Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Yield: 43.1 %

Procedure:
To an oven-dried flask under N2 was added N-[5-bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.53 g, 0.005 mol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (0.45 mg, 0.6 mmol), copper(I) iodide (73 mg, 0.38 mmol), and trimethylsilylacetylene (1.26 g, 0.013 mol). Next, TEA (5.19 g, 0.05 mol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ES-LC/MS m/z=314 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([C:45](=[O:46])[CH2:44][O:43][CH3:42])[C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:23])([F:24])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])=[N:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncc(Cl)cn1
Yield: 71.7 %

Procedure:
In a solution of 0.27 g of N-(5-chloro-2-pyrimidinyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 11, 0.08 g of triethylamine and a catalytic amount of 4-(dimethylamino)pyridine in 5 mL of tetrahydrofuran, 0.08 g of methoxyacetyl chloride was added at room temperature with stirring, and stirred at the same temperature for 0.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was passed through short-pass silica gel column that was eluated with ethyl acetate, and thereby insoluble material was removed. The solvent was distilled off under reduced pressure, and purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (3:7) to obtain 0.22 g of the aimed product as colorless resinous substance.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[F:12]/[C:13](=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:14](O)=[O:15]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:14](=[O:15])/[C:13](/[F:12])=[CH:17]/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:4]2
Reactant: O=C(O)/C(F)=C/c1ccccc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)/C(F)=C/c1ccccc1

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and Z-2-fluoro-3-phenylpropenoic acid; MS (ES+) 275 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:2]=1.[H][H]>[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:2]=1
Reactant: OCCCCC#Cc1cnc2ccccc2c1
Reactant: [H][H]
Agent: [Pd]
Product: OCCCCCCc1cnc2ccccc2c1

Procedure:
3-Quinolinehexanol was prepared by reduction of 13.5 g of 6-(3-quinolinyl)-5-hexyn-1-ol over 1.0 g of 10% palladium on carbon at 1 atmosphere of hydrogen. The crude product obtained after filtration and evaporation was chromatographed over silica gel by high pressure liquid chromatography eluting with 2% methanol-dichloromethane. The first product to elute amounted to 0.95 g which was evaporatively distilled to yield 0.76 g (6%) of 6-[3-(1,2,3,4-tetrahydro)quinolinyl]hexanol, bp 180°-185° C./0.1 mm. The second product to elute amounted to 9.1 g which was evaporatively distilled to give 8.3 g (61%) of 3-quinolinehexanol, bp 195°-205° C. 0.25 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH2:6][O:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH3:16])[N:9]=1.Cl.C([N:37]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:25][C:26]=1[CH3:27])[CH2:6][O:7][C:8]1[C:12]([C:13]([NH2:37])=[O:15])=[CH:11][N:10]([CH3:16])[N:9]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(C)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(C)cc2C(N)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0.90 g), 1-hydroxy-1H-1,2,3-benzotriazole ammonia complex (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxamide (0.71 g, yield 79%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 168-169° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]12[CH2:22][CH2:21][CH2:20][N:11]1[C@@H:12](C(Cl)(Cl)Cl)[O:13][C:14]2=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(Cl)(=O)C>CO>[CH3:12][O:13][C:14]([C@:10]1([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:22][CH2:21][CH2:20][NH:11]1)=[O:15]
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12COCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)[C@]1(COCc2ccccc2)CCCN1
Temperature: 0 °C
Yield: 87.8 %

Procedure:
A solution of Intermediate 85b (6.39 g, 17.9 mmol) and sodium methoxide (580 mg, 10.8 mmol) in MeOH (100 mL) was stirred at RT for 18 h. The mixture was cooled to 0° C., then acetyl chloride (28.4 g, 359 mmol) added. This mixture was stirred at reflux for 1 h, then cooled and concentrated in vacuo. The residue was divided, applied to SCX-2 cartridges (3×70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound as a pale yellow oil (3.92 g, 87%). 1H NMR (400 MHz, CDCl3): 1.62-1.86 (3H, m), 1.07-2.13 (1H, m), 2.48 (1H, br s), 2.93-3.11 (2H, m), 3.69-3.78 (4H, m), 4.53 (1H, d, J 12.9), 4.55 (1H, d, J 12.9), 7.21-7.37 (5H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
To a solution of 5-hydroxy indole (4.56 gm, 0.034 moles) in DMF (20 ml), potassium carbonate (9.43 gm, 0.068 moles), ethyl bromoacetate (6.29 gm, 0.0377 moles) were added and the reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 6.2 gm (82%) of product as solid.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:7]=1)=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C

