Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(C)=O.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)([O-:7])=[O:6]>CO>[CH3:1][O:16][C:15](=[O:17])[CH2:14][CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:19][CH:18]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: COC(=O)CCOc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
Neat AcCl (0.27 mL; 3.8 mmol) was added to a suspension of 3-(4-nitro-phenoxy)-propionic acid (1.591 g; 7.53 mmol) in dry MeOH (8.0 mL). A soln formed followed by a ppt. After sitting at 4° C. overnight, product was collected by filtration as a white microcrystalline solid (1.316 g; 78%). The mother liquor contained pure product by HPLC. LC-MS 226 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8]C=O)[N:5]=[C:4]([C:11](=[N:17][O:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.P(Cl)(Cl)(Cl)=O>C(O)C>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([C:11](=[N:17][O:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]=1
Reactant: CCOC(=O)C(=NOC)c1nc(Cl)cc(NC=O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1nc(N)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 2-(4-chloro-6-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (17 g) in ethanol (255 ml) was added dropwise phosphoryl chloride (14.7 g) under cooling in an ice bath. The mixture was stirred for 1.5 hours at ambient temperature and evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water and adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The organic layer was separated out, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with n-hexane to give ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (9.99 g), mp 136°-142° C.
Reaction SMILES: [CH2:1]([CH:3]([C:7](=O)[CH3:8])[C:4](=O)[CH3:5])[CH3:2].[NH2:10][NH2:11]>C(O)C>[CH3:8][C:7]1[C:3]([CH2:1][CH3:2])=[C:4]([CH3:5])[NH:11][N:10]=1
Reactant: CCC(C(C)=O)C(C)=O
Reactant: NN
Solvent: CCO
Product: CCc1c(C)n[nH]c1C
Reaction time: 5 h
Yield: 123.9 %

Procedure:
At room temperature, to a mixture of 3-ethyl-2,4-pentanedione 5 g and ethanol 50 ml was added hydrazine one hydrate 2.9 g and the resulting mixture was stirred for five hours. The ethanol was distilled off and the resulting residue was subjected to a silica gel column chromatography to give 3,5-dimethyl-4-ethyl-1H-pyrazole 6.0 g.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:20]([NH2:28])=[O:27])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Yield: 93.6 %

Procedure:
4-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridin-2-ylamine (193 mg, 0.73 mmol) is dissolved in DCM (7 mL) and benzoyl isocynate (215 mg, 1.46 mmol) is added. The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (7 mL) and potassium carbonate (151 mg, 1.10 mmol). The mixture is heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (45 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 210 mg of the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=[O:27])[NH:14][CH2:15][CH:16]1[CH2:19][N:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:17]1)(C)(C)C.[C:28]1([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([S:43]([C:46]3[CH:54]=[CH:53][C:49](C(O)=O)=[CH:48][CH:47]=3)(=[O:45])=[O:44])[CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:18]2[CH2:17][CH:16]([CH2:15][NH:14][C:13](=[O:27])[C:49]3[CH:48]=[CH:47][C:46]([S:43]([N:36]4[C:37]5[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:35]4)(=[O:45])=[O:44])=[CH:54][CH:53]=3)[CH2:19]2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(F)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CN(c2ccc(F)cc2)C1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reaction time: 16 h
Yield: 11.9 %

