Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11]C)=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:26]([O:35]C(OC(C)(C)C)=O)[C:25]([C:43]([F:46])([F:45])[F:44])=[CH:24][CH:23]=1>>[C:31]([O:30][C:28]([C:27]1[C:26]([OH:35])=[C:25]([C:43]([F:44])([F:45])[F:46])[CH:24]=[CH:23][C:22]=1[CH2:21][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[CH:4]=[CH:5][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:7][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(Cl)c1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)ccc(C(F)(F)F)c1O
Yield: 15 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl (2-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (150 mg, 0.54 mmol) obtained in Example (23-3) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (455 mg, 1.0 mmol) obtained in Example (28-5), the title compound was obtained as a colorless compound (46 mg, three-step total yield: 15%).
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].CN1C=CN=C1.[CH3:28][O:29][C:30](Cl)=[O:31].O>C(Cl)Cl>[CH3:28][O:29][C:30]([O:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5])=[O:31]
Reactant: COC(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)ON(C)C(=O)C(C)Nc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Yield: 35.4 %

Procedure:
3 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide and the product prepared from 0.8 g N-methylimidazole and 0.9 g of methoxycarbonylchloride were reacted as a stirred suspension in 30 ml of methylene chloride for 3 hours. The resulting mixture was poured into water. The methylene chloride layer was dried and evaporated to give 1.2 g (33% yield) of yellow solid product, m.p. 112°-113° C., (d,l) isomer form.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:11]([NH2:12])=[C:10]([F:19])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:19])[CH:9]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
12.8 g of ethyl chloroformate are added while stirring to a solution of 20 g of 4-chloro-2-fluoro-5-isopropoxyaniline in 100 ml of methylene chloride at room temperature. 9.4 g of pyridine are subsequently added dropwise during 20 minutes at 20° C. while stirring and cooling. The reaction mixture is stirred for 20 minutes, washed three times with in each case 200 ml of a solution of 20 ml of 2N hydrochloric acid in 200 ml of water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. There is obtained ethyl N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-carbamate, m.p. 89°-91° C.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[C:3]([C:14]([O:16]CC)=O)[N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:19](=[N:22]O)([NH2:21])[CH3:20]>>[CH3:20][C:19]1[N:22]=[C:14]([C:3]2[N:2]=[CH:1][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:12]=[CH:13][C:4]=23)[O:16][N:21]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)c1ncn2c1cnc1ccccc12
Product: Cc1noc(-c2ncn3c2cnc2ccccc23)n1

Procedure:
M.p. 269°-270° C., from ethyl imidazo[1,5-a]quinoxaline-3-carboxylate and acetamide oxime. (Compound 11)
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:1]1(=[O:12])[O:13][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C1Cc2ccccc2C(=O)O1
Temperature: 25 °C
Yield: 100 %

Procedure:
2 g (11.1 mmol) of homophthalic acid was dissolved in 30 ml toluene, and 1.6 ml (16.7 mmol) of acetic anhydride was added. The mixture was heated to the reflux temperature and reacted for 0.5 h. Then, the reaction mixture was cooled to the room temperature and concentrated to dry in a reduced pressure to obtain 1.8 g of a product as a pale yellow solid with the yield of 100%. m.p. 140-142° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=1[Cl:24]>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=1[Cl:24]
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Clc1nc2ccccc2o1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
In xylene (10 ml), 2-chlorobenzoxazole (743 μl, 6.51 mmol) and ethyl 4-amino-3-chlorophenylacetate (1.30 g, 6.51 mmol) were heated under reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with chloroform (50 ml). The mixture was washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (9:1, v/v) eluate fractions, ethyl (4-(2-benzoxazolyl)amino-3-chlorophenyl)acetate (1.70 g, 79%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:18][C:19]1([CH3:24])[CH2:20][O:21][C:8]([CH2:9][S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:17][CH2:22]1
Reactant: CCOC(=O)CSCC(=O)c1ccc(C)cc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CSCC1(c2ccc(C)cc2)OCC(C)(C)CO1
Yield: 61 %

