Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.Cl>ClCCl>[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]2)=[O:14])=[CH:11][CH:10]=1
Reactant: OC1CCCNC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCCC(O)C1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 3-hydroxypiperidine (0.6 g, 5.93 mmol), 4-fluorobenzoic acid (0.83 g, 5.93 mmol), HOBT (0.8 g, 5.93 mmol), EDCI.HCl (1.7 g, 8.9 mmol) and dry triethylamine (1.66 mL, 11.86 mmol) in dry dichloromethane (30 mL) was kept under stiffing overnight at ambient temperature, under nitrogen atmosphere. HCl 1N (30 mL) was then added and the phases separated. The organic layer was washed with HCl 1N (30 mL), with NaOH 1N (30 mL×2 times), then with water (30 mL). Evaporation of the organic solvent afforded (4-fluoro-phenyl)-(3-hydroxy-piperidin-1-yl)-methanone as a white oil (0.7 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]3[CH:16]=[C:17]([C:20]4[C:21](C)=[N:22][N:23]([C:25]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:24]=4)[CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:45][C:46]1[S:47][CH:48]=[C:49]([CH3:51])[N:50]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:62]=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:51][C:49]1[N:50]=[C:46]([NH:45][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([C:11]3[N:15]4[CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([C:25]([C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=6)([C:38]6[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=6)[C:26]6[CH:31]=[CH:30][CH:29]=[C:28]([CH3:62])[CH:27]=6)[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)=[CH:10][C:2]=2[F:1])[S:47][CH:48]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1csc(N)n1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2ncc(-c3ccc(C(=O)O)c(F)c3)n2c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4ncc(-c5ccc(C(=O)Nc6nc(C)cs6)c(F)c5)n4c3)cn2)c1
Yield: 87.2 %

Procedure:
58 mg 2-fluoro-4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl] benzoic acid (compound in Example 470) and 13 mg 2-amino-4-methyl-1,3-thiazole were allowed to react for 12 hours with 49 mg benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate and 17 μL triethylamine in 2 mL dichloromethane. The reaction solution was purified by an NH silica gel column to give 59 mg N1-(4-methyl-1,3-thiazol-2-yl)-2-fluoro-4-[6-(3-methyl-trityl-1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl] benzamide as colorless crystals. This product was subjected to deprotection of the trityl group by the same method as in Example 68, to give 42 mg of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([F:21])=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 80 °C

Procedure:
A 50 mL Schlenk tube was charged with (3-fluorophenyl)boronic acid (140 mg, 1.0 mmol), 5-bromo-2-fluorobenzoic acid (263 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.05 mmol) and cesium carbonate (1.3 g, 4.0 mmol). Ethanol (5 mL) and toluene (5 mL) were added and the tube was sealed and heated at 80° C. for 3 h. The cooled mixture was transferred to a flask, washing with ethanol, and concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The aqueous phase was acidified with 1.0 N aqueous HCl (10 mL) and extracted with EtOAc (3×10 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo. 1H-NMR showed the desired product, 3′,4-difluoro-[1,1′-biphenyl]-3-carboxylic acid, was slightly contaminated with 2-fluorobenzoic acid. The impure product (215 mg, ˜92%) was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH:18]=[O:19])=[CH:7]2.[CH3:20][Li]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]([CH:18]([OH:19])[CH3:20])=[CH:7]2
Reactant: [Li]C
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3)nc12
Solvent: C1CCOC1
Product: Cc1cccc2cc(C(C)O)c(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a solution of 8-methyl-2-phenylquinoline-3-carboxaldehyde (211 mg, 0.85 mmol) in THF (6 mL) cooled to −78° C. was added methyllithium (1.6N solution in ether, 0.6 mL, 0.93 mmol). After 1 h a further portion of methyllithium (0.2 mL, 0.32 mmol) was added. The reaction was allowed to warm to r.t. before being quenched with water (10 mL). The THF was removed in vacuo and the residue partitioned between DCM (100 mL) and water (30 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 5-25% EtOAc in heptane) gave the title compound as a white solid (145 mg, 65%). δH (CDCl3) 8.42 (s, 1H), 7.70 (d, J 12 Hz, 1H), 7.60-7.63 (m, 2H), 7.42-7.55 (m, 5H), 5.23-5.31 (m, 1H), 2.80 (s, 3H), 1.87 (d, J 3.6 Hz, 1H), 1.47 (d, J 6.4 Hz, 3H). LCMS (ES+) 264.16 (M+H)+, RT 4.03 minutes (Method 4).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogen carbonate (1.31 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.71 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then 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 to give the title compound as colorless crystals (0.26 g, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:9])[C:7]=1[Br:8].[C:21]12([CH2:31][CH2:32][OH:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.[OH-].[Na+].[Cl-].[Na+]>O1CCOCC1>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[N:4]=[CH:3][C:2]=1[O:33][CH2:32][CH2:31][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: O=C(Cn1ncc(Br)c(Br)c1=O)NCc1ccncc1
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(Cn1ncc(OCCC23CC4CC(CC(C4)C2)C3)c(Br)c1=O)NCc1ccncc1
Yield: 9 %

