Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.[OH2:10]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N+:6]([O-:10])[CH:5]=[CH:4][N:3]=1
Reactant: O
Reactant: N#Cc1nccnc1Cl
Agent: O=S(=O)(O)O
Product: N#Cc1c(Cl)ncc[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Chloro-3-cyanopyrazine (5.00 g, 35.94 mmol) in concentrated H2SO4 (35 mL) at 0° C. was treated portionwise with K2S2O8 (11.65 g, 43.95 mmol), warmed to room temperature, stirred for 24 hours, treated with water, and extracted with chloroform. The organic extract was washed sequentially with water, saturated NaHCO3 and brine, dried (MgSO4) and concentrated to provide the title compound. MS (DCI/NH3) m/e 173 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1)[CH3:3].[CH3:25][I:26]>CC(C)=O>[I-:26].[N:16]1([CH2:15][C:7]2[N:6]([CH2:5][CH2:4][N+:2]([CH3:25])([CH3:1])[CH3:3])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CN(C)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reactant: CI
Solvent: CC(C)=O
Product: C[N+](C)(C)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Product: [I-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.5 %

Procedure:
The free base of 1-[1-(N,N-dimethyl-aminoethyl)-1H-benzimidazol-2-ylmethyl]-1H-benzotriazole (100 mg, 0.312 mmol) was dissolved in anhydrous acetone. Methyl iodide (44 mg, 0.312 mmol) was added with stirring under N2 at room temperature. After 3 hours, the white solid was filtered and dried under vacuum to give 19.5 mg (14%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].Cl[C:12]([O:15]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1>O1CCOCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH:4][C:12]([NH:23][CH:24]1[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]1)=[O:15]
Reactant: Cc1cc(F)c(N)c(Br)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1COCCO1
Product: Cc1cc(F)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Br)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 129.9 %

Procedure:
2-Bromo-6-fluoro-4-methylaniline (5.2 g, 25.5 mmol) (D31) was dissolved in 1,4-dioxane (40 ml) and bis(trichloromethyl)carbonate (9.3 mmol, 2.7 g) was added at room temperature and the mixture was heated to 60° C. for 15 minutes and it was then brought up to 100° C. for a further 15 minutes. The mixture was then cooled to room temperature, filtered and the solvent was thoroughly evaporated; the crude was redissolved in dichloromethane (40 ml) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (2 eq., 51 mmol, ˜10.2 g) was added at room temperature very slowly. The mixture was stirred at room temperature for 1.5 hours, the solvent was then evaporated totally and the crude material was then left under vacuum for 10 minutes; dichloromethane was added again and the mixture obtained was filtered to afford the solid that is the first batch (5.2 g) of the desired product; the solvent was evaporated from the organic filtrate and the mixture obtained was re-dissolved into dichloromethane and filtered again to afford the second batch (1 g) of the desired product; the solvent was evaporated from the organic filtrate and the mixture obtained was re-dissolved into diethyl ether, filtered again, washed with methanol then with diethyl ether to afford the third batch (1.5 g) of the desired product. The three batches were combined to afford 7.7 g of the title compound, 70%, M++H=432.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:13](=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)[C:13](=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccncc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc(-c2ccncc2)cc1
Yield: 40.1 %

Procedure:
A mixture of 4-benzyloxycarbonyl-1-(4-bromobenzyl)-2-piperazinone (807 mg), 4-pyridylboric acid (244 mg), tetrakis (triphenylphosphine)palladium (69 mg), 2M sodium carbonate solution (2 ml), toluene (8 ml) and ethanol (2 ml) was refluxed overnight. After the mixture was cooled, ethyl acetate was added to the reaction solution. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (283 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13](Cl)(Cl)=[O:14].C(N(CC)CC)C>C(Cl)Cl>[O:14]=[C:13]1[NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:10]=3[C:11]=2[O:12]1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc2cccnc2c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2ccc3cccnc3c2o1
Reaction time: 8 h
Yield: 91 %

Procedure:
A suspension of 7-amino-8-hydroxyquinoline (3.2 g, 20.0 mmol) in methylene chloride (50 ml) was treated with 25 ml of 1.6M phosgene gas in methylene chloride. Triethylamine (12 ml) was slowly added and the reaction was stirred overnight. The reaction mixture was partially concentrated and water was added. After treating the resulting mixture with aqueous ammonium hydroxide a precipitate formed which was filtered and dried giving 3.4 g (91% yield) of solid. M.P. >300° C.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH:6]=[CH:7]1)[CH2:4][CH2:3][C:2]2=O.N1CCCC1.CC1C=CC([S:22](O)(=O)=O)=CC=1.O.[S].[N:28]#[C:29][NH2:30]>C1CCCCC1>[S:22]1[C:3]2[CH2:4][CH:5]3[O:8][CH:1]([C:2]=2[N:28]=[C:29]1[NH2:30])[CH2:7][CH2:6]3
Reactant: O=C1CCC2C=CC1O2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CN
Agent: [S]
Solvent: C1CCNC1
Solvent: O
Solvent: C1CCCCC1
Product: Nc1nc2c(s1)CC1CCC2O1
Reaction time: 18 h
Yield: 911.1 %

