Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([Cl:48])=[C:42]([CH:47]=1)[C:43]([O:45][CH3:46])=[O:44]>CN(C)C=O.O>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[C:38]([NH:37][C:4]([C:3]2[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=2)=[O:6])[CH:39]=[CH:40][C:41]=1[Cl:48]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(NC(=O)c2ccc(C(F)(F)F)nc2C)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 2-methyl-6-trifluoromethylnicotinic acid (4.77 g; 23 mmol) in dimethyl formamide (100 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.46 g; 23 mmol) and 1-hydroxy-7-azabenzotriazole (3.17 g; 23 mmol) and the resulting solution was stirred at room temperature for 30 minutes. To this was added a solution of methyl 5-amino-2-chlorobenzoate (3.6 g; 19 mmol) in dimethyl formamide (25 ml) and the resulting solution stirred at room temperature for 18 hours. Water (200 ml) was added to the reaction mixture and this was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (2×300 ml). The organic layer was dried (magnesium sulphate), filtered and evaporated to give 2-chloro-5-[(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-amino]-benzoic acid methyl ester (6.6 g, 94%).
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1O[S:5]([CH2:8][CH2:9][CH2:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:7])=[O:6].[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:31][N:32]1[CH2:33][CH2:34][CH:35]([N:38]2[CH2:43][CH2:42][N:41]([S:5]([CH2:8][CH2:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])(=[O:6])=[O:7])[CH2:40][CH2:39]2)[CH2:36][CH2:37]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCCS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(S(=O)(=O)CCC[C@@H]3CCCN3C(=O)OC(C)(C)C)CC2)CC1

Procedure:
(S)-tert-Butyl 2-(3-(perfluorophenoxysulfonyl)propyl)pyrrolidine-1-carboxylate (2.8 g, 6.099 mmol) and 1-(1-methylpiperidin-4-yl)piperazine (1.676 g, 9.148 mmol) were dissolved in tetrahydrofuran (40 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.7 ml, 18.297 mmol) was added under an inert gas and the mixture was refluxed for 2 h. Ethyl acetate and saturated sodium bicarbonate solution (50 ml of each) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with saturated sodium bicarbonate solution (40 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/methylene chloride/ammonia (25% aq) (300:100:50:1). Yield: quantitative
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][C@@H:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1.NC1CNC(C(OC)=O)C1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CCOC(C)=O.O>[C:34]([NH:7][C@@H:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: COC(=O)C1CC(N)CN1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
To a 250-mL three-necked round bottom flask, with mechanical stirring, was charged 4.8 g (56.8 mmol) of sodium bicarbonate followed by 48 mL water. To this stirred solution was charged (2S,4S)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate hydrochloride A (4 g, 14.2 mmol; prepared from commercially available methyl 4-aminopyrrolidine-2-carboxylate) and EtOAc (40 mL) (two hazy layers observed). The reaction mixture was cooled to 5-10° C. with an ice-bath. Benzoyl chloride (2.0 g, 14.2 mmol) in 8 mL EtOAc was charged dropwise over 10 min maintaining temperature between 5-10° C. The mixture was stirred at 5-10° C. for 1 h and monitored by LC, which showed less than 0.5% by area of benzoyl chloride. The stirring was stopped and the phases were separated. The lower aqueous phase was extracted with EtOAc (2×20 mL). The combined EtOAc layer was washed with 1N HCl (20 mL), saturated NaHCO3 aqueous solution (20 mL), brine (20 mL) and dried with Na2SO4. The EtOAc solution was filtered and the filtrate was evaporated to give 4.87 g of (2S,4S)-1-tert-butyl 2-methyl 4-benzamidopyrrolidine-1,2-dicarboxylate B as a white solid (98.2% yield). NMR conforms to structure. HPLC area percent: 99.3%. 