Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[F:22])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:36][C:32]3[CH:33]=[N:34][CH:35]=[C:30]([N:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)[CH:31]=3)=[C:3]([CH3:23])[C:4]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=3[F:22])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinoline (26.0 mg, 0.078 mmol) and 5-morpholinopyridin-3-amine in toluene to give 7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.58 (1H, dd, J=6.2, 2.8 Hz), 8.39 (1H, ddd, J=9.1, 4.4, 2.9 Hz), 8.11 (1H, br. s.), 8.03 (1H, dd, J=9.4, 5.9 Hz), 7.78 (2H, dd, J=9.8, 2.5 Hz), 7.64 (1H, br. s.), 7.29-7.42 (2H, m), 6.44 (1H, t, J=2.2 Hz), 3.77-3.87 (4H, m), 3.04-3.19 (4H, m), 2.19 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=478.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 86.2 %

Procedure:
A heterogenous reaction mixture of 2-(S)-iodomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (compound (4) obtained from above, 25 g, 0.08 mol), triethylamine (11.2 mL, 8.12 g, 0.08 mol) in methanol (250 mL) and 5% palladium on carbon (2.5 g, 10 wt %, Pd/C) was allowed to react at room temperature under a blanket of hydrogen gas overnight and until HPLC showed less than 1% starting material (˜7 hours). The reaction mixture was filtered and the filtrate was concentrated to a residue. The residue was dissolved in distilled water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with 1 M aqueous H3PO4 (2×100 mL) followed by saturated NaHCO3 (233 100 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (12.78 g, 85.9% yield). 1H NMR (CDCl3): δ 1.16 (d, 3H, CH3), 1.47 (s, 9H, 3×CH3), 1.50–1.82 (m, 2H, CH2), 1.84–2.03 (m, 2H, CH2 ), 3.34 (m, 2H, CH2) and 3.86 (m, 1H, CH); [M+H]+ at m/z 186.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].Cl.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OC)=O.O>[C:8]1([NH:14][NH:15][CH:1]=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COC=O
Product: O=CNNc1ccccc1
Reaction time: 12 h
Yield: 99.8 %

Procedure:
25 g of K2CO3 are added to a solution of 20 g of phenylhydrazine hydrochloride in 150 ml of methyl formate and 60 ml of water, and the mixture is refluxed for 1 hour and left at AT for 12 hours with stirring. The precipitate formed is filter-dried, and washed with a propan-2-ol/petroleum ether mixture. 18.8 g of the expected compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3ccccc3n2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a degassed solution of 2-chloro-quinoline (1.00 g, 6.11 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 7.33 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.96 g, 8.56 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (3.39 mg, 0.0061 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.37 mg, 0.0061 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 4 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 1.0 g (50%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.28-1.41 (m, 2H), 1.42 (s, 9H), 1.93-1.94 (m, 2H), 2.95-3.02 (m, 2H), 3.87-3.92 (m, 2H), 4.11-4.19 (m, 1H), 6.74 (d, J=8.9 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 7.10-7.16 (m, 1H), 7.42-7.51 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H). 13C NMR (75 MHz, DMSO): δ28.07, 31.49, 42.41, 46.52, 78.52, 113.21, 121.03, 122.80, 125.52, 127.42, 128.89, 136.18, 147.82, 153.92, 156.13. MS (ISP): 328.5 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([O:26]C)=[O:25])=[O:21])[CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:3]1.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([OH:26])=[O:25])=[O:21])[CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:3]1
Reactant: COC(=O)c1ccccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2ccccc2C(=O)O)CC1
Temperature: 80 °C
Yield: 7 %

