Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([F:8])([F:7])[F:6].O.[NH2:11][NH2:12]>CO>[F:6][C:5]([F:8])([F:7])[CH2:4][C:3]([NH:11][NH2:12])=[O:2]
Reactant: NN
Reactant: COC(=O)CC(F)(F)F
Solvent: O
Solvent: CO
Product: NNC(=O)CC(F)(F)F
Yield: 57.8 %

Procedure:
A solution of 3,3,3-trifluoro-propionic acid methyl ester (24.6 g, 173 mmol) in methanol (173 mL) was treated with hydrazine hydrate (8.4 mL, 173 mmol). The resulting mixture was then heated under reflux for 16 h and filtered. The filtrate was adsorbed on silica, evaporated and chromatographed (SiO2, dichloromethane:methanol=95:5 to 90:10). The title compound (14.2 g, 58%) was obtained as a white solid. MS: m/e=142.1 [M]+.
Reaction SMILES: [NH:1]([C:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[C@H:2]([C:7]([O:9]CC1C=CC=CC=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CO.[Pd]>[NH:1]([C:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Yield: 74.9 %

Procedure:
A solution of N-phenylacetyl-L-Leu-OBzl (14 g) in methanol (140 ml) was hydrogenated over 10% palladium on carbon (1.4 g) at 3 atmospheric pressure of hydrogen for 2 hours. After removal of the catalyst by filtration, the filtrate was concentrated in vacuo. The residue was triturated with diisopropyl ether to give N-phenylacetyl-L-Leu-OH (7.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]3([CH3:23])[CH3:22])[C:7]=1[O:8][CH3:9].CN(C)[CH:28]=[O:29]>C1COCC1>[CH3:21][C:16]1([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]2[CH:11]=[C:10]([C:6]3[C:7]([O:8][CH3:9])=[C:2]([CH:3]=[CH:4][C:5]=3[O:24][CH3:25])[CH:28]=[O:29])[CH:19]=[CH:18][C:17]1=2
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72.2 %

Procedure:
To a solution of 6-(5-bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthalene (0.24 g, 0.55 mmol) in anhydrous THF (6 mL) was added at −78° C. under argon n-BuLi (1.6 M in hexane, 0.7 mL, 1.1 mmol). The solution was stirred for 5 minutes at −78° C. and N,N-dimethylformamide (0.13 mL, 1.65 mmol) was added. The reaction mixture was stirred 2 hours at −78° C. then quenched with aqueous ammonium chloride and brought to room temperature. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed and silica gel (eluent: ethyl acetate/hexane, 1:9) to give 0.14 g (72%) of 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxy-benzaldehyde. 1H NMR (500 MHz; CDCl3): δ 1.29 (s, 6 H); 1.32 (s, 6 H); 1.72 (s, 4 H); 3.37 (s, 3 H); 3.83 (s, 3 H); 6.83 (d, J=9.0 Hz, 1 H); 7.14 (dd, J1=2.0 Hz, J2=8.5 Hz, 1 H); 7.33 (d, J=8.0 Hz, 1 H); 7.36 (s, 1 H); 7.85 (d, J=8.5 Hz, 1 H); 10.29 (s, 1 H).
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[N+:13]([CH:4]1[C:3](=[O:12])[CH:2]2[CH:6]([CH:7]3[CH2:10][CH:1]2[CH2:9][CH2:8]3)[C:5]1=[O:11])([O-:15])=[O:14]
Reactant: O=C1CC(=O)C2C3CCC(C3)C12
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: O=C1C2C3CCC(C3)C2C(=O)C1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a stirred suspension of tricyclo [5,2,1,02,6 ] decane-3,5-dione (0.82g; 0.05 mole) in dry ether (8ml.) was added fuming nitric acid (1ml.) at -20° C. After stirring for 1hr. at 20° C the solid was filtered, washed with cold, dry ether and recrystallised from methanol, m.p. 167° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH:28]([C:32](O)=[O:33])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:32]([CH:28]3[O:29][CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]3)=[O:33])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 4 h
Yield: 123.1 %