1H NMR (DMSO-d6, δ, ppm): 8.46 (d, J=6.6 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.56-7.44 (m, 3 H), 4.48-4.41 (m, 1H), 4.27 (t, J=7.8 Hz, 1H), 3.79-3.71 (m, 1H), 3.69 (d, J=11.7, 3 H). 3.34-3.25 (m, 1H), 2.59-2.50 (m, 1H), 2.08-1.99 (m, 1H), 1.38 (d, J=18.9 Hz, 9H). MS (m/z, positive ESI, for M+H): 349.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([OH:16])=[C:4]([N+:17]([O-])=O)[CH:3]=1>[Ni].O.CCOC(C)=O>[NH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(Cl)cc(CCc2ccccn2)c1O
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cl)cc(CCc2ccccn2)c1O
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a vigorously stirred suspension of Raney Nickel (3.5 g of a 50% slurry in water, washed with ethanol then EtOAc) in EtOAc (20 ml) is added 4-chloro-2-nitro-6-[2-(pyridin-2-yl)ethyl]phenol (2.09 g, 7.50 mmole) in EtOAc (10 ml). The solution is stirred vigorously overnight under an atmosphere of hydrogen. After this time no starting material is visible by TLC analysis. The solution is decanted from the Raney Nickel. The Raney Nickel was washed several times with EtOAc and the washings combined with the reaction mixture solution. Concentration in vacuo yielded a brown oil which is purified by flash chromatography (SiO2 ; 30% EtOAc in hexane) to yield a pale orange oil (1.88 g, 100%). This was recrystallised from EtOAc/pentane to give the title compound as a pale yellow crystalline solid (1.55 g, 83%), m.p. 91-92° C. dH (250 MHz, CDCl3) 11.5 (bs, 1H), 8.49 (dd, J=5.6, 2.0 Hz, 1H), 7.63 (dt, J=7.7, 1.7 Hz, 1H ), 7.20-7.16 (m, 2H), 6.54 (d, J=2.5 Hz, 2H), 3.84 (bs, 2H ), 3.30-3.25 (m, 2H ), 3.06-3.02 (m, 2H).
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][CH2:12][C:13]([C:16](F)=[O:17])([F:15])[F:14])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].S(=O)(=O)(O)[OH:20]>>[C:1]([C:5]([C:8]([O:11][CH2:12][C:13]([C:16]([OH:17])=[O:20])([F:14])[F:15])([F:9])[F:10])([F:6])[F:7])([F:2])([F:3])[F:4]
Reactant: O=S(=O)(O)O
Reactant: O=C(F)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)F
Product: O=C(O)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)F

Procedure:
The crude product CF3CF2CF2OCH2CF2COF was rectified under nitrogen at ordinary pressure using a 10-stage Oldershaw rectification column to give 2020 g of CF3CF2CF2OCH2CF2COF. Its boiling point was 78° C. A 30-g portion of the CF3CF2CF2OCH2CF2COF obtained was hydrolyzed by gradually pouring the same into 30 g of dilute sulfuric acid with stirring. The product was washed several times with dilute sulfuric acid and then distilled under reduced pressure to give 20.5 g of pure CF3CF2CF2OCH2CF2COOH. The thus-obtained CF3CF2CF2OCH2CF2COOH had a boiling point of 84° C. at a pressure of about 2.7×103 Pa. A 5.9-g portion of the CF3CF2CF2OCH2CF2COOH obtained was dissolved completely in 29.8 g of pure water. The pH of the solution was 1.28. The pH was adjusted to 7 by adding an aqueous solution of sodium hydroxide dropwise. The resulting aqueous solution contained 19.8% by mass of CF3CF2CF2OCH2CF2COONa. The aqueous solution was dried under vacuum at 80° C., and the melting point of the CF3CF2CF2OCH2CF2COONa obtained (solid salt) was measured by DSC and found to be 191.8° C. A 0.2% (by mass) aqueous solution of this CF3CF2CF2OCH2CF2COONa had a surface tension of 68.5 mN/m. The surface tension of a 2.0% (by mass) aqueous solution thereof was 48.0 mN/m.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:26])[C:13]([NH:15][N:16]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]1[C:22]([O:24]C)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29][CH:28]=1>>[Br:21][C:18]1[CH:19]=[CH:20][N:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])[C:17]=1[C:22](=[O:24])[NH:33][C:31]1[CH:32]=[N:27][CH:28]=[N:29][CH:30]=1
