Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.[NH2:24][C:25]1[CH:29]=[CH:28][S:27][C:26]=1[C:30]([NH:32][C:33]1[CH:38]=[C:37](Cl)[CH:36]=[CH:35][N:34]=1)=[O:31].N1C=CC=CC=1.[Cl:46]CCl>>[Cl:46][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30]([C:26]2[S:27][CH:28]=[CH:29][C:25]=2[NH:24][C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:7])(=[O:8])[NH2:5])=[CH:23][CH:22]=2)=[O:20])=[O:31])=[N:34][CH:35]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Cl)cc1
Reactant: ClCCl
Reactant: Nc1ccsc1C(=O)Nc1cc(Cl)ccn1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1-c1ccc(C(=O)Nc2ccsc2C(=O)Nc2ccc(Cl)cn2)cc1

Procedure:
A solution of 4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)benzoyl chloride (1 equiv), 3-amino-2-(4-chloro-2-pyridinyl)aminocarbonyl thiophene (1 equiv), pyridine (5 equiv) in dichloromethane was stirred at rt overnight. The mixture was diluted with dichloromethane, washed with water, dried over Na2SO4, filtered and evaporated. The residue was refluxed with 1 mL of TFA for 2 h. After evaporation, reverse phase HPLC gave the title product. ES-MS 513(M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH2:12][CH3:13])=[C:4]([F:14])[C:3]=1Br.[Cu](C#N)[C:17]#[N:18].N.[CH3:22][N:23](C)C=O>>[CH2:12]([O:11][C:5]1[C:4]([F:14])=[C:3]([C:22]#[N:23])[C:2](=[CH:7][C:6]=1[O:8][CH2:9][CH3:10])[C:17]#[N:18])[CH3:13]
Reactant: CN(C)C=O
Reactant: CCOc1cc(Br)c(Br)c(F)c1OCC
Reactant: N#C[Cu]C#N
Agent: N
Product: CCOc1cc(C#N)c(C#N)c(F)c1OCC
Temperature: 150 °C
Reaction time: 3 h

Procedure:
After dissolving the 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (480 g) in dimethylformamide (1400 ml), copper cyanide (345 g) was added and the mixture was stirred at 150° C. for 3 hours. Saturated aqueous ammonia was added to the reaction mixture, and then the mixture was stirred overnight and extraction was performed with toluene. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (513 g) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:17]1([C:2]2[CH:3]=[C:4]([N:8]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10][CH2:9]3)[CH:5]=[N:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(N2CCN3CCC2CC3)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: c1ccc(-c2cncc(N3CCN4CCC3CC4)c2)cc1

Procedure:
0.87 g (3.1 mmol) of 4-(5-bromo-3-pyridyl)-1,4-diazabicyclo[3.2.2]nonane is introduced into a 50 ml three-necked round-bottomed flask, 0.39 g (3.15 mmol) of phenylboronic acid, 0.11 g (0.095 mmol) of tetrakis(triphenylphosphine)palladium, 3.3 ml of aqueous 2 M sodium carbonate solution, 6.5 ml of benzene and 0.15 ml of ethanol are added and the mixture is refluxed for 16 h.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2C[CH2:15][N:10](CC2)C1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N#CCl>C1COCC1>[C:16]1([S:22]([N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:15]#[N:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1CN2CCN1CC2
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: N#CCl
Solvent: C1CCOC1
Product: N#CN(c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a 3 liter 3-necked flask equipped with a stirrer, addition funnel, thermometer, and drying tube was charged 93.1g (1.0 mole) of aniline, 111g (1.1 moles) of triethylene diamine and 250 ml. of tetrahydrofuran. To this reaction mixture was added dropwise a solution of 176.6g (1 mole) of benzenesulfonyl chloride in 300 ml. of tetrahydrofuran. The reaction mixture was stirred at room temperature for 2.5 hours and was then filtered. To the filtrate was added 111g of triethylene diamine and this solution was added dropwise to a solution of 87g (1.41 moles) of cyanogen chloride in 100 ml. of THF which was maintained at -5° C. with cooling. After this addition was complete the stirred reaction mixture was allowed to return to room temperature over a 16 1/2 hour period. The reaction mixture was filtered and the filament was added to water to precipitate the product. The product was recrystallized from aqueous methanol to yield 218g (84.7%) of N-benzene sulfonyl phenyl cyanamide, m.p. 65°-66° C.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].C[Si](C)(C)[O:8][C:9]1[CH2:12][CH2:11][C:10]=1[O:13][Si](C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:2]([CH:4]1[C:10](=[O:13])[CH2:11][CH2:12][C:9]1=[O:8])([CH3:3])[CH3:1]
Reactant: CC(C)C=O
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)C1C(=O)CCC1=O
Yield: 16.6 %