Procedure:
2-{4,5-Dibromo-6-oxopyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (48 mg, 0.119 mmol) and 1-adamantanethanol (92 mg, 0.510 mmol) in 1,4-dioxane (2 mL) were stirred with 6 M aqueous sodium hydroxide (50 μL, 0.300 mmol) at 100° C. for 6 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 0/1) to give the desired product (9% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)c(Cl)ccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3ccc(Cl)c(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 7,8-dichloro-1,4,5,6-tetrahydroazepino[4, 5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate(0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2.5 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed by crystallization from MeOH/EtOAc to give 1.5 g (81%) of a white solid: mp 132.5-135.0° C.; IR (diffuse reflectance) 2974, 1747, 1683, 1465, 1450, 1416, 1365, 1303, 1255, 1216, 1195, 1170, 1155, 1115, 803 cm−1; MS (EI) m/z 440 (M+), 442, 440, 386, 385, 384, 311, 300, 298, 57, 56; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.13; H, 5.98; N, 6.36.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:9][I:10]>CC(C)=O>[I-:10].[C:1]([C:3]1[CH:4]=[N+:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(C#N)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
3-Cyanopyridine (1) (104 g, 1 mol) and methyl iodide (150 g, 1.06 mol) in acetone (500 ml) was stirred for 5 hours at room temperature. Then more methyl iodide (20 g, 0.14 mol) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was filtered, and the solid product was washed with acetone (100 ml) and then thoroughly with ether. After drying, 199 g (0.81 mol, 81%) of the title compound were obtained, M.P. 145°-150° C.
Reaction SMILES: [OH:1][C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>C(O)C>[ClH:25].[ClH:25].[OH:1][C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=3)[N:31]=2)[CH2:7][CH2:8]1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(C(O)(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: Cl
Yield: 78.3 %

Procedure:
427 mg of 4-(hydroxydiphenylmethyl)-1-piperidinepropanamine and 235 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 160° C. for 3.5 hours. After cooling, ethanol and saturated aqueous sodium bicarbonate were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The solution was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methnol:triethylamine (50:5:1). The desired fraction was collected, concentrated, dissolved in 5 ml of ethyl acetate; 0.23 ml of 4N-hydrogenchloride in ethyl acetate was added, followed by concentration. Ethylether was added to the residue; the powder was collected by filtration and dried to yield 216 mg of the title compound. amorphous
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:20]
Reactant: CCCCCCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), hexylamine (0.330 g, 3.26 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-hexyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.06 g, 83.3% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[OH:16])[CH2:11][CH2:10]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH2:3].[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)([OH:16])[CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH2:10][CH2:11]2)=[CH:22][CH:21]=1.[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH2:10][CH2:11]2)([OH:16])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O
Product: OCCCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.2 %

