Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].C(O[CH2:27][CH3:28])(=O)C.O1C[CH2:32][CH2:31][CH2:30]1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:30][CH2:31][CH2:32][CH:27]=[CH2:28])=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: CON(C)C(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCCCC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-1-pentene (5 g) was gently heated with magnesium turnings (1 g) in anhydrous tetrahydrofuran (25 mL) until reaction started. The mixture was left to reflux without further heating to give the Grignard reagent, then allowed to cool to room temperature. 2′,4′-Dichloro-biphenyl-4-carboxylic acid methoxy-methyl-amide (2 g) was dissolved in anhydrous tetrahydrofuran (25 mL) and chilled in an ice bath. The above Grignard reagent was added dropwise with vigorous stirring. Following addition, the mixture was allowed to warm to room temperature and stirring continued for 2 hours. Saturated NH4Cl solution (50 mL) was added and the mixture extracted with petrol. Drying with Na2SO4 and evaporation gave an oil. Column chromatography (petrol:ethyl acetate) gave the title compound as a clear oil which solidified overnight. 13C NMR (CDCl3): δ 23.4, 33.3, 37.8, 115.3, 127.4, 128.0, 129.7, 129.9, 131.9, 133.1, 134.5, 136.3, 138.0, 138.4, 142.8 and 199.9. 1H NMR (CDCl3): δ 1.85 (2H, t, J=7.0 Hz), 2.18 (2H, t, J=7.0 Hz), 3.03 (2H, t, J=7.3 Hz), 5.01 (2H, m), 5.87 (1H, m), 7.28 (2H, d, J=8.2 Hz), 7.31 (1H, s), 7.52 (2H, m) and 8.00 (2H, m).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C.CCOC(C)=O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:15]([N:1]2[C:9]3[C:4](=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:16]([O:18][CH3:19])=[O:17])=[CH:25][CH:24]=1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(C=O)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-indole-4-carbaldehyde (2.0 g, 13.79 mmol) in DMF (50 mL) was added NaH (0.66 g, 16.55 mmol) at 0° C. After stirring for 30 min at 0° C., a solution of methyl 2-bromo-2-(4-chlorophenyl)-acetate (4.67 g, 17.92 mmol) in DMF (20 mL) was added dropwise. The reaction was allowed to warm to rt and stirred for an additional 1 hr. Then it was diluted with EtOAc (200 mL) and quenched with water. The organic layer was separated and washed with brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified via column chromatography (0-20% EtOAc/hexanes) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][C:24]([OH:26])=O)[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:26])[CH:17]=1)([OH:15])[C:11]([F:14])([F:12])[F:13]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC(=O)O)c1)C(F)(F)F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC(=O)N2CCOCC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
{4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-pyridin-2-yloxy}-acetic acid (180 mg) and morpholin (0.04 mL) in DMF (6 mL), were treated with 4-methyl-morpholine (0.140 mL) and HBTU (241 mg). The reaction mixture was stirred at r.t. for 17 h. The reaction mixture was diluted with water (50 mL) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 70:30) to give the title compound as white solid (134 mg). MS (m/e)=492.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CN(C)C(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CN(C)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
290 mg of dimethylamine hydrochloride was coupled to 1 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N HCl, 0.1 N NaOH and brine, dried (MgSO4) and evaporated to afford tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate. 1.1 g of tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate was treated with TFA (4 mL) containing trace amounts of H2O for 2 h. The reaction mixture was evaporated, and then added 0.1 N HCl. The resulting solid was filtered and washed with H2O to yield 2-chloro-4-(dimethylcarbamoyl)benzoic acid. 100 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(dimethylcarbamoyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4-dimethylterephthalamide. MS (Q1) 414.1 (M)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([S:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Cn1ccnc1Sc1ccnc(Cl)c1
Yield: 73.7 %

