Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH2:23]OS(C)(=O)=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.O>ClCCl>[Cl:1][C:2]1[CH:22]=[C:21]([CH2:23][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(COS(C)(=O)=O)cc3Cl)c2n1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(Cn4ccnc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of methyl 3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in dichloromethane (6.0 ml) was added imidazole (193 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was washed with diethyl ether, and collected by filtration to give the objective compound (213 mg) as a pale-yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:22])([N:16]3C[CH2:20][S:19][CH2:18][CH2:17]3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:23][C:24]([C:26]2[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])=[CH:4][CH2:3]1.OO.CCOC(C)=O>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([NH:16][CH2:17][CH2:18][S:19][CH3:20])[CH3:22])[CH:11]=[CH:10][C:9]=2[NH:23][C:24]([C:26]2[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)N3CCSCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: OO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSCCNC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-methyl-1-thiomorpholin-4-yl-ethyl)-phenyl]-amide (as prepared in Example 14, step (e), 38.0 mg, 0.0820 mmol) in 0.5 mL of DCM at RT was added titanium (IV) isopropoxide (24.0 μL, 0.0820 mmol). The mixture was cooled to 0° C. and H2O2 (18 μL, 0.16 mmol, 30 wt % in H2O) was added. After stirring at 0° C. for 0.5 h and at −20° C. for 16 h, the mixture was treated with EtOAc (50 mL) and washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (15-25% EtOAc/DCM) to afford the title compound (33 mg, 80%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.6 Hz), 7.99 (s, 1H), 7.49 (dd, 1H, J=8.6, 2.3 Hz), 7.37 (d, 1H, J=2.3 Hz), 5.74 (m, 1H), 2.91-3.07 (m, 8H), 2.31 (m, 2H), 2.08 (m, 2H), 1.60 (t, 2H, J=6.3 Hz), 1.42 (s, 6H), 1.09 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C26H33N5O3S, 494.2 (M−H). found 494.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][N:7]([C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCCC1C
Yield: 82.3 %

Procedure:
A mixture of 3.3 g (0.0093 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-57) in 30 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 2.5 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-57). This material was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26](Br)[CH3:27].[H-].[Na+]>CN(C)C=O.O1CCCC1>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)[CH3:27]
Reactant: CCBr
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
Compound 1 (1.69 g) obtained in Example 1 was dissolved in a mixed solvent of N,N-dimethylformamide (12.5 ml) and tetrahydrofuran (12.5 ml), and ethyl bromide (817.3 mg) and sodium hydride (300 mg, 60% mineral oil dispersion) were added thereto, followed by stirring at room temperature for 3 hours. Ice was added to the reaction solution, and the mixture was subjected to partitioning between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give Compound 3 (1.54 g).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C1(C)C=CC=CC=1>[C:15]([O:14][C:12](=[O:13])[CH2:11][NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNCCc1ccccc1
Temperature: 95 °C
Yield: 48.9 %

Procedure:
A solution of 12.6 ml (100 mmol) phenethylamine in 50 ml toluene was treated at RT with 7.4 ml (200 mmol) tert-butyl bromoacetate and heated at 95° C. for 4 h. After cooling (0° C.), filtration and evaporation of the filtrate, the residue was suspended in pentane, cooled (0° C.), filtrated and evaporated to give 11.5 g (98%) of phenethylamino-acetic acid tert-butyl ester as an oil, MS: 236 (MH+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:15].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:5]([CH:6]=[N:19][OH:20])[C:4]=1[OH:15]
Reactant: NO
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(C=NO)c(O)c(C(F)(F)F)c1

