Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([F:26])([F:25])[F:24])=[CH:11][C:10]=1[C:27]([N:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])C1C=CC=CC=1>CO.[Pd]>[CH2:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37][N:29]1[C:27]([C:10]1[CH:11]=[C:12]([C:23]([F:26])([F:25])[F:24])[C:13]([OH:15])=[CH:14][C:9]=1[OH:8])=[O:28]
Reactant: O=C(c1cc(C(F)(F)F)c(OCc2ccccc2)cc1OCc1ccccc1)N1Cc2ccccc2C1
Agent: [Pd]
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)c(O)cc1O)N1Cc2ccccc2C1
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-trifluoromethyl-phenyl)-(1,3-dihydro-isoindol-2-yl)-methanone (140 mg, 0.28 mmol) in methanol (5 mL) was hydrogenated at atmospheric pressure over 10% palladium on charcoal (34 mg) for 4 hours. A further portion of catalyst was added (31 mg) and hydrogenation continued for a further 1.5 hours. The mixture was filtered through Celite, eluting with methanol, then the filtrate was concentrated in vacuo to afford the title compound as a white solid (91 mg, quant.). 1H NMR (DMSO-d6) 10.79 (1H, s), 10.70 (1H, s), 7.40-7.35 (2H, m), 7.31-7.35 (3H, m), 6.61 (1H, s), 4.79 (2H, br.s), 4.68 (2H, br.s). MS: [M+H]+ 324.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[C:11]([N:21]2[C:33](=[O:34])[C:32]3[S:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[C:24]=3[CH2:23][CH2:22]2)(B2OC(C)(C)C(C)(C)O2)[CH:10]=[C:9]([F:35])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[NH:50][N:49]=[C:48]([CH:51]3[CH2:53][CH2:52]3)[CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CC#N>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:21]2[C:33](=[O:34])[C:32]3[S:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[C:24]=3[CH2:23][CH2:22]2)=[CH:10][C:9]([F:35])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]([CH:51]3[CH2:52][CH2:53]3)[NH:49][N:50]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Reactant: CC(=O)OCC1C=CC(F)=CC1(B1OC(C)(C)C(C)(C)O1)N1CCc2c(sc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 51.4 %

Procedure:
A 25 mL sealed vial was charged with (4-fluoro-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methyl acetate 212b (580 mg, 1.16 mmol), 136d (300 mg, 0.97 mmol), CH3COONa (160 mg, 1.94 mmol), K3PO4 (410 mg, 1.94 mmol), PdCl2(dppf) (100 mg, 0.12 mmol), CH3CN (12 mL), and H2O (1 mL). The mixture was heated at 110° C. for 2 hours. The reaction mixture was evaporated and the residue was purified by flash column eluting with 50:1 methylene chloride/methanol containing 0.5% triethylamine to give 136e as a black solid (300 mg, 52%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[C:39]1([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:39]1([N:45]2[CH2:50][CH2:49][N:48]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[C:8]([C:12]4[C:16]5[S:17][CH:18]=[CH:19][C:15]=5[O:14][N:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:47][CH2:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N2CCN(CCCOc3cccc(-c4noc5ccsc45)c3)CC2)cc1
Yield: 94 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 1-phenylpiperazine and potassium carbonate essentially as described above in example 4 except that the column is eluted with a mixture of dichloromethane:methanol (98:2). Combine the appropriate fractions and concentrate to give the title compound (0.36 g, 94% Yield) as an oil. Combine the appropriate fractions and concentrate to give the title compound (0.50 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=420 m/e.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO.[Pd]>[NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Yield: 94.8 %

Procedure:
A solution of 2.20 g (5.15 mmol) Cbz-Trp-NHBn in 60 mL of MeOH was subjected to hydrogenolysis over Pd/C to give 1.43 g (4.88 mmol, 95%) of Trp-NHBn. Characteristic analytical data are as follows: mp 112°-114° C.; 1H NMR (300 MHz, CDCl3) δ8.40-7.00 (m, 11H, Ar), 4.44 (d, J=6 Hz, 2H, CH2 --N), 3.77 (dd, J=4 Hz, 9H, H-α), 3.42 (dd, J=4, 14 Hz, 1H, H-β), 2.98 (dd, J=9, 14 Hz, 1H, H-β); mass spectrum (EI), m/e 293 (M+), 277 (M+ -NH2), 130 (M+ -H2N--CH--CONH-Bn); [α]D25 +42.1° (c=1.02, MeOH).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].[Br:13][C:14]1[N:19]2[C:20](=[O:23])[NH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[Br:13][C:14]1[N:19]2[C:20](=[O:23])[N:21]([CH2:2][CH2:1][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ccc2ccccc2n1
