Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24](F)=[C:25]([Cl:28])[CH:26]=2)[CH:21]=[CH:20][N:19]=1.[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][C:25]=2[Cl:28])[C:18]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:19][CH:20]=[CH:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccc1
Reactant: Fc1cc2ccnc(Cl)c2cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
289.8 mg (1.44 mmol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl-ester were dissolved in 10 ml of dimethyl acetamide and 57.6 mg (1.44 mmol) of sodium hydride (60%) were added. The reaction mixture was stirred at room temperature. After 30 minutes a solution of 310 mg (1.44 mmol) of 1,7-dichloro-6-fluoro-isoquinoline (5) in 3 ml of dimethyl acetamide was added and the mixture was stirred at room temperature for 1 h to complete conversion. Then 155.7 mg (1.44 mmol) of benzyl alcohol followed by 57.6 mg (1.44 mmol) of sodium hydride (60%) were added and stirring was continued at room temperature. To reach complete conversion, 0.5 equivalents of benzyl alcohol and sodium hydride were added twice, after 2 h and standing overnight. For working up, the solvent was evaporated, the residue was taken up in dichloromethane, washed twice with H2O, dried with MgSO4 and evaporated. Final purification was accomplished by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]([CH:9]=O)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:11][C:12]([CH:23]=[CH:24][C:25]1[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28][CH2:27][C:26]=1[CH3:33])=[CH:13][CH2:14]P(=O)(OCC)OCC.CS(C)=O.CC(C)([O-])C.[K+]>O1CCCC1.CCCCC>[CH3:8][CH2:7][O:6][C:4](/[CH:3]=[C:2](\[CH:9]=[CH:14]\[CH:13]=[C:12](/[CH:23]=[CH:24]\[C:25]1[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28][CH2:27][C:26]=1[CH3:33])\[CH3:11])/[CH3:1])=[O:5]
Reactant: CCOC(=O)C=C(C)C=O
Reactant: CCOP(=O)(CC=C(C)C=CC1=C(C)CCCC1(C)C)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCCCC
Product: CCOC(=O)/C=C(C)\C=C\C=C(C)/C=C\C1=C(C)CCCC1(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a solution of 57 mg (0.40 mmole) of ethyl 3-methyl-4-oxobutenoate [prepared according to a procedure described by R. W. Curley, Jr., et al., J. Org. Chem., 51, 256 (1986); an alternate synthesis has been described by A. Guingant, et al., J. Org. Chem., 52, 4788 (1987); the compound is commercially available from Fluka Chemical Corp., Ron Kon Koma, N.Y. 11779.] and 132 mg (0.388 mmole) of 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid diethyl ester (produced in accordance with Example X) in 3.5 mL of 6:1 (v/v) anhydrous tetrahydrofuran:dimethyl sulfoxide, protected from atmospheric moisture and maintained at a temperature of approximately 5° C. by use of an ice water bath, was added 43 mg (0.38 mmole) of potassium tert-butoxide. This mixture was subsequently stirred in the cold for 10 minutes and then at room temperature for 6 hours. The product was isolated by dilution of the mixture with 30 mL of 1:1 (v/v) pentane:ether and subsequent washing of the organic layer with 30 mL portions of 10% aqueous sodium chloride (3×30 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure, followed by filtration through a small column of silica gel (15 mL, 60-200 mesh, elution with 75 mL of hexane--4% ether) to remove any unreacted starting materials, afforded 76 mg (61% yield) of ethyl retinoate shown by high-field (300 MHz) NMR analysis to be predominantly the all trans stereoisomer. The product was characterized by three broad singlets of equal intensity at δ 2.37, 2.02, and 1.73 (3 vinyl methyls). For tables listing spectroscopic properties of retinoids, see: R. S. H. Liu, et al. Tetrahedron, 40, 1931-1969 (1984). Ethyl retinoate was also prepared in a similar manner from ethyl 3-methyl-4-oxobutenoate and 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid diisopropyl ester (produced in accordance with Example XI).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)nc1
Yield: 67 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromo-5-methylpyridine, the title compound was obtained in the same manner as in Example 107. Yield: 67%. Melting point: 228-229° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]1[CH:14]1[CH2:16][CH:15]1[C:17](O)=O)[CH3:2].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:33][N:34]1[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([CH3:41])[C:35]1=[NH2+:42].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]1[CH:14]1[CH2:16][CH:15]1[C:17]1[N:42]=[C:35]2[C:36]([CH3:41])=[N:37][CH:38]=[C:39]([CH3:40])[N:34]2[N:33]=1)[CH3:2]
Reactant: CCn1cc(-c2ccccc2)nc1C1CC1C(=O)O
Reactant: Cc1ncc(C)n(N)c1=[NH2+]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccccc2)nc1C1CC1c1nc2c(C)ncc(C)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of 2-(1-ethyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylic acid (103 mg, 0.4 mmol) in DMF (3.0 mL) was added 1-amino-3,6-dimethylpyrazin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (135 mg, 0.400 mmol) followed by O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (128 mg, 0.400 mmol) and triethylamine (0.277 mL, 2.000 mmol) at rt. After 1 h stirring at rt, the reaction mixture was heated at 70° C. for 15 h. The crude was purified by prep HPLC using Phenomenex column and MeOH—H2O-TFA as eluent (25% to 100% over 12 min gradient; 40 mL/min flow). Collected the pure fractions and removed solvent. Prepared HCl salt by adding MeOH (3 mL) and 1.0 M HCl (3 mL) and removing solvent. Obtained 2-(2-(1-ethyl-4-phenyl-1H-imidazol-2-yl)cyclopropyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine, 1.0HCl (85 mg, 0.202 mmol, 50.6% yield) as a white solid. 1H NMR (500 MHz, METHANOL-d4) δ 8.13 (d, J=0.9 Hz, 1H), 7.99 (s, 1H), 7.80-7.78 (m, 1H), 7.77-7.75 (m, 1H), 7.58-7.50 (m, 2H), 7.40-7.22 (m, 1H), 4.38 (q, J=7.3 Hz, 2H), 3.29-3.25 (m, 1H), 3.10-3.08 (m, 1H), 2.98 (s, 3H), 2.85 (s, 3H), 2.21-2.18 (m, 2H), 1.60 (t, J=7.4 Hz, 3H); MS (ESI) 359 (M+H); Rf=1.99 (Condition A).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].CCCCCC.C([Li])CCC.[Br:23]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:23][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)n1ccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide obtained in Step A (6.74 g) in tetrahydrofuran (75 mL) was added dropwise n-butyllithium hexane solution (1.3 M, 31.1 mL) over 15 min at −78° C. The reaction mixture was stirred at −78° C. for 15 min, and a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (13.8 g) in tetrahydrofuran (25 mL) was added dropwise thereto over 10 min. The reaction mixture was stirred at −78° C. for 15 min, and then at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:14])[CH:9]([CH:11]2[CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.CCCCCC>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[CH:9]([CH:11]2[CH2:13][CH2:12]2)[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C1CC1)C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
After 15 minutes 1-(4-chlorophenyl)-2-cyclopropylpropan-1-ol (44.72 g, 212 mmol) in dry dichloromethane (330 ml) was added over approximately 35 minutes. After 75 minutes triethylamine (154 ml), 1105 mmol) was added and the mixture allowed to warm to room temperature. Hexane was added and the mixture washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried and evaporated in vacuo. Chromatography [SiO2, hexane-ethyl acetate (100:0) to (90:10)] gave 1-(4-chlorophenyl)-2-cyclopropylpropan-1-one (38.0 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[CH:8]N(C)C)=[N:4][CH:3]=1.[N+]([O-])([O-])=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]([NH2:31])=[NH2+:30])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25].[OH-].[Na+].[CH:34](O)(C)C>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:34][N:31]=[C:29]([NH:28][C:20]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=3)[N:30]=2)=[N:4][CH:3]=1
Reactant: CN(C)C=Cc1ncc(Cl)s1
Reactant: CC(C)O
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(Nc2nccc(-c3ncc(Cl)s3)n2)cc(OC)c1OC
Yield: 35 %

