Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=O.Cl.[CH2:12]([O:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl.CN(C)CCCN=C=NCC>O>[OH:1][CH2:2][C@@H:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([NH:20][O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: CCCC[C@H](CO)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCC[C@H](CO)C(=O)NOCc1ccccc1
Temperature: 16.5 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 102.39 g of (2R)-2-(hydroxymethyl)hexanoic acid, 123.0 g of O-benzylhydroxylamine hydrochloride and 2.25 L of water. Adjust the pH by adding one equivalent of NaOH to a pH of 4-5. Stir the reaction mixture at 18° C.±3° C. (external temperature: 15-18° C.) for 30 minutes to give a cloudy solution. Add 161.3 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCl) over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.). Wash the funnel once with 50 mL of water. Stir the thick suspension at 20° C.±3° C. for 2 hours. Filter the solids through a polypropylene filter cloth and a Büchner funnel then wash the flask and filter cake once with 0.5 L of water. Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours, then dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours to give 162 g of (2R)-2-(hydroxymethyl)-N-(phenylmethoxy)hexanamide (C3) as a white solid in 95% yield. m.p. 100-102° C.; [α]D25=+0.556 (c, 1.0, MeOH).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][C@H:16]3[C@H:20]([NH2:21])[CH2:19][O:18][CH2:17]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:31]([C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32]>ClCCl>[C:31]([C:34]1[CH:35]=[C:36]([NH:40][C:41]([NH:21][C@H:20]2[C@H:16]([NH:15][CH:12]3[CH2:11][CH2:10][CH:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([F:3])=[CH:23][CH:22]=4)[CH2:14][CH2:13]3)[CH2:17][O:18][CH2:19]2)=[O:42])[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32]
Reactant: N[C@@H]1COC[C@H]1NC1CCC(Cc2ccc(F)cc2)CC1
Reactant: CC(=O)c1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2COC[C@H]2NC2CCC(Cc3ccc(F)cc3)CC2)c1
Yield: 66.1 %

Procedure:
To a stirring solution of (3S,4S)-N3-[4-(4-fluorobenzyl)cyclohexyl]tetrahydro-3,4-furandiamine dihydrochloride (20 mg, 0.055 mmol) and triethylamine (100 μL, 0.72 mmol) in dichloromethane (1 mL) was added 3-acetylphenyl isocyanate (7.1 mg, 0.050 mmol). The resulting solution was immediately concentrated, and the resulting residue was purified by flash column chromatography (100% ethyl acetate then 5% triethylamine in ethyl acetate then 10% methanol in ethylacetate containing 5% triethylamine) to yield the desired urea (15 mg, 60%) as an oily white solid. MS (ESI) 454 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1([N:28]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[N:30]=[CH:29]1)[C:24](=[S:27])[NH:25][CH3:26].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:27][C:24](=[N:25][CH3:26])[C:19]2([N:28]3[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[N:30]=[CH:29]3)[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]2[OH:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CNC(=S)C1(n2cnc([N+](=O)[O-])c2)CCCCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.5 %

Procedure:
21.7 ml (160 mmol) of 4-methoxybenzyl chloride and 32.94 g (238 mmol) of potassium carbonate were added to a solution of 45.23 g (159 mmol) of the 2-hydroxy-N-methyl-1-(4-nitroimidazol-1-yl)cyclohexanecarbothioamide (L form) prepared in the Example 17 in 300 ml of N,N-dimethylformamide. The obtained mixture was stirred at room temperature for 17 hours to give a yellowish-brown suspension. Water and common salt were added to this suspension and the obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue (65.5 g) was recrystallized from dichloromethane/ethyl acetate to give 42.78 g of the title compound as a light yellowish-brown crystal (yield: 66%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:20][CH2:21][CH2:22][C:23]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]1=2)=[O:24]
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1c2ccccc2-c2ccccc2-c2ccccc21
Yield: 94 %

