Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.S(Cl)(Cl)=[O:3].[CH3:6][C@H:7]1CN[C@H:10](C)[CH2:9][NH:8]1.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:7]([N:8]([CH2:9][CH3:10])[C:20](=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:6]
Reactant: Cc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H]1CN[C@@H](C)CN1
Agent: Cl
Product: CCN(CC)C(=O)c1ccccc1

Procedure:
The product (25 mmol) was treated with 2M ethanolic hydrochloric acid (20 mL). The solvent was evaporated and the residue shaken with toluene and evaporated again to remove residual ethanol. The resulting yellow solid was suspended in dichloromethane, 2.7 mL (37.5 mmol) of thionyl chloride was added, and the mixture was stirred at room temperature for one hour. The solvent was evaporated, and the residue was taken up in toluene and evaporated again to drive off the excess thionyl chloride. The crude product (approximately 25 mmol) was then treated with trans-2,5-dimethylpiperazine (28.5 g, 0.25 mol) in toluene as described in Example1. The product was purified by chromatography on silica gel (Waters Prep 500, dichloromethane:ethanol:triethylamine/100:1.5-3:0.1), to give 3.71 g (38%) of (±)-4-α-(trans-2,5-dimethyl-1-piperazinyl)-3-aminobenzyl)-N,N-diethylbenzamide as a yellow solid.
Reaction SMILES: ClC1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][CH3:19])=[O:5].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33].Cl[CH2:40][Cl:41]>>[C:32]([N:18]([CH3:19])[NH:17][C:12]1[C:11]2[C:16](=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:40]=3[Cl:41])[CH:8]=[CH:9][CH:10]=2)[N:15]=[CH:14][CH:13]=1)(=[O:34])[CH3:33]
Reactant: CNNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: ClCCl
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 240 h

Procedure:
To a stirred suspension of 8-(2,6-dichlorobenzoylamino)-4-(2-methylhydrazino)quinoline (500 mg) and triethylamine (700 mg) in dichloromethane (5 ml) was added acetic anhydride (155 mg) at ambient temperature, and the mixture was allowed to stand for 10 days at the same temperature. The mixture was diluted with dichloromethane, washed with water and evaporated in vacuo. The obtained residue was dissolved in methanol (10 ml), and a 28%0 solution of sodium methoxide in methanol (0.53 ml) was added thereto under ice-cooling. The mixture was stirred for 1 hour at the same temperature, and neutralized with 1N hydrochloric acid. The mixture was concentrated in vacuo and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate) and crystallized from ethanol to give 4-(2-acetyl-2-methylhydrazino)-8-(2,6-dichlorobenzoylamino)quinoline (544 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Na+].O.C(O)(=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=C([O-])c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Reaction time: 5 h

Procedure:
Sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (3.0 g) was suspended in ethyl acetate (100 ml) and water (100 ml) with stirring. Acetic acid (1.0 ml) was added to give two clear phases which were separated. The ethyl acetate layer was dried over magnesium sulfate and concentrated to give an oil which crystallised after a few minutes. Toluene (100 ml) was added and the solution was re-evaporated to give a white solid. Left at 20 mBar for 5 hours at 45° C. 2.69 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][Br:8])([O-:3])=[O:2].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Br-:8].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
A solution of 3-nitrobenzylbromide (5 gm, 23 mmol) and triphenylphosphine (6.1 gm, 23 mmol) were stirred in toluene at 75° C. for 6 hr. After cooling to rt, the crystalline product was isolated by filtration. The product was washed with toluene and dried in vacuo.
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:4]([OH:6])=[O:5])#[N:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[OH:26].CCN=C=NCCCN(C)C.Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([CH:3]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:4]([O:6][CH2:18][CH3:19])=[O:5])#[N:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[O:26][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: N#CC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)C(C#N)Cc1c[nH]c2ccccc12
Product: N#CC(Cc1c[nH]c2ccccc12)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Cyano-3-(3-indolyl)propionic acid from Step a, 2,4,5-trichlorophenol (394 mg, 2 mmol) and EDCl (392 mg, 2 mmol) were combined in methylene chloride (10 mL) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was added to 20 mL of 10% citric acid solution and the aqueous mixture was extracted with methylene chloride. The methylene chloride was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1:4 to 1:2) to give 210 mg (37% yield from ethyl 2-cyano-3-(3-indolyl)propionate) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][O:8][CH2:9]Cl)=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[N:16][C:17](=[O:20])[NH:18][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][O:8][CH2:9][N:18]2[CH:19]=[C:14]([Cl:13])[CH:15]=[N:16][C:17]2=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(COCCl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Product: COc1ccc(COCn2cc(Cl)cnc2=O)cc1
Yield: 52 %

