Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[O:5].C([O-])(O)=O.[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[CH2:22]([O:21][C:19]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCC(N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A 2 L 3-necked flask equipped with a magnetic stirrer and a thermometer was charged with 25.0 g of glutamic acid γ-ethyl ester (Sigma Chemical Co., St. Louis, Mo., 63178) and 1 L of distilled water. The solution was heated to 60° C. with stirring and treated with 30 g of NaHCO3 followed by 25 mL of benzyl chloroformate (Aldrich). The flask was allowed to cool to RT and stirring was continued for 2 h. The mixture was extracted with ethyl ether (5×100 mL) and the ether extracts were discarded. The aqueous phase was acidified to a congo red end point by addition of concentrated aqueous HCl and the resulting emulsion was extracted with CH2Cl2 (5×100 mL). The combined CH2Cl2 extracts were washed with 0.05 N aqueous HCl (2×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to a volume of 50 mL. The solution was chilled in an ice water bath and triturated with addition of 200 mL of pentane. The resulting solid was collected by vacuum filtration and dried in vacuo to afford 37.0 g (83%) of N-((benzyloxy)carbonyl)5-O-ethyl-L-glutamic acid as a white powder, m.p. 82-84° C.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13])=[O:5].[C:25](Cl)(=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>N1C=CC=CC=1>[C:25]([O:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][N:7]1[C:8](=[O:13])[CH2:9][CH2:10][C:11]1=[O:12])=[O:5])(=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCC(O)CC(=O)ON1C(=O)CCC1=O
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCC)CC(=O)ON1C(=O)CCC1=O

Procedure:
To a solution of 5.6 g of N-[3(R,S)-hydroxytetradecanoyloxy]succinimide in 150 ml pyridine cooled to 0° are added 4.9 g of tetradecanoylchloride and the reaction mixture maintained at 4° for 12 hours. Excess reagent is destroyed with water, the mixture concentrated by evaporation and the residue chromatographed over silica gel (toluene/ethylacetate=95/5) to obtained the title compound as a syrup.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C3SC=CC=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:55])[C:35]([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)C>C(O)C>[C:11]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:10]=[CH:9][CH:8]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([CH2:18][CH2:19][O:20][C:40]3[C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:37]([CH2:36][C:35]([CH3:47])([O:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:34]([OH:33])=[O:55])=[CH:38][CH:39]=3)[N:4]=2)[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1cccc2ccccc12)Oc1ccccc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)c2ccccc12
Temperature: 55 °C
Yield: 7 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 3, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (see Ex. 12, Part B) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100·1) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of hew hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150·1), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to produce a white solid (7%). MS [EI+] 590 (M+H)+, [EI−] 588 (M−H)+
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[NH2:19])=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1.[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[NH:19][S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])=[CH:12][CH:13]=1
Reactant: NC1CCCC1c1ccc(Cl)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(4-chloro-phenyl)-cyclopentylamine oxalate salt (200 mg, 0.70 mmol), methylene chloride (5.0 mL) and the solution was cooled to 0° C. DBU (0.84 mL, 5.60 mmol) and isopropylsulfonyl chloride (0.47 mL, 4.20 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 116 mg (55%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@H:14]([CH3:15])[CH2:13][N:12]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)=[O:17])[C@@H:11]([CH3:28])[CH2:10]2)=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].O.[Cl-].[NH4+]>CO.[Fe]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]([N:12]2[CH2:13][C@@H:14]([CH3:15])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:5]=3)[CH2:10][C@@H:11]2[CH3:28])=[O:17])=[CH:24][CH:23]=1
Reactant: C[C@@H]1CN(C(=O)Nc2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(C(=O)Nc2ccc(N)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
A 450 mg portion of trans-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethyl-4′-nitropiperazine-1-carboxanilide synthesized in Example 1-4 was dissolved in 8 ml of methanol, and the solution was mixed with 4 ml of water, 280 mg of iron powder and 30 mg of ammonium chloride and heated under reflux for 5 hours. The reaction solution was again mixed with 280 mg of iron powder and 30 mg of ammonium chloride and further heated under reflux for 2 hours. The reaction solution was filtered through celite, and the solvent in the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine in that order and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by a silica gel column chromatography (methanol-chloroform) to obtain 260 mg of the title compound as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:28]=[C:27]([CH3:29])[O:26][N:25]=4)=[CH:20][C:19]=3[CH3:30])=[CH:14][CH:13]=2)=[O:11])=[CH:5][C:4]=1[N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1.Cl.N1C=CC=CC=1>C(=O)(O)[O-].[Na+]>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:28]=[C:27]([CH3:29])[O:26][N:25]=4)=[CH:20][C:19]=3[CH3:30])=[CH:16][CH:17]=2)=[O:11])=[CH:5][C:4]=1[N:31]1[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1
Reactant: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1N1CCN(C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(O)c(N5CCN(C)CC5)c4)cc3)c(C)c2)no1
Yield: 30.5 %

