Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[N:9]=1)[CH3:4]>O.C1COCC1>[CH2:3]([C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)[CH3:4]
Reactant: CCOC(=O)c1csc(CC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (1.405 g, 58.68 mmol) in water (13.75 mL) was sonicated for 10 min before being added to a stirred mixture of ethyl 2-ethylthiazole-4-carboxylate (2.78 g, 15.01 mmol) in THF (55 mL). The reaction was stirred art RT overnight. The solution was diluted with water and extracted with EtOAc (×3). The organic extracts were discarded. The aqueous was acidified with 2M HCl and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to give the sub-title compound as a brown oil which solidified on standing to give a waxy solid. Yield: 1.02 g
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH3:16])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)(O)[O:13]C1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH3:16])[C:14]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:23]=1)=[O:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1N(C(=O)OCc2ccccc2)COC1(O)c1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(OCc2ccccc2)cc1
Yield: 87.9 %

Procedure:
In toluene (50 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (3.8 g) prepared in Example 1. After adding Amberlist (300 mg), the mixture was reacted at room temperature. At the end of the reaction, Amberlist was filtered off, the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: chloroform) to give the title compound (3.1 g) as pale yellow crystals in a yield of 88%.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[NH:13][CH:12]([CH3:17])[CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[N:13]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]([CH3:17])[CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2c(c3ccccc31)CC(C)NC2=O
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1c2c(c3ccccc31)CC(C)N(c1cccnc1)C2=O
Yield: 34.3 %

Procedure:
Using analogous reaction conditions as described in Example 1, 9-ethyl-3-methyl-2,3,4,9-tetrahydro-b-carbolin-1-one (I-42d: 0.1 g, 0.4386 mmol) was reacted with 3-bromo-pyridine (0.069 g, 0.4386 mmol), 1,4-dioxane (15 mL), copper iodide (0.008 g, 0.0438 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.018 mg, 0.1315 mmol) and potassium phosphate (0.232 g, 1.096 mmol) to afford the crude product. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 46 mg of the product (34% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])=[CH:19][C:18]=1[C:30]([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:23](=[O:24])[CH:22]([O:21][C:20]2[CH:28]=[CH:29][C:17]([Cl:16])=[C:18]([C:30]([F:32])([F:33])[F:31])[CH:19]=2)[CH2:26][CH3:27])=[CH:4][CH:5]=1
Reactant: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)Cl
Reactant: NCc1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)NCc1ccncc1
Yield: 42.9 %

Procedure:
In 50 ml of toluene were dissolved 1.3 g (0.012 mole) of 4-(aminomethyl)pyridine and 1.0 g (0.010 mole) of triethylamine. Thereto was added dropwise a solution of 3.0 g (0.010 mole) of 2-(4-chloro-3-trifluoromethylphenoxy)-butyroyl chloride in 30 ml of toluene at room temperature with stirring, and the mixture was treated according to the same procedure as in Synthesis Example 10. The resultant oily substance was subjected to silica gel column chromatography by eluting with toluene to obtain 1.6 g of N-(4-pyridylmethyl)-2-(4-chloro-3-trifluoromethylphenoxy)-butyramide showing nD19 1.5228 as pale yellow oil.
Reaction SMILES: [CH2:1]1[N:3]([CH2:4][CH:5]([OH:15])[CH2:6][N:7]2[C:11]([N+:12]([O-:14])=[O:13])=[N:10][CH:9]=[CH:8]2)[CH2:2]1.[C:16]([OH:19])(=[O:18])[CH3:17].C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:12]([C:11]1[N:7]([CH2:6][CH:5]([OH:15])[CH2:4][NH:3][CH2:1][CH2:2][O:19][C:16](=[O:18])[CH3:17])[CH:8]=[CH:9][N:10]=1)([O-:14])=[O:13]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1nccn1CC(O)CN1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCNCC(O)Cn1ccnc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 58 %