Procedure:
Add trifluoroacetic acid (2 mL) to [1-(4-fluoro-phenyl)-azetidin-3-ylmethyl]-carbamic acid tert-butyl ester (135 mg, 0.482 mmol) causing much gas evolution. Rotary evaporate the reaction solution (40° C.; azeotroping 3× with CH2Cl2). Dissolve this material in anhydr CH2Cl2 (3 mL). Add 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.53 mmol, 1.1 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 140 mg, 0.73 mmol, 1.5 equiv), and 4-(dimethylamino)pyridine (DMAP; 270 mg, 2.3 mmol, 4.7 equiv). After stirring 16 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (10-45% EtOAc/hex) to yield 31 mg (12%) of N-[1-(4-fluoro-phenyl)-azetidin-3-ylmethyl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide as a light-yellow foam. MS (m/e): 539.99 (M+1); 538.16 (M−1).
Reaction SMILES: IC.[O:3]([CH2:6][CH3:7])CC.[Li].[C:9]1([NH:15][C:16]2(C(O)=O)[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:9]1([NH:15][C:16]2([C:6](=[O:3])[CH3:7])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Li]
Solvent: CI
Solvent: O
Product: CC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To start the reaction, a small amount of a solution of 78.1 parts of iodomethane in 70 parts of dry 1,1'-oxybisethane is dropped to a stirred solution of 6.9 parts of lithium in 70 parts of dry 1,1'-oxybisethane. After the addition of 70 parts of dry 1,1'-oxybisethane, the remainder of the solution is added dropwise at reflux temperature. Stirring at reflux is continued for 30 minutes. Then there were added portionwise 16.2 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid (a violent reaction occurs whereby reflux temperature is maintained). Upon completion, stirring at reflux is continued for 1h. 30. The reaction mixture is decomposed by the dropwise addition of 300 parts of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The first fraction is collected and the eluent is evaporated. The residue is crystallized from 14 parts of 2,2'-oxybispropane, yielding 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]ethanone; mp. 100.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14].[CH2:24](O)[CH3:25]>Cl>[N:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:9]=1[CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([O:15][CH2:24][CH3:25])=[O:14]
Reactant: CCO
Reactant: Nc1ccccc1NC(=O)CC(CC(=O)O)c1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=O)CC(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1

Procedure:
N-(2-Aminophenyl)-3-(4-chlorophenyl)glutaramic acid (2.04 g) is dissolved in a mixture of ethanol (20 ml) and conc. HCl (5 ml) and heated to reflux overnight. The ethanol is removed in vacuo and the aqueous layer is neutralised with 10M NaOH. Saturated sodium bicarbonate solution (40 ml) is added and the aqueous layer is extracted twice with dichloromethane (50 ml). The combined organic layers are dried (sodium sulfate) and concentrated. The residue is purified by flash chromatography (dichloromethane/3% methanol/1% triethyl amine) on silica gel to afford ethyl 4-(2-benzimidazolyl)-3-(4-chlorophenyl)butanoate (1.39 g) as yellowish solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=O)=O>N1C=CC=CC=1>[CH:1]1([CH2:7][C:8]([O:10][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=3)[CH:32]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCCC1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)CC3CCCCC3)ccc2c1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 2.5 g of cyclohexylacetic acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture, and stirred for 24 hours at room temperature. The insolubles were removed by filtration and ethyl ether was added to the filtrate. The precipitate was collected by filtration and recrystallized from a dimethylformaldehyde-ether mixture to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl cyclohexylacetate methanesulfonate.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[CH:15][CH:16]=1>CN(C=O)C>[Br:10][C:11]1[C:12]([O:7][CH:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: OC1CCSCC1
Reactant: Clc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccnc1OC1CCSCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL reaction tube, equipped with a reflux condenser and under a nitrogen atmosphere, was added a solution consisting of tetrahydro-2H-thiopyran-4-ol (1.04 g, 8.78 mmol) in DMF (2 mL). The mixture was cooled to the 0° Celsius, and then treated with NaH (0.540 g, 60% dispersion in mineral oil, 13.5 mmol). When the addition was complete, the reaction was warmed to rt and stirred 30 min before adding 3-bromo-2-chloropyridine (1.3 g, 6.8 mmol), and heating at 130° Celsius for 10 hours. The reaction mixture was cooled to rt and carefully quenched with H2O, concentrated to remove the solvent, and extracted with water (20 mL) and EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified by FCC to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[CH:3]=[C:4]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CC1(c2ccc([N+](=O)[O-])c(Cl)c2)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1(c2ccc([N+](=O)[O-])c(Nc3ccc(Cl)cc3Cl)c2)OCCO1
Temperature: 200 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A mixture of 2-(3-chloro-4-nitrophenyl)-2-methyl-1,3-dioxolane (8 g), 2,4-dichloroaniline (10.6 g), cupric oxide (0.8 g) and potassium carbonate (5.4 g) was stirred for 3 hours at 200° C. Ethyl acetate (100 ml) was added to the mixture, stirred and filtered. The filtrate was washed with water, dried and evaporated to dryness. The oil (15.5 g) was purified by column chromatography on silica gel (150 g) eluting with toluene to give an oil of 2-[3-(2,4-dichlorophenylamino)-4-nitrophenyl]-2-methyl-1,3-dioxolane (9.7 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.N[C:17](N)=[O:18]>ClC(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:17]2=[O:18])[CH:2]=1
Reactant: Nc1ccccc1NCc1cccnc1
Reactant: NC(N)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccccc2n1Cc1cccnc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A mixture of 25 parts of N-(3-pyridinylmethyl)-1,2-benzenediamine and 11 parts of urea is melted together to 180°-190° C. and the melt is stirred for 30 minutes at this temperature. The reaction mixture is cooled and dissolved in a mixture of trichloromethane and methanol. The solvent is evaporated and the residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 24 parts (86%) of 1,3-dihydro-1-(3-pyridinylmethyl)-2H-benzimidazol-2-one; mp. 160.5° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([Br:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cc(Br)ccc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(Br)ccc2oc1=O
Temperature: 25 °C
Yield: 70.2 %

