Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:27][CH2:26][O:25][C:5]2=[C:6]([CH:24]=1)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:22]#[N:23].[CH2:28]([O:31][CH3:32])[C:29]#[CH:30].N1CCCC1.[Cl-].[NH4+]>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:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[NH:7][C:6]1[CH:24]=[C:2]([C:30]#[C:29][CH2:28][O:31][CH3:32])[CH:3]=[C:4]3[O:27][CH2:26][O:25][C:5]=13)=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)#[N:23]
Reactant: C#CCOC
Reactant: COc1cc2ncc(C#N)c(Nc3cc(Br)cc4c3OCO4)c2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Product: COCC#Cc1cc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2c(c1)OCO2
Temperature: 80 °C
Yield: 21.9 %

Procedure:
A mixture of 4-(5-bromo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline (0.15 g), methyl 2-propynyl ether (0.049 g), tetrakis(triphenylphosphine)palladium(0) (0.02 g) and pyrrolidine (2 ml) was stirred and heated to 80° C. for 8 hours. The resultant mixture was cooled to ambient temperature, poured into a dilute aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and with a saturated brine solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.032 g); NMR Spectrum: (CDCl3) 3.4 (s, 3H), 3.77 (s, 3H), 4.04 (s, 3H), 4.24 (s, 2H), 5.97 (s, 2H), 6.65 (br s, 1H), 6.73 (d, 1H), 6.78 (d, 1H), 6.99 (s, 1H), 7.38 (s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=O)[CH2:13][CH2:14][C:15](=[O:17])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26].CN(C)C=O.C1(OP(N=[N+]=[N-])(=O)OC2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C>[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:26][C:18](=[O:20])[C@H:12]([CH2:13][CH2:14][C:15](=[O:17])[NH2:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of Nα -benzyloxycarbonyl-L-glutamine, 56 g., and L-tryptophan methyl ester hydrochloride, 56 g., in 300 ml. of dimethylformamide at 5° C. is added diphenylphosphorazidate, 47.5 ml., in 100 ml. of dimethylformamide dropwise over ten minutes followed by 61.6 ml. of triethylamine over one hour. The mixture is stirred in an ice bath for three hours and at room temperature for 18 hours. After evaporation the residue is dissolved in 1 l. of ethyl acetate and washed successively with 500 ml. of 1N hydrogen chloride solution, 500 ml. of a saturated solution of sodium bicarbonate and 500 ml. water. The ethyl acetate layer is separated, dried, evaporated and 74.2 g. of Nα -benzyloxycarbonyl-L-glutaminyl-L-tryptophan methyl ester is obtained by recrystallization from methanol; m.p. 197°-198° C.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([O:15]C)[CH:6]=1)(C)(C)C.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[Al+3].[Cl-].[Cl-].[Cl-]>CN(C=O)C.C1(C)C(C)=CC=CC=1>[N:17]1([S:11]([C:8]2[CH:9]=[CH:10][CH:5]=[CH:6][C:7]=2[OH:15])(=[O:12])=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(C)(C)C)ccc1S(=O)(=O)Cl
Reactant: C1CCNC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of 4-tert-butyl-2-methoxybenzenesulfonyl chloride (258 mg, 0.99 mmol) in DMF (6 ml) was added pyrrolidine (70 mg, 0.99 mmol) and the solution was stirred at ambient temperature for 30 minutes, and concentrated in vacuo. The residue was dissolved in xylene (10 ml) and then added to mixture of AlCl3 (525 mg, 3.39 mmol) in xylene (5 ml). The resulting mixture was stirred for 18 h at 70° C. After colling the mixture was poured into stirred ice-cold water, and extracted with ether (2×30 ml). The ether layer was dried over sodium sulfate, filtered and concentrated to give 120 mg of subtitle compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:21]([C:23]1[S:27][C:26](=[N:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39](I)=[CH:38][CH:37]=2)[N:24]=1)[CH3:22].C(OCC)(=O)C>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[C:12]([N:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:39]2[CH:40]=[CH:41][C:36]([CH2:35][N:25]3[N:24]=[C:23]([CH2:21][CH3:22])[S:27][C:26]3=[N:28][C:29](=[O:34])[C:30]([F:31])([F:33])[F:32])=[CH:37][CH:38]=2)=[N:8][N:9]=[N:10]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Reactant: CC(C)(C)n1nnnc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnnn3C(C)(C)C)cc2)c(=NC(=O)C(F)(F)F)s1