Procedure:
N-(3,4-Dichlorophenyl)piperazine-1-carboxamide hydrochloride (467 mg) and 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (347 mg) were dissolved in dry THF (10 mL) followed by addition of N,N-diisopropylethylamine (0.52 ml) and HATU (628 mg) and the reaction was stirred for 4 h. The solvent was evaporated under reduced pressure then redissolved in ethyl acetate (50 ml) followed by washing with sat. aqueous NaHCO3 (20 ml), 10% w/v citric acid (aq.) (15 ml) and brine (15 ml). The organic layer was dried (MgSO4), filtered and evaporated. Purification by chromatography (1:1 EtOAc:hexanes 1:1 to EtOAc neat) afforded the title compound (900 mg) as an impure foam contaminated with N,N,N′,N′-tetramethylurea. The product was used without further purification.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]3[C:24]=2[C:25]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=2)=[N:26][CH:27]=[N:28]3)[CH2:10]1)(C(C)(C)C)(C)C.C(#N)C>FC(F)(F)C(O)=O>[Cl:43][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[F:42])[NH:35][C:25]1[C:24]2[C:29](=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:23]=2[O:22][CH2:21][C@H:11]2[NH:12][CH2:13][C@H:9]([OH:8])[CH2:10]2)[N:28]=[CH:27][N:26]=1
Reactant: COc1cc(OC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(OC[C@@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
tert-Butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (860 mg) was dissolved in trifluoroacetic acid (40 ml) and stirred at room temperature for 24 hours. The reaction mixture was then concentrated in vacuo, and excess water was added, followed by the careful addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with 3% methanol in DCM and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a light brown foam. Trituration with cold acetonitrile gave (3R,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxy-quinazolin-5-yl}oxy)methyl]-pyrrolidin-3-ol as an off-white solid (394 mg, 69%); NMR spectrum (DMSO-d6) 10.50-10.00 (br, 1H), 8.49 (s, 1H), 8.25 (dd, 1H), 7.90-7.84 (m, 1H), 7.44 (t, 1H), 6.82 (d, 1H), 6.76 (d, 1H), 4.92 (br s, 1H), 4.38 (dd, 1H), 4.32 (br s, 1H), 3.92-3.86 (m, 4H), 3.77-3.23 (br s, 1H), 3.09 (dd, 1H), 2.83 (d, 1H), 1.88 (dd, 1H), 1.74-1.65 (m, 1H); Mass spectrum MH+ 419.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd]Cl>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:34]3[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)cc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cn1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
Similar to Example 57, a mixture of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole (200 mg, 0.547 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinylamine (302 mg, 1.38 mmol), PdCl2 (dppf) (45 mg, 0.0551 mmol) and aq. K2CO3 (2M, 4 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 24 hrs. The mixture was cooled to room temperature, diluted with H2O, extracted with CH2Cl2 (4×), and the combined organic extracts were dried (Na2SO4), and the solvents removed under vacuum. Chromatography on alumina, eluting with CH2Cl2/EtOAc (100:0 to 80:20) to CH2Cl2/MeOH (100:0 to 98.5:1.5), followed by recrystallization from CH2Cl2/MeOH/i-Pr2O gave 2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4,5′-bipyrimidine-2′-amine (157 mg, 66% yield): mp 281-285° C.; 1H NMR (DMSO-d6) δ 9.09 (s, 2H), 8.35 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (t, Jjw=52.8 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 2H), 3.82 (m, 4H), 3.77 (m, 4H).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]>C(O)C.[Pt]=O>[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([NH:2][CH3:1])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CN
Agent: O=[Pt]
Solvent: CCO
Product: CNC1CCN(C(C)=O)CC1

Procedure:
9.9 g of methylamine in 50 ml of ethanol are added to 14.4 g of 1-acetyl-4-oxopiperidine in 100 ml of ethanol. The mixture is then hydrogenated in the presence of platinum oxide at room temperature and atmospheric pressure, filtered and evaporated.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=1[NH2:26]>>[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=1[NH:26][C:20](=[O:22])[CH2:19][CH2:18][C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1
Reactant: CCCCCCCCCCCCn1nnc(CCC(=O)O)n1
Reactant: Nc1ccc(F)cc1F
Product: CCCCCCCCCCCCn1nnc(CCC(=O)Nc2ccc(F)cc2F)n1