Procedure:
To a solution of TiCl4 (1.47 g, 7.77 mmol) and isobutyraldehyde (559 mg, 7.75 mmol) in DCM (16 ml) under N2 at −78° was added a solution of 1,2-bistrimethylsilyloxycyclobutene (1.97 g, 8.56 mmol) in DCM (16 ml) maintaining a temperature of less than −70°. After 30 min the reaction was poured into water, extracted into DCM, washed (H2O×2), dried (MgSO4) and the solution concentrated in vacuo to yield a clear oil. To this oil was added TFA (20 ml) and the solution heated at reflux for 24 h. The solution was concentrated in vacuo and the residue purified by chromatography (SiO2; 50:50 EtOAc/hexane) to give the title compound as an off-white solid (180 mg, 17%). δH (d6-DMSO) 2.61 (1H, sept, J 7.0 Hz), 2.29 (4H, s), 1.04 (6H, d, J 7.0 Hz). m/z (ESI, 70V) 141 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][N:35]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:34][CH2:33]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(COc2ccc(C3CCNCC3)c(OCc3ccccc3)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
In a 25 ml round-bottomed flask, 0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine in 10 ml of tetrahydrofuran is dissolved in the presence of 0.26 ml of N,N-diisopropylethylamine. 0.17 ml of benzoyl chloride is added and the mixture is then stirred for 24 hours at ambient temperature. The reaction mixture is extracted with ethyl acetate and then the organic phases are combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 0.5 g of [4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is obtained. Yield=80%.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2=[O:23])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[Cl:38][C:39]1[CH:40]=[C:41]([N:46]=[C:47]=[O:48])[CH:42]=[CH:43][C:44]=1[Cl:45]>ClCCl>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:47]([NH:46][C:41]3[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=3)=[O:48])[CH2:19][C:18]2=[O:23])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1CNCCN1CC1CCCN(Cc2ccccc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CN(C(=O)Nc2ccc(Cl)c(Cl)c2)CCN1CC1CCCN(Cc2ccccc2)C1
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a mixture of 1-[(1-benzylpiperidin-3-yl)methyl]piperazin-2-one dihydrochloride (83 mg) in dichloromethane (10 mL) was added N,N-di-iso-propylethylamine (0.1 mL). After 1 minute dimethylformamide (1 mL) was added followed by 3,4-dichlorophenyl isocyanate (47 mg). The solution was stirred for 5 minutes and then partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (92 mg, 84%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=[O:8])[CH2:4][C:5](=[O:7])[CH3:6].[NH2:11][C:12]([NH2:14])=[O:13].[CH:15](OCC)(OCC)OCC.CO[Na].Cl>C(O)C>[C:5](/[C:4](/[C:3](=[O:8])[C:2]([F:10])([F:9])[F:1])=[CH:15]\[NH:11][C:12]([NH2:14])=[O:13])(=[O:7])[CH3:6]
Reactant: CCOC(OCC)OCC
Reactant: NC(N)=O
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: CO[Na]
Agent: Cl
Solvent: CCO
Product: CC(=O)/C(=C\NC(N)=O)C(=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of 1,1,1-trifluoropentane-2,4-dione (200 g, 1.30 mol) in ethanol (200 mL) were added urea (78 g, 1.30 mol) and CH(OEt)3 (211.5 g, 1.43 mol). The mixture was stirred at 80° C. for 4 h. The resulting slurry was filtered. The filter cake was suspended in methanol (300 mL) and MeONa (77.2 g, 1.43 mol) was added. The mixture was stirred at reflux for 5 h, followed by slow addition of HCl (4N) to pH 3 at rt. The resulting slurry was filtered and the filter cake was dried under vacuum to give compound (E)-1-(2-acetyl-4,4,4-trifluoro-3-oxobut-1-en-1-yl)urea (196 g, 67.3% yield) as a white solid. 1H NMR (DMSO-d6 300 MHz): (Z/E) δ 10.15-10.13 (m, 1H), 8.64 (s, 1H), 7.69-7.66 (m, 2H), 2.25 (s, 3H). LC-MS MS (ESI) m/z 206.8 [M−18+H]+.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[C:4](=[O:11])[NH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCOCC1.CC(N(C)C)=O>[Cl:28][C:27]1[C:22]([N:8]2[CH2:9][CH2:10][C:5]3[C:4](=[O:11])[NH:3][CH:2]=[N:1][C:6]=3[CH2:7]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=c1[nH]cnc2c1CCNC2
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: O=c1[nH]cnc2c1CCN(c1ncccc1Cl)C2
Temperature: 150 °C