Procedure:
Using the method of Example 3, Step A, 1-methyl-1H-imidazole-2-thiol (720 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(1-methyl-1H-imidazol-2-ylthio)pyridine (1.05 g, 74% yield) as an oil. 1H NMR (CDCl3) δ 8.17 (d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 6.88 (s, 1H), 6.80 (d, 1H), 3.70 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:25]([C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:15][CH:25]([C:29]3[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCC(OS(C)(=O)=O)c1ccc(C(=O)OCC)cc1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (140 mg, 0.585 mmol) in N,N-dimethylformamide (2 mL) was added to a suspension of 60% sodium hydride (27.2 mg, 0.679 mmol) in N,N-dimethylformamide (2 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. A mixture of ethyl 4-(1-(methylsulfonyloxy)butyl)benzoate (0.170 g, 0.566 mmol) in N,N-dimethylformamide (3 mL) was then added at room temperature. The reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-15% ethyl acetate in heptanes) gave ethyl 4-(1-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-ylamino)butyl)benzoate (25.0 mg, 10%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.98-8.05 (m, 4H), 7.67 (d, J=8.19 Hz, 2H), 7.53 (d, J=9.36 Hz, 1H), 7.44 (d, J=8.19 Hz, 2H), 6.57 (d, J=9.36 Hz, 1H), 5.56-5.67 (m, 1H), 4.82-4.93 (m, 1H), 4.34 (q, J=7.22 Hz, 2H), 1.79-2.01 (m, 2H), 1.36 (t, J=7.22 Hz, 3H), 1.28-1.54 (m, 2H), 0.96 (t, J=7.32 Hz, 3H). MS (M+1): 444.1.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=2[Cl:33])=[CH:18][C:14]=1[C:15](Cl)=[O:16].O>CN(C)C=O>[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][C:24]=2[Cl:33])=[CH:18][C:14]=1[C:15]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:16]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[C@@H:12]([NH:20]C(OC(C)(C)C)=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[C@@H:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Reaction time: 1.5 h

Procedure:
2-((S)-2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (2.4 g, 5.919 mmol) was mixed in dichloromethane (25 mL) in an ice-bath. Trifluoroacetic acid (18 mL, 235 mmol) was added and the solution was stirred for 1.5 hours. The reaction mixture was evaporated and the residue was triturated with ether. The suspension was stirred vigorously for 10 minutes and then filtered. The solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvents gave 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as an off white solid (1.58 g, 87%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17].C(N(CC)CC)C>O1CCCC1>[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH:17][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cccc(C)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 25 g of 4-trifluoromethylbenzoyl chloride in tetrahydrofuran was added to 14.5 g of 2,6-dimethylaniline and 16.7 ml of triethylamine in tetrahydrofuran. The reaction was stirred at ambient temperature overnight, chilled, and filtered. The filtrate was evaporated in vacuo and the residue therefrom was dissolved in chloroform, washed sequentially with 1M hydrochloric acid, 1M sodium hydroxide, water, and a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated in vacuo. Crystallization from methanol provided the desired title product in 85% yield, m.p. 206-207° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(O)(=O)C>C(O)C.O.[Zn]>[C:1]([C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc2c1
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4N)nc2c1

Procedure:
In a 100 ml round-bottomed flask under an argon atmosphere, dissolve 1.58 g of an equimolar mixture of 4-(5-cyano-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 10 ml of ethanol and 10 ml of water and 10 ml of acetic acid, at room temperature, add 1.2 g of zinc in three stages, and stir for approximately one hour to two hours between each addition. Add Celite and filter. The filtrate is concentrated under pressure. The crude product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (9/1 by volume) and then a mixture of dichloromethane and ammonia as a 7N solution in methanol (95/5 by volume). In this way, we obtain 1.4 g of 4-(5-cyano-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a white powder, which is used as it is in the following stage.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][C:24]([F:38])([F:37])[F:23])=[CH:29][CH:30]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]([F:19])[F:20])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(difluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-(3,3,3-trifluoropropoxy)benzoic acid obtained in the preparation process of Example 33 (33a) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>C(OCC)(=O)C>[CH3:23][S:24]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:26])=[O:25]
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2)cc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2.00 g (10.1 mmol) of 2-methyl-5-phenylbenzyl alcohol was dissolved in 100 ml of ethyl acetate, and to this solution was added 4.2 ml (30.3 mmol) of triethylamine and the mixture was cooled to 0° C. To the reaction mixture was slowly dropped 1.73 g (15.1 mmol) of methanesulfonyl chloride, and the reaction mixture was controlled to room temperature. After stirring for 1 hours at room temperature, the reaction mixture was made acidic by addition of 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and saturated saline sequentially, dried over anhydrous magnesium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=4/1 (v/v)), to obtain 2.79 g of 2-methyl-5-phenylbenzyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][N+]([O-])=O)[CH:3]=1.S(=O)(=O)(O)[OH:13].NC1C([N+]([O-])=O)=C(Cl)C=CN=1>>[NH2:8][C:4]1[C:3]([OH:13])=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])Nc1cc(Cl)ccn1
Agent: Nc1nccc(Cl)c1[N+](=O)[O-]
Product: Nc1nccc(Cl)c1O

