Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:12][CH3:13])=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1.[I-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[NH2:26]>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[NH:26][CH2:3][C:4]1[C:5]([NH:12][CH3:13])=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1
Reactant: CNc1nc(SC)ncc1CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CNc1nc(SC)ncc1CNc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Yield: 97 %

Procedure:
15.85 g (5-Chloromethyl-2-methylsulfanyl-pyrimidin-4-yl)-methyl-amine hydrochloride, 1.979 g sodium iodide, and 34.49 mL N—N-diisopropylethylamine were solved in 150 ml acetonitrile and cooled to 0° C. 17.085 g 2-Chloro-5-nitro-phenylamine dissolved in 150 ml acetonitrile were added slowly under stirring. The reaction mixture was stirred at room temperature for 48 hrs, then the solvent was evaporated. The residue was solved in a mixture of water/acetic acid ethyl ester (1:1), stirred and the crystalline product was isolated by filtration and dried for 48 h under vacuum at 40° C. The two phases of the mother liquor were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, the solvent was evaporated and the residue was rubbed with diethyl ether. Both residues were combined and gave of the title product in 97% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CSc1ccc(O)cc1C
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSc1ccc(Oc2ccnc(Cl)c2)cc1C
Reaction time: 3 h

Procedure:
A solution of 17 gm (0.1 mol) of 3-methyl-4-methylmercaptophenol and 15.9 gm (0.1 mol) of 2-chloro-4-nitropyridine in 150 ml of acetonitrile was mixed with 13.8 gm (0.1 mol) of K2CO3 and stirred for 3 hours under reflux. It was then cooled and poured into 300 ml of water. The oil which separated out was separated off and taken up in methylene chloride, and the solution was washed with dilute sodium hydroxide solution and with water. The organic solution was then dried over Na2SO4 and concentrated by evaporation. The oil which remained was crystallized from hexane.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1c(Br)ccc(OC(F)F)c1OC
Temperature: 70 °C
Yield: 45.5 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (500 mg, 1.858 mmol) in acetonitrile (20 mL) was added potassium carbonate (769 mg, 5.57 mmol) and ethyl 2-bromoacetate (568 mg, 3.71 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of Ethyl 2-(6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)acetate as solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1
Reactant: Cc1cccc(Br)n1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cccc(C)n2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-6-methylpyridine. ESI-MS (m/z): 418 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[S:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[S:25]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:29]3[S:23][C:24](=[S:25])[NH:26][C:27]3=[O:28])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(4-chlorophenyl)methoxy]benzaldehyde (0.40 g, 1.62 mmol) was dissolved in acetic acid (8.1 ml) while stirring. To this solution was added sodium acetate (0.47 g, 5.7 mmol) followed by the addition of rhodanine (0.22 g, 1.65 mmol). The reaction mixture was heated to the reflux temperature and maintained at this temperature. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[S:8][C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc2ccsc2c1
Reactant: Fc1ccc(Br)cc1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2cc(-c3ccc(F)cc3)sc2c1
Yield: 54.1 %

Procedure:
To a 5 mL microwave vial was added a solution of 6-methoxybenzo[b]thiophene (400 mg, 2.44 mmol) in anhydrous DMA (3 mL) followed by 1-bromo-4-fluorobenzene (448 mg, 2.56 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos palladacycle 1st generation, 97 mg, 0.12 mmol), trimethylacetic acid (746 mg, 7.31 mmol) and potassium carbonate (1.01 g, 7.31 mmol). The microwave vial was sealed, purged with nitrogen and subjected to microwave irradiation at 150° C. for 2 h. Upon completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified via trituration 2× with heptane and the remaining triturate (containing some product) was concentrated and purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford 2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (340 mg, 1.32 mmol, 54% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=3.79-3.93 (m, 3H), 7.01 (dd, J=8.59, 2.53 Hz, 1H), 7.24-7.42 (m, 2H), 7.56 (d, J=2.53 Hz, 1H), 7.67-7.86 (m, 4H). LC/MS (m/z, MH+): 258.8.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:18](C=O)C>C1COCC1>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: Cc1c(F)ccc(C(=O)O)c1Cl