Procedure:
was prepared as described in Example 3 from chloromethyl 4-methoxybenzyl ether (see Preparation 4a and 4b) (10 mmol) and 5-chloropyrimidin-2-one (10 mmol) in 52% yield (1.45 g), m.p. 118° C. 1H NMR (CDCl3): δ3.77 (OMe), 4.57 (CH2Ph), 5.27 (CH2O), 6.6-7.3 (Ph), 7.63 and 8.35 (H-4, H-6, J 4 Hz). IR(KBr): 1670 cm1 (CO).
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH2:20]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(O)C(C)C>[CH2:20]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:37][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCc1cccc(NCCCCOCc2ccccc2)c1
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CC(C)CO
Product: OC[C@H]1O[C@@H](n2c(NCc3cccc(NCCCCOCc4ccccc4)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Yield: 30.5 %

Procedure:
2-Chloro-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.14 g) and 3-(4-benzyloxybutylamino)benzylamine (0.36 g) were suspended in isobutanol (5 mL). To the mixture was added triethylamine (0.56 mL), and the mixture was refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (0.08 g).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Br[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([CH3:49])([CH3:48])[CH2:43]1)=O>>[CH3:48][C:44]1([CH3:49])[CH2:45][CH2:46][CH2:47][N:42]([CH2:40][CH2:39][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:43]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCC(C)(C)C3)cc2)c1
Yield: 101.7 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: NC(N)=O.[CH:5]([OH:7])=[O:6].[NH:8]1CC[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11]>O.Cl.NC(N)=N>[NH2:8][C@H:9]([C:10]([OH:12])=[O:11])[CH2:13][C:5](=[O:7])[OH:6]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=CO
Agent: Cl
Agent: N=C(N)N
Agent: NC(N)=O
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
An aliquot (30 ul) of the urea soluble fraction was diluted with ten volumes of water, and the insoluble fusion protein was pelleted by centrifugation. The protein was then dissolved in 30 ul of 6M guanidine hydrochloride, and 70 ul 98% formic acid added (Digestion 1). In a parallel experiment, 70 ul 98% formic acid was added to an aliquot (30 ul) of the urea fraction directly (Digestion 2). Following two days incubation at 42° C., ten volumes of water were added, and the insoluble proteins were pelleted by centrifugation. The pellet was resuspended in 1X treatment buffer (100 ul), and 10 ul was used per well on 12.5% SDS-polyacrylamide gel. FIG. 10 shows a sample of the cleaved products (Digestion 1 and Digestion 2) both on a Commassie-stained gel and an immunoblot (using HIVI positive human serum as primary antibody). Only two major bands are visible on the Commassie-stained gel. These represent the products of cleavage at the unique Asp-Pro bond: the CKS portion, MW=26.5 kDa and the p41 portion, MW=23.5 kDa. Peptide sequencing confirmed that the lower molecular weight band was indeed the p41 peptide, and that the amino terminal residue was proline which results from expected cleavage between the Asp and Pro.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:13][CH2:14][C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[SH:26]>C1COCC1.O>[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[S:26][CH2:13][CH2:14][C:15]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:16]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=C(Cl)CCBr
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1SCCC(=O)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a solution of K2CO3 (3.6 g, 26 mmol) in THF (20 ml) was added pyrrolidine (2.1 ml, 26 mmol) at room temperature, then the mixture was cooled to −78° C. and 3-bromopropanoyl chloride (1.0 g, 5.83 mmol) was added slowly. After it was stirred for 30 min, 2-amino-4-chlorobenzenethiol (837 mg, 5.24 mmol) was added to the mixture and the reaction was stirred at room temperature for 3 hours. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0˜30% EtOAc in hexane) to yield the title compound (760 mg, 46%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13]2[N:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15]([O:17][CH2:18]C)=[O:16])=[CH:2]1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:32])C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:13]3[N:23]=[CH:22][CH:21]=[CH:20][C:14]=3[C:15](=[O:16])[O:17][C:18]2=[O:32])=[CH:2]1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NCCc1c[nH]c2ccccc12
Product: O=c1oc(=O)n(CCc2c[nH]c3ccccc23)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 60A for the product of Example 3A (0.164 g, 53%). MS (DCI) m/z 325 (M+NH4)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][CH:26]([C:28]1[S:32][C:31]([CH:33]=[O:34])=[N:30][CH:29]=1)[CH3:27].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:33]([C:31]3[S:32][C:28]([CH:26]([OH:25])[CH3:27])=[CH:29][N:30]=3)=[O:34])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(O)c1cnc(C=O)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Yield: 93.7 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.00 g), 5-(1-hydroxyethyl)-1,3-thiazole-2-carbaldehyde (0.47 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (77 mg), triethylamine (0.16 mL), tetrahydrofuran (6 ml) and ethanol (6 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate, and the fraction was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.36 g, yield 94%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 506 (MH+).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[O-:16][CH2:17][CH3:18].[Na+].O>C(O)C>[CH2:17]([O:16][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:18]
Reactant: CC[O-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 2-nitro-4-trifluoromethyl-benzonitrile (71.7 g, 318.5 mmol) in anhydrous ethanol (400 mL) at room temperature was added sodium ethoxide (238 mL, 637 mmol, 21% solution in ethanol) dropwise over a period of 30 min. The reaction mixture was stirred at room temperature for 1 h. Water (1 L) was added, and the mixture was stirred for 15 min. The solids were filtered off, washed with water, and dried in the vacuum oven (40° C.) overnight to give 2-ethoxy-4-trifluoromethyl-benzonitrile (64 g, 93% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[C:11](Cl)=[N:12][CH:13]=[C:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:15]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:11]1[C:10]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:15][C:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:13][N:12]=1
Reactant: OB(O)c1ccco1
Reactant: Clc1ncc(Cn2ccnc2)cc1Br
Product: c1coc(-c2cc(Cn3ccnc3)cnc2-c2ccco2)c1