Procedure:
9H-Tribenz[b,d,f]azepine (0.17 g, 0.70 mmol, prepared similarly as described by H. C. Axtell et al., J.Org.Chem. 56, 3906 (1991)) was suspended in dry toluene (5 ml). 3-Chloropropionyl chloride (0.13 g, 1.0 mmol) and triethylamine (0.1 ml) were added and the mixture was heated at reflux temperature for 1.5 hour. Saturated aqueous sodium bicarbonate (10 ml) was added, and the phases were separated. The organic phase was washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo, affording 220 mg, (94%) of crude 3-chloro-1-(9H-tribenz[b,d,f]azepine-9-yl)propan-1-one as a foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[N:20]O)[CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]([NH2:20])[CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=NO)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CC(N)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Yield: 60 %

Procedure:
A solution of 6-(1-hydroxyimino-ethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.0 g, 3.44 mmol), dissolved in MeOH (50 mL), was hydrogenated under a pressure of 40 psi in the presence of 50% RaNi/H2O (3 mL) for 5 hours. The catalyst was filtered off and the solvent evaporated. The crude amine was purified by chromatography (SiO2, 15% of 2.0M NH3/MeOH in CH3CN) to give 0.57 g (60%) of the title compound as a white solid. m.p: 73-75° C.
Reaction SMILES: [CH:1]1[C:6]2[O:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH2:10][C:11](=O)[CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC1C=CC=CC=1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:11]2[CH2:10][C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[O:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:12]=2)[CH2:22][CH2:21]1
Reactant: O=C1Cc2ccccc2Oc2ccccc2C1
Reactant: CN1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Cc3ccccc3Oc3ccccc3C2)CC1

Procedure:
5H-Dibenz[b,g]oxocin-6(7H)-one (3 g) was dissolved in a mixture of methylbenzene (30 ml) and N-methylpiperazine (2.25 ml) and the solution was refluxed for sixteen hours, with water being removed via a Dean and Stark trap. The reaction mixture was then evaporated to dryness and the product re-treated, as described above, a further two times. The final residue was triturated with methanol to give 6-(4-methyl-1-piperazinyl)-5H-dibenz[b,g]oxocine. M.P. 127° C.
Reaction SMILES: C1(O)C=CC=CC=1.FC(F)(F)S(OC[P:15]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[PH:15](=[O:24])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=P(COS(=O)(=O)C(F)(F)F)(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: Oc1ccccc1
Product: O=[PH](OCc1ccccc1)OCc1ccccc1
Reaction time: 3 h
Yield: 88 %

