Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[C@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C1C=CC=CN=1)C.[F:40][C:41]1[CH:46]=[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH:44]=[CH:43][C:42]=1[OH:58].Cl>C(N(CC)CC)C.C(Cl)Cl>[F:40][C:41]1[CH:46]=[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH:44]=[CH:43][C:42]=1[O:58][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:1]2[CH:6]=[CH:5][C:4]([C:7]([O:28][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:20]([F:29])([F:30])[F:19])=[O:8])=[CH:3][CH:2]=2)=[CH:15][CH:14]=1)=[O:17]
Reactant: O=C(Cl)c1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCCCCCCCCOc1ccc(O)c(F)c1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(OC(=O)c2ccc(-c3ccc(C(=O)OC(CCCCCC)C(F)(F)F)cc3)cc2)c(F)c1
Reaction time: 8 h

Procedure:
Into methylene chloride (20 ml) were added 4,4'-biphenyldicarboxylic acid chloride (0.5 g), (R)-(+)-1,1,1-trifluoro-2-octanol (0.15 g), triethylamine (0.09 g) and dimethylaminopyridine (0.03 g) and the mixture was left to stand for 8 hours in order to allow a reaction to proceed. Thereto were added 2-fluoro-4-decyloxyphenol (0.22 g) and triethylamine (0.09 g), and the mixture was left to stand for 8 hours in order to allow a reaction to proceed. The product was made acidic with 1N hydrochloric acid and extracted with methylene chloride. The extracted layer was washed with 1N aqueous sodium carbonate solution, water, aqueous sodium chloride solution (saturated) and water, in this order, until it was neutralized. After the product was dried over anhydrous magnesium sulfate, it was distilled under reduced pressure to remove the solvent. A solid product thus obtained was purified by silica-gel column chromatography until the titled compound (0.48 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc(C)o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(CBr)o1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 6.2 parts of ethyl 5-methyl-2-oxazolecarboxylate and 191 parts of dry tetrachloromethane there were added 7.1 parts of N-bromosuccinimide and a few parts of benzoylperoxide under a nitrogen atmosphere. The whole was stirred for 1 hour at reflux temperature. After cooling, the reaction mixture was filtered and the filtrate was evaporated, yielding 11 parts (100%) of ethyl 5-(bromomethyl)-2-oxazolecarboxylate (interm. 21).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:8]1[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[F:18])[O:6][CH3:7])C.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([F:18])[C:8]([CH:5]([O:6][CH3:7])[C:4]([OH:19])=[O:3])=[C:13]([F:14])[CH:12]=1)[CH3:17]
Reactant: CCOC(=O)C(OC)c1c(F)cc(OCC)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(F)c(C(OC)C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To (4-ethoxy-2,6-difluoro-phenyl)-methoxy-acetic acid ethyl ester (4.0 g, 14.58 mmol, 1.0 equiv), dissolved in THF (75 mL) and methanol (15 mL), was added a solution of 1 M LiOH (17.5 mL) and the reaction mixture stirred at rt for 4 h. A solution of 1 M HCl (25 mL) was added, the organic solvents removed by evaporation under reduced pressure and the residue extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 3.5 g (98%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][Br:9])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>FC(F)(F)C(O)=O>[Br:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(CCBr)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCBr)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 500 mL pear flask was charged 4-methoxyphenethyl bromide (0.727 ml, 4.65 mmol) in trifluoroacetic acid (9.30 ml). The solution was cooled to 0° C. In a 50 mL Erlenmeyer flask was added nitric acid (0.231 ml, 4.65 mmol) and trifluoroacetic acid (2.0 mL). The nitric acid solution was added to the reaction dropwise via syringe. The reaction was stirred at room temperature for 2 hours. The solvent was removed on a rotovap and the residue taken up into ethyl acetate. The reaction was washed with 1N HCl, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated onto silica gel. The reaction was purified by flash chromatography (10% ethyl acetate:hexanes for 20 minutes, then to 50% ethyl acetate:hexanes over 20 minutes) to provide the title compound. MS (DCI) m/e 277 (M+NH4).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:21]2[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[NH:23][C:22]2=[O:29])[CH:5]=[C:6]([CH3:20])[C:7]=1/[CH:8]=[CH:9]/[S:10]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[C-:30]#[N:31].[K+].C([O-])(=O)C.[NH4+:37]>CO>[NH2:37][C:16]1([C:30]#[N:31])[CH2:17][CH2:18][N:13]([S:10](/[CH:9]=[CH:8]/[C:7]2[C:6]([CH3:20])=[CH:5][C:4]([N:21]3[C:25]([CH3:26])([CH3:27])[C:24](=[O:28])[NH:23][C:22]3=[O:29])=[CH:3][C:2]=2[CH3:1])(=[O:12])=[O:11])[CH2:14][CH2:15]1
Reactant: [NH4+]
Reactant: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC(=O)CC1
Reactant: [C-]#N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC(N)(C#N)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a solution of (E)-1-(3,5-dimethyl-4-(2-((4-oxopiperidin-1-yl)sulfonyl)vinyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (994 mg, 2.37 mmol) in methanol (24 mL), potassium cyanide (188 mg, 2.84 mmol) and ammonium acetate (237 mg, 3.08 mmol) were added at room temperature. The mixture was stirred at 60-70° C. for three hours. The reaction mixture was cooled, concentrated under reduced pressure, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to afford (E)-4-amino-1-((4-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2,6-dimethylstyryl)sulfonyl)piperidine-4-carbonitrile (681 mg, 68%).
