Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[F:33])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: Fc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccccc2F)C(=O)O1
Temperature: -60 °C

Procedure:
In analogy with Example 1h), 5.0 g (16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] dissolved in 75 ml of THF are deprotonated, at -75° C., with 32.7 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated with 2.1 ml (18.0 mmol) of o-fluorobenzyl bromide (Fluka; Buchs/Switzerland) at -75° C. initially (heating to a maximum of -60° C. over a period of 60 min). Column chromatography (SiO2, hexane/ethyl acetate, 3:1) affords the title compound: TLC Rf (D)=0.61.
Reaction SMILES: CC[O:3][C:4]([C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[C:17]([NH2:19])=[O:18])=[O:7])=O.[NH3:20]>C(O)C>[C:17]([C:10]1[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]([C:4]([NH2:20])=[O:3])=[O:7])(=[O:18])[NH2:19]
Reactant: N
Reactant: CCOC(=O)C(=O)Nc1cccc(OC)c1C(N)=O
Solvent: CCO
Product: COc1cccc(NC(=O)C(N)=O)c1C(N)=O
Reaction time: 2 h

Procedure:
2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (5.0 g, 0.0188 mole) is added to 50 ml of ethanol saturated with ammonia at 0°-5° C., and the mixture is stirred in an ice-bath for 2 hours, then filtered. The cake is washed with ethanol, giving 1.41 g of the title compound, m.p. 252°-255° C., after crystallization from water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(C)C=CC=CC=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22](=[O:25])[CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Oc1ccc(Cl)cc1
Yield: 88.5 %

Procedure:
Into a mixture of p-chlorophenol (20.0 g, 156 mmol), pyridine (14.8 g, 187 mmol), and toluene (150 ml), propionic acid chloride (17.3 g, 187 mmol) was added dropwise, and the resultant mixture was stirred for 1 hour at room temperature. Water (150 ml) was added and the aqueous layer was discarded. The organic layer was concentrated and distilled under reduced pressure (bp. 73°-76° C./0.2 mmHg), thereby obtaining a propionic acid-p-chlorophenyl ester (25.6 g, 138 mmol, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=1
Reactant: Brc1ccnc(Br)c1
Reactant: C1CCNC1
Solvent: CCO
Product: Brc1cc(N2CCCC2)ccn1
Product: Brc1ccnc(N2CCCC2)c1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
2,4-Dibromopyridine (1.0 g, 4.22 mmol) was dissolved in ethanol (40 mL) and pyrrolidine (1.733 ml, 21.11 mmol) was added. The reaction mixture was stirred at 70° C. for 20 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a pale yellow solid. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) to afford 2-bromo-4-(pyrrolidin-1-yl)pyridine (460 mg) as a white solid, and 4-bromo-2-(pyrrolidin-1-yl)pyridine (260 mg) as a white solid. LCMS (Method F, ES-API): RT 0.79 min, m+H=227.1/229.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([O:30][CH:31]([CH3:33])[CH3:32])[C:15]([N:17]2[CH:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])[CH:8]=1)(=O)=O.[CH2:36]([OH:39])[C:37]#[CH:38].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:22]([CH:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH:14]([O:30][CH:31]([CH3:32])[CH3:33])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:38]#[C:37][CH2:36][OH:39])[CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#CCO
Reactant: CC(C)OC(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)C(=O)N1C(=O)OCC1Cc1ccccc1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(Cc1cccc(C#CCO)c1)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
390 mg of 3-[3-(4-Benzyl-2-(oxo)-oxazolidin-3-yl)-2-isopropoxy-3-oxo-propyl]-phenyl trifluoromethanesulfonate was dissolved in 2 ml of N,N-dimethylformamide, 85 mg of propargyl alcohol, 8 mg of copper iodide, 45 mg of tetrakis (triphenylphosphine) palladium and 0.3 ml of triethylamine were added in succession, and the mixture was stirred overnight at 50° C. under a nitrogen atmosphere. The reaction solution was filtered through silica gel, and the filtrate was dissolved in ethyl acetate, washed with water, 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 207 mg of the title compound as a colorless oil in the 3:2 hexane-ethyl acetate fraction.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)[OH:5]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br