Procedure:
A solution of 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol (2.12 g, 10.0 mmol) in acetone (20 cm3) prepared as described in Example 1(a) was treated with ethanoic acid (2.5 mol equivalents) at 25° C. then warmed to 50° C. for 15 minutes. The resulting mixture was cooled to 20° C., stirred with a decolourising charcoal (0.3 g) and excess anhydrous potassium carbonate for 30 minutes, filtered and concentrated under reduced pressure to give 1-(2-nitro-1-imidazolyl)-3-(2-acetoxyethylamino)-2-propanol (1.58 g, 58.0%) in the form of a pale yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:22][CH2:23][CH2:24][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:21]
Reactant: OCCBr
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc2scc(Cn3c(=O)n(CCBr)c4ccccc43)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
To the stirred solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (100 mg, 0.34 mmol), 2-Bromo-ethanol (0.03 mL, 0.41 mmol) and triphenylphosphine (107 mg, 0.41 mmol) in THF (2.0 mL) is added DIAD (0.082 mL, 0.41 mmol) in a dropwise manner. The mixture is stirred at room temperature for 20 hr and then another 0.03 mL of 2-Bromo-ethanol, 107 mg of triphenylphosphine and 0.08 mL of DIAD are added. The reaction is continued for another 24 hr and then the solvent is removed under vacuum and the residue is purified by flash column chromatography to give 75 mg (55%) of 1-(2-Bromo-ethyl)-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4F)=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[O:47]1CCOC[CH2:48]1.[OH-].[K+].CO>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:34][CH2:35][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:37][CH2:38]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:20]=4[O:47][CH3:48])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: CCOC(=O)CCN[C@H]1CC[C@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)CC1
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@H](NCCC(=O)O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of trans-ethyl 3-({4-[4-amino-3-(4-{[2-fluoro-4-trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoate (0.04 g, 0.06 mmol), p-dioxane (4 mL), potassium hydroxide (0.02 g, 0.31 mmol), a trace amount of methanol and water (0.4 mL) were heated at 80° C. for 1 hour. The mixture was stirred at ambient temperature overnight and at 80° C. for 4 hours. The solvents were evaporated and the residue was purified by preparative HPLC to yield trans-3-({4-[4-amino-3-(3-methoxy-4-{[2-methoxy-4-trifluoromethylbenzoyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoic acid (0.04 g, 0.06 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.72 (s, 1H), 8.61(d, 1H), 8.28 (d, 1H), 8.24 (s, 1H), 7.61(s, 1H), 7.53 (d, 1H), 7.33 (s, 1H), 7.29 (d, 1H), 4.72 (m, 1H), 4.20 (s, 3H), 4.05 (s, 3H), 1.44-3.61 (m, 13H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 6.36 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c(CN3CCNCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0301 g, 0.0654 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)-methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0221 g, 94%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:26]=3)[CH:21]=2)=[C:16]([CH:19]=1)[C:17]#N.[BH4-].[Na+].[OH2:41]>ClCCl.CO>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:26]=3)[CH:21]=2)=[C:16]([CH2:17][OH:41])[CH:19]=1
Reactant: O
Reactant: N#Cc1cc(F)ccc1-c1ccc2cc(S(=O)(=O)c3ccccc3)ccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc2cc(-c3ccc(F)cc3CO)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of diisobutylaluminium hydride (1M in dichloromethane, 700 μL, 0.70 mmol) was added to 5-fluoro-2-[6-(phenylsulfonyl)-2-naphthyl]benzonitrile (66 mg, 0.17 mmol) in dichloromethane (2 mL) at −78° C. under nitrogen and allowed to warm to 0° C. during 2 hours. It was quenched with ammonium chloride (3 mL), diluted with water (75 mL) and extracted into ethyl acetate (2×50 mL). These extracts were washed with water and brine then dried (MgSO4), filtered and solvent removed in vacuo to give the crude aldehyde as a foam. This foam (67 mg, 0.17 mmol) was suspended in methanol (4 mL) at 0° C. under nitrogen and sodium borohydride (35 mg, 0.92 mmol) added. It was stirred at this temperature for 30 minutes then allowed to return to ambient temperature over 30 minutes. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×30 mL). These extracts were washed with water and brine then dried (MgSO4), filtered and solvent removed in vacuo. Purification by flash column chromatography eluting with a 10-40% ethyl acetate/isohexane gradient gave {5-fluoro-2-[6-(phenylsulfonyl)-2-naphthyl]phenyl}methanol (31 mg, 46%). 1H NMR (500 MHz, CDCl3) δ 8.62 (1H, s), 8.03-8.01 (3H, m), 7.94 (1H, d, J=8.6 Hz), 7.90 (1H, dd, J=1.7, 8.7 Hz), 7.82 (1H, s), 7.60-7.50 (4H, m), 7.35 (1H, dd, J=2.5, 9.6 Hz), 7.29 (1H, dd, J=5.6, 8.4 Hz), 7.11-7.05 (1H, m), 4.60 (2H, d, J=5.1 Hz), 1.67 (1H, t, J=5.5 Hz); m/z (ES+) 393 [MH+].
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.B.CSC.CO>O1CCCC1>[N:1]1[C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2cccnc2Oc2ccccc21
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)CNc1cccnc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A mixture of 2.8 g of pyrido[2,3-b][1,4]benzoxazepin-6(5H)-one, 10 ml of tetrahydrofuran and 3 ml of 10M borane-dimethylsulfide in tetrahydrofuran is stirred at room temperature overnight and then refluxed for 3 hours. To the mixture is added dropwise under argon, 5 ml of methanol. The solvent is removed under vacuum and methanol added. The solvent is removed under vacuum and 12 ml of 2N NaOH added to the residue. The mixture is refluxed for 2 hours and extracted with ethyl acetate. The extract is washed with 2N citric acid, H2O, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum. The residue is chromatographed on a column (2"×18") of silica gel (32° g) with hexane-ethyl acetate (1:1) as solvent to give 0.78 g of crystals, m.p. 172°-174° C.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:2]([C:7]([N:9]2[CH2:14][C:13](=O)[CH2:12][CH2:11][CH:10]2[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([NH:43][CH:13]1[CH2:14][N:9]([C:7]([C:2]2[C:1]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:10]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:19])[CH2:11][CH2:12]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Reactant: NCc1ccccc1
Product: O=C(NCC1CCC(NCc2ccccc2)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12

