Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](F)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:25]#[N:26].[Na+].O.C(OCC)C>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:25]#[N:26])=[C:11]([C:14]([F:15])([F:17])[F:16])[C:10]([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1-c1ncccc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
1.95 g (5.1 mmol) of 3-chloro-2-[5-fluor-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine and 0.30 g (6.1 mmol) of sodium cyanide are suspended in 20 ml of acetonitrile and the reaction mixture is then stirred under reflux for 16 hours. After cooling, the reaction mixture is poured onto a water/diethyl ether mixture. The aqueous phase is extracted three times with diethyl ether. The combined organic phases are washed twice with water and once with saturated sodium chloride solution and then dried over magnesium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. The crude product is purified by means of flash chromatography on silica gel. This gives 1.7 g of 3-chloro-2-[5-cyano-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine (84%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH3:1].[NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2-c2cn[nH]c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N
Product: c1nc2c(c(-c3cn[nH]c3)n1)CCNC2
Reaction time: 3 h
Yield: 41 %

Procedure:
To the product of Example 4, step a (81 mg, 0.27 mmol) in DCM (3 mL) was added TFA (0.27 mL). After stirring 3 h the mixture was concentrated in vacuo and loaded directly on a column. Chromatography on SiO2 eluting with 2 M NH3 in MeOH/DCM afforded the desired product as a white solid (22 mg, 41%). MS (ESI) mass calcd. 201.10. m/z found 202.0 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(C(=O)O)cc3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 4-hydrazino-benzoic acid according to example 43 gave the desired product. MS: M=437.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][S:14]([O:11][CH2:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[CH:6][C:7]=1[F:12])(=[O:16])=[O:15]
Reactant: N#Cc1cc(F)c(CO)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(F)c(C#N)cc1F
Temperature: 0 °C

Procedure:
To an ice cooled solution of 2,5-difluoro-4-hydroxymethylbenzonitrile (3.10 g, 0.0183 mol; see step (iii) above) and methanesulfonyl chloride (2.21 g, 0.0192 mol) in 60 mL of methylene chloride was added triethyl amine (1.95 g, 0.0192 mol) with stirring. After 1.5 h at 0° C. the mixture was washed with water, dried (Na2SO4) and evaporated. The product could be used without further purification. Yield: 4.5 g (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:5][NH:6][C:7]1[C:8]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:9]=2[N:10]=[C:11]([CH2:13]Cl)[N:12]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].CCOCC.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CN(C=O)C.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:5][NH:6][C:7]1[C:8]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:9]=2[N:10]=[C:11]([CH2:13][NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:12]=1
Reactant: NCCCO
Reactant: COc1ccc(CNc2nc(CCl)nc3sc4c(c23)CCCC4)cc1Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(CNCCCO)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
A solution of 2 g of 4-(3-chloro-4-methoxybenzylamino)-2-chloromethyl-5,6,7,8 tetrahydrobenzothieno[2,3-d]pyrimidine in 10 ml of DMF is treated with 5 ml of 3-aminopropanol and heated at 80° for one hour. It is then diluted with water and extracted with ethyl acetate. The crystalline product obtained after customary work-up is dissolved in alcoholic HCl and treated with ether until turbidity. 2.1 g of 4-(3-chloro-4-methoxybenzylamino)-2-(3-hydroxypropylaminomethyl)-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine are obtained in the form of its dihydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][O:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCOc1ccc(C=O)cc1
Yield: 98.8 %