Procedure:
To a solution of [2-(5-Chloro-thiazol-2-yl)-vinyl]-dimethyl-amine (450 mg) in isopropanol (10 ml) was added N-(3,4,5 trimethoxyphenyl)guanidinium nitrate (560 mg) (prepared using a procedure similar to that described in WO9719065) and sodium hydroxide (80 mg). The resulting mixture was heated to reflux for 6 hours, then cooled to ambient and concentrated. The mixture was diluted with water (20 ml) and extracted with ethylacetate (20 ml), the organic phase was removed, washed with water, brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography (30% ethylacetate/petroleum ether) to afford the sub-titled compound as an orange solid (260 mg, 35%); IR (solid) 1570, 1508, 1453, 1422 cm−1; 1H NMR (400 Mhz, CDClS) δ 3.8 (3H, s), 3.95 (6H, s), 7.15 (1H, s), 7.50 (1H, m), 7.75 (1H, s), 8.6 (1H, d); MS (ES+) 379.2 (M+1), (ES−) 377.2 (M−1).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH3:39][O:40][C:41]1[CH:56]=[CH:55][C:44]([C:45]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)=[O:46])=[CH:43][CH:42]=1>>[OH:46][C:45]([C:35]1[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=1)[C@@H:8]1[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]1[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])([C:44]1[CH:55]=[CH:56][C:41]([O:40][CH3:39])=[CH:42][CH:43]=1)[C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: COc1ccc(C(O)(c2ccc(OC)cc2)c2cn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c(=O)[nH]c2=O)cc1

