Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])[CH:14]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37])(=[NH:32])=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:32]=[S:30]([C:33]2[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=2)[C:36]([O:38][CH3:39])=[O:37])([CH3:29])=[O:31])=[O:7])=[CH:9][C:10]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=2)=[O:21])[CH:14]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Reactant: COC(=O)c1cccc(S(C)(=N)=O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Temperature: 60 °C
Reaction time: 16.5 h

Procedure:
To a solution of 6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinic acid (68 mg, 0.18 mmol), methyl 3-(S-methylsulfonimidoyl)benzoate (42 mg, 0.198 mmol), and N,N-diisopropylethylamine (0.063 ml, 0.36 mmol) in 1.5 ml DMF at room temperature was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (88 mg, 0.198 mmol). The reaction was heated at 60° C. for 3.5 hours, then at 48° C. for 16.5 hours. The mixture was partitioned between EtOAc and dilute brine. The EtOAc layer was washed with NaHCO3 solution, dilute HCl, NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The dark foam was chromatographed eluting with hexane/acetone yielding light pink solid (38 mg, 37%).
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].Br[CH2:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[Cl:33])=O>>[Cl:33][C:32]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:25]1[N:10]=[C:11]([C:12]2[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=2[CH3:17])[S:22][CH:24]=1
Reactant: O=C(CBr)c1cnccc1Cl
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Agent: Cc1ccc(C([O-])=S)s1
Product: COC(=S)c1cc(-c2nc(-c3cnccc3Cl)cs2)c(C)s1
Yield: 80.4 %

Procedure:
Methyl 4-4-(4-chloro(3-pyridyl))(3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 240 mg (0.970 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-1-(4-chloro(3-pyridyl))ethan-1-one (1.06 mmol; 250 mg) in a manner similar to Example 22, step (a) to afford 286 mg (77% yield) of methyl 4-[4-(4-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:21]2[NH:22][C:23](=[O:30])[C:24]([CH:27]([CH3:29])[CH3:28])([CH3:26])[N:25]=2)=[C:7]([CH:20]=1)[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:9])[CH3:2].[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:21]2[NH:22][C:23](=[O:30])[C:24]([CH:27]([CH3:29])[CH3:28])([CH3:26])[N:25]=2)=[C:7]([CH:20]=1)[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:9])[CH3:2]
Reactant: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)NCCCCCC(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)NCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution of methyl 6-[5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinamido]-hexanoate (5.14 g, 12.35 mmol) in tetrahydrofuran is treated with 2N sodium hydroxide (15 mL). The resulting mixture is stirred at room temperature for 24 hours. After this period, the reaction mixture is concentrated in vacuo to obtain a residue. The residue is cooled with an ice bath and acidified with concentrated hydrochloric acid. The resulting precipitate is isolated by vacuum filtration and washed with water to give the title product as a white solid, mp 76-81° C.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:35])([O:28]C3CCCCO3)[CH3:27])[CH:17]=2)=[CH:10][C:9]=1[CH2:36][OH:37]>C1COCC1.O>[OH:37][CH2:36][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:35])([OH:28])[CH3:27])[CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][C:8]=1[CH2:7][OH:6]
Reactant: CC(C)(CCCCc1cccc(C=Cc2ccc(CO)c(CO)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCc1cccc(C=Cc2ccc(CO)c(CO)c2)c1
Temperature: 40 °C

Procedure:
0.09 ml of concentrated sulphuric acid are added to 44 mg (0.1 mmol) of [2-hydroxymethyl-5-(2-{3-[5-methyl-5-(tetrahydropyran-2-yloxy)hexyl]-phenyl}vinyl)phenyl]methanol in 1 ml of THF and 1 ml of water. The solution is heated at 40° C. for 48 hours. Water is added and the mixture is extracted with ether. The organic phase is dried over magnesium sulphate and concentrated. The product is triturated in an ether-hexane mixture and is then filtered and dried.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][N:19]([CH:28]=[O:29])[O:20]CC2C=CC=CC=2)[C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH2:14])=[O:13])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@H:7]([CH2:18][N:19]([CH:28]=[O:29])[OH:20])[C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH2:14])=[O:13])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Solvent: CO
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC1CCCC1)CN(O)C=O
Reaction time: 3 h
Yield: 112.4 %

