Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].O[Li].O>O.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2cccc(C#N)c2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(COc2ccnn2-c2cc(C(=O)O)ccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-[5-[(3-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (1.0 eq) and LiOH.H2O (3.0 eq) in a mixture of water (2 mL) and THF (2 mL) was stirred at room temperature for 30 min. Diluted with another 2 mL water, and the mixture was washed with ethyl acetate twice (6 mL×2). The water phase was acidified with 1N HCl (pH=3), filtered and dried the solid to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ 5.36 (2H, s), 6.03 (1H, s), 7.61-7.64 (2H, m), 7.77-7.78 (1H, m), 7.82-7.84 (2H, m), 7.96 (1H, s), 8.09 (1H, s), 8.69 (1H, d, J=4.4 Hz), 13.92 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=2.106 min. [M+H] Calc'd for C17H12N4O3, 321; Found, 321.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[C:18](O)=[C:17]([S:26]([CH3:29])(=[O:28])=[O:27])[C:16]1=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:33]>>[CH2:8]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[C:18]([Cl:33])=[C:17]([S:26]([CH3:29])(=[O:28])=[O:27])[C:16]1=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 90 °C

Procedure:
Triethylamine (1.2 mL, 8.6 mmol) was added to a suspension of 1-benzyl-4-hydroxy-3-(methylsulfonyl)-[1,8]-naphthyridin-2(1H)-one (114) (0.94 g, 2.9 mmol) in neat POCl3 and heated at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in water, neutralized by solid NaHCO3, and extracted by dichloromethane. The organic layer was subsequently washed by saturated NaHCO3 solution, water and brine, dried over Na2SO4, and evaporated to yield 1-benzyl-4-chloro-3-(methylsulfonyl)-[1,8]-naphthyridin-2(1H)-one (115) as yellow solid. Yield 0.92 g (92%), mp 191° C. 1H-NMR (DMSO-d6): δ 3.50 (s, 3H), 5.65 (s, 2H), 7.28 (m, 5H), 7.55 (m, 1H), 8.70 (dd, J=1.6, 8.4 Hz, 1H), 8.84 (dd, J=1.6, 4.4 Hz, 1H); EIMS m/z 349 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1)=[O:7].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:5]([CH2:4][CH2:3][C:2]([F:19])([F:18])[F:1])[C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1)=[O:7]
Reactant: COC(=O)c1ccc(C(=O)NCCC(F)(F)F)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCC(F)(F)F)C(=O)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of methyl 6-[(3,3,3-trifluoropropyl)carbamoyl]nicotinate (2.4 g, 8.6 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% suspension in mineral oil) (1.3 g). The reaction mixture was stirred at ambient temperature for 1 h. Methyl iodide (3.42 g, 5.0 mL, 24.1 mmol) was added and the reaction mixture was stirred over night and then added water (20 mL). The reaction mixture was stirred for another 30 min and then extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with citric acid and the formed precipitate was filtered off and dried in vacuum oven to yield 1.12 g (47%) of the title compound; 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (d, 1 H), 8.49 (d, 1 H), 7.78-7.91 (dd, 1 H), 3.80 (t, 1 H), 3.61-3.73 (m, 1 H), 3.16 (d, 3 H), 2.46-2.76 (m, 2 H); MS (ESI) m/z 277[M+H+].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:14](Cl)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>>[F:5][C:6]1[CH:11]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: COc1ccccc1F
Reactant: CCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCC(=O)c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.4 %

Procedure:
Aluminum chloride (6.5 g, 48.8 mmol) was added to a stirred mixture of 1-fluoro-2-methoxybenzene (5.0 mL, 44.4 mmol) and hexanoyl chloride (7.5 mL, 53.3 mmol) at room temperature. The mixture warmed and HCl evolution occurred. The resulting mixture was stirred at room temperature for 45 minutes and then partitioned between EtOAc (100 mL) and water (100 mL). The EtOAc layer was washed with water (100 mL), aqueous K2CO3 (100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to yield crude 1-(3-fluoro-4-methoxyphenyl)-1-hexanone (9 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH2:11].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](N1C=CN=C1)=[S:20].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)=[S:20]