Procedure:
5,6,7,8-Tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (1.5 g, 10 mmol) was dissolved in a mixture of dioxane-dimethylacetamide (2 ml, 3:1) and 2,3-dichloropyridine was added (1.5 g, 10 mmol), followed by DIEA (1.7 ml; 10 mmol). The mixture was heated at 150° C. for 2 hours in a microwave (Personal Chemistry, Smith Creator). The solvents were evaporated and the residue was dissolved in a 3:1 mixture of chloroform-isopropanol and washed with water. The organic layer washed with brine, dried over soldium sulphate, filtered and evaporated to give a yellow solid (3 g). The crude material was used for the subsequent step.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[CH3:10][NH:11][CH3:12].[CH2:13]=O>C(O)(C)C>[CH3:10][N:11]([CH2:13][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[OH:9])[CH3:12]
Reactant: CNC
Reactant: CCc1cccc(O)c1
Reactant: C=O
Solvent: CC(C)O
Product: CCc1ccc(CN(C)C)c(O)c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a 25 mL round bottom flask equipped with a mechanical stirrer and a thermometer was added 4 mL (%Wt/Vol. Phenol to Solvent--50%) of isopropanol, followed by 2.0 grams (0.0164 mole--1.0 equiv.) of m-ethylphenol and then 2.22 grams (0.0197 mole--1.2 equiv.) of an aqueous 40% N,N-dimethylamine solution. The mixture was stirred at ambient temperature to effect dissolution, and 0.59 gram (0.0197 mole--1.2 equiv.) of paraformaldehyde was added. The reaction mixture began to exotherm so it was cooled to ambient temperature where it stirred for 17 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue, and the residue was taken up in heptane and water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 2.8 grams of 2-[(N,N-dimethylamino)methyl]-5-ethylphenol (88.7% yield). Gas Chromatography (GC) analysis of the product indicated the presence of about 7% of an impurity. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#N.S(=O)(=O)(O)[OH:23].[OH2:27]>>[C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:23])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: O
Product: O=C(O)c1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Temperature: 150 °C

Procedure:
50 grams (0.183 mole) of the product of Example 1 was reacted with a mixture of 250 mls of conc. sulfuric acid and 50 mls of distilled water. This solution was heated to 150° C. for 6 hours, cooled and the mixture poured into ice. The precipitant solid was filtered, washed with water and air dried. This solid was recrystallized from absolute ethyl alcohol to give 4.0 grams (7.5%) yield of a white solid that melts at 243°-244° C. Calculated for C17H12N2O3C, 68.6; H, 4.04; N, 9.5. Found: C, 69.8; H, 4.13; N, 9.59.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].O[C:18]12[CH2:25][CH2:24][N:21]([CH2:22][CH2:23]1)[CH2:20][CH2:19]2.C(N(CC)CC)C>CN(C)C=O.C(Cl)(Cl)Cl>[N:21]12[CH2:24][CH2:25][C:18]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)([CH2:23][CH2:22]1)[CH2:19][CH2:20]2
Reactant: OC12CCN(CC1)CC2
Reactant: O=C(O)C(=O)c1cccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OC12CCN(CC1)CC2)C(=O)c1cccs1
Temperature: 25 °C

