Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:6]=1[C:7](O)=[O:8].C1C=CC2N(O)N=NC=2C=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[N+:14]([C:10]1[C:6]2[C:7](=[O:8])[NH:1][CH2:2][CH2:3][NH:4][C:5]=2[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: NCCNc1cccc([N+](=O)[O-])c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: O=C1NCCNc2cccc([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirred solution of 2-(2-amino-ethylamino)-6-nitro-benzoic acid (0.35 g, 0.0013 mol) in DMF (10 mL) was added HOBt (0.22 g, 0.0016 mol), BOP (0.71 g, 0.0016 mol) and N-methylmorpholine (0.18 mL, 0.0016 mol) at 0° C. under nitrogen. The reaction was stirred for at 0° C. for 1 h then warmed to room temperature overnight. The reaction was diluted with ethyl acetate (20 mL) and washed with water, 10% aqueous HCl, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by ISCO purification using 5-15% methanol-methylene chloride to give desired 6-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.22 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 9.9 (s, 1H), 7.41 (t, 1H, J=7.6 Hz), 7.12 (d, 1H, J=7.6 Hz), 6.95 (d, 1H, J=7.6 Hz), 3.92 (broad s, 1H), 3.25 (m, 2H), 2.73 (m, 2H); MS (m/e) 208 (M+1).
Reaction SMILES: [OH:1][CH:2]([NH:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:11]=1)=[O:9])[C:3]([F:6])([F:5])[F:4].[H-].[Na+].[CH3:31]I>ClCCl.CN(C=O)C.CCCCCC>[CH3:31][O:1][CH:2]([NH:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)[N:11]=1)=[O:9])[C:3]([F:6])([F:5])[F:4]
Reactant: CI
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(O)C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(OC)C(F)(F)F)c1

Procedure:
0.6 g (0.0015 mol) of N-(1-hydroxy-2,2,2-trifluoroethyl)-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide was dissolved in a mixed solvent of dichloromethane and DMF. The obtained solution was mixed with 0.064 g (ca. 60% in mineral oil; 0.0015×1.1 mol) of NaH and then with 0.42 g (0.0015×2.0 mol) of methyl iodide, followed by treating the solution under reflux for about 8 hours. The reaction solution was distributed in hexane-saturated sodium bicarbonate water and washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2Br)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[N:71]1[CH2:72][CH2:73][N:68]([CH3:67])[CH2:69][CH2:70]1)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cc(=O)c2cc(OCC)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(OCC)cc(N3CCN(C)CC3)c2o1
Temperature: 80 °C
Yield: 94.3 %

Procedure:
Into a 100 mL, 3 neck round bottom flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet is added 350 mg (1.03 mmol, 1.0 equiv.) of 8-Bromo-6-ethoxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (Reference Example 23b), 18.9 mg (0.02 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 77 mg (0.123 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 1 g of 4 A molecular sieves and 60 mL of dry toluene. To the stirred suspension is then added 113 mg, 1255 μL, (1.13 mmol, 1.1 equiv.) of 1-methylpiperazine, followed by 470 mg (1.44 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 3 days. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous earth, with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 40% methanol in methylene chloride as eluent, yielded 350 mg (75%) of the desired product as a yellow solid. Mass Spec.: calc. for [C19H24N2O5+H]+ Theor. m/z=361; Obs.=361
