Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[C:9]1([C:15]2([NH2:19])[CH2:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN1C(=O)CCC1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:19][C:15]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:16][CH2:17][CH2:18]2)=[N:6][CH:7]=1
Reactant: NC1(c2ccccc2)CCC1
Reactant: Fc1ccc(Br)cn1
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1ccc(NC2(c3ccccc3)CCC2)nc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 6.7 %

Procedure:
To a 20 dram vial was added 5-bromo-2-fluoropyridine (250 mg, 5.0 mmol, 1.0 equiv), 1-phenylcyclobutanamine (1.0 g, 7 mmol, 1.4 equiv), and NMP (1 mL). The reaction was heated to 120° C., stirred for 72 h, and then diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography to give 102 mg (26%) of 5-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1n[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1nc(C)c2ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
3-Methyl-1H-indazole (6.157 g, 44.6 mmol) in CH2Cl2 (100 mL) was treated with acetic anhydride (22.75 g, 223 mmol), triethylamine (22.5 g, 228 mmol) and DMAP (0.54 g, 4.5 mmol). The mixture was stirred 1 h at 20° C., poured into water (100 mL) and extracted with CH2Cl2 (2×100 mL). The extracts were dried (Na2SO4), concentrated and the residue recrystallised from hexane to give the title compound (4.12 g, 66%) as a white crystalline solid; mp 70°-71° C. (from hexane); 1H NMR (360 MHz, CDCl3) δ 8.41 (d, J=8.4 Hz, 1H, indazole), 7.64 (d, J=8.4 Hz, 1H, indazole), 7.54 (t, J=8.4 Hz, 1H, indazole), 7.35 (t, J=8.4 Hz, 1H, indazole), 2.75 (s, 3H, Ac), 2.58 (s, 3H, Me); MS (CI+) m/e 175 (M+H+); Anal. calcd for C10H10N2O: C, 68.95; H, 5.97; N, 16.08. Found: C, 68.80; H, 5.58; N, 16.18.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=[O:4].[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:2]([CH3:17])[C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)=[O:4])=[CH:24][CH:23]=1
Reactant: COCOc1ccc(O)cc1
Reactant: CC(Br)C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCOc1ccc(OC(C)C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.91 g (9.3 mmol) of 2-bromo-N-(4-(trifluoromethoxy)phenyl)propanamide, 1.58 g (10 mmol) of 4-(methoxymethoxy)phenol, 1.52 g (11 mmol) of powdered, anhydrous potassium carbonate and 35 ml of acetonitrile was warmed, under N2, at reflux for a period of 5.5 hours and then stirred at room temperature overnight. The resulting mixture was poured into water and extracted with two portions of ether. The combined organic layers were washed twice with 5 percent aqueous NaOH, treated with charcoal and MgSO4, filtered and the filtrates evaporated to dryness. The residue was recrystallized from hexane to leave 1.77 g (49 percent of theoretical) of the above-named product as a colorless solid, m.p. 115°-116° C. The product is identified on the basis of IR and NMR analyses.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:54])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:47])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:54])[N:20]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:46]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:47])=[CH:44][CH:45]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2ccc(C(=O)N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C(=O)N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.33 g), sodium hydrogen carbonate (1.83 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-1-[4-(morpholin-4-ylcarbonyl)benzyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.16 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.46 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.01 g, 78%).
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1.[H-].[Na+].[CH:16](I)([CH3:18])[CH3:17].O>CN(C)C=O>[CH:16]([N:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1)([CH3:18])[CH3:17].[CH:16]([N:2]1[CH:3]=[C:4]2[C:5]([N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9]2=[O:10])=[N:1]1)([CH3:18])[CH3:17]
Reactant: O=c1c2cn[nH]c2nc2n1CCS2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc2c(=O)n3c(nc2n1)SCC3
Product: CC(C)n1ncc2c(=O)n3c(nc21)SCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %
Yield: 29 %