Procedure:
To 8-oxabicyclo[3.2.1]octan-2-one (prepared as described in Vogel et al. Tetrahedron 1993, 49 (8), 1649-1664) (1.1 g, 9.0 mmol) in cyclohexane (10 mL) was added pyrrolidine (0.78 mL, 9.4 mmol) and p-TsOH.H2O (0.085 g, 0.45 mmol). The flask was equipped with a Dean-Stark trap that was pre-filled with cyclohexane. The mixture was warmed to reflux and was allowed to stir for 18 hours with the Dean-Stark trap. This mixture was concentrated and redissolved in methanol (15 mL). Sulfur (0.29 g, 9.0 mmol) was added and the mixture stirred for 15 min. Cyanamide (0.38 g, 9.0 mmol) was then added and the mixture was stirred for 72 hours at ambient temperature. The crude mixture was concentrated under reduced pressure and purified by flash column chromatography (SiO2, 20% hexanes in ethyl acetate) to give the title compound (0.75 g, 4.1 mmol, 46% yield). MS (DCI/NH3) m/z 183 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][N:12]=[N+]=[N-])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: [N-]=[N+]=NCc1ccc2c(N)n[nH]c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc2c(N)n[nH]c2n1
Reaction time: 64 h

Procedure:
A mixture of 3-amino-6-azidomethyl-7-azaindazole (60 mg, 0.317 mmol), triphenylphosphine (416 mg, 1.59 mmol) and water (86 mg, 4.76 mmol) in THF (10 mL) was stirred for 64 h. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica (chloroform/ammonia, methanol gradient, 5-10% methanol) to give the title compound as a yellow solid:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=N[CH:33]=1>>[N:13]1([C@H:11]2[CH2:10][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:26]5[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:12]2)[CH2:14][CH2:18][CH2:33][CH2:15][CH2:16][CH2:17]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: OB(O)c1cncnc1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 71A for the product of Example 1E, and substituting 2-methoxypyrimidine-5-boronic acid (Frontier Scientific, Inc., Logan, Utah, USA) for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.78 (s, 2H) 8.07 (d, J=8.24 Hz, 1H) 7.98 (d, J=1.83 Hz, 1H) 7.59 (dd, J=8.39, 1.68 Hz, 1H) 4.09 (s, 3H) 3.78-3.86 (m, 1H) 3.33-3.44 (m, 1H) 2.45-2.65 (m, 8H) 1.58-1.75 (m, 8H). MS: (M+H)+=395.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C

Procedure:
30 g (165.6 mmol) of 2-methyl-3-nitrobenzoic acid is added to 150 ml of methanol, and it is refluxed for two days after 2.9 ml of concentrated sulfuric acid is added. After cooling, the crystallizate (25.55 g=79%) is suctioned off and thus incorporated into the next stage.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[N:7][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:10]=1[C:11]#[N:12]>N1C=CC=CC=1>[C:13]1([C:8]2[CH:9]=[C:10]3[C:11]([NH2:12])=[N:7][NH:6][C:5]3=[N:2][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cc(-c2ccccc2)nnc1Cl
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: Nc1n[nH]c2nnc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (0.7 ml, 14.3 mmol) was added to a stirred solution of 3-chloro-6-phenyl-pyridazine-4-carbonitrile (cf J. Med. Chem., 1999, 42, 730; 1.024 g, 4.7 mmol) in pyridine (10 ml). The reaction mixture was stirred at reflux for 6 hours, cooled and the resulting solid was filtered and dried in vacuo, affording the title compound as a solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].[C:23]1([CH2:29][CH:30]=[CH2:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:31]=[CH:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1
Reactant: C=CCc1ccccc1
Product: CCCOc1ccccc1-c1nc2c(C=CCc3ccccc3)cccc2c(=O)[nH]1
Yield: 63.9 %

Procedure:
The title compound is prepared analogously to the method of Example 1, starting with the compound from Example III and 3-phenyl-1-propene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:28])[N:12](CC4C=CC(OC)=CC=4OC)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.O.C([O-])(O)=O.[Na+].CC(C)=O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:28])[NH:12][CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]ccc2nc(-c3ccc(Cl)cc3)sc12
Temperature: 70 °C
Yield: 116.9 %