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 5-phenyl-1-tert-butyl-1H-tetrazole (1.0 g) in tetrahydrofuran (20 ml) was added dropwise n-butyl lithium (1.6M hexane solution, 3.5 ml) keeping the temperature below -20° C., followed by stirring at -5° C. for one hour. Zinc chloride (1.0M diethyl ether solution, 6.0 ml) was added dropwise to the reaction mixture keeping the temperature below -30° C., followed by stirring at room temperature for 2 hours. To the resulting mixture were added 5-ethyl-3-(4-iodobenzyl)-2-trifluoroacetylimino-1,3,4-thiadiazoline (1.2 g) and tetrakis(triphenyl-phosphine)palladium (100 mg), and they were heated under reflux overnight. Ethyl acetate (100 ml) was added to the reaction mixture, and the resulting mixture was washed with 10% aqueous citric acid solution and dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was separated by column chromatography on silica gel, whereby 830 mg of the title compound was obtained in the oily form.
Reaction SMILES: [CH3:1][C:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[C:3]([O:5]C)=[O:4].O.[OH-].[Li+]>C1COCC1.CO>[CH3:7][C:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)Sc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Sc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Methyl 2-methyl-2-(phenylthio)propanoate (1.126 g, 5.35 mmol) was dissolved in THF (15 mL) and methanol (5 mL). That solution was treated with an aqueous solution of lithium hydroxide monohydrate (1.12 g, 26.8 mmol in 5 mL of water). The reaction mixture was stirred at rt overnight. The volatiles were removed and the remaining aqueous solution was acidified with a 1 N HCl solution to pH 2. Ethyl acetate was added and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated to provide the desired carboxylic acid as a white solid (1.020 g, 97.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24]C)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1([CH3:16])[CH3:15])=[O:9].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[C:18]([OH:24])=[CH:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1([CH3:16])[CH3:15])=[O:9]
Reactant: COc1ccc(F)cc1-c1ccc(C(=O)N2CCCC2(C)C)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCCN1C(=O)c1ccc(-c2cc(F)ccc2O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step c) (0.6 g) in DCM (10 mL) was treated with 1.0 M boron tribromide in DCM (5 mL) and the reaction was stirred at rt overnight. The reaction was diluted with DCM and washed with ice water, dried (MgSO4) and concentrated under reduced pressure to give the sub titled product as a solid (0.5 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][OH:15]>C(O)CCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][OH:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: NCCO
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Cl)ccc1NCCO
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 1,4-dichloro-2-nitrobenzene (I-1, Aldrich, Wis.; 38.4 g, 0.2 mol) and 2-aminoethanol (24.4 g, 0.4 mol, 2 eq.) in n-butanol (100 mL) was refluxed overnight. The solvent was evaporated and the residue was dispersed in petrol ether (600 mL) and stirred overnight. The solids were filtered to give intermediate I-2 as a yellow powder (37 g, 86%). 1H-NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 8.19˜8.20 (d, 1H, J=2.4 Hz), 7.39˜7.42 (dd, 1H, J1=2.4 Hz, J2=9.2 Hz), 6.87˜6.90 (d, 1H, J=9.6 Hz), 3.95˜3.98 (t, 2H, J=5.2 Hz), 3.49˜3.53 (dd, 2H, J1=4.8 Hz, J2=10.4 Hz). MS (ESI): m/z 217 (M+H+).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C2CC(OC)OC2OC)=CC=1.[CH3:22][O:23][CH:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)=[CH:27][CH:26]([O:43][CH3:44])[O:25]1>>[CH3:22][O:23][CH:24]1[CH:28]([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)[CH2:27][CH:26]([O:43][CH3:44])[O:25]1
