Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH3:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[NH:38]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:37]3[NH:38][C:39]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[C:32]([CH3:31])[CH:40]=4)=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(n1)c(I)cn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ncc(Br)nc34)[nH]c2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
A solution of 2-bromo-7-iodo-5-trityl-5H-pyrrolo[2,3-b]pyrazine (6) (100 mg, 0.1766 mmol), 6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (7) (47 mg, 0.1766 mmol) in acetonitrile (5 mL) was added cesium carbonate (115.74 mg, 0.3532 mmol). The resulting reaction mixture was degassed, purged with nitrogen for 10 min followed by the addition of Pd(PPh3) Cl2.DCM (7.06 mg, 0.0088 mmol) to the reaction mixture, which was again degassed, purged with nitrogen for another 15 min. The final reaction mixture was stirred for 2 h at 90° C. in a seal tube. After completion of the reaction, the contents were allowed to cool to RT and was diluted with DCM (25 mL) and filtered through Celite bed. The organic layer was concentrated to get the crude. The resulting oil was purified by flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 27% ethyl acetate in hexane to afford pale yellow solid (30 mg) of compound 2-bromo-7-(6-methyl-1H-indol-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazine (8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].S(F)([O-])(=O)=O.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=C[OH2+])[CH3:17].O.[OH-].[K+]>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[N:10][NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH3:17]
Reactant: CCOC(=O)CN1CCCCC1=C[OH2+]
Reactant: NNc1ccc(Cl)cc1Cl
Agent: O=S(=O)([O-])F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CN1CCCCC1=NNc1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 17.7 parts of 2,4-dichlorophenylhydrazine in methylene chloride was added dropwise to the above reaction mixture containing [1-(2-ethoxy-2-oxoethyl)piperidin-2-ylidene]methyloxonium fluorosulfate while keeping the temperature of the reaction less than 30° C. After the addition was completed the reaction was stirred for an additional 30 minutes. The reaction mass was then poured into 1000 parts of water. The pH was raised to 12.0 with 20% potassium hydroxide solution. The crude product was extracted with three successive portions of 1000 parts of methylene chloride. The organic extracts of the product were dried over anhydrous sodium sulfate. The solution of the product was filtered to remove the drying agent. The solvent was removed at a reduced pressure of 50-300 mm with a rotary evaporator leaving the crude product which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[NH:10][C:11](=[O:13])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.O>CN(C)C=O>[CH:19]1([CH2:22][O:13][C:11]2[N:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[N:10]=2)[CH2:21][CH2:20]1
Reactant: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(OCC3CC3)nc3sccc23)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 500 mg of 4-phenyl-1,2 -dihydrothieno[2,3-d]pyrimidin-2-one in 10 ml of dimethylformamide is added 100 mg of 63 % sodium hydride. After stirring at 60°C for 1 hour, 590 mg of cyclopropylmethyl bromide is added dropwise thereto. The mixture is heated at 120°C for 4 hours, then cooled to room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-(cyclopropylmethoxy)-4-phenylthieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 86.5°- 87.5°C. From the second fraction 1-cyclopropylmethyl-4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 191° - 191.5°C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH3:87][O:88][C:89](=[O:93])[C@H:90]([CH3:92])[NH2:91]>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:91][C@@H:90]([CH3:92])[C:89]([O:88][CH3:87])=[O:93])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: COC(=O)[C@H](C)N
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 162.4 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (533 mg) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with L-alanine methyl ester hydrochloride (283 mg) in a similar manner as described in Example 24-(i) to give the titled compound (604 mg) as a colorless powder.
Reaction SMILES: Cl.Cl.CNN(NC)C(N)=[N:7][S:8][CH2:9][CH2:10][CH3:11].C[CH2:16][N:17]([CH:21](C)C)[CH:18](C)C.C1C(C[Cl-]C([O-])=O)=CC=C([N+:35]([O-])=O)C=1.O>C(Cl)Cl>[CH3:21][N:17]([CH3:16])[C:18]([NH2:35])=[N:7][S:8][CH2:9][CH2:10][CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCSN=C(N)N(NC)NC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCSN=C(N)N(C)C
Temperature: 0 °C
Yield: 126.9 %

Procedure:
N,N-Dimethylaminopropyl thioguanidine dihydrochloride (1.71 mmol, 400 mg) was suspended in dry DCM and cooled to 0° C. under N2 atm. DIEA (6.0 mmol, 775 mg) was then added over 5 min. and the mixture stirred until it became homogeneous (5-10 min). A solution of 4-nitrobenzylchloroformate (2.05 mmol, 445 mg) in dry DCM (10 mL) was then added via syringe over 15 minutes and the resulting mixture was allowed to warm to rt overnight. The crude reaction mixture was then washed with DI water and 50% brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the resulting residue by column chromatography on silica get with 9:1 ACN:DI water afforded the desired product (106, 350 mg, 40% yield) as a white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CC2CCNC2)CC1