Reactant: O=c1[nH]nc2cccc(Br)n12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(Br)n12
Temperature: 130 °C
Yield: 9.3 %

Procedure:
2-Vinylquinoline (1-2) (218 mg, 1.40 mmol) and triazolopyridinone 2-3 (250 mg, 1.17 mmol) were placed in a microwave vial and dissolved in NMP (2 mL). To the mixture was added catalytic powdered KOH (10 mg, 0.18 mmol), and the vial was capped and heated at 130° C. under microwave irradiation for 20 min. After cooling, the mixture was diluted with CH2Cl2 (100 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography (40 g cartridge), eluting with 25-100% EtOAc/hexanes. The fractions containing the desired product (2-4) were pooled, and after solvent removal in vacuo, 40 mg (9%) of a white solid were obtained. 1H NMR (400 MHz, CHCl3-d): δ 8.08 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.69 (m, 1H), 7.50 (app t, J=7.6 Hz, 1H) 7.32 (d, J=8.8 Hz, 1H), 7.00 (d, J=11.6 Hz, 1H), 6.81 (dd, J=9.6, 7.2 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 4.51 (t, J=7.2 Hz, 2H), 3.52 (t, J=7.2 Hz, 2H). HRMS (ES) 369.0346 (M+H) found, 369.0349 required.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.C>[OH-].[OH-].[Pd+2].O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH2:29][CH3:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=NO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1nc(CC)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
Intermediate (17c) (3.5 g, 7.7 mmol) was dissolved in ethanol (100 mL, 2 mol). Pearlman's Catalyst, wet (0.1:0.4:0.5, palladium hydroxide:carbon black:water, 660 mg) was added. The mixture was degassed and stirred at room temperature under hydrogen for 3 hours. The palladium was filtered off and the solute was concentrated to yield intermediate (17d) (3.3 g). MS m/z: [M+H+] calcd for C26H31N3O4, 450.2; found 450.3.
Reaction SMILES: [C:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[C:4]=1[CH3:33])#[N:2].O.[CH:35]([B-](F)(F)F)=[CH2:36].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.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:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:18][CH:19]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH:35]=[CH2:36])[C:4]=1[CH3:33])#[N:2]
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c(C)c1OS(=O)(=O)C(F)(F)F
Reactant: C=C[B-](F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
To a solution of methyl 4-cyano-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (2.80 g) in THF (25.0 mL)-water (5.00 mL) were added potassium vinyltrifluoroborate (0.85 g), cesium carbonate (6.23 g) and tetrakis(triphenylphosphine)palladium(0) (0.38 g), and the mixture was stirred at 80° C. for 16 hr under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (0.80 g).
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O.O1CCOCC1>[O:7]=[C:6]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][N:5]1[CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]1
Reactant: COC(CN(C(=O)Nc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2ccn(-c3ccccc3)c2=O)CC1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
tert-Butyl 4-(1-(2,2-dimethoxyethyl)-3-phenylureido)piperidine-1-carboxylate (1.29 g, 3.17 mmol) was dissolved in a mixture of water (5 ml) and methanesulfonic acid (5 ml, 77 mmol). Reaction was heated to 100° C. and held with stirring for 20 minutes. Mixture was cooled to room temperature. Sodium carbonate (3.75 g, 35.4 mmol) was slowly added to the mixture. Mixture was made basic with aqueous sodium bicarbonate. 1,4-Dioxane (20 ml) was added to the mixture followed by di-tert-butyl dicarbonate (1.0 g, 4.58 mmol). Mixture stirred at room temperature for 18 hours. Reaction was quenched with aqueous ammonium chloride. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as white solid in 59% yield. MS (M−C5H8O2+H)+=244.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)(=O)=O.[CH3:22][CH2:23][O:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1)=[O:26]>[Pd].[Zn].C(OCC)(=O)C.ClCCl.C1C=CC=CC=1.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:33][C:30]2[CH:29]=[CH:28][C:27]([C:25]([O:24][CH2:23][CH3:22])=[O:26])=[CH:32][CH:31]=2)=[O:16])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCCCCc1ccc(Cl)cc1