Procedure:
DIEA (35.6 μL, 0.2 mmol) was added to 6-bromo-3-carboxy-coumarin (50.0 mg, 0.19 mmol) and HATU (77.7 mg, 0.2 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.9 mg, 0.19 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 61.4 mg of product in 68% yield: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4cccnc4F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromo-4-methylpyridine
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH:13]=C)[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8](=[O:11])[CH2:9][CH3:10])[CH2:12][CH:13]=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(C(=O)CC)(c1ccccc1)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 17.2 %

Procedure:
4,4-diphenyl-6-hepten-3-one (144 mg) was dissolved in a mixture of dioxane and water (3:1, 11 ml). A 10% aqueous osmium tetroxide solution (0.5 ml) was added. The resultant solution was stirred at room temperature for 5 min. A solution of sodium periodate (550 mg) in water was then added dropwise. The reaction mixture was allowed to stir for 16 hours. Water was added, and the aqueous mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water (once) and dried (MgSO4). Rotary evaporation of the solution gave a crude product which was purified by preparative thin layer chromatography (PTLC) on silica gel. Development with hexane/ethyl acetate (2:1) produced three bands. The lowest band (Rf 0.66) was scraped off the plate and eluted with methanol to yield 25 mg of 3,3-diphenyl-4-oxo-hexanal.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:13][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])n(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
Into a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (3.00 g, 17.5 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL). Potassium carbonate (4.84 g, 35.0 mmol, 2.00 equiv) and CH3I (2.98 g, 21.0 mmol, 1.20 equiv) were added at 0° C. The resulting solution was stirred for 2 h at 40° C. in an oil bath. After cooling to ambient temperature, the solids were removed by filtration followed by the addition of 120 mL of ice water. The mixture was extracted with 3×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from ether. This resulted in 1.10 g (34%) of methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate as a white solid. m/z (ES+) 186 (M+H)+. 1H-NMR, (300 MHz, DMSO-d6, ppm): ˜7.57 (s, 1H), 4.22 (s, 3H), 3.91 (s, 3H). The filtrate was concentrated under vacuum and the crude product (2 g) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 56.5% in 10 min); Detector, uv 254 nm. The fractions containing pure compound were combined and concentrated to yield 470 mg (15%) of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate as a white solid. m/z (ES+) 186 (M+H)+. 1H-NMR, (300 MHz, DMSO-d6, ppm): □□ 7.64 (1H, s), 4.24 (3H, s), 3.87 (3H, s).
Reaction SMILES: Cl.[K].[C:3]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:8]([Cl:17])[N:7]=1)([OH:5])=[O:4].[CH3:18]O>>[CH3:18][O:4][C:3]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:8]([Cl:17])[N:7]=1)=[O:5]
Reactant: CCCCc1c(Cl)cc(C(=O)O)nc1Cl
Reactant: CO
Agent: Cl
Agent: [K]
Product: CCCCc1c(Cl)cc(C(=O)OC)nc1Cl

