Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(Cl)CCl.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]=[C:22]([CH2:26][CH2:27][C:28](O)=[O:29])[C:21]1=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:28](=[O:29])[CH2:27][CH2:26][C:22]1[C:21](=[O:31])[N:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24][CH:23]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CCC1=CCCN(Cc2ccccc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)CCC1=CCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 91 %

Procedure:
40 mg of 1,2-phenylenediamine (0.37 mmol), 77 mg of EDC (0.4 mmol) and 1 mg of DMAP (3 M %) were added to reaction solution dissolving 3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid prepared by above Example 8 in 1 ml of methylene chloride under Argon atmosphere. After the mixture was stirred for 13 hrs at room temperature, the resulting mixture was diluted with ethyl acetate and washed with 10% NaOH solution (10 ml). Then the residue was extracted with 50 ml of chloroform, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:20) as an eluant to give 96 mg of N-(2-amino-phenyl)-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide (g2) (yield: 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:6][C:7]=1[CH3:8].C[Li].C([Li])(C)(C)C.N1([CH:34]=[O:35])CCCCC1>O1CCCC1>[CH3:8][C:7]1[C:2]([CH:34]=[O:35])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:6]=1
Reactant: O=CN1CCCCC1
Reactant: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Br
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1C=O
Temperature: 78 °C
Reaction time: 2 h

Procedure:
(5-Bromo-6-methyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (34, 1.7 g, 4.93 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled at 78° C. under a nitrogen atmosphere. To this mixture was added methyllithium (1.6 M in diethyl ether, 5.91 mmol) dropwise over 20 minutes. After the addition of methyllithium was completed, the reaction mixture was stirred at −78° C. for 2 hours. To this mixture was added tert-butyllithium (1.7 M in pentane, 10.85 mmol) and the mixture was stirred for 4 hours. The reaction mixture was maintained at −78° C., and 1-piperidinecarboxaldehyde (0.60 mL, 5.42 mmol) was added dropwise. The reaction was allowed to stir at −78° C. for an additional 2 hours and warming to 25° C. was achieved from the slow evaporation of the dry ice/acetone cooling bath. The reaction was quenched with ice cold saturated sodium chloride and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. Concentration under reduced pressure afforded an orange oil (35, 1.4 g, 4.93 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:21]C)[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44].C[Si](I)(C)C.C(O)C.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:21])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:23][C:24]([F:25])([F:26])[F:27])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44]
Reactant: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1cc(OC(F)(F)F)ccc1CNC(=O)c1cn(CC(F)(F)F)c2c(O)c(N3CCC(C(=O)O)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.6 %

Procedure:
150 mg (0.237 mmol) of the compound of Example 47 are provided in 3 ml of dichloromethane, 943 μl of trimethylsilyliodide (6.63 mmol) are added and the mixture is stirred for 4 days at room temperature. In order to destroy the excess trimethylsilyliodide the reaction mixture is cooled to 0° C., and a mixture of 414 μl of Ethanol (7.1 mmol) and 575 μl of pyridine (7.1 mmol) is added. After 5 min the volatile components are removed on a rotary evaporator. The residue is stirred in 5 ml of a water-acetonitrile mixture (1:1) and the solid is collected by filtration. It is dried under high vacuum. 136 mg of the title compound are obtained (91% of theory).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:16]1[CH:56]=[CH:55][C:19]([O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>O.C(OCC)(=O)C>[C:13]([C:16]1[CH:17]=[CH:18][C:19]([O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:47]5[NH:3][C:4](=[O:7])[O:5][N:48]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)=[CH:55][CH:56]=1)(=[O:15])[CH3:14]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.17 g), sodium hydrogen carbonate (0.28 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(4-acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.10 g) was added, and the mixture was stirred at 90° C. for 18 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.034 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.032 mL) were added, and the mixture was stirred at room temperature for 1 hr. N,N′-Carbonyldiimidazole (0.034 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.032 mL) were added, and the mixture was stirred at room temperature for 18 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was heated under reflux in ethanol (4 mL)-20% sulfuric acid (2 mL) for 5 hr. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate-hexane) to give the title compound as a colorless solid (0.027 g, 24%).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][O:23][CH3:24].[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>CCCCCC.O1CCCC1>[Cl:14][C:15]1[C:16]([O:21][CH2:22][O:23][CH3:24])=[C:17]([CH:31]([C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28][CH2:27][O:26][CH3:25])[OH:32])[CH:18]=[CH:19][CH:20]=1
