Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:8]([CH:9]([NH:13][CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(#N)C>[CH3:14][N:13]([CH:9]([C:8]1[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][CH:5]=[N:6][CH:7]=1)[CH:10]([CH3:12])[CH3:11])[C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNC(c1cncnc1C(F)(F)F)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)C(c1cncnc1C(F)(F)F)N(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
6 g (26 mmol) of 4-trifluoromethyl-5-[1-(N-methylamino)-2-methylpropyl]pyrimidine and 3.6 g (26 mmol) of potassium carbonate were dissolved in 150 ml of acetonitrile, and 4 g (26 mmol) of phenylacetyl chloride was dropwise added, followed by stirring at room temperature for 3 hours. To the reaction solution, 200 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude crystals were washed with n-hexane to obtain 7.7 g (yield: 85%) of N-methyl-N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)propyl]phenylacetamide as colorless transparent crystals (melting point: 106-109° C.).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[CH:12][C:11]([N:24]=[N+]=[N-])([Cl:23])[NH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Zn].C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[CH:12][C:11]([NH2:24])([Cl:23])[NH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=NNC(Cl)(N=[N+]=[N-])C=C1Nc1ccc(Br)cc1F
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1=NNC(N)(Cl)C=C1Nc1ccc(Br)cc1F
Reaction time: 3 h

Procedure:
To the stirred solution of 6-azido-4-(4-bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid tert-butyl ester (122 mg, 0.30 mmol) in 5 ml of mixed solvents (3:1 v/v, dichloromethane/acetic acid) is added zinc powder (98 mg, 1.5 mmol) at room temperature. After three hours, the reaction mixture is poured into ethyl acetate (50 ml). The organic layer is washed with water, saturated NaHCO3 (30 ml×3) and saturated NaCl (30 ml×3). The organic layer is dried over Na2SO4, and concentrated. The residue is purified by flash column chromatography to provide the desired product.
Reaction SMILES: C1(P(=C=[CH:21][C:22]([O:24][CH3:25])=[O:23])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[OH:37])[CH:32]=O)[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29]1[CH:30]=[C:31](/[CH:32]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])[CH:34]=[CH:35][C:36]=1[OH:37])[CH3:27]
Reactant: COC(=O)C=C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1cc(C=O)ccc1O
Solvent: Cc1ccccc1
Product: CCOc1cc(/C=C/C(=O)OC)ccc1O
Reaction time: 1 h

Procedure:
2.1 g (6.32 mmol) of methyl (triphenylphosphoranylidene)acrylate are added, at room temperature, to a solution of 1.0 g (6.01 mmol) of 3-ethoxy-4-hydroxybenzaldehyde and 10 ml of toluene. The reaction is then allowed to continue for 1 hour at room temperature, the reaction suspension is clarified by filtration over a silica gel bed and the filtrate is evaporated down. Chromatography of the residue over silica gel using toluene/ethyl acetate gives methyl 3(E)-(3-ethoxy-4-hydroxyphenyl)acrylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]O)[CH:2]=1.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:15])[CH:2]=1
Reactant: Cc1ccccc1
Reactant: OCc1cccnc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccccc1Cc1cccnc1

Procedure:
A quantity of 1.2 g 3-pyridyl carbinol in 15 ml 1.8 M aluminum chloride in nitrobenzene was reacted with 10 ml of toluene during 3 days at 80° C. The reaction mixture was poured on HCl/ice and extracted with toluene. The organic phase was washed with water, dried and the solvent was evaporated. The desired product was obtained as viscous oil, containg 8.5% nitrogen.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)=[N:9][O:10][C:11]=2[C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:32][O:33][C:34](=[O:41])[C@@H:35]([NH2:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>>[CH3:32][O:33][C:34](=[O:41])[C@@H:35]([NH:40][C:12]([C:11]1[O:10][N:9]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])=[CH:19][CH:20]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13])[CH2:36][CH:37]([CH3:39])[CH3:38]
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2noc(C(=O)O)c2-c2ccccc2)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1onc(-c2ccc(NC(=O)Nc3ccccc3)cc2)c1-c1ccccc1
Yield: 83 %