Procedure:
Synthesized using 2-furanylboronic acid (123 mg, 1.10 mmol) and 6 (150 mg, 0.55 mmol) according to Method C. Yellow solid. Yield: 108 mg, 0.37 mmol, 67%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.19 (s, 2H), 6.26 (dd, J=3.5, 0.6 Hz, 1H), 6.41 (dd, J=3.5, 0.9 Hz, 1H), 6.41-6.48 (m, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.12 (bs, 1H), 7.49-7.50 (m, 2H), 7.60 (bs, 1H), 7.61 (d, J=2.2 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=47.9, 110.0, 111.6, 111.7, 111.7, 119.0, 124.8, 130.0, 130.4, 136.0, 137.3, 142.8, 143.3, 146.8, 147.4, 149.9, 151.7; MS (ESI): m/z=292.09 [M+H]+.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[O:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[N:10]1.C(N(C(C)C)C(C)C)C>C(O)C>[O:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:2]2[CH2:6][S:5][C:4](=[O:7])[N:3]=2)=[N:10]1
Reactant: NCc1ccon1
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2ccon2)CS1
Yield: 49.5 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (700 mg) in ethanol (20 mL) were added (isoxazol-3-ylmethyl)amine hydrochloride (707 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.42 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (513 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1cccc(OC)c1
Yield: 54 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (103 mg, 0.368 mmol) was reacted with 3-methoxy phenyl boronic acid (2 eq) to give 3-[2-(3-methoxy-phenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid ethyl ester (70 mg, 54%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.Cl.Cl[CH2:24][CH2:25][N:26]([CH2:28][CH2:29]Cl)[CH3:27].O>O1CCCC1>[Br:11][C:12]1[CH:20]=[C:19]2[NH:18][C:17](=[O:21])[C:16]3([CH2:29][CH2:28][N:26]([CH3:27])[CH2:25][CH2:24]3)[C:15]2=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: CN(CCCl)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 9.40 mL, 9.40 mmol) was added dropwise to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 0.40 g, 1.89 mmol) in tetrahydrofuran (4 mL) at −78° C. The mixture was stirred for 30 minutes, then 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (0.36 g, 1.89 mmol) was added and the mixture was warmed to room temperature. After stirring overnight, water was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated. Purification of the residue by reverse phase chromatography (0% CH3CN in H2O to 100% CH3CN in H2O) gave the title compound as a yellow oil (0.17 g, 31%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].N1C[CH2:15][CH2:14][CH2:13]1.CC(C)=O>C1(C)C=CC=CC=1>[OH:11][C:7]1[CH:8]=[C:9]2[C:4]([C:2](=[O:3])[CH2:1][C:14]([CH3:15])([CH3:13])[O:10]2)=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: CC(=O)c1ccc(O)cc1O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2ccc(O)cc2O1
Yield: 33.8 %

