Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([P:3]2(=[O:17])[CH2:15][CH2:16][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:18]([O:26][CH2:27][CH3:28])=[O:25])[CH2:2][CH2:1]2)[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (INTERMEDIATE 58) (0.45 g, 1.78 mmol) and diethyl malonate (0.285 g, 1.78 mmol) were added to a 15 mL round-bottomed flask. DMSO (10 mL) was added to give a brown solution. Potassium carbonate (0.368 g, 2.67 mmol) was added. The reaction was heated to 75° C. and stirred at that temp for 1 h. The reaction was cooled to RT, and the solution was poured into an HCl solution (1N, 40 mL). The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were dried (Na2SO4) and concentrated to give the crude product. The crude product was added to a silica gel column (40 g) and eluted with MeOH/DCM (0-5%). The collected fractions were concentrated to give the product (0.3 g, 41%).
Reaction SMILES: [CH2:1]([C:4]1([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=O)[C:7]2=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]=[N+]=[N-])=[CH:10][CH:11]=[C:6]2[CH2:5]1)[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:4]1([CH2:19][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:7]2=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][CH:11]=[C:6]2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)N2CCCCC2)Cc2ccc(OCCCN=[N+]=[N-])cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1(CN2CCCCC2)Cc2ccc(OCCCN)cc21