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(F)ccc(C(N)=O)c1Cl

Procedure:
To a solution (60 ml) of 2-chloro-4-fluoro-3-methylbenzoic acid (5.66 g) synthesized by a known method in THF were added thionyl chloride (10.7 g) and DMF (0.2 ml) with stirring under ice-cooling, and the mixture was stirred at 70° C. for 3 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in dry THF (50 ml) and added dropwise to a mixture of concentrated aqueous ammonia (130 ml) and THF (86 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated crystals were collected by filtration, washed with diethyl ether and dried to give 2-chloro-4-fluoro-3-methylbenzamide (4.82 g) as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)COC1C=CC(S(NC[C@H](N2CCN(S(C)(=O)=O)CC2)C(O)=O)(=O)=O)=CC=1)#[N:2].C(C1C=C(C=CC=1)[CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][CH2:53][C@H:54]([N:59]2[CH2:64][CH2:63][N:62]([S:65]([CH3:68])(=[O:67])=[O:66])[CH2:61][CH2:60]2)[C:55]([NH:57][OH:58])=[O:56])(=[O:51])=[O:50])=[CH:45][CH:44]=1)#N>>[C:1]([C:3]1[CH:4]=[CH:5][C:33]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([NH:52][CH2:53][C@H:54]([N:59]3[CH2:60][CH2:61][N:62]([S:65]([CH3:68])(=[O:66])=[O:67])[CH2:63][CH2:64]3)[C:55]([NH:57][OH:58])=[O:56])(=[O:50])=[O:51])=[CH:45][CH:44]=2)=[CH:34][CH:35]=1)#[N:2]
Reactant: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3cccc(C#N)c3)cc2)C(=O)NO)CC1
Reactant: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3cccc(C#N)c3)cc2)C(=O)O)CC1
Product: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3ccc(C#N)cc3)cc2)C(=O)NO)CC1

Procedure:
In a manner analogous to example 3.8, using 264 mg (0.5 mmol) of (S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid, 107 mg (40%) of (S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide are obtained in the form of a beige powder with a melting point of 108° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:14][C:15]([C:17]12[CH2:24][N:21]([CH2:22][CH2:23]1)[CH2:20][CH2:19][CH2:18]2)=O)C.O.[OH-].[Na+]>O1CCCC1>[N:21]12[CH2:24][C:17]([CH2:15][OH:14])([CH2:23][CH2:22]1)[CH2:18][CH2:19][CH2:20]2
Reactant: CCOC(=O)C12CCCN(CC1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC12CCCN(CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of 1.0 N lithium aluminum hydride/tetrahydrofuran (55 mL, 55 mmol) under nitrogen was treated dropwise with a solution of 1-azabicyclo[3.2.1]octane-5-carboxylic acid ethyl ester (9.17 g, 50 mmol) in anhydrous tetrahydrofuran (20 mL), stirred for 30 minutes at room temperature, refluxed for one hour, and cooled (0° C.). In sequence, water (2.1 mL), 15% sodium hydroxide solution (2.1 mL) and water (6.3 mL) were carefully added dropwise, and the mixture was filtered through Celite (the solid was washed with tetrahydrofuran) and concentrated in vacuo to afford 6.50 g (92%) of viscous, colorless oil, which can be used as is or can be solidified on cooling; mp 44°-47° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:16][CH:17]=[C:18]([C:20](O)=[O:21])[N:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)Cl.[CH3:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=1[NH2:30].NC1C=CC=CC=1.[H-].[Na+]>CN(C=O)C.C1COCC1.Cl>[CH3:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=1[NH:30][C:20]([C:18]1[N:19]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[NH:16][CH:17]=1)=[O:21]
Reactant: COc1ccc(-c2nc(C(=O)O)c[nH]2)cc1OC1CCCC1
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C(=O)Nc3c(C)cccc3C)c[nH]2)cc1OC1CCCC1
Yield: 14.9 %

Procedure:
A mixture of 2-(3-cyclopentyloxy-4-methoxyphenyl)-imidazole-4-carboxylic acid (400 mg, 1.32 mmol) and SOCl2 (10 ml) containing DMF (1 drop) was heated to reflux for 2 hours. The volatiles were removed in vacuo and to the residue was added toluene (25 ml) and the solvent evaporated. This procedure was repeated to remove dissolved gaseous by-products. The residue was dissolved in THF (10 ml) and added dropwise at 0° C. over 10 minutes, to a solution of the salt of 2,6-dimethylaniline (510 μl, 4.14 mmol) in THF (30 ml) (formed by adding a solution of the aniline in THF (15 ml) to a suspension of NaH (167 mg, 4.14 mmol) is THF (15 ml) at room temperature). The resultant solution was stirred at room temperature for 48 hours, diluted with 1N HCl (20 ml) and the mixture extracted with methylene chloride (2×50 ml). The combined organics were dried over Na2SO4 and the volatiles removed in vacuo. Flash chromatography (SiO2 ; CH2Cl2 :EtOH (97:3)) afforded 2-(3-cyclopentyloxy-4-methoxyphenyl)-imidazole-4-carboxylic acid-2,6-dimethylphenyl amide (80 mg, 15%) as a pale yellow solid, mp 118-122° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C@@H:9]([OH:37])[CH:10]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:11][C:12]([CH3:24])([CH3:23])[CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C@H:8]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C@@H:9]([OH:37])[CH:10]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:11][C:12]([CH3:24])([CH3:23])[CH2:13][CH2:14][OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCO[Si](C)(C)C(C)(C)C)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCO)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a stirred solution of the product of Step 3 (3.47 g, 5.2 mmol) in tetrahydrofuran (25 mL) was added tetrabutylammonium fluoride (6.2 mL, 1M in tetrahydrofuran) over 15 minutes. After stirring at ambient temperature for 2 hours, the reaction was concentrated in vacuo and partitioned in ether/water (1:1; 200 mL). The layers were separated and the aqueous phase was extracted with ether (50 mL). The combined organic layers were washed with water (100 mL), dried (magnesium sulfate), concentrated in vacuo and purified by silica gel chromatography (4% methanol in chloroform) to afford the title compound (2.78 g, 97%) as a white foam.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:6]=2[O:5][C:4](=[O:13])[CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].C(N(CC)CC)C.C(O)=O.Cl>C(OCC)(=O)C>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:6]=2[O:5][C:4](=[O:13])[C:3]=1[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1
Reactant: O=c1cc(O)c2ccc(O)cc2o1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=c1oc2cc(O)ccc2c(O)c1Cc1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
4,7-Dihydroxy-2-oxo-2H-1-benzopyran (500 mg, 2.81 mmol) and 3-nitrobenzaldehyde (424 mg, 2.81 mmol) were added to a mixture of triethylamine (1.57 mL, 11.23 mmol) and formic acid (1.07 mL, 28.07 mmol), and the obtained mixture was stirred at 100° C. for 2 hours. A 5N hydrochloric acid aqueous solution was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate, and then concentrated under reduced pressure to yield the title compound (300 mg, 34%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:31]OCCOC.[N+](=C)=[N-]>C(O)(=O)C.CCOCC>[CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([O:28][CH3:31])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COCCOC
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Agent: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)OC)CC2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 415 mg. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide and 15 ml. of 1,2-dimethoxyethane is added a solution of 1.5 mmoles of diazomethane in 5 ml. of ether. The reaction mixture is stirred at room temperature for 16 hours, and then the excess diazomethane is decomposed by the addition of a few drops of acetic acid. The total solvents are removed by evaporation in vacuo, and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with 1 N sodium hydroxide, followed by water, followed by saturated sodium chloride solution, and then dried using sodium sulfate. Evaporation of the dried ethyl acetate solution in vacuo affords the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([NH:18][NH2:19])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C(O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]=[N:19][NH:18][C:16]([C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])=[CH:22][CH:23]=1