Procedure:
A solution of phenol 17 (123 mg, 0.19 mmol) and dibenzyl trifluoromethansulfonyloxymethanphosphonate YY (120 mg, 0.28 mmol) in CH3CN (1.5 mL) at room temperature was treated Cs2CO3 (124 mg, 0.38 mmol). The mixture was stirred for 3 h and partitioned in CH2Cl2 and saturated NaHCO3. The organic layer was washed with 0.1N HCl, saturated NaCl, dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (10% MeOH/CH2Cl2) affording phosphonate 18 (154 mg, 88%). 1H NMR (CDCl3) δ 7.96 (s, 1H), 7.68 (d, 2H), 7.35 (m, 10H), 7.10 (d, 2H), 6.97 (d, 2H), 6.80 (d, 2H), 5.63 (d, 1H), 4.96-5.24 (m, 6H), 4.37 (m, 1H), 4.20 (d, 2H), 3.84 (s, 3H), 3.52-3.95 (m, 7H), 2.55-3.20 (m, 8H), 1.48-2.00 (m, 7H), 1.02 (m, 2H). 31P NMR (CDCl3) δ 20.3.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.S(Cl)([Cl:25])=O>CN(C=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([Cl:25])(=[O:17])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-phenoxybenzenesulfonic acid (3.14 g, 12.64 mmol) in thionyl chloride (9 ml) was refluxed for 4 h in presence of DMF (2 drops). After cooling to room temperature, diethyl ether (20 ml) was added and the resulting white solid was separated by filtration. The filtered solution was evaporated in vacuo to give 4-phenoxybenzenesulfonyl chloride as a brown oil which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:21][C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: Clc1nc2ccccc2n2ccnc12
Product: c1ccc2c(c1)nc(NC1CCCCC1)c1nccn12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with cyclohexylamine, according to a procedure that is similar to that followed in example 3, there is obtained 4-cyclohexylaminoimidazo[1,2-a]quinoxaline. m.p. (DSC)=94.0° C. (onset); IR (KBr): 3227, 2924, 1560 cm-1 ; 1H-NMR (CDCl3): δ7.85 (1H,d, J=2 Hz), 7.8÷7.4 (3H,m), 7.4÷7.1 (2H,m), 6.0 (1H,d), 4.2 (1H,m), 2.3÷1.95 (3H,m), 1.95÷0.9 (6H,m); UV (EtOH): λmax =225, 242, 283, 294, 316, 330 nm. Elementary analysis for C16H18N4 (m.w.266.35): calcd. C 72.15, H 6.81, N 21.03%; found C 72.25, H 7.04, N 21.19%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][O:33][CH2:34][CH:35]=[CH:36][CH2:37]O)=[CH:30][C:29]=1[CH3:41].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[F:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][O:33][CH2:34][CH:35]=[CH:36][CH2:37][I:25])=[CH:30][C:29]=1[CH3:41]
Reactant: II
Reactant: Cc1cc(COCC=CCO)ccc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(COCC=CCI)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (2.6 g, 9.9 mmol) in anhydrous 40 mL DCM was added imidazole (1.4 mg, 20.4 mmol) and iodine (2.5 mg, 9.9 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then 4-(4-Fluoro-3-methylbenzyloxy)but-2-en-1-ol (1.3 g, 6.2 mmol) in 10 mL DCM was added to the mixture. The resulting mixture was stirred at 0° C. for 2 h and the temperature was slowly raised to room temp over a period of 2 h. 20 mL of 10% sodium thiosulfate was added and extracted with more DCM (3×30 mL). The combined DCM layer was washed with brine (2×30 mL) and dried over sodium sulfate. Evaporation of solvent left the crude product as an oil from which the product was isolated by Flash column chromatography eluting with 0% to 10% ethyl acetate/hexane to give the title compound, 1.5 g, as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:8]([NH2:11])=[N:9][CH:10]=1.[CH3:21][N:22]([CH2:24][C:25](O)=[O:26])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([C:4]#[C:3][CH2:2][NH:1][C:25](=[O:26])[CH2:24][N:22]([CH3:23])[CH3:21])=[CH:6][C:7]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3-aminoprop-1-ynyl)-3-benzothiazol-2-ylpyridin-2-ylamine (10.0 mg, 0.0357 mmol), dimethylaminoacetic acid (4.05 mg, 0.0392 mmol), TBTU (17.2 mg, 0.0535 mmol), DMF (1 mL, 0.01 mol) and DIPEA (0.03 mL, 0.0002 mol) was stirred at rt for 30 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.66 (br. s., 6H), 3.54 (br. s., 2H), 4.28 (s, 2H), 7.42-7.47 (m, 1H), 7.53 (td, J=7.7, 1.3 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 8.15 (d, J=1.8 Hz, 1H). MS (ES+): m/z=366.13 (100) [MH+]. HPLC: tR=2.43 min (ZQ3, polar—5 min).
Reaction SMILES: CN1CCCC1=O.C(N(C(C)C)CC)(C)C.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:19])=[O:18].[CH3:27][O:28][C:29]([C:31]1[O:40][C:34]2=[N:35][CH:36]=[CH:37][C:38](Cl)=[C:33]2[CH:32]=1)=[O:30]>O>[CH3:27][O:28][C:29]([C:31]1[O:40][C:34]2=[N:35][CH:36]=[CH:37][C:38]([O:26][C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)=[C:33]2[CH:32]=1)=[O:30]
Reactant: COC(=O)c1cc2c(Cl)ccnc2o1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2o1
Temperature: 140 °C
Reaction time: 5 h
Yield: 4.7 %