Reactant: S=C(Nc1ccccn1)n1ccnc1
Reactant: NCCc1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1CCNC(=S)Nc1ccccn1
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A solution of 2-(2,6-difluorophenyl)ethylamine (0.43 g, 2.7 mmol) and 1-[(2-pyridyl)thiocarbamoyl]imidazole (0.55 g, 2.7 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 27 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.08 g (10%) of the titled product as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:32]=1[C:31](=[O:34])[C:30]1[CH:35]=[CH:36][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:28][CH:29]=1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(OC(F)(F)F)cc2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans 5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 4-(trifluoromethoxy)phenacyl bromide (Preparation is described in Example 189).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[Br:9][C:10]1[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]([S:24]([CH3:27])(=[O:26])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=1>CN(C=O)C.Cl>[Br:9][C:10]1[N:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([CH3:3])([S:24]([CH3:27])(=[O:26])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(CCc1ccc(Br)nc1)S(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C(C)(CCc1ccc(Br)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A solution of methyl iodide (633 uL, 10.2 mmol, 2.2 equiv), potassium carbonate (895 mg, 6.5 mmol, 1.4 equiv), and ethyl 4-(6-bromopyridin-3-yl)-2-(methylsulfonyl)butanoate (1620 mg, 4.6 mmol, 1.0 equiv) in DMF (15 mL) was allowed to stir at room temperature overnight. The reaction was diluted with 0.5 M hydrochloric acid (220 mL) and was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water (170 mL) and sodium thiosulfate (170 mL, 10% aq. solution), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (7:3 heptane/ethyl acetate) to provide the title compound as a white solid (1107 mg, 66%). MS (LCMS) m/z 364.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.22 Hz, 3H) 1.69 (s, 3H) 2.12-2.23 (m, 1H) 2.39-2.59 (m, 2H) 2.69-2.79 (m, 1H) 3.02 (s, 3H) 4.27 (qd, J=7.16, 2.73 Hz, 2H) 7.35-7.43 (m, 2H) 8.20 (d, J=1.95 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:34][C:32]=2[NH2:33])[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[N:28]1([C:31]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:34][C:32]=2[NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=2[CH3:24])[CH2:29][CH2:30][O:25][CH2:26][CH2:27]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (39.0 mg, 0.110 mmol) and 2,5-dimorpholinoaniline in toluene to give N-(2,5-di-4-morpholinylphenyl)-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.21 (2H, d, J=7.6 Hz), 7.78 (1H, t, J=7.6 Hz), 7.69 (1H, t, J=7.2 Hz), 7.47 (1H, d, J=9.2 Hz), 7.40 (1H, d, J=7.4 Hz), 6.98-7.09 (2H, m), 6.40 (1H, br. s.), 6.24 (1H, br. s.), 3.90 (4H, m), 3.78 (4H, m), 2.74-3.33 (8H, m), 1.95 (3H, m). Mass Spectrum (ESI) m/e=595.3 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([CH3:14])=[N:9][C:10]([Br:13])=[CH:11][CH:12]=2)[C:3]1=[O:15].C1COCC1.[CH3:21][C:22]([O-:24])=[O:23].[K+]>C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>[C:22]([O:24][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([CH3:14])=[N:9][C:10]([Br:13])=[CH:11][CH:12]=2)[C:3]1=[O:15])(=[O:23])[CH3:21]
Reactant: Cc1nc(Br)ccc1N1CCC(Br)C1=O
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCN(c2ccc(Br)nc2C)C1=O
Temperature: 70 °C
Yield: 51.3 %

Procedure:
A 500 mL round-bottom flask was charged with crude 3-bromo-1-(6-bromo-2-methylpyridin-3-yl)pyrrolidin-2-one from step A (18.5 g), THF (50 mL), 18-Crown-6 (576 mg, 2.18 mmol) and KOAc (12.84 g, 131 mmol). The mixture was heated at 70° C. under argon overnight. After cooling the reaction mixture to room temperature, ethyl acetate (50 mL) was added. The organic layer was separated and washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to a dark solid, which was purified by flash chromatography (silica gel, 20-100% ethyl acetate/hexane) to give 1-(6-bromo-2-methylpyridin-3-yl)-2-oxopyrrolidin-3-yl acetate (8.9 g, 65% yield for two steps) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (q, J=8.3 Hz, 3H), 5.43 (t, J=8.2 Hz, 1H), 3.47-4.03 (m, 3H), 2.62-2.90 (m, 1H), 2.38-2.56 (m, 4H), 2.06-2.32 (m, 5H); MS (ESI) 314 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:11]1([NH:10][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Solvent: C1CCOC1
