Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:12]([C:15]1[N-:19][N:18]=[N:17][N:16]=1)(O)=[O:13].[K+].[NH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])[CH2:26][CH2:25]1.N1C=CC=CC=1>CC#N>[N:16]1[NH:17][N:18]=[N:19][C:15]=1[C:12]([NH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])[CH2:26][CH2:25]1)=[O:13]
Reactant: O=C(O)c1nnn[n-]1
Reactant: NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)c1nn[nH]n1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Under nitrogen, oxalyl chloride (58 μl, 0.657 mmol) was dissolved in MeCN (0.5 ml) and cooled to −20° C. DMF (25 μl, 0.329 mmol) was added and the reaction mixture was stirred for 15 minutes. Potassium 5-carboxytetrazol-1-ide (50 mg, 0.329 mmol) was added and the reaction mixture was stirred for a further 20 minutes. A suspension of 3,5-dichlorobenzyl 4-(2-aminoethyl)piperidine-1-carboxylate (Example 3, step 1) (109 mg, 0.329 mmol) and pyridine (32 μl, 0.394 mmol) in MeCN (2 ml) was added and after warming to RT, the reaction mixture was heated at reflux for 1 hr then was allowed to cool. The mixture was evaporated under reduced pressure and the crude product was purified by preparative LC-MS. The product fractions were evaporated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure to afford the title product.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][CH:5]=1.[CH:12](Br)=[CH2:13].CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:10][C:7]1[N:6]=[CH:5][C:4]([C:3]2[CH:13]=[CH:12][O:1][N:2]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(Cl)=NO)cn1
Reactant: C=CBr
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccon2)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To crude N-hydroxy-6-methylnicotinimidoyl chloride in 10 mL toluene was added vinyl bromide (1 M in THF, 11 mL, 11.0 mmol), followed by bis(tributyltin)oxide (2.12 g, 1.87 mL, 3.67 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to isolate 155 mg (26%, for two steps) of the title compound as a white solid. HPLC/MS: retention time=0.39 min, [M+H]+=161.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH:5]=O.N1CCCC1.O.C1(C)C=CC([S:21](O)(=O)=O)=CC=1.[S].[N:27]#[C:28][NH2:29]>>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]1[S:21][C:28]([NH2:29])=[N:27][CH:5]=1
Reactant: N#CN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=CCCC(F)(F)F
Agent: [S]
Solvent: O
Solvent: C1CCNC1
Product: Nc1ncc(CC(F)(F)F)s1

Procedure:
A mixture of 4,4,4-trifluorobutyraldehyde (Matrix), pyrrolidine, p-toluenesulfonic acid monohydrate, sulfur and cyanamide were processed using the method described in Example 136A to obtain the title compound. MS (ESI+) m/z 183 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[C:10](\[CH3:14])/[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:16][NH:17][O:18][CH3:19].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[C:10](\[CH3:14])/[C:11]([N:17]([O:18][CH3:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C/C(=C\c1ccc(F)c(Cl)c1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)/C(C)=C/c1ccc(F)c(Cl)c1
Yield: 47.9 %

Procedure:
A mixture of Example 9B (11.9 g, 55.45 mmol), N,O-dimethylhydroxylamine hydrochloride (5.7 g, 58 mmol), 1-hydroxybenzotriazole hydrate (7.88 g, 53.8 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (11 g, 57.58 mmol) and diisopropylethyl amine (47.4 g, 63.9 mL, 370 mol) was stirred in DMF (400 mL) at ambient temperature overnight. The solution was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with saturated sodium bicarbonate solution, 1N HCl, water, brine, dried over Na2SO4, filtered, and evaporated in vacuo. The resulting material was chromatographed (SiO2, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to leave the title compound (6.85 g, 48% yield). 1H NMR (300 MHz, CDCl3) δ ppm 7.39 (dd, J=7.12, 2.37 Hz, 1H), 7.10-7.21 (m, 2H), 6.71 (s, 1H), 3.69 (s, 3H), 3.28 (s, 3H), 2.10 (s, 3H). MS (DCI+) 258 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N+:8]=1[O-:14])=[O:5])[CH3:2].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+]>CO.O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N+:8]=1[O-:14])=[O:5])[CH3:2]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)Nc1cccc(Br)[n+]1[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)Nc1cccc(SCc2ccccc2)[n+]1[O-]

Procedure:
A suspension of 1.0 g (0.0038 mole) of 2-ethoxycarbonylamino-6-bromopyridine-1-oxide, as prepared in Step 2 of Example 3, in 25 ml of methanol containing equivalent amounts of benzyl mercaptan and sodium methoxide, is heated under reflux for 2 hours. The reaction mixture is diluted with 150 ml water and the impure product is collected by filtration. Recrystallization from ethyl acetate-cyclohexane gave white needles having a m.p. of 139.8°-140.2° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=2)[NH:20][N:21]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(Nc2cc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 200 °C

