Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)(=O)C.[Ni]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:12]=[N:13][N:14]=[CH:15]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(-n2cnnc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(=O)O
Product: Cc1cc(-n2cnnc2)ccc1N

Procedure:
A solution of 4-(3-methyl-4-nitrophenyl)-1,2,4-triazole (1.0 g) in acetic acid (25 cm3) was hydrogenated at 25° and 60 p.s.i. (4.13×105Pa) pressure over Raney nickel (0.2 g) for 2 hours. The mixture was then filtered through "Solkafloc" (Trade Mark for a cellulose based filtering agent), the solvent was evaporated in vacuo and the residue was partitioned between chloroform (100 cm3) and aqueous sodium carbonate solution (20 cm3). The aqueous phase was further extracted with chloroform (3×50 cm3) and the combined and dried (MgSO4) organic extracts were concentrated to afford an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:ethyl acetate, 1:9. Combination and evaporation of the appropriate fractions afforded a solid which was recrystallised from ethyl acetate/hexane to give 4-(4-amino-3-methylphenyl)-1,2,4-triazole, m.p. 152°-154° (0.67 g).
Reaction SMILES: [F-].[K+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]1[C:17]([NH:19][C@H:20]([C:24]([NH:26][CH:27]([C:36](=[O:39])[CH2:37]Br)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18].[F:40][C:41]1[C:46]([F:47])=[CH:45][C:44]([F:48])=[C:43]([F:49])[C:42]=1[OH:50]>CN(C=O)C>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]1[C:17]([NH:19][C@H:20]([C:24]([NH:26][CH:27]([C:36](=[O:39])[CH2:37][O:50][C:42]1[C:43]([F:49])=[C:44]([F:48])[CH:45]=[C:46]([F:47])[C:41]=1[F:40])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]1[C:17]([NH:19][C@H:20]([C:24]([CH:28]([CH:27]([NH2:26])[C:36](=[O:39])[CH2:37][O:50][C:42]1[C:41]([F:40])=[C:46]([F:47])[CH:45]=[C:44]([F:48])[C:43]=1[F:49])[C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:18]
Reactant: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)C(C)C)n(C)c2ccccc12
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cc1c(C(=O)N[C@H](C(=O)C(C(=O)OC(C)(C)C)C(N)C(=O)COc2c(F)c(F)cc(F)c2F)C(C)C)n(C)c2ccccc12
Product: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
Potassium fluoride (21.6 mg, 0.37 mmol) was added to a solution of N-[(1-methyl-3-isobutyl-indole-2-cabonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (86.1 mg, 0.149 mmol) and 2,3,5, 6-tetrafluorophenol (27.0 mg, 0.163 mmol in DMF (2.0 ml). After stirring at room temperature for 3 hours, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, washed with saturated NaHCO3 solution, and brine, dried over sodium sulfate, and concentrated. The residue was triturated with ether to give the titled product, N-(1-methyl-3-isobutyl-indole-2-cabonyl)-valinyl-3-amino-4-oxo-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester as a white solid (43.8 mg, 44%). TLC (hexane/EtOAc, 50/50): Rf=0.50.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13]>C(OCC)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCOCC
Product: N#Cc1ccc(NCC(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 4-amino-benzonitrile and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 204-206° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:20]C1C=CC(O)=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-:39].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH3:20])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:39][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:8][C:7]=1[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](C)Nc1ccc(OCC(=O)OC(C)(C)C)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-(2-benzoylphenyl)tyrosine methyl ester (0.97 g), t-butyl bromoacetate (0.55 ml), cesium carbonate (1.14 g), and acetone (15 ml) was stirred at room temperature for 1.5 hours and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (1.42 g, Rf=0.65: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=3:1 as the eluant).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([C@@H:16]2[S:22][C@H:21]([CH:23]([C:25]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:12](=[O:48])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49][C:50]([Si:53](Cl)([CH3:55])[CH3:54])([CH3:52])[CH3:51]>C1COCC1.C(OCC)(=O)C.[N+]([O-])([O-])=O.[Ag+]>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([C@@H:16]2[S:22][C@H:21]([CH:23]([C:25]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[OH:24])[C@@H:19]([OH:20])[C@@:17]2([Si:53]([C:50]([CH3:52])([CH3:51])[CH3:49])([CH3:55])[CH3:54])[OH:18])[C:12](=[O:48])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2S[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)[C@H](O)[C@@H]2O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2S[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
Compound 21 (200 mg, 0.3 mmol), silver nitrate (100 mg, 0.6 mmol), and TBDMS-Cl (70 mg, 0.45 mmol) were dissolved in dry THF and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to give Compound 23 (100 mg) in 45% yield. The 3-protected analog (N-benzoyl-1-[5-(4,4′-dimethoxytrityl)-3-(t-butyldimethylsilyl)-4-thio-β-D-ribofuranosyl]cytosine) was also isolated as a minor product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:8])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:8]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3cccc([N+](=O)[O-])c3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3cccc(N)c3)ccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{5-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (190 mg, 415 μmol) in a mixture of ethanol and water (4:1, 10 mL) was added palladium on carbon (38 mg, 10% w/w Pd) and ammonium formate (130 mg, 2.06 mmol). The suspension was heated to reflux for 2 hours, cooled to room temperature and filtered through a pad of Celite®. The filtrate was then evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=3.85 min, MH+ 429].