Procedure:
The reaction of 4-chloro-2-nitraminopyridine with concentrated sulfuric acid at 40° gives, according to Example I-2, 2-amino-4-chloro-3-nitropyridine. The procedure of Example I-2 is then followed with this intermediate to give 2-amino-4-chloro- 3-pyridinol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O)(C)(C)C.[ClH:30]>ClCCl.C(OCC)(=O)C>[ClH:30].[ClH:30].[ClH:30].[CH3:29][N:27]([C:24]1[CH:23]=[CH:22][C:21]([C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:26][CH:25]=1)[CH3:28]
Reactant: CN(C)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1ccc([C@H]2CNCCN2)cc1
Reaction time: 8.5 h
Yield: 96 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-(N,N-dimethylamino) phenyl)piperazine (556 mg, 1.37 mmol) in dichloromethane (4 mL) was added 4 N hydrogen chloride in ethyl acetate (4 mL). After stirring for 8.5 h, the white precipitate was collected and dried in vacuo to afford (S)-2-(4-(N,N-dimethylamino) phenyl)piperazine trihydrochloride (413 mg, 96%) as white crystals.
Reaction SMILES: Br[CH2:2]/[C:3](=[C:8](\[CH3:13])/[C:9]([O:11][CH3:12])=[O:10])/[C:4]([O:6][CH3:7])=[O:5].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[CH3:13]/[C:8](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](\[CH2:2][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)/[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)/C(C)=C(/CBr)C(=O)OC
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)/C(C)=C(/CN1CCCCC1)C(=O)OC
Reaction time: 4 h
Yield: 9 %

Procedure:
To a solution of dimethyl 2-bromomethyl-3-methylmaleate (32 mg, 0.13 mmol) in anhydrous dimethylformamide (450 μL) was added piperidine (21 mg, 0.25 mmol) at room temperature, and the mixture was left standing at 50° C. for 4 h. The reaction mixture was directly concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 3:2) to give 3 mg of the title compound as oil (yield: 39%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([N:26]2[CH2:27][CH2:28][N:23]([CH2:13][C:14]3[CH:22]=[CH:21][C:20]4[O:19][CH2:18][O:17][C:16]=4[CH:15]=3)[CH2:24][CH2:25]2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1ccc(O)cc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1ccc(O)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of N-(4-hydroxyphenyl)glycine (11.38 g, 68.1 mmol) in N,N-dimethylformamide (DMF) (150 mL) were added under ice cooling 1-piperonylpiperazine (15.0 g, 68.1 mmol), 1-hydroxybenzotriazole monohydrate (10.43 g, 68.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.66 g, 81.7 mmol), and the resulting solution was stirred for 30 minutes under ice cooling and for 4.5 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution (400 mL), and extracted with ethyl acetate (400 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to leave the resulting product solidified in a powdered form. Ethyl acetate was added, and the resulting product was filtered off and washed with ethyl acetate, to thereby yield 18.58 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[NH2:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11]([NH:26][C:22]2[S:21][CH:25]=[CH:24][N:23]=2)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCOCC1)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)-3-(tetrahydropyran-4-yl)propionic acid (Preparation 46, 10.40 g, 37.2 mmol) was condensed with thiazol-2-ylamine employing the procedure described in EXAMPLE 65 to afford 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=362.1 [M+H]+. The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=332.1 [M+H]+. A solution of NaNO2 (2.11 g, 30.5 mmol) in H2O (20 mL) was added slowly to a stirred mixture of the above aniline (9.40 g, 28.4 mmol), 12M HCl (30 mL), and H2O (30 mL) at 0° C. After 1 h, the resulting diazonium salt solution was added over 15 min to a mixture of CuCl2.2H2O (1.29 g, 7.6 mmol) in AcOH (64.5 mL) and H2O (3.2 mL) which had been saturated previously with SO2. The mixture was stirred for 1.5 h, treated with H2O (200 mL) and extracted with EtOAc (300+150 mL). The combined EtOAc extracts were washed with H2O (2×200 mL), filtered, and dried (MgSO4). Filtration and solvent evaporation provided the title compound: m/z (ES+)=466.1 [M+MeCN+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.COCCOC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH3:15])[CH2:28][CH2:27]3)[C:9]2=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=C1CCN(c2ccc(Br)cc2)C1=O
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1N1CCN(CC2CCN(c3ccc(Br)cc3)C2=O)CC1
Yield: 81.4 %

Procedure:
1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone and 2.00 g of 4-(2-methoxyphenyl)piperazine were mixed with 5 ml of ethylene glycol dimethyl ether. The mixture was refluxed for 2 hours and then cooled. Thereto was added water. The mixture was subjected to extraction with ethyl acetate twice. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain an oily material. The oily material was purified by silica gel column chromatography using a mixed solvent of chloroform/methanol=40/1 to obtain 1.88 g of oily 1-(4-bromophenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]methyl-2-pyrrolidinone.