Procedure:
Oxalyl chloride (1.5 ml, 0.017 mol) was added to a solution of oxothien-2-yl-acetic acid (2.24 g, 0.014 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 0° C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was dissolved in CHCl3 (30 ml) and added to a suspension of 1.1 g (0.009 mols) of 4-hydroxy-1-azabicyclo[2.2.2]octane, 1.8 ml of triethylamine (0.013 mols), 0.6 g (0.9 mmols) of N-(methylpolystyrene)-4-(methylamino) pyridine at 70° C. The mixture was refluxed for 1 hour, cooled, filtered and washed with water. The title product was extracted with a solution of diluted HCl, washed with CHCl3, basified with K2CO3 and extracted again with CHCl3. After removal of the solvent 1.47 g (45%) of a solid was obtained. 1H-NMR (dmso): δ 2.0 (m, 6H), 2.9 (m, 6H), 7.35 (m, 1H), 8.05 (m, 1H), 8.3 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O1CCCC1.O.[NH2:26][NH2:27]>O>[N:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:26][NH2:27])=[O:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1ccc(N2CCCCC2)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NNC(=O)c1ccc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 6-(1-piperidyl)nicotinate (5.00 g) in a mixed solvent of ethanol (25 ml) and tetrahydrofuran (10 ml) was added hydrazine monohydrate (11.0 ml). The solution was refluxed for 6 hours, during which period additional hydrazine monohydrate (11.0 ml) was added to the mixture. After cooling to ambient temperature, the reaction mixture was added to water (100 ml) and then stirred for 20 minutes at ambient temperature. The resulting precipitates were filtered, washed with water, and dried to give 6-(1-piperidyl)nicotinoylhydrazine (3.44 g), as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(F)cc1I
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(F)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 5-fluoro-3-iodo-pyridin-2-ylamine (4 g, 16.8 mmol) in THF (50 mL) and trimethylsilylacetylene (4.7 mL, 33.6 mmol) is treated with PdCl2(PPh3)4 (353 mg, 0.5 mmol), CuI (96 mg, 0.5 mmol) and triethylamine (7 mL, 50.4 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 10%-35% EtOAc in heptane to afford 5-fluoro-3-trimethylsilanylethynyl-pyridin-2-ylamine (3.3 g, 94%). MS: 209 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H), 7.30 (m, 1H), 4.89 (s, NH2, 2H), 0.25 (s, 9H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[N:17]2[N:40]=[CH:41][N:42]=[C:16]2[N:15]1[CH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[C:16]4[N:17]([N:40]=[CH:41][N:42]=4)[C:18]=3[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:26][CH:25]=2)[NH:34]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A mixture of hydroxylammonium chloride (1 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-oxo-7-pentyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.48 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.37 g, 68%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH2:38][CH:39]=[CH2:40])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]>OP([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH2:38][CH:39]4[CH2:40][O:9]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: C=CCc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC4CO4)cc3)cc2)CC1
Reaction time: 8 h

Procedure:
m-Chloroperbenzoic acid (77%, 0.565 g, 2.52 mmol) was washed 4× with a solution of sodium phosphate dibasic (0.1 M aq., 7 mL) then dissolved in CH2Cl2 (4 mL). The solution was added to 1-[4′-(4-Allyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.244 g, 0.63 mmol) in CH2Cl2 (3 mL) followed by sodium phosphate dibasic (0.1 M aq., 7 mL). After 3.5 hours an additional portion of m-chloroperbenzoic acid (0.55 g) was rinsed 4× with sodium phosphate dibasic (0.1 M aq., 7 mL) and added to the reaction and stirring continued overnight. The reaction was then submitted to standard aqueous workup and purified via silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[C:3]([F:16])([F:15])[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[C:18](#[N:21])[CH:19]=[CH2:20].[ClH:22].C(N(CC)CC)C>C(#N)C>[Cl:22][CH:19]([CH2:20][S:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]([F:16])([F:15])[CH:2]([Cl:17])[Cl:1])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[C:18]#[N:21]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)C(Cl)Cl)cc1
Reactant: Cl
Reactant: C=CC#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CC(Cl)CS(=O)(=O)c1ccc(OC(F)(F)C(Cl)Cl)cc1
Temperature: 115 °C

Procedure:
2-Chloro-3-((4-(2,2-dichloro-1,1-difluoroethoxy)phenyl)sulfonyl)propanenitrile (hereinafter "Compound") is prepared by mixing together 4-(2,2-dichloro-1,1-difluoroethoxy)benzenesulfonyl chloride with substantially two molecular proportions of acrylonitrile in the presence of acetonitrile, cupric chloride and triethylamine hydrochloride whereby the following reaction takes place: ##STR1## In the process, 4-(2,2-dichloro-1,1-difluoroethoxy)-benzenesulfonyl chloride (1 molar proportion), acrylonitrile (2 molar proportions), acetonitrile, anhydrous cupric chloride (.02 molar proportion) and triethylamine hydrochloride (0.032 molar proportion) are placed in a reaction vessel which is cooled, evacuated to about 2 mm mercury pressure, sealed and heated in an oil bath at about 115° C. for about six hours. The vessel is opened and the product is isolated by crystallization from methanol to give the title compound as a white, crystalline solid, melting at 109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:10]\[CH:11]=O)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:11]/[CH:10]=[C:9](\[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(/C(=C\C=O)c2cccnc2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)c1cccnc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-3-(3- pyridinyl)-2-propenal (5.25 g was reacted with (carbomethoxymethylene)triphenylphosphorane (7.4 g) in dichloromethane (40 mL) for 17 hours at room temperature. The crude ester was isolated in the usual way and was purified by HPLC to give 4.6 g of the ester. A portion was crystallized twice from ether-hexane to give the analytical sample of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid methyl ester, mp 75°-76° C.