Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[N:17][OH:18])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1.C(N(CC)CC)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(#N)C>[NH2:1][C:2]1[N:6]([C:7](=[N:17][O:18][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(N)n(C(=NO)c2cccc([N+](=O)[O-])c2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)ON=C(c2cccc([N+](=O)[O-])c2)n2nc(C)cc2N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
7.4 g (0.028 mol) of 5-amino-1-(3-nitro-benzohydroximoyl)-3-methyl-pyrazole are treated in 90 ml of absolute acetonitrile with 4 ml (0.028 mol) of triethylamine and then, with stirring at room temperature, are treated dropwise with a solution of 5.55 g (0.029 mol) of 4-tosyl chloride in 150 ml of absolute acetonitrile. Stirring is continued for 1 hour and then the mixture is evaporated to dryness. The residue is treated with water and ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated under vacuum. The oily residue obtained in this way is crystallised from ethanol. 8.5 g (72%) of 5-amino-3-methyl-1-(O-tosyl-3-nitrobenzohydroximoyl)-pyrazole with a m. pt. of 156°-158° C. are obtained. The substance is light-sensitive. On recrystallising twice from ethanol, the m. pt. is 165°-169° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH:2]=[CH:14][N:15]([CH3:17])[CH3:16])=[CH:5][CH:6]=1)#[N:9]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(C#N)cc1
Product: CN(C)C=CC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A mixture of 4-acetylbenzonitrile (51.84 g, 0.357 mol) and N,N-dimethylformamide dimethyl acetal (142 ml, 1.07 mol) was heated to reflux for 1.5 h. The reaction was cooled to room temperature and the resultant crystalline mass collected by filtration and washed with diethyl ether (4×100 ml) to give 1-(4-cyanophenyl)-3-dimethylaminopropen-1-one as an orange solid (44.56 g). An additional crop of this product (11.40 g) could be obtained by partially concentrating the filtrate. δH (d6DMSO) 8.01 (2H, d, J 8.2 Hz), 7.87 (2H, d, J 8.2 Hz), 7.75 (1H, d, J 12.2 Hz), 5.83 (1H, d, J 12.2 Hz), 3.15 (3H, bs), 2.92 (3H, bs). MS (ESI) 201 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:28].O1CCOCC1>CCOCC>[ClH:28].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0.22 M solution of 1-tert-butyl 2-methyl (2S,4S)-4-[((4-bromophenyl)sulfonyl)oxy]pyrrolidine-1,2-dicarboxylate (prepared as described in WO2006/119061) in Et2O at 0° C. was added dropwise a 4M solution of HCl in dioxane (25 eq.) and the resulting mixture was stirred at RT for 16 h, after which time a solid product was formed. The suspension was filtered and the filter cake was washed with cold Et2O. The solid product was dried in vacuo and the product used without further purification. MS (ES+) C12H14BrNO5S requires: 363. Found: 364, 365 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH3:20])[CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH2:32]Br>CN(C=O)C>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH2:32][N:7]1[C:6]2[CH:22]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH3:20])[CH:14]=2)[C:8]1=[O:21]
Reactant: Fc1cccc(Cl)c1CBr
Reactant: CSc1cccc(N2C(=O)Nc3cc(F)ccc3S2(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1cccc(N2C(=O)N(Cc3c(F)cccc3Cl)c3cc(F)ccc3S2(=O)=O)c1
Yield: 46.1 %

Procedure:
The title compound (74 mg, 0.15 mmol) was subsequently prepared from 6-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (110 mg), K2CO3 (180 mg, 1.30 mmol) and 2-chloro-6-fluorobenzyl bromide (89 uL, 0.65 mmol) in DMF (5 mL) using the methods of (115).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>[O-]CC.[Na+]>[C:14]([CH:13]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: CCOc1ccc(CC#N)cc1OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(OCC)c(OCC)c1