Procedure:
The title compound was prepared from 4-phenyl-3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 83% yield. Mass (ES−): 525 (M−−1); 1H NMR (DMSO-d6) δ: 0.75, 0.81 (2×d, 6H), 1.35-1.58 (m, 3H), 3.66 (s, 3H), 4.49 (m, 1H), 6.96 (t, 1H), 7.27 (t, 2H), 7.44 (d, 2H), 7.54 (m, 3H), 7.56 (d, 2H), 7.66 (d, 2H), 7.82 (m, 2H), 8.72 (br, 1H), 8.95 (br, 1H), 9.31 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.O[C@@H:11]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C@H:11]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1
Reactant: COc1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](O)c3ccccc3)CC2)c1
Product: COc1cccc(O[C@@H](CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 3-methoxyphenol and N-(3-{1-[(2S)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 472.9 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[FH:7].N[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.N([O-])=O.[Na+].[OH-].[Na+]>CCCCCC>[F:7][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1
Reactant: N#Cc1ccc(N)cn1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: N#Cc1ccc(F)cn1
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To hydrogen fluoride-pyridine (100 ml) was added 5-amino-2-cyanopyridine (24.5 g, 0.206 mol) under ice cooling. The resulting mixture was stirred for 10 minutes. To the reaction mixture was added sodium nitrite (15.6 g, 0.226 mol). The resulting mixture was stirred at room temperature for 10 minutes, and then stirred at 50° C. for 2 hours. To the reaction mixture was added a 20% aqueous solution of sodium hydroxide. The resulting mixture was extracted with diethyl ether. The organic layer thus obtained was dried over sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (16.0 g, 0.131 mmol, 64%) as colorless needle crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][N:7]=1)=O)C.[CH3:17][Mg]I>C1COCC1>[O:3]=[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][N:7]=1)[CH3:17]
Reactant: CCOC(=O)c1nnc(-c2ccccn2)s1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(=O)c1nnc(-c2ccccn2)s1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl)-pyridine (2 gm) in THF (40 ml) was added methyl magnesium iodide (15 ml, 1.4 M solution in THF) at −40° C. over a period of 15 minutes. The reaction mixture was stirred for 2 h at −40° C. It was quenched by addition of aqueous ammonium chloride solution (20 gm) and stirred at 0° C. over a period of 10 minutes. It was extracted with ethyl acetate (100 ml×2). Combined organic layers was washed with water and evaporated under vacuum to provide a title compound in 1.5 gm quantity (86%) as off white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3F)cn(C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 93.3 %

Procedure:
A mixture of Example 17C (0.02 g, 0.060 mmol), 2,4-difluorophenol (2) (0.012 g, 0.090 mmol), and cesium carbonate (0.029 g, 0.090 mmol) in DMSO was heated at 110° C. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (0.025 g, 0.056 mmol, 94% yield).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5](Cl)[N:4]=1.[CH3:11][OH:12]>>[Cl:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([O:12][CH3:11])[N:4]=1
Reactant: CO
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: [Na]
Product: COc1cc(N)cc(Cl)n1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.84 g (44.0 mmol) sodium in 40 mL MeOH was added 6.72 g (40.0 mmol) 2,6-dichloro-pyridin-4-ylamine. The reaction mixture was stirred at 150° C. for 30 min under microwave irradiation. The solvent was evaporated and ice water was added. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]([OH:19])[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH:13]3[O:19][C:16](=[O:18])[CH2:15][CH2:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2)o1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(-c3ccc(F)cc3)o2)O1