Procedure:
To a solution of 2-bromobenzaldehyde (3.15 ml, 27.0 mmol) and THF (135 ml) at 0° C. was added (4-chlorophenyl)magnesium bromide solution (29.7 ml, 1M in THF, 29.7 mmol). The reaction was stirred at 0° C. for 30 min before addition of a saturated solution of ammonium chloride. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage to afford (2-bromophenyl)(4-chlorophenyl)methanol. To a solution of DCM (100 ml) and oxalyl chloride (2.471 ml, 28.2 mmol) at −78° C. was added DMSO (3.34 ml, 47.0 mmol) and the reaction stirred at −78° C. for 15 min. After 15 min a solution of (2-bromophenyl)(4-chlorophenyl)methanol in DCM (25 ml) was added dropwise and stirred for 15 min at −78° C. before addition of Et3N (9.84 ml, 70.6 mmol). The cold bath was removed and the reaction was warmed to room temperature. To this solution was added water and the layers separated. The aqueous was extracted with DCM and the combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (2-bromophenyl)(4-chlorophenyl)methanone. m/z (ESI) 295, 297 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:19]
Reactant: O=Cc1ccccc1
Reactant: Brc1ccc2ccccc2c1
Product: OC(c1ccccc1)c1ccc2ccccc2c1

Procedure:
Using general procedure B, 2-bromonaphthalene was reacted with benzaldehyde to give naphthalen-2-yl-phenyl-methanol as a colorless solid.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19]>CC(O)CCC>[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH:19][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: COc1ccc2c(Cl)cnnc2c1
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: COc1ccc2c(Nc3ccc(C)c(O)c3)cnnc2c1

Procedure:
A suspension of 4-chloro-7-methoxycinnoline hydrochloride (196 mg, 0.85 mmol) and 3-hydroxy-4-methylaniline (123 mg, 1 mmol) in 2-pentanol (5 ml) was heated at reflux for 2 hours. After cooling, the solid was filtered off, washed with isopropanol, ether and dried under vacuum to give 4-(3-hydroxy-4methylanilino)-7-methoxycinnoline as the hydrochloride salt (yellow solid, 215 mg, 80%).
Reaction SMILES: [ClH:1].N[C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2([CH3:19])[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)=[CH:5][CH:4]=1.N([O-])=O.[Na+].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28]>CC(C)=O.O>[Cl:1][CH:27]([CH2:28][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2([CH3:19])[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)=[CH:5][CH:4]=1)[C:26]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CC1(COc2ccc(N)cc2)CCc2ccccc2O1
Reactant: Cl
Reactant: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3ccccc3O2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.7 ml of concentrated aqueous hydrochloric acid was dropped, whilst ice-cooling, into a solution of 500 mg of 2-(4-aminophenoxymethyl)-2-methylchroman (prepared as described in Preparation 4) in 5 ml of acetone, and then a solution of 170 mg of sodium nitrite in 2 ml of water was added dropwise to the resulting mixture. When the dropwise additon was complete, 2 ml of ethyl acrylate were added, and the reaction mixture was heated to 40° C. 10 mg of cuprous oxide were then added gradually, and the mixture was stirred for 30 minutes. At the end of this time, the acetone was distilled off under reduced pressure, and the residue was extracted with benzene. The benzene extract was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected of silica gel column chromatography eluted with a 10:1 dy volume mixture of hexane and ethyl acetate, to afford 350 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([OH:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:1]([S:8][C:9]1[NH:10][C:11](=[O:18])[C:12]2[NH:13][CH2:14][N:15]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1nc(SCc2ccccc2)nc2nc[nH]c12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(SCc2ccccc2)nc2c1NCN2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (3.88 mmol) of 2-benzylthio-6-hydroxypurine was dissolved in 20 ml of dimethylformamide and 0.816 ml (5.82 mmol) of triethylamine was added to the solution. Under ice cooling, 1.62 g (5.82 mmol) of tritylchloride was added to the mixture following stirring at room temperature overnight. After 400 ml of water was added, a precipitate was collected by filtration and washed with n-hexane and with ethyl acetate. Recrystallization from ethanol afforded 0.785 g (yield, 40%) of Compound o as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: CC(C)OC(=O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OC(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 63.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.38 g, 5 mmol) was reacted with isopropyl morpholine-3-carboxylate hydrochloride (1.05 g, 5 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (1.79 g, 63%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(OC)(C)C>O.C(O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 72.3 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and ethanol (7.5 ml). The mixture was heated to reflux and stirred until the starting material was no longer detectable by HPLC. Then, 58 ml of MTBE was dripped into the solution over 1.5 h. Turbidity appeared in the solution. The mixture was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with MTBE (50 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.21 g (72.3%) of fluvastatin sodium Form XIV.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:17]=[CH:16][C:9]2[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[O:13][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].C(Cl)Cl.CO>C(O)(=O)C>[C:3]([C:6]1[CH:17]=[CH:16][C:9]2[C:10](=[O:15])[C:11]([Br:1])=[C:12]([CH3:14])[O:13][C:8]=2[CH:7]=1)(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(=O)cc(C)oc2c1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc2c(=O)c(Br)c(C)oc2c1
Reaction time: 2 h
Yield: 19 %