Product: O=C(CCCCCBr)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromohexanoyl chloride (1.00 mL, 6.53 mmol) in THF (35 mL) at 0° C. was added dropwise a solution of aniline (0.60 mL, 6.53 mmol) and TEA (1.09 mL, 7.84 mmol) in THF (5 mL) The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was filtered, the solids rinsed with EtOAc, and the filtrate reduced under vacuum. The residue was partitioned between H2O (15 mL) and EtOAc (20 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL) and the organic layers combined, washed with HCl (1 N), brine, dried over MgSO4, and filtered. Concentration under reduced pressure left a brown oil which was passed through a plug of silica gel (30% EtOAc/hexanes) under aspiration. Concentration under reduced pressure left 67 as a solid (1.55 g, 5.74 mmol, 88%). TLC Rf 0.36 (25% EtOAc/hexanes); 1H-NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.57 (d, 2H), 7.27 (t, 2H), 7.01 (t, 1H), 3.53 (t, 2H), 2.30 (t, 2H), 1.81 (t, 2H), 1.63 (m, 2H), 1.42 (m, 2H); MS (ESI+) calcd for C12H16BrNO 268+270. found 269+271 [M+H]+.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37].C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37]
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: O=C(O)C1CCCCN1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCCC4C(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and piperidine-2-carboxylic acid (25.6 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 19 mg of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (2H, dd, J=8.35, 2.20 Hz), 7.77 (2H, dd, J=7.91, 1.54 Hz), 7.52-7.64 (5H, m), 5.20 (1H, d, J=18.24 Hz), 3.67 (2H, br. s.), 2.87-3.01 (2H, m), 1.99-2.21 (2H, m), 1.69-1.88 (4H, m), 1.64 (2H, dq, J=15.24, 7.59 Hz), 1.39-1.56 (3H, m), 0.92 (3H, t, J=7.36 Hz). MS (m+1)=503. HPLC Peak RT=3.47 minutes (Analytical Method A). Purity=88%.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:1][CH:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccc(F)cc2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 4-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(4-fluorophenoxy)ethyl)benzoate (490 mg, 35%).
Reaction SMILES: [NH2:1][C:2](=[N:34]O)[C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([NH2:28])=[N:26]O)=[C:23]([F:31])[CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>[C].[Pd].C(O)(=O)C>[NH2:34][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([NH2:28])=[NH:26])=[C:23]([F:31])[CH:22]=3)[CH2:13][CH2:12]2)=[CH:32][CH:33]=1
Reactant: NC(=NO)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)c(F)c3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N=C(N)c1ccc(OCCCN2CCC(CCCOc3ccc(C(=N)N)c(F)c3)CC2)cc1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To an acetic acid (2.0 mL) suspension of 56 mg of 4-{3-[1-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-4-piperidinyl]propoxy}-2-fluoro-N′-hydroxybenzamidine was added 0.043 mL of acetic anhydride at room temperature, which was then stirred at the same temperature for one hour. To this mixture was added 5.0 mg of 5% palladium-carbon, which was then stirred under hydrogen atmosphere for 2 hours. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. Thereto were added 6.0 mol/L hydrochloric acid and water, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (silica gel: ODS-AM120-S50 from YMC, eluent; water). The resultant residue was dissolved in 5.0 mL of water, to which a 5.0 mol/L sodium hydroxide aqueous solution was then added to adjust the pH to 12.2. The solution was stirred under cooling with ice for 20 minutes, and the precipitate was collected by filtration to provide 43 mg of 4-{3-[1-(3-{4-[amino(imino)methyl]phenoxy}propyl)-4-piperidinyl]propoxy}-2-fluorobenzamidine as white solid form.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][CH2:19][NH2:20]>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][CH2:19][NH:20][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1
Reactant: ClCCN1CCc2sccc2C1
Reactant: COc1ccc(CCN)cc1OC