Agent: [Pd]
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)CCCCCc2ccc(Cl)cc2)cc1
Temperature: 115 °C
Reaction time: 6 h

Procedure:
A mixture of 55 g. of mossy zinc, 5.4 g. of mercuric chloride, 90 ml. of water, and 3 ml. of concentrated hydrochloric acid is stirred for 5 minutes, and the solution is decanted. To the residue is suquentially added 35 ml. of water, 80 ml. of 37% hydrochloric acid, 45 ml. of toluene, and 30.0 g. of 5-p-chlorobenzoylvalerica cid. This mixture is refluxed at 115° C. for 28 hours, with the addition of 25 ml. of concentrated hydrochloric acid at 6 hour intervals. The solution is cooled, diluted with 100 ml. of water, and the organic layer is separated and saved. The aqueous layer is extracted with three 100 ml. portions of ether. The ether extracts and organic layer are combined, washed with 100 ml. of water, then 100 ml. of brine, dried over magnesium sulfate, and evaporated to an oil. This oil is distilled on a Kugelrohr apparatus collecting the fraction that boils at 160°-170° C. (60 mm.), giving 22.0 g. of 6-(p-chlorophenyl)hexanoic acid as an oil. To a solution of 19.0 g. of this oil in 200 ml. of benzene is added dropwise 33.1 g. of sulfonyl chloride. The mixture is refluxed 5 hours, cooled, and evaporated three times from 250 ml. of benzene, to yield 21.09 g. of brown liquid. This liquid is dissolved in 200 ml. of dichloromethane, and a solution of 28.4 g. of benzocaine in 200 ml. of dichloromethane is added, and the mixture is stirred overnight. The mixture is filtered, and the filtrate is extrcted with 100 ml. of 10% hydrochloric acid, 100 ml. of saturated sodium bicarbonate solution, and 100 ml. of brine; then it is dried over magnesium sulfate and evaporated to a solid. The solid is boiled in 400 ml. of toluene, treated with 1 g. of charcoal, filtered, and boiled down, giving 23.0 g. of crystalline solid. A 4.1 g. portion of this solid, 100 mg. of 10% palladium on carbon, and 50 ml. of ethyl acetate are hydrogenated in a Parr apparatus giving, after crystallization from toluene, 3.81 g. of the desired product as colorless crystals, m.p. 107°-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1O.[OH-].[Na+]>O>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[N:12]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cc(F)ccc1O
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Br)cc1-c1nc2cc(F)ccc2o1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g) and 2-amino-4-fluoro-phenol (0.586 g) placed in a round bottom flask was added polyphosphoric acid (10 g). The mixture was heated at 200° C. for 16 hours. After cooling, water (75 ml) was added and the mixture was stirred for 30 min. The mixture was basified to pH 12 with concentrated sodium hydroxide solution (6N and 2N). The solid was filtered, washed with water (150 ml×2), and ether (50 ml×2) to afford 5-bromo-3-(5-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (1.0 g). NMR Spectrum: (DMSOd6) 7.53 (ddd, 1H), 7.93 (dd, 1H), 7.99-8.06 (m, 3H), 8.52 (d, 1H), 8.56 (d, 1H); Mass spectrum: M+H+ 308-310
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl.C1(OC)C=CC=CC=1>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCNCC1
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a stirred solution of N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]benzamide (2 g, 4.3 mmol) in dichloromethane (80 mL) and anisole (2.4 mL) was added trifluoroacetic acid (8.4 mL, 109 mmol). After stirring for 4 h, the solvent was removed in vacuo. The residue was suspended in ether, sonicated for 0.25 h, stirred vigorously for 15 h, and filtered to give 1.93 g (94%) of a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3]1.[H][H]>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C@@H:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3]1
Reactant: [H][H]
Reactant: CC(=O)NCC1CC(=O)c2ccccc2O1
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CC(=O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