Procedure:
5-(Hydroxy-1,1-bis(4-methoxyphenyl)methyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (but using 4,4'-dimethoxybenzophenone instead of benzophenone).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]/[C:4]([OH:6])=O.C(#N)C.C(OP(Cl)(=O)OCC)C.[NH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([OH:38])=[C:33]([CH3:39])[CH:32]=1>C(N(CC)CC)C>[CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]/[C:4]([NH:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([OH:38])=[C:33]([CH3:39])[CH:32]=1)=[O:6]
Reactant: Cc1cc(N)cc(C)c1O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C\C(=O)O
Agent: CCOP(=O)(Cl)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C\C(=O)Nc1cc(C)c(O)c(C)c1
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
Under ice-cooling, to a solution of 0.9 g of 3,7,11-trimethyl-(2Z,6E)-2,6,10-dodecatrienoic acid in 10 m of acetonitrile are added 578 mg of triethylamine, then 854 mg of diethylphosphorochloridate. After the mixture is stirred for 30 minutes, 522 mg of 4-amino-2,6-dimethylphenol is added and the reaction mixture is stirred at room temperature. Ice chips are added into the reaction mixture, the mixture is extracted with isopropyl ether and the extracted with 10% hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, followed by drying and then evaporation of the solvent. The residue is purified by silica gel column chromatography [solvent: ethyl acetate-hexane (1:3)] to give 580 mg of 4-[3,7,11-trimethyl-(2Z,6E)-2,6,10-dodecatrienoylamino]-2,6-dimethylphenol
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([O:10]CC)=[CH2:9])=[CH:4][N:3]=1.C1C(=O)N([Br:20])C(=O)C1>C1COCC1.O.CCOC(C)=O.[F-].[K+]>[Br:20][CH2:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:9]
Reactant: C=C(OCC)c1cnc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CBr)c1cnc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of 2-bromo-5-(1-ethoxyvinyl)pyrazine (0.65 g, 2.84 mmol) in THF and water was added NBS (0.505 g, 2.84 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, then diluted with EtOAc and aq. KF. The two phase mixture was stirred for 20 min at rt before being filtered through diatomaceous earth (Celite®). The filtrate was washed with sat. NaHCO3, sat. NaCl, dried over anhydrous Na2SO4, concentrated. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield 2-bromo-1-(5-bromopyrazin-2-yl)ethanone (0.38 g) as a yellow oil. LC/MS (Cond. N-1): [M+H]+ 280.91, RT=2.945 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][C:18]2[NH:19][CH:20]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:22]=2)[CH2:14][S:13]1.[CH2:27](Br)[CH:28]([CH3:30])[CH3:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[C@@H:15]([CH2:17][C:18]2[NH:19][CH:20]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:22]=2)[CH2:14][S:13]1
Reactant: CC(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](Cc2nc(CC(C)C)c[nH]2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](Cc2nc(CC(C)C)c[nH]2)N1CC(C)C

Procedure:
(L)-Histidinol was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-(1-(isobutylimidazoly)methyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(1-(isobutylimidazolyl)methyl)-1,3-thiazolidine.
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>ClC(Cl)C>[CH3:24][CH2:23][C:22]([N:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CCC(=O)Cl
Reactant: c1ccc(CCN2CCC(Nc3ccccc3)CC2)cc1
Solvent: CC(Cl)Cl
Product: CCC(=O)N(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Reaction time: 10 h