Procedure:
To a mixture of 4-chloro-2-phenylquinoline (J. Het. Chem., 20, 1983, 121-128)(0.53 g, 2.21 mmol) in diphenylether (5 mL) was added 3-amino-5-methylpyrazole (0.43 g, 4.42 mmol) and the resulting mixture heated at 200° C. overnight with stirring. The reaction mixture was cooled to ambient temperature then petroleum ether (20 mL) was added and the resulting precipitate was isolated by filtration. The crude solid was purified by flash chromatography (SiO2, gradient DCM-MeOH) to afford V-4 as a white solid: mp 242-244° C.; 1H NMR (DMSO) δ2.27(3H, s), 6.02(1H, s), 7.47(2H, d), 7.53-7.40(2H, br m), 7.67(1H, m), 7.92(1H, m), 8.09(2H, d), 8.48(2H, m), 9.20(1H, s), 12.17(1H, br s); IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SiH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Si:26]([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:4]=2)([CH3:27])[CH3:28])=[CH:22][CH:21]=1
Reactant: COc1ccc([SiH](C)C)cc1
Reactant: C=CCc1ccc(F)c(Oc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 150 °C

Procedure:
To a mixture of 1.14 g (0.005 mole) of 3-(4-fluoro-3-phenoxyphenyl)-1-propene and 0.004 g (0.00001 mole) of hydrogen hexachloroplatinate hydrate in 1 mL of tetrahydrofuran under nitrogen was added slowly 0.83 g (0.005 mole) of (4-methoxyphenyl)dimethylsilane. After completion of addition the reaction mixture was diluted with a mixture of petroleum ether and ethyl acetate. This solution was treated with activated carbon and then was filtered through a short column of silica gel. The solvent was evaporated under reduced pressure, leaving a residue. This residue was heated at 150° C. at 0.1 mm of Hg to remove impurities. The pot residue was a light brown liquid weighing 1.25 g. The ir and proton nmr spectra confirmed that this residue was (4-methoxyphenyl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane, compound 37 of Table 1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41]O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl.O.CCCCCC>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][I:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 6.6 g (25 mmol) of triphenylphosphine in 125 mL of CH2Cl2 was added 1.7 g (25 mmol) of imidazole followed by 6.3 g (25 mmol) of iodine, and the mixture was stirred at rt for 30 min, after which 2.0 g (8.32 mmol) of 1-t-butoxycarbonyl-4-(2-hydroxyethyl) piperidine (from EXAMPLE 113, Step A) was added in CH2Cl2 and the mixture was stirred overnight at rt . The mixture was diluted with H2O, the phases were separated, and the organic phase washed with sat'd NaCl and 0.25 M Na2SO3 solution. The aqueous phase was then extracted 3× with CH2Cl2, and the combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated to provide a white solid. The solid was taken up in hexane, filtered and washed with hexane. The filtrate was concentrated. Flash chomatography on 100 g of silica gel using 17:3 v/v hexanes/EtOAc as the eluant afforded 2.8 g (96%) of the title compound: 1H NMR (500 MHz) δ 1.11 (dq, J=4.4, 8.2, 2H), 1.46 (s, 2H), 1.55-1.63 (m, 1H). 1.66 (d, J=12.6, 2H), 1.78 (q, J=7.1, 2H), 2.65-2.75 (2H), 5.22 (2H), 3.22 (t, J=7.1, 2H), 4.1 14.15 (5H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([CH3:17])[C:14]([Cl:18])=[C:13]([CH3:19])[C:9]=2[C:10](=[O:12])[CH:11]=1)=O)C.[NH3:20]>C(O)C>[Cl:18][C:14]1[C:15]([CH3:17])=[CH:16][C:8]2[O:7][C:6]([C:4]([NH2:20])=[O:3])=[CH:11][C:10](=[O:12])[C:9]=2[C:13]=1[CH3:19]
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c2c(C)c(Cl)c(C)cc2o1
Solvent: CCO
Product: Cc1cc2oc(C(N)=O)cc(=O)c2c(C)c1Cl