Procedure:
A mixture of methyl 2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoate (500 mg, 1.17 mmol), NaOH (5.0 mL of 1.0 M, 5.0 mmol), and 1,4-dioxane (5 mL) was heated at 80° C. for 1.5 h. The mixture was cooled to rt before it was concentrated in vacuo. The solid residue was taken up in water and was washed with ethyl acetate which was discarded. The aqueous layer was acidified with 1N HCl and was extracted with ethyl acetate (2×). The combined organics were washed with brine, dried over sodium sulfate, and were concentrated in vacuo to give 2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoic acid (33 mg, 75%) as a white solid. ESI-MS m/z calc. 403.2. found 404.2 (M+1)+; Retention time: 2.31 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.65 (t, J=7.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.36 (br s, 2H), 7.28 (t, J=7.7 Hz, 1H), 7.08 (dd, J=13.8, 6.3 Hz, 2H), 4.39 (br s, 1H), 4.10 (s, 3H), 3.30-3.12 (m, 2H), 2.05-1.86 (m, 4H), 1.85-1.74 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1cc(Cl)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Cl)ccc1NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A mixture of 2-amino-5-chloroanisole (157 mg, 1 mmol), thiophene-2-sulfonyl chloride (183 mg, 1 mmol), and pyridine (0.25 mL, 3 mmol) in methylene chloride (3 mL) was stirred at room temperature for 16 hours. The mixture was then partitioned between methylene chloride and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 290 mg (96%) of the title compound. MS (ESI) m/e 304 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[C:19](O)(=[O:21])[CH3:20].[OH-].[Na+]>C(OC(=O)C)(=O)C>[C:19]([O:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: CCc1ccc(O)c(C(=O)c2ccc(Cl)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(OC(C)=O)c(C(=O)c2ccc(Cl)cc2)c1

Procedure:
2-Hydroxy-5-ethyl-4'-chlorobenzophenone (3 g), in acetic anhydride (10 ml) and acetic acid (1 ml) were refluxed for 3.5 hours, and allowed to cool. The mixture was poured into dilute NaOH solution and extracted with chloroform. The chloroform was washed with 10% NaHCO3 solution (50 ml), dried (MgSO4) and evaporated to leave an oil which was distilled, b.p. 160°-165° C. at 3.5 mm/Hg (2.3 g) to give the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[C:5]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:4]=2[C:3]=1[F:23].[CH2:24]([C:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1)[CH:25]=[CH2:26]>CN(C1C=CN=CC=1)C>[CH2:24]([C:27]1([S:30]([N:11]2[C:5]3[C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]([F:23])[C:4]=3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:32])=[O:31])[CH2:29][CH2:28]1)[CH:25]=[CH2:26]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c(F)c4ncoc4c32)CC1
Yield: 55.8 %

Procedure:
Intermediate I-21a was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-15a: 250 mg, 0.561 mmol), 1-allyl-cyclopropanesulfonyl chloride (202 mg, 1.12 mmol), TEA (228 mL, 1.68 mmol) and DMAP (25 mg) using procedures analogous to those described above for Intermediate I-19a to afford 180 mg of the product (55.3% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.Cl[C:24]1[CH:31]=[N:30][CH:29]=[C:28]([Cl:32])[C:25]=1[C:26]#[N:27].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[C:3]([O:22][C:24]2[CH:31]=[N:30][CH:29]=[C:28]([Cl:32])[C:25]=2[C:26]#[N:27])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: Oc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Reactant: N#Cc1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1c(Cl)cncc1Oc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Yield: 7.3 %

Procedure:
A mixture of 5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-ol (0.060 g, 0.16 mmol), 3,5-dichloroisonicotinonitrile (0.030 g, 0.18 mmol) and Cs2CO3 (0.057 g, 0.18 mmol) was stirred in DMSO (2 mL) at 100° C. overnight. The solution was cooled, quenched with water, extracted with EtOAc, dried, and concentrated. The crude material was purified by flash chromatography gave the desired product (0.006 g, 7% yield) as a white solid. 1H NMR (CDCl3) δ 8.55 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 7.12-7.26 (m, 5H), 6.87 (s, 1H), 6.37 (s, 1H), 2.89 (bs, 4H).
Reaction SMILES: C(O)(=O)[C@H:2]([C:4]1C=CC=C[CH:5]=1)[OH:3].[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:5][CH2:4][CH2:2][OH:3])[CH2:14]1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: C[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H]1CCCN(CCCO)C1
Yield: 77.2 %