Reactant: COCOc1ccccc1Cl
Reactant: COCOc1ccccc1C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccccc1C(O)c1cccc(Cl)c1OCOC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.6M solution of n-butyl lithium in hexane (140 ml) was placed in a 1 l flask and cooled in an ice bath. To this was added with stirring 34 ml of tetramethylethylenediamine and, after a 10 min reaction period, 34.5 g of 1-chloro-2-methoxymethoxybenzene (dropwise over a 30 min period). A pale orange suspension formed and this was stirred for 4 hours continuing the ice bath cooling. A solution of 34.5 g of 2-methoxymethoxybenzaldehyde in 30 ml of tetrahydrofuran was added with stirring and cooling. The reaction was exothermic. When the addition was complete, the mixture was allowed to warm to room temperature and was then quenched carefully with water. The resulting mixture was poured into a mixture of 1 l of ethyl acetate and 500 ml of aqueous ammonium chloride. The phases were separated and the organic phase was extracted twice with water and once with brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a viscous, pale orange oil. This was purified by filtration chromatography, eluting with mixtures of hexane and dichloromethane starting with pure hexane and ending with pure dichloromethane, to obtain 52.2 g (77 percent of theory) of the title compound as a pale yellow oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[C:7]([CH3:18])[CH:6]=1)=O.[Br:19][C:20]1[CH:21]=[CH:22][C:23](N)=[N:24][CH:25]=1.[CH2:27](O)C>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[C:7]([CH3:18])[CH:6]=3)[CH:27]=2)[CH:25]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1cc(C(=O)CBr)ccc1NC(=O)C(F)(F)F
Reactant: CCO
Product: Cc1cc(-c2cc3ccc(Br)cn3c2)ccc1NC(=O)C(F)(F)F
Yield: 28 %

Procedure:
N-(4-(2-bromoacetyl)-2-methylphenyl)-2,2,2-trifluoroacetamide (3.0 g; 9.26 mmol) and 5-bromopyridin-2-amine (1.5 g; 8.67 mmol) were dissolved in 20 mL ethanol. The mixture was refluxed overnight, and the solvent was removed. CH2Cl2 was added to precipitate a solid, which was filtered and washed with CH2Cl2, to afford 1.0 g (yield 28%) of product as a yellow powder. 1H NMR (300 MHz; DMSO-d6), δ 11.1 (s, 1H, NH), 9.14 (s, 1H, Ar—H), 8.60 (s, 1H, Ar—H), 7.90-7.76 (m, 4H, Ar—H), 7.46 (d, 3JHH=8.0 Hz, 1H, Ar—H), 2.19 (s, 3H, Ar—CH3).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@H:13]([C:26]([N:28]([C@@H:40]([CH3:48])[CH:41]([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[CH2:43]([O:42][CH:41]([O:45][CH2:46][CH3:47])[C@@H:40]([N:28]([CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[C:26]([C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4](=[O:11])[NH:3][CH2:1][CH3:2])=[O:27])[CH3:48])[CH3:44]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 47 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:10]/[C:11](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:28]\[OH:29])=[CH:5][CH:4]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccncc1)c1ccc(N(C)C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccncc1)c1ccc(N(C)C)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=360.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][C:12]#N)[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=2)[CH:3]=1.[OH-:22].[Na+].C[OH:25]>>[Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][C:12]([OH:25])=[O:22])[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(CC#N)c2n1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(CC(=O)O)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetonitrile (2.47 g, 7.25 mmol) in methanol (36 mL) was added sodium hydroxide (25% in water, 12 mL). The reaction was warmed to reflux and held there overnight. The reaction was cooled to room temperature, concentrated to remove the methanol. The resulting residue was diluted with diethyl ether (20 mL), cooled to 0° C., and made acidic by the cautious addition of concentrated hydrochloric acid with stirring. The resulting suspension was extracted with 1:1 diethyl ether/ethyl acetate (2×). The organics were washed with brine, dried over magnesium sulfate, and concentrated to give 2.47 g (100%) as an off white solid. 1H-NMR (CDCl3, 500 MHz) δ 9.98 (bs, 1H), 8.04 (s, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.17 (d, J=0.9 Hz, 1H), 5.70 (s, 2), 4.04 (s, 2H), 3.61 (t, J=8.2 Hz, 2H), 0.91 (t, J=8.2 Hz, 2H), −0.05 (s, 9H), 13C NMR (126 MHz, CDCl3) δ ppm 174.5, 146.7, 128.4, 128.0, 125.1, 123.2, 122.5, 118.6, 81.9, 67.9, 36.9, 17.9, −1.4. Mass spec.: 341.11 (MH)+.