Procedure:
A solution of 5.0 grams (0.041 mole) of 4-hydroxybenzaldehyde, 9.5 grams (0.041 mole) of p-toluene sulfonic acid 2-methoxyethyl ester, and 6.3 grams (0.046 mole) of anhydrous potassium carbonate in 50 mL of dimethylsulfoxide (DMSO) was stirred at ambient temperature for about 72 hours. The reaction mixture was then partitioned between 300 mL of an aqueous mixture of 10% lithium chloride and 100 mL of ethyl acetate. The ethyl acetate portion was washed three times; first, with 100 mL of an aqueous mixture of 10% sodium hydroxide, second, with 100 mL of an aqueous mixture of 10% lithium chloride, and, third, with 100 mL of brine. The resultant organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 7.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:25]=[C:26]([CH:34]([N:36]5[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]5)[CH3:35])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)=[O:22])=[CH:16][C:15]=3[F:49])[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:49][C:15]1[CH:16]=[C:17]([NH:20][C:21](=[O:22])[NH:23][C:24]2[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([CH:34]([N:36]3[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]3)[CH3:35])[CH:25]=2)[CH:18]=[CH:19][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH:12]=1
Reactant: CC(c1cc(NC(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)c(F)c2)cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1cc(NC(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)c(F)c2)cc(C(F)(F)F)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Dissolve the compound obtained in Step 1 (230 mg, 0.33 mmol) in DCM (15 mL), add trifluoroacetic acid (400 mg), stir at room temperature for 2 hrs. Remove the volatiles, partition the residue in EtOAc and saturated NaHCO3 solution, and separate the organic layer, dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=3:1) affords the title compound (173 mg, 88.3%). MS: (M+1): 588.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25](O)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2n1C
Reactant: C1CCNC1
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CCCC3)cc2n1C
Yield: 39 %

Procedure:
The title compound was prepared as a colorless amorphous in 39% yield (45 mg) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (100 mg, 0.27 mmol, STEP 2 of Example 19) and pyrrolidine (38 mg, 0.53 mmol) by the same manner in STEP 3 of Example 11.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](O)[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([Cl:21])[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1cc(O)nc(SCc2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1cc(Cl)nc(SCc2ccccc2)n1
Temperature: 20 °C

Procedure:
A mixture of 72 g (0.28 mole) of 2-benzylthio-4-hydroxy-6-n-propylpyrimidine (from Part A) and 100 ml of phosphorus oxychloride was heated at reflux for three hours, and was then allowed to cool to 20° C. After evaporating in vacuo the residue was poured into ice water with vigorous stirring. The mixture was extracted with three 75 ml portions of diethyl ether, and the extracts were dried over magnesium sulfate and evaporated to provide a yellow oil residue of 2-benzylthio-4-chloro-6-n-propylpyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([O:16][CH3:17])=[O:15])[NH:7][N:6]=1)=[O:4].N1C=CC=N1.[H-].[Na+].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:25]([N:7]1[C:8]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1C(=O)OC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The synthesis of this compound was done by tritylation of trimethyl-3,4,5-pyrazoletricarboxylate (1680 mg, 6.94 mmol) using a procedure similar to the one described in examples 2 and 3 for the synthesis of other tritylated pyrazole derivatives. The starting pyrazole reacted with sodium hydride (405 mg, 10.13 mmol) in dry dimethylformamide (80 mL) for 30 min at room temperature. Then, trityl chloride (1935 mg, 6.94 mmol) was added and the reaction mixture stirred overnight at room temperature. After removal of the solvent under vacuum, the resulting residue was washed with distilled water, n-hexane, and finally dried under vacuum to afford the title compound, as a white microcrystalline solid. Yield: 90% (3.034 g, 6.26 mmol).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[N+:23]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])=S.[Na+].[Na+]>C(O)C.O>[CH2:1]([NH:8][C:9]1[C:10]([NH2:23])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cccc1OCc1ccccc1
Agent: [Na+]
Agent: [O-]S([O-])=S
Solvent: O
Solvent: CCO
Product: Nc1c(NCc2ccccc2)cccc1OCc1ccccc1
Yield: 91.5 %