Procedure:
(3S)-3-methylpiperidin(S)-(+)-mandelate (19.9 g, 79.1 mmol), 3-bromo-1-propanol (10 g, 71.9 mmol) and potassium carbonate (14.9 g, 108 mmol) were mixed in THF (200 mL), and heated under reflux for 30 hours. The insoluble matter was separated by filtration, the filtrate was concentrated, and ethyl acetate and hexane were added to the residue. The resulting insoluble matter was separated by filtration, the filtrate was concentrated and evaporated under reduced pressure to obtain the intended product (9.6 g, 85%) as a colorless oil. (3S)-3-methylpiperidin (S)-(+)-mandelate was synthesized according to the method described in a reference (J. Org. Chem., 1987, Vol. 52, p. 5466).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:8]([OH:14])[C:7]([CH:15]([CH3:17])[CH3:16])=[CH:6][C:5]=1[OH:18])[CH2:2][CH3:3].[CH:19](OC)(OC)OC.[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27].C(=O)([O-])O.[Na+]>CO>[CH3:19][O:29][C:28]1([CH3:30])[CH2:26][CH2:27][C:6]2[C:5](=[C:4]([CH2:1][CH2:2][CH3:3])[C:9]([C:10]([CH3:11])([CH3:13])[CH3:12])=[C:8]([OH:14])[C:7]=2[CH:15]([CH3:17])[CH3:16])[O:18]1
Reactant: COC(OC)OC
Reactant: CCCc1c(O)cc(C(C)C)c(O)c1C(C)(C)C
Reactant: C=CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCc1c2c(c(C(C)C)c(O)c1C(C)(C)C)CCC(C)(OC)O2
Temperature: 3 °C

Procedure:
Dissolve 2-propyl-3-t-butyl-4-hydroxy-5-isopropylphenol (2.0 mol) and trimethyl orthoformate (0.3 L) in methanol (1.2 L) and degas. Place under a nitrogen atmosphere and cool to 3° C. and add concentrated sulfuric acid (5 mL). Add, by dropwise addition, methyl vinyl ketone (340 mL, 4.0 mol) and stir without cooling for 44 hours. Pour into aqueous sodium hydrogen carbonate and extract into ethyl ether. Dry (MgSO4) and evaporate the solvent in vacuo to give 2-methoxy-2-methyl-7-t-butyl-5-isopropyl-8-propyl-chroman-6-ol.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[I:13])=[O:5].[OH:14]S(O)(=O)=O>>[I:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[C:3]2=[O:14]
Reactant: O=C(C=NO)Nc1ccccc1I
Reactant: O=S(=O)(O)O
Product: O=C1Nc2c(I)cccc2C1=O
Temperature: 85 °C
Yield: 87 %

Procedure:
2-(hydroxyimino)-N-(2-iodophenyl)acetamide (3.2 g, 0.011 mmol) was added to conc. H2SO4 (15 mL) in small portions at 60° C. The reaction mixture was further heated at 85° C. for 5 h. After the reaction completion, the reaction mixture was cooled to room temperature and poured into crushed ice. A brown color solid product precipitated. It was then filtered and washed with chilled water several times, then dried in a vacuum oven to get 2.9 g of the required product as a red coloured solid (87%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[N:4][CH:3]=1.[CH2:17]([C:24]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:17]([C:24]1([OH:30])[CH2:29][CH2:28][N:27]([C:10]([C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:6]=[CH:7][N:2]=[CH:3][N:4]=2)=[O:12])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccccc1-c1ccncn1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccccc1-c1ccncn1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A suspension of 2-(pyrimidin-4-yl)benzoic acid hydrochloride (0.20 g), 4-benzyl-4-hydroxypiperidine (0.24 g), HATU (0.48 g) and triethylamine (0.59 mL) in DMF (3.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=[C:17]([NH2:29])[CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN1C(=O)CCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH3:13])[C:10]([NH:29][C:17]1[CH:16]=[C:15]([Cl:14])[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:12])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Temperature: 40 °C
Reaction time: 60 h