Procedure:
tert-Butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]pyrrolidine-1-carboxylate (440 mg) was stirred in a mixture of trifluoroacetic acid (5 ml) and dichloromethane (10 ml) for one hour at room temperature. The reaction mixture was concentrated in vacuo to give the title compound as a trifluoro acetate salt (350 mg).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:11]=1>CO>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[N:11]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:23])=[O:4])[O:14][N:13]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2OC)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1noc(CCCCC(=O)O)n1
Reaction time: 3 h
Yield: 101.6 %

Procedure:
Add 2 N sodium hydroxide (20 mL) to a solution of 5-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]pentanoic acid methyl ester (4.00 g, 13 mmol) in methanol (100 mL) at room temperature under nitrogen and stir the mixture for 3 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL) and wash with diethyl ether (200 mL). Adjust the aqueous layer to pH 1 with 2 N HCl and collect the solids by vacuum filtration to afford 5-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]pentanoic acid (3.65 g, 99%). APCI mass spectrum m/z 275 [C14H16N2O4−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])[C:12]([O:23][CH3:24])=[C:11]([C:25]([N:27]2CCS[C:28]2=S)=[O:26])[CH:10]=1)[CH3:2].CN.C(O)(C)C.CO>ClCCl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])[C:12]([O:23][CH3:24])=[C:11]([C:25](=[O:26])[NH:27][CH3:28])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1cc(C(=O)N2CCSC2=S)c(OC)c(C(=O)N2CCSC2=S)c1
Agent: CN
Solvent: CO
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1cc(C(=O)NC)c(OC)c(C(=O)N2CCSC2=S)c1

Procedure:
To a solution of compound 6B (2.3 g, 4.25 mmol) in dichloromethane, a mixture of 0.2 mL methylamine solution (40% wt in water, d=0.902) and 10 mL isopropanol was added dropwise over 24 h, the completeness of reaction was monitored by TLC. The reaction mixture was then directly applied onto a gradient flash silica column (1-5% methanol in dichloromethane). The desired product was obtained as a thick, yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[N:6]=1.[Br:21]Br>CC(O)=O>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:21])[CH:8]=[C:7]([O:11][CH2:12][P:13]([O:15][CH2:16][CH3:17])([O:18][CH2:19][CH3:20])=[O:14])[C:5]=2[N:6]=1
Reactant: CCOP(=O)(COc1cccc2sc(N)nc12)OCC
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOP(=O)(COc1cc(Br)cc2sc(N)nc12)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-amino-4-(diethylphosphonomethyloxy)benzothiazole (1 mmole) in AcOH (6 mL) was cooled to 10° C. and treated with bromine (1.5 mmole) in AcOH (2 mL). After 5 min the mixture was stirred at room temperature for 2.5 h. The yellow precipitate was collected via filtration and washed with CH2Cl2 to give 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1>O1CCCC1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:49]2[CH:50]=[CH:51][C:46]([O:45][CH3:44])=[CH:47][CH:48]=2)[CH2:4][O:3]1
Reactant: COc1ccc(O)cc1
Reactant: CC1(C)OCC(CCCCO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OCCCCC2COC(C)(C)O2)cc1

Procedure:
1.74 g (10 mmol) of 2,2-dimethyl-4-hydroxybutyl-1,3-dioxolane from Example 1a, 3.41 g (13 mmol) of triphenylphosphine, 2.26 g (13 mmol) of diethyl azodicarboxylate and 3.72 g (30 mmol) of 4-methoxyphenol were dissolved in 30 ml of absolute tetrahydrofuran (THF) and boiled under reflux for 1 h. The solvent was removed by distillation, and the residue was chromatographed on silica gel using ethyl acetate (EA)/n-heptane (1:4).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].[NH2:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:5][C:3]1([C:2]([F:7])([F:6])[F:1])[NH:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:4]1
Reactant: CC(=O)C(F)(F)F
Reactant: NC(CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
55.13 g (492.0 mmol) of 1,1,1-trifluoroacetone in toluene (1.35 l) were admixed with 45 g (328.0 mmol) of rac-2-amino-2-phenylethanol and 8.24 g (32.8 mmol) of pyridinium p-toluenesulphonate. The reaction mixture was boiled under reflux on a water separator for 16 h. The mixture was cooled to 0° C., and the solids formed were filtered off and dried under high vacuum. This gave 68.6 g (77% of theory, purity 85%) of the target compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[CH:8]=1.[CH3:19][O-:20].[Na+]>C(OCC)C.C(OCC)(=O)C>[CH3:19][O:20][C:1](=[O:5])[C:2]([C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[CH:8]=1)=[O:3]
Reactant: c1cc2c3c(c1)ccn3CCC2
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 83.8 %