Procedure:
A solution of 50.1 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester in 750 parts of warm ethanol was saturated with dry ammonia. After 2 hours a solid had precipitated out and the slurry was heated on the steam bath to remove excess ammonia. The solid was filtered off and crystallised from dimethylformamide to give 42.3 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxamide, melting point >300°C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][NH2:14])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)[CH3:11]
Reactant: CCCCC(CC)CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCC(CC)CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of cyanuric chloride (0.2 mol, 36.8 g) in acetone (300 ml) is introduced dropwise into crushed ice (100 g) in a round-bottom flask, with vigorous stirring, followed by a solution of 2-ethylhexylamine in acetone (100 ml), while maintaining the temperature between 0° and 5° C., and finally a solution of sodium carbonate (11.2 g, 0.1 mol) in 300 ml of water. The mixture is left stirring for one hour at 0°-5° C. The oil is extracted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate. After evaporation of the solvent, 2-(2-ethylhexylamino)-4,6-dichloro-s-triazine (52 g, yield=95%) having the following characteristics, is obtained:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:38][CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42])[CH:36]=O>>[CH3:42][CH:41]([CH2:40][CH2:39][CH:38]=[C:35]([CH3:36])[CH3:34])[CH:43]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=CCCC(C)C=O
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)=CCCC(C)C=CCc1ccccc1
Yield: 74.1 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.20 g, 7.15 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.5 mL, 7.15 mmol, 1.0 equiv.) and 2,6-dimethylhept-5-enal (1.51 g, 10.7 mmol, 1.5 equiv.), 1.21 g (74%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15](C(=O)N)[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.O.C(#[N:45])C>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH2:45])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(C(N)=O)CC2)nc1
Reactant: CC#N
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(N)CC2)nc1
Temperature: 65 °C

Procedure:
A solution comprising 4-carbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid ethyl ester (step a) (2.04 g, 7.36-mmol) and bis(trifluoroacetoxy) iodobenzene (3.80 g, 8.83 mmol) in acetonitrile (13 ml) is treated with water (5 ml) and heated to 65° C. for 30 hours. The solvent is partially removed in vacuo and the resulting solution is acidified to pH1 using 12 M HCl. The solution is extracted with ethyl acetate and this organic portion is discarded. The aqueous portion is basified to pH 8-9 using 2M potassium carbonate solution and then extracted with ethyl acetate and dichloromethane. The organic portions are washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue is triturated with diethyl ether followed by diethyl ether/ethyl acetate (1:1, 5×0.7 ml) and dried in vacuo to yield the title compound as an off-white solid. MS (ES+) m/e 250 (MH+)
Reaction SMILES: [CH2:1]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1C=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CCCC.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][Mg][Br:36])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[O:46][CH2:47][C:48]([CH3:51])([CH3:50])[N:49]=1.C1(CCCCCCCCO)C=CC=CC=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(Cl)Cl>[C:13]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:36])[CH:20]=[CH:19][CH:18]=[CH:17][CH:14]=1.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]2[O:46][CH2:47][C:48]([CH3:51])([CH3:50])[N:49]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Reactant: Br[Mg]CCCCCCCCc1ccccc1
Reactant: CCCCCCCCCCCCc1ccccc1C=O
Agent: BrC(Br)(Br)Br
Agent: OCCCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: BrCCCCCCCCc1ccccc1
Product: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Reaction time: 24 h

Procedure:
Following the procedures of Example 1(a), (b) and (c), to 8-phenyloctylmagnesium bromide (from 24.25 mmoles of 8-phenyloctyl bromide and 21.27 mmoles of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmoles) in tetrahydrofuran (20 ml). [The 8-phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride as described in Example 5(a).] After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmoles) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmoles). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccncc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C

Procedure:
A mixture of 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (1g) (2.0 g, 3.90 mol), pyridine-4-boronic acid (540 mg, 4.39 mol), 1,2-dimethoxyethane (8 mL) and aqueous Na2CO3 (2 M, 1.93 mL, 3.90 mol) was mechanically stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (75 mg, 0.06 mmol) and heated to reflux (95° C.) for 2 h. Added another portion of Pd(Ph3)4 (75 mg, 0.06 mmol) and heated to reflux (95° C.) for further 2 h. The red-brown mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 solution (3×50 mL) and brine (2×50 mL). The organic fraction was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-(5-pyridin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:12]2[N:13]([CH:18]3[CH2:22][CH2:21][C:20]([CH3:23])([CH3:24])[CH2:19]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:36][CH:35]=1
Reactant: CC1(C)CCC(n2nc3c(c2OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC3)C1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC1(C)CCC(n2nc3c(c2-c2ccc(Cl)cc2)CCNCC3)C1
Yield: 17.6 %