Procedure:
1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-L-prolinamide (24 g, 0.060 mol) was dissolved in MeOH (500 mL) and degassed. Catalyst (10% Pd/C, Degussa type, wet, 2.4 g) was added and the mixture was stirred under a hydrogen balloon for 3 hours. After degassing, the suspension was filtered through Celite, washing with methanol, and the filtrate was concentrated. The resulting foam was dissolved in ethyl acetate (50 mL) and diluted with toluene (˜500 mL.) This solution was then concentrated to a slurry (˜100 mL) and diluted with hexanes (200 mL.) Filtration, washing with hexanes and drying afforded the product 1-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-L-prolinamide (21 g, 113% yield). The excess yield is due to residual toluene. LC/MS m/z 312 (MH+)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[N-:13]=[N+:14]=[N-:15].[Na+]>>[N:13]([CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[N+:14]=[N-:15]
Reactant: CCO[Si](C)(CCCCl)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCO[Si](C)(CCCN=[N+]=[N-])OCC
Temperature: 140 °C

Procedure:
1.0 mole of 3-chloropropylmethyldiethoxysilane and 1.1 moles of sodium azide were heated in the presence of 5 mole percent of the catalyst described in Example 1 (a) for three hours under stirring at 140° C. After the distillation under reduced pressure there was obtained the 3-azidopropylmethyldiethoxysilane in a yield of 94 weight percent.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=O)[CH:9]=[C:10]([CH:13]=1)[CH:11]=O)[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:9]=[C:10]([CH2:11][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:13]=1)[CH3:2]
Reactant: CCC(CC)COc1cc(C=O)cc(C=O)c1
Reactant: CC(C)CNCCCNCCCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(CC)COc1cc(CNCCCNCCCNCC(C)C)cc(CNCCCNCCCNCC(C)C)c1
Reaction time: 24 h

Procedure:
5-(2-Ethylbutoxyl)isophthalaldehyde (0.20 g, 0.88 mmol) and MeOH (15 mL) were added to a round-bottom flask. To the solution was added N1-(3-aminopropyl)-N3-isobutylpropane-1,3-diamine (0.33 g, 1.76 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (0.13 g, 3.52 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) and EtOAc (50 mL) were added and the reaction mixture stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product a clear oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.S(C1C=CC(C)=CC=1)(O[CH2:22][CH:23]1[O:25][CH2:24]1)(=O)=O>CN(C)C=O>[O:25]1[CH2:24][CH:23]1[CH2:22][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cc(OCC2CO2)c2cccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
297 g of cesium carbonate was added to 600 ml of dimethylformamide. Further, 83.5 g of 5-hydroxyquinoline was added. The mixture was stirred at 25°-30° C. for 30 minutes. To the reaction mixture was slowly added 109 g of glycidyl tosylate. The resulting mixture was stirred at 25°-30° C. for 15 hours. The reaction mixture was poured into 3 liters of ice water, followed by stirring and extraction with 2 liters of ethyl acetate. The aqueous layer was subjected to extraction with 2 liters of ethyl acetate. The organic layers were combined and washed twice with 2 liters of water. The ethyl acetate layer was dried over anhydrous Glauber's salt and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 76.8 g (yield: 66%) of intended 5-(2,3-epoxypropoxy)quinoline as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:12][CH2:11][CH:10]([CH2:13][CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:11][CH:10]([CH2:13][CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CNC(c2cccc(Cl)c2)O1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CN(C(=O)CC(C)C)C(c2cccc(Cl)c2)O1