Procedure:
A mixture of 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.17 g, 6.19 mmol), 4-chloro-6-(2-phenylethynyl)pyridin-2-amine B3a (1.09 g, 4.76 mmol), triethylamine (3.63 ml, 25.7 mmol) HATU (2.89 g, 7.61 mmol) and NMP (3.75 ml) is stirred at 40° C. for 60 h. 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (0.72 g, 3.81 mmol) and HATU (1.45 g, 3.81 mmol) is added to the mixture and stirring continued for 48 h at 60° C. At RT water is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 712 mg (37%). HPLC-MS: M+H=400; tR=2.27 min (*Method—2).
Reaction SMILES: [CH:1]([N:4]([CH2:6][CH:7]([OH:22])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:5])([CH3:3])[CH3:2].[CH3:23][Cl:24]>CC(C)=O>[Cl-:24].[C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]([OH:22])[CH2:6][N+:4]([CH:1]([CH3:3])[CH3:2])([CH3:23])[CH3:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)N(C)CC(O)COc1ccccc1-c1ccccc1
Reactant: CCl
Solvent: CC(C)=O
Product: CC(C)[N+](C)(C)CC(O)COc1ccccc1-c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of 10.0 g (0.033 moles) of 1-(N-isopropyl-N-methylamino)-3-(2-phenylphenoxy)propan-2ol and 30 ml of acetone, placed in a pressure container cooled in a Dry Ice-acetone bath is added 30 ml of methyl chloride. The container is sealed and mixture stirred at room temperature for about 8 days, after which time the mixture is again cooled in a Dry Ice-acetone bath. The container is opened slowly to permit reduction of any excess pressure and the solvent and excess methyl chloride is removed by evaporation under reduced pressure. The material remaining is dissolved in 30 ml of absolute ethanol, which then is evaporated under reduced pressure. The latter procedure is repeated and the residue is crystallized from anhydrous acetone to afford [3-(2-phenylphenoxy)-2-hydroxypropyl]isopropyldimethylammonium chloride melting at about 124°-127° C. and represented structurally by the following formula ##STR7##
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:14][CH2:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH2:7]1)=[O:5])C.[CH3:15][CH2:16]OCC>>[CH2:15]([C:11]1[S:12][C:8]2[CH2:7][CH:6]([CH2:4][OH:5])[CH2:14][CH2:13][C:9]=2[N:10]=1)[CH3:16]
Reactant: CCOC(=O)C1CCc2ncsc2C1
Reactant: CCOCC
Product: CCc1nc2c(s1)CC(CO)CC2
Yield: 86 %

Procedure:
The compound is prepared by reduction of the above derivative (III) with AlLiH4 within ether, at room temperature. B.p.0.5 =142°-144° C. Yield: 86%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[ClH:9].[ClH:9].[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C1CNCCN1
Product: Cl
Product: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Yield: 64 %

Procedure:
A mixture of 4-nitrobenzylchlorine and piperazine was treated according to the general preparation 1 to obtain N-(4-nitrobenzyl) piperazine dihydrochloride, yield 64%, mp 242-244° C. The N1-(4-nitrobenzyl)-N4-[(4-acetamido) phenacyl] piperazine dihydrochloride (0.75 g, 1.5 mmol) could be preparated according to the general preparation 2, and then reduced according to the general preparation 3 to obtain 0.61 g of the title compound, yield 80%, mp 150-151° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[N+:23]1([O-])[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.C1C=CC2N([OH:43])N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][N+:18]([O-:43])([C:30](=[O:31])[CH2:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: Clc1ccc2c(c1)OCc1cccnc1C2N1CCNCC1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1cc[n+]([O-])cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccncc1)[N+]1([O-])CCN(C2c3ccc(Cl)cc3OCc3cccnc32)CC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
1-(8-Chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-yl)-piperazine (420 mg, 1.33 mmol), 4-pyridineacetic acid 1-oxide (280 mg, 2.07 mmol), HOBT (290 mg, 2.14 mmol), and EDCI (470 mg, 2.45 mmol) were stirred at 0C in DMF (5 ml, anhydrous). NMM (0.5 ml, 4.53 mmol) was added, and the reaction mixture was stirred overnight at 20° C. The solvent was evaporated off, and the residue was extracted with methylene chloride (200 ml) and water (100 ml). The organic layer was separated and dried (MgSO4), filtered and evaporated, yielding an oil which was chromatographed on silica gel and eluted with 20%methanol/ethylacetate containing 2% ammonium hydroxide. The product was obtained as a light yellow solid, 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-yl)-1-(4-pyridine-acetyl)-piperazine N1-oxide. MS (FAB, M+H)=451.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.O>CN1CCCC1=O>[CH:37]1([S:40]([NH:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:17]=4)=[N:7][N:6]3[CH:29]=2)(=[O:42])=[O:41])[CH2:39][CH2:38]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NS(=O)(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (400 mg, 0.97 mmol) in 1-methyl-2-pyrrolidone (4.0 mL) were added triethylamine (404 μL, 2.90 mmol) and cyclopropanesulfonyl chloride (204 mg, 1.45 mmol), and the mixture was stirred at 70° C. for 16 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone) and precipitated from hexane/ethyl acetate to give the title compound (74 mg, 16%) as a white powder.