Reaction SMILES: FC(F)(F)C(N[C@@H:6]1[C:14]2C(=CC=C(OC)C=2)C(=O)[CH2:7]1)=O.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].IC(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:6]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25])([CH3:14])[CH3:7]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccc(C=O)c1
Reaction time: 24 h
Yield: 85 %

Procedure:
Step AU (1). A solution of 3-hydroxybenzaldehyde (67 g, 549 mmol), 2-iodopropane (100 g, 588 mmol) and K2CO3 (130 g, 942 mmol) in 400 mL DMF was stirred for 18 h. To the above solution was added 2-iodopropane (20 g, 117 mmol) and K2CO3 (20 g, 145 mmol) and the mixture was stirred for another 24 h. The reaction mixture was poured into 300 mL water which was extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (100 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo to afford 77 g (85% yield) of 3-isopropoxybenzaldehyde as an oil. 1H NMR (300 MHz, CDCl3) δ 1.29-1.31 (d, 6H) 4.5-4.6 (m, 1H) 7.0-7.1 (m, 1H) 7.3-7.4 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH2:52])[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C.CCOC(C)=O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)c1ccc(OC[C@@H](C)N)c(OC)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC[C@@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a stirred solution of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (459 mg, 0.96 mmol) and ethyl (R)-3-methoxy-4-(2-aminopropoxy)benzoate (242 mg, 0.96 mmol) in DMF (5 mL) was added Et3 N (200 μl, 1.43 mmol), and the resulting mixture was stirred for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 360 mg (69%) ethyl (R)-3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a colorless crystalline solid. 1H-NMR (CDCl3) δ 1.23–1.28 (m, 3 H), 1.38–1.41 (t, 3 H, J=7.3 Hz), 2.32 (s, 3 H), 3.50–4.13 (m, total 11 H), 4.36 (q, 2 H, J=7.3 Hz), 6.65–8.13 (series of m, total 12 H).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[S:28]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])(=[O:29])[CH3:27]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Linoleyl alcohol (10.0 g, 37.5 mmol) was weighed into a 500 mL round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with DCM (100 mL) and triethylamine (7.84 mL, 1.5 equiv.) and cooled to 0° C. Methanesulfonyl chloride (4.35 mL), 1.5 equiv.) was measured in a PP syringe and added slowly to the stirring reaction mixture. TLC analysis (7.5% EtOAc/Hexanes) showed the reaction was complete within 1 hr. The reaction was diluted with DCM (100 mL) and washed with saturated bicarbonate solution (2×200 mL). The organic phase was dried over MgSO4, filtered and concentrated to give 12.53 g (97%) of colorless oil that was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=4)[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 72 h
Yield: 40.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (273 mg, 0.835 mmol), 1-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 137 mg (40.8%) of the desired product as a solid.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7](O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10]C=2)=[CH:4][CH:3]=1.[C:17]([OH:20])(=O)C.OO.C(Cl)[Cl:24]>FC(F)(F)C(O)=O>[Cl:24][C:12]1[CH:11]=[CH:10][C:7]2[O:6][C:5]3[CH:15]=[CH:16][C:2]([CH2:17][OH:20])=[CH:3][C:4]=3[C:8]=2[CH:13]=1
Reactant: ClCCl
Reactant: OC(Oc1ccc(F)cc1)c1ccccc1
Reactant: CC(=O)O
Agent: OO
Solvent: O=C(O)C(F)(F)F