Procedure:
Four and two-tenths grams of 2-(m-chlorophenyl)-5-ethyl-1,3-oxazolidine was combined with 1.7 g of pyridine in 25 ml of methylene chloride and 2.4 g of isovaleroyl chloride was added dropwise with stirring and the mixture was stirred overnight. The mixture was washed with 50 ml of 5% NaOH and 200 ml of water, dried with MgSO4 and stripped under vacuum. The yield was 2.4 g, nD30 1.5490. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[N+:12]([O-])=O>CO>[CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:12]
Reactant: CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: CO
Product: CNc1c(N)cccc1N
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a flask was added 0.30 g (1.5 mmol) of N-methyl-2,6-dinitroaniline and 40 ml of methanol. The flask was purged with nitrogen followed by the addition of 0.03 g of 10% palladium on carbon. The flask was evacuated and pressurized to 2-3 psig hydrogen and stirred for 1 h. After completion as determined by HPLC, the reaction was filtered through GF/F filter paper. The filtrate was evaporated to give 0.2 g (95%) of product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24](Cl)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O.ClCCl>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:5]([NH:6][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:4]([O:3][CH3:2])=[O:15])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reaction time: 3.5 h
Yield: 93.6 %

Procedure:
200 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol), and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and 16.6 ml of octanoyl chloride (0.1 mol) was slowly added, following by stirring for 3-4 hours. 200 ml of water was added to the reacted material, followed by extraction with 400 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by separation by column chromatograph using hexane and ethyl acetate (Hex:EA=2:1), thereby obtaining a white solid (30.1 g, 93.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][SH:5].C(=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26](SCC(O)=O)[CH2:27][OH:28])=[CH:22][CH:21]=1.C1CCCCC1.C(OCC)(=O)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][S:5][CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])=[CH:21][CH:22]=1)[CH2:27][OH:28]
Reactant: COC(=O)CS
Reactant: O=C(O)CSC(CO)c1ccc(-c2ccccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CSC(CO)c1ccc(-c2ccccc2F)cc1

Procedure:
20 gm of the product thus obtained were reacted with 8.75 gm of thioglycolic acid methyl ester and 11.5 gm of potassium carbonate in 70 ml of dimethyl sulfoxide. From the obtained reaction product (oil, Rf -value: 0.4 on carrier 1 with cyclohexane/ethyl acetate = 2:1) [1-(2'-fluoro-4-biphenylyl)-2-hydroxy-ethylthio]acetic acid, m.p. 115°-117° C (from cyclohexane/ethyl acetate = 1:2, was obtained by hydrolysis. Preparation of end products of the formula I:
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[Li]CCCC>C1COCC1.CCCCCC>[CH2:1]([C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1[B:15]([OH:20])[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1ncc(Br)c1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1ncc(B(O)O)c1Cc1ccccc1
Temperature: -78 °C
Yield: 39 %

Procedure:
5-Benzyl-4-bromo-1-methyl-1H-pyrazole (0.27 g; 1.06 mmol) was dissolved in 5.0 ml anhydrous THF and cooled down to −78° C. Afterwards was added Triisopropyl borate (0.46 ml; 2.01 mmol) and n-BuLi; 1.6 mol/1 in Hexane; (0.69 ml; 1.11 mmol). It was stirred for 1 hour within the desired product was formed. It was warmed to 25° C. and quenched with water. It was purified with reverse phase chromatography by using basic conditions.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1)[CH3:20]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 85.9 %