Procedure:
In two neck round bottom flask equipped with condenser pressure equalizing funnel and calcium chloride guard tube, a solution of 28.0 (0.10 moles) of 4-anilino N-phenethyl piperidine prepared in step II, in 150 ml of dichloroethane was taken. To this solution, 9.25 gm (0.10 moles) of propionyl chloride was added drop wise through pressure equalizing funnel with continuous stirring. After the completion of the addition, the mixture was further stirred for 10 hrs. After the completion of the reaction, the reaction mixture was washed with 20% sodium hydroxide solution. The aqueous phase was extracted with 2×100 ml of dichloromethane. The combined organic extract was dried over sodium sulphate and concentrated to give crude fentanyl. The crude product was recrystallised from petroleum ether (60 to 80° C.) to give colourless crystals of pure fentanyl having mp 82 to 83° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=[CH2:5].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl>CN(C)C=O>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([C:4]([CH3:3])=[CH2:5])[C:7]1=[O:15]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: ClCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCCCl)c2ccccc21
Reaction time: 2 h

Procedure:
To a stirred suspension of 3.2 parts of a sodium hydride dispersion 70% in 9 parts of N,N-dimethylformamide is added dropwise, during a 2 hours-period, a mixture of 17.4 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 70.5 parts of 1,5-dichloropentane and 45 parts of N,N-dimethylformamide at 25°-30° C. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is filtered over hyflo and the filtrate is evaporated. The residue is taken up in 90 parts of methylbenzene and the whole is stirred with activated charcoal. The latter is filtered off. The filtrate is washed with water, dried, filtered and evaporated in an oil-bath at 120° C. (water-jet), yielding 1-(5-chloropentyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [Na+].[CH2:2]([C:8]1[S:12][C:11](OB(O)[O-])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)=[C:20]([F:35])[CH:19]=1.C(=O)([O-])O.[Na+]>C1COCC1.O.CC(OC)(C)C.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>[F:35][C:20]1[CH:19]=[C:18]([C:11]2[S:12][C:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][CH:10]=2)[CH:23]=[CH:22][C:21]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=1
Reactant: CCCCCCc1ccc(OB([O-])O)s1
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)c(F)c2)s1

Procedure:
A mixture of 3.30 g (13.1 mmol) of 5-hexylthiophen-2-ylhydroxyboronic acid sodium salt, 4.20 g (13.1 mmol) of 4-bromo-2-fluoro-4′-pentylbiphenyl, 2.2 g (26.2 mmol) of sodium hydrogencarbonate and 0.70 g (0.61 mmol) of tetrakis(triphenylphosphine)palladium(0) in THF/water (1:1) is heated under reflux for 6 h. The mixture is diluted with MTBE, and the organic phase is separated off. The aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to completion, and the residue is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from methanol/pentane (5:1). 2-(2-Fluoro-4′-pentylbiphenyl-4-yl)-5-hexylthiophene is obtained as a colourless solid having an m.p. of 44° C.
Reaction SMILES: [NH:1]1[BH:6][NH:5][BH:4][NH:3][BH:2]1.[CH3:7][C:8]#[C:9][CH3:10]>[C-]#[O+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Rh]>[CH:7]([B:2]1[NH:3][BH:4][NH:5][BH:6][NH:1]1)=[CH:8][CH2:9][CH3:10]
Reactant: B1NBNBN1
Reactant: CC#CC
Agent: [Rh]
Agent: [C-]#[O+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC=CB1NBNBN1
Yield: 10.1 %

Procedure:
As in the previous examples, borazine (1.618 g, 20.1 mmol) and 2-butyne (20 mmol) were reacted in the presence of RhH(CO)(PPh3)3 (0.0165 g, 0.018 mmol) for four hours at room temperature. Fractionation of the resulting reaction mixture gave 0.2702 g (2.01 mmol) of B-butenyl-borazine stopping in a -55° C. trap. GLC analysis of the product indicates that it is composed of a 3:2 mixture of B-trans-(2-cis-butenyl)borazine and B-trans(1-butenyl)borazine. Pure samples of each isomer were prepared by preparative G.L.C.
Reaction SMILES: [C:1]([NH:9][C:10]([C:37](=[O:39])N)=[CH:11][C:12]1[N:13]=[C:14]([F:36])[N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CC(C)=[O:43]>>[C:1]([NH:9][C:10]([C:37]([OH:43])=[O:39])=[CH:11][C:12]1[N:13]=[C:14]([F:36])[N:15]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: NC(=O)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)NC(=O)c1ccccc1
Agent: Cl
Product: O=C(O)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)NC(=O)c1ccccc1

Procedure:
The azlactone from Example 67 was suspended in acetone and heated for 10 minutes on a steam bath. Addition of 2N HCl and extractive work-up gave 4-(2-benzoylamino-2-carboxyvinyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 6.88 (s, 1H); 6.95-7.7 (m, 19H); 8.1-8.3 (m, 2H); 13.09 (br s, 1H).