Procedure:
A solution of benzyl-(3-benzyloxy-2-nitro-phenyl)-amine (8.116 g, 24.3 mmol) in 500 mL ethanol was added to a solution of sodium thiosulfite (29.0 g, 162.8 g.) in 350 mL water at 100° C. while stirring. The reaction mixture was heated for 30 minutes at this temperature, and then cooled and concentrated in vacuo. The off-white solid which precipitates was filtered and dried overnight under a stream of nitrogen to give 6.77 g (22.24 mmol, 91.5%) of N*1*-Benzyl-3-benzyloxy-benzene-1,2-diamine. MS: 305 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].C(N(CC)CC)C.[Cl:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([F:19])=[C:14](Cl)[N:13]=1>CO>[Cl:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([F:19])=[C:14]([NH:2][NH2:3])[N:13]=1
Reactant: NN
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: NNc1nc(Cl)nc(Cl)c1F
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To hydrazine monohydrate (289 μL, 5.96 mmol) and triethylamine (830 μL, 5.96 mmol) in MeOH (15 mL) was added a solution of 2,4,6-trichloro-5-fluoropyrimidine (1.0 g, 4.96 mmol) in MeOH (15 mL), and the mixture was stirred overnight. When the reaction was complete as determined by LCMS, the solution was concentrated in vacuo, and the resulting crude product was purified by RP-HPLC to provide 2,4-dichloro-5-fluoro-6-hydrazinopyrimidine (358 mg, 32%). LCMS: (M+H)+: 196.9.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:3]1([CH2:2][CH2:1][NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NCCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NCCC1CCCCC1

Procedure:
Phenethylamine (50 g) was dissolved in 1000 mL of glacial acetic acid in a pressure vessel, followed by addition of platinum oxide (15 g). After shaking under 4 atm of hydrogen for 48 h, the reaction was filtered and the acetic acid was removed under reduced pressure. The residue was taken up in water (1000 mL), basified with 5N NaOH, and washed with ether (5×250 mL). The ether extracts were washed with brine (250 mL), dried (MgSO4), filtered and concentrated to afford a light yellow oil which was purified by fractional distillation at atmospheric pressure (bp 185° C., 49.5 g, 94%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][C:15](=[O:19])[NH:16]2)=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(NC(=O)c3ccncc3)cc2N1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1Cc2cc([N+](=O)[O-])c(NC(=O)c3ccncc3)cc2N1
Reaction time: 2 h

Procedure:
5.5 g. (21.7 mMol) 6-isonicotinoylaminoindolin-2-one are dissolved portionwise in 20 ml. concentrated sulphuric acid, cooled with ice and 2.19 g. (21.7 mMol) potassium nitrate dissolved in concentrated sulphuric acid slowly added dropwise thereto. After 2 hours, the solution is poured on to ice, neutralised and filtered with suction. The residue is substantially dissolved in 2N hydrochloric acid, filtered, treated with Floridin (fullers' earth), filtered with suction and neutralised. There are obtained 4.5 g. (70% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=1
Reactant: Cc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Yield: 69.9 %

Procedure:
2′,4′,6′-Trimethylbiphenyl-3-carbaldehyde (2.36 g, 10.5 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (0.40 g, 10.6 mmol) was added to this solution. After stirring under ice-cooling for 3 hr, aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-1:2) to give the title compound (1.66 g, yield 70%) as a colorless oil.
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[C:20](=[O:28])[CH:19]=1)[C:12](OCC)=O)=[O:10]>CO.O>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[C:20](=[O:28])[CH:19]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCCCn1ccc(CC(C=O)C(=O)OCC)cc1=O
Agent: [Na]
Solvent: CO
Solvent: O
Product: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Temperature: 0 °C

Procedure:
To a stirred solution of sodium (6.77 g) in methanol (120 ml) was added nitroguanidine (27.25 g. containing 25% water) and methanol (30 ml). The mixture was refluxed for 45 minutes and then was added dropwise ethyl α-formyl-β-(N-n-butyl-2-oxo-4-pyridyl)propionate (54.85 g) in methanol (150 ml) over 90 minutes. The reaction mixture was refluxed for 23 hours and evaporated under reduced pressure to give an oil. This oil was dissolved in water (200 ml) and extracted with chloroform (3×65 ml). The combined chloroform extracts were washed with water (2×35 ml). The combined aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid whereupon a brown oil came out of solution. This was dissolved with warming in isopropanol (75 ml) and cooled at 0° C. overnight to yield after filtration, washing and drying in vacuo 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one as a solid (19.46 g), recrystallisation from aqueous acetic acid gave material with m.p. 198°-201° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:3]=1.[CH3:15][N:16]1[CH2:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH3:14][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=3)[N:6]([CH3:7])[N:5]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(C)n1-c1cc(Br)n(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1-c1cc(C2=CCN(C)CC2)n(C)n1
Yield: 67.7 %