Procedure:
N-((5-(Benzylamino)-1-(biphenylcarbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according general procedure N using N-((1-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and benzyl amine. (ESI) 555 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:17])[F:18])=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2C(F)(F)F)cc1

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-trifluoromethylphenyl)benzamide (243.0 mg, 0.474 mmol) and acetic anhydride (0.13 ml, 1.40 mmol), the procedure of Inventive Example 94 was repeated to obtain 265.0 mg quantitative) of the title compound in a colorless amorphous form.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(#N)C.C(N(C(C)C)CC)(C)C>CCOC(C)=O.Cl>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 150 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (1.200 g, 5.992 mmol) and 4-fluoronitrobenzene (0.705 g, 4.99 mmol) were placed in a 30 mL microwave vial then acetonitrile (20 mL) followed by diisopropylethylamine (1.778 mL, 9.986 mmol) were added. The reaction was heated under microwave irradiation at 150° C. for 15 minutes. The reaction mixture was diluted with EtOAc (200 mL) and 2 M aq. HCl (150 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL), the organics were combined and washed with brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I74) (1.040 g, 65%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 8.06-7.99 (m, 2H), 7.03-6.97 (m, 2H), 6.88 (d, J=7.5 Hz, 1H), 4.01-3.93 (m, 2H), 3.62-3.47 (m, 1H), 3.13-3.02 (m, 2H), 1.85-1.74 (m, 2H), 1.44-1.30 (m, 11H).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:22]1[C:27]([F:28])=[CH:26][C:25]([Br:29])=[CH:24][N:23]=1>>[Br:29][C:25]1[CH:26]=[C:27]([F:28])[C:22]([C:15]2[CH:14]=[CH:13][C:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:17][CH:16]=2)=[N:23][CH:24]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ncc(Br)cc3F)cc2)CC1