Reaction SMILES: O[C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.C[Si](C#[N:18])(C)C.S(=O)(=O)(O)O>C(OCC)(=O)C.O.CCOCC.[OH-].[Na+]>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([NH2:18])([CH3:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5]1
Reactant: CC1(C)CC(C)(C)CC(C)(O)C1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CC1(C)CC(C)(C)CC(C)(N)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To a vigorously stirred solution of 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane (3.4 g; 20 mmol) and trimethylsilyl cyanide (2.58 g; 26 mmol; 1.3 eq.) in ethyl acetate (4 ml), 95% sulfuric acid (3.2 ml; 60 mmol; 3.1 eq) are added during 1 hour keeping the temperature at −10° C. for 15 min, and then allowing the mixture to reach ambient temperature. After stirring at ambient temperature for 15 hours, the mixture is diluted with 20 ml ice water. Subsequently, the mixture is refluxed with stirring for 10 hours, cooled to ambient temperature, diluted with 40 ml water and 20 ml ether and neutralized with 20% aqueous sodium hydroxide until a pH of 10. The organic phase is separated and dried. Dry hydrogen chloride is passed through the solution until the ether becomes acidic. Solvent is removed and the residue is washed with ether to give 3.1 g Neramexane in the form of its hydrochloride.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1.[C:21](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:21][O:17][C:16](=[O:18])[CH2:15][C:13]1[CH:14]=[C:9]([Br:8])[CH:10]=[CH:11][C:12]=1[O:19][CH3:20]
Reactant: CC(=O)O
Reactant: COc1ccc(Br)cc1CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.306 mL, 0.612 mmol) was added to a solution of (5-bromo-2-methoxy-phenyl)-acetic acid (100 mg, 0408 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (103.7 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCc1ccc(Cl)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of 4-chlorophenethylamine (5.0 g, 32 mmol) and DIEA (6.0 ml, 35 mmol) in anhydrous DCM (100 ml) was cooled at −5° C. and methanesulfonyl chloride (2.75 ml, 35 mmol) was added dropwise. The resulting mixture was stirred at −5° C. for 1 hour. Then the reaction mixture was washed with a 1N aqueous solution of HCl (2×100 ml) and a saturated aqueous solution of NaHCO3 (100 ml). The aqueous layers were extracted with DCM (100 ml). The organic layers were combined, dried (MgSO4) and the solvent was removed under reduced pressure to give 7.4 g (98%) of the title compound as a pale yellow powder. HPLC, Rt: 2.6 min (purity: 95.1%). LC/MS, M+(ESI): 234.1, M−(ESI): 232.1.