Procedure:
A solution of 1-allyl-5-(3-azidopropoxy)1-(1-piperidinylcarbonyl)benzocyclobutene (19.5 g) in THF (200 ml) is added dropwise to a stirred suspension of LAH (5.26 g) in THF (82 ml) under nitrogen. The reaction mixture is refluxed for one hour, quenched with water, 15% aqueous NaOH and water, filtered and evaporated in vacuo affording an oil which is chromatographed (silica gel: 5% triethylamine/methanol) affording the desired product as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:8])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
(E)-4-formyl-N-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}benzamide (100 mg, 0.27 mmol) was dissolved in methanol (1.1 mL) and the solution was added with sodium borohydride (120 mg, 2.72 mmol), stirred at room temperature for 1 hour, added with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 79 (10 mg, 10%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:14][N:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:12]2)[CH:7]=[C:6]([CH3:19])[C:5]=1[C:20]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([O:41]C)=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1>O.C(O)(C)C>[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:14][N:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH2:12]2)[CH:7]=[C:6]([CH3:19])[C:5]=1[C:20]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CN(S(C)(=O)=O)C6)cc5C)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(OC2CN(S(C)(=O)=O)C2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Aqueous NaOH solution (1 M; 39 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(1-(methylsulfonyl)azetidin-3-yloxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-1, 50 mg) in water (0.5 mL) and isopropanol (0.5 mL) at ambient temperature. The mixture is stirred at ambient temperature for 12 hours. The mixture is concentrated and acidified with 10% aqueous citric acid solution. The resulting mixture is extracted with dichloromethane, and the extract dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:30→0:100) to give the title compound. Yield: 35 mg.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8])=[CH:5][NH:4][C:3]=1[C:13]([O:15]C)=O.[OH-].[Li+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][CH2:53][C:54]1[C:55]([F:71])=[C:56]([O:61][C:62]2[CH:63]=[C:64]([CH:67]=[C:68]([Cl:70])[CH:69]=2)[C:65]#[N:66])[C:57]([Cl:60])=[CH:58][CH:59]=1>C1COCC1.O.CN(C=O)C>[Cl:1][C:2]1[C:6]([C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8])=[CH:5][NH:4][C:3]=1[C:13]([NH:52][CH2:53][C:54]1[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([O:61][C:62]2[CH:63]=[C:64]([C:65]#[N:66])[CH:67]=[C:68]([Cl:70])[CH:69]=2)[C:55]=1[F:71])=[O:15]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: COC(=O)c1[nH]cc(C(=O)NCCO)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cc(C(=O)NCCO)c3Cl)c2F)c1
Temperature: 35 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of methyl 3-chloro-4-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate (0.048 g, 0.195 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (0.047 g, 1.946 mmol). The reaction mixture was stirred overnight at 35° C. The solvent was evaporated and the resulting solid placed under high vacuum. To the intermediate mixture was added DMF (1 mL), HATU (0.089 g, 0.234 mmol), DIPEA (0.051 ml, 0.292 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.061 g, 0.195 mmol). The solution was stirred for 4 h at RT. Purification was accomplished by HPLC. The desired fractions were neutralized with saturated sodium bicarbonate, extracted with EtOAc (3×5 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated to afford 3-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N4-(2-hydroxyethyl)-1H-pyrrole-2,4-dicarboxamide (0.039 g, 38% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.25 (br. s., 1H) 8.15 (t, 1H) 7.83 (d, 1H) 7.78 (t, 1H) 7.51-7.56 (m, 2H) 7.48 (dt, 2H) 7.37 (t, 1H) 4.57 (d, 2H) 3.46 (t, 2H) 3.25 (q, 2H). MS: m/z 525.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.[N+:16]([C:19]1[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[N+:16]([C:19]1[CH:20]=[C:21]([CH2:25][C:26]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH3:15])=[O:27])[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1cccc([N+](=O)[O-])c1)CC2
Yield: 64 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (20.0 g, 0.096 m) in methylene chloride (300 ml) under nitrogen at ambient temperature was added m-nitrophenylacetic acid (17.5 g, 0.096 m) and then portionwise dicyclohexylcarbodiimide (20.7 g, 0.1 m) and the mixture stirred for 3 hours. The precipitated solid was removed by filtration and the filtrate evaporated to an oily residue. This was treated with 100 ml methanol and 50 ml ether and the solid precipitate collected by filtration and washed with methanol and dried to give N-(3-nitrophenylacetyl)- 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as a yellow solid, 22.0 g (64% yield), m.p. 120°-121°.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:18][C:19]1[C:20]([CH3:36])=[N:21][O:22][C:23]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][S:30][C:29]=1[C:33]([NH2:35])=[O:34])(=[O:27])=[O:26].[H-].[Na+]>O>[Br:18][C:19]1[C:20]([CH3:36])=[N:21][O:22][C:23]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][S:30][C:29]=1[C:33]([NH:35][S:1]([C:4]1[C:16]2[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[O:34])(=[O:27])=[O:26]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(N)=O)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
Dansylchloride (90.2 mg, 0.328 mmol) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfonamide (Example 89) (100 mg, 0.273 mmol) and NaH (43.7 mg, 60% dispersion in mineral oil, 1.10 mmol). The reaction was stirred at room temperature for 1 hour. Water was added to quench the reaction and THF was stripped off on a rotavap. The aqueous residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4). The solid was filtered and the filtrate concentrated. The residue was recrystalized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(5-dimethylamino-1-naphthyl)sulfonylaminocarbonyl]thiophene-3-sulfonamide (55 mg., 34% yield) as a white powder (m.p. 184°-186° C.).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10](=[CH2:13])[C:11]#[N:12].[OH-].[Na+]>O>[C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:13]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: C=C(Cl)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccnn1-c1ccccc1
Reaction time: 6 h

Procedure:
To a mixture consisting of 680 parts water, 216 parts of phenylhydrazine and 164 parts of 2-chloroacrylonitrile 220 parts of a 30% sodium hydroxide solution are added dropwise at room temperature. After six hours the reaction is completed. The resulting 1-phenyl-5-aminopyrazole is isolated from that phase which has been separated by the addition of sodium chloride.
Reaction SMILES: [C:1]([O:5][P:6]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=5)[O:30][CH:31]=4)=[CH:20][CH:21]=3)[O:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:52]O)(C)(C)C.S(=O)(O)[O-].[Na+]>O1CCCC1.C(#N)C.CCCCCCCCCC>[P:6]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:33]=5)[O:30][CH:31]=4)=[CH:20][CH:21]=3)[O:16][CH:15]=2)=[CH:10][CH:9]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:52]
Reactant: CC(C)(C)OO
Reactant: CC(C)(C)OP(Oc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCCCCC
Solvent: CC#N
Product: CC(C)(C)OP(=O)(Oc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step 1, 3-{4-[bis(tert-butoxy)phosphinooxy]phenyl}-7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)chromen-4-one, in a mixture of tetrahydrofuran (20 mL) and acetonitrile (10 mL) was added 6 mL of tert-butyl hydroperoxide in decane (5M-6M). The reaction mixture was stirred at room temperature for 1 hour, chilled in an ice bath, and 50 mL of 5% sodium bisulfite was added. The resulting mixture was stirred for 15 minutes, after which the ice bath was removed. The mixture was extracted with methylene chloride, the organic extract dried over sodium sulfate, and solvent removed under reduced pressure. The residue was purified by biotage column chromatography, eluting with 1:1 ethyl Acetate/hexanes mixture, to afford ditert-butyl 4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenyl phosphate.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[N:12]1([C@@H:9]2[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2cccn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@@H](n2cccn2)CC1
Yield: 95.3 %