Procedure:
By following the procedures outlined in Examples 1 and 3, 3,4-diethoxyphenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide solution to give ethyl 3-cyano-3-(3',4'-diethoxyphenyl)pyruvate. This compound is similarly reacted with 3,4-diethoxyphenylacetonitrile which results in the formation of 2,5-di-(3',4'-diethoxyphenyl)-3,4-dioxoadiponitrile. The latter is refluxed with water, acetic acid and sulfuric acid to give 3,4,3',4'-tetraethoxypulvinic acid which is treated with acetic anhydride to give the corresponding acid lactone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][C:15]([NH:18][CH:19]1[NH:24][CH2:23][CH2:22][NH:21][CH:20]1C1C=NC=CN=1)([CH3:17])[CH3:16]>>[CH3:17][C:15]([NH:18][C:19]1[C:20]([N:21]2[CH2:22][CH2:23][N:24]([C:11]([C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[CH:5]=3)=[O:13])[CH2:19][CH2:20]2)=[N:21][CH:22]=[CH:23][N:24]=1)([CH3:14])[CH3:16]
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CC(C)(C)NC1NCCNC1c1cnccn1
Product: CC(C)(C)Nc1nccnc1N1CCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with 5-fluoroindole-2-carboxylic acid (0.44 g) and 3-(1,1-dimethylethylamino)-2-pyrazinylpiperazine (2.50 mmol), a solid is obtained which is recrystallized from ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2onc3ccccc23)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2onc3ccccc23)cc1
Yield: 59.1 %

Procedure:
A mixture of 14.9 g (0.071 mole) of 3-(4'-methylphenyl)-2,1-benzisoxazole, 12.7 g (0.071 mole) of N-bromosuccinimide, 0.1 g of dibenzoyl peroxide and 200 ml of carbon tetrachloride was heated at reflux under illumination by a flood lamp for 20 hr. The mixture was filtered while hot and the filtrate was washed twice with 5% aqueous sodium hydroxide, dried over sodium sulfate and concentrated. The residue was dissolved in acetonitrile and filtered to remove insoluble material. The filtrate was concentrated and the residue was recrystallized twice from ethanol and once from 2-propanol (charcoal) to yield 12.1 g (59%) of solid, m.p. 146°-147° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>C(#N)C>[Br:19][C:12]1[C:13]([NH:15][CH2:16][C:17]#[CH:18])=[N:14][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:31]3[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=3)(=[O:35])=[O:34])=[CH:3][CH:4]=2)=[N:10][CH:11]=1
Reactant: C#CCNc1nc(Nc2ccc(N)cc2)ncc1Br
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCNc1nc(Nc2ccc(NS(=O)(=O)c3cn(C)cn3)cc2)ncc1Br

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2,4-diamine (100 mg, 0.3 mmole prepared in analogy to procedure 21) was dissolved in acetonitrile (10 ml) and triethylamine (1 ml) and 1-Methyl-1H-imidazole-4-sulfonyl chloride (120 mg, 0.66 mmole) was added at room temperature. The reaction mixture was stirred under reflux for 5 hours, the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (ethyl acetate: hexanes 1:1). Yield 41 mg of 1-Methyl-1H-imidazole-4-sulfonic acid [4-(5-b bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-amide. ESI-MS: 463.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and dodecanoic acid to yield (3aR,4S,7aR)-4-dodecanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.80 min; UPLC Method I
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[N:17]=[N:18][N:19](CCCC=CC)[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:5]1[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:30]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]3[N:17]([CH2:10][CH2:11][CH2:12][CH2:7][CH:8]=[CH2:9])[N:18]=[N:19][N:20]=3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC=CCCCn1nnc(-c2ccc3[nH]c(CCCC)nc(=O)c3c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCCCn1nnnc1-c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c(=O)c2c1
Yield: 175.4 %

Procedure:
A mixture of 1.7 g of 2-butyl-6-[2-(4-hexenyl)-2H-tetrazol-5-yl]-4(1H)-quinazolinone, 1.9 g of 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile and 3.0 g of potassium carbonate in 100 ml of acetone is refluxed for 24 hours. The reaction mixture is filtered and the filtrate evaporated to a residue which is purified by chromatography on silica gel by elution with 30% ethyl acetate-hexanes to give 2.3 g of the desired product as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([OH:15])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([F:10])[CH:5]=[C:4]2[C:3]=1[CH2:11][CH2:12][C:13]2=[O:15]
Reactant: COc1c(F)ccc(CCC(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1c(F)cc2c(c1Cl)CCC2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-chloro-4-fluoro-3-methoxyphenyl)propanoic acid (20.74 g, 88 mmol) in benzene (440 mL) was added DMF (0.14 mL, 1.8 mmol) followed by gradual addition of oxalyl chloride (15.4 mL, 177 mmol) during 25 minutes. After 2 hours, the reaction mixture was evaporated under vacuum to give a yellow oil. The oil was dissolved in 100 mL of benzene and evaporated under vacuum. This process was then repeated. The resulting oil was dissolved in dichloromethane (500 mL) and solid aluminum chloride (12.9 g, 96.7 mmol) was added during 5 minutes using a solid addition funnel. After 20 minutes, the reaction mixture was poured onto ca 1000 cc of ice. When most of the ice had melted, the layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed successively with 2N HCl, water and brine. After drying over sodium sulfate, the solution was evaporated under vacuum to give a yellow solid. Flash chromatography through silica gel eluting with EtOAc/hexanes/dichloromethane (10:95:95) gave 4-chloro-6-fluoro-5-methoxyindanone as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Yield: 103.2 %