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=1.[OH-].[Na+].O1CCCC1.Cl>O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[N:21][C:12]=1[CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cccc(OCc2ncc3ccccc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(OCc2ncc3ccccc3n2)c1

Procedure:
A mixture of 5.50 g (0.01869 moles) of 3-(2-quinazolinylmethoxy)benzoic acid methyl ester, 30.1 ml (0.0301 moles) of 1N sodium hydroxide and 22 ml of tetrahydrofuran is heated at reflux for 50 minutes. The mixture is allowed to come to room temperature and evaporated in vacuo giving a solid residue. After the addition of water and filtration through Celite the filtrate is acidified with 2.4M hydrochloric acid. The resulting precipitate is filtered, washed with water until the washings are pH 6. The precipitate is dried overnight in a vacuum desiccator and azeotroped with toluene on a rotoevaporator. Drying in vacuo gives the title compound, 4.75 g colorless solid, m.p. 221°-224° C.; IR (KBr) 1695, 1576, 1285, 1220 cm-1 ; NMR (DMOS-d6) 9.73 (s, 1H), 7.34-8.22 (8H, aromatic) 5.56 (2H, s), 3.43 (1H, broad).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.N1CCCC1>C(O)C>[CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:22]2\[C:23](=[O:28])[NH:24][C:25]3[C:21]\2=[CH:20][C:19]([F:18])=[CH:27][CH:26]=3)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2]
Reactant: CCNCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNC1
Solvent: CCO
Product: CCNCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Yield: 95.6 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (99 g), ethanol (400 mL), 5-fluoro-2-oxindole (32 g) and pyrrolidine (1.5 g) were refluxed for 3 hours with stirring. The mixture was cooled to room temperature and the solids collected by vacuum filtration. The solids were stirred in ethanol at 60° C., cooled to room temperature and collected by vacuum filtration. The product was dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (75 g, 95% yield). 1H-NMR (dimethylsulfoxide-d6) δ 1.03 (t, 3H, CH3), 2.42, 2.44 (2×s, 6H, 2×CH3), 2.56 (q, 2H, CH2), 2.70, 3.30 (2×t, 4H, 2×CH2), 6.85, 6.92, 7.58, 7.72, 7.76 (5×m, 5H, aromatic, vinyl and CONH), 10.90 (br s, 1H, CONH), 13.65 (br s, 1H, pyrrole NH). MS m/z 369 [M−1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(OCC)(=O)C>C1COCC1>[Cl:21][CH2:20][CH2:19][CH2:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-chlorophenylacetic acid (1 g) in THF (30 mL) was stirred at −78° C. for 20 minutes. n-Butyl lithium (2.66 M solution in hexane, 4.41 mL) was added to the solution, and the reaction solution was stirred at −78° C. for one hour. Thereafter, the reaction solution was stirred at 0° C. for one hour, 1-bromo-3-chloropropane (0.638 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 18 hours. Thereafter, ethyl acetate and 1 N aqueous 2hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.55 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)([CH3:29])[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH2:27])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H]>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH:1]([CH3:29])[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH2:27])=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)cc1)C(N)=O)C(C)C
Yield: 54.5 %

Procedure:
Fmoc-N-Me-Val-N-Me-Tyr(Bzl)-NH2(802 mg, 1.29 mmol) was dissolved in a mixed solution of MeOH (6 ml) and ethyl acetate (6 ml), mixed with 20% palladium hydroxide-carbon (150 mg), followed by stirring in a hydrogen atmosphere at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol 10:1) to give the titled compound (216 mg, 55%).
