Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7](/[C:9](=[CH:16]\[CH:17]([CH3:19])[CH3:18])/[CH:10]=[CH:11]/[C:12](OC)=[O:13])[CH3:8].C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[CH2:7]([C:9](=[CH:16][CH:17]([CH3:18])[CH3:19])[CH:10]=[CH:11][CH2:12][OH:13])[CH3:8]
Reactant: CCC(/C=C/C(=O)OC)=C\C(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(C=CCO)=CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a suspension of lithium aluminum hydride (5.41 g) in ethyl ether (550 ml) was added a solution of methyl (E,E)-4-ethyl-6-methyl-2,4-heptadienoate (35 g) in ethyl ether while keeping the temperature below 30° C. When addition was completed, the mixture was allowed to stir at room temperature for one hour. To this resultant mixture at 10° C. Were added dropwise ethyl acetate (100 ml) and a saturated solution of potassium sodium tartrate (50 ml). The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give 4-ethyl-6-methyl-2,4-heptadiene-1-ol (23.98 g) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[C:16]1([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:8])=[N:10][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)cn1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cn1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a stirred solution of 5-phenylamino-pyridine-2-carboxylic acid (0.26 g, 0.00121 mol) in DMF (2 mL) was added DIPEA (0.471 g, 0.00364 mol), HOBt (0.196 g, 0.00145 mol) and EDCI.HCl (0.278 g, 0.00145 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.203 g, 0.00146 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.32 g (88%) of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 300.13 (M+1)+, 97%. To a stirred solution [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester (0.32 g, 0.00107 mol) in a mixture of THF (5 mL), methanol (10 mL) and H2O (2 mL) was added LiOH.H2O (0.134 g, 0.00321 mol) at ambient temperature and the resulting mixture was stirred for 2 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.26 g (90%) of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]2)[CH2:70][CH2:69]1.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)=[O:31])[C:8]([N:77]2[CH2:76][CH2:75][N:74]([CH:71]3[CH2:72][CH2:73][O:68][CH2:69][CH2:70]3)[CH2:79][CH2:78]2)=[O:10])=[CH:4][C:3]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 100 mg (0.18 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid, 65 mg (0.20 mmol) TBTU and 35 μL (0.18 mmol) triethylamine in 10 mL THF was stirred for 1 h at RT. Then 40 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the reaction solution was stirred overnight. 20 mL semisaturated NaHCO3 solution was added, extracted twice with 40 mL EtOAc and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: C(OC(N1CC[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S@@:23](C)=[O:24])CC1)=O)C1C=CC=CC=1.C([C@](C([O-])=O)(O)[C@](CC)(O)C([O-])=O)C.[CH2:40]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53](C2C=CC=CC=2SC)[CH2:52][CH2:51]1)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(OO)(C)(C)C>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH2:40]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([C:22]2[C@@H:17]([CH3:14])[C:18](=[S:23]=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH2:52][CH2:51]1)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C[S@@](=O)c1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CSc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1C(C2CCN(C(=O)OCc3ccccc3)CC2)=CC=CC1=S=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
N-Benzyloxycarbonyl-4-[(R*)-2-methylsulfinylphenyl]-piperidine. To a solution of diethyl-D-tartarate (3.4 mL) in dichloromethane (50 mL) was added titanium tetraisopropoxide (3.0 mL) followed by water (0.18 mL). The resulting solution was stirred vigorously for 30 minutes, treated with N-benzyloxycarbony-4-(2-methylthiophenyl)piperidine (3.41 g), and cooled to -15° C. The reaction mixture was treated with tert-butylhydroperoxide (2 mL) drop wise over a period of 1 minute, and stirred at -15° C. for 40 hours. Water (4 mL) was added, and the solution was stirred vigorously for 1 hour and filtered through a bed of diatomous earth. The filtrate was stirred with 5% aqueous sodium hydroxide (100 mL) for 1 hour and was washed with brine (50 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers were washed (brine), dried (anhydrous sodium sulfate), and evaporated to give a solid product which was crystallized from diisopropyl ether to afford N-Benzyloxycarbonyl-4-[(R*)-2-methyl-sulfinylphenyl]piperidine (3.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Temperature: 120 °C
Yield: 40.2 %

Procedure:
A mixture of 8-bromo-5-hydroxy-2-oxo-3-phenyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (91 mg, 0.19 mmol), 3-tributylstannanyl-pyridine (0.092 mL, 0.29 mmol) and PdCl2(PPh3)2 (27 mg, 0.038 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified sequentially by flash chromatography (10-100% EtOAc/hexanes+1% AcOH) and preparative TLC (5% MeOH/CH2Cl2) to give 36 mg of the title compound. MS: (+) m/z 472.41 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH:18]([N:21]([C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=4)[CH2:22][C:23]#[CH:24])[C:12]=3[CH:13]=2)[N:8]=1)=[O:4]>FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:39])([CH3:38])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH:18]([N:21]([C:25]4[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=4)[CH2:22][C:23]#[CH:24])[C:12]=3[CH:13]=2)[N:8]=1)=[O:4]
Reactant: C#CCN(c1ccc(C(=O)OC(C)(C)C)cc1)C1CCc2cc3nc(COC(=O)C(C)(C)C)[nH]c(=O)c3cc21
Solvent: O=C(O)C(F)(F)F
Product: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(COC(=O)C(C)(C)C)[nH]c(=O)c3cc21
Yield: 114 %

Procedure:
A solution of tert-butyl 4-[N-((6RS)-2-(2,2-dimethylpropionyloxymethyl)-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-benzoate (80 mg, 0.15 mmol) in trifluoroacetic acid (5 ml) was stirred at room temperature with protection from the light for 1.5 h. The solvent was removed in vacuo and the residue triturated with 1:1 diethyl ether and hexane to yield the desired product as a white solid (81 mg, TFA salt); m.p. 133° C.; 1H-NMR (DMSO-d6) δ 1.23 (s, 9H, CO2CMe3), 2.22 (m, 1H, 7-H), 2.50 (m, 1H, 7-H), 3.03 (m, 2H, 8-H), 3.14 (s, 1H, propargyl CH), 3.97 (AB system, J=18.8 Hz, 2H, propargyl CH2), 4.95 (s, 2H, 2-CH2), 5.79 (t, J=8.6 Hz, 1H, 6-H), 7.03 (d, J=9.0 Hz, 2H, 3′-H, 5′-H), 7.51 (s, 1H, 9-H), 7.81 (d, J=6.6 Hz, 2H, 2′-H, 6′-H), 7.83 (s, 1H, 5-H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([OH:35])=[O:34])=[C:18]([CH2:21][S:22][C:23]3[N:27]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:26]=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([OH:35])=[O:34])=[C:18]([CH2:21][S:22][C:23]3[N:27]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:26]=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csnn1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCN(C)C)CS[C@H]12)c1csnn1
Yield: 26.6 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (350 mg.) and 7-amino-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (600 mg.) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (230 mg.).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5.00 g, 26.8 mmol) in DCM (200 ml) was added DIPEA (9.85 ml, 56.4 mmol) and then 4-(trifluoromethyl)benzenesulfonyl chloride (7.22 g, 29.5 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then reduced to dryness in vacuo, to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[C:22]([N+:26]([O-:28])=[O:27])=[C:21]([NH2:29])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:19]2[N:20]=[C:21]([NH2:29])[C:22]([N+:26]([O-:28])=[O:27])=[C:23]([NH2:25])[N:24]=2)[N:6]=1
Reactant: Nc1nc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: Fc1ccccc1Cc1n[nH]c2cccnc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc(N)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
A solution of 600 mg (2.64 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridine from example 4A, 501 mg (2.64 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine [Bitterli et al., Helv. Chim. Acta 1951, 34, 835], 48.4 mg (0.053 mmol) of tris(dibenzylideneacetone)dipalladium, 75.5 mg (0.158 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 1.20 g (3.70 mmol) of cesium carbonate in a degassed mixture of 10 ml of toluene and 10 ml of DMF is heated at 90° C. for 4 h. Cooling to room temperature is followed by filtration with suction and washing with THF. The solid is stirred with 100 ml of water and again filtered off with suction. 572 mg (57% of theory) of the desired compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:41]>ClCCl>[C:43]1([O:42][C:40]([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][N:8]3[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]4[C:26]5[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=5[CH:21]=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)=[O:41])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(C(=O)Oc5ccccc5)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of 2-isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (0.22 g, 0.55 mmol) and N,N-diisopropylethylamine (0.19 mL) in dichloromethane (5.0 mL) was added phenyl chloroformate (70 μL). The mixture was stirred at room temperature for 10 min, then concentrated in vacuo and purified via preparative reverse phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (98.4 mg, 0.13 mmol, 24%). (m/z): [M+H]+ calcd for C30H39N5O3 518.32. found 518.6. 