Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:16](#[N:20])[CH2:17][C:18]#[N:19].N1CCCCC1>C(O)C>[C:18]([C:17]1[C:16](=[NH:20])[O:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)#[N:19]
Reactant: N#CCC#N
Reactant: O=C(c1ccccc1)c1ccccc1O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(-c2ccccc2)c2ccccc2oc1=N
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a mixture of 2-hydroxybenzophenone (2.0 g, 10 mmol) and malononitrile (661 mg, 10 mmol) in ethanol (15 mL) was added piperidine (0.5 mL, 5.0 mmol). The mixture was stirred under 0-5° C. for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 1.2 g (48%) of the title compound. 1H NMR (CDCl3): 7.74-7.29 (m, 7H), 7.20-7.13 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:3]=1.Cl.[NH2:21][C:22]1[C:27]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:26][CH:25]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[N:23]=1>>[ClH:1].[NH2:21][C:22]1[N:23]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[O:18][CH3:19])[N:3]=3)[CH2:36]2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2ccccc2OC)nc1Cl
Agent: Cl
Product: COC(=O)c1ccc(-c2ccccc2OC)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1

Procedure:
Analogously to the preparation of Example 8, 255 mg (0.84 mmol) of methyl 2-chloro-6-(2-methoxyphenyl)pyridine-3-carboxylate (Example 17A) and 299 mg (0.92 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) were used to obtain, after purification of the crude product by means of preparative HPLC (method 10), 275 mg (58% of theory) of the product in solid form.
Reaction SMILES: CI.[C:3](=O)([O-])O.[K+].[O:8]=[C:9]1[C:18]2[CH:19]=[C:20]([S:23][CH2:24][C:25]([OH:27])=[O:26])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:14]2[CH:13]=[CH:12][S:11][C:10]1=2>CN(C=O)C>[O:8]=[C:9]1[C:18]2[CH:19]=[C:20]([S:23][CH2:24][C:25]([O:27][CH3:3])=[O:26])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:14]2[CH:13]=[CH:12][S:11][C:10]1=2
Reactant: O=C([O-])O
Reactant: O=C(O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
Methyl iodide (6.5 mL, 104 mmol) and potassium hydrogencarbonate (17.0 g, 170 mmol) were added to a DMF (200 mL) solution of the compound obtained in Example 21 (26.1 g, 85 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 24.0 g (88%) of the captioned compound.
Reaction SMILES: [C@@H:1]1([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([OH:13])[C:11]=3[N:10]=[CH:9]2)[O:7][C@H:4]([CH2:5][OH:6])[CH:3]=[CH:2]1>C(O)C.O.[Pd]>[C@@H:1]1([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([OH:13])[C:11]=3[N:10]=[CH:9]2)[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Yield: 79.4 %

Procedure:
A solution of the olefin 8 (0.38 g, 1.6 mmol) in a mixture of ethanol-water (4:1) (70 ml) was hydrogenated in the presence of 10% Pd/C (0.07 g) at 50 psi for 6 h. The mixture was filtered through celite, the filtrate was concentrated, and cooled. The solid obtained was filtered and dried to yield 0.3 g (78%) of 11: mp softens at 184°-186° C., but does not melt up to 300° C.; 1H NMR (DMSO-d6) δ 1.72-2.48 (4H, m, 2' and 3'-H), 3.21-3.67 (2H, m, 5'-H), 4.17-4.38 (1H, m, 4'-H), 4.72 (1 H br s, OH, exchangeable), 6.20 (1H, dd, J=3.81 Hz, 4.1 Hz, 1'-H), 7.90 (1H, s, 8-H), 8.15 (1H, s, 2-H), 12.20 (1 H, br s, NH).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].B(F)(F)F.[CH3:34]COCC>CO>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:34])=[O:6]
Reactant: CCOCC
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: FB(F)F
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 95 %