Solvent: O
Product: COc1ccc(CCNCCN2CCc3sccc3C2)cc1OC
Temperature: 110 °C

Procedure:
Into a two liter reactor, fitted with an oil-bath and stirring means and under nitrogen circulation, were poured 201.5 g (1 mol) of 5-(2-chloroethyl)-4,5,6,7-tetrahydro-thieno-(3,2-c)-pyridine and slowly, under stirring, 181 g (1 mol) of 3,4-dimethoxyphenethylamine. The reacting mixture was warmed at 110° C. under stirring for two hours. The oily mixture obtained was cooled to about 70°-80° C. and then poured into icy water; after separation, washing, extraction with diethyl ether and drying, the residue was dissolved in a mixture of petroleum ether and isopropyl ether (50/50 by volume) and passed through a silica gel column. Elution was with acetone. The fraction containing the desired compound was evaporated to dryness, treated with diethyl ether and finally with acetone. Yield 163 g (47%) of a white crystalline powder soluble in water, melting at 260° C. (Tottoli) with decomposition, the analysis and NMR of which showed a good correspondence with the formula C19H26N2O2S.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1.[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH2:10]([O:9][C:4]1[CH:3]=[C:2]([B:17]([OH:20])[OH:18])[CH:7]=[CH:6][C:5]=1[F:8])[CH3:11]
Reactant: CCOc1cc(Br)ccc1F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)ccc1F
Reaction time: 4 h
Yield: 67.9 %

Procedure:
To a solution of 9A (3.86 g, 17.6 mmol) in THF (60 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 14.3 mL, 22.8 mmol). The mixture was stirred at −78° C. for 40 min before trimethyl borate (3.63 mL, 33 mmol) was added. The reaction was left stirring from −78° C. to rt over 4 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 9B (2.2 g, 69% yield) was collected as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.03 Hz, 3H) 4.11 (q, J=7.03 Hz, 2H) 7.03 (dd, J=11.42, 8.35 Hz, 1H) 7.18-7.29 (m, 2H) 7.35 (d, J=7.91 Hz, 1H).
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[NH:14][C:13](=[O:15])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(=O)O[C@H](C)c1nccc(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of (R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 17.8 g, 97.8 mmol) and triethylamine (9.9 g, 97.8 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (11.21 g, 97.8 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil, 24.1 g (94%). 1H NMR (CDCl3, 300 MHz) δ 0.99 (t, 3H), 1.54 (d, 3H), 1.68 (m, 2H), 2.48 (t, 2H), 3.81 (s, 3H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (CI) 261 (MH+); [α]D+28.8 (c 1.0, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)([CH3:18])[CH3:17].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:24]=[CH:25][C:20]([NH:19][CH:16]([CH3:17])[CH3:18])=[N:21][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(NC(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)Nc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N-isopropyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: N[C@H](C(O)=O)C[SeH].[Li]CCCC.CN(C)CCN(C)C.[CH2:21]([N:23]([CH2:34][CH3:35])[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH3:22].[CH3:36][S:37]C>C1COCC1>[CH2:34]([N:23]([CH2:21][CH3:22])[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[S:37][CH3:36])[CH3:35]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1
Reactant: CSC
Agent: CN(C)CCN(C)C
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(OC)cc1SC
Reaction time: 0.25 h

Procedure:
Sec-BuLi (1.4 M in cyclohexane, 11.34 mL, 15 mmol) was carefully added to a mixture of N,N,N′,N′-tetramethylethane-1,2-diamine (2.2 mL, 15 mmol) in anhydrous THF at −78° C. N,N-Diethyl-4-methoxybenzamide (3 g, 14.4 mmol) dissolved in 5 mL of anhydrous THF was added dropwise to the reaction mixture which was allowed to stir for 1 h Dimethyl sulfide (2.5 mL, 28.8 mmol) was then added to the reaction. After stirring for 15 min, the cooling bath was removed and the mixture was stirred overnight. The reaction was diluted with ethyl acetate and washed with a solution of saturated sodium bicarbonate, water and then brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 20 to 80% ethyl acetate in hexanes to obtain the product as a light yellow oil. Yield=2.51 g. MS (M+H)+ 254.