Procedure:
In 50 ml of dimethylformamide was dissolved 2.50 g (12.9 mmol) of Compound 1 prepared in Example 1, and 0.77 g (19.3 mmol) of sodium hydride (60%) and 1.92 ml (19.3 mmol) of isopropyl iodide were added to the solution, followed by stirring at room temperature for 2 hours. After addition of water and evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1). The first and second main fractions gave 1.89 g (62%) of Compound 30 and 8.88 g (29%) of Compound 31, respectively. Each compound was recrystallized from ethanol for purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][N:19]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:30]([NH2:31])=[N:29][C:28]([NH2:32])=[C:27]([Cl:33])[N:26]=2)=[O:24])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:51](Br)[CH:52]=[CH2:53]>CC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:53]([N+:19]([CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:30]([NH2:31])=[N:29][C:28]([NH2:32])=[C:27]([Cl:33])[N:26]=1)=[O:24])([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[CH:52]=[CH2:51]
Reactant: COc1ccc(CCCN(CCCc2ccc(OC)cc2)CCNC(=O)c2nc(Cl)c(N)nc2N)cc1
Reactant: C=CCBr
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CC[N+](CCCc1ccc(OC)cc1)(CCCc1ccc(OC)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (2-{bis-[3-(4-methoxy-phenyl)-propyl]-amino}-ethyl)-amide trifluoroacetate (Intermediate D) (0.20 g, 0.31 mmol) in acetone (5 mL) is added sodium carbonate (99 mg, 0.94 mmol) followed by allyl bromide (0.082 mL, 0.94 mmol). The reaction mixture is heated at reflux for 72 h, cooled to RT then filtered to remove inorganic salts. The filtrate is concentrated and purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) affords the title compound. M+ 567. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (1H, t), 7.76 (2H, br), 7.16 (2H, br), 7.11 (4H, d), 6.85 (4H, d), 5.95 (1H, ddt) 5.62 (1H, d), 5.57 (1H, d), 3.99 (2H, d), 3.72 (6H, s), 3.58-3.54 (2H, m), 3.30 (2H, t), 3.24-3.20 (4H, m), 2.50 (4H, t), 1.97-1.78 (4H, m).
Reaction SMILES: [Br:1]Br.[C:3]([C:11]1[C:12](=[O:21])[N:13]([CH3:20])[C:14](=[O:19])[N:15]([CH3:18])[C:16]=1[CH3:17])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O>[C:3]([C:11]1[C:12](=[O:21])[N:13]([CH3:20])[C:14](=[O:19])[N:15]([CH3:18])[C:16]=1[CH2:17][Br:1])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Bromine (0.497 mL, 9.68 mmol) was added to a solution of 5-benzoyl-1,3,6-trimethyl pyrimidine-2,4(1H,3H)-dione (step 2) (2.5 g, 9.68 mmol) in chloroform (50 mL) with stirring under nitrogen. The mixture was heated to 55° C. for 2 h. A further portion of bromine (0.25 mL, 0.5 equiv) was added and heating continued at 55° C. for a further 30 min. The mixture was cooled to RT, diluted with CHCl3 (50 mL) and poured into saturated sodium thiosulfate solution (150 mL). The layers were separated and the aqueous phase was extracted with CHCl3 (50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and filtered under reduced pressure. The solvent was evaporated under reduced pressure to afford a pale yellow solid. This solid was dissolved in hot EtOAc (50 mL) and slowly evaporated until crystallisation was observed. The resulting white solid was collected by reduced pressure filtration and washed with cold EtOAc (10 mL) and dried in air. The compound was further dried under vacuum at 50° C. for 2 h. The title product was isolated as white micro needles.
Reaction SMILES: [N:1]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:2]=1[CH2:3][C:4]([OH:6])=O.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:41][CH:42]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(OCC)(=O)C>[C:51]1([CH:42]([NH:41][C:4]([CH2:3][C:2]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:1]=2)=[O:6])[CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: NC(CCN1CCCCC1)c1ccccc1
Reactant: O=C(O)Cc1ccc2ccccc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc2ccccc2n1)NC(CCN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a solution of 1.73 g (10 mmol.) of quinaldinic acid and 1.53 g (10 mmol.) of 1-hydroxybenzotriazole monohydrate in 50 ml of ethyl acetate was dropwise added over a period of 20 min. under chilling with ice a solution of 2.06 g (10 mmol.) of N,N'-dicyclohexylcarbodiimide in 10 ml of ethyl acetate. After the addition was complete, the resulting mixture was stirred for 2 hours at room temperature and chilled with ice. To the chilled mixture was dropwise added over a period of 30 min. a solution of 2.18 g (10 mmol.) of 1-(3-amino-3-phenylpropyl)piperidine in 8 ml of ethyl acetate. After the addition was complete, the mixture was stirred overnight at room temperature. Precipitated insolubles were filtered off and then the insolubles were washed with ethyl acetate. The filtrate and the washings were combined and washed twice with a saturated aqueous sodium hydrogencarbonate solution and once with a saturated aqueous sodium chloride solution. The mixture was then dried over sodium sulfate, and was evaporated under reduced pressure to remove the solvent. The residue was crystallized after addition of n-hexane. The resulting crystals were washed three times with n-hexane and dissolved in 35 ml of ethyl acetate. The resulting solution was allowed to stand overnight in a refrigerator. Precipitated insolubles were filtered off and the insolubles were washed with ethyl acetate. The filtrate and the washings were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 40 g, CHCl3 and CHCl3 /CH3OH (30:1)) to obtain 3.07 g (yield: 82%) of the subject compound as a pale yellow crystalline product.
Reaction SMILES: C(O[C:4](=[O:35])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:27])([F:26])[F:25])=[N:17]3)[CH2:8][C@@H:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.[NH3:36].[C-]#N.[Na+]>CO>[CH2:28]([C@H:7]1[CH2:8][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:26])([F:25])[F:27])=[N:17]3)[CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH2:36])=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N
Reactant: CCOC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCN(CC(N)=O)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reaction time: 24 h
Yield: 79 %