Procedure:
A solution of cis-4-pyrazol-1-yl-cyclohexanecarboxylic acid ethyl ester (95 mg, 0.427 mmol) in 1,4-dioxane (4.3 ml) and 2 M aqueous sodium hydroxide solution (2.2 ml, 4.4 mmol) was stirred at room temperature for 20 h. The pH was adjusted to 2 by addition of 2 M aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (79 mg, 95%) as light brown solid. MS m/e: 193 ([M−H]−)
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:14]([O:15][CH:16]([F:18])[F:17])=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[CH2:20]([O:22][C:23]([C:25]1[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]2=[N:27][C:26]=1[CH2:34][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24])[CH3:21].[H-].[Na+]>CS(C)=O>[CH:1]1([O:6][C:7]2[C:14]([O:15][CH:16]([F:18])[F:17])=[CH:13][CH:12]=[CH:11][C:8]=2/[CH:9]=[CH:34]/[C:26]2[N:27]=[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]3[C:25]=2[C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(OC(F)F)c1OC1CCCC1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccccn12
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2ccccn12
Yield: 76.6 %

Procedure:
Prepared by the reaction of 2-(cyclopentyloxy)-3-(difluoromethoxy)benzaldehyde (3.595 g, 14.040 mmol) with 3-ethyloxycarbonylimidazo[1,2-a]pyridine-2-yl-methyl(triphenyl)phosphonium bromide (7.0 g, 12.763 mmol) in the presence of NaH (0.561 g, 23.375 mmol) in anhydrous DMSO (15 mL) to afford 4.325 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.44 (t, J=6.9 Hz, 3H), 1.55-1.61 (m, 2H), 1.67-1.75 (m, 2H), 1.84-1.93 (m, 4H), 4.40-4.50 (m, 2H), 4.72-4.78 (m, 1H), 7.20 (t, J=74.7 Hz, 1H), 7.22-7.30 (m, 3H), 7.55-7.65 (m, 2H), 7.75 (d, J=8.7 Hz, 1H), 7.91 (d, J=16.8 Hz, 1H), 8.05 (d, J=16.2 Hz, 1H), 8.24 (d, J=5.1 Hz, 1H); APCI-MS (m/z) 443.28 (M)+.
Reaction SMILES: C[S-].[Na+].Br[C:5]1[CH:6]=[C:7]([C:16]2[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH:8]=[C:9]2[C:14]=1NC(=O)C=C2.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>CO.C(Cl)(Cl)Cl.O>[CH3:29][CH:28]1[C:9]2[C:24](=[C:5]([CH3:14])[CH:6]=[C:7]([C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[CH:8]=2)[NH:25][C:26](=[O:30])[CH2:27]1
Reactant: Cc1ccc(-c2cc(Br)c3[nH]c(=O)ccc3c2)c(C)n1
Reactant: CN1CCCC1=O
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2cc(C)c3c(c2)C(C)CC(=O)N3)c(C)n1