Procedure:
Thionyl chloride (35.8 grams, 0.305 mole) was added to a benzene solution of 2-chloro-4-nitrobenzoic acid (60.3 grams, 0.3 mole) and the mixture heated to reflux during 5 hours until the evolution of hydrogen chloride had ceased. Aluminum chloride (100 grams, 0.72 mole) was added slowly to the stirred solution during a 3.5 hour period and the temperature rose to 48° C. After the addition, the mixture was warmed to 80° C. for 2 hours, cooled, poured onto ice-water (one liter), concentrated hydrochloric acid (90 ml.) added and the mixture warmed at 40° C. for 3 hours. Benzene extraction followed by successive treatment with 5% aqueous sodium hydroxide, water and calcium chloride yielded, after removal of benzene, a reddish black residue purified by filtration. The pale yellow solid so obtained was further characterized as having a melting point equal to 95.5° C.-96.5° C. in 44% yields.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[N:9]=[CH:8][CH:7]=1.[NH4+].[Cl-]>CN(C=O)C.O>[N:1]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[N:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: COc1ccc(OC)c2c(Cl)ccnc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC)c2c(N=[N+]=[N-])ccnc12
Temperature: 90 °C
Yield: 84.5 %

Procedure:
16.7 g of NaN3 are added to a solution of 10 g (44.7 mmol) of 4-chloro-5,8-dimethoxyquinoline in a DMF/H2O mixture (160 mL/60 mL). The reaction medium is heated at 90° C. for 2 h 30 min. After cooling, the mixture is hydrolyzed with 500 mL of saturated NH4Cl solution and is extracted with CHCl3 (3 times 150 mL) After drying over MgSO4, the organic phases are concentrated on a rotary evaporator and the DMF is then removed under vacuum (2 mmHg). 8.7 g of azide are obtained in the form of a brown powder.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([Cl:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[ClH:37].[ClH:1].[CH3:3][O:4][C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:10][CH2:9]1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Yield: 22.1 %

Procedure:
2.4 g (7.1 millimoles) of 2,3,4-trimethoxybenzylpiperazine dihydrochloride, 1.8 g (7.5 millimoles) of bis(4-fluorophenyl)methyl chloride [see J. Chem. Soc. Perkin II, 1051 (1977)] and 5.0 ml (36 millimoles) of triethylamine were heated under reflux for 9 hours in 80 ml of xylene. The reaction mixture was allowed to cool to room temprature, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of 2 ml of conc. hydrochloric acid and 20 ml of ethanol was added to the resulting oily product, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol-ether gave 0.85 g of 1-(2,3,4-trimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride. The product showed the same property values as the compound obtained in Example 4.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=4[C:7]=3[CH:6]=2)(=[O:4])=[O:3])[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CN1CCN(S(=O)(=O)c2ccc3[nH]c(=O)c4[nH]cc(C(=O)O)c4c3c2)CC1

Procedure:
8-(4-Methyl-piperazine-1-sulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is prepared according to synthesis 25, from 440 mg (0.75 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 164 μl (1.48 mmol) of 1-methyl-piperazine to give, after washing with water, 340 mg (65%) of 8-(4-methyl-piperazine-1-sulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a white solid.
Reaction SMILES: C(N(CC)CC)C.O[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[C:16](#[N:20])[CH2:17][C:18]#[N:19]>CO>[NH2:20][C:16]1[O:15][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[C:17]=1[C:18]#[N:19]
Reactant: N#CCC#N
Reactant: O=C1CCCCC1O
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1c(N)oc2c1CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
2.1 4.8 ml of triethylamine are added dropwise to a solution of 11.0 g of 2-hydroxycyclohexanone and 9.6 g of malononitrile in 25 ml of methanol, and the mixture is stirred at room temperature for a further 4 hours. The crystals which deposit are separated off and washed with methanol, giving 12.8 g of 2-amino-4,5,6,7-tetrahydrobenzofuran-3-carbonitrile (“BA”), m.p. 179°.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=1)=[O:22]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 32.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(4-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl isocyanate (1.0 mmol) according to the procedure in General Method B. The producft was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (111 mg, 32%). EI-MS m/z 340 (M−H)−
Reaction SMILES: O=[C:2]([CH2:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4]#[N:5].[NH2:14][NH2:15]>CCO>[CH3:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][C:2]1[CH:3]=[C:4]([NH2:5])[NH:14][N:15]=1
Reactant: NN
Reactant: Cc1cccc(CC(=O)CC#N)c1
Solvent: CCO
Product: Cc1cccc(Cc2cc(N)[nH]n2)c1