Procedure:
[(S)-2-Benzyl-4-(8-methoxy-2-trifluoromethyl-quinolin-5-yl)-piperazin-1-yl]-acetic acid ethyl ester in a 7 N solution of ammonia in MeOH (10 mL) was treated with catalytic amount of sodium cyanide and allowed to stir for 24 h. The reaction mixture was then evaporated, washed with water and air dried to afford the title compound as a yellow solid (180 mg, 79%). LC/MS (Method B) 2.57 min, [M+1]+ 459.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9](OCC)(=O)[CH2:10][C:11]([CH3:13])=O.P(Cl)(Cl)([Cl:20])=O.[NH4+]>>[NH2:7][C:3]1[CH:2]=[C:1]2[C:6]([C:11]([CH3:13])=[CH:10][C:9]([Cl:20])=[N:8]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cccc(N)c1
Agent: [NH4+]
Product: Cc1cc(Cl)nc2cc(N)ccc12
Reaction time: 1 h

Procedure:
To 27 g (251 mmol) of m-phenylenediamine was added 32 ml (251 mmol) of ethyl acetoacetate, followed by stirring at 200 degrees for 1 hour. After standing to cool, the crystals were washed with hexane. To 9.5 g (54 mmol) of the crystals was added 15 ml of phosphorus oxychloride, followed by heating under reflux for 2 hours. After standing to cool, the reaction mixture was poured onto ice-water and basified with a saturated ammonium aqueous solution. The resulting crystals were collected by filtration and washed with water. The crystals were washed with methanol and the filtrate was evaporated, to give 4.85 g of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[C:20]([Cl:26])[C:21]([C:23]([NH2:25])=[O:24])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:27][CH3:28])=[CH:10][CH:9]=1)(=O)=O.[CH3:29][NH2:30]>O>[Cl:26][C:20]1[C:21]([C:23]([NH2:25])=[O:24])=[CH:22][C:17]2[N:16]=[C:15]([CH2:27][CH3:28])[N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][NH:30][CH3:29])=[CH:13][CH:12]=3)[C:18]=2[CH:19]=1
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCOS(C)(=O)=O)cc1
Reactant: CN
Solvent: O
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCNC)cc1
Yield: 60 %