Reaction SMILES: C[Si]([CH2:5][C:6]([NH2:8])=[O:7])(C)C.Cl[Si:10]1(Cl)[CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:6]([NH:8][Si:10]1([NH:8][C:6](=[O:7])[CH3:5])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:5]
Reactant: Cl[Si]1(Cl)CCC1
Reactant: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Product: CC(=O)N[Si]1(NC(C)=O)CCC1

Procedure:
When 1.72 g of trimethylsilylacetamide was mixed with 0.92 g of 1,1-dichlorosilacyclobutane in 5 g of methylene chloride, a white precipitate formed. The precipitate dissoved upon shaking and slowly recrystallized as white needles. There was no trimethylchlorosilane detected in the residual fluid, indicating that the expected reaction to form 1,1-diacetamidosilacyclobutane did not occur.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([CH3:14])=[O:13])=[CH:10][C:4]=2[O:3]1.[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[CH3:1][C:2]1([CH3:15])[O:6][C:5]2[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([NH:11][C:12]([CH3:14])=[O:13])=[CH:10][C:4]=2[O:3]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)OC(C)(C)O2
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
18.4 g of 2,2-dimethyl-5-acetamino-1,3-benzodioxole were nitrated at 15°-25° C. in 90 ml of glacial acetic acid by the dropwise addition of 9.5 ml of nitric acid (d=1.4) in 30 ml of glacial acetic acid. After stirring at room temperature for 3 hours, the suspension was poured into ice/water and the crystals were removed by filtration under suction. These were made into a paste with methanol and again suction filtered. There were obtained 22.0 g (98.2% of theory) of 2,2-dimethyl-5-acetamino-6-nitro-1,3-benzodioxole of melting point 173°-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10](OCC)=[O:11])=O)=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[C:8]3[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:11])[NH:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ccccc1C(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(Cl)nc2)c2ccccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-(6-chloronicotinoyl)benzoate (0.599 g, 2.1 mmol) and hydrazine hydrate (0.35 mL, 6.2 mmol) in ethanol (6 mL) was stirred at 75° C. for 1 hour, concentrated, and azeotroped with toluene to provide the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.65 (dd, J=2.7, 0.6, 1H), 8.44-8.25 (m, 1H), 8.13 (dd, J=8.3, 2.5, 1H), 8.08-7.82 (m, 2H), 7.82-7.59 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[H][H]>C1C=CC=CC=1>[CH3:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: [H][H]
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1

Procedure:
5 g/hr of the solution dissolved 10% by weight of 4-formylbiphenyl in a benzene was continuously fed in the hydrogenation reactor, while keep the hydrogen pressure under 10 atm and the reaction temperature at 130° C. Product water was removed from the reaction product solution by phase separation and then benzene was distilled off to obtain 4-methylbiphenyl. The conversion of 4-formylbiphenyl was 99.3% and the selectivity to 4-methylbiphenyl was 99.0% by mole. A small amount of 4-biphenylmethanol and high boiling point products was further contained in 4-methylbiphenyl. Product water was separated from the reaction product solution and then the 4-biphenylmethanol and high boiling point by-products were removed by distillation, whereby 4-methylbiphenyl with a purity of 98% by weight or above was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[CH:18][N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:21]C1C=C(Cl)N=C([N+]([O-])=O)N=1>>[ClH:21].[ClH:21].[N:11]1([C:14]2[C:19]([NH2:20])=[CH:18][N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncncc2N)CC1
Product: Cl
Product: Nc1cncnc1N1CCNCC1

Procedure:
4-Piperazin-1-yl-pyrimidin-5-ylamine dihydrochloride was prepared by the procedures described in Example 34, Step 3, substituting (2R)-{1-(4-chlorobenzyl)-2-[4-(1H-indazol-5-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester with 4-(5-aminopyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (prepared from 4,6-dichloro-nitropyrimidine according to the procedures described in U.S. Pat. No. 5,563,142). LCMS (APCI+) m/z 180 [M+H]+; Rt=1.12 minutes.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][P:17]([O-:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[P:17]([Cl:1])([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:26]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Product: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Dibenzyl chlorophosphate was prepared by adding N-chlorosuccinimide (1.28 g) to a stirred solution of dibenzylphosphite (2.5 g) in benzene (100 ml) at room temperate. After 2 hrs at room temperature the solid (succinimide) was filtered off and the filtrate concentrated to about 5 ml, which was added dropwise to a solution of phenyl 2,3,4-tri-O-acetyl-D-mannoside (3.3 g) in dry pyridine (15 ml) at 0° C. with sting over 1 hour and the mixture allowed to stand at room temperature over night. The mixture was then heated at 40° C. for 2 hours. The solvent was evaporated off under reduced pressure and the residue chromatographed on a silica gel column (silica gel 60; 2.5×50 cm). Initial fractions eluted with methylene chloride were discarded and subsequent elution with ehloroform gave phenyl 2,3,4-tri-O-acetyl-D-mannoside 6-dibenzylphosphate (2.6 g). Calculated for C32H35O12P.2H2O; C, 56.6%; H, 5.8%. Found: C, 56.7%; H, 5.8%.
