Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:7][C:5]([NH2:6])=[C:4]([N+:18]([O-])=O)[CH:3]=1.Cl>[Zn].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: Nc1cc(Oc2ccc(Cl)cc2Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(Cl)cc2Cl)cc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (20 g, 96.61 mmol) in DMSO (200 ml) was added 2,4-dichlorophenol (15.8 g, 96.93 mmol) and potassium carbonate (26.7 g, 193.18 mmol). The resulting solution was stirred overnight at 90° C. and then quenched by the addition of water (1000 ml). The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline as a yellow solid (23 g, 71%). Next, the 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline (22 g, 65.96 mmol) was added to ethanol (200 ml) and hydrogen chloride (16 ml, 197.9 mmol). This was followed by the addition of Zn powder (21.4 g, 395.8 mmol) at room temperature in portions. The resulting solution was stirred for 4 h at 85° C. and then concentrated under vacuum. The residue was dissolved in water (500 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with ethyl acetate (4×200 ml). The combined organic layers were dried and concentrated under reduce pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to afford 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine as a red oil (15 g, 75%). Finally, a solution of 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine (14 g, 46.12 mmol) in heptafluorobutanoic acid (150 ml) was stirred overnight at 80° C. in an oil bath. The reaction was then quenched by the addition of water (400 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 2%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-dichlorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (10.4705 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:4]=2[N:5]=[C:6]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])[N:7]=1
Reactant: NC(CO)CO
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(C(F)(F)F)cc3)c2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(C(F)(F)F)cc1
Yield: 45 %

Procedure:
A solution of 4-Chloro-2-methylsulfinyl-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.29 g, 0.75 mmol) in dichloromethane (30 mL) was mixed with a solution of serinol (0.075 g, 0.82 mmol) in DMF (0.75 mL). The resultant mixture was stirred at room temperature for 1 hour before concentrated under vacuum. Flash chromatography (EtOAc:Hexane, 3:1) then provided the title compound (0.14 g, 45%): MS (ES) m/z 415 (M+H)+; 1H-NMR(CDCl3) δ 2.25 (s, br, 2H), 3.66 (m, br, 5H), 6.15 (m, br, 1H), 6.55 (d, J=9.2 Hz, 1H), 7.36 (m, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.92 (d, J=9.2 Hz, 1H).
Reaction SMILES: C([C:3]([C:12]#[N:13])([CH:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])[C:4]([OH:6])=[O:5])C.CO.[OH-].[Na+]>O1CCCC1>[C:12]([CH:3]([CH:7]([CH:9]1[CH2:10][CH2:11]1)[CH3:8])[C:4]([OH:6])=[O:5])#[N:13]
Reactant: CCC(C#N)(C(=O)O)C(C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C1CC1)C(C#N)C(=O)O
Yield: 86.1 %

Procedure:
39.8 g (0.22 mol) of ethyl 2-cyano-3-cyclopropylbutanoic acid were refluxed for 4 hours in a mixture of in each case 150 ml of methanol, tetrahydrofuran and 2 N sodium hydroxide solution. For working-up, 200 ml of 2 N sodium hydroxide solution were added and the mixture was extracted repeatedly with diethyl ether. The aqueous phase was subsequently acidified by adding hydrochloric acid and also extracted with ether. After this organic phase had been dried and concentrated, 29 g (yield 86%) of 2-cyano-3-cyclopropylbutanoic acid were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH:15]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH2:14][C@@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:7][CH:6]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: CCOC(=O)C(CCBr)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@H](CCOc1ccc(CCCO)cc1)NC(=O)OCc1ccccc1
Yield: 52.7 %