1H NMR (300 MHz, MeOD-d3): δ (ppm) 1.14-1.28 (m, 2H), 1.39-1.53 (m, 6H), 1.52-1.62 (m, 2H), 1.70-1.78 (m, 2H), 1.92-2.06 (m, 4H), 2.82-2.97 (m, 6H), 3.32-3.38 (m, 2H), 3.43-3.50 (m, 1H), 3.52-3.69 (m, 2H), 4.04-4.12 (m, 1H), 4.18-4.26 (m, 1H), 6.91-6.98 (m, 1H), 7.08-7.13 (m, 1H), 7.21-7.28 (m, 1H), 7.45-7.50 (m, 1H), 7.73-7.77 (m, 1H), 7.81-7.87 (m, 1H), 9.02-9.32 (brs, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([OH:16])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[N+:35]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42])([O-:37])=[O:36]>ClCCl.CN(C=O)C>[N+:35]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH:42][C:14]([C:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])=[O:16])([O-:37])=[O:36]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(F)c(-c2ccccc2)cc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(F)c(-c2ccccc2)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
A stirring slurry of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid (1.0 g, 4.06 mmol) in dichloromethane (8.2 mL, 0.5 M) was treated with oxalyl chloride (1.1 mL, 12.2 mmol) and DMF (1 drop). The mixture was heated to 40° C. until the solution was clear (1–2 h). Next, the mixture was allowed to cool to room temperature, concentrated under reduced pressure, and then diluted with dichloromethane (8.2 mL, 0.5 M). To the stirring mixture at 0° C. was added diisopropylethyl amine (1.8 mL, 10.2 mmol) followed by 3-nitrobenzylamine hydrochloride salt (1.2 g, 6.1 mmol). Stirring under nitrogen, the solution was gradually warmed to room temperature and stirred overnight. The mixture was then diluted with dichloromethane and washed with 2N HCl (2×50 mL) and saturated aq NaCl (1×100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford a yellow oil. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide (1.0 g, 65%) as a yellow solid: Rf 0.33 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (bd t, J=6.2 Hz, 1 H), 8.10 (dd, J1=7.2 Hz, J2=2.4 Hz, 1 H), 7.84 (d, J=9.3 Hz, 1 H), 7.79 (d, J=7.5 Hz, 1 H), 7.63 (t, J=8.0 Hz, 1H), 7.52–7.43 (m, 5 H), 7.40–7.34 (m, 1H), 7.20 (d, J=12.9 Hz, 1H), 4.61 (d, J=6.0 Hz, 2 H), 3.96 (s, 3H).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([S:25][CH:26]([CH3:30])[CH2:27][CH:28]=[O:29])=[CH:21][CH:20]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:29][CH:28]([CH2:27][CH:26]([S:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([F:31])([F:17])[F:32])=[CH:20][CH:21]=1)[CH3:30])[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: CC(CC=O)Sc1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CC(C)Sc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 99 %

Procedure:
15.1 Grams of methyl acetoacetate were dissolved in 20 ml of water, and 19.4 g of a 28% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 1.64 g of sodium acetate and 6.44 g of tetrabutylammonium bromide were added thereto and then 60.3 g of a toluene solution containing 38.8% of 3-(4-trifluoromethylphenylthio)butanal were added thereto. The mixture was stirred at 45°-50° C. for 10 hours and then at room temperature for 12 hours. After the mixture had been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 34.24 g of crude 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-heptanone (purity: 82.7%, yield: 99.0%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:11]1([C:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CC=C(N2CCCCC2)CC1
Temperature: 25 °C

Procedure:
A flask equipped with a Dean-Stark trap and a reflux condenser was charged with 1-acetyl-piperdin-4-one (100 g, 0.71 mol) and toluene (1 L). Piperidine (63.4 g, 0.75 mol) and p-toluenesulfonic acid monohydrate (0.27 g, 1.4 mmol, 0.2 mol %) were added, and the resulting solution was heated at reflux for 8 h. The mixture was cooled to rt and concentrated to give a crude product which was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[C:7]1=[O:17].Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:7]1=[O:17]
Reactant: ClCCCN1CCOCC1
Reactant: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)c3cccc(OCCCN4CCOCC4)c3C2=O)c(OC)c1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
A mixture of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-isoindole-1,3-dione (313 mg, 1.00 mmol), 4-(3-chloropropyl)morpholine (160 mg, 1.11 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (5 mL) was heated at 60° C. for 18 hours. The mixture was diluted with ethyl acetate and extracted twice with 1N hydrochloric acid. The aqueous extracts were made basic with solid potassium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4) and concentrated to give a yellow solid which was recrystallised from methanol/petrol then ethyl acetate/chloroform/petrol to give the title compound (298 mg, 68%) as an off-white solid. 1H NMR (methanol-d4) 7.72 (1H, t), 7.41 (1H, d), 7.39 (1H, d), 7.02 (1H, d), 6.51 (1H, d), 6.43 (1H, dd), 4.72 (2H, s), 4.27 (2H, t), 3.81 (3H, s), 3.76 (3H, s), 3.68 (4H, t), 2.61 (2H, t), 2.50 (4H, m), 2.05 (2H, qn). MS: [M+H]+ 441.