Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[NH4+].[Cl-]>CCCCCC.CCOCC>[OH:17][C:11]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1
Reactant: c1cscn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2nccs2)CCCCC1
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of n-BuLi (22 mL of a 2.5M solution in hexane, 55 mmol) in anhydrous ether (60 mL) at −78° C. was slowly added a solution of thiazole (3.94 g, 46 mmol) in anhydrous ether (30 mL). The resulting mixture was stirred for 1 h and then cyclohexanone (9.6 mL, 93 mmol) in ether (25 mL) was added over 5 min. The mixture was stirred for 2.5 h at −78° C. and then sat. aq. NH4Cl was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 4:1 to 7:3) provided the 2-[(1-Hydroxy)cyclohexyl]thiazole compound (5.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCC(F)(F)F)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 80 °C
Yield: 27.9 %

Procedure:
To a stirring mixture of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.28 mmol) in DMF (0.47 mL) at 20° C. was added 4-bromo-1,1,1-trifluorobutane (50 mg, 0.28 mmol). The resulting reaction mixture was heated at 80° C. for 60 min. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (18 mg, 0.039 mmol) as a yellow oil. MS: [M+H]+=466.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH:25]([CH2:38][C:39]3([OH:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:26][N:27](C)[C:28](OCC[Si](C)(C)C)=O)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[N+](CC)(CC)(CC)CC.[F-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH:25]([CH2:38][C:39]3([OH:45])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:26][NH:27][CH3:28])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1)[C@@H]1CCCN(C(=O)NC(CN(C)C(=O)OCC[Si](C)(C)C)CC2(O)CCCCC2)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Product: CNCC(CC1(O)CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc(F)c2)C1
Temperature: 45 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of (3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-piperidine-1-carboxamide (17.8 mg, mmol) in anhydrous THF (1 mL) was added Et4NF (3 mg). The solution was stirred at 45° C. for 2 h and evaporated under reduced pressure. The residue was purified by prep HPLC to give (3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(methylamino)propan-2-yl)piperidine-1-carboxamide (9.5 mg, 58%) as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.32 (q, 1H), 7.16 (m, 1H), 7.14 (m. 1H), 6.94 (m, 1H), 4.42 and 4.28 (two isomers in a 3:2 ratio, d, 1H), 4.15 (m, 1H), 3.95 and 3.84 (two isomers on 3 to 2 ratio, d, 1H), 3.32 (m, 1H), 3.26 (s, 3H), 3.14 (dd, 1H), 2.95 (m, 1H), 2.70 (s, 3H), 2.60-2.39 (m 3H), 1.94 (t, 2H), 1.79-1.22 (m, 20H), 1.00 (m, 1H); MS m/z 508 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17]C)=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([CH3:19])=[N:6]1.[Br-].[Br-].[Br-].B>C(Cl)Cl>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([Cl:1])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:17])=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([CH3:19])=[N:6]1
Reactant: COc1cc2c(C)nn(Cc3c(Cl)cccc3Cl)c2cc1C(=O)O
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(C(=O)O)c(O)cc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a suspension of the compound [179](7.4 mg) in methylenechloride (0.2 mL) was added 1M methylenechloride solution of borane tribromide (0.2 mL) under ice-cooling, and then the reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative liquid chromatography to give the titled compound (3.7 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[OH:10]O.O>C(O)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N+:7]([O-:10])[CH:8]=1
Reactant: COc1ccc(C)nc1
Reactant: OO
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C)[n+]([O-])c1
Reaction time: 8 h

Procedure:
A solution consisting of 5-methoxy-2-methylpyridine (12.3 g.) and 30% hydrogen peroxide (12 ml.) dissolved in glacial acetic acid (50 ml) was heated in a steam bath for a period of 12 hours and then allowed to stand overnight (~16 hours) at room temperature (~25° C.). Water (5 ml.) was next added to the mixture, followed by manganese dioxide until effervescence ceased. The resulting mixture was then filtered and the recovered filtrate was subsequently evaporated under reduced pressure to afford crude 5-methoxy-2-methylpyridine-N-oxide (yield, 13.5 g.) as the residual oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2oc(N3CCNCC3)nc2c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
In 200 ml of acetonitrile were dissolved 33.6 g (0.39 mole) of piperazine and 10.0 g (0.065 mole) of 2-chlorobenzoxazole, and 9.0 g (0.065 mole) of potassium carbonate and a catalytic amount of potassium iodide were added thereto. The mixture was refluxed by heating for 11 hours under stirring. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=9:1) to obtain 7.54 g of 1-(2-benzoxazolyl)piperazine as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:40](=[O:41])[CH2:39][N:23]3[CH2:24][CH2:25][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:22]3=[O:21])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-((4-chlorophenyl)(phenyl)methyl)piperazine (0.29 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.21-7.47 (m, 19H), 4.37 (s, 1H), 4.14-4.15 (br s, 2H), 3.40-3.48 (m, 4H), 3.35 (t, J=6.7 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.22-2.28 (m, 4H); MS (DCI+) m/z 564 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:17]=1.O.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)=[N:7][C:6]=2[CH:17]=1
Reactant: CSC1=Nc2cc(O)ccc2Nc2cscc21
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)N=C(N1CCN(c3ccccc3)CC1)c1cscc1N2