Procedure:
To a solution of 5-(5-bromo-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D65) (500 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (443 mg) and tripotassium phosphate (657 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (179 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (500 mg) as a brown oil. MS (ES): C22H20N2O2S requires 376. found 377.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[Cl:12]CCCl.[Cl-].[P+]=O>CN(C=O)C>[Cl:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: ClCCCl
Reactant: Cc1cc([N+](=O)[O-])cnc1O
Agent: O=[P+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1Cl
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A 350 ml three-necked round-bottomed flask equipped with a magnetic bar, a thermometer, a dropping funnel and a reflux condenser is charged with 3-methyl-5-nitro-pyridin-2-ol (23.1 g), and 1,2-dichloroethane (150 ml). Phosphorous oxide chloride (17 ml) is added dropwise. Into this mixture DMF (11.5 ml) is added dropwise at room temperature. The reaction mixture is heated at 70° C. under stirring for 0.5 hour. After cooling the mixture to ambient temperature, it is concentrated in vacuo at 50° C., to obtain a brown oily gum. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 7:3 (v:v) gives 23.34 g of the compound as a light yellow solid (MP: 40-42° C.).
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[CH2:10][CH2:9][N:8]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:26][C:27]([CH3:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][C:27](=[O:28])[CH3:29])[CH:15]=3)[CH2:10][CH2:9][N:8]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1C1CCCCC1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CC(=O)COc1ccc2c(c1)C(C1CCCCC1)N(C(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Tert-butyl 1-cyclohexyl-7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (700 mg) was dissolved in acetonitrile (12 mL). 1-chloroacetone (0.2 mL), potassium carbonate (438 mg), and tetra-n-butylammonium iodide (78 mg) were added thereto, followed by stirring at 60° C. for 16 hours. Then, water was added to the mixture which was then extracted with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain tert-butyl 1-cyclohexyl-7-(2-oxopropoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (818 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:34]([Cl:37])(=[O:36])[CH3:35].Cl>ClCCl.C(O)C>[ClH:37].[C:25]([C:19]1[CH:20]=[CH:21][C:22]2[O:23][CH2:24][C@H:14]3[C@H:15]([C:17]=2[CH:18]=1)[CH2:16][N:12]([CH2:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([NH:3][C:34](=[O:36])[CH3:35])[CH2:5][CH2:6]1)[CH2:13]3)#[N:26]
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](CCN2C[C@H]3COc4ccc(C#N)cc4[C@@H]3C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 699 mg (2.1 mmol) of the compound of Example 1 in 15 ml of dichloromethane there are added, at ambient temperature, 354 μl of triethylamine (1.2 eq.) and then 164 μl of acetyl chloride (1.1 eq.). After stirring for 2 hours at ambient temperature, the mixture is washed with water and dried (MgSO4). Evaporating off the solvent followed by purifying on a silica column using a mixture of dichloromethane/methanol/ammonium hydroxide (97/3/0.3) as eluant yields, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].I[CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:21][CH3:22])[CH:17]=1)=[O:11]
Reactant: CCI
Reactant: CC(C(=O)c1ccc(=O)[nH]c1)c1ccc(Cl)cc1Cl
Product: CCn1cc(C(=O)C(C)c2ccc(Cl)cc2Cl)ccc1=O

Procedure:
In analogy to Example 195, 5-[2-(2,4-dichloro-phenyl)-propionyl]-1H-pyridin-2-one (Example 201, step 4) was alkylated with iodoethane to give the title compound as a colorless oil. MS (m/e)=324.2 [M+H+].
Reaction SMILES: [OH2:1].[ClH:2].[CH3:3][NH:4][C@H:5]([C:14]([NH:16][C@@H:17]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:23])[CH2:18][CH2:19][S:20][CH3:21])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.OO>C(O)(=O)C>[OH2:13].[ClH:2].[CH3:3][NH:4][C@H:5]([C:14]([NH:16][C@@H:17]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:23])[CH2:18][CH2:19][S:20](=[O:1])[CH3:21])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1.[CH3:3][NH:4][C@H:5]([C:14]([NH:16][C@@H:17]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:23])[CH2:18][CH2:19][S:20](=[O:1])[CH3:21])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1.[ClH:2]
Reactant: CN[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CCSC)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CN[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CCS(C)=O)C(=O)NCCCc1ccccc1
Yield: 119.6 %

Procedure:
A solution of N-methyl-L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide monohydrochloride hydrate (4:1) (690 mg.) and aqueous hydrogen peroxide (3%, 1.95 ml.) in acetic acid (10 ml.) was stirred at room temperature, then stripped of volatiles. The residue was purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel (350 g.) using ammonium acetate (0.2%) in methanol-water (1:1) as the eluant. A solution of the product, which appeared in fractions 4-5 (centered at k'=2.0), in methanol (20 ml.) and hydrochloric acid (0.01 N, 100 ml.) was concentrated (to 60 ml.), filtered and lyophilized, affording as an amorphous solid N-methyl-L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide S-oxide monohydrochloride hemihydrate (558 mg.; [α]D25 +59.8°, c=1, methanol), whose free base is the compound of Formula II wherein Q is Met(O), R1 is methyl, R2 and R5 are each hydrogen and R4 is (CH2)nY wherein n is 3 and Y is phenyl.