Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:1]
Reactant: COC(=O)c1cc(CO)cc(OC)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)cc(OC)c1
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(hydroxymethyl)-5-methoxybenzoate (2.18 g, 9.82 mmol) in DCM (100 mL), Dess-Martin periodinane (5 g, 11.79 mmol) was added at rt. After 30 min stirring, the mixture was poured into a mixture of aqueous 1 M Na2S2O3 (30 mL) and aqueous saturated NaHCO3 (30 mL), and it was extracted with DCM three times. The combined organic layers were concentrated in vacuo and methyl 3-formyl-5-methoxybenzoate residue white solid (˜80% purity) was used directly for the next step reaction without further purification and identification.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:8])[CH3:7]>O>[CH3:7][C:6]1[O:8][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:10](=[O:11])[CH:9]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(=O)c2ccccc2o1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
Concentrated sulphuric acid (30 g) is added to acetyl acetophenone (15 g) obtained as above described. After cooling at room temperature, water is added until precipitation of a white powder, which is isolated by filtration under vacuum and washed with cold water. 2-methyl-4H-1-benzopyran-4-one (10 g) is obtained (m.p.=71° C.; yield=74%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:37]([NH:36][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)=[O:38])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc5ccccc45)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.00 mmol) and 1-naphthylisocyanate (0.17 g, 1.00 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.20 g, 2.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 3 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-naphthalen-1-yl-urea as a white solid (0.39 g, 89% yield); mp 250-252° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 6.96 (97.91%); 1H NMR (DMSO-d6) δ 1.94-2.06 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.54-2.67 (m, 1H, CHH), 2.84-3.00 (m, 1H, CHH), 4.26-4.46 (m, 2H, CHH), 4.50 (d, J=4.9 Hz, 2H, CH2 and CHH), 5.11 (dd, 1H, CH), 7.17 (t, 1H, NH), 7.38-7.62 (m, 6H, Ar), 7.72 (d, J=7.7 Hz, 1H, Ar), 7.90 (d, 1H, Ar), 8.01 (d, 1H, Ar), 8.12 (d, 1H, Ar), 8.69 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.95, 47.13, 51.58, 116.73, 121.38, 121.98, 122.26, 123.00, 125.43, 125.61, 125.74, 125.89, 126.97, 128.34, 130.36, 133.69, 134.98, 142.45, 144.72, 155.66, 167.95, 170.99, 172.85; LCMS: MH=443; Anal. Calcd for C25H22N4O4: C, 67.86; H, 5.01; N, 12.66. Found: C, 67.50; H, 4.96; N, 12.34.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][O:24][CH3:25]>CC#N>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(C(=O)OC)ccc1OC
Temperature: 25 °C

Procedure:
A solution of methyl-3-hydroxy-4-methoxybenzoate (Aldrich) (89.3 g, 0.49 mol), K2CO3 (100.5 g, 0.727 mol) and 1-bromo-3-methoxy-propane (80 g, 0.523 mol) in CH3CN (1100 mL) is refluxed for 6 h. After completion of the reaction, the mixture is cooled to RT and concentrated under reduced pressure. The residue is taken up into AcOEt (500 mL) and washed with water. The aqueous layer is back-extracted twice with AcOEt, and the combined organic extracts are dried over MgSO4, filtered and concentrated to afford the title compound which is further used in the next step without purification. tR (HPLC, CC 70/4 Nucleosil 3 C18HD column, 20 to 100% CH3CN in H2O in 2, then 4 min with 100% CH3CN, CH3CN and H2O with 0.1% TFA, flow: 1.5 mL/min): 3.07 min.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:19]([O:21]CC)=O)[CH3:4].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:4][C@H:3]1[N:5]2[C:9]3[N:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=[CH:13][C:8]=3[CH:7]=[C:6]2[C:19](=[O:21])[NH:1][CH2:2]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@@H](C)CN)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)nc3n21
Temperature: 60 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of diethyl 1-[(2S)-1-aminopropan-2-yl]-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (2.17 g, 6.80 mmol) in ethanol (40 mL) is added potassium carbonate (2.82 g, 20.4 mmol). The mixture is stirred at 60° C. for 16 h and is then cooled to room temperature. The ethanol is removed in vacuo and the aqueous mixture is acidified to pH 5 with 1N aqueous hydrochloric acid. The resulting solid is collected by filtration and dried in vacuo to afford the title compound as a pale yellow solid (1.40 g, 84%). LCMS: 246.64 (M+H+).