Procedure:
A mixture of the product of Example 1 (91 mg) and pyridine hydrochloride (2 g) was heated to 180°-190° for 8 h. Sodium bicarbonate (8%; 30 ml) was added and the mixture extracted with dichloromethane (2×25 ml). The dried extracts were evaporated to give a dark oil. This material was chromatographed on silica gel (Merck 7729, 10 g) eluting with System A (200:8:1) to give the title compound as a colourless foam (27 mg).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][OH:7])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cn1c(CO)c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (0.26 g) was added to a solution of the product from Example 27 step b) (0.5 g) in DMF (5 ml) and the solution stirred at room temperature for 20 mins. Water (5 ml) was added and the mixture stirred for a further 30 mins. The reaction was diluted with further water (50 ml), extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid Filtered off and dried to yield the title compound as a white solid (48 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.O.N.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2nc(O)ccc2c1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2nc(Cl)ccc2c1
Temperature: 115 °C
Yield: 98 %

Procedure:
A solution of 2,6-quinolinediol 10 (5 g) in POCl3 (21 ml) and DMF (3.4 ml) is stirred for 12 h at room temperature, then heated for 1 h at 115° C. The reaction is poured into water (100 ml) at 0° C. and neutralized with a 32% aqueous NH3 solution. The solid obtained by filtration is washed with acetone, and the resulting organic phase is evaporated to give 2-chloro-6-quinolinol 11 as a solid. No further purification is needed.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([NH:15][S:16]([CH:19]([CH:24]([CH3:26])[CH3:25])[C:20]([O:22][CH3:23])=[O:21])(=[O:18])=[O:17])[N:8]=1.N1C=CC=CC=1>ClCCl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([N:15]([C:1](=[O:3])[CH3:2])[S:16]([CH:19]([CH:24]([CH3:26])[CH3:25])[C:20]([O:22][CH3:23])=[O:21])(=[O:18])=[O:17])[N:8]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)C(C(C)C)S(=O)(=O)Nc1nc(OC)cc(OC)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C(C)C)S(=O)(=O)N(C(C)=O)c1nc(OC)cc(OC)n1
Reaction time: 2 h

Procedure:
Acetyl chloride (0.35 g) was added to a stirred, cooled mixture of the product of Example 1 (1.5 g) and pyridine (0.39 g) in dichloromethane (20 ml). Stirring was continued for 2 hours and the mixture was allowed to stand overnight. The organic solution was washed with water (twice), dried over magnesium sulfate and run down under vacuum. The residue was triturated with ether to yield a white solid, 0.38 g (23%), mp 100°-101.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:24]=2)=[O:42])=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(CS(=O)c2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfanyl)phenyl]-1-benzofuran-2-sulfonamide (124 mg, 0.237 mmol) in CH2Cl2 (5 ml) was added mCPBA (57 mg, ˜0.237 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly loaded onto Celite and purified by flash column chromatography on silica gel (50-100% EtOAc in hexane) to yield the title compound (78 mg, 61%).
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([NH2:33])[N:30]([CH3:34])[N:29]=2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:32]=[C:31]([NH:33][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)[N:30]([CH3:34])[N:29]=2)=[CH:26][CH:27]=1
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1N
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2ccc(Cl)cc2)cc1NCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-(4-chlorophenyl)-1-methyl-1H-pyrazole-5-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=20:1) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:17][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[CH2:6][CH2:7][N:8]2[C:12](=[O:15])[CH2:13][CH3:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCC(=O)c2c1ccc(O)c2Cl
Yield: 91.5 %