Procedure:
Under argon atmosphere, to a mixture of 5-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole (100 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (105 mg), and N,N-dimethylformamide (2 mL) were added a 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (32 mg), and cesium carbonate (256 mg), followed by reacting them at 80° C. for 1 hour. After leaving to be cooled, ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 4-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazol-5-yl]-1-methyl-1,2,3,6-tetrahydropyridine (72 mg) as a brown oily substance.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH:7][CH2:8][N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.[CH2:22]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:16]1([N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:7]=[CH:6][CH2:5][N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(=O)OCC=CCN(c1ccccc1)c1ccccc1
Product: C(=CCN(c1ccccc1)c1ccccc1)CN(Cc1ccccc1)Cc1ccccc1

Procedure:
Following the general procedure of Example 11 by replacing 1-acetoxy-4-dibenzylamino-2-butene with 1-acetoxy-4-diphenylamino-2-butene and replacing dicyclohexylmethylamine with dibenzylamine, the title compound is obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[S:14][C:13]=3[CH:12]([OH:24])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[S:14][C:13]=3[C:12](=[O:24])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1CCCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.6 %

Procedure:
The reaction mixture was quenched with saturated sodium bisulfite then was cooled to rt and insoluble materials were removed by filtration. The pH of the filtrate was adjusted to 9 by the addition of a saturated NaHCO3 solution and the organic layer was separated. To the aqueous layer was added saturated NH4Cl solution (5 mL) and it was then extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The obtained residue, 4-(4-chlorophenyl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-8-ol (3.17 g, 8.30 mmol), was dissolved in methylene chloride (1217 mL, 580 mmol) and Dess-Martin periodinane (3.9 g, 9.20 mmol) was added. The reaction mixture was stirred for 16 h at rt. The reaction mixture was neutralized to pH ˜7 by the addition of NaHCO3, the organic layer was separated, and the aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The obtained residue was purified by column chromatography (SiO2, elution with 0-100% EA/hexane) to give the title compound as a white solid (1.34 g, 50% yield). LCMS: (AA) ES+ , 354. 1H NMR (400 MHz, DMSO-d6) δ: 8.51-8.54 (dd, J=1.5 Hz, J=4.5 Hz, 2H), 8.12-8.18 (m, 1H), 7.51-7.54 (dd, J=1.5 Hz, J=4.5 Hz, 2H), 7.34-7.38 (m, 2H), 7.15-7.17 (br s, 2H), 7.13-7.14 (br s, 1H), 4.26-4.31 (m, 1H), 3.10-3.28 (m, 1H), 2.05-2.15 (m, 1H), 1.80-1.90 (m, 2H), 1.50-1.72 (m, 2H).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[CH2:9]Br.C(=O)(O)[O-].[Na+].[CH2:21]([C:28]1[NH:29][C:30]2[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:34]=[CH:33][C:31]=2[N:32]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(OCC)(=O)C>[CH2:21]([C:28]1[N:32]([CH2:9][C:8]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:7]=2[Cl:6])[C:31]2[CH:33]=[CH:34][C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:30]=2[N:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: CCOC(=O)c1ccc2nc(Cc3ccccc3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 14 %

Procedure:
N,N-dimethylformamide (15 ml), 2,4-dichlorobenzyl bromide (4.45 g) and sodium bicarbonate (1.23 g) are added to 2-benzyl-5-ethoxycarbonyl-benzimidazole (2.37 g) (example 11) and the solution is heated for one hour at 60° C. After adding ethyl acetate (70 ml) and water (70 ml) and separating the solution, the organic layer is washed with water three times and extraction is performed on the aqueous layer using ethyl acetate three times. By concentrating the obtained organic layer under reduced pressure, a mixture of 2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole (0.49 g) and 2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonylbenzimidazole (0.52 g) is obtained. Separation and purification is performed using medium pressure silica gel column chromatography (eluate: hexane/ethyl acetate=1/4˜0/100).