Reactant: NNC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Product: COc1ccc(C=NNC(=O)c2[nH]c3ccccc3c2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 1C (1.76 g, 7.0 mmol) and p-anisaldehyde (894 mL, 7.35 mmol) in ethanol (120 mL) was refluxed for 18 hours, cooled to room temperature, and filtered. The resulting solid was washed with ethanol and dried under vacuum to provide
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)(=O)=O)=CC=1.[C:29](O)(=[O:34])[CH2:30][C:31]([OH:33])=[O:32].[CH2:36]([CH:38]([CH2:42][CH3:43])[C:39]([NH2:41])=[O:40])[CH3:37].CC[O-].[Na+]>C(O)C>[CH2:36]([CH:38]([CH2:42][CH3:43])[C:39]([NH2:41])=[O:40])[CH3:37].[C:29]([O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:18]=1)(=[O:34])[CH2:30][C:31]([O-:33])=[O:32]
Reactant: CCCCCCCC(=O)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(O)CC(=O)O
Agent: CCC(CC)C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCC(=O)c1ccc(CCOC(=O)CC(=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-(4-Octanoyl phenyl)ethyl p-toluene sulfonate prepared in the step D-1 (500 mg), diethyl acetamide malonate (810 mg) and sodium ethylate (313 mg) were dissolved in anhydrous ethanol (1.5 ml)—anhydrous N,N-dimethylformamide (6 ml) to obtain a solution. The solution was stirred under atmosphere of nitrogen at 60° C. overnight. The reaction solution was poured into ice water, extracted with ether, and washed with saturated saline solution. The extracted solution was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (1:0→3:1) as an eluate to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (417 mg) in the form of colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([CH3:19])[N:9]2[CH3:20])=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:33]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl>[Br:33][CH2:19][C:10]1[N:9]([CH3:20])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12](=[O:13])[C:11]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)n(C)n(-c2ccc(F)cc2)c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CBr)n(C)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (1.2 g, 4.3 mmol) and azobisisobutyronitrile (AIBN) (0.09 g, 0.06 mmol) in DCM is added N-bromosuccinimide (NBS) (0.9 g, 4.3 mmol) in three portions at RT. The resulting reaction mixture is stirred at RT overnight. The mixture is concentrated and the residue is purified by silica gel column chromatography eluting with PE:EtOAc (4:1) to give the product as a white solid (1.3 g, 84% yield). MS (m/z) 357.0 (M+H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[Cl:16][C:12]1[C:13]([Cl:15])=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2cc(Cl)c(Cl)cc2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cc(Cl)c(Cl)cc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5,6-dichlorobenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5,6-dichlorobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]1[N:12]=[CH:11][O:10][N:9]=1)([O-])=O>CC(C)=O.[Cl-].[Cl-].[Ti+2]>[NH2:1][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1/[CH:6]=[CH:7]/[C:8]1[N:12]=[CH:11][O:10][N:9]=1
Reactant: O=[N+]([O-])c1ccccc1C=Cc1ncon1
Agent: [Ti+2]
Agent: [Cl-]
Solvent: CC(C)=O
Product: Nc1ccccc1/C=C/c1ncon1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Titanous chloride solution (15% w/v, 380 ml.) was added during 25 min. to a stirred solution of 3-o-nitrostyryl-1,2,4-oxadiazole (10.85 g.) in acetone (1 litre). After 30 min. more, the acetone was removed, and solid sodium hyrdogen carbonate was added to the stirred solution until the pH was 6-7. The mixture was extracted thoroughly with ethyl acetate solution was washed with water, then dried (MgSO4) and evaporated, leaving trans-3-o-aminostyryl-1,2,4-oxadiazole (7.5 g., 80%), m.p. 108°- 109°, λmax. 240, 280- 281, 350 nm, ε 14000, 12800, 6200 [Found (after sublimation): C, 64.2; H, 5.2; N, 22.1 C10H9N3O requires C, 64.2; H, 4.85; N, 22.45%].
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:31])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:31][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (400 mg, 1.94 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (523 mg, 2.33 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (18 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (102) as white solid (681 mg, 85%).