Procedure:
Ethyl {[2-(4-methylphenyl)-2-oxoethyl]thio}acetate (12.2 g, 48.4 mmol) was dissolved in benzene (350 ml). 2,2-Dimethyl-1,3-propanediol (40.3 g, 0.387 mol) and p-toluene sulfonic acid (1 g) were added. The mixture was stirred at reflux in a Dean-Stark apparatus for two hours, cooled and concentrated under reduced pressure. CH2Cl2 was added and the organic phase was washed twice with brine and dried (MgSO4). Filtration and concentration under reduced pressure afforded a crude oil, which was purified by flash-chromatography (hexane:EtOAc 8:1) to afford 10.0 g (61%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])C(OC)=O)=[CH:5][C:4]=1[N+:15]([O-])=O.[C:18]([O:21][CH2:22]C)(=[O:20])C>[Pd].C(O)C>[NH2:15][C:4]1[CH:5]=[C:6]([CH2:9][CH2:14][C:18]([O:21][CH3:22])=[O:20])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CCOC(C)=O
Reactant: COC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(OC)c(N)c1
Yield: 95 %

Procedure:
Methyl 4-methoxy-3-nitrophenylpropanoate (2.70 g, 11.3 mmol), 10% palladium on carbon (200 mg) and a mixed solvent (100 mL) of ethyl acetate with ethanol (1:1 v/v) were mixed and hydrogenation was carried at an initial pressure of 294.3 kPa. After completion of the hydrogenation, the catalyst was removed by filtration and the filtrate was concentrated to obtain 2.35 g (95%) of the title compound as a yellow oily product.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1>CN1C(=O)CCC1>[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)#[N:3]
Reactant: N#C[Cu]
Reactant: COC(=O)Cc1ccc(Br)cc1
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc(C#N)cc1
Temperature: 200 °C

Procedure:
5.1 g (56.7 mmol) of copper(I) cyanide were added to a solution of 10 g (43.7 mmol) of methyl 4-bromophenylacetate in 44 ml of NMP, and, in a microwave oven, the mixture was then heated to 200° C. for 60 min. The reaction mixture was then purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 5:1). This gave 4.65 g (61% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10]C)=O.Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[N:18]3[CH:17]=[C:16]([C:19]([NH2:21])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: COC(=O)c1sc(C)cc1N
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc3ccc(C(N)=O)cn3c(=O)c2s1
Yield: 14.6 %

Procedure:
A mixture of 2.7 g (0.0158 mol) of 3-amino-5-methyl-2-thiophene-carboxylic acid, methyl ester (German Patent No. 1055007, Apr. 16, 1959) and 2.5 g (0.0158 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) is heated in an oil bath at 180°-190° C. for one hour. The mixture is cooled and then suspended in hot chloroform and filtered to give 0.6 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide; mp 375°-377° C. after recrystallization from pyridine.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[CH2:24][O:25][CH3:26].[C:27](=O)([O-])[O-:28].[K+].[K+]>COCCOC.CO>[CH3:26][O:25][CH2:24][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[CH2:2][O:28][CH3:27])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1COC
Yield: 27.7 %

Procedure:
A mixture of 4-chloromethyl-8-(2,6-dichlorobenzoylamino)-3-methoxymethylquinoline (70 mg) and potassium carbonate (26 mg) in 1,2-dimethoxyethane and methanol was refluxed for 2 hours. After cooling, the mixture was partitioned between saturated ammonium chloride solution and dichloromethane, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and crystallized from isopropyl alcohol to give 3,4-bis(methoxymethyl)-8-(2,6-dichlorobenzoylamino)quinoline (19.2 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: NCCCCC(=O)O
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)CCCCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 99.7 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and 5-aminopentanoic acid (0.61 g, 0.0052 mol) were refluxed as above overnight. Crystallisation of the product from EtOH yielded 1.51 g (72%) of 103 as a white solid: mp=223° C.; Rf 0.79 (A): Rf 0.92 (C): Rf 0.36 (D): IR (cm−1): 2750–3375 (OH), 3084 (C═CH), 2665 (C—H), 1767 (C═O), 1705 (bs, C═O), 1620 (C═C), 1486 (C═C), 1402 (CH2), 1382 (C—O), 1302 (C—O), 732 (C═CH); MS m/z (rel intensity) 291 (15), 290 (100).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.BrN1C(=[O:19])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:12][C:11]1[C:2]([CH:1]=[O:19])=[CH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc2ccccc2cc1C=O