Reaction SMILES: Br[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][C:5]2[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:9](=[O:16])[CH2:8][O:7][C:6]=2[N:17]=1.CC1(C)C(C)(C)OB([C:32]2[CH:46]=[CH:45][C:35]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[O:16]=[C:9]1[CH2:8][O:7][C:6]2[N:17]=[C:2]([C:32]3[CH:46]=[CH:45][C:35]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:34][CH:33]=3)[C:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][C:5]=2[N:10]1[CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC(F)(F)F)C(=O)CO3)cc1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-7-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.103 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (41.3 mg, 0.124 mmol), and cesium carbonate (168 mg, 0.517 mmol) in a mixture of 1,4-Dioxane (1937 μl) and water (646 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdCl2(dppf)-CH2Cl2Adduct (16.87 mg, 0.021 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown solid. The resulting residue was purified via Biotage (0-45% cyclohexane:EtOAc; 10 g column) to give the title compound (45 mg, 85%) as off-white solid. 1H NMR (500 MHz, CDCl3): 7.36 (1H, s), 7.32-7.26 (5H, m), 7.17-7.13 (4H, m), 4.96 (2H, s), 4.77 (1H, br), 4.63-4.58 (2H, q), 4.28 (2H, s), 1.48-1.45 (9H, br).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>ClCCl>[C:37]([NH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)c4ccccc4)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
3-((4-(4-Aminobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.203 mmol, 0.080 g) and triethylamine (1.015 mmol, 0.103 g) were dissolved in dichloromethane (12 mL) and the stirred mixture was cooled to 0° C. Benzoyl chloride (0.305 mmol, 0.043 g) was added and the reaction mixture was allowed to reach room temperature and stir overnight. Water was added to the reaction and the organic layer was then separated, dried (sodium sulfate) and concentrated under vacuum. The residue was purified by silica column chromatography (dichloromethane/methanol (5% to 10%)) and coevaporated with dichloromethane (×3) and diethyl ether (×3) to give the title compound (93 mg). MS (ESI) m/z 499.8 [M+H]+
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=1)[O:5][CH2:6][CH3:7])[CH3:2].[CH2:14]([Br:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br-:21].[CH2:14]([N:12]1[CH:11]=[CH:10][N+:9]([CH3:13])=[C:8]1[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(OCC)c1nccn1C
Product: CCOC(OCC)c1n(Cc2ccccc2)cc[n+]1C
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A reaction mixture of 8 g (43 mmol) of 2-(diethoxymethyl-1-methyl-imidazole and 7.44 g (43 mmol) of benzyl bromide was stirred at room temperature overnight. The mixture was triturated with ethyl acetate and decanted to afford 15.1 g (98.3%) of 3-benzyl-2-(diethoxymethyl)-1-methylimidazolium bromide (Formula VI: A=1-methylimidazole;Y=CH--(OC2H5)2 ;R1 =R6 =H;Z- =Br-).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31]>CC(O)C>[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][O:27][C:28]([C:29]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:14]([C:13]([O:19][CH3:20])=[O:18])=[C:15]([CH3:17])[NH:32][C:30]=1[CH3:31])=[O:33]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COC(=O)CC(C)=O
Reactant: C/C(N)=C/C(=O)OCC1CCCO1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1ccccc1C(F)(F)F

Procedure:
A solution of 90 ml (118.8 g; 0.68 mol) of 2-trifluoromethyibenzaldehyde, 75 ml (79.23 g; 0.68 mol) of methyl acetoacetate and 126.38 g (0.68 mol) of (tetrahydrofuran-2-ylmethyl)-3-aminocrotonate in 700 ml of 2-propanol, was refluxed in the absence of light along 10 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:16]([N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH3:24])[CH3:2].[C:26]1([N:32]2[CH:36]=[CH:35][C:34]([CH:37]=O)=[N:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:16]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:37][C:34]3[CH:35]=[CH:36][N:32]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:33]=3)[CH2:19][CH2:18]2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH3:24])[CH3:2]
Reactant: CCOC(=O)COc1c(C)cc2cccnc2c1N1CCCNCC1
Reactant: O=Cc1ccn(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)COc1c(C)cc2cccnc2c1N1CCCN(Cc2ccn(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A mixture of (8-[1,4]diazepan-1-yl-6-methyl-quinolin-7-yloxy)-acetic acid ethyl ester (600 mg, 1.75 mmol), 1-Phenyl-1H-pyrazole-3-carbaldehyde (300.8 mg, 1.75) and NaBH(OAc)3 (408 mg, 1.92 mmol) in DCE (5 ml) was stirred at rt for 3 hrs. The reaction was then diluted with DCE (20 ml), filtered, and purified by flash column chromatography on silica gel to give the desired product (500 mg, 57%). MS (ES) m/z 500.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](O)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: OCc1onc(-c2ccccc2)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 1 g, 3.89 mmol) in THF (10 mL), cooled to −10° C., was added N-methylmorpholine (0.470 mL, 4.28 mmol) followed by isobutyl chloroformate (0.562 mL, 4.28 mmol) over a period of 3 min. After 15 min. at −10° C., this heterogeneous reaction mixture was added to a suspension of sodium borohydride (0.191 g, 5.06 mmol) in THF (12 mL) and methanol (3.0 mL) at −78° C. over a period of 10 min. using a Pasteur pipette. The reaction mixture was stirred at −78° C. for 10 min. The reaction mixture was allowed to warm to −20° C. over a period of 30 min. and quenched by the slow addition of AcOH in water (1:9 mL). The reaction mixture was allowed to come to room temperature, concentrated under reduced pressure and the residue partitioned between ethyl acetate (60 mL) and water (10 mL). The ethyl acetate layer was separated and washed sequentially with sat. aq. sodium bicarbonate (10 mL), brine (10 mL), dried over sodium sulfate and concentrated. The resulting oil was subjected to silica gel column chromatography using hexane/ethyl acetate to yield (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (0.44 g, 1.809 mmol, 46.5% yield) as an oil. 1H NMR (500 MHz, CDCl3) δ ppm 2.21 (br. s., 1H), 4.97 (s, 2H), 7.47-7.56 (m, 3H), and 7.65 (d, J=6.60 Hz, 2H); LCMS M+1=244.
Reaction SMILES: [Na].C(O)C.[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)[CH3:6].Br[CH:15]([CH2:17][CH2:18][CH2:19][C:20]([O:23][CH3:24])([CH3:22])[CH3:21])[CH3:16]>O>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:15]([CH3:16])[CH2:17][CH2:18][CH2:19][C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[CH:9][CH:8]=1)[CH3:6]
Reactant: COC(C)(C)CCCC(C)Br
Reactant: CCc1ccc(S)cc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCc1ccc(SC(C)CCCC(C)(C)OC)cc1
Reaction time: 0.67 h

Procedure:
To 3.5 g. of sodium in 150 ml. of ethanol is added 18.8 g. of p-ethylphenyl mercaptan. The mixture is stirred for about 40 minutes and then 30 g. of 2-bromo-6-methoxy-6-methylheptane is added. The reaction mixture is heated under reflux for about 35 minutes, allowed to cool and then diluted with water. The reaction is worked up by extraction with ether, washing with water and drying over magnesium sulfate to yield 5-methoxy-1,5-dimethylhexyl p-ethylphenyl sulfide which can be purified by chromatography. ##STR15##