Procedure:
After adding N-methylpyrrolidone (4.0 ml), diisopropylethylamine (1.3 ml) and para-nitrophenol (822 mg) to 4-chlorofuro[2.3-b]pyridine-2-carboxylic acid methyl ester (1.0 g), the mixture was heated and stirred at 140° C. for 5 hours. After cooling, water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Tetrahydrofuran was used for recrystallization to obtain the title compound (70 mg).
Reaction SMILES: [Br:1][C:2]1(CC([O-])=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH2:3]1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][Br:17])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=CCC(Br)(CC(=O)[O-])c2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)c2ccccc12
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-methylnaphthaleneacetate (14.98 g, 67.75 mmol), N-bromosuccinimide (12.1 g, 67.8 mmol) and 2,2′-azobis(isobutyronitrile) (50 mg) in carbon tetrachloride (50 ml) was heated under reflux for 0.5 hr. After cooling the reaction solution to room temperature, white precipitate was filtered off, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was evaporated under reduced pressure to give a crude product of 1-bromo-4-(bromomethyl)naphthalene as a pale-yellow liquid. The obtained liquid was dissolved in N,N-dimethylformamide (30 ml), sodium acetate (11.1 g, 136 mmol) was added and the mixture was stirred at 60° C. for 6 hrs. After cooling to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=20/1-6/1) to give the objective substance.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[N:23]1CCO[CH2:25][CH2:24]1.C(OC(Cl)=O)C(C)C>C1COCC1>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([NH:23][CH2:24][CH3:25])=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
To a solution of Boc-Ser(Bzl), (6.0 gm, 20.3 mmol) and N-methylmorpholine, 2.3 mL, (20.9 mmol) in 50 mL of THF, was added isobutylchloroformate (2.7 mL, 20.8 mmol), at -15° C. The solution was stirred for a few minutes, and gaseous ethylamine was bubbled through the mixture. The mixture was allowed to stir at -15° C. for 30 min. It was then filtered and the filtrate was concentrated to dryness. The resulting residue was dissolved in ethyl acetate (100 mL), and was washed successively with 1M HCl (2×50 mL), water (50 mL), 10% Na2 CO3 (2×50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 6.0 gm of a white powder. The structure was supported by NMR data.
Reaction SMILES: [Br-].[OH:2][C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([O:6][CH:7]1[CH2:12][CH2:11][N+:10]([CH2:14][C:15](=[O:22])[NH:16][C:17]2[CH:21]=CO[N:18]=2)([CH3:13])[CH2:9][CH2:8]1)=[O:5].[Br:35][CH2:36][C:37]([NH:39]C1C=CON=1)=O.BrCC(NC1C=NC=CN=1)=O>>[Br-:35].[OH:2][C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:4]([O:6][CH:7]1[CH2:12][CH2:11][N+:10]([CH3:13])([CH2:14][C:15](=[O:22])[NH:16][C:17]2[CH:21]=[N:39][CH:37]=[CH:36][N:18]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(CBr)Nc1ccon1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Agent: O=C(CBr)Nc1cnccn1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2cnccn2)CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1

Procedure:
This compound is prepared by an analogous method to 4-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Example 13) by replacing 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) with 2-bromo-N-pyrazin-2-yl-acetamide (Intermediate G).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5](=[O:7])[N:6]=1.[Cl:8][C:9]1[CH:27]=[C:26]([CH:28]=C2SC(=O)NC2=O)[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:8][C:9]1[CH:27]=[C:26]([CH:28]=[C:4]2[S:3][C:2](=[NH:1])[NH:6][C:5]2=[O:7])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:21])([F:22])[F:23]
Reactant: N#Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2Cl)c(C(F)(F)F)c1
Reactant: NC1=NC(=O)CS1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=N)NC3=O)cc2Cl)c(C(F)(F)F)c1