Procedure:
77.5 ml of a 10% solution of bromine in acetic acid are added at 60° C., under an inert atmosphere, to a solution of 8.8 g (40.10-3 mol) of 7-acetyl-2-methyl-4H-1-benzopyran-4-one in 80 ml of acetic acid. The reaction mixture is kept at 60° C. for 2 hours and is then left to stand for 12 hours. It is concentrated under reduced pressure and the residue is then neutralized with a saturated solution of sodium bicarbonate. After extraction with ethyl acetate, the organic phase is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and concentrated to dryness. After chromatography on silica gel using a methylene chloride/methanol mixture (12/1 v/v) as the eluent, 2.3 g (yield: 19%) of the expected product are obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1Br)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[F:20][CH2:21][C:22](OCC)=[O:23].[Cl-].[NH4+]>O1CCCC1.C(OC(=O)C)C>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:22](=[O:23])[CH2:21][F:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CF
Reactant: CC(C)(C)NS(=O)(=O)c1sccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1sccc1C(=O)CF
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
2.98 g (0.0mole) of N-t-butyl-3-bromo-2-thiophenesulfonamide was dissolved in 50mi of dry tetrahydrofuran and the mixture was cooled to -78° C. under nitrogen gas. To the reaction solution was slowly added dropwise 8.4 ml of n-butyl lithium (2.5N) and then the temperature of the mixture was raised slowly to -20° C. and again cooled to -78° C. 1.2 g (0.011 mole) of ethyl fluoroacetate was added slowly to the reaction mixture. The temperature of the mixture was raised again slowly to -20° C. and then the mixture was stirred for 10 minutes. To the reaction mixture was added 100 ml of 5% aqueous ammonium chloride solution, and then added 100 ml of ethylacetate to separate the organic layer. The extracted organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjeced to column chromatography on silica gel to obtain 2.0 g (Yield: 72%) of the pure title compound as a liquid.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[F-:23].[K+]>CS(C)=O.O>[F:23][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(Oc2ccccc2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1c(F)cncc1-c1ccc(Oc2ccccc2)cc1
Temperature: 120 °C
Yield: 68.5 %