Procedure:
A solution of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.643 g) and N-chlorosuccinimide (1.068 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residual solid was recrystallized from chloroform to give 5-chloro-6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.74 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:4]=2[O:3]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[OH-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:12][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][C:4]=2[O:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC1(C)CCc2ccc(O)cc2O1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)CCc2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Temperature: 110 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
2,3-Dihydro-2,2-dimethyl-7-hydroxy-4H-1-benzopyran (2.0 g) synthesized as in Referential Example 19, 1.8 g of p-chloronitrobenzene, 0.9 g of potassium hydroxide, 20 ml of N,N-dimethylformamide and 10 ml of toluene were put into a flask equipped with the DeanStark condenser, and were heated to 110° C. While removing evaporated water as an azeotrope with toluene, the reaction was carried out for 1 hour. After cooling, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvents were evaporated. The residue was purified by column chromatography to give 2.8 g (yield 84%) of the desired product as a brown liquid.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:44]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:44])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OCCCSC)cc3)oc2C)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OCCCS(C)=O)cc3)oc2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(2-methyl-5-{4-[3-(methylsulfanyl)propoxy]phenyl}furan-3-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.37 g) synthesized in Example 259 (1) was dissolved in methanol (9 mL) and water (1 mL), OXONE (221 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (283 mg, 91%) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(CC(=O)OC)cn2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(CC(=O)O)cn2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 8, (700 mg, 1.56 mmoles) was taken up in a mixture of THF (14 ml), 2 eq. 1N NaOH (3.3 ml) and H2O (10 ml). The reaction mixture was stirred at room temperature under N2 for 2 hours. The THF was removed in vacuo. The aqueous phase was extracted with ether, then acidified with HCl and extracted into CHCl3. The combined organic extracts were dried and concentrated. The residue was triturated with ether to afford the title compound, m.p. 154°-156°. Analysis, calculated: C, 57.92; H, 5.79; S, 7.36. Found: C, 57.93; H, 5.83; S, 7.59.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccccc2)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:36]I>C1(C)C=CC=CC=1.CC#N>[F:1][C:2]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([F:11])[CH2:3][I:36]
Reactant: OCC(F)(F)c1ncccn1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: FC(F)(CI)c1ncccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
A homogeneous solution of 2,2-difluoro-2-pyrimidin-2-yl-ethanol (689 mg, 4.31 mmol), as prepared in the previous step, PPh3 (1.69 g, 6.44 mmol), and imidazole (590 mg, 8.67 mmol) in toluene (5.8 mL) and CH3CN (2.9 mL) was stirred at 0° C. for 5 min, and was then treated with I2 (1.61 g, 6.34 mmol) in two portions and stirred at 0° C. for another 5 min. The resulting brown opaque slurry was then heated at 90° C. for 19 h, and then allowed to cool to rt. The mixture was filtered, the beige filter cake was washed with toluene (3×10 mL), and the combined brown filtrates were concentrated. Silica flash chromatography of the residue (2:1 hex/EtOAc eluent) afforded the title compound as a pale yellow oil (849 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:23]2[O:24][C:25]([CH2:28]Cl)=[N:26][N:27]=2)[CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2[O:24][C:25]([CH2:28][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH2:13][CH2:14][CH3:15])=[N:26][N:27]=2)[CH:20]=[N:19][CH:18]=1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.3 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.46 (s, 1H), 7.97 (s, 1 H), 7.81 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 5.96 (s, 2H), 2.95-2.87 (m, 2H), 1.75-1.48 (m, 2H), 0.93 (t, J=7.3 Hz, 3H); MS (ES) m/z 457 (M+1).