Reactant: COC1C=C(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Agent: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Product: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran, 4′-(2,5-dimethoxy-2,5-dihydro-furan-3-yl)-biphenyl-4-carbonitrile (260 mg, 0.846 mmol) was reduced in 2 hours to give 260 mg (99%) of 4′-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitrile as a white solid, mp 149-50° C., which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C(O[CH2:13][C:14]([N:16]([C@@H:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][C@H:22]1[NH:30][C:31]([C:33]1[NH:34][C:35]2[C:40]([CH:41]=1)=[CH:39][C:38]([Cl:42])=[CH:37][CH:36]=2)=[O:32])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])(=O)C>C1COCC1>[Cl:42][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:31]([NH:30][C@@H:22]1[CH2:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:21]1[N:16]1[C:14](=[O:15])[CH2:13][O:19][C:18](=[O:20])[CH2:17]1)=[O:32])=[CH:41]2
Reactant: CC(=O)OCC(=O)N(CC(=O)O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CN([C@@H]2c3ccccc3C[C@H]2NC(=O)c2cc3cc(Cl)ccc3[nH]2)C(=O)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
Potassium carbonate (20 mg) and MeOH (1 mL) were added to a solution of N-{(1R,2R)-1-[N-(2-acetoxyacetyl)-N-(carboxymethyl)amino]-2,3-dihydro-1H-inden-2-yl}-5-chloroindole-2-carboxamide (Example 35, 184 mg, 0.38 mmol) in THF (5 mL) and the reaction was stirred at ambient temperature for 24 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in water and acidified to pH 2.0 and then extracted into EtOAc (3×10 mL). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:4) to afford the title compound (50 mg, 31%) as a white solid.
Reaction SMILES: C[N:2]([CH3:15])/[CH:3]=[CH:4]/[C:5]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1CN.CN1C(=O)N(C)CCC1>CCOC(C)=O.CCCCCC>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:15][N:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:9][CH:10]=[C:11]([C:13]#[N:14])[CH:12]=2)[C:7]1=[NH:8]
Reactant: CN(C)/C=C/c1cc(C#N)ccc1C#N
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(Cn2ccc3cc(C#N)ccc3c2=N)c(OC)c1

Procedure:
The product from Example 147 Part A (1.85 g, 9.38 mmol) and 2,4-dimethoxybenzylamine (2.6 mL, 15.03 mmol) were heated with 5 mL of DMPU at 140° C. for 3 h under N2. The reaction mixture was cooled, and EtOAc/hexane (1:2) was added. The precipitate formed was filtered and dried in vacuo to give 2.5 g of the desired product. 1H-NMR (400 MHz, DMSO-d6) δ 3.72 (s, 3H, 3.81 (s, 3H), 4.95 (s, 2H), 6.10 (d, J=7.03 Hz, 1H, 6.44 (d, J=7.91 Hz, 1H), 6.57 (s, 1H), 7.02 (d, J=8.35 Hz, 1H), 7.22 (d, J=6.15 Hz, 1H) 7.68 (d, J=7.91 Hz, 1H), 7.94 (s, 1H), 8.34 (d, J=7.91 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12](OCC)(=O)C>>[N+:8]([C:6]1[CH:7]=[C:2]2[CH:1]=[CH:12][NH:11][C:3]2=[N:4][CH:5]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])cnc1N
Reactant: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1

Procedure:
5-Nitro-1H-pyrrolo[2,3-b]pyridine 506 of is prepared by reacting 3-methyl-5-nitro-pyridin-2-ylamine 505 with t-butyloxycarbonyl anhydride in an appropriate solvent (e.g. ethyl acetate and hexanes). Concentration and extraction provides a Boc-protected intermediate that is then reacted with 2 equivalents of butyllithium in an appropriate polar solvent (e.g. tetrahydrofuran) with cooling (e.g. 0° C.), followed by the addition of dimethylformamide and stirring for 30 minutes to one hour, followed by addition of 5.5 M HCl. Isolation by conventional means (e.g. extraction and silica gel chromatography) provides 506. (Hands et. al., Synthesis 1996, 877-882.)