Procedure:
3-Oxo-4-m-tolyl-butyronitrile (2.5583 gms.) is then suspended in 50 mL of anhydrous EtOH. This suspension is treated with 1.0 mL of anhydrous hydrazine, and subsequently heated to refluxing temperature for 1 day. The reaction mixture is concentrated in vacuo. The residue is then triturated with isopropanol to precipitate out the 5-(3-methyl-benzyl)-2H-pyrazol-3-ylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])O.[Na+].[Cl:15][C:16]1[C:24]([C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>O1CCCC1>[Cl:15][C:16]1[C:24]([C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:19]
Reactant: Nc1cc(O)ccc1F
Reactant: N#CC1(c2cccc(C(=O)Cl)c2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cc(O)ccc3F)c2Cl)CC1
Yield: 100 %

Procedure:
A two-layer mixture of a solution of 3-amino-4-fluorophenol (9.00 g, 70.8 mmol) in tetrahydrofuran (50 mL) and aqueous sodium hydrogen carbonate (13.9 g, 166 mmol) solution (100 mL) was vigorously stirred, while adding dropwise a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in tetrahydrofuran (60 mL). The reaction mixture was stirred at room temperature for 1 hr. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from hexane/ethyl acetate (120 mL/40 mL) to give the title compound (23.4 g, 100%) as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:18])([C:15](=[O:17])[CH3:16])[CH2:12][CH:13]=[CH2:14].[OH-].[Na+]>C(O)C.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:16][C:15](=[O:17])[C:11]([CH3:18])([CH3:10])[CH2:12][CH:13]=[CH2:14])=[CH:4][CH:3]=1
Reactant: C=CCC(C)(C)C(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCC(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
40 ml of water are added to a solution of 56.2 g (0.4 mol) of 4-chlorobenzaldehyde and 50.4 g (0.4 mol) of 4,4-dimethyl-1-hexen-5-one in 200 ml of ethanol and directly thereafter a solution of 1.2 g of sodium hydroxide in 12 ml of water is added. The mixture is initially stirred for 1 hour at room temperature, then 0.8 g of solid sodium hydroxide is added and the mixture is stirred for a further 16 hours. It is then diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed three times with water, dried and concentrated. 92 g (92.5% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-1,6-heptadien-3-one are obtained in the form of a yellow oil. ##STR32##
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)=[CH2:2].[CH:8]([C:11]([CH3:21])([N:14]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]1=[O:20])[C:12]#[N:13])([CH3:10])[CH3:9].C(Cl)(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH:8]([C:11]([CH3:21])([N:14]1[C:18](=[O:19])[C:17]2[C:16](=[CH:2][CH:1]=[C:3]3[CH:7]=[CH:6][S:5][C:4]3=2)[C:15]1=[O:20])[C:12]#[N:13])([CH3:10])[CH3:9]
Reactant: C=Cc1ccsc1
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)C(C)(C#N)N1C(=O)c2ccc3ccsc3c2C1=O
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of 3-vinylthiophene (10.0 g, 0.0908 mol), α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1- acetonitrile (18.3 g, 0.0953 mol) and chloroform is stirred at 50° C. for 20 hours and at room temperature for one week. The mixture is concentrated in vacuo to give a yellow oil residue, which is column chromatographed on silica gel using methylene chloride as an eluent to afford a yellow oil. The oil is taken up in dioxane and treated with dichlorodicyano-p-benzoquinone, (17.2 g, 0.0760 mol), stirred for 21 hours at 100° C., cooled to 25° C. and filtered (the filter cake is washed once with benzene). The filtrate is concentrated in vacuo to give an orange semisolid residue. The residue is washed through neutral alumina with methylene chloride:hexanes (1:1) and flash chromatographed on silica gel using hexane:ethyl acetate (4:1) as an eluent to afford the title product as a pale yellow solid, 4.21 g (15.6%), mp 99°-107° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][N:7]=1)C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:17])=[O:3])=[N:7][CH:8]=2)[CH:16]=[N:15][N:14]=[N:13]1