Procedure:
Add oxalyl chloride (1.05 mL, 12.08 mmol) dropwise to a solution of 5,6dihydro-4H-pyrolo[3,2,1-ij]quinoline (1.67 g, 10.6 mmol) in 150 mL of anhydrous diethyl ether at 0° C. and stir the resulting solution at 0° C. for 40 minutes. Cool the mixture to −78° C. and slowly add sodium methoxide (42 mL, 21 mmol, 0.5 M in methanol). Upon completion of the addition, remove the dry ice bath and allow the reaction to warm to 20-24° C. over 2 hours. Dilute the mixture with ethyl acetate (200 mL), wash with water (100 mL) and separate the layers. Wash the organic layer with saturated aqueous sodium chloride (50 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure. Dissolve the residue in ethyl acetate (100 mL), filter through a 2 inch plug of coarse silica gel, and concentrate under reduced pressure to give the title compound as a yellow solid (2.16 g, 84%).
Reaction SMILES: [CH:1]1([CH2:10][CH:11]=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH:1]1([CH2:10][CH:11]=[N:14][OH:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NO
Reactant: O=CCC1C=Cc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=CCC1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-indene-1-yl)acetaldehyde (1.5 g, 9.5 mmol), hydroxylamine hydrochloride (836 mg, 12.0 mmol), and sodium acetate (1.04 g, 12.7 mmol) were combined in methanol (50 ml) and stirred at ambient temperature overnight. The mixture was evaporated to dryness in vacuo and the residue treated with water and extracted with ether. The ether layer was washed with water, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel coulmn eluted with 15% EtOAc in hexane followed by 22% EtOAc in hexane. The product fraction was evaporated to dryness in vacuo to provide 2-(1H-indene-1-yl)acetaldoxime.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1
Reactant: CCCC(C)CBr
Reactant: COc1ccc(O)cc1
Solvent: CO
Product: CCCC(C)COc1ccc(OC)cc1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
Sodium metal (6.99 g, 304 mmol) was dissolved in dry methanol (120 ml) under Ar to give a 2.5M solution of sodium methoxide. A solution of 4-methoxyphenol (31.4 g, 253 mmol) in dry methanol (150 ml) was added and this mixture was heated to reflux for 30 min. After cooling to room temperature, a solution of 1-bromo-2-methylpentane (46.0 g, 279 mmol) in dry methanol (100 ml) was added. The mixture was then heated to reflux for 16 hours. The solvent was removed in vacuo, the residue dissolved in ether (200 ml), washed with dilute aqueous sodium hydroxide (250 ml) and water (500 ml), dried over MgSO4 and concentrated in vacuo again. Distillation at 80° C./0.5 mm Hg afforded 14.0 g (27%) 1-methoxy-4-(2'-methylpentyloxy) benzene, 1H NMR (250.1 MHz, CDCl3): δ=0.94(t,3H), 1.02 (d, 3H), 1.16-1.56 (m, 4H), 1.93 (m, 1H), 3.64-3.82 (m, 2H), 3.77 (s, 3H), 6.81-6.89 (m, 4H), 13C NMR (100.6 MHz, CDCl3): δ=14.3, 17.0 (both CH3), 20.1, 35.8 (both CH2), 33.0 (CH), 55.7 (OCH3), 73.9 (OCH2), 114.6, 115.4 (arom. CH), 153.5, 153.6 (ipso C). IR(film): 2956(m), 1509(s), 1232(s), 1045(m), 824(m) cm-1, MS(EI): m/z (%)=208 (100), 124 (32), Calcd. for C13H20O2 : C 74.96, H 9.68 found: C 75.03, H 9.70.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:15].[Na+].I[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1([O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1
Reactant: CCCCCI
Reactant: [OH-]
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CCCCCOC1(Br)C=CC(c2ccccc2)=CC1
Temperature: 90 °C
Reaction time: 3.75 h

Procedure:
4-Bromo-4′-hydroxybiphenyl (12.5 g 50.2 mmol) was added to a solution of NaOH (2.28 g, 97% pure, 55.2 mmol) in deionized H2O (150 ml). followed by the addition of 1-iodopentane (11.9 g, 60.2 mmol) and tetrabutylammonium bromide (0.82 g. 2.51 mmol). The mixture was stirred at 90° C. for 3.75 h until the solids went into solution. Then, as the reaction proceeded, the desired product began to precipitate. The mixture was slowly cooled and then filtered to provide a solid which was washed with deionized water until the pH of the filtrate was neutral and then dried for 16 h in a vacuum oven at 30° C.
Reaction SMILES: [CH3:1][S:2][CH:3]([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:19]I.O>O1CCCC1>[CH3:1][S:2][C:3]([CH3:19])([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5]
Reactant: CI
Reactant: CSC(C)C(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSC(C)(C)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 59.5 %