Procedure:
Mix 2-(4-chloro-phenyl)-5-(2,4-dimethoxy-benzyl)-5H-thiazolo[5,4-c]pyridin-4-one (24.6 g, 59.6 mmol) in trifluoroacetic acid (143 mL) and heat at 70° C. for 2 h. Cool the mixture to room temperature and add water (325 mL) and saturated NaHCO3 (710 mL) with stirring. Add acetone (180 mL) and stir the resulting slurry for one hour at room temperature. Filter and wash the solids with water (110 mL) and then acetone (110 mL). Dry the solids in a vacuum oven at 60° C. overnight. Triturate the solids three times with CH3CN (700 mL) at 60° C. and filter. Dry the solids in a vacuum oven at 60° C. overnight to obtain 18.3 g (117%) of the title compound that still contains salt impurities. 1H NMR (400 MHz, DMSO-d6) δ11.86 (s, 1H), 8.12 (d, 2H, J=8.2), 7.65 (d, 2H, J=8.7), 7.49 (t, 1H, J=6.0), 6.91 (1H, J=6.6).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([CH3:11])[C:4]=1[O:12][CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:7]1[C:6]([CH3:10])=[C:5]([CH3:11])[C:4]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:8]=1[CH3:9])=[O:25]
Reactant: COc1c(C)cc(C)c(C)c1OC
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1c(C)c(C)c(C(=O)CCCCCBr)c(C)c1OC
Reaction time: 0.75 h
Yield: 16.6 %

Procedure:
A solution of 2.956 g (16 mmol) of 1,2-dimethoxy-3,4,6trimethylbenzene in 10 mL of methylene chloride was added to 2.40 g (18 mmol) of aluminum chloride and 3.80 g (18 mmol) of 6-bromohexanoyl chloride in 30 mL of methylene chloride cooled in an ice bath. The solution was kept at 3° for 45 minutes and then at 23° for 42 hours. An additional 2.0 g of aluminum chloride and 3.0 g of 6-bromohexanoyl chloride were added and the reaction mixture was stirred at reflux for 22 hours. Workup as in Example 16 and purification by HPLC using 4% ethyl acetate-hexane gave 0.95 g of 6-bromo-1-(3,4-dimethoxy-2,5,6-trimethylphenyl)-1-hexanone as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave a molecular ion at m/z 356 (C17H25BrO3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OC1C=CC(C(OC2C3C(=C(OC(=O)C4C=CC(O)=CC=4)C4C(C=3)=CC=CC=4)C=CC=2OC(=O)C2C=CC(O)=CC=2)=O)=CC=1>>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: ClCc1ccccc1
Agent: O=C(Oc1ccc2c(OC(=O)c3ccc(O)cc3)c3ccccc3cc2c1OC(=O)c1ccc(O)cc1)c1ccc(O)cc1
Product: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Yield: 47.6 %

