acid (205 mg, 1.80 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 96 mg, 0.045 mmol) and 2M aqueous solution of K2SO4 (0.90 mL, 1.80 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (145) as white solid (107 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[N:15](OCCC(C)C)=[O:16].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[N:15][OH:16])[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)C(=NO)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5,6-Dimethoxy-1-indanone (0.078 moles, 15 g) is dissolved in absolute ethanol (550 ml), thermostated at 50° C., and added with isoamyl nitrite (0.086 moles, 11.9 ml) and conc. HCl (11.9 ml). After a few minutes the product precipitates. The reaction is kept at 50° C. for further 3 hours, then cooled at r.t. and the solid is filtered washing with absolute ethanol (50 ml) and ethyl ether (100 ml). The product is dried in oven under vacuum at r.t. Yield: 16.3 g (94.4%)
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].Cl.C(N=C=NCCCN(C)C)C.Cl>O1CCCC1.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[N:15]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:3]
Reactant: Cc1ccccc1N
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccccc2C)c1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 18.6 %

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (3 g, 19.5 mmol) in tetrahydrofuran (30 mL) and N,N-dimethylformamide (10 mL) was added 2-methylaniline (2.09 g, 19.5 mmol), and the mixture was stirred at room temperature for 7 hr. 4-Dimethylaminopyridine (119 mg, 0.974 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.48 g, 23.4 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 17 hr. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=1/1) to give the title compound (882 mg, 19%) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>COCCOC>[F:26][C:22]1[C:23]([F:25])=[CH:24][C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][C:34]([F:33])([F:46])[F:45])=[C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH:21]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1cc(F)c(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1cc(F)c(F)cc1-c1ccccc1OC(F)(F)F
Yield: 68.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4,5-difluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/2M Na2CO3 (0.443 ml, 0.863 mmol) was treated with 2-trifluoromethoxybenzeneboronic acid (72 mg, 0.351 mmol) and Pd[PPh3]4 (54 mg, 0.046 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate in hexanes gradient to afford the product as a white, crystalline solid (81 mg, 68%). MS m/e 509.24 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][CH:22]=1)[CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27][C:28]([CH3:36])([CH3:37])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=1)[CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg of tert-butyl 2-[[4-[[[2-[(2-methyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]methyl]phenyl]thio]-2-methyl-propanoate are dissolved in 5 ml of dichloromethane and reacted with I ml of trifluoroacetic acid. The mixture is stirred at room temperature for 20 h and then concentrated and purified chromatographically (dichloromethane/methanol 50+1). This gives 174 mg of the title compound as a solid foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:17][C:18]([CH3:27])([CH3:26])[CH:19]([NH2:25])[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[CH3:17][C:18]([CH3:27])([CH3:26])[CH:19]([NH:25][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:20]1[S:21][CH:22]=[CH:23][N:24]=1
Reactant: CC(C)(C)C(N)c1nccs1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(Cl)cn1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2,2-Dimethyl-1-thiazol-2-yl-propylamine (CAN 1247122-26-4) as starting materials and isolated (72 mg, 51%) as white solid; MS (ESI, m/z): 408.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([NH2:26])([C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)[CH3:19]>>[CH3:17][C:18]([NH:26][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)[CH3:19]
Reactant: Cc1cc(C(C)(C)N)on1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: Cc1cc(C(C)(C)NC(=O)c2cccc(-c3cccc(Cl)c3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-(3-methyl-isoxazol-5-yl)-ethylamine as starting materials, MS (EI): 356.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O-:35])=[O:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[Na+].[NH2:38][OH:39].Cl>O>[OH:36][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[NH:38][OH:39])=[CH:8][C:7]=1[S:9]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[O:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C(=N)NO)ccc2O)c(OCC(=O)O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
Method 2) To a stirred solution of 117 g of sodium [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetate in 1.17 L of water was added 56 g of 50% aqueous hydroxylamine solution at room temperature, and the mixture was stirred at 70° C. for 4 hours. To the reaction mixture was added dropwise 1 mol/L hydrochloric acid at room temperature, and the mixture was stirred at the same temperature over night. The obtained solid was collected by filtration to give 110 g of [4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonyl-amino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCCc1ccccc1
Reactant: CCOC(=O)COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCCCCc2ccccc2)cc1
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A solution of ethyl (4-hydroxyphenoxy)acetate (0.49 g, 2.5 mmol), 4-phenylbutyl bromide (0.59 g, 2.8 mmol), potassium carbonate (0.69 g, 5.0 mmol) and potassium iodide (30 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 30 min., and further at 50° C. for 3 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated brine. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (0.62 g, yield 76%). oil.