Reactant: Nc1cncnc1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cncnc1
Yield: 62.3 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(benzyloxycarbonylamino)propanamido)-3-bromo-1H-pyrrole-2-carboxylate (0.81 g, 1.91 mmol) and pyrimidin-5-amine (1.45 g, 15.3 mmol) following the experimental procedure described in Preparation 44a. 0.58 g (62% yield) of the desired compound were obtained.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][N:10]1[C@@H:13]([CH3:14])[C@@H:12]([CH2:15][CH:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[C:11]1=[O:28].O.S([O-])(O)(=O)=[O:31].[Na+]>O1CCOCC1.CCOC(C)=O>[C:22]1([CH:19]2[CH2:20][CH2:21][CH:16]([CH2:15][C@H:12]([C@@H:13]([NH:10][O:9][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][O:3]3)[CH3:14])[C:11]([OH:28])=[O:31])[CH2:17][CH2:18]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)([O-])O
Reactant: C[C@H]1[C@@H](CC2CCC(c3ccccc3)CC2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NOC1CCCCO1)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of 3 N sodium hydroxide (18.7 mL) is added dropwise to a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(4-phenylcyclohexylmethyl)-4-methylazetidin-2-one (3.6 g, 0.010 mol) in dioxane (50 mL) at 25° C. and the mixture is stirred for 18 h. Water (10 mL) is added to the reaction mixture and an additional 5 mL of 3 N sodium hydroxide is added dropwise and the mixture is stirred an additional 8 h. The reaction mixture is mixed with water (200 mL), 1 M sodium hydrogen sulfate (60 mL) and EtOAc (100 mL). The aqueous phase is extracted with EtOAc. The combined organic phase is washed with water and saturated sodium chloride solution, dried (sodium sulfate) and concentrated in vacuo to give 3.44 g (92%) of (2R,3S)-2-(4-phenylcyclohexylmethyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as a white solid. The product is used without further purification:
Reaction SMILES: [Cl-].[CH3:2][C:3]([CH:25]=[CH:26][CH:27]=[C:28]([CH3:35])[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])=[CH:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:36][C:37](=[CH:40][CH:41]=[CH:42][CH:43]=[C:44]([CH3:47])[CH:45]=O)[CH:38]=O.CO.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CCCCCCC>[CH3:34][C:32]([CH3:33])=[CH:31][CH2:30][CH2:29]/[C:28](/[CH3:35])=[CH:27]/[CH:26]=[CH:25]/[C:3](/[CH3:2])=[CH:4]/[CH:5]=[CH:45]/[C:44](/[CH3:47])=[CH:43]/[CH:42]=[CH:41]/[CH:40]=[C:37](\[CH3:36])/[CH:38]=[CH:5]/[CH:4]=[C:3](\[CH3:2])/[CH:25]=[CH:26]/[CH:27]=[C:28](\[CH3:35])/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33]
Reactant: CC(C)=CCCC(C)=CC=CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C=O)=CC=CC=C(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCCC
Solvent: O
Product: CC(C)=CCC/C(C)=C/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(\C)CCC=C(C)C
Temperature: 30 °C
Reaction time: 3 h
Yield: 203.7 %

Procedure:
203.0 g of 3,7,11-trimethyldodeca-2,4,6,10-tetraen-1-yl-triphenylphosphonium chloride salt solution (purity 58.4%, E isomer/Z isomer ratio=3.4:1) and 14.4 g of 2,7-dimethyl-2,4,6-octatriene-1,8-dial were added into 55 ml of methanol. After 316 m; of an ethyl acetate/n-heptane (w/w=1:1) solvent mixture were added, the solution mixture was heated to 30° C. Then 470.0 g of a potassium carbonate solution by dissolving 170.0 g of potassium carbonate powder in 300 g of water were added dropwise. The solution mixture was heated to 60° C. and stirred for 3 hours. Thereafter, the temperature of the solution mixture was raised to 100° C. to remove as much organic solvents as possible, then cooled to 80° C. and stirred for 16 hours. 95.9 g of lycopene wet cake were obtained by filtration. Acetone and water were added to the wet cake separately for washing and rinsing treatments. After filtration and drying, 24.6 g of synthetic lycopene crystal were obtained. HPLC analysis revealed the lycopene crystal contained 75.7% of all-E-lycopene, 19.2% of 5Z-lycopene and 3.1% of other Z-isomers. UV assay of the lycopene=99.0%.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a solution of 5-bromovanillin (2.00 g, 8.65 mmol) in acetone (50 mL) was added potassium carbonate (1.4 g, 10.38 mmol) and dimethylsulfate (1 mL, 10.38 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 1.88 g of 3-bromo-4,5-dimethoxybenzaldehyde (89%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C:10]23[C:16]([CH3:18])([CH3:17])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH4+]>CCO>[Cl:21][C:5]1[C:6]([NH:9][C:10]23[C:16]([CH3:17])([CH3:18])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)=[C:7]2[N:8]=[C:32]([C:31]3[CH:30]=[CH:29][C:28]([N:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)=[CH:35][CH:34]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CC12CCC(Nc3c(Cl)cnc(N)c3N)(CC1=O)C2(C)C
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC12CCC(Nc3c(Cl)cnc4[nH]c(-c5ccc(N6CCOCC6)cc5)nc34)(CC1=O)C2(C)C
Temperature: 70 °C

Procedure:
4-(2,3-diamino-5-chloropyridin-4-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (10) (300 mg, 0.971 mmol), 4-morpholinobenzaldehyde (167 mg, 0.873 mmol) were taken in EtOH (15 ml) to which ammonium acetate (112 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with ethanol to afford the desired product (466 mg, 23%) as a yellow solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.91 (3H, s), 0.92 (3H, s), 1.09 (3H, s), 1.40-1.50 (1H, m), 1.70-1.80 (2H, m), 2.40-2.60 (1H, m), 3.00-3.10 (1H, m), 3.20-3.30 (4H, m), 3.72-3.80 (5H, m), 5.37 (1H, s), 7.09 (2H, d, J=8.8 Hz), 7.99 (2H, d, J=8.8 Hz), 8.02 (1H, s), 13.15 (1H, s). LCMS (254 nm): [M+H]+ 480.20 (95.88%) HPLC: 95.55% (220 nm)
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1I.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CC(C)([O-])C.[Na+]>O1CCOCC1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]([N:46]2[CH2:51][CH2:50][N:49]([C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:23])[CH2:48][CH2:47]2)=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Fc1cnccc1I
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCNCC2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCN(c3ccncc3F)CC2)CC1
Temperature: 100 °C
Yield: 43 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.184 g) and tri-o-tolylphosphine (0.244 g) were added to a suspension of 3-fluoro-4-iodopyridine (4.46 g), 1-[1-(t-butoxycarbonyl)piperazin-4-ylcarbonyl]piperazine (3.0 g) and sodium t-butoxide (2.12 g) in dry 1,4-dioxane (40 ml) under an atmosphere of argon. The mixture was heated at 100° C. for 18 hours. The mixture was cooled, diluted with diethyl ether (200 ml) and washed with saturated brine (40 ml). The aqueous layer was back-extracted with diethyl ether (2×100 ml). The ether layers were all combined, washed with saturated brine (2×100 ml), dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on alumina (N32-63) using 0.1-0.4% methanol in dichloromethane as eluent to give 1-(t-butoxycarbonyl)-4-[1-(3-fluoro-4-pyridyl)piperazin-4-ylcarbonyl]piperazine (1.7 g) as an orange solid: NMR (CDCl3): 1.47 (s, 9H), 3.25 (m, 8H), 3.45 (m, 8H), 6.75 (dd, 1H), 8.20 (dd, 2H); m/z 394 (M+1).