Procedure:
A solution of sodium methanethiolate (15 cm3 of a 2.0M solution in methanol) was added at room temperature to a solution of 8-bromo-6-[2,6-dimethylpyrid-3-yl]-2-(1H)-quinolone (0.50 g) and cuprous iodide (0.15 g) in N-methyl-2-pyrollidone (12 cm3). After heating at 160° for 48 hours the cooled mixture was diluted with chloroform (100 cm3) and water (50 cm3). The separated aqueous phase was further extracted with chloroform (3×50 cm3), and the combined and dried (MgSO4) chloroform extracts were evaporated in vacuo to given an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform. Combination and evaporation of appropriate fractions gave a solid which was recrystallised from ethyl acetate to afford 6-[2,6-dimethyl-pyrid-3-yl]-8-thiomethyl-2-(1H)-quinolone 0.25 H2O, m.p. 146.5°-148.5° (0.04 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:10]([C:8]([CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[O:9])=[C:11]([CH2:12][CH2:13][C:14]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[O:16])[CH:17]=1
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C

Procedure:
3.10 g (0.01 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 1.70 g (0.011 mol) of 1,1'-carbonyldiimidazole are stirred at room temperature for 1 hour in 30 ml of tetrahydrofuran. Then, 1.2 ml (0.011 mol) of 1-methylpiperazine are added thereto at -70° and the mixture is left to warm to room temperature overnight. After concentration of the solution, the residue is extracted first with methylene chloride/2N hydrochloric acid and then with methylene chloride/concentrated aqueous ammonia solution, dried with sodium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with methylene chloride-methanol (20:1) and crystallization from ethyl acetate/hexane gives N-[3-[4-chloro-2-[2-[(4methyl-piperazin-1-yl)carbonyl]ethyl]-benzoyl]propyl]acetamide as white crystals with melting point 126°-128°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:15][C:4]2[C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:30])([F:28])[F:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1Oc1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Oc1ccccc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-chloro-2-phenoxy-pyridin-3-ylamine (60 mg, 0.27 mmol) in anhydrous pyridine (0.5 mL) was added drop wise a solution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (76 mg, 0.27 mmol) in pyridine (0.5 mL). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 7.89-7.87 (m, 2 H), 7.81 (m, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 7.35 (t, J=8.4 Hz, 1 H), 7.25-7.19(m, 2 H), 6.76 (d, J=8.0 Hz, 2 H). MS m/z: 463.0 (M+H).
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([Br:16])=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[NH:6]2.[NH:17]1[CH2:21][CH2:20][N:19]=[C:18]1S(O)(=O)=O.Br>C(O)C(C)C>[Br:16][C:4]1[C:3]([NH:2][C:18]2[NH:19][CH2:20][CH2:21][N:17]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:15])[C:8]([CH3:13])([CH3:14])[NH:9]2
Reactant: CC1(C)Nc2ccc(N)c(Br)c2NC1=O
Reactant: O=S(=O)(O)C1=NCCN1
Agent: Br
Solvent: CC(C)CO
Product: CC1(C)Nc2ccc(NC3=NCCN3)c(Br)c2NC1=O

Procedure:
A mixture of 6-amino-5-bromo-1,2-dihydro-2,2-dimethyl-3-(4H) - quinoxalinone hydrobromide (479 mg, 1 mmol) and 2-imidazoline-2-sulfonic acid (224 mg, 1.5 mmol) in isobutanol (5 ml) is heated at reflux until the starting hydrobromide material is consumed. The solvent is removed in vacuo and the residue chromatographed on silica gel with CHCl3 : CH3OH saturated with NH3 (g) elution to yield the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]([CH3:28])[C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]([N:20]([CH3:28])[C@H:12]2[C@@H:13]3[O:17][C:16]([CH3:18])([CH3:19])[O:15][C@@H:14]3[C@@H:10]([CH2:9][OH:8])[CH2:11]2)[CH:26]=1
Reactant: CN(c1cc(Cl)ncn1)[C@@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(c1cc(Cl)ncn1)[C@@H]1C[C@H](CO)[C@H]2OC(C)(C)O[C@H]21
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a stirred solution of N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-N-methylpyrimidin-4-amine (400 mg, 0.93 mmol) in THF (10.0 mL) was added 1M solution of tetra-n-butylammonium fluoride in THF (1.00 mL, 1.00 mmol), and the mixture was stirred for 2 h. After quenching by addition of brine (20.0 mL), the resulting mixture was extracted with ethyl acetate (3×40.0 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 40 to 100% ethyl acetate in DCM to afford the title compound (261 mg, 89%) as a colorless oil. LC/MS: Rt=1.24 min, ES+ 314.2 (AA standard).