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].C(C1C=CC=CC=1)C.C(S)CCCCCCCCCCC.C(OOC1(OOC(C)(C)C)CC(C)CC(C)(C)C1)(C)(C)C>>[CH:1]([CH2:12][C:10](=[CH2:11])[C:9]([OH:14])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C=C(C)C(=O)O
Agent: CC1CC(C)(C)CC(OOC(C)(C)C)(OOC(C)(C)C)C1
Agent: CCCCCCCCCCCCS
Solvent: CCc1ccccc1
Product: C=C(CC=Cc1ccccc1)C(=O)O

Procedure:
A mixture of 78.0 parts by weight of styrene, 2.0 parts by weight of methacrylic acid, 20 parts by weight of ethylbenzene, 0.02 parts by weight of n-dodecyl mercaptan, and 0.03 parts by weight of 1,1-bis(t-butylperoxy)-3,3,5-trimethylcyclohexane as an initiator was continuously supplied into a coil type complete mixing reactor at a rate of 2.5 l/hr. so that the reaction mixture was allowed to undergo polymerization at a temperature of 150° C. for an average retention time of 2 hours with a polymer solid concentration of 47%. Subsequently, the polymerization solution was introduced into a 230° C. devolatizing apparatus where the unreacted monomers and the solvent were removed to obtain a styrene-methacrylic acid copolymer. The copolymer thus obtained exhibited a styrene/methacrylic acid weight ratio of 96/4, a weight-average molecular weight of 120,000 and a number-average molecular weight of 63,000 (hereinafter referred to as "SMAA-3").
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:9]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[O:31]=[C:32]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1>C1COCC1>[O:14]=[C:12]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9](=[O:22])[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]1[C:32]1([OH:31])[CH2:33][N:34]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: O=C1CN(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(C2C(=O)N(Cc3ccccc3)CC(=O)N2Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.38 h
Yield: 49.6 %

Procedure:
To a solution of commercially available 1,4-bis(phenylmethyl)piperazine-2,5-dione (2.0 g, 6.8 mmol) in dry THF (50 mL) at −78° C. was added lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.4 mL, 6.8 mmol). The resulting reddish brown suspension was stirred for 23 min at −78° C., and then a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (770 mg, 4.5 mmol) in THF (10 mL) was added over 30 min by syringe pump. The mixture became a bright yellow solution as it was allowed to warm to room temperature over 3 hours. The mixture was quenched with saturated aqueous ammonium chloride. Water was added to dissolve precipitated salts, and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (60% ethyl acetate:40% hexanes) to provide 1,1-dimethylethyl 3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate as a colorless foam (1.04 g, 2.23 mmol, 50% yield). 1H NMR. (400 MHz, CDCl3): 7.39-7.29 (m, 7H), 7.23-7.19 (m, 3H), 5.34 (d, 1H), 4.82 (d, 1H), 4.58 (d, 1H), 4.37 (d, 1H), 4.37 (d, 1H), 4.22 (d, 1H), 4.15 (s, 1H), 4.08 (d, 1H), 3.97 (d, 1H), 3.75 (d, 1H), 3.74 (d, 1H), 3.67 (d, 1H), 3.64 (br s, 1H), 1.43 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:19][C:20]1[C:25](F)=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=1[F:30]>CN(C)C=O>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([O:18][C:25]2[C:24]([F:27])=[C:23]([F:28])[C:22]([F:29])=[C:21]([F:30])[C:20]=2[F:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.7 %

Procedure:
A stirred suspension of sodium hydride (60% in oil, 1.6 g) in 50 ml of dimethylformamide was treated with 7.0 g of 1-acetyl-4-hydroxy-4-phenylpiperidine in 100 ml of dimethylformamide. After the evolution of gas had ceased, the mixture was cooled to ice bath temperature and a solution of 6.88 g of hexafluorobenzene in 50 ml of dimethylformamide was added, dropwise. After stirring for 20 hours at ambient temperature the mixture was poured into ice water and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane to yield 9.06 g (73.5%) of 1-acetyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 115°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([C:15]([O:17][CH3:18])=[O:16])[C:12](=O)[CH3:13])[C:3]=1[C:4]([OH:6])=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[Si](OCC)(OCC)OCC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CO.O.CN(C)C=O>[CH3:18][O:17][C:15]([C:11]1[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][CH:8]=2)[C:4](=[O:6])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]=1[CH3:13])=[O:16]