Procedure:
2,3-Dimethylnaphthalene (20.0 g), N-bromosuccinimide (22.8 g) and benzoyl peroxide (0.2 g) were refluxed in carbon tetrachloride (160 ml) for 12 hr. After cooling, the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was dissolved in chloroform. This solution was added dropwise to a vigorously stirred solution of hexamethylenetetramine (1.2 equiv) in chloroform (100 ml) and the mixture was heated at reflux for 12 hr. After cooling the salt was filtered off and was washed with several portions of hexane. The dried salt was heated at reflux with a 50% aqueous acetic acid solution (20 ml/g) for 2 hr. Concentrated hydrochloric acid (2 ml/g) was added and the mixture was heated at reflux for a further 15 min. the solution was poured onto ice-water and the resulting mixture was extracted with ether. The dried (MgSO4) organic fraction was evaporated and the residue was purified by recrystallization (twice) from hexane to give 3-methylnaphthalene-2-carboxaldehyde as cream-coloured clusters, mp 119° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.75 (3H,s); 7.32-7.98 (5H,m); 8.24 (1H,s); 10.27 (1H,s). 6-Methylnaphthalene-2-carboxaldehyde was similarly prepared from 2,6-dimethylnaphthalene and was obtained as a white solid, mp 120° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.58 (3H,s); 7.38-8.07 (5H,m); 8.30 (1H,s); 10.14 (1H,s).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[S:21])[NH2:20])[C:3]=1[S:22]([CH3:24])=[O:23].[CH2:25]1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].CI>O1CCCC1.C(=O)=O>[CH3:25][S:21][C:19]([C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[NH:20]
Reactant: CS(=O)c1c(C(N)=S)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 0.28 h
Yield: 99.2 %

Procedure:
To a stirred solution of 1.00 gram (0.0024 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbothioamide, (Compound 4, prepared as described in applicants' copending U.S. patent application Ser. No. 08/418,680, entitled "PESTICIDAL 1-ARYLPYRAZOLE-3-THIOCARBOXAMIDES", filed concurrently herewith, incorporated by reference herein in its entirety and relied upon) and a few crystals of 18-crown-6 in 30 milliliters of dry tetrahydrofuran, was added 0.27 gram (0.00244 mole) of potassium tertiary-butoxide, and the mixture was strirred for a few minutes. A 0.16 milliliter (0.00264 mole) portion of methyl iodide was then injected into the reaction mixture, followed by stirring for a two-hour period. An additional 0.08 milliliter (0.0013 mole) portion of methyl iodide and 0.09 gram of potassium tertiary-butoxide were added and stirring was continued for a period of 17 minutes. The mixture was neutralized by passing in gaseous CO2 for about 10 minutes and volatiles were then removed under reduced pressure. The residue was taken up in dichloromethane and filtered, and the filtrate was evaporated to give the product as a crude residue. This was chromatographed on silica, eluting with 2:1 ethyl acetate/hexane, followed by a second chromatography employing 4:1 chloroform/acetone as the solvent, resulting in 0.67 gram (0.00155 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidothioic acid methyl ester (99.2% purity) having a melting point of 206.5° C. This compound is referred to hereinafter as Compound 2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]([CH2:11][C:12]3[CH:13]=[C:14]([C:18]4[CH:22]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:20][C:19]=4[S:27]([NH:30]C(C)(C)C)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:9][N:10]=2)=[CH:2]1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47]>C(Cl)Cl.O>[CH2:49]([O:48][C:46]([NH:30][S:27]([C:19]1[S:20][C:21]([CH2:23][CH:24]([CH3:25])[CH3:26])=[CH:22][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:13]=1)(=[O:29])=[O:28])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccsc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 3-[3-(2-thiophen-3-yl-imidazol-1-ylmethyl)-phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (38.2 mg, 0.0744 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.2 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (35.5 mg, 0.335 mmol), water (2 mL) and butyl chloroformate (11.4 μL, 0.0893 mmol) and the reaction mixture was stirred for 5 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound as a white solid in 67% yield, over two steps, (28 mg, 0.050 mmol).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5](=[O:13])(=[O:12])[N:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:7].[NH3:15]>>[C:8]([N:6]([CH3:7])[S:5]([CH2:4][C:3]([NH2:15])=[O:2])(=[O:13])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: N
Reactant: COC(=O)CS(=O)(=O)N(C)C(C)(C)C
Product: CN(C(C)(C)C)S(=O)(=O)CC(N)=O
Yield: 84 %