Reaction SMILES: [OH:1][C@@:2]([CH3:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:4].B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[OH:1][C@@:2]([CH3:23])([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:4]
Reactant: COc1ccc(C[C@](C)(O)C(=O)Nc2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: C[C@](O)(Cc1ccc(O)cc1)C(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
(S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide (6c) (0.20 g, 0.63 mmol) was dissolved in dry CH2Cl2 (20 mL). BBr3 (6 mL of 1.0 M CH2Cl2 solution) was added dropwise with stirring via a syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. in a ice bath and hydrolyzed by adding water (25 mL). EtOAc (50 mL) was added to partition the solution. The organic layer was separated; the aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica-gel with hexanes/EtOAc (3/7 v/v) to afford a white solid product, (S)-2-hydroxy-N,3-bis(4-hydroxyphenyl)-2-methylpropanamide (6g), 0.12 g, 65.6% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[C:18]([NH:22][NH2:23])(=O)[CH2:19][CH3:20].C(O)CCC>C(Cl)(Cl)Cl.CCCCCC>[CH2:19]([C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1)[CH3:20]
Reactant: CCC(=O)NN
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A mixture of 5.0 g. of 3-chloro-6-(α,α,α-trifluoro-m-tolyl)pyridazine, 3.40 g. of propionic acid hydrazide and 100 ml. of n-butanol is refluxed for 48 hr. The solvent is removed under vacuum and the residue dissolved in chloroform. The solution is passed through a column of hydrous magnesium silicate and the eluent concentrated to give 3.0 g. of crystals (from CHCl3 -hexane), m.p. 183°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[N:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=3)[O:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+].O1CCCC1.Cl>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=3)[O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:28][CH:29]=1
Reactant: COC(=O)COc1cccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(OCC(=O)O)c2)cc1
Yield: 100.3 %

Procedure:
A solution of the compound (153 mg, 0.393 mmol) of Example 1-1 in an aqueous 1N lithium hydroxide solution (1.0 ml), terahydrofuran (1.0 ml) and methanol (1.0 ml) was stirred for 30 minutes at room temperature. Thereto was added diluted hydrochloric acid and the solution was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (148 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Fc1ccccc1S
Product: COc1ccc2c(Sc3ccccc3F)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 305 was used, starting from 2-fluoro-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-fluoro-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 381 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[C:27]([Cl:28])=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([O:29][CH2:30][C:31]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]([F:39])[C:32]=2[F:40])[CH:16]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C.O>[Cl:28][C:27]1[C:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([CH3:13])[N:3]=2)=[CH:16][C:17]([O:29][CH2:30][C:31]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]([F:39])[C:32]=2[F:40])=[C:18]([CH:26]=1)[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Reactant: COc1nc(C)nc(Cl)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1cc(Cl)c(Nc2nc(C)nc(OC)c2[N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 105 °C
Yield: 49.1 %

Procedure:
A mixture of 4-chloro-6-methoxy-2-methyl-5-nitropyrimidine (0.14 g), ethyl 2-[4-amino-5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)phenoxy]acetate (0.23 g) and N,N-diisopropylethylamine (0.11 mL) in acetonitrile (3 mL) was stirred at 105° C. in a reaction vessel equipped with a reflux condenser for 17 hours. The reaction mixture was cooled to room temperature. To the reaction mixture were added ethyl acetate and water, and the resulting mixture was stirred at room temperature for 30 minutes. The organic layer was separated, and washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−2/3) to give ethyl 2-[5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-(6-methoxy-2-methyl-5-nitropyrimidin-4-ylamino)phenoxy]acetate (0.16 g). To this material were added tetrahydrofuran (4 mL), methanol (2 mL) and 10% platinum-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL). To the solution was added 1,1′-carbonyldiimidazole (88 mg) at room temperature. To the mixture was added sodium hydride (55%, 59 mg) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2−3/7) to give the title compound (70 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8]([CH2:11][C:12](=O)[CH3:13])(=O)[CH3:9]>C(O)(C)C>[CH3:7][C:5]1[CH:6]=[C:2]2[N:1]=[C:8]([CH3:9])[CH:11]=[C:12]([CH3:13])[N:3]2[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(=O)CC(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)n2nc(C)cc2n1

Procedure:
A mixture of 9.7 g of 3-amino-5-methylpyrazole, 13 ml of acetylacetone and 50 ml of isopropanol is heated under reflux for 3 hours. After distilling isopropanol off, the residue is dissolved in dichloromethane, washed with water and dried over anhydrous magnesium sulfate when chloroform is distilled off, 12.7 g of the title compound is obtained as crystals. mp. 70°-73° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl.[CH2:6]([N:13]1[CH2:17][CH:16]([C:18]2[S:19][C:20]([Br:24])=[C:21]([Br:23])[CH:22]=2)[CH:15]([C:25](Cl)=[O:26])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:6]([N:13]1[CH2:17][CH:16]2[CH:15]([C:25](=[O:26])[C:22]3[C:21]([Br:23])=[C:20]([Br:24])[S:19][C:18]=32)[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C1CN(Cc2ccccc2)CC1c1cc(Br)c(Br)s1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2c(sc(Br)c2Br)C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
A slurry of AlCl3 (2.38 g, 18 mmol) in CH2Cl2 (21 ml) was cooled to 0° C. under N2. Next, a solution of the product from step d) (3.0 g, 6 mmol) in CH2Cl2 (9 ml) was added dropwise over 5 minutes and the reaction mixture was stirred for an additional 45 minutes at 0° C. The reaction was poured into ice cold 2M NaOH (100 ml) and extracted with CH2Cl2 (2×100 ml). The organic layer was dried (MgSO4), evaporated, and purified by silica-gel chromatography using a gradient of 0-50% ethyl acetate in hexane to give the subtitle product (696 mg, 27%). 1H NMR (300 MHz, CDCl3, ppm) 2.39-2.49 (m, 2H); 2.92 (br d, J=9 Hz, 1H); 3.24 (br d, J=9 Hz, 1H); 3.34-3.40 (m, 1H); 3.54 (d, J=13 Hz, 1H); 3.60 (d, 13 Hz, 1H); 3.76-3.81 (m, 1H); 7.13-7.32 (m, 5H); MS calculated for C16H13Br2NOS+H 428, observed 426, 428, 430.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][C:11]1=[O:16].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:19]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>CO.C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:13]2[CH2:14][CH2:15][N:10]([C:4]3[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=3[CH3:2])[C:11](=[O:16])[CH2:12]2)=[O:23])=[C:20]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:19]=1
Reactant: Cc1ccc(N2CCNCC2=O)c(C)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a mixture of 1-(2,4-dimethylphenyl)piperazin-2-one hydrochloride (1.2 g), 4-bromo-2-methanesulfonylbenzoic acid (1.4 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (2.1 g) were added chloroform (7.5 mL), methanol (7.5 mL) and N-methylmorpholine (550 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform) to give 4-(4-bromo-2-methanesulfonylbenzoyl)-1-(2,4-dimethylphenyl)piperazin-2-one (2.24 g).