Procedure:
0.05 moles of the aldehyde from Step A, 0.12 moles of hydroxylamine hydrochloride and sodium acetate (0.12 moles) are dissolved in a mixture of ethanol (100 ml.) and water (30 ml.). The reaction mixture is refluxed for 2 hours, cooled and water added until no more precipitate forms. The solid that separates is crystallized from ethanol to yield 3-trifluoromethyl-5-tert-butyl salicylaldehyde oxime.
Reaction SMILES: [F:1][C:2]([F:35])([C:31]([F:34])([F:33])[F:32])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[O:8][C:9]([F:22])([F:21])[CH2:10][O:11][CH2:12][C@@H:13]([F:20])[CH2:14][O:15][CH2:16][CH2:17][CH2:18]Cl.FC(F)(C(F)(F)F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COC[C@@H](F)CO.BrCCCCl.[CH2:72]([C:79]1[CH:80]=[N:81][C:82]([C:85]2[CH:90]=[CH:89][C:88]([OH:91])=[CH:87][CH:86]=2)=[N:83][CH:84]=1)[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78]>C(#N)C.CN(C)C=O>[CH2:72]([C:79]1[CH:84]=[N:83][C:82]([C:85]2[CH:86]=[CH:87][C:88]([O:91][CH2:18][CH2:17][CH2:16][O:15][CH2:14][C@H:13]([F:20])[CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:24])([F:23])[C:6]([F:26])([F:25])[O:5][C:4]([F:28])([F:27])[C:3]([F:30])([F:29])[C:2]([F:35])([F:1])[C:31]([F:34])([F:33])[F:32])([F:22])[F:21])=[CH:89][CH:90]=2)=[N:81][CH:80]=1)[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78]
Reactant: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: F[C@@H](COCCCCl)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: ClCCCBr
Agent: OC[C@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCc1cnc(-c2ccc(OCCCOC[C@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The starting material, 3-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropoxy)propyl chloride, was prepared by combining 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropanol (20 g, 39.4 mmol) and 1-bromo-3-chloropropane (18.6 g, 118 mmol). The resulting compound (2.0 g, 3.4 mmol) was then combined with 5-heptyl-2-(4-hydroxyphenyl)pyrimidine (0.9 g, 3.4 mol) in acetonitrile/dimethyl formamide (1:1, 20 mL) using essentially the procedure of Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography, eluting with 30:1 toluene/ethyl acetate, followed by Kugelrohr distillation (180-90° C. at 0.01 torr; yield 0.96 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18].C(N(C(C)C)C(C)C)C.[CH3:28][O:29][CH2:30]Cl>COCCOC>[CH3:28][O:29][CH2:30][O:1][CH:2]1[CH2:7][C:6]([N+:14]([O-:16])=[O:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18]
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: COCOC1CC(c2ccccc2)([N+](=O)[O-])CN(C)C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 50 mg (0.2 mmol) rac-3-hydroxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one and 52 ul (0.3 mmol) N-ethyl diisopropylamine in 1,2-dimethoxyethane were added 23 ul (0.3 mmol) chloromethyl methyl ether at room temperature. After 1 hour, the solution was heated in a 60° C. oil bath for 20 hours. The mixture was cooled to room temperature. 52 ul (0.3 mmol) N-ethyl diisopropylamine and 23 ul (0.3 mmol) chloromethyl methyl ether were added. The mixture was heated in a 60° C. oil bath for 4 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed once with water. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 30 mg (51%) of the title compound as a yellow oil. MS (m/e): 295.2 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[C:1]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(CCO)CC1
Reaction time: 16 h
Yield: 93.6 %

Procedure:
Benzoyl chloride (13.3 mL, 0.115 mole) was added dropwise over 0.5 hour to a 0° C. solution of 4-piperidineethanol (14.8 g, 0.115 mole) and dry triethylamine (18 mL, 0.13 mole) in dichloromethane with mechanical stirring. After 16 hours at room temperature, the mixture was quenched with 1.0 M aqueous NaOH (150 mL), then extracted with ethyl acetate (1 L). The organic phase was extracted further with H2O (125 mL), then brine (125 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with chloroform to 6% methanol in chloroform, followed by concentration in vacuo and drying at 100° C. under high vacuum for 1.5 hour to yield a viscous oil (25.1 g, 94%). IR (neat): 3409 cm-1 (s,br), 1613(s). HRMS: Calculated for C14H19NO2 : 233.1416; found: 233.1410.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]5)[CH:21]=[CH:20][CH:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:5][CH:4]=1)=[CH2:2].[OH2:37].C[N+]1([O-])CCOCC1.[OH2:46]>CC(C)=O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[OH:37][CH:1]([C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:23]=[C:22]([N:24]5[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]5)[CH:21]=[CH:20][CH:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:5][CH:4]=1)[CH2:2][OH:46]
Reactant: C=Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncc(C(O)CO)n5)cc43)n2)CC1
Yield: 67 %

Procedure:
A mixture of tert-butyl 4-[6-[6-(6-vinylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperazine-1-carboxylate (513 mg; 1.06 mmol), N-methylmorpholine-N-oxide monohydrate (744 mg, 6.35 mmol) and 2.5% solution of osmium tetroxide in tert-butanol (0.6 ml, 0.04764 mmol) in 20 ml of acetone and 2.5 ml of water was stirred at room temperature for 24 hours. The mixture was filtered, mixed with water and extracted with EtOAc. The organic extracts were washed with water, 5% aq. citric acid, sat. aq. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was triturated with ethyl ether, the precipitate was collected by filtration and washed with ethyl ether affording tert-butyl 4-(6-(6-(6-(1,2-dihydroxyethyl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (424 mg, 67%). MS (ESI) m/z: 519.3 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Cl)cc1Br
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(Cl)cc1Br