Procedure:
To 2.02 g of 2-methylthio-4'-(trifluoromethyl)propiophenone dissolved in 20 ml of tetrahydrofuran was added under ice-cooling 0.33 g of a 60% aqueous solution of sodium hydride, and the mixture was reacted at room temperature with stirring until no bubbles were produced. After an addition of 1.27 g of methyl iodide, the mixture was stirred at room temperature for a further 2 hours. The resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography using n-hexane to obtain 1.27 g of an oily product of 2-methylthio-4'-(trifluoromethyl)isobutyrophenone (yield: 59.5%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:17][C:18]1[S:19][C:20](Cl)=[N:21][N:22]=1>C(O)C>[NH2:17][C:18]1[S:19][C:20]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[N:21][N:22]=1
Reactant: Nc1nnc(Cl)s1
Reactant: CCCCNCCCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)c1nnc(N)s1

Procedure:
28 parts of dibutylamine and 25 parts of triethylamine are added to 27 parts of 2-amino-5-chloro-1,3,4-thiadiazole in 200 parts of ethanol. The reaction mixture is heated under reflux for 2 hours and then concentrated to dryness. The residue is suspended in 250 ml of water and filtered. The 2-amino-5-dibutylamino-1,3,4-thiadiazole obtained in this manner can be recrystallised from ethanol/water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[N:9])[S:5][C:6]=1Br.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([CH3:20])[CH:12]=1.O1[CH2:26][CH2:25]OCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[C:4]([C:8]#[N:9])[S:5][C:6]=2[C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][C:25]=2[CH3:26])=[C:13]([CH3:20])[CH:12]=1
Reactant: N#Cc1cc(Br)c(Br)s1
Reactant: C1COCCO1
Reactant: Cc1cc(Cl)ccc1B(O)O
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: O
Product: Cc1cc(Cl)ccc1-c1cc(C#N)sc1-c1ccc(Cl)cc1C
Temperature: 90 °C
Yield: 84 %

Procedure:
A round-bottomed flask was charged with 4,5-dibromothiophene-2-carbonitrile (534 mg, 2.00 mmol), 4-chloro-2-methylphenylboronic acid (818 mg, 4.80 mmol) and Pd(PPh3)4 (136 mg, 0.10 mmol). After degassed, dioxane (10 mL) and aqueous sodium carbonate (5 mL, 2M, 10 mmol) was added. The reaction mixture was heated to 90° C. The progress of the reaction was monitored by TLC. After the reaction was complete, 50 mL of water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:CH2Cl2=2:1). 0.60 g (84%) of product was obtained as clear oil.
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]([C:8]([O:10][CH2:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1)=[O:9])[CH2:6][CH3:7])[CH3:4].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C(Cl)Cl.C(Cl)Cl.CO.[NH4+].[OH-]>[CH3:39][O:38][C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([O:26][CH3:25])[C:35]=1[O:36][CH3:37])[C:30]([N:16]1[CH2:15][CH2:14][NH:13][CH:12]([CH2:11][O:10][C:8]([N:5]([CH2:6][CH3:7])[CH2:3][CH3:4])=[O:9])[CH2:17]1)=[O:31]
Reactant: CCN(CC)C(=O)OCC1CNCCN1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)OCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Yield: 53.2 %

Procedure:
19.86 g (86 mmol) of 2-(N,N-diethylaminocarbonyloxymethyl)piperazine dihydrochloride prepared in accordance with step 2.2 of Example 2 are dissolved in 400 ml of CH2Cl2 and 42 ml (3.5 equivalents) of triethylamine in a 1 liter ground-necked conical flask on which is fitted an addition funnel, and which is immersed in an ice bath. A solution containing 19.83 g (86 mmol) of 3,4,5-trimethoxybenzoyl chloride in 200 ml of CH2Cl2 is added dropwise to the solution thus obtained. The reaction is monitored by thin-layer chromatography, using a CH2Cl2/MeOH/NH4OH mixture (80/20/0.5 v/v/v) as eluent, until the starting amine has disappeared. The solution is then washed with saturated NaHCO3 solution and then with water until a neutral pH is obtained. The organic phase is then dried (MgSO4), filtered and evaporated and the residue obtained is chromatographed on a column of silica gel with an MeOH/CH2Cl2 mixture (1/99 v/v) as eluent. 18.75 g of 4-(3′,4′,5′-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine are thus obtained in the form of a viscous oil. Yield: 53.33%.