Procedure:
The mixture constituted by 306 mg of 4-hydroxybenzenepropanol, 770 mg of ethyl 4-bromo-2-[[(phenylmethoxy)carbonyl]amino]butanoate and 740 mg of Cs2CO3 in 10 ml of acetonitrile is heated under reflux for 45 minutes, the solid is filtered, washed with dichloromethane then the filtrate is evaporated under reduced pressure until 1.5 g of crude product is obtained which is purified by chromatography on a silica column (Kieselgel 60; 40-63 μm) eluting with a dichloromethane/methanol mixture 95/5. 440 mg of expected product is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1.[CH3:24][N:25]1[CH2:29][C:28](=O)[O:27]C1=O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O1CCOCC1>[OH:19][CH:17]([CH:13]1[C:12](=[O:20])[N:11]2[CH:14]1[C:15]([CH3:16])=[C:9]([S:8][CH:5]1[CH2:4][CH:3]([CH2:2][NH:1][C:28](=[O:27])[CH2:29][NH:25][CH3:24])[O:7][CH2:6]1)[CH:10]2[C:21]([OH:23])=[O:22])[CH3:18]
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Reactant: CN1CC(=O)OC1=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNCC(=O)NCC1CC(SC2=C(C)C3C(C(C)O)C(=O)N3C2C(=O)O)CO1

Procedure:
The title compound is prepared by the procedure of Example 47 using 0.068 g of product from Example 46 in 2.0 ml of sodium phosphate buffer (pH 8.5) and 0. 029 g of 3-methyl -2,5-oxazolidinedione, prepared by the procedure described in J. Org. Chem., 34, No. 1, 243(1969), in 1 ml of dioxane to give 0.036 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[NH2:14][OH:15]>CO.CC(O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[N:14][OH:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: NO
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(=NO)CCC2
Reaction time: 1 h

Procedure:
To a solution of 7-methoxytetralone (15 g) in MeOH (175 mL), NH2OH (50% in H2O, 15.7 mL) and AcOH (4 mL) was added. After stirring for 1 hour, the solution was concentrated until a solid began to appear. The reaction was poured into dilute aqueous NaHCO3 (500 mL), and the resulting solid was filtered to provide the title compound (17.8 g): 1H NMR (DMSO-d6) δ 11.08 (s, 1H), 7.35 (s, 1H), 7.08 (d, 1H), 6.84 (d, 1H), 3.71 (s, 3H), 2.62-2.49 (m, 4H), 1.77-1.64 (m, 2H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10]([O:12][N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.8 %

Procedure:
To a suspension of Fmoc-Phe (1.9442 g, 5.0186 mmol, 1.0 eq) and N-hydroxysuccinimide (0.6095 g, 5.2959 mmol, 1.06 eq) in methylene chloride (50 ml) cooled in an ice bath, was added DCC (1.0880 g, 5.2731 mmol, 1.05 eq). The mixture was stirred at room temperature overnight. The resulting DCU was removed by filtration and the filtrate was condensed and dried in vacuo to give 2.7664 g of white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]3[CH2:18][CH2:17][CH2:16][C:11]3=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1.C([Sn](CCCC)(CCCC)[C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)CCC>C1(C)C=CC=CC=1>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]3[CH2:18][CH2:17][CH2:16][C:11]3=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(Br)c3)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Solvent: Cc1ccccc1
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(-c4ccco4)c3)cc21

Procedure:
A suspension of the product obtained in Step A (200 mg, 0.50 mmol), 222 μl (0.66 mmol) of 2-(tributylstannyl)furan and 30 mg (0.025 mmol) of tetrakistriphenylphosphine in 4 ml of toluene is refluxed for 45 minutes. The toluene is evaporated off in vacuo and the residue is chromatographed on SiO2 (CH2Cl2/acetone 96/4) to yield the title product.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][CH2:4][NH:5][C:6]([C@H:8]1[O:12][C@@H:11]([N:13]2[C:17]3[N:18]=[C:19]([C:23]#[C:24][CH2:25][CH:26]4[CH2:31][CH2:30][CH:29]([C:32]([O:34]C)=O)[CH2:28][CH2:27]4)[N:20]=[C:21]([NH2:22])[C:16]=3[N:15]=[CH:14]2)[C@H:10]([OH:36])[C@@H:9]1[OH:37])=[O:7]>CO>[CH2:4]([NH:5][C:6]([CH:8]1[CH:9]([OH:37])[CH:10]([OH:36])[CH:11]([N:13]2[CH:14]=[N:15][C:16]3[C:17]2=[N:18][C:19]([C:23]#[C:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH:29]([C:32](=[O:34])[NH:2][CH3:1])[CH2:28][CH2:27]2)=[N:20][C:21]=3[NH2:22])[O:12]1)=[O:7])[CH3:3]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Reactant: CN
Solvent: CO
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CCC4CCC(C(=O)NC)CC4)nc32)C(O)C1O
Temperature: 70 °C
Reaction time: 120 h
Yield: 48 %