Procedure:
4-[2-Chloro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile was prepared using 2-amino-thiazol-4-one and 4-[2-Chloro-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethylbenzonitrile according to General Procedure C. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (br, 1H), 9.24 (br, 1H), 8.40 (d, J=1.56 Hz, 1H), 8.08 (dd, J=8.6 and 1.95 Hz, 1H), 7.90 (d, J=1.96 Hz, 1H), 7.65 (d, J=2.35 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J=8.61 Hz, 1H), 7.07 (d, J=8.61 Hz, 1H). LC/MS (m/z) [M+1]+424.2 (calculated for C18H10ClF3N3O2S 424.0).
Reaction SMILES: C[O:2][C:3]1[CH:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([O:14]C)=[CH:6][CH2:5][CH:4]=1.Cl>O>[CH3:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[C:7](=[O:14])[CH2:6][CH2:5][CH2:4][C:3]1=[O:2]
Reactant: COC1=CCC=C(OC)C1CCC(C)C
Agent: Cl
Solvent: O
Product: CC(C)CCC1C(=O)CCCC1=O
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
A suspension of ether 6 (84.0 g, 400 mmol) and 1N HCl (25 mL) was heated to 90° C. while stirring vigorously. After about 15 minutes the mixture became exothermic and a clear homogeneous liquid resulted. The reaction mixture was stirred for an additional 15 minutes at this temperature and cooled to room temp. During this process the product solidified, and the mixture was diluted with water (500 mL) and filtered. The solid was suspended in hexanes (250 mL), stirred, filtered and dried to give 68.0 g (93.4%) of 7. MS m/z 183 (M+1); 1H NMR (300 MHz, CDCl3) δ 9.5-9.0 (br s, 1H), 2.5 (t, 4H), 2.3-2.2 (m, 2H), 2.0-1.9 (m, 2H), 1.6-1.5 (m, 1H), 1.2-1.1 (m, 2H), 0.9 (d, 6H); 13C NMR (CDCl3) δ 206.0, 188.1, 117.2, 40.1, 38.1, 33.3, 28.6, 23.0, 21.2, 20.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1Br
Product: COC(=O)c1ccc(C)c(Br)c1

Procedure:
n.m.r. δ values include 2.40 (s, 3 H), 3.90 (s, 3 H), 7.25 (d, 1 H), 7.80 (d, 1 H), 8.15 (s, 1 H), from 3-bromo4-methylbenzoic acid (2.63 g) and acetyl chloride(1.8 mL).
Reaction SMILES: C([NH:5][S:6](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[N:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[S:6]([NH2:5])(=[O:7])=[O:8])=[CH:16][CH:15]=1
Reactant: CC(C)(C)NS(=O)(=O)/C=C/c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)/C=C/c1ccncc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
(E)-N-tert-Butyl-2-(4-pyridyl)ethenesulfonamide (3.8 g) was dissolved in trifluoroacetic acid (38 ml) and the mixture was stirred in an oil bath at 50° C. for 4 hr. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in trifluoroacetic acid (19 ml) and stirred in an oil bath at 50° C. for 45 min. The reaction mixture was concentrated to dryness under reduced pressure and the residue was partitioned between chloroform:methanol (9:1) and a saturated aqueous solution of sodium hydrogen carbonate. The aqueous layer was extracted twice with chloroform:methanol (9:1) and once with ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted 4 times with ethyl acetate. All extracts with ethyl acetate were combined, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was powdered from diethyl ether to give (E)-2-(4-pyridyl)ethenesulfonamide (2.34 g) as a pale-brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:14])[NH:12][CH:13]=1.CC([O-])=O.[Na+].[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]([C:30](=O)[CH3:31])[C:27]([NH2:29])=[O:28])=[CH:23][C:22]=1[F:35]>C1COCC1.CO>[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]2[N:12]3[CH:13]=[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[N:10]=[C:11]3[NH:14][C:30]([CH3:31])=[C:26]2[C:27]([NH2:29])=[O:28])=[CH:23][C:22]=1[F:35]
Reactant: CC(=O)C(=Cc1ccc(Cl)c(F)c1)C(N)=O
Reactant: COc1ccccc1-c1c[nH]c(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
A mixture of 4-(2-methoxyphenyl)-1H-imidazol-2-amine (0.85 g, 4.5 mmol) and NaOAc (267.3 mg, 4.95 mmol) in THF (5 mL) and MeOH (1.5 mL) was stirred at room temperature for 20 min and followed by addition of 2-(4-chloro-3-fluorobenzylidene)-3-oxobutanamide (1.09 g, 4.5 mmol). The reaction mixture was then heated to 70° C. for 2 h and evaporated under reduced pressure. The residue was suspended in THF, and the slurry mixture was filtered to give 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxamide (1.01 g, 54.4%) as a yellow solid.