Product: OCc1ccc2oc3ccc(Cl)cc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Example 26 (6.4 g, 14 mmol) in methylenechloride (40 ml) and trifluoroacetic acid (20 ml) was stirred at RT for 0.5 h, then evaporated to dryness. The residue was dissolved in 100 ml water and 100 ml methylenechloride, then neutralized to pH 8 by 0.5 N NaOH, the organic phase was washed by water, dried over Na2SO4, evaporated to give the deprotected intermediate which was mixed with acetic acid (100 ml) and 30% H2O2 (2.5 ml). The mixture was stirred at RT for 2 hr, evaporated, purified by flash chromatography (methylenechloride/methanol, 15/1 saturated by 28% aqueous ammonia) and recrystallization in 50 ml ethyl acetate to give 4 g Example 45 as a white solid.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.O>O1CCCC1.[Zn]>[CH:2]1([CH:16]([OH:17])[C:15]([N:12]2[C:11](=[O:20])[C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:9]([CH3:8])[O:14][CH2:13]2)([CH3:19])[CH3:18])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Reactant: BrC1C=CCCC1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)C2C=CCCC2)CO1
Temperature: 20 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 1-bromocyclohex-2-ene (7.2 g) in tetrahydrofuran was added dropwise during 0.5 hour to a stirred mixture of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (4.0 g) and zinc powder (3.2 g) in tetrahydrofuran below -20° C. under an inert atmosphere. The mixture was stirred for 1 hour below -20° C. and warmed to 20° C. Ethyl acetate and water were added and the organic phase washed (brine), dried (magnesium sulphate), evaporated and purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (5:2) to give 1-(cyclohex-2-enyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-ol (5.1 g), NMR: 1.41(s,3H), 1.53(s,3H), 1.85(s,3H), 1.40-2.05(6H), 2.24(1H), 3.49(1H), 4.32(d,1H), 5.1 1(d 5.24(d,1H), 5.60(1H), 5.76(1H), 7.20-7.40(5H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:22]3[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][C:11](=O)[C:10]2=3)[CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+].C(O)C.O>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:22]3[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=3)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(C2C3=C(CCCC3=O)NC3=C2C(=O)CCC3)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cccc(C2C3=C(CCCC3)NC3=C2C(=O)CCC3)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinedione (3.18 g), sodium borohydride (2.50 g) and 50 mL of ethanol was stirred at 70° C. overnight. The mixture was treated with abut 300 mL of water, stirred for several hours and the solid collected by suction filtration, slurried on the funnel with a little ethanol and sucked dry on the funnel. The solid (1.87 g) was combined with 0.49 g of material from a previous run and the combined material was chromatographed, with methanol:dichloromethane (2.5:97.5) as elutent. The solvent evaporated and the residue taken up in 50 mL of methanol and about 20 mL of methylene chloride. The solution was concentrated on a steam bath until crystals started to form, was treated with an equal volume of ethyl acetate and refrigerated overnight. The title compound was obtained as bright yellow crystals (1.16 g); mp 246°-249° C.; NMR: 1.47 (broad s,2, CH2), 1.65-1.87 (m,6, CH2), 2.11 (m,4, CH2), 2.39-2.51 (m,2, CH2), 4.25 (s,1, CH), 7.41-7.57 (m,4, Ar), 8.45 (s,1, NH); (CI, CH4) MS: m/z=305(M+1). Analysis for C20H20N2O: Calculated C, 78.92; H, 6.62; N, 9.20; Found: C, 78.64; H, 6.65; N, 9.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Oc1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCCOc1ccc(Cl)cc1

Procedure:
A mixture of p-chlorophenol (25 g), acrylonitrile (30 ml) and a solution of benzyltrimethylammonium hydroxide (8 ml of a 40 wt % solution in methanol) were heated at reflux over the weekend. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to give 3-(4-chlorophenoxy)propionitrile.