Procedure:
A mixture of 3.8 g (0.014 mole) of 4-[5-(4-fluorophenyl)-2-furanyl]-4-hydroxybutanoic acid and 60 ml of 10% hydrochloric acid was warmed at 45° for 2 hrs and then cooled in an ice bath. The solid was filtered, washed with water and air-dried to yield 3.3 g (95%). An analytical sample was prepared by dissolving a sample in ethyl acetate (Darco), diluting with hexane and drying the resulting solid in a vacuum pistol at room temperature, m.p. 57°-59°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([Li])CCC.CCCCCC.Br[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[N:43]=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]([C:50]3[CH:51]=[CH:52][CH:53]=[C:48]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:42][N:43]=4)[N:49]=3)=[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: c1ccc(-c2csc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2c(-c3cccc(-c4ccccn4)n3)sc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
After placing 3.5 g of 3,4-diphenylthiophene and 60 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 11 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 4.1 g of a zinc chloride/tetramethylethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 3.8 g of 2-bromo-6-(2-pyridyl)pyridine and 0.52 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, the organic layer was extracted, and the concentrate obtained using an evaporator was purified by recrystallization to obtain 4.5 g of 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene. After placing 3.3 g of the 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene and 80 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 6.2 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 2.4 g of a zinc chloride/tetramethyl-ethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 2.2 g of 2-bromo-6-(2-pyridyl)pyridine and 0.30 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, and the organic layer was extracted. The organic layer was concentrated with an evaporator and purified by column chromatography and recrystallization to obtain 1.1 g of BPPDPT.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]3[CH2:14][CH2:13][CH2:12][C:11]=3[C:6]=2[O:5][C:4]([C:15]([OH:17])=[O:16])=[CH:3]1.[H][H]>C(O)(=O)C.[Pd]>[O:5]1[C:6]2[C:11]3[CH2:12][CH2:13][CH2:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH2:2][CH2:3][CH:4]1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(=O)c2ccc3c(c2o1)CCC3
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)C1CCc2ccc3c(c2O1)CCC3
Yield: 106.9 %

Procedure:
A mixture of intermediate (3-a) (0.09 mol) in acetic acid (200 ml) was hydrogenated with palladium on activated carbon (1 g) as a catalyst. After uptake of hydrogen (3 eq.), the catalyst was filtered off. The solvent was evaporated. The residue was vacuum dried, yielding 21 g of (±)-2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-carboxylic acid (interm. 4-a).
Reaction SMILES: C(O[C@@H:5]1[C@@H:10]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@H:9]([O:18][C:19](=[O:21])[CH3:20])[C@@H:8]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:7][C@@H:6]1Br)(=O)C.C(OCC)(=[O:30])C>>[C:19]([O:18][C@@H:9]1[C@@H:8]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:7][C:6]([OH:30])=[CH:5][C@H:10]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])(=[O:21])[CH3:20]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](NC(=O)C(F)(F)F)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1OC(O)=C[C@@H](NC(=O)C(F)(F)F)[C@@H]1OC(C)=O
Reaction time: 2.5 h