Procedure:
The subtitle compound (3.66 g, 84%) was prepared as a white solid from aqueous ammonia solution (10 ml, s.g.=0.88) and methyl (N-tert-butyl-N-methylsulfamoyl)acetate (from step (a), 4.7 g, 21 mmol), using the method of Example 1(b). m.p. 105-109° C.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:23]([NH:22][CH2:20][CH3:21])=[O:24]
Reactant: CCN=C=O
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 209a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 209bW) and ethyl isocyanate in 100% yield as a white solid. MS 289 (MH+).
Reaction SMILES: CN([CH:4]=[N:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)C.C[O-].[Na+].[C:19](#[N:21])[CH3:20].Cl>O.C1(C)C=CC=CC=1>[O:10]=[C:8]1[C:7]2[C:6](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:5][CH:4]=[C:20]1[C:19]#[N:21]
Reactant: CC#N
Reactant: COC(=O)c1ccccc1N=CN(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1c[nH]c2ccccc2c1=O

Procedure:
A stirred mixture of 1.03 g of methyl 2-(dimethylaminomethyleneamino)benzoate, 0.54 g of sodium methoxide, 1.04 ml of acetonitrile, and 10 ml of toluene was refluxed for 18 h. The mixture was cooled, treated with water, and brought to pH 3 by addition of dilute HCl. The resulting solid was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethanol to give a solid, mp 290-300° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:30][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[O:6][CH:5]1[CH2:31][O:32][CH3:33])[N:14]=[CH:13][N:12]=[C:11]3[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][Si](C)(C)C)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][CH2:3][CH:4]1[O:30][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[O:6][CH:5]1[CH2:31][O:32][CH3:33])[N:14]=[CH:13][N:12]=[C:11]3[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1
Reactant: COCC1Oc2cc3ncnc(Nc4cccc(C#C[Si](C)(C)C)c4)c3cc2OC1COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc4c(cc23)OC(COC)C(COC)O4)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The titled compound of Example 47 (34 mg, 0.073 mmol) was dissolved in 5 ml of methanol, and then added potassium carbonate (26 mg), followed by stirring for 24 hours at a room temperature. Water was added to the reaction mixture, which was then extracted with methylene chloride, dried over MgSO4 and concentrated. The resulting residue was purified by a column chromatography(mobile phase: hexane:ethylacetate:methanol=20:30:1 (v:v:v)) to prepare the titled compound (6 mg, 21%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[N+:29]([C:32]1[CH:45]=[CH:44][C:35]([C:36]([O:38][C@H:39]2[CH2:43][CH2:42][NH:41][CH2:40]2)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(#N)C>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:41]2[CH2:42][CH2:43][C@H:39]([O:38][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:45][CH:44]=3)[CH2:40]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Reactant: O=C(O[C@H]1CCNC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O[C@H]1CCN(CCc2ccc(Cl)cc2)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
4-Chlorophenethyl tosylate (683 mg, 2.20 mmol), sodium carbonate (236 mg, 2.20 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to a solution of (S)-3-(4-nitrobenzoyloxy)pyrrolidine (472 mg, 2.00 mmol) in acetonitrile (10 ml), and they were heated under reflux at 90° C. for 8 hours. The solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-chlorophenethyl)-3-(4-nitrobenzoyloxy)pyrrolidine in the form of a light yellow oil (315 mg, 42%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].Br[CH2:16]CCCCC(O)=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:16])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: O=C(O)CCCCCBr
Product: COC(=O)CCCCCCCCCCBr
Yield: 90 %

Procedure:
12.0 grams (45 mmole) of 11-bromoundecanoic acid was treated in the same manner as described above for 6-bromohexanoic acid to yield greater than 90% methyl 11-bromoundecanoate.
Reaction SMILES: [NH2:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15]([Cu])#[N:16]>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:6]#[N:7])=[CH:8][C:9]=1[C:15]#[N:16]
Reactant: N#Cc1cc(I)c(N)cc1C(F)(F)F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C#N)c(C(F)(F)F)cc1N

Procedure:
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (1.5 mmoL), CuCN (1.7 mmoL) in NMP (10 mL) was heated at 150° C. for 4 hrs. The reaction mixture was passed through a pad of Celite. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield the title compound as a brown solid.