Reactant: Nc1ccccc1
Reactant: COC(=O)C(C(C)=O)c1cccc(Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CCO[Si](OCC)(OCC)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c(Cl)cccc12
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of 2-chloro-6-(1-methoxycarbonyl-2-oxo-propyl)-benzoic acid (4 g, 15 mmol), aniline (1.369 ml, 15 mmol) and tetraethoxysilane (6.65 ml, 30 mmol) in methanol (20 ml) was sealed and heated under microwave irradiation at +150° C. for 20 min. The obtained solution was diluted with water (150 ml) and extracted with ethyl acetate (2×300 ml). The combined organic solution was dried (MgSO4) and evaporated. The obtained crude enamine (2-chloro-6-(1-methoxycarbonyl-2-phenylamino-propenyl)-benzoic acid) was dissolved in dimethylformamide (80 ml) followed by addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 4.3 g, 22.5 mmol) and 1-hydroxybenzotriazole (HOBT, 3.04 g, 22.5 mmol). It was stirred for 16 hours and partitioned between water (250 ml), diethyl ether (250 ml) and ethyl acetate (150 ml). The organic phase was washed with 0.5 M NaOH (2×100 ml), brine (2×200 ml), dried (MgSO4) and evaporated to give 4.25 g of brown oil, which was used in the next step without further purification. Yield 87%. LC-MS (m/z) 328.0 (MH+); tR=1.36. 1H NMR (500 MHz, CDCl3): 2.02 (s, 3H), 3.98 (s, 3H), 7.23 (d, 2H), 7.44-7.55 (m, 6H).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:16]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH3:19]>O1CCOCC1>[CH2:16]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]2=[O:8])=[O:26])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C1CCCCCN1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCOc1ccc(C(=O)C2CCCCNC2=O)cc1
Reaction time: 3 h
Yield: 561.5 %

Procedure:
To a 1 liter flask equipped with drying tube, condenser and overhead stirrer is charged 0.13 moles of caprolactam, 0.16 moles of triethylamine and 150 ml of dioxane. The resultant solution is heated to reflux, and a solution of 0.13 moles of 4-butoxybenzoyl chloride in 50 ml of dioxane is added over 15 minutes. The mixture is refluxed with stirring for 3 hours followed by stirring at room temperature for a further 18 hours. The mixture is filtered, and the solvent removed by rotary evaporation leaving a brown oil which is recrystallized from 25 ml of carbon tetrachloride to yield 0.73 moles of 4-butoxybenzoyl caprolactam which NMR shows to be 90% pure. The 4-butoxybenzoyl caprolactam has a melting point of approximately 87-92° C. 1H NMR reveals 0.9 ppm (t, 3H); 1.2-1.8 ppm (m, 12H); 2.7 ppm (m, 2H); 3.8 ppm (m, 2H); 4 ppm (t, 2H); 6.9 ppm (d, 2H); 7.5 ppm (d, 2H). 13C NMR provides 14 ppm (s); 20 ppm (s); 24 ppm (s); 29 ppm (d); 31 ppm (s); 39 ppm (s); 46 ppm (s); 68 ppm (s); 114 ppm (s); 128 ppm (s); 131 ppm (s); 162 ppm (s); 174 ppm (s); 178 ppm (s). IR (cm−1) at 2933, 1677, 1604, 1254.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>CN(C)C=O>[C:14]([C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[O:10][CH2:2][CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:15]
Reactant: CCOC(=O)/C=C/CBr
Reactant: N#Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C=CCOc1cccc(C#N)c1

Procedure:
1 g (3.9 mmol) of ethyl 4-bromocrotonate, 465 mg (3.9 mmol) of 3-hydroxybenzonitrile, 539 mg (3.9 mmol) of potassium carbonate and 647 mg (3.9 mmol)) of potassium iodide were stirred in N,N-dimethylformamide at room temperature for 3 days. 1 N hydrochloric acid was added to the reaction liquid. After the extraction with ethyl acetate, the extract was washed with 1 N aqueous sodium hydroxide solution and saturated aqueous common salt solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.