Reactant: CCOC(=O)Cc1ccc(-n2cnnn2)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-n2cnnn2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture ethyl[5-(1H-tetrazol-1-yl)pyridin-2-yl]acetate (0.19 g, 0.81 mmol) in THF (4 mL) was added 1.4 M LiOH (aq.) (2.9 mL) at room temperature. The mixture was stirred 3 hours at room temperature. The reaction was acidified with citric acid until pH about 3˜4. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give [5-(1H-tetrazol-1-yl)pyridin-2-yl]acetic acid: 1H-NMR (400 MHz, MeOD) δ 9.83 (s, 1H), 9.02 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 3.95 (s, 2H).
Reaction SMILES: Br[C:2]([F:19])([F:18])[S:3]([C:6]1[N:10]=[CH:9][N:8]([C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1)(=[O:5])=[O:4].[CH2:20]([S:22]SCC)[CH3:21].P([O-])([O-])(O)=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[CH2:13]([N:12]([CH2:15][CH3:16])[C:11]([N:8]1[CH:9]=[N:10][C:6]([S:3]([C:2]([F:19])([F:18])[S:22][CH2:20][CH3:21])(=[O:5])=[O:4])=[N:7]1)=[O:17])[CH3:14]
Reactant: CCSSCC
Reactant: CCN(CC)C(=O)n1cnc(S(=O)(=O)C(F)(F)Br)n1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSC(F)(F)S(=O)(=O)c1ncn(C(=O)N(CC)CC)n1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a stirred solution of 10 g (0.028 mol) 3-(bromodifluoromethylsulfonyl)-1-(N,N-diethylcarbamoyl)-1,2,4-triazole (as prepared in Example 1) and 6.81 ml (0.055 mol) diethyl disulfide in a mixture of 30 ml N,N-dimethylformamide and 20 ml water at 0° C. was added 5.9 g (0.042 mol) sodium hydrogen phosphate and 7.23 g (0.042 mol) sodium dithionite. After 2 h, the reaction mixture was diluted with 100 ml water and extracted with ethyl acetate (3×100 ml). The combined resulting organic layers were washed with saturated sodium chloride solution, dried over MgSO4 and evaporated. Preparative LC purification of the residue with 40% ethyl acetate-hexane gave 5.45 g (57% yield) of the desired 1-(N,N-diethylcarbamoyl)-3-[difluoro(ethylthio)methylsulfonyl]-1,2,4-triazole as a colorless oil having n D 25 = 1.5063 .
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[CH:1]
Reactant: COC(=O)CCc1ccccc1O
Reactant: C#CCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCCCCOc1ccccc1CCC(=O)OC
Temperature: 25 °C
Reaction time: 100 h
Yield: 76.8 %

Procedure:
A mixture of 0.98 g (10 mmol) of 5-hexyn-1-ol, 1.98 g (11 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 2.88 g (11 mmol) of triphenylphosphine, 1.91 g (11 mmol) of diethyl azodicarboxylate, and 220 mL of dry tetrahydrofuran was stirred at room temperature for 100 hr and then concentrated under reduced pressure. The residue was triturated with 9:1 hexane-ether. The solid was filtered with suction and washed with the same solvent mixture. The filtrate and washes were combined and concentrated in vacuo. Flash chromatography of the residue on silica gel, eluting with 9:1 hexane-ether gave 2 g (77%) of 2[(5-hexynyl)oxy]benzenepropanoic acid methyl ester as a colorless oil.