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].P.[C:23]1([CH2:29][SH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Pd]>[CH2:29]([S:30][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Agent: [Pd]
Agent: P
Product: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriate solvent is added base under nitrogen atmosphere, followed by Pd catalyst, phosphine ligand and phenylmethanethiol. The reaction is generally carried out at high temperature (80-130° C., prefer 90-110° C.) and normally complete within several hours (8-24 h, prefer 12-18 h). Methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([Cl:18])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[Br:26][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16]([F:17])[C:2]=2[Cl:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OCc1c(Cl)ccc(F)c1Cl
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. A stirring solution of 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.07 g, 0.03 mol) in acetonitrile was cooled to 0° C. using an ice bath. To this solution was added NBS (5.33 g, 0.03 mol) portionwise. The reaction was stirred at 0° C. for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc (500 mL), and purified via silica gel chromatography. The solvents were then removed in vacuo to yield 5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (5.8 g, 0.015 mol, 51%) as a white crystaline solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26](OCC)=[O:27])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].OC1C=CC=CC=1[N:38](CC)N1C(C([O-])=O)=CC(NC2C=CC=CC=2OC)=NC1.[CH2:59]([OH:61])C>[Pd]>[OH:25][CH2:24][C:20]1[CH:19]=[C:18]([NH:17][C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:59](=[O:61])[N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:26]([NH2:38])=[O:27])[N:4]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCN(c1ccccc1O)N1CN=C(Nc2ccccc2OC)C=C1C(=O)[O-]
Reactant: CCO
Reactant: CCOC(=O)c1nc(Nc2cccc(CO)c2)nc(Nc2ccccc2OC)c1N
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3cccc(CO)c3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Ethyl 5-amino-2-(3-(hydroxymethyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl-5-nitro-2-(3-(hydroxy(ethyl)phenylamino)-6-(2-methoxy-phenylamino)pyrimidine-4-carboxylate (0.35 g, 0.797 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.087 g) was added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 h, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using biotage chromatography (50-100% ethyl acetate in hexanes) to afford the title compound (0.277 g, 85%). MS (ESI) m/z 410.5 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[C:28]([O:37][CH2:38][CH3:39])(=[O:36])[C:29]1[C:30](=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH2:31]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:8]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[C:28]([O:37][CH2:38][CH3:39])=[O:36])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
Triethylamine (1.86 ml) and octadecanoyl chloride (3.67 g) were added to a solution of ethyl anthranilate (2.00 g) in methylene chloride (20 ml). After being stirred for 30 minutes at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding 5.45 g of the aimed compound as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C@@H:11]2[CH2:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)=[CH:19][CH:18]=3)[CH2:12]2)[N:7]=1)=O)C.[NH3:32]>>[F:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([N:13]2[C:14](=[O:16])[CH2:15][C@@H:11]([C:8]3[N:7]=[C:6]([C:4]([NH2:32])=[O:3])[O:10][N:9]=3)[CH2:12]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)no1
Reactant: N
Product: NC(=O)c1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)no1
Temperature: 50 °C
Yield: 44 %

Procedure:
3-{(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (0.110 g, 0.25 mmol) was dissolved in 3.5 ml of ammonia (2 M solution in methanol). The resulting mixture was stirred at 50° C. for half an hour. The mixture was cooled at 0° C. and a solid precipitated. The reaction mixture was filtrated and the solid washed with hexane and dried under vacuum. The residue was suspended in ethyl acetate and heated to reflux. Diethyl ether was added and the suspension cooled to 0° C. and filtrated to yield the title compound as a light brown solid (0.045 g, 44% of theory). MS (m/e)=397.4 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)=[CH:15][C:14]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[OH:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:27])=[CH:22][CH:21]=2)=[CH:15][C:14]=1[CH3:29]
Reactant: BrCc1ccccc1
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl bromide (0.13 mL) was added to a mixture of 4′-(2-hydroxyethoxy}-3′,5′-dimethylbiphenyl-4-carboxylic acid (0.29 g) and potassium carbonate (0.17 g) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:ethyl acetate/n-hexane=1/3-1/2) to afford the title compound (0.38 g).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH2:34].C[Al](C)C.C(O)(=O)C>C1C=CC=CC=1.O>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](=[O:30])[NH2:34])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN
Reactant: CCOC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(N)=O)co2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-oxazol-2-yl)azetidine (1.70 g, 3.77 mmol) (obtained as described in Reference Example 21(3)) in benzene (38 ml) was added a solution of 0.67M methylamine-trimethylaluminium in benzene (13.7 ml) at room temperature under an atmosphere of nitrogen, and then the mixture was stirred in water bath (50° C.) for 4 hour. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) was added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-carbamoyl-1,3-oxazol-2-yl)azetidine (0.83 g, yield 52%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[I:30]I>CCCCC.C(Cl)Cl>[I:30][CH:5]1[CH:6]2[CH2:7][C:2]([CH3:1])([C:8](=[O:9])[NH:10]2)[CH2:3][CH2:4]1
Reactant: II
Reactant: CC1(C(N)=O)CC=CCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC12CCC(I)C(C1)NC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methylcyclohex-3-ene-1-carboxamide, 52b, (5.0 g, 35.9 mmol) dissolved in 100 mL of pentane and CH2Cl2 was cooled to 0° C. and treated with triethylamine (11.0 mL, 79.0 mmol) and trimethylsilyl-triflate (14.3 mL, 79.0 mmol) sequentially. The resulting mixture was stirred for 1 hour at room temperature. The lower layer was removed via pipette. The upper pentane layer was concentrated in vacuo and the resulting residue was dissolved in THF (100 mL). To the stirred reaction was added iodine (20.1 g, 79.02 mmol) and the reaction was allowed to stir overnight at room temperature. After quenching with Na2SO3 and NaHCO3, the reaction was partitioned between CH2Cl2 and water. The organic layers were combined, dried over Na2SO4, concentrated in vacuo to a dark yellow oil (9.5 g) that was used without further purification.