Procedure:
A mixture of 2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl methanesulfonate (step 1, 304 mg, 0.72 mmol), a solution of methyl amine (40% in methanol, 10 ml) and water (5 ml) in a sealed tube was heated overnight at 100° C. The reaction mixture was partitioned between dichloromethane (30 ml) and water (30 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with brine (50 ml) and dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with dichloromethane/methanol (10:1) to afford 154 mg (60%) of the title compound as yellow solids.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1c(F)cccc1F
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1c(F)cccc1F
Yield: 90.8 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2,6-difluoro phenyl isocyanate(3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.91 g, 91%). EI-MS m/z 308(M-H)-
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH2:31])=[CH:29][C:24]=2[O:23][CH2:22]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][NH:31][C:15]([CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[O:17])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: NCc1ccc2c(c1)OCO2
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCc2ccc3c(c2)OCO3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and C-benzo[1,3]dioxol-5-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-Ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C20H21NO7 [M+H]+: 388.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A′ above and using phenylacetyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH3:2].[CH2:14]=O.[CH:16]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH2:17]>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:14][CH:16]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:28])([F:30])[F:29])(=[O:19])=[O:20])[CH2:17][N:6]1[CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:13])[CH3:2]
Reactant: C=O
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)CNC1CCOCC1
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1C1CCOCC1

Procedure:
In analogy to the procedure described in example 343d, (tetrahydro-pyran-4-ylamino)-acetic acid ethyl ester (CAS Reg. No. 1153226-50-6) was reacted with paraformaldehyde and 1-ethenesulfonyl-2-trifluoromethyl-benzene (example 243c) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:38]=[C:37]([CH3:39])[C:31]3[N:32]([CH3:36])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:36][N:32]1[C:31]2[C:37]([CH3:39])=[CH:38][C:28]([C:26]([C:22]3[CH:21]=[C:20]([N:15]4[CH2:14][CH2:13][CH:12]([N:10]5[C:9](=[O:18])[NH:8][C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)=[N:11]5)[CH2:17][CH2:16]4)[N:25]=[CH:24][N:23]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35]
Reactant: O=c1[nH]c(-c2ccccc2)nn1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC(n4nc(-c5ccccc5)[nH]c4=O)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
98 mg (0.40 mmol) 5-phenyl-2-piperidin-4-yl-2,4-dihydro-[1,2,4]triazol-3-one, 0.12 g (0.40 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.14 mL (0.80 mmol) DIPEA were combined in 3 mL DMF and stirred for 48 h at RT. The mixture was diluted with MeOH, suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[I:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[I-:11].[CH2:12]([N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCI
Reactant: Cc1nc2ccccc2s1
Product: CCCCCCC[n+]1c(C)sc2ccccc21
Product: [I-]

Procedure:
A solution of 2-methylbenzothiazole (10.0 g, 0.067 mol) and 1-iodoheptane (110 mL, 0.67 mol) in 100 mL of acetronitrile was refluxed under nitrogen for 48 hours. The mixture was cooled, filtered, and the solid formed was washed with diethyl ether and recrystallized from ethanol-ethyl acetate to give 3-heptyl-2-methylbenzothiazolium iodide as a light purple solid, mp 110-113° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].[C:10](OC(=O)C)(=[O:12])[CH3:11].[OH-].[Na+].[OH-].[K+]>>[C:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: C=Cc1ccc(O)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
Pittet et al. in U.S. Pat. No. 4,316,995 describe a method for preparing p-vinylphenol. In that method, p-hydroxybenzaldehyde is first reacted with malonic acid using ethylenediamine as catalyst to give pHCA, which is decarboxylated in situ at a temperature of 115 to 120° C. to form impure p-vinylphenol. The p-vinylphenol is isolated from the reaction mixture and reacted with acetic anhydride in the presence of a base, such as sodium hydroxide or potassium hydroxide, to form 4-acetoxystyrene, which is separated from the reaction mixture and hydrolyzed in the presence of a strong base to give purified p-vinylphenol. The yield of 4-vinylphenol was about 31%.