Procedure:
34.3 g (0.15 mol) of 2-naphthalenesulfonyl chloride, dissolved in 250 ml of tetrahydrofuran, were added dropwise to 25 g (0.15 mol) of ethyl 3-aminobenzoate and 63 ml (0.45 mol) of triethylamine in 400 ml of tetrahydrofuran at 0° C. The mixture was then heated to reflux for 1 h. The organic solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was dried and concentrated in vacuo. 55 g (100%) of the product were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:26])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[C:20]1([N:19]2[C:18](=[O:26])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:9]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1
Reactant: O=Cc1ccccn1
Product: O=c1c2ccccc2nc(C=Cc2ccccn2)n1-c1ccccc1
Yield: 52 %

Procedure:
The title compound was synthesized according to General Procedure B using picolinaldehyde and compound 27. After cooling, the precipitate formed was filtered off, washed with water, dried and recrystallized from ethanol to yield compound 43 (0.49 g, 52%). M. Wt. 325. LCMS [M+H]+=326.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([CH3:9])=O)[CH3:2].[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:7]([CH3:9])=[N:20][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)nn(-c2ccccn2)c1-c1ccccc1
Yield: 64.4 %

Procedure:
6.0 grams 3-benzoyl-levulinic acid ethyl ester, 2.7 grams 2-hydrazino-pyridine and 25 milliliters glacial acetic acid were mixed and the mixture was heated to the boiling temperature under reflux for 3 hours. The reaction mixture was worked up by a procedure analogous to that described above. 5.0 grams 3-methyl-5-phenyl-1-(2-pyridyl)-pyrazol-4-acetic acid ethyl ester, melting at 89°-90° C., were obtained, representing a yield of 64%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]([O:19][CH2:20][CH2:21][NH2:22])([CH3:18])[CH3:17].C(N(CC)CC)C>>[CH:16]([O:19][CH2:20][CH2:21][NH:22][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CC(C)OCCN
Solvent: CCN(CC)CC
Product: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 88.4 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.50 g, 5.16mmol), 2-aminoethyl isopropyl ether (0.533 g, 5.16 mmol) and triethylamine (1.42 mL, 10.32 mmol) were reacted to form the desired product (1.63 g, 89%). LC-MS (m/z) 357.0 (M+).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH:7](=O)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[OH-].[K+]>[C:1]([C:3](=[CH:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: O=C/C=C/c1ccccc1
Reactant: N#CCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: N#CC(=CC=Cc1ccccc1)C(=O)O
Temperature: 35 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of cyano acetic acid in 200 ml of 10% aqueous potassium hydroxide was added trans-cinnamaldehyde (26 g). The mixture was stirred at 35° C. for 2 hrs. and acidified with 100 ml of conc. hydrochloric acid. The solid was collected and washed to yield 2-cyano-5-phenyl-2,4-pentadienoic acid (36 g, 90% yield), m.p. 196° C. Recrystallized from ethanol yielded pure product, m.p. 211° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>O>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cccc(O)c1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (2.0 g, 13 mmol) in absolute ethanol (20 mL) was added sulfuric acid (2.0 mL, 37 mmol). The resulting mixture was stirred at 90° C. for 16 hours. The reaction was cooled to room temperature then diluted with water (20 mL). The mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum to give ethyl 3-hydroxy-2-methylbenzoate (116a, 2.4 g, 99% yield) as yellow oil.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[C:14]([CH3:18])=[CH:13][C:12]=3[OH:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]12([C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:14]([CH3:18])=[C:15]([Br:17])[CH:16]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Yield: 91.8 %