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].CC([O:19]O)(C)C.[OH-].[Na+].CCOCC.O>CO>[CH:2]([C@@H:3]1[O:19][C@H:4]1[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:1]
Reactant: COC(=O)c1cccc(/C=C/C=O)c1
Reactant: CC(C)(C)OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cccc([C@@H]2O[C@H]2C=O)c1
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
Methyl 3-(3-oxo-1E-propenyl)benzoate (0.67 g, 3.52 mmol) and 10 ml of methanol was added dropwise to 0.58 ml of 70% 1,1-dimethylethylhydroperoxide (4.2 mmol) in 5 ml of methanol. The pH was maintained at pH 8.0-8.5 throughout with 1N sodium hydroxide. The mixture was stirred at about 35° C. for 1.5 hrs. The reaction mixture was poured into ether/water and the ether layer was washed 3× with water and 1× with brine, dried over sodium sulfate, and concentrated. Flash chromatography using 10:1 followed by 2:1 hexane/ethyl acetate provided the product, methyl trans-3-(3-formyloxiranyl)benzoate as the pure trans epoxide.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:19][C:20]([NH2:22])=[S:21].II.[O-]S([O-])(=S)=O.[Na+].[Na+]>CCO>[NH2:22][C:20]1[S:21][C:8]([C:9]#[N:10])=[C:6]([C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[N:19]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: NC(N)=S
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1sc(N)nc1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-fluorobenzoylacetonitrile (50 g, 306 mmol, 1 eq.) in EtOH (600 mL) was added pyridine (24.7 mL, 306 mmol, 1 eq.). The resulting mixture was stirred at 70° C. for 15 min then cooled to r.t. A previously stirred suspension of thiourea (46.7 g, 613 mmol, 2 eq.) and iodine (77.8 g, 306 mmol, 1 eq.) in EtOH (300 mL) was then slowly added. After 1 h at r.t. a cold 1 M Na2S2O3 solution (360 mL) was added under stirring. The resulting precipitate was filtered, washed with water, and finally dried under vacuo to afford 2-Amino-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].Cl>C(O)(=O)C>[CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([N+:16]([O-:18])=[O:17])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: Cc1ccc2cc3ccccc3cc2c1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc2cc3ccccc3c([N+](=O)[O-])c2c1
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
Synthesis of 2-methyl-9-nitroanthracene ##STR12## Nitration of 2-methylanthracene (Source Aldrich) was carried out using the same procedure as in example 1 to yield the 2-methyl-9-nitroanthracene as a yellow solid. 2-Methylanthracene (2.0 g; 0.010 mole) was suspended in glacial acetic acid (25 ml) and to the stirred solution was added concentrated nitric acid (0.6 ml; 0.014 mole). The solution was stirred in a water bath at 20-25° C. for 4 hours, until the solution became clear. To the clear solution a mixture of conc. HCl and acetic acid (20 ml; 1:1) was added via a dropping funnel over a period of 15 minutes. A yellow solid precipitated out. The solution was stirred for further 30 minutes and filtered under suction. The product was treated by the same method as described in example 1 to give the 2-methyl-9-nitroanthracene as a yellow solid (1.8 g; 73%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([F:32])[CH:34]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2cccc(F)c2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 3-fluorobenzyl bromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.38 (m, 2H) 6.91-7.10 (m, 4H) 6.67-6.81 (m, 1H) 5.74-5.95 (m, 2H) 5.18-5.50 (m, 1H) 4.12-4.30 (m, 2H) 3.62-3.74 (m, 3H) 2.61-2.77 (m, 2H) 2.07-2.17 (m, 2H) 1.93-2.08 (m, 3H) 1.05 (s, 9H); LCMS (m/z) ES+=533 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C@H:19]1[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]1>CN(C=O)C>[CH3:24][C:21]1([CH3:25])[O:20][C@H:19]([CH2:18][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:23][O:22]1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2cccc([N+](=O)[O-])c2)O1
Temperature: 160 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
3-Nitrophenol (130; 2.0 g, 14.37 mmol) was taken up in 20 mL of anhydrous DMF along with anhydrous potassium carbonate (4.96 g, 35.93 mmol) and (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (131; 2.55 mL, 18.68 mmol). The resulting reaction mixture was heated in the microwave reactor, with stirring, at 160° C. for 4 h. The crude reaction mixture was rinsed with water, filtered and extracted with dichloromethane (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography using ethyl acetate:pentanes to obtain the desired product 132 as an amber-colored oil (52%).