Procedure:
using isopropyl 2-bromo-4-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2-bromo-4-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.86 ppm (s, 1H), 7.74 ppm (s, 1H), 5.23 ppm (m, 1H), 3.42 ppm (s, 3H), 2.96 ppm (m, 2H), 2.82 ppm (m, 2H), 2.18 ppm (m, 2H), 1.35 ppm (d, 6H),
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9]I)[C:4]#[N:5].CN(C=O)C.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CC(C)=O>[F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9][N:31]1[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:37])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCCI)N1C(=O)c2ccccc2C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: N#CC(CF)(CCCCN1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoromethyl-2-phthalimido-6-iodo-hexanenitrile (9.0 g, 22.5 mmol), dry DMF (30 ml), and potassium phthalimide (4.2 g, 1 equivalent) is stirred and heated at 80° C. for 4 hours. The DMF is removed under reduced pressure (0.1 mm Hg), and the residue is taken up in chloroform. The chloroform mixture is filtered, and the filtrate is washed with 2 N NaOH, 2 N HCl, and water. Evaporation of solvent gives a residue which, when dissolved in the minimum amount of acetone, crystallizes upon addition of ether. After standing at 5° C. overnight, the colourless crystals are collected (7.0 g), mp (Kofler) 136° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]12[CH2:22][CH:13]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=31)[CH2:12][NH:11][CH2:10][CH2:9]2.[C:23]1([CH2:29][C:30](Cl)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH2:30]([N:11]1[CH2:10][CH2:9][CH:8]2[CH2:22][CH:13]([CH:14]([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=32)[CH2:12]1)[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1c2ccccc2C2CCNCC1C2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OC1c2ccccc2C2CCN(CCc3ccccc3)CC1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of anhydrous toluene was added to 1 g of 2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one and 2 g of triethylamine, and 1 g of phenylacetyl chloride was added dropwise to the mixture over a period of 30 minutes under ice cooling and agitation. After completion of the dropwise addition, the mixture was agitated for 1 hour at room temperature. The reaction mixture liquid was washed twice with 50 ml of water and the toluene layer was dried with anhydrous sodium sulfate and filtered. Toluene was removed from the filtrate by distillation under reduced pressure, and the residue was dissolved in 20 ml of anhydrous dioxane and the solution was heated and refluxed for 6 hours together with 0.3 g of lithium aluminum hydride. Then, excess lithium aluminum hydride was decomposed with drops of ethyl acetate, and 50 ml of saturated aqueous solution of Rochelle salt was added and the mixture was shaken. The resulting solution was extracted with ether, and the ether extract was subjected to distillation to remove ether therefrom. The residue was subjected to vacuum distillation to obtain 0.9 g of a fraction of 4-phenethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol boiling at 148° to 152° C. (bath temperature) under 1 mmHg. The product was a light-yellow oil.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21](=[O:23])[CH3:22]>C1COCC1>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21]1([CH3:8])[CH2:22][O:23]1
Reactant: CC(=O)c1c(F)cc(F)cc1F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2c(F)cc(F)cc2F)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents were stirred for 10 min. after which the solution of 1-(2,4,6-trifluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored for completion. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:50]([O:54][CH3:55])(=[O:53])[CH:51]=[CH2:52].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:55][O:54][C:50](=[O:53])[CH:51]=[CH:52][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(Br)ccc23)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
Combine 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (0.15 g, 0.36 mmol), tri-o-tolylphosphine (0.38 g, 1.26 mmol), tribuytlamine (0.12 mL, 0.5 mmol), methyl acrylate (0.065 ml, 0.72 mmol), anhydrous toluene (3 mL), and DMF (1.5 mL). Bubble nitrogen gas through the solution for 20 minutes. Add palladium acetate (4.0 mg, 0.018 mmol). Heat the reaction mixture at 80° C. for 48 hours. Chromatograph the residue on silica gel (elute with 2% methanol/methylene chloride, then 4% methanol/methylene chloride). Further purification by preparative HPLC affords the title compound 42 mg (28%) as a yellowish solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][CH2:14][O:15][CH3:16])=[C:10](C=O)[CH:9]=[CH:8]2)[CH3:2].ClC1C=CC=C([C:26](OO)=[O:27])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][CH2:14][O:15][CH3:16])=[C:10]([O:27][CH3:26])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1cccc2ccc(C=O)c(OCOC)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cccc2ccc(OC)c(OCOC)c12
Reaction time: 2 h
Yield: 74.8 %

Procedure:
220 g of 8-ethyl-1-methoxymethoxy-2-naphthalenecarbaldehyde was dissolved in 1540 ml of dichloromethane, to which 186 g of 80 to 85% m-chloroperbenzoic acid was added portion by portion. The reaction solution generated heat and was gently refluxed. The reaction solution was ice-cooled, to which 200 ml of a saturated sodium thiosulfate aqueous solution was added. The precipitated insoluble matters were removed by filtration and washed with dichloromethane. The filtrate was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, 254 g of the resultant residue was dissolved in 500 ml of methanol, to which 89 g of potassium hydroxide preliminarily dissolved in 200 ml of water was added, followed by refluxing for 20 minutes. The reaction solution was poured into 700 mo of cooled 2N hydrochloric acid and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, from which the solvent was distilled off. 278 g of the resultant residue was dissolved in 600 ml of N,N-dimethylformamide, to which 500 g of anhydrous potassium carbonate and 256 g of methyl iodide were added, followed by agitation at 60° C. for 2 hours. The insoluble matters were filtered off and washed with ethyl acetate. Water was added to the resultant filtrate, which was extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, the resultant residue was purified by silica gel column chromatography to obtain 166 g of the caption compound as a yellow oily substance.