Procedure:
4-(trans-4-pentylcyclohexyl)benzeneboronic acid and 2,5-dibromo-3-fluoropyridine are reacted analogously to Example 1 to give 5-bromo-3-fluoro-2-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine. ##STR36##
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17](O)=O)[CH:11]=[C:10]([CH3:20])[N:9]=2)[N:3]=1.[CH3:21][NH:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:22]([CH3:21])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]=3)[CH:11]=[C:10]([CH3:20])[N:9]=2)[N:3]=1
Reactant: CNc1ccccc1N
Reactant: Cc1cc([C@@H]2C[C@H]2C(=O)O)cc(-n2nc(C)nc2C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropanecarboxylic acid (25-3) (45 mg, 0.165 mmol), N1-methylbenzene-1,2-diamine (28 mg, 0.231 mmol), EDC.HCl (47 mg, 0.248 mmol), HOBt (38 mg, 0.248 mmol), diisopropylethylamine (85 mg, 0.660 mmol), and tetrahydrofuran (3 mL) was stirred at room temperature overnight and evaporated. Acetic acid (3 mL) was added and the mixture was heated at 95° C. for 1 hour, cooled to room temperature, and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (5-10% methanol in DCM) and reverse phase (10-100% acetonitrile in water) to give trans-2-(2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (25-4) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.74-7.65 (m, 1H), 7.38 (br s, 1H), 7.34-7.20 (m, 3H), 6.98 (br s, 1H), 3.81 (s, 3H), 2.83 (s, 3H), 2.78-2.67 (m, 1H), 2.54 (s, 3H), 2.46-2.36 (m, 1H), 2.41 (s, 3H), 2.12-2.02 (m, 1H), 1.80-1.69 (m, 1H). LRMS m/z (M+H) 359 found, 359 required. m.p. 157-159° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:13]=[CH:14][CH3:15])([CH3:12])([CH3:11])[CH3:10].[ClH:16]>O1CCCC1.C([Li])CCC.C(OCC)(=O)C>[ClH:16].[ClH:16].[C:9]([NH:13][CH:14]([CH3:15])[CH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccc(O)cn1
Reactant: CC=NC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Cc1ccc(O)cn1)NC(C)(C)C

Procedure:
To the suspension of 9.8 g of 2-methyl-5-pyridinol in 200 ml of tetrahydrofuran, 135 ml of 1.6 molar n-butyllithium are added during 30 minutes while stirring under nitrogen at -20°. After 3 hours 10 g of t-butyliminoethane are added during 30 minutes at said temperature and the resulting mixture is processed as described in Example 4, except that the final solution is acidified with hydrogen chloride in ethyl acetate, to yield the 2-(2-t-butylaminopropyl)-5-pyridinol dihydrochloride melting at 218°-220°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccccc2Cl)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4Cl)nnn3C)c2)nc1
Temperature: 120 °C
Yield: 75.6 %

Procedure:
A mixture of 4-(2-chlorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (322 mg, 1.24 mmol), methyl 6-chloronicotinate (213 mg, 1.24 mmol) and potassium carbonate (343 mg, 2.48 mmol) in DMF (7 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 30 to 100% ethyl acetate in heptane) afforded the title compound (370 mg, 76%) as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[N:23]=1.O>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1)[O:19][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)[N:23]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
16 mg (0.39 mmol) of 95% sodium hydride were added at 0° C. to a solution of 86 mg (0.37 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 100 mg (0.37 mmol) 2-chloromethyl-6-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at r.t overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was dried at 40° C. to give 145 mg (84%) of the title compound as white powder.