Procedure:
To a solution of cholic acid (300 g, 0.73 mol) in 1.1 L methanol is added boron trifloride etherate. The mixture is refluxed for 1 h. After cooling, a solid precipitate 2 is collected by filtration. The mother liquor is kept in a refrigerator to give another crop of product The combined product (295 g, 95%) is dried under vacuum and used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9](O)=[O:10])=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCOc1ccc(F)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCCCOc1ccc(F)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
3-(4-Fluorophenoxy)propanoic acid (16.6 g, 90 mmol) was stirred in 100 mL of tetrahydrofuran under a nitrogen atmosphere. The solution was cooled to 5° C. and borane (120 mL, 120 mmol, 1M in tetrahydrofuran) was added dropwise at a rate to keep the temperature of the reaction near 5° C. Once the addition was complete, the solution was allowed to stir at room temperature overnight. The reaction was then cooled below 10° C. and 18 mL of a tetrahydrofuran/water mixture was added. The tetrahydrofuran was removed by evaporation under reduced pressure and the resulting cloudy mixture was diluted with about 200 mL of water. This mixture was extracted three times with diethyl ether. The combined extracts were washed with water, twice with 10% aqueous sodium bicarbonate, and once with brine. The combined extracts were then dried over sodium sulfate, filtered, and concentrated to give 15.24 g of a product oil. Yield: 99%. MS(FD) M+ 171.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH:13][CH3:14].C1COCC1.Cl.[CH2:21]([S:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=O)[CH3:22].C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[C:3]2[N:13]([CH3:14])[C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[S:23][CH2:21][CH3:22])=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1c(N)cc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(Cl)c2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a mixture of 3-chloro-N2-methyl-5-trifluoromethylbenzene-1,2-diamine (1.12 g) and THF (5 ml), 2-ethylsulfanylbenzoic acid hydrochloride (1.00 g) was added under ice-cooling, heated to room temperature, and stirred for 1 hour. Sodium hydrogen carbonate (0.46 g) was added thereto, and then the reaction mixture was allowed to stand overnight. The reaction mixture was heated to 66° C., and stirred under reflux for 1.5 hours. After the mixture was cooled to room temperature, 2-ethylsulfanylbenzoic acid hydrochloride (0.5 g) was added at room temperature. After the reaction mixture was allowed to stand at room temperature overnight, sodium hydrogen carbonate (1.00 g) was added, and stirred. The reaction mixture was ice-cooled, and then water was added under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.48 g of 7-chloro-2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter referred to as Present Compound 71).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2S(C)(=O)=O)[N:4]=1.[CH3:24][O-:25].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[O:25][CH3:24])[N:4]=1
Reactant: COc1cc(OC)nc(-n2c(S(C)(=O)=O)nc3ccccc32)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(-n2c(OC)nc3ccccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
1-(4,6-dimethoxypyrimidin-2-yl)-2-methylsulfonylbenzimidazole (0.40 g) was dissolved in tetrahydrofuran (20 ml), and sodium methylate (0.50 g) was added thereto under cooling with ice, followed by stirring for 1 hour. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the mixture was purified by silica gel column chromatography to obtain 0.40 g of the desired product as a white powder (m.p. 121-122° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](O)[C:7]=1[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:17]1[C:8]2=[CH:9][CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cccc(O)c1CCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc2c1CCCCO2
Reaction time: 18 h
Yield: 59.9 %

Procedure:
A solution of 4-[2-ethoxycarbonyl-6-hydroxyphenyl]butan-1-ol (5.14 g, 21.6 mmol) in THF (20 ml) was added dropwise to an ice bath cooled solution of triphenyl phosphine (7.37 g, 28.1 mmol) and diethyl azodicarboxylate (4.89 g, 28.1 mmol) in THF (60 ml). The reaction was stirred for 18 hr and then concentrated in vacuo. The residue was purified by chromatography on silica gel using methylene chloride as the eluent to give the product as an oil (2.85 g, 60%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:14][C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:47]([O:51][NH2:52])([CH3:50])([CH3:49])[CH3:48].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:47]([O:51][NH:52][C:15](=[O:17])[CH2:14][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccc3ccccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)C)Cc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetic acid hydrochloride (1.49 g, 3.35 mmol), 1-hydroxybenzotriazole (0.539 g, 3.52 mmol), 4-methylmorpholine (1.55 mL, 14.9 mmol), and O-t-butylhydroxyl amine hydrochloride (0.464 g, 3.70 mmol) are dissolved in methylene chloride (50.0 mL), and the reaction is cooled to 0° C. To this solution is added N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.35 g, 7.04 mmol), and the reaction is allowed to warm up to room temperature and stir overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with saturated sodium bicarbonate, brine, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (1% methanol/methylene chloride) to give N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide.
Reaction SMILES: N1C=CC=CC=1.[P:7]([Cl:10])(Cl)[Cl:8].[CH:11]([NH:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>CCOCC>[Cl:8][P:7]([Cl:10])[N:14]([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12]
Reactant: ClP(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)N(C(C)C)P(Cl)Cl
Temperature: -70 °C
Yield: 36.3 %