Reaction SMILES: C(ON=O)(C)(C)C.[C:8]1([C:14]([CH2:16]Br)=[CH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)N)([O-:20])=[O:19].NC1C=CC=CC=1>CC#N>[N+:18]([C:21]1[CH:22]=[C:23]([CH2:16][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH2:15])[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)([O-:20])=[O:19]
Reactant: C=C(CBr)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: Nc1ccccc1
Product: C=C(Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25.5 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of t-butylnitrite (119 μl, 1.0 mmol) and 2-phenyl-3-brompropene (0.99 g, 5.0 mmol) in CH3CN (0.5 ml) was 3,5-dinitroaniline (92 mg, 0.5 mmol) added during 10 minutes, while maintaining the temperature of the reaction mixture at 23-28° C. At the end of the addition of the aniline extra t-butylnitrite (119 μl, 1.0 mmol) was added to the reaction mixture which then was heated to 35° C. for 5 minutes. The reaction mixture was stirred at 22° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) succeeded by crystallization from heptane gave 50 mg (35%) of 3,5-dinitro-1-(2-phenyl-2-propenyl)benzene as bright yellow needles. 1H NMR (CDCl3, 400 MHz) δ 8.88, (t, 1H, J=2.1 Hz), 8.42, (d, 2H, J=2.1 Hz), 7.42-7.37, (m, 2H), 7.36-7.24, (m, 3H), 5.65, (s, 1H), 5.22, (d, 1H, J=0.8 Hz), 4.08, (s, 2H).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[CH:5]=[CH:4][N:3]=1.[CH2:14]([Zn]CC)[CH3:15].O.Cl>O1CCOCC1>[Cl:13][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:14][CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1c(Cl)ccnc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(Cl)ccnc1CC
Temperature: 40 °C
Yield: 63 %

Procedure:
Ethyl 2-bromo-4-chloropyridine-3-carboxylate (1.5 g, 5.7 mmol) was dissolved in anhydrous dioxane (45 mL). A solution of diethyl zinc (4.6 mL, 5.1 mmol, 1.1 M in toluene) was added dropwise, and then was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (62 mg, 85 μmol). The mixture was heated at 40° C. overnight, and then water plus 1 N HCl were added. The reaction mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-15% hexane/ethyl acetate to afford ethyl 4-chloro-2-ethylpyridine-3-carboxylate (687 mg, 57% yield).
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:26])=[C:21]([C:23](=O)[CH3:24])[CH:22]=1>CO.C(O)(=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:26])=[C:21](/[C:23](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:24])[CH:22]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CNS(=O)(=O)c1cccc(C(=O)NN)c1
Solvent: CC(=O)O
Solvent: CO
Product: CNS(=O)(=O)c1cccc(C(=O)N/N=C(\C)c2cc(Cl)ccc2O)c1
Temperature: 120 °C
Yield: 36.7 %

Procedure:
3-(hydrazinecarbonyl)-N-methylbenzenesulfonamide (120 mg, 0.523 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (89 mg, 0.523 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-3-(2-(1-(5-chloro-2-hydroxyphenyl)ethylidene)hydrazinecarbonyl)-N-methylbenzenesulfonamide (75 mg, 0.192 mmol, 36.8% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.21 (m, 1H), 8.06 (m, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.59 (t, 1H, J=8.0 Hz), 7.39 (d, 1H, J=2.4 Hz), 7.18 (m, 1H), 6.90 (d, 1H, J=8.0 Hz), 2.56 (s, 3H), 2.36 (5, 3H). Mass [M+H]+: 382.1
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:12][C:11]=1[Cl:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(OC(=O)COC1C=CC(CCC([N:71]2[CH2:92][CH2:91][C:74]3([NH:78]/[C:77](=[N:79]/[C:80]([C:82]4[C:87]([NH2:88])=[N:86][C:85]([NH2:89])=[C:84]([Cl:90])[N:83]=4)=[O:81])/[NH:76][CH2:75]3)[CH2:73][CH2:72]2)=O)=CC=1)(C)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:71]2[CH2:92][CH2:91][C:74]3([NH:78]/[C:77](=[N:79]/[C:80]([C:82]4[C:87]([NH2:88])=[N:86][C:85]([NH2:89])=[C:84]([Cl:90])[N:83]=4)=[O:81])/[NH:76][CH2:75]3)[CH2:73][CH2:72]2)=[O:20])=[CH:12][C:11]=1[Cl:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-(4-tert-butoxycarbonylmethoxy-3-chloro-phenyl)-propionic acid (Intermediate B) (4 g, 12.71 mol) in DMF (80 ml) at RT was treated with HATU (4.83 g, 12.71 mmol), N-methylmorpholine (5.73 ml, 52.1 mmol) followed by 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (WO09074575, Ex. 38, page 123) (5.31 g, 13.34 mmol). The resulting mixture was stirred at RT for 1 h and then diluted with water (500 ml). The resulting solid was collected by filtration and rinsed with water. Purification by chromatography on silica eluting with 0-7% 7N ammonia in MeOH/DCM afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (2H, br hump), 7.34 (1H, d), 7.14 (1H, dd), 6.90 (1H, d), 6.87 (2H, br hump), 4.74 (2H, s), 3.65 (1H, m), 3.57 (1H, m), 3.43 (2H, s), 3.37 (2H, m), 2.75 (2H, t), 2.62 (2H, t), 1.62 (4H, m), 1.43 (9H, s).