Procedure:
A solution of 7-hydroxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-phenylpiperazine and glacial acetic acid is heated at 140°-160° C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][CH:5]=1.[O-:27][C:28]#[N:29].[Na+]>O.C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:28]([NH2:29])=[O:27])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CN)cc2)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CNC(N)=O)cc2)cc1

Procedure:
To a solution of 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine hydrochloride obtained by Example 70 (150 mg) in water (8 ml) and ethanol (4 ml) was added sodium cyanate (100 mg) under ice cooling.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:34]1[O:38][C:37]([CH2:39][CH2:40][CH2:41][OH:42])=[CH:36][CH:35]=1)[CH3:33].[CH3:43][N:44]1[N:48]=[N:47][C:46]([C:49]2[CH:54]=[C:53]([CH3:55])[C:52](O)=[C:51]([CH3:57])[CH:50]=2)=[N:45]1>O>[CH2:32]([C:34]1[O:38][C:37]([CH2:39][CH2:40][CH2:41][O:42][C:52]2[C:51]([CH3:57])=[CH:50][C:49]([C:46]3[N:47]=[N:48][N:44]([CH3:43])[N:45]=3)=[CH:54][C:53]=2[CH3:55])=[CH:36][CH:35]=1)[CH3:33]
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Reactant: CCc1ccc(CCCO)o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCc1ccc(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)o1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Diethyl azodicarboxylate (DEAD, 4.84 g; 27.8 mmol) was added under nitrogen to a stirred and cooled (-20° C.) solution of triphenylphosphine (7.37 g; 27.8 mmol), 5-ethyl-2-(3-hydroxypropyl)furan (Intermediate 1c) (3.9 g; 25.3 mmol), and 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (5.69 g; 27.8 mmol). The mixture was stirred at -20° C. for 1/2 h, and then was allowed to warm to room temperature overnight. Water (50 mL) was added to the mixture and the layers were separated. The aqueous layer was extracted with ether (3×50 mL), the organic layer was washed with 10% NaOH solution (3×50 mL), water, and dried over magnesium sulfate. The solvent was concentrated in vacuo to yield a residue and purified by MPLC column chromatography (ethyl acetate/hexane, 3:7) to afford 5.63 g (65%) of 5-ethyl-2-[3-[2,6-dimethyl-4-(2-methyl-tetrazol-5-yl)phenoxy]propyl]furan (Formula II; R3 =5-ethyl, R4 =hydrogen, R1,R2 =3,5-dimethyl, R5 =2-methyltetrazol-5-yl, Y=1,3-propylene).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C([O-])(=O)C.[Na+].[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1>O.C(O)C>[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:3][OH:2])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: [NH3+]O
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(Cc2ccccc2)=NO)cc1
Yield: 70.9 %