Procedure:
A solution of 16.8 g (0.040 mol) of 4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinepentanoic acid ethyl ester in 100 mL of dry (freshly distilled from lithium aluminum hydride) tetrahydrofuran was added dropwise to a solution of 3.8 g (0.100 mol) of lithium aluminum hydride in 100 mL of dry tetrahydrofuran while stirring vigorously at ambient temperature for 1 h and the excess lithium aluminum hydride was quenched by successive, dropwise additions of 4 mL of water, 4 mL of a 15% sodium hydroxide solution, and 12 mL of water. The solution was allowed to stir for 30 min, filtered, and the filtrate concentrated under reduced pressure to yield 11.5 g (98%) of an off-white solid. A portion of the solid was recrystallized from ethyl acetate/petroleum ether (30°-60° C.) to give the title compound as a white solid, mp 103°-105° C.
Reaction SMILES: C([CH2:5][CH2:6][C@@:7](O[SiH](C)C)([N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[CH:10]1)[CH3:8])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.C([O:46]C(C)C)(C)C>O1CCCC1.C(O)C>[OH:46][CH2:5][CH2:6][C@H:7]([N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[CH:10]1)[CH3:8]
Reactant: C[SiH](C)O[C@](C)(CCC(C)(C)C)n1cnc(-c2cccnc2)c1
Reactant: CC(C)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](CCO)n1cnc(-c2cccnc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-[1-[(1R)-3-tertbutyldimethylsiloxy-1-methylpropyl]-1H-imidazol-4-yl]-pyridine (30) (1.12 g, 3.24 mmol) in 4 mL tetrahydrofuran was added 4 mL of 1M tetrabutylammonium flouride, and the reaction was stirred for 10 min. Hydrochloric acid in ethanol was added, followed by isopropyl ether. The solids were collected by filtration and recrystallized from acetonitrile to provide 0.51 g of product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:16]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]2[N:15]=[CH:14][NH:13][CH:12]=2)=[O:18])[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq. ), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCI (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: Cc1cc(Br)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 96.1 %

Procedure:
4.2 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-4-bromoaniline, 1.42 g of pyridine and 1.74 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 4.73 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-bromoaniline are obtained as colorless needles.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl.C(OCC)(=O)C>[CH3:28][S:29]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:19])([F:18])[F:20])[CH:5]=1)=[O:16])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@](O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@](O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
439 mg of chiral diol (5C) of Example 22 was dissolved in 20 ml of dichloromethane. The solution was cooled to 0° C. (ice). 170 mg of triethylamine was added. 174 mg of methanesulfonyl chloride was dissolved in 5 ml of dichloromethane and slowly added to the diol solution. After the addition was completed, the mixture was allowed to warm to room temperature. After 25 minutes at room temperature, the reaction mixture was analyzed with HPLC; there was still 27% of diol present. Next 70 mg of methanesulfonyl chloride was added. After 10 minutes at room temperature, the reaction was completed. 60 ml of ethyl acetate and 60 ml of 0.5 N aqueous HCl were added. The organic layer was washed subsequently with 60 ml of water and 60 ml of saturated NaHCO3, dried (Na2SO4), filtrated and evaporated to dryness. Purification of the residue by column chromatography (Merck silica gel 60; eluens:ethyl acetate) afforded the title compound as a green/black oil. Isolated yield: 473 mg. 1H-NMR confirmed the expected structure (2S-enantiomer). HPLC: 94% purity.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8](O)[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[N:4]1)[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH2:1]([N:3]1[C:7]([CH:8]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C(O)CC(C)C
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 3.3 %

Procedure:
Using 1-{1-ethyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}-3-methylbutan-1-ol (0.39 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.28 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.02 g, 4%) was obtained as a white solid.