Procedure:
The title compound (25.6 mg) was prepared as in Example 177, Steps C and D, using 203.3 mg of 2-(3,3-dimethyl-cyclopentyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 221 Step A) and 204.1 mg of 4-chlorophenylboronic acid. MS (ESI): exact mass calculated for C20H26ClN3, 343.89; found, m/z 344.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 4.62-4.54 (m, 1H), 3.43-3.39 (m, 2H), 3.32-3.28 (m, 2H), 3.20-3.16 (m, 2H), 2.79-2.75 (m, 2H), 2.19-2.03 (m, 2H), 1.99-1.94 (m, 1H), 1.80-1.73 (m, 2H), 1.49-1.40 (m, 1H), 1.16 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [C:1](Cl)([Cl:3])=[S:2].O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[O:10][C:11]1[N:15]([CH3:16])[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=1>O1CCOCC1>[ClH:3].[N:6]([C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[O:10][C:11]1[N:15]([CH3:16])[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=1)=[C:1]=[S:2]
Reactant: Cn1c(Oc2cccc(N)c2)nc2ccccc21
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Cl
Product: Cn1c(Oc2cccc(N=C=S)c2)nc2ccccc21
Reaction time: 3 h
Yield: 36.2 %

Procedure:
An amount of 35 g of thiophosgene, 250 ml of dioxane and 100 ml of water is placed into a sulphating flask and cooled to 0° to 5°; an addition is then made dropwise, within 30 minutes, of a solution of 61 g of 2-(3'-aminophenoxy)-1-methylbenzimidazole in 200 ml of dioxane. The mixture is stirred for 3 hours at 0° to 5°; it is afterwards further stirred for 15 hours at room temperature. After dilution with 600 ml of water, the precipitate is separated and stirred, for 7 hours at 10°, into a solution of 10 g of thiophosgene in 500 ml of acetone. The product is separated and recrystallized from acetonitrile to obtain 29.3 g of (3'-isothiocyanophenoxy)-1-methylbenzimidazolehydrochloride, M.P. 154° to 158°C.
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.C1(C)C=CC(S([N:40]=[N+:41]=[N-:42])(=O)=O)=CC=1.Cl[Si](C)(C)C>C1COCC1.C1(C)C=CC=CC=1>[N:40]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1)=[N+:41]=[N-:42]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-1-triphenylmethylimidazole in THF was treated with t-butyllithium at -70° for 2 hours. A solution of toluene-p-sulphonyl azide in toluene was added, followed after 10 minutes by chlorotrimethylsilane, and the mixture allowed to come to 0°. Work-up and chromatography on magnesium silicate gave 4-azido-2-fluoro-1-triphenylmethylimidazole. This was dissolved in ether and treated with triphenylphosphine at 25°, to precipitate 2-fluoro-1-triphenylmethyl-4-(triphenylphosphimino)imidazole. A solution of this compound in EtOAc was treated for 10 minutes at 25° with propionyl chloride. Aqueous work-up, followed by magnesium silicate chromatography gave 2-fluoro-4-propionylamino-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.05 (t, 3H); 2.2 (q, 2H); 6.95 (s, 1H); 7.05-7.4 (m, 15H); 9.05 (s, 1H).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[CH2:12]([N:14](CC)CC)C.[O:19]1CCC[CH2:20]1>C(OCC)=O>[N+:14]([CH:8]([CH3:9])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])#[C-:12].[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][CH:20]=[O:19])([CH3:5])([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCOC=O
Product: CC(C)(C)OC(=O)CCNC=O
Product: [C-]#[N+]C(C)C(=O)OC(C)(C)C

Procedure:
Tert-butyl isocyanopropionate was synthesised in two steps from commercially available β-alanine tert-butyl ester hydrochloride (NovaBiochem) as follows. To a solution of β-alanine tert-butyl ester hydrochloride (2 g, 11 mmol) in tetrahydrofuran (5 mL) and ethyl formate (5 mL) was added triethylamine (12 mmol, 1.7 mL). The flask was fitted with a reflux condenser and the mixture was heated for 4 hours, after which another quantity of ethyl formate was added (1 mL). An hour later, the mixture was filtered over silica gel. The silica gel was washed with ethyl acetate. The volatiles were removed from the filtrate, yielding N-formyl β-alanine tert-butyl ester (1.4 g, 11 mmol). 13C-NMR (50 MHz, CDCl3) δ 171.2, 163.4, 80.8, 34.7, 33.4, 22.7; 1H-NMR (200 MHz, CDCl3, TMS) δ 8.15 (s, 1H), 6.31 (broad s, 1H), 3.52 (q, 2H, J=6.1 Hz), 2.47 (t, 2H, J=6.2 Hz), 1.46 (s, 9H). This compound (0.65 g, 3.8 mmol) was subjected to the dehydration conditions described for the above nitrile to afford tert-butyl isocyanopropionate (0.50 g, 3.2 mmol, 85%) as a yellowish liquid. The colour darkened during storage at 4° C. (up to two months), but this did not greatly affect the quality of the product. 1H-NMR (200 MHz, CDCl3, TMS) δ 3.64 (m, 2H), 1.48 (s, 9H).