35.1 g of N-(4-oxochroman-2-ylmethyl)acetamide are suspended in 90 ml of toluene, and 1.6 ml of a 10 millimolar solution consisting of [Rh((S)-ToIBINAP)(COD)Cl] in toluene, are added under inert conditions. This suspension is hydrogenated in an autoclave at 100 bar of hydrogen and 100° C. After 12 hours, enantiomerically pure (>99% ee) (R)-N-(4-oxochroman-2-ylmethyl)acetamide is crystallised by cooling to room temperature. Drying gives 31.04 g of (R)-N-(4-oxochroman-2-ylmethyl)acetamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=3)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=3)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1
Reactant: COc1ccc(CC[C@H](CC(=O)O)NC(=O)[C@@H]2CCCN(C(=O)/C=C/C3CCN(C(=O)OC(C)(C)C)CC3)C2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CC[C@H](CC(=O)O)NC(=O)[C@@H]2CCCN(C(=O)/C=C/C3CCNCC3)C2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine (1.33 g) in ethyl acetate (10 ml) was added 4N HCl in 1,4-dioxane (5.53 ml) at 0° C., and the reaction mixture was stirred for 3 hours at room temperature. The precipitates were filtered, washed with diethyl ether and resolved in water, neutralized with saturated aqueous NaHCO3, desalted by using the resin of HP-20 eluting with isopropanol:H2O=(1:1), then freeze-dried to give N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine as a white powder (0.88 g, 79.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[CH3:21].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH2:20]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=3[S:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:28])=[CH:25][CH:24]=1)[CH3:21]
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
To a well stirred solution of 2-(4'-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.300 g, 1.11 mmol) and 4-ethoxybenzoyl chloride (0.555 g, 3.01 mmol) in CH2Cl2 (45 ml) was added AlCl3 (0.502 g, 3.76 mmol) portion-wise over a 15 minute period. After 45 minutes, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 70:30 EtOAc/hexanes) afforded the title compound (0.389 g, 0.93 mmol, 84%) as a white solid. Recrystallization (EtOAc/hexanes) afforded a highly pure, crystalline sample with mp 124°-125° C. 1H-NMR (CDCl3, 360 MHz): δ=7.77 (d,J=8.9 Hz, 2H, ArH), 7.52 (d,J=8.9 Hz, 1H, 8.8 Hz, 2H, ArH), 7.31 (d,J =2.4 Hz, 1H, ArH), 6.95 (dd,J=8.9,2.4 Hz, 1H, ArH), 6.76 (d,J=8.8 Hz, 2H, ArH), 6.75 (d,J=8.9 Hz, 2H, ArH), 4.01 (q,J=7.0 Hz, 2H, CH2), 3.88 (s,3H, --OCH3), 3.74 (s,3H, --OCH3), 1.39 (t,J=7.0, 3H, CH3); 13C-NMR (CDCl3, 90 Mhz): δ=193.1, 163.1, 159.7, 157.6, 142.3, 140.0, 134.0, 132.3, 130.6, 130.2, 126, 124.0, 114.7, 114.0, 114.0, 104.3, 63.7, 55.6, 55.2, 14.6. HRMS (EI) M+ calcd for C25H22O4S 418.1239, found 418.1241. Anal. Calcd for C25H22O4S: C, 71.75; H, 5.30; S, 7.66. Found: C, 71.68; H, 5.30; S, 7.61.
Reaction SMILES: [CH3:1][CH:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[C:12]([CH2:14][CH2:15][OH:16])[C:10](=[O:11])[NH:9][C:7]1=[O:8].O[N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][CH:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[C:12]([CH2:14][CH2:15][O:16][N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])[C:10](=[O:11])[NH:9][C:7]1=[O:8]
Reactant: CC(CCCn1cc(CCO)c(=O)[nH]c1=O)C(=O)O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCCn1cc(CCON2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)C(=O)O
Temperature: 25 °C
Yield: 91.8 %

Procedure:
1-(4-Methylcarboxybutyl)-5-(2-hydroxyethyl)uracil (13.2) no (6.213 g. 23 mmol) was dissolved in anhydrous tetrahydrofuran. N-Hydroxyphthalimide (7.505 g, 46 mmol) and triphenylphosphine (12.046 g, 46 mmol) were added and the solution stirred at ambient temperature. Diethylazodicarboxylate (9.95 g, 57 mmol) was added in 0.5 ml aliquots over 10 minutes, the reaction was then stirred for a further hour. The product was recrystallized twice from chloroform : diethyl ether mixtures to yield 1-(4-methylcarboxybutyl)-5-(2-phthalimidooxyethyl)uracil (13.3) (8.77 g, 91.8%). The structure was confirmed by mass spectroscopy and proton NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]3)=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/c2ccc(N)cc2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: COc1ccc(/C=C/c2ccc(N3CC(C(=O)O)CC3=O)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of (E)-4-[2-(4-methoxy-phenyl)-vinyl]-phenylamine with itaconic acid yields the (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a brown solid; MS: m/e=336 (M−H)+.