Procedure:
Using 3-hydroxy-4-methylbenzoic acid (20.3 g, 0.13 mole)and benzyl chloride (50.8 g, 0.40 mole), the reaction was carried out in the same manner as described in Example 1, (1). The resulting crude solid was recrystallized from ethanol to give 15.0 g of 3-benzyloxy-4-methylbenzoic acid as white crystals having a m.p. of 159°-161° C.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][O:8]/[N:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:21][C:20]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)([C:22]([F:25])([F:24])[F:23])[O:19][N:18]=2)=[CH:13][C:12]=1[CH3:34])(C)(C)C.C(O)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:28]1[CH:27]=[C:26]([C:20]2([C:22]([F:24])([F:23])[F:25])[O:19][N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11](/[CH:10]=[N:9]/[O:8][CH2:7][C:6]([OH:35])=[O:5])=[C:12]([CH3:34])[CH:13]=3)[CH2:21]2)[CH:31]=[C:30]([Cl:32])[CH:29]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)OC(C)(C)C
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of [1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-meth-(E)-ylideneaminooxy]-acetic acid tert-butyl ester (i.e the product of Step 1, 531 mg) in CH2Cl2 (20 mL) was treated with formic acid (0.25 mL, 0.30 g) and stirred at room temperature over night. Trifluoroacetic acid (0.50 g) was added and the mixture stirred until tlc (thin layer chromatography) indicated completion of the reaction. The organic layer was washed with water three times, dried (Na2SO4) and evaporated to give the title compound (502 mg, 80%) that was used in the next step without further purification. NMR indicated the absence of the tert butyl ester.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=3)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.C(P(CCCC)CCCC)CCC.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=3)[O:21][CH2:35][CH2:36][CH2:37][OH:38])(=[O:11])=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of 3-(benzo-2,1,3-thiadiazole-4-sulfonyloxy)-5-methylphenol (645 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a pale yellow oil (615 mg, 82%). 1H-NMR (300 MHz, CDCl3) δ 8.35 (d, J=8.7 Hz, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 6.59 (s, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.80 (t, J=6.0 Hz, 2H), 2.21 (s, 3H), 1,96 (m, 2H), 1.65 (br s, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:12]1[C:16](Br)=[CH:15][S:14][CH:13]=1.Cl>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:12]1[C:16]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][S:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Brc1cscc1Br
Reactant: CCCCCCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCc1cscc1CCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
2 M octylmagnesium bromide (100 milliliters, 0.2 mol) in anhydrous ethyl ether was added to a well-stirred mixture of dichloro[1,3-bis(diphenylphosphino)-propane]nickel(II) (0.2 gram) and 3,4-dibromothiophene (20.16 grams, 0.0833 mol) in 200 milliliters of anhydrous ethyl ether in a 500 milliliter round bottom flask cooled with an ice bath under an inert atmosphere. The nickel complex reacted immediately with the Grignard reagent and the resulting reaction mixture was allowed to warm up to room temperature. An exothermic reaction started within 30 minutes and the ethyl ether began to reflux gently. After stirring for another 2 hours at room temperature, the reaction mixture was refluxed for 6 hours, then cooled in an ice bath, and hydrolyzed with aqueous 2N hydrochloric acid. The organic layer was separated and washed successively with water, brine, and again with water, dried over anhydrous sodium sulfate, and filtered. After evaporation of the solvent, the residue was distilled under reduced pressure through Kugelrohr apparatus to provide 21.3 grams of 3,4-dioctylthiophene as a colorless liquid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(-c3ccccc3)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
N-Bromosuccinimide (25.9 gm) was added to a cold solution of 6-methyl-2-phenylbenzoxazole (30 gm) in carbon tetrachloride (250 ml). Benzoyl peroxide (500 mg) was added and the mixture was heated under reflux for 3 hr. in the presence of u.v. light. The solid residue was filtered off. The filtrate was evaporated down slightly, treated with carbon and allowed to cool. The crystals which were formed were recrystallised from benzene to yield 6-bromomethyl-2-phenylbenzoxazole, m.p. 162°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][CH:25]=[N:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][CH2:28][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCCn1cccn1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCn1cccn1

Procedure:
Compound XIVa was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(1H-pyrazol-1-yl)ethanol following the general procedure for the Mitsunobu reaction described in Example 20.
Reaction SMILES: I[CH:2](C)C.[ClH:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[C@@H:25]3[C@@H:20]([CH2:21][CH:22]=[CH:23][CH2:24]3)[C:19](=[O:26])[N:18]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:33][C:34]4C=C5C(C=CC(=O)O5)=CC=4)[CH2:29][CH2:28]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]>>[ClH:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[CH:25]3[CH:20]([CH2:21][CH:22]=[CH:23][CH2:24]3)[C:19](=[O:26])[N:18]([CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:2])[CH2:29][CH2:28]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CC(C)I
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(C)C)CC3)C(=O)C3CC=CCC23)cc1OC

Procedure:
Prepared from 2-iodopropane and starting compound A1 as described for compound 18. M. p. 158-159° C.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Cl:8])[C:3](Br)=[O:4].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][Cl:8])[C:3]([N:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CNc1ccccc1
Reactant: O=C(Br)C(Br)CCCl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C(=O)C(Br)CCCl)c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2-Bromo-4-chlorobutanoyl bromide (80.3 g, 300 mmol) was slowly added to a solution of N-methylaniline (34.5 g, 320 mmol) and triethylamine (33.5 g, 330 mmol) in toluene (340 mL). The reaction was exothermic, and the mixture was cooled to maintain the temperature at about 40° C. After the addition was complete, the resulting thick mixture was stirred for 30 minutes, 150 mL water was added, and the mixture was stirred further. The aqueous and organic phases were separated, and the organic phase was washed with 5% hydrochloric acid and with water. The toluene was evaporated completely under slight vacuum to yield 86.3 g 2-bromo-4-chloro-N-methyl-N-phenylbutanamide (98% yield, approximately 95-96% pure). The triethylamine may be recovered from the aqueous phase by addition of base and separation.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH2:18][CH3:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(C(C)=O)c1
Yield: 98 %

Procedure:
A solution of 3-acetylbenzoic acid (4.00 g, 24.366 mmol) and concentrated sulfuric acid (0.078 mL, 1.462 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give ethyl 3-acetylbenzoate as a brown powder (4.59 g, 98%).