Procedure:
To a solution of 2-(1-adamantyl)-4-bromo-5-methylphenol (6.53 g, 20.34 mmol) in acetone (65 mL) was added benzyl bromide (3.48 g, 20.34 mmol) followed by K2CO3 (3.51 g, 25.43 mmol). The mixture was stirred and heated at reflux for 24 h under argon. Acetone was removed at reduced pressure, and then 2 N HCl (80 mL) was added. The mixture was extracted with EtOAc (300 mL), and the organic layer was washed with H2O and brine and dried. After removal of solvent, the residue was purified by chromatography on a silica gel using hexane to give 7.68 g (80%) of 5-(1-adamantyl)-4-benzyloxy-2-methylphenyl bromide as a white solid, mp 138-139° C. IR 2903, 2848, 1163 cm−1; 1H NMR (CDCl3) δ 1.71 (bs, 614, AdCH2), 2.02 (bs, 3H, AdCH), 2.08 (bs, 6H, AdCH2), 2.33 (s, 3H, CH3), 5.07 (s, 2H, C6H5CH2), 6.80 (s, 1H, 3-ArH), 7.33 (s, 1H, 6-ArH), 7.3-7.5 ppm (m, 5H, C6H5).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][CH2:8][CH2:9][NH:10][N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(OCC)(=O)C>[OH:7][CH2:8][CH2:9][N:10]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cl
Reactant: OCCNN=Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)N(CCO)N=Cc1ccccc1

Procedure:
This acylation is performed in the following manner: 1.08 g (10-2 moles) of ethyl chloroformate in 5 ml of anhydrous ethyl acetate are added dropwise to a solution containing 10-2 moles of benzaldehyde (2-hydroxyethyl)hydrazone and 0.79 g (10-2 moles) of anhydrous pyridine in 20 ml of anhydrous ethyl acetate, with stirring in the cold. The reaction mixture is left at 0° C. with stirring for 2 hours and then it is filtered. The product obtained is washed with 10 ml of water and then dried and recrystallized from a mixture of ethyl acetate and petroleum ether. It has a melting point of 69.5° C. The reaction yield is 62%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.OS(O)(=O)=O.[OH-].[Na+]>CC(O)=O.O>[F:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.1 %

Procedure:
A mixture of acetophenone (7.02 gm, 58.4 mmol), p-fluorobenzaldehyde (7.24 gm, 58.4 mmol) and concentrated H2SO4 (10 ml) in glacial HOAc (116 ml) was stirred at room temperature for 2 days. The solution was poured into H2O (250 ml) and neutralized with 10% NaOH (200 ml). The aqueous layer was extracted once with Et2O and the Et2O layer was washed successively with H2O, saturated NaHCO3 (2×) and brine, then dried (MgSO4). Filtration and removal of the solvent afforded a yellow solid which was recrystallized from hot hexane to give (E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one (7.94 gm, 60%) as light yellow needles.
Reaction SMILES: [CH3:1]NCCNC.C[Al](C)C.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:22]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:30]=3)=[CH:27][CH:28]=2)[N:21]=[C:20]([C:39](OC)=[O:40])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:22]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:30]=3)=[CH:27][CH:28]=2)[N:21]=[C:20]([C:39](=[O:40])[CH3:1])[CH:19]=1
Reactant: CNCCNC
Reactant: COC(=O)c1cc(-c2ccccc2Cl)n(-c2ccc(-c3cccc(S(C)(=O)=O)c3)nc2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2ccccc2Cl)n(-c2ccc(-c3cccc(S(C)(=O)=O)c3)nc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.1 %

Procedure:
To a stirred solution of N,N′-dimethylethylenediamine (56 μL, 0.52 mmol) in toluene (3 mL, anhyd) at 0° C. was added dropwise a 2.0M solution of trimethylaluminum in hexanes (0.75 mL, 1.5 mmol). After addition was complete the flask was removed from the ice-water bath and allowed to warm to ambient temperature. After 50 min the reaction mixture was charged slowly with a solution of methyl 5-(2-chlorophenyl)-1-{6-[3-(methylsulfonyl)phenyl]pyridin-3-yl}-1H-pyrazole-3-carboxylate (0.22 g, 0.47 mmol) in toluene (3 mL, anhyd) and then heated at reflux. After 90 min the reaction mixture was allowed to cool to ambient temperature and quenched by addition of 1N HCl. The resulting mixture was extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 30:70 to 60:40) to yield the title compound (47 mg, 22%) as a white solid. 1H-NMR (DCM-d2): δ 8.65 (m, 1H), 8.57 (m, 1H), 8.30 (m, 1H), 7.99 (m, 1H), 7.79-7.87 (m, 2H), 7.71 (m, 1H), 7.36-7.47 (m, 4H), 7.02 (s, 1H), 3.09 (s, 3H), 2.68 (s, 3H); MS(ES): 452 [M+H]+.