Procedure:
2,4,6-Tri-O-acetyl-1-bromo-1,3-dideoxy-3-trifluoroacetamido-α-D-glucopyranose [Chem. Ber. 104, 1 (1971)] is added to the cooled mixture at 5°-15° and continued stirring for 2.5 hours at 5°. When the reaction is complete as measured by TLC (ethyl acetate-SSB, 1:2) the mixture is filtered over a pad of filter-aid and washed with methylene chloride.
Reaction SMILES: [CH2:1](OCC)[CH3:2].[C:6]([C:10]1[CH2:14][CH2:13][C:12](=O)[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].Cl>O>[CH2:1]([C:13]1[CH2:12][CH:11]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:14]=1)[CH3:2]
Reactant: CCOCC
Reactant: CC(C)(C)C1=CC(=O)CC1
Agent: Cl
Solvent: O
Product: CCC1=CC(C(C)(C)C)=CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
A 300 ml three neck flask equipped with a magnetic stirrer and a three-way cock was charged with 200 ml of diethyl ether and 52 ml (154 mmol) of a diethyl ether solution of 3.0-Methylmagnesium bromide under nitrogen atmosphere. 3-tert-Butylcyclopentenone 17.8 g (129 mmol) was added dropwise in one hour on an ice and water bath. The solution was stirred at room temperature for 20 hours, and then the reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ether. The organic layers thus obtained were combined and washed twice with a saturated sodium hydrogen carbonate aqueous solution, twice with water and twice with a saturated salt solution. The organic layer was dried on magnesium sulfate, and the solvent was removed by distillation. Then, the residue was purified by column chromatography to obtain 20.2 g (GC purity: 75%) of a pale yellow transparent liquid. The yield was 78%. The product was identified by means of a 1H-NMR spectrum. The measurement results thereof are shown below.
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>CN(C)C=O>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([O:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2)=[O:23]
Reactant: O=C=NCCCl
Reactant: O=c1[nH]cnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCl)Oc1ncnc2nc[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of hypoxanthine (6.8 g, 50 mmoles) in dimethylformamide (200 ml) there is added triethylamine (5.05 g, 50 mmoles) and then at 15° to 20° C., 2-chloroethylisocyanate (5.8 g, 55 mmoles is dripped in. The reaction mixture is stirred at this temperature until dissolution of the solid (approx. for 2 hours), thereafter poured into an ice-water mixture (750 ml), the precipitate of the title product is separated by suction, washed with acetone and dried at room temperature. The yield is 8.2 g (67.8%) of compound Ib, m.p. 320°-240° C. (with decomposition), UV absorption spectrum (in dimethylsulfoxide), λ max 275 nm (log ⃝3.76).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.[BH4-].[Na+]>C1C=CC=CC=1>[C:12]1([CH2:18][CH2:19][CH2:20][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: O=c1[nH]c2ccc(NCCCc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-amino-2-benzoxazolone (6.00 g) and molecular sieves 4A (10.0 g) in dry benzene (100 ml) was added 3-phenylpropanal (5.25 ml), and then the mixture was stirred at room temperature for 1 hour. Methanol (150 ml) was combined with this and sodium borohydride (1.50 g) was added in portions at room temperature. The reaction mixture was filtered, the filtrate was concentrated and 5% sodium bicarbonate was added. The organic material was extracted with dichloromethane. The dichloromethane phase was separated, washed with brine. Drying and removal of solvent under reduced pressure gave a crude product which was crystallized from hot ethanol to afford 7.07 g of the title compound: mp 129°-130° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:34])[CH2:16][NH:17][C:18]([CH3:33])([CH3:32])[CH2:19][CH2:20][N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[CH:22]2)=[CH:11][C:10]=1[NH:35][S:36]([C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[NH:47][CH2:46][CH2:45][CH2:44]2)(=[O:38])=[O:37])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:33][C:18]([NH:17][CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:35][S:36]([C:39]2[CH:40]=[CH:41][CH:42]=[C:43]3[C:48]=2[NH:47][CH2:46][CH2:45][CH2:44]3)(=[O:37])=[O:38])[CH:11]=1)[OH:34])([CH3:32])[CH2:19][CH2:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[CH:22]1
Reactant: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2cccc3c2NCCC3)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(O)c(NS(=O)(=O)c2cccc3c2NCCC3)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
0.10 g palladium (5% on activated charcoal) were added to a solution of 0.20 g (0.41 mmol) (R)-1,2,3,4-tetrahydro-quinoline-8-sulphonic acid (2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-phenyl)-amide in 20 mL ethanol. The reaction mixture was shaken in an autoclave under a hydrogen pressure of 20 psi at ambient temperature for 6 h. The hydrogen pressure was released, the palladium filtered off and the filtrate was freed from solvent using the rotary evaporator. The residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 0.20 g (0.31 mmol, 75%) (R)-1,2,3,4-tetrahydro-quinoline-8-sulphonic acid(5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-amide were obtained as a colourless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:26]([O:28][CH2:29][CH2:30][C:31](=[NH:34])[NH:32]O)[CH3:27]>>[CH2:26]([O:28][CH2:29][CH2:30][C:31]1[N:34]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:32]=1)[CH3:27]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: CCOCCC(=N)NO
Product: CCOCCc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.655 mmol) of the compound from Example 7A and 355 mg (approx. 2.152 mmol) of 3-Ethoxy-N-hydroxypropanimidamide were reacted Yield: 389 mg (49% of theory)