Procedure:
To a sealed tube containing 10 mL 2.0 M methylamine in methanol was added 16.5 mg (0.03 mmol) of ATL146e. The flask was sealed and allowed to stir at 70° C. for 120 hours. The vessel was cooled to 0° C., opened, and the solvent was removed in vacuo to yield 8.0 mg (48%) of JR3065 as a white solid after the residue was purified by RP-HPLC. 1H NMR (CD3OD-d4) 8. 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 486.3 (MH+, 100), 313.4 (35).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1>CN(C)C=O>[N:1]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: N#CCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(CN2CCCC2)cc1

Procedure:
0.446 mL (5.44 mmol) of pyrrolidine and 1.366 g (9.882 mmol) of potassium carbonate are added to 20 mL of dimethylformamide. 1.038 g (4.941 mmol) of (4-bromomethyl-phenyl)-acetonitrile are added with stirring and the mixture is stirred for 12 hours at RT. The reaction mixture is evaporated down in the rotary evaporator and the residue is extracted with EtOAc and water. The organic phase is dried over magnesium sulphate and the solvent is removed using the rotary evaporator.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[CH:7]=1
Reactant: COc1cccc(N)c1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc(OC)c2)c1
Yield: 82.8 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 3-methoxyphenylamine (0.189 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.44 g, 82%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.60 (3H, s), 3.71 (3H, s); 6.52-6.74 (3H, m); 6.63 (1H, d, J=16.0 Hz); 7.07 (1H, m); 7.43-8.05 (5H, m); 10.27 ppm (1H, br s).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][O:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[CH:21]=[N+:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:17][O:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[CH:21]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-methoxy-benzylidene)-piperidinium chloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH3:24][N:25]([CH3:30])[S:26]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:23])[CH2:15][CH2:14]1)(=[O:28])=[O:27]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: CN(C)S(=O)(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and dimethylsulfamoyl chloride
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[O:14][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)I
Reactant: Oc1c(Cl)cc(I)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(Cl)cc(I)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 2-iodopropane (3.7 g, 21.77 mmol, 1.00 equiv), 2,6-dichloro-4-iodophenol (5 g, 17.31 mmol, 0.80 equiv) and potassium carbonate (9.2 g, 66.09 mmol, 3.04 equiv) in N,N-dimethylformamide (50 mL) was stirred for overnight at 50° C. The resulting solution was diluted with 300 mL of ethyl acetate then washed with 3×100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with petroleum ether (100%) to give 4.6 g (64%) of 1,3-dichloro-5-iodo-2-isopropoxybenzene as a light yellow oil. 1H-NMR (300 MHz, CDCl3): δ 7.60 (s, 2H), 4.63-4.54 (m, 1H), 1.34 (d, J=5.1 Hz, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].I[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1
Reactant: CC(C)I
Reactant: Oc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoro-5-hydroxypyridine (6.000 g, 53.05 mmol) in N,N-dimethyl formamide (50 mL) cooled with an ice bath was added NaH (2.80 g, 60%, 70.0 mml) in several potions. After the addition, the mixture was stirred at 0° C. for 10 minutes. 2-iodopropane (6.5 mL, 65.00 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was poured into water, extracted with ether (2×), the combined extracts were washed with 1N NaOH (1×), water (1×), brine (1×), dried over MgSO4 and concentrated to give the product that was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:34][O:33][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][O:27]4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylic acid (103 mg) in DMF (2 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (35.8 mg), HOBt (48.8 mg), and EDCI (56.1 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1) to give (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (76 mg) as pale yellow form.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:9]2[CH:15]=[C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][C:10]=2[NH:11][N:12]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:7][C:8]1[C:9]2[CH:15]=[C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][C:10]=2[N:11]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[N:12]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc2c(N)n[nH]c2s1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(N)c2cc(C(=O)OC(C)(C)C)sc21
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
A solution of ethyl chlorocarbonate (4.90 mL, 51.7 mmol) in tetrahydrofuran (THF, 60 mL) was slowly added to a mixture of tert-butyl 3-amino-1H-thieno[2,3-c]pyrazole-5-carboxylate (12.0 g, 50.2 mmol) and diisopropylethylamine (DIEA, 51.5 mL, 301 mmol) in THF (300 mL), maintaining the temperature between −5 and −10° C. The reaction was kept at the same temperature for 5 minutes then allowed to reach room temperature. The obtained mixture was evaporated to dryness under vacuum and the residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The resulting raw material was triturated with diethyl ether to give 13.7 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([CH:6]=[C:7]([CH3:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[NH2:5].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24].CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:5][C:26]([NH:25][C:23](=[O:24])[C:22]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:21]=2[F:20])=[O:27])[CH:6]=[C:7]([CH3:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)cc1Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2c(F)cccc2F)c(C)c(Cl)c1Oc1ccc(Cl)cc1Cl
Yield: 96.8 %

