Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH3:47][NH:48][C:49](=[O:72])[C@@H:50]([NH:59][C:60](=[O:71])[C@H:61]([NH:69][CH3:70])[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:58])[CH3:57].C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@@H:22]([C:23](=[O:25])[N:69]([C@@H:61]([C:60](=[O:71])[NH:59][C@H:50]([C:49](=[O:72])[NH:48][CH3:47])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:58])[CH3:57])[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH3:70])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[CH3:21])([CH3:15])([CH3:16])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CNC(=O)[C@H](CCCCNC(C)=O)NC(=O)[C@@H](Cc1ccccc1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](CCCCNC(C)=O)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68.1 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (313 mg, 1.63 mmol) was added at 0° C. to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (537 mg, 1.63 mmol) and 1-hydroxy-7-azabenzotriazole (222 mg, 1.63 mmol) in dichloromethane (20 ml) and N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of the crude hydrochloride salt of (2S)-6-acetylamino-2-((2R)