Procedure:
In a manner similar to Example 34, 2-dodecyl-2H-tetrazole-5-propanoic acid was condensed with 2,4-difluoroaniline to give the title compound, mp 86°-87° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N+:5]([O-])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17]>>[OH:17][CH:7]1[C:6]2[N:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12][C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1cc2c([n+]([O-])c1)CCCC2
Product: N#Cc1cnc2c(c1)CCCC2O
Temperature: 23 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a solution of 3-cyano-5,6,7,8-tetrahydroquinoline 1-oxide (645 mg, 3.7 mmol) was added dropwise under ice cooling trifluoroacetic anhydride (6.22 g, 4.18 ml, 29.6 mmol). The light yellow solution was stirred at 23° C. for 18 h. The mixture was quenched with 1 N NaOH solution and stirred vigorously for 30 min., then extracted twice with dichloromethane, the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the 8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (562 mg, 3.23 mmol, 87.1% yield) as a white solid. MS (ISP): m/z=175.1 [(M+H)+].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:29][CH3:30])=[CH:20][CH:21]=[C:22]([C:23]#[C:24][Si](C)(C)C)[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:23]([C:22]1[C:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]([O:29][CH3:30])=[CH:20][CH:21]=1)#[CH:24]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C#C[Si](C)(C)C)ccc(OC)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Temperature: 60 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
A mixture of 17 mg (0.04 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trimethylsilanylethynyl-1H-benzoimidazole and 0.5 ml 1N NaOH in 2 ml THF/methanol (1:1) is stirred for 1 hour at 60° C. The reaction mixture is cooled to room temperature and poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified on 0.5 mm silica gel plates (hexane:EtOAc=3:1) to afford 7 mg of the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]2([OH:24])[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(#N)C>[Pt].C(O)(C)C>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][C:17]1([OH:24])[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CN1CCC(O)(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)CC1
Agent: [Pt]
Solvent: CC#N
Solvent: CC(C)O
Product: CN1CCC(O)(CNc2c(N)c(Cl)nc3ccccc23)CC1

Procedure:
A mixture of 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}-1-methylpiperidin-4-ol (14.05 g), 5% platinum on carbon (1.1 g), acetonitrile (280 mL), and isopropanol (84 mL) was placed under hydrogen pressure on a Parr apparatus overnight. The reaction mixture was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to provide crude 4-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}-1-methylpiperidin-4-ol. This material was dissolved in 240 mL of acetonitrile.
Reaction SMILES: OC[CH:3]([C:6]1[N:7]=[C:8]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][CH:10]=[CH:9]2)CO.[Se](=O)=[O:21]>C(OCC)(=O)C>[CH:3]([C:6]1[N:7]=[C:8]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:21]
Reactant: OCC(CO)c1nc2ccccc2c2ccccc12
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: O=Cc1nc2ccccc2c2ccccc12
Yield: 42 %

Procedure:
In the next step, a mixture of 6-(2-hydroxy-1-hydroxymethyl)-phenanthridine (24) (6 g, 31 mmoles) and finely powdered selenium dioxide (3.8 g, 34 mmoles) is refluxed in ethyl acetate (125 ml) for 10 hours. The deep red solution that form is then filtered while hot through celite, before evaporating to dryness. The resulting solid is digested in warm 1M hydrochloric acid (125 ml), filtered and partially neutralized with sodium bicarbonate. The initial red precipitate is filtered off before completely neutralizing the solution. The resulting pale yellow solid is filtered off and recrystallized from acetone/petroleum ether to give 2.7 g of 6-formylphenanthridine (yield=42%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[CH:14]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[CH:14]=1
Reactant: COC(=O)c1cccn2cc(C)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cn2cccc(C(=O)O)c2n1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
Methyl 2-methylimidazo[1,2-a]pyridine-8-carboxylate (4 g, 21 m moles) was dissolved in a mixture of ethanol (45 ml) and water (20 ml), and sodium hydroxide (2.5 g, 63 m moles) was added thereto and refluxed under heating for 30 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (40 ml) was added to the concentrate, and the mixture was adjusted to pH 4 with conc. hydrochloric acid. The precipitating crystals were collected by filtration to give the object compound (2.3 g, yield 64%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CCCCCCCC(=O)c1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
4′-(2-Hydroxy ethyl)octanophenone (1.0 g) prepared in the step B was dissolved in dichloromethane (10 ml) to obtain a solution. p-Toluene sulfonyl chloride (923 mg) and pyridine (383 mg) were added to the solution with cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, ice water was added to the solution, the solution was stirred at room temperature for 20 minutes. Dichloromethane layer was washed with 2% hydrochloric acid, sodium bicarbonate solution, and water. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from hexane-ethyl acetate (10:1) to obtain 2-(4-octanoyl phenyl)ethyl p-toluene sulfonate (950 mg) in the form of colorless crystal.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][C@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[Si:17]([O:7][C@@H:6]1[C@@H:2]([F:1])[CH2:3][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5]1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H]1C[C@H](O)[C@@H](F)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1