Reaction SMILES: CNC.Cl[C:5]1[CH:15]=[C:14](Cl)[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]>>[O:7]([CH2:8][C:9]([OH:11])=[O:10])[C:6]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:5]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: CNC
Product: O=C(O)COc1ccccc1

Procedure:
Dimethylamine salt of 2,4-dichlorophenoxy acetic acid--2,4-D tank-mixed
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2)=[O:31]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4cccc(Cl)c4)ccc3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 3-chlorobenzoyl chloride (0.25 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, then 4% aqueous HCl (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 3-chloro-N-[2-(2,6-dioxo-piperidin-3yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.49 g, 88% yield); mp 293-295° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.50 (98.62%); 1H NMR (DMSO-d6) δ 1.96-2.03 (m, 1H), 2.31-2.45 (m, 1H), 2.57-2.63 (m, 1H), 2.85-2.98 (m, 1H), 4.31 (d, 1H, J=17.4 Hz), 4.45 (d, 1H, J=17.4 Hz), 4.60 (d, 2H, J=6.0 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 7.46-7.50 (m, 1H), 7.53-7.55 (m, 2H), 7.61-7.65 (m, 1H), 7.70 (d, 1H, J=7.8 Hz), 7.85-7.89 (m, 1H), 7.95 (t, 1H, J=1.7 Hz), 9.27 (t, 1H, J=6.0 Hz), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 122.1, 122.9, 126.0, 127.1, 127.2, 130.4, 130.5, 131.2, 133.2, 136.1, 142.2, 143.6, 164.9, 167.9, 170.9, 172.8; LCMS: MH=412, 414; Anal. Calcd for C21H18ClN3O4+0.1H2O: C, 60.98; H, 4.43; N, 10.16. Found: C, 60.71; H, 4.36; N, 10.30.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([O:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[C:28]([C:32]([NH:34][CH3:35])=[O:33])=[CH:27][CH:26]=[CH:25]6)=[CH:16][CH:17]=[N:18]4)=[CH:13][C:12]=3[O:36][CH3:37])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:42](C)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH3:42])[C:6]2([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([O:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[C:28]([C:32]([NH:34][CH3:35])=[O:33])=[CH:27][CH:26]=[CH:25]6)=[CH:16][CH:17]=[N:18]4)=[CH:13][C:12]=3[O:36][CH3:37])[CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(NCC6CC6)CC5)c(OC)cc34)ccc12
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(N(C)CC6CC6)CC5)c(OC)cc34)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound of Example 13 (40 mg) was mixed with HCHO (2 eq, 37% in H2O), NaBH(OAc)3 (2 eq) in DCM (5 ml) and stirred at RT for 3 hours. The reaction was evaporated and purified with silica gel column to give the titled product (20 mg). Mass: (M+1), 512
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=1)[CH:10]=2)=[O:5])C.[C:26]([O:30][C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][NH2:34])([CH3:29])([CH3:28])[CH3:27]>CCO>[C:26]([O:30][C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][NH:34][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=1)[CH:10]=2)=[O:5])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O
Yield: 59.2 %

Procedure:
A mixture of 7-(4-chloro-3-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (45 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (65 mg) in EtOH (0.5 mL) was microwaved at 145° C. for 3 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (36 mg). LC MS ESI+: 489 (M+1)+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:27][C:28]1[CH:29]=[C:30]([C:35](=[O:63])[C:36](=[C:54]2[NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[NH:55]2)[C:37]([C:39]2[CH:40]=[C:41]([S:45]([NH:48][C:49](=[NH:53])[C:50]([OH:52])=O)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:31]=[C:32]([F:34])[CH:33]=1>O.CN(C=O)C.C(N(CC)CC)C>[F:34][C:32]1[CH:31]=[C:30]([C:35](=[O:63])[C:36](=[C:54]2[NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[NH:55]2)[C:37]([C:39]2[CH:40]=[C:41]([S:45]([NH:48][C:49](=[NH:53])[C:50]([N:3]([CH3:4])[CH3:2])=[O:52])(=[O:46])=[O:47])[CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:29]=[C:28]([F:27])[CH:33]=1
Reactant: N=C(NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1)C(=O)O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
Dimethylamine hydrochloride (31 mg), triethylamine (0.05 mL), HOBt (51 mg) and WSC.HCl (73 mg) were added to a DMF (5 mL) solution of [({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino](imino)acetic acid (40 mg), followed by stirring at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain 2-[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino]-2-imino-N,N-dimethylacetamide (28 mg).