Procedure:
Into a magnetically stirred solution of 3-chloro-4-(2,4-dichlorophenoxy)-2,5-dimethylaniline (1.5 grams, 4.73 mmol) prepared in Part B in toluene (15 milliliters) under nitrogen atmosphere was added neat 2,6-difluorobenzoyl isocyanate (1.3 grams, 7.10 mmol) and the mixture was refluxed for a period of 1 hour. The reaction mixture was allowed to cool and hexane (3 milliliters) was added to induce crystallization. The resultant precipitate was filtered and washed successively with hexane and toluene to give pure 1-[3-chloro-4-(2,4-dichlorophenoxy)-2,5-dimethylphenyl]-3-(2,6-difluorobenzoyl) urea (2.29 grams, 4.58 mmol, 97%) as a white solid having a melting point of 188° C.-190° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[C:12]([O:14][CH3:15])=[O:13])[C@H:3]1[OH:24].[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C.C(Cl)(=O)OCC.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:17]([O:16][C:7]1[C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[C@@H:3]([OH:24])[C@H:2]([NH:1][C:25]([O:28][CH2:29][CH3:30])=[O:27])[CH2:11][CH2:10]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2C(=O)OC)[C@H]1O

Procedure:
To a solution of 1.0 g. of trans-2-amino-6-benzyloxy-1-hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene in 20 ml. of ethyl acetate are added 5 ml. of water and 400 mg. of ethyl chlorcarbonate, and with stirring at room temperature, 1.0 g. of anhydrous potassium carbonate is added in small portions. After one-hour stirring, the organic layer is recovered, washed with water, dried and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-n-hexane to obtain trans-6-benzyloxy-2-ethoxycarbonylamino-1-hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene as colorless needles melting at 147°-148° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[CH3:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[C:26](N)[CH:27]=[CH:28][CH:29]=2)[N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[N:24]=[C:23]([CH3:22])[CH:32]=[CH:31]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cc1ccc2cccc(N)c2n1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3ccc(C)nc23)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 66 mg (0.417 mmol) of 2-methylquinolin-8-amine was added. The resulting mixture was stirred at room temperature for one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (97 mg, 93.3% yield).