Reaction SMILES: Cl.Cl.C([N:7](CCC1C=CC(OCCCCC2C=CC(O)=C([C@@H](C3C=CC=CC=3)CCN(C(C)C)C(C)C)C=2)=CC=1)C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=2)=[CH:13][C:12]=1[C@@H:31]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:32][CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=O)(C)(C)C.[CH2:83]([O:90][C:91]1[CH:96]=[CH:95][C:94]([C@@H:97]([O:100][Si:101]([C:104]([CH3:107])([CH3:106])[CH3:105])([CH3:103])[CH3:102])[CH2:98]Br)=[CH:93][C:92]=1[CH2:108][OH:109])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>C(=O)([O-])O.[Na+].ClCCl>[NH3:7].[CH2:83]([O:90][C:91]1[CH:96]=[CH:95][C:94]([C@@H:97]([O:100][Si:101]([C:104]([CH3:107])([CH3:106])[CH3:105])([CH3:103])[CH3:102])[CH2:98][NH:30][CH2:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([OH:10])=[C:12]([C@@H:31]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:32][CH2:33][N:34]([CH:35]([CH3:36])[CH3:37])[CH:38]([CH3:40])[CH3:39])[CH:13]=3)=[CH:27][CH:26]=2)=[CH:93][C:92]=1[CH2:108][OH:109])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCN(C(=O)Oc3ccc(CCCCOc4ccc(CCN)cc4)cc3[C@H](CCN(C(C)C)C(C)C)c3ccccc3)C(C)(C)C)cc2)ccc1O)C(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(CO)c3)cc2)ccc1O)C(C)C
Product: N
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-{4-[4-(2-aminoethyl)phenoxy]butyl}-2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol tert-butyl{2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}carbamate bis hydrochloride salt (Preparation 13, 1.30 g, 2.26 mmol), was dissolved in a mixture of saturated aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was separated, dried (magnesium sulphate) and the solvent removed in vacuo The residue was dissolved in acetonitrile (10 ml) and {2-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}methanol (Prepared according to WO2004/032921, 1.02 mg, 2.26 mmol), sodium hydrogen carbonate (570 mg, 6.78 mmol) were added, and heated to 85° C. and stirred overnight. After cooling the solvent was removed in vacuo and the residue was dissolved in dichloromethane (30 ml) and washed with water (2×20 ml) then brine (20 ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95/5/1 to 90/10/1 by volume) to furnish the title compound as a gum, 388 mg.
Reaction SMILES: [N:1]#[C:2][NH2:3].C(OC(=O)[N:10]([CH2:23][CH3:24])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)(C)(C)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:29]>>[NH2:1][C:2]1[N:3]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH:10][CH2:23][CH3:24])=[CH:19][CH:18]=2)[S:22][C:27]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:29]
Reactant: N#CN
Reactant: CCN(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1cccc(F)c1
Product: CCNCCOc1ccc(Nc2nc(N)c(C(=O)c3cccc(F)c3)s2)cc1

Procedure:
This compound was prepared from cyanamide, ethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester of Example 129D and 2-bromo-1-(3-fluorophenyl)ethanone (Maybridge Chemical) following a procedure similar to Example 123. Mass spectrum (ES) MH+=401.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[C:37]([O:45][CH3:46])=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[C:37]=5[O:45][CH3:46])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: COc1c(F)cccc1B(O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5OC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-fluoro-2-methoxyphenylboronic acid.