Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.O1CCCC1.N1C=CC=CC=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1cnccn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C

Procedure:
A 47 g quantity of 2,6-di-tert-butyl-1,4-benzoquinone and 20 g of aminopyrazine were added to 300 ml of tetrahydrofuran and dissolved therein with heating. To the solution was added a yellow suspension (which had been prepared by adding 12 ml of titanium tetrachloride dropwise with ice-cooling and stirring to a solution of 35 ml of pyridine in 200 ml of dichloroethane), and the mixture was refluxed with heating for 1 hour. To the reaction mixture was added a suspension of 70 ml of pyridine, 24 ml of titanium tetrachloride and 200 ml of dichloroethane. The resulting mixture was refluxed with heating for 2 hours. Again a suspension of 17 ml of pyridine, 6 ml of titanium tetrachloride and 100 ml of dichloroethane was added thereto and the resulting mixture was refluxed with heating for 30 minutes. Then, the reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with ethyl acetate. The filtrate was concentrated and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:10→1:1), and washed with cold hexane, thereby giving 58 g of 2,6-di-tert-butyl-4-pyrazinylimino-2,5-cyclohexadien-1-one (Compound 1a) as a yellow solid.
Reaction SMILES: C[C@@H]1CNC[C@H]1C1NC(=O)C2C=NN(C3CCOCC3)C=2N=1.C([N:30]1[CH2:34][C@@H:33]([CH2:35][CH3:36])[C@H:32]([C:37]2[NH:38][C:39](=[O:52])[C:40]3[CH:45]=[N:44][N:43]([CH:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[C:41]=3[N:42]=2)[CH2:31]1)C1C=CC=CC=1>>[CH2:35]([C@@H:33]1[CH2:34][NH:30][CH2:31][C@H:32]1[C:37]1[NH:38][C:39](=[O:52])[C:40]2[CH:45]=[N:44][N:43]([CH:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[C:41]=2[N:42]=1)[CH3:36]
Reactant: CC[C@@H]1CN(Cc2ccccc2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Product: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one but substituting 6-[(3S,4S)-1-benzyl-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one provided the title compound. 400 MHz 1H NMR (CD3OD) δ 8.02 (s, 1H), 4.97 (m, 1H), 4.09-4.06 (m, 2H), 3.78-3.58 (m, 4H), 3.34-3.34 (m, 1H), 3.16-3.11 (m, 1H), 2.68 (d, J=8.7 Hz, 1H), 2.63 (m, 1H), 2.32-2.27 (m, 2H), 1.90-1.87 (m, 2H), 1.69 (m, 1H), 1.57 (m, 1H), 0.97 (t, J=7.5 Hz, 3H). MS: (M+H m/z 318.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[NH2:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(O[C:24]([CH2:26][C:27]1[NH:31][C:30]2[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:29]=2[N:28]=1)=O)C>C(Cl)Cl.C(O)C>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[CH2:5][C:4]1[CH:17]=[CH:18][C:19]2[NH:20][C:24]([CH2:26][C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:29]=4[N:28]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: Nc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(Cc3nc4cc(CN5C(=O)c6ccccc6C5=O)ccc4[nH]3)nc2c1
Temperature: 185 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A finely ground mixture of 2-(3,4-diaminobenzyl)isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1H-benzimidazole-5-carboxylic acid (0.93 g, 3.75 mmol) was heated 1 hour at 185° C. under nitrogen. The mixture was suspended in 1:1 methylene chloride/ethanol (20 mL) and stirred vigorously for 1 hour. The solids were collected by filtration, washed with 1:1 methylene chloride/ethanol (3×20 mL) and dried to provide 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1H-benzoimidazole-5-carboxylic acid (0.98 g, 29% yield); 1H-NMR (300 Mhz, DMSO-d6): 12.45 (broad s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J=7.5 Hz), 7.43 (s, 1H), 7.11 (d, 1H, J=7.2 Hz), 4.82 (s, 2H), 4.48 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][S:26]([CH2:25][CH2:24][CH2:23][CH2:22][Cl:21])(=[O:28])=[O:27])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Product: CCCN(CCC)C(=O)c1cc(NS(=O)(=O)CCCCCl)cc(C(=O)OC)c1

Procedure:
Description 92 was prepared in an analogous manner to Description 91 from 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) and 4-chloro-butane-1-sulfonyl chloride.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(C(C)C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 3-isopropyl-phenol (5.00 g, 36.2 mmols) in 50 mL of acetone was added K2CO3 (7.50 g, 54.3 mmols) and iodomethane (10.3 g, 72.5 mmols). The resulting solution was heated to 50° C. and stirred for 18 hours, cooled to room temperature, and concentrated under reduced pressure. The residual oil was dissolved in Et2O and washed with H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The crude methyl ether was used without further purification.