Procedure:
300 ml abs. ether, 81 ml anhydrous pyridine and 87.5 ml PCl3 (1 Mol) are pre-cooled with stirring to -70° C. in a 2 l three-neck, round-bottomed flask with a 500 ml dropping funnel, KPG stirrer, thermometer and acetone/dry ice bath. 142 ml diisopropylamine (1 Mol) in 250 ml abs. ether are added dropwise to it within 2 hours and the temperature is maintained at ca -60 to -65° C. After completing the addition, the thickened pulpy reaction mixture is allowed to reach room temperature and is diluted with about 600 ml abs. ether to make it more easily stirrable. After a further 3 hours stirring at room temperature the precipitate which forms is aspirated over a glass filter and washed several times with ether. After drawing off the ether at normal pressure, it is freed of unreacted PCl3, diisopropylamine and pyridine in a water-jet vacuum and then the remaining oil is fractionally distilled under an oil-pump vacuum (Kp 46° C./0.35 Torr). 73.4 g of the phosphane is obtained which corresponds to 36% of the theoretical yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccnc(N2CCNCC2)c1
Yield: 18.8 %

Procedure:
A solution of 2-chloro-4-nitropyridine (4.89 g), and piperazine (7.90 g) in pyridine (90 ml) was heated under reflux for 5 hours and then evaporated. The residue was dissolved in water and the solution was basified with sodium bicarbonate (to pH 8-9) and then continuously extracted with dichloromethane. The extract was dried (Na2SO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (98:2:1) first gave a solid that was crystallised from ethyl acetate/hexane to give 1-[4-nitro-2-pyridinyl]piperazine (1.21 g), m.p. 92°-93° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:23]=[O:24])C>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:23]=[O:24])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCc1[nH]c2ccccc2c1C=O
Temperature: 40 °C

Procedure:
2-Ethylindole (0.5 g, 3.4 mmol) dissolved in DMF (2 mL) was added to a cold (0° C.) premixed (30 minutes) mixture of DMF (1.15 mL) and phosphorous oxychloride (0.64 g, 4.16 mmol). After addition of 2-ethylindole, the mixture was heated to 40° C. for 1 h, water (5 mL) was added and the pH adjusted to 5 by means of 1 N sodium hydroxide. The mixture was subsequently extracted with diethyl ether, the organic phase isolated, dried with MgSO4 and evaporated to dryness affording 2-ethylindole-3-carbaldehyde (300 mg).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:27])=O>ClCCl.CN(C)C=O>[Cl:27][C:19]([C:18]1[CH:22]=[CH:23][C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]2)=[CH:16][CH:17]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C

Procedure:
0.330 g of trans-4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoic acid is placed in 10 mL of dichloromethane with stirring, at room temperature, under a nitrogen atmosphere. 0.12 mL of oxalyl chloride (1.42 mmol, 1.4 eq.) and 2 drops of dimethylformamide are successively added. The reaction medium is stirred for 2 hours and concentrated under vacuum. The tert-butyl trans-4-(4-chlorocarbonylphenyl)cyclohexaneacetate formed is dissolved in 8 mL of acetonitrile and placed under nitrogen. The mixture is cooled in an ice bath and 0.17 g of potassium thiocyanate (1.75 mmol, 1.7 eq.) is added. The reaction mixture is stirred at room temperature for 1 hour 30 minutes. 0.380 g of cyclopentyloxyacetic acid hydrazide (2.40 mmol, 2.32 eq.) dissolved in 5 mL of acetonitrile is then added and the mixture is refluxed for 2 hours 30 minutes and then left to stand at room temperature for 36 hours. The precipitate formed is filtered off and washed with acetonitrile. The filtrate is diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated under vacuum. The residue is dissolved in 5 mL of dichloromethane; 3 mL of trifluoroacetic acid are added and the reaction medium is stirred for 1 hour 30 minutes and concentrated under vacuum. After triturating in methanol, ethanol and ethyl acetate, the residue is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 3% to 5%. After triturating in ethanol, 0.070 g of trans-{4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyl}acetic acid is obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([NH2:11])=O)[CH2:5][CH2:4]1.[BH4-].[Na+].II.CO>C1COCC1>[F:1][C:2]([F:12])([F:13])[CH:3]1[CH2:4][CH2:5][CH:6]([CH2:9][NH2:11])[CH2:7][CH2:8]1
Reactant: NC(=O)C1CCC(C(F)(F)F)CC1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NCC1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Yield: 9.7 %