Reaction SMILES: [N:1]([C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:5]([O:7]C)=O)=[C:2]=[S:3].[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].O.C(O)(=O)C>O1CCCC1>[CH3:9][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:1][C:2](=[S:3])[N:17]([NH:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:5]1=[O:7]
Reactant: NNc1ccccn1
Reactant: COC(=O)C(C)(N=C=S)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC1(c2ccccc2)NC(=S)N(Nc2ccccn2)C1=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
2 g (9 mmol) of methyl 2-isothiocyanato-2-phenylpropionate are dissolved in 30 ml of tetrahydrofuran. A solution containing 0.99 g of 2-hydrazinopyridine and 10 ml of tetrahydrofuran is added: the temperature of the mixture rises from 20° to 30° C. and a solid precipitates. The mixture is allowed to met for 0.5 hour at 30° C. and then is cooled to 5° C. A solution containing 1 g of potassium tert-butoxide and 10 ml of tetrahydrofuran is then added: the mixture becomes violet in color. The mixture is left to return to room temperature and is left to react for 2 hours. The mixture is poured into 150 ml of water. The mixture is neutralized with acetic acid. The product is extracted with 150 ml of ethyl acetate. The solution is washed with water, dried over magnesium sulfate and then treated with active charcoal. The solution is concentrated and the product is crystallized from 20 ml of diethyl ether. The above-mentioned product is filtered and is dried under vacuum. 1.6 g (yield: 60%) of 5-methyl-5-phenyl-3-(2-pyridylamino)-2-thiohydantoin is obtained as a pale-yellow solid melting at 80° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:17])(=O)[CH2:14][CH3:15].[CH2:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:19].CO>O1CCCC1.C(OCC)(=O)C>[CH2:18]([N:20]([C:13](=[O:17])[CH2:14][CH3:15])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCNCCc1ccc(O)cc1
Reactant: CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(=O)N(CC)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
To a stirred solution of carbonyldiimidazole (14.13 g, 87.12 mmole) in tetrahydrofuran (109 ml) at 5° C., was added dropwise a solution of propionic acid (6.5 ml, 87.12 mmole) in tetrahydrofuran (73 ml) over 30 minutes. After stirring for 20 minutes, N-ethyl tyramine (12.0 g, 72.6 mmole) in tetrahydrofuran (73 ml) was added over 20 minutes. The reaction was allowed to warm to room temperature and stir for 4 hours. Methanol (7.3 ml) was added and stirring was continued for 30 minutes. The reaction was worked up by diluting with ethyl acetate and extracting with 1N hydrochloric acid, saturated sodium bicarbonate, then brine. The organic layer was dried over sodium sulfate, evaporated to dryness, and chromatographed on silica gel using a methylene chloride-methanol gradient to give N-ethyl,N-propionyl tyramine (6.95 g, 43%):