Procedure:
A solution of the (1S,3S,4S)-ethyl 3-fluoro-4-hydroxycyclopentanecarboxylate (6.73 g, 38.2 mmol, 1.0 equiv), TBSCl (11.5 g, 76.4 mmol, 2.0 equiv) and imidazole (12 g, 0.17 mol, 4.0 equiv) in DMF (10 mL) was stirred at rt for 4 h. After this time the free alcohol was consumed by tlc analysis. The DMF was removed in vacuo and the residue was partitioned between ether and water. The layers were separated and the organic layer washed with brine, dried over Na2SO4 filtered, and evaporated. (1S,3S,4S)-ethyl 3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentanecarboxylate was isolated in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:11]=[C:10]([N:22]2[CH:23]=[CH:24][C:20]([CH3:19])=[N:21]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
20.85 g of methyl 2-chloro-4-fluorobenzoate were dissolved in 150 ml of N-methylpyrrolidone, 30.68 g of potassium carbonate and 9.38 ml of 3-methylpyrazole were added thereto, and the mixture was stirred at 120° C. for 3 hours. Additionally, thereto was added 1.79 ml of 3-methylpyrazole, and the mixture was stirred at 120° C. for 3 hours. The reaction solution was cooled, mixed with water, and extracted with EtOAc. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (hexane-EtOAc (20:1)) to obtain 9.25 g of methyl 2-chloro-4-(3-metyl-1H-pyrazol-1-yl)benzoate.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:30])([C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:18]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:18][C:17]([F:16])([F:30])[C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])(=[O:8])=[O:9]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
6.8 g of trifluoromethanesulfonic anhydride was added dropwise to 5.0 g of 2,2,3,3,4,4,5,5,5-nonafluoropentanol at 0° C., and the mixture was stirred at room temperature for 5 hours and at 100° C. for 3 hours. Thereafter, the reaction mixture was poured to ice water and then extracted with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 4.7 g of 2,2,3,3,4,4,5,5,5-nonafluoropentyl trifluoromethanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[NH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CCN(CC)CCOCCN
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: CCN(CC)CCOCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and commercially available 2-(2-aminoethoxy)-N,N-diethylethanamine, the title compound was obtained; MS (Found M+1=402).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH:12](Br)[CH3:13])[N:3]=1.[OH:15][CH2:16][C:17]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>>[Br:1][C:2]1[N:3]=[C:4]([CH:12]([O:15][CH2:16][C:17]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(Br)n1

Procedure:
This compound was prepared according to the experimental condition of Intermediate 2 from 2-bromo-6-(1-bromoethyl)-4-(trifluoromethyl)pyridine and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate to afford the titled compound. 1HNMR (CDCl3 400 MHz) δ7.41 (m, 3H), 7.36 (m, 4H), 5.07 (q, 1H), 4.34 (m, 2H), 3.80 (m, 2H), 3.05 (m, 2H), 2.25 (m, 2H), 1.96 (m, 2H), 1.55 (s, 9H), 1.43 (d, 3H). Mass Spec.: 544.44 (MH)+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])OC4C=CC=CC=4)=[CH:16][C:15]=3[F:30])[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:33]=[C:34]([CH:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:31][C:32]4[CH:33]=[C:34]([CH:42]([N:44]5[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[CH2:46][CH2:45]5)[CH3:43])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=4)=[O:29])=[CH:16][C:15]=3[F:30])[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)c(F)c1)Oc1ccccc1
Reactant: CC(c1cc(N)cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1cc(NC(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)c(F)c2)cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 75.8 %

Procedure:
Add phenyl N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]-3-fluoro-phenyl]carbamate (220 mg, 0.53 mmol), tert-butyl 4-[1-[3-amino-5-(trifluoromethyl)phenyl]-ethyl]piperazine-1carboxylate (165 mg, 0.442 mmol) and DIEA (120 mg, 0.88 mmol) in THF (10 mL), stir the reaction under N2 at 80° C. for 12 hrs. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (230 mg, 75.6%).