Procedure:
300 ml of 5 N hydrochloric acid in methanol are added to 28.6 g (0.1 mol) of the potassium salt of 2-carboxy-4,6-dichloro-5-n-butyl-pyridine and the mixture is heated for 8 hours under reflux. It is then evaporated to dryness and hydrochloric acid which still adheres is distilled off with toluene. The residue is rendered alkaline with 2 N sodium carbonate solution and extracted with ether. The ether phases are combined, dried with sodium sulphate and evaporated. Distillation of the residue in a bulb tube at a temperature of 140°-160° at 0.3 mm Hg yields 2-methoxycarbonyl-4,6-dichloro-5-n-butyl-pyridine of the formula ##STR31##
Reaction SMILES: [CH2:1]([C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[I:14]I.O>C(OCC)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([I:14])=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: II
Reactant: CCCCCc1cccc(F)c1F
Solvent: CCOCC
Solvent: O
Product: CCCCCc1ccc(I)c(F)c1F
Temperature: -70 °C

Procedure:
3-Pentyl-1,2-difluorobenzene is metalated according to 1a) or 1b). A solution of 0.1 mol of iodine in 100 ml of diethyl ether is added slowly at -70° C. The mixture is subsequently stirred for a further hour at -70° C. and warmed to 0° C., and water is added to the solution. After washing with sodium hydrogen sulfite solution and dilute sodium hydroxide solution the mixture is worked up as customary.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[SH:9][CH2:10][C:11](O)=[O:12]>Cl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:11](=[O:12])[CH2:10][SH:9])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)CS
Agent: Cl
Product: O=C(CS)Nc1ccc(O)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-aminophenol (4.0 g, 36.7 mmol) and mercaptoacetic acid (2.93 g, 38.5 mmol) under an atmosphere of carbon dioxide was heated to reflux (oil bath temperature ˜120° C.) for 4 hours. The mixture was cooled and diluted with 2 N hydrochloric acid (˜100 mL). A purple solid, 1.3 g, was collected by filtration and washed with water. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM, to give a colorless solid, 1.03 g (15%). MS m/z 184 (MH+). 1H NMR(DMSO-d6) δ 2.08 (t, 1H), 3.24 (s, 2H), 6.70 (d, 2H), 7.35 (d, 2H), 9.21 (br s, 1H) and 9.83 (s, 1H). Anal. calcd for C8H9NO2S: C, 52.44; H, 4.95; N, 7.64. Found: C, 52.57; H, 4.95; N, 7.40.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:20][C:21]1([CH3:35])[C:26](=[O:27])[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]1>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2([OH:27])[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:22][C:21]2([CH3:35])[CH3:20])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
A solution of 1-Bromo-4-fluorobenzene (5.32 mL, 48.4 mmol) in THF (100 mL) was cooled to −78° C., and treated with the dropwise addition of 1.6 M BuLi in hexane (30.2 mL, 48.4 mmol), at a rate which did not allow the temperature of the reaction to exceed −60° C. The mixture was stirred at −78° C. for 30 minutes, then treated with the dropwise addition of a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (5 g, 22.00 mmol) in THF (50 mL) at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred at −78° C. for 1.5H, then allowed to warm to 10° C. and quenched with saturated NH4Cl (50 mL). The layers were separated, and the organic phase was concentrated in-vacuo. The aqueous was extracted with ethyl acetate (100 mL), and the organic phase was combined with the residue from the original organic phase. This solution was washed 3× with water, 1× with brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was digested with hexanes (70 mL), and the resulting white powder was collected by filtration, rinsed with hot hexanes, and dried under vacuum to yield the title compound (3.3 g, 10.20 mmol, 46.4% yield). MS (ESI+)=324.4, (M+H)+, 250.3, (M-tBuOH)+.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccccc2Cl)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(2-chlorophenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 8, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.