Reaction SMILES: O1CCC[CH2:2]1.C[Mg]I.CON(C)[C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.Cl>O>[Cl:21][C:16]1[CH:15]=[C:14]([CH2:13][C:12](=[O:22])[CH3:2])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CON(C)C(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Agent: C[Mg]I
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran, 75 mL, was cooled to 0° C., and 10.3 mL of methylmagnesium iodide (3.0M in diethyl ether) was added dropwise during a 30 minute period. The reaction mixture was maintained at <2° C. during the addition. Upon completion of addition, 7.0 grams (0.028 mole) of N-methoxy-N-methyl-3,4-dichlorophenylacetamide was added dropwise during a 45 minute period. The reaction mixture temperature was maintained between -2° C. and +2° C. throughout the addition. Upon completion of addition, the reaction mixture was stirred at about 0° C. for 1.5 hours. After this time, 50 mL of aqueous 2N hydrochloric acid was added dropwise to the reaction mixture. The reaction mixture temperature was maintained at <4° C. throughout the addition. The reaction mixture was then taken up in 100 mL of water and extracted with two 150 mL portions of diethyl ether. The combined extracts were washed with 100 mL of an aqueous solution saturated with sodium chloride. The extracts were then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which weighed 6.6 grams. The 6.6 grams isolated here was combined with 3.2 grams of the same material prepared in an analogous manner. The combination was subjected to column chromatography on silica gel. Elution was accomplished using 50% methylene chloride in petroleum ether, then gradually increasing to 75% methylene chloride in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of (3,4-dichlorophenyl)acetone. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl-].[CH3:2][N:3]([CH3:34])[C:4]1[CH:33]=[CH:32][C:7]([CH:8]=[N:9][N+:10]2[CH:14]=[CH:13][N:12]([N:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:11]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1.[C:35](=[O:38])([O-])[OH:36].[Na+]>>[C:35]([O-:36])(=[O:38])[CH3:2].[CH3:24][N:23]([CH3:25])[C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[N:15][N+:12]2[CH:13]=[CH:14][N:10]([N:9]=[CH:8][C:7]3[CH:32]=[CH:33][C:4]([N:3]([CH3:2])[CH3:34])=[CH:5][CH:6]=3)[C:11]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: O=C([O-])O
Agent: CN(C)c1ccc(C=Nn2cc[n+](N=Cc3ccc(N(C)C)cc3)c2-c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Product: CC(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
95 mg of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-phenylimidazolium chloride are suspended in 10 ml of saturated sodium hydrogen carbonate solution and the suspension is stirred at room temperature for 18 hours. The product (1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-phenylimidazolium hydrogen carbonate) is filtered, washed with water and ether. The still moist product is subsequently dissolved in 10 ml of methanol and treated with 2 ml of glacial acetic acid. The solution is evaporated at room temperature in a vacuum and the residue is crystallized from methanol/ether. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-phenyl imidazolium acetate of melting point 167°.
Reaction SMILES: C([O:3][C:4](=[O:23])/[C:5](=[N:16]/[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)C.[OH-].[Li+].O>C(O)C>[CH:18]1([O:17]/[N:16]=[C:5](\[C:6]2[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][CH:11]=2)/[C:4]([OH:23])=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
(E)-Cyclopentyloxyimino-(4-methanesulfonyl-phenyl)-acetic acid ethyl ester (60 mg, 0.18 mmol) was dissolved in ethanol (1.75 mL) and cooled to 0° C. A 2.0 N solution of lithium hydroxide in water (258 μL, 0.52 mmol) was added dropwise and the cooling bath was removed. After stirring 40 min, the reaction mixture was diluted with chloroform (30 mL) and washed with 0.2 M aqueous potassium bisulfate (20 mL). The aqueous phase was extracted with chloroform (30 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford (E)-cyclopentyloxyimino-(4-methanesulfonyl-phenyl)-acetic acid as a clear, colorless film that was used without further purification.