Procedure:
To a solution of 2,4-dihydroxy acetophenone (6.00 g, 39.4 mmol) and pyrrolidine (15.0 mL, 181 mmol) in toluene (200 mL), acetone (22.9 g, 394 mmol) was added. After heated to reflux for 16 hrs, the solvents were removed and the residue was added HCl (2.0 N, 100 mL) and brine (200 mL) then the mixture was extracted with EtOAc (150×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by SGC (eluting with petroleum ether/ethyl acetate=6/1) to give target compound (2.56 g, 33%) as a brown yellow solid. LCMS (ESI) m/z: 191.1 [M−H]+; 1H-NMR (500 MHz, CDCl3): δ 7.79 (d, J=8.0 Hz, 1H), 6.49 (dd, J=8.5, 2.0 Hz, 1H), 6.36 (d, J=2.0 Hz, 1H), 2.68 (s, 2H), 1.45 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClOC(C)(C)C.[CH2:15]([S:17][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])[CH3:16].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:19](=[O:20])[C:18]2([CH2:23][CH2:22][OH:21])[S:17][CH2:15][CH3:16]
Reactant: CCSC1CCOC1=O
Reactant: Nc1ccc(Cl)cc1
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCSC1(CCO)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the stirred solution of 5.6 g p-chloroaniline in 150 ml of methylene chloride is added dropwise 4.7 ml of t-butyl hypochlorite in 20 ml of methylene chloride at -65°. After ten minutes, the solution of 5.75 g of 2-ethylmercaptobutyrolactone in 20 ml of methylene chloride is added dropwise and the temperature held at -65° for two hours. Then the solution of 6.1 ml of triethylamine in 20 ml of methylene chloride is added dropwise and the mixture is allowed to warm up to room temperature. 50 ml of water are added with stirring and the precipitate filtered off, to yield the 5-chloro-3-(2-hydroxyethyl)-3-ethylmercapto-2-oxindole melting at 132°-135°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[O:10][C:11]1[C:16]([F:17])=[C:15](F)[N:14]=[CH:13][N:12]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[N:35][O:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32]>C(#N)C>[Cl:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[O:10][C:11]1[N:12]=[CH:13][N:14]=[C:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30](=[N:35][O:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])[C:16]=1[F:17]
Reactant: CON=C(C(=O)OC)c1ccccc1O
Reactant: Fc1ncnc(Oc2ccccc2Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CON=C(C(=O)OC)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
40 g (0.29 mol) of ground potassium carbonate and 58 g (0.24 mol) of 4-(2-chlorophenoxy)-5,6-difluoropyrimidine are added to a solution of 50 g (0.24 mol) of methyl 2-(2-hydroxyphenyl)-2-methoxyiminoacetate in 600 ml of acetonitrile, and the mixture is stirred at 25° C. for 18 hours. The reaction mixture is poured into 3 l of ice-water and the resulting solid is filtered off with suction. This gives 102 g (98.7% of theory) of methyl 2-{2-[6-(2-chlorophenoxy)-5-fluoro-pyrimidin-4-yloxy]-phenyl}-2-methoxyiminoacetate.