Procedure:
A mixture of 3-chloro-5-(4-phenoxyphenyl)isonicotinonitrile (11.8 g, 38.5 mmol) and potassium fluoride (11.17 g, 192 mmol) in DMSO (500 mL) was heated to 120° C. for 10 days. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3×400 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in dichloromethane-hexanes (1:2), gave 3-fluoro-5-(4-phenoxyphenyl)isonicotinonitrile as tan solid (7.66 g, 69% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.67 (1H, s), 8.64 (1H, s), 7.52-7.62 (2H, m), 7.36-7.46 (2H, m), 7.20 (1H, t, J=7.42 Hz), 7.05-7.17 (4H, m); MS (ES+) m/z: 291 (M+H); LC retention time: 4.118 min (analytical HPLC Method A).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:13]([Cl:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([Cl:11])=[O:10])([O-])=O.[N+:16](C1C=C(C(O)=O)C=C(C=1)C(O)=O)([O-:18])=[O:17].S(Cl)(Cl)=O>CN(C)C=O>[N+:16]([C:7]1[C:8]([C:9]([Cl:11])=[O:10])=[CH:12][CH:4]=[CH:5][C:6]=1[C:13]([Cl:15])=[O:14])([O-:18])=[O:17]
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A mixture of 100 g of 5-nitroisophthaloyl dichloride (prepared by taking a mixture of 60.0 g of 5-nitroisophthalic acid, 300 ml of thionyl chloride and one ml of dimethylformamide, stirring at room temperature for 30 minutes followed by refluxing for one hour; allowing the solution to stand 24 hours, followed by evaporation to a small volume in vacuo-re-evaporating with toluene and then diluting the resulting liquid with 250 ml of hexane, followed by stirring and cooling until the resulting oil is solidified; and grinding the product to a powder, and recrystallizing twice from carbon tetrachloride to afford 47.4 g of nitroisophthaloyl chloride) 100 g of 2-methoxyethanol (dried over molecular sieves) and 400 ml of acetonitrile (dried over molecular sieves) is heated to boiling on a steam bath. Heating is continued for 15 minutes, then the mixture is cooled to room temperature and is poured into 2 liters of cold water with vigorous stirring. The precipitate formed (129 g) is collected by filtration, air dried and set aside. The above filtrate is extracted with benzene. The benzene extract is washed with water, dilute sodium bicarbonate and water and is dried over anhydrous sodium sulfate. The solvent is evaporated to give a mixture of crystals and oily liquid. This material is combined with the precipitate set aside above and dissolved in 580 ml of hot ethyl alcohol. The resultant solution is neutralized with 5.0 ml of 5N sodium hydroxide and is slowly diluted with 450 ml of water. The solution is allowed to crystallize at room temperature then is placed in a chill room for 16 hours. The product is collected by filtration, then is recrystallized and filtered as above from 450 ml of ethyl alcohol and 350 ml of water to give 92.1 g of 5-nitroisophthalic acid bis(2-methoxyethyl)ester as colorless needles.
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=[O:12])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>[Br-].C([N+](CC)(CC)CC)C.O>[CH:1](=[CH:10][C:11]([O:13][CH2:14][CH:16]1[O:18][CH2:17]1)=[O:12])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=CC=Cc1ccccc1
Reactant: ClCC1CO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: O
Product: O=C(C=CC=Cc1ccccc1)OCC1CO1
Temperature: 110 °C

Procedure:
To 9.0 g of cinnamylideneacetic acid (manufactured by Lancaster) were added 3.5 g of tetraethylammonium bromide (manufactured by Wako Pure Chemical) and 100 ml of epichlorohydrin (manufactured by Wako Pure Chemical), the mixture was heated to reflux at 110° C. for 3 hours, 50 ml of distilled water was added thereto and an organic layer was separated and concentrated in vacuo at 80° C. to give 17.3 g of glycidyl cinnamylideneacetate. An epoxy equivalent of this glycidyl cinnamylideneacetate was 444.3.
Reaction SMILES: [C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C1C=CC=CC=1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:13][CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(N)c1cccc2ccccc12
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1ccc(Cl)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 23.6 grams (0.138 mole) of α-naphthylethylamine and 20.2 grams (0.20 mole) triethylamine in 150ml of dry benzene, there is added dropwise a solution of 24.8 grams (0.142 mole) of p-chlorobenzoyl chloride in 150 ml of benzene. After stirring overnight at room temperature the salts are filtered off and the filtrate is concentrated in vacuo. The resultant residue is crystallized from methylene chloride/hexane to give N-(p-chlorobenzoyl)-α-naphthylethylamine, m.p. 117°-118° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:17][C:18]1[C:22](B(O)O)=[C:21]([CH3:26])[O:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[CH3:17][C:18]1[C:22]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:21]([CH3:26])[O:20][N:19]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1noc(C)c1-c1cnccc1N1CCC(C(N)=O)CC1
Yield: 17 %

Procedure:
General procedure E was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (100 mg, 0.35 mmol), 3,5-dimethyl-4-isoxazole boronic acid (74 mg, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 5 mol %), acetonitrile (4 mL) and 0.5 M sodium carbonate (1.1 mL, 0.53 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 97:3-80:20, biotage 25+S) to furnish the title compound as a white solid (18 mg, 17%), along with 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide (10 mg, 10% RSM), LC-MS (ESI, 4 min) Rt 0.76 min, m/z 301 (100%, [M+H]+); m/z (ESI, Rt 1.22 min) C16H20N4O2 requires 300.1587, found [M+H]+ 300.1591.