Procedure:
Hydroxylammonium chloride (4.19 g, 60.2 mmol) and sodium acetate (7.42 g, 90.4 mmol) are dissolved in 20 ml of water. To this solution 9.72 g (40.1 mmol) of 1-(4-methylsulfanyl-phenyl)-2-phenyl-ethanone in 60 ml of ethanol are added. The reaction mixture is heated to reflux for 18.5 hr. The reaction mixture was concentrated by rotary evaporation and poured into water. The resulting white solid is filterd and washed with water. After drying under reduced pressure, recrystallization from hexane-CH2Cl2 affords 7.32 g of a white solid (71%). 1H NMR (CDCl3), δ[ppm]: d 2.45 (s, 3H), 4.20 (s, 2H), 7.16-7.20 (m, 3H), 7.24-7.27 (m, 4H), 7.54 (d, 2H), 9.03 (s, 1H).
Reaction SMILES: [CH:1]1(/[C:4](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5]/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[CH:5]=[C:4](/[CH:1]2[CH2:3][CH2:2]2)\[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)C2CC2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
As in Example 115, (2E,4Z)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid (1.95 g) and 4-nitrophenol (1.33 g) in 15mL of dichloromethane was reacted with 1,3-dicyclohexylcarbodiimide (1.66 g) and the mixture was stirred at room temperature for 18 hours. After the work up. the crude ester was crystallized from 2-propanol to furnish 1.9 g of (2E,4Z)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 115.5°-116.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1([NH2:13])[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[CH:4]=[CH2:5].[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][N:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:22]2=[O:25])=[CH:17][C:16]=1F>CC(N(C)C)=O>[CH2:3]([C:6]1([NH2:13])[CH2:11][CH2:10][CH:9]([O:12][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:15]=2[Cl:14])[C:22](=[O:25])[N:21]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH:20]=[CH:19]3)[CH2:8][CH2:7]1)[CH:4]=[CH2:5]
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Reactant: C=CCC1(N)CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCC1(N)CCC(Oc2cc3ccn(Cc4ccc(OC)cc4)c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
155 mg (3.86 mmol) of sodium hydride (60%) were suspended in 3 mL of dimethyl acetamide and 220 mg (1.42 mmol) of 4-allyl-4-amino-cyclohexanol (16), dissolved in 1 mL of dimethyl acetamide, were added dropwise. After 1 h, 409 mg (1.29 mmol) of 2-(4-methoxy-benzyl)-6-fluoro-7-chloro-2H-isoquinolin-1-one (10), dissolved in another 2 mL of dimethyl acetamide, were added. The reaction mixture was stirred at room temperature until the reaction was complete. The mixture was quenched by dropwise addition of water, extracted with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 148 mg of the title compound (17) as diastereomeric mixture. Rt=1.35 min, 1.40 min (Method B). Detected mass: 453.3 (M+H+).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.BrCCBr.[Si:14]([O:21][CH2:22][C:23](N(OC)C)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][CH2:22][C:23]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Agent: [Mg]
Solvent: BrCCBr
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
To a suspension of magnesium turnings (2.10 g, 85.7 mmol) in anhydrous THY (120 mL), was added slowly at RT 1-bromo-3-fluorobenzene (10.0 g, 57.2 mmol) and 1,2-dibromoethane (0.10 mL). After stirring for 40 min under argon, the mixture was cooled to −78° C., and 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (9.3 g, 40 mmol) was added. The resulting mixture was warmed to 0° C. and stirred for 2 h. The reaction was quenched with saturated NH4Cl (5.0 mL), and the insoluble material was filtered. The filtrate was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (20:1) to afford 10.3 g (93%) of 2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethanone (58a) as oil. LCMS (ESI) m/z: 268.0[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:14](=O)[CH2:15][CH3:16])[C:10](=[O:13])[CH2:11][CH3:12].Cl.[NH2:25]O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:14]([CH2:15][CH3:16])=[N:25][O:13][C:10]=1[CH2:11][CH3:12]
Reactant: NO
Reactant: CCC(=O)C(CCCCOc1ccc(OC)cc1Cl)C(=O)CC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1CCCCOc1ccc(OC)cc1Cl

Procedure:
4-[4-(2-Chloro-4-methoxyphenoxy)butyl]-3,5-diethylisoxazole [I; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)4, R is C2H5 ] was prepared from 16.2 g. of 4-[4-(2-chloro-4-methoxyphenoxy)butyl]-3,5-heptanedione and 3.3 g. of hydroxylamine hydrochloride in 65 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a yellow oil, b.p. 180°-190° C. (0.1 mm.); yield 9.3 g.; MIC=6 μg/ml (herpes 2).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15]>CCCCCCC.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: COCCCCCCCCCCCC(=O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCCCCCCCCCCCCO
Yield: 78.2 %

Procedure:
The title compound was prepared by the method of Example 3 using the title product of Example 1 (3 g, 13 mmol) instead of the title product of Example 2. Chromatography by of the crude residue on silica gel using 50--50 ethyl acetate heptane gave the title compound (2.2 g) as a white powder, m.p. 32.6-36.7° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis and mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][OH:11])=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([C:52](=[O:60])[C:53]3[CH:58]=[CH:57][C:56](O)=[CH:55][CH:54]=3)[C@@H:44]([CH3:61])[CH2:43]2)[C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:39]([N:38]([C:35]1[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=1)[C@H:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]([C:52]([C:53]2[CH:58]=[CH:57][C:56]([O:11][CH2:10][CH:6]3[CH2:7][CH2:8][CH2:9][CH:5]3[C:3]([O:2][CH3:1])=[O:4])=[CH:55][CH:54]=2)=[O:60])[C@@H:44]([CH3:61])[CH2:43]1)(=[O:41])[CH3:40]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: COC(=O)[C@@H]1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCC1COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
Trans-2-Hydroxymethyl-cyclopentanecarboxylic acid methyl ester (0.127 g, 0.81 mmol) was dissolved in 10 ml toluene at room temperature with PPh3 (0.211 g, 0.81 mmol), then added N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]acetamide (0.1 g, 0.23 mmol) and stirred for 5 min. DEAD (0.141 g, 0.81 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (45% dichloromethane/55% ethyl acetate) to afford methyl 2-[(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)methyl]cyclopentanecarboxylate (0.12 g, 90%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:13]3[CH2:15][CH2:14]3)(O)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:31]3[C:30]4[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=4)[NH:33][CH:32]=3)([CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(O)(c1ccc2c(c1)OCO2)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCO4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.91 mmol) of the compound from Example 143A and 0.27 ml (3.49 mmol) of trifluoroacetic acid were added to 516 mg (2.91 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 377 mg (35% of theory) of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: CSc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CSc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-methylthio-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p. 252°-254° C.) and piperazine at 50° C.