Procedure:
At 0° C. a solution of 4-trifluoromethylcyclohexanecarboxylic acid amide (1.38 g, 7.07 mmol) in THF (20 ml) was added to a suspension of sodium borohydride (0.64 g, 16.97 mmol) in THF (20 ml). A solution of iodine (1.79 g, 7.07 mmol) in THF (20 ml) was added dropwise. The reaction mixture was heated to reflux for 16 hours. It was cooled to 0° C. Methanol (40 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in tert-butyl methyl ether (100 ml) and a 20% aqueous solution of sodium hydroxide. The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×70 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using DCM/methanol/25% aqueous ammonia (first 100:10:1; then 50:10:1) as eluent, to give 124 mg of ((4-trifluoromethylcyclohexyl)methyl)amine.
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][C:42]([F:45])([F:44])[F:43])[CH:40]=1)[C:35]([OH:37])=O>>[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][C:42]([F:45])([F:44])[F:43])[CH:40]=1)[C:35]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:5])=[O:37]
Reactant: O=C(O)c1cc(Br)cc(OC(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Br)cc(OC(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) and 3-bromo-5-(trifluoromethoxy)benzoic acid (CAS RN 453565-90-7) after a reaction time of 16 hours. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (60%). MS (ESI): m/z=501.03 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][C:31]1=[O:36]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:33]4[CH2:34][CH2:35][NH:30][C:31](=[O:36])[CH2:32]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1CNCCN1
Product: O=C1CN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CCN1
Yield: 28 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and piperazinone to give the title compound in 28% yield; NMR Spectrum: 2.70 (t, 2H), 2.89 (t, 2H), 3.09 (s, 2H), 3.14-3.17 (m, 2H), 4.45 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.73 (br s, 1H), 7.87 (t, 1H), 7.92 (s, 1H), 8.29 (s, 1H), 8.48 (br s, 1H), 8.59 (s, 1H); Mass Spectrum: 495 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].CS(C)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[S:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: Nc1ccccc1S
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(-c2nc3ccccc3s2)cc(OC)c1OC
Yield: 84.6 %

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (19.7 g, 0.1 mol), 2-aminobenzenethiol (11.2 cm3, 0.105 mol) and dimethylsulfoxide acid (75 cm3) was heated under reflux for 24 hours. The cooled solution was added to water and extracted into ethyl acetate (3×50 cm3). The combined organic layers were dried (MgSO4), filtered and the filtrate evaporated down under reduced pressure. The solid residue was recrystallised from ethyl acetate to give 25.5 g (85.0%) of the desired product, mpt. 135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:7]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[N:10]([CH3:20])[C:9]2=[O:18])[CH:7]=1
Reactant: O=c1[nH]c2cc(F)ccc2n1-c1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(=O)n(-c2cc(Cl)ccc2O)c2ccc(F)cc21

Procedure:
A mixture of 1,3-dihydro-1-(5-chloro-2-hydroxyphenyl)-5-fluoro-2H-benzimidazol-2-one (300 mg, 1.1 mmol), anhydrous potassium carbonate (415 mg) and Iodomethane (68 μl) in 10 ml absolute acetone was refluxed for 5 hours. The mixture was filtered, concentrated in vacuo and the crude product was subjected to column chromatography using methylene chloride:acetone (20:1) as eluent. The fraction containing the product was concentrated in vacuo and the title compound was obtained as white crystals, M.p. 247°-250° C.