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][NH2:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1.[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][C:16]1[CH:15]=[C:14]([Cl:13])[CH:19]=[C:18]([Cl:20])[CH:17]=1)=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 41 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with (3,5-dichlorophenyl)-methanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-(3,5-dichlorobenzyl)isonicotinamide was obtained as a colorless solid in 41% yield: mp 248-251° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.01 (br s, 1H), 9.42 (br s, 1H), 8.63-8.54 (m, 2H), 8.06 (s, 2H), 7.60-7.39 (m, 7H), 4.53-4.51 (d, J=4.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([CH3:15])[CH2:11][C:12](O)=[O:13].C(Cl)(=O)C([Cl:19])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([CH3:15])[CH2:11][C:12]([Cl:19])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccccc1CC(C)CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1CC(C)CC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-methoxyphenyl)-3-methylbutyric acid (24 mmol, crude from previous reaction) in dichloromethane (36 mL) was added oxalyl chloride (2 M in DCM, 36 mL). The reaction was stirred for 1 h at room temperature. All volatiles were removed in vacuo and the crude residue used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.S(=O)(=O)(O)O.[F:12][C:13](I)([F:15])[F:14].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].CS(C)=O>[CH3:1][C:2]1[C:3]([C:13]([F:15])([F:14])[F:12])=[N:4][NH:5][CH:6]=1
Reactant: FC(F)(F)I
Reactant: Cc1cn[nH]c1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: Cc1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Yield: 45 %

Procedure:
0.047 g (0.25 mmol) of ferrocene was weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 0.07 ml (0.88 mmol) of 4-methylpyrazole, 1.7 ml of dimethyl sulfoxide, 1.7 ml of a 1 N dimethyl sulfoxide solution of sulfuric acid, 0.7 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.15 ml of a 30% hydrogen peroxide aqueous solution, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40° C. to 50° C. Thereafter the resulting solution was cooled to room temperature. Formation of 4-methyl-3-trifluoromethylpyrazole (19F-NMR yield: 45%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. The subsequent procedure was conducted in the same manner as in Example 1 and 4-methyl-3-trifluoromethylpyrazole was obtained as a colorless oil (0.054 g, yield: 36%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: CC(C)Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Nc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
6-Amino-9-benzyl-2-(isopropylamino)purine (71 mg, 0.25 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (73 mg, yield 81%).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH3:7])=[C:5](I)[S:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.CCCCCC>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[C:6]([CH3:7])=[C:5]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[S:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1
Reactant: Cc1c(I)sc(C2OCCO2)c1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
2-(3-Bromo-5-iodo-4-methylthien-2-yl)-1,3-dioxolane (12.4 g, 33.1 mmol), 4-methoxyphenylboronic acid (5.5 g, 36 mmol), K2CO3 (15 g, 110 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium [II] (1.3 g, 1.6 mmol) were combined in 20% aqueous dimethoxyethane (130 mL) and heated at 75° C. After 3 h, the cooled mixture was filtered through Celite and washed with ethyl acetate (350 mL). The filtrate was washed with 1 N aqueous NaOH and brine (350 mL each), dried (K2CO3) and concentrated in vacuo to give the crude product (13.1 g) as a dark solid which was pre-adsorbed on silica gel (40 g). Flash chromatography (600 g silica, gradient 2.5%-5% ethyl acetate-hexane) gave the title compound (9.5 g, 81%, m.p. 103-04° C.) as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[CH3:27][N:28]1[C:32](=[O:33])[NH:31][N:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:31]1[C:32](=[O:33])[N:28]([CH3:27])[N:29]=[N:30]1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Br)c2)=NO1
Reactant: Cn1nn[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cn1nnn(Cc2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2Br)c1=O
Yield: 32.2 %

Procedure:
A solution of 3-[3-bromo-4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0.3 g), 1-methyl-1,4-dihydro-5H-tetrazol-5-one (0.06 g) and potassium carbonate (0.16 g) in N,N-dimethylformamide (10 mL) was stirred for 3 hours at room temperature. After the reaction mixture was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{2-bromo-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-4-methyl-1,4-dihydro-5H-tetrazol-5-one (0.1 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=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.CCOC(C)=O>[C:10]1([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cccc(Br)n1
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: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of commercially available 6-bromopicolinaldehyde (3.000 g; 16.12 mmol), phenylboronic acid (3.009 g; 24.19 mmol), and Pd(PPh3)4 (931 mg; 0.80 mmol) in toluene (40 ml) and aq. 2 M Na2CO3 (34 ml) was heated to reflux, under nitrogen, for 4 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded 6-phenylpicolinaldehyde as a pale yellow oil. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 184.17 g/mol.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][C:17]([I:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH2:24]>C(O)(C)(C)C>[F:1][C:2]1[C:19]([F:20])=[CH:18][C:17]([I:21])=[CH:16][C:3]=1[C:4]([C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][NH:24][N:23]([CH3:22])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:5]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(I)cc(F)c1F
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=CNN(C)C(=O)OC(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
A solution of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-2-propenoate (Preparation 21, 7.80 g) in tert-butanol (40 mL) is cooled with a cold water bath and a solution of tert-butyl 1-methylhydrazinecarboxylate (2.92 g) in tert-butanol (4 mL) is added. The cooling bath is removed, the mixture is stirred for 5 min at ambient temperature, and then is heated in an oil bath at 45° C. for 40 min. The reaction mixture is poured into 100 mL of crushed ice/water and extracted two times with ethyl acetate. The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude product is purified by chromatography, using 300 g of silica gel, packed and eluted with EtOAc/heptane (1/3), to afford 8.95 g (92%) of the title compound as a yellow oily foam. Physical characteristics: 1H NMR (CDCl3) δ8.14, 8.07, 7.59-7.49, 7.46-7.41, 4.07, 3.30, 3.26, 1.50, 1.09, 0.97; MS (ESI+) m/z 511 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[N:7]=[C:6]([C:13]3[O:14][CH:15]=CC=3)[CH:5]=[CH:4][C:3]1=2.[O:18]=[O+][O-].O=O.CSC.CI.C([O-])([O-])=O.[K+].[K+]>CO.CN(C=O)C.O>[CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[N:7]=[C:6]([C:13]([O:14][CH3:15])=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: O=[O+][O-]
Reactant: CC1CCC(C)c2nc(-c3ccco3)ccc21
Agent: O=C([O-])[O-]
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc2c(n1)C(C)CCC2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,8-Dimethyl-2-(2-furyl)-5,6,7,8-tetrahydroquinoline (3 g) was dissolved in 100 ml of methanol. Ozone generated from oxygen at -78° C. was introduced into the obtained solution for 10 minutes. The resulting system was saturated with nitrogen gas, followed by the addition of 7 ml of dimethyl sulfide. The temperature of the mixture was raised to room temperature and the resulting reaction mixture was concentrated to give about 3 g of a crude product. This crude product containing a carboxylic acid was dissolved in 10 ml of DMF, followed by the addition of 1 ml of methyl iodide and 3.6 g of K2CO3. The obtained mixture was stirred at room temperature for one hour, followed by the addition of 30 ml of water. The obtained mixture was extracted with ethyl acetate (50 ml×2) and the organic phase was washed with a saturated aqueous solution of common salt, dried over MgSO4 and concentrated. The obtained mixture was purified by column chromatography to give 1.6 g of the objective compound.
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[S:15]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:1]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1)(=[O:17])(=[O:16])[CH3:14]
Reactant: OCCCCC1Cc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC1Cc2ccccc21
Yield: 96 %

Procedure:
4-(benzocyclobutan-1-yl)-butyl mesylate was prepared, in a yield of 96%, by treating 4-(benzocyclobutan-1-yl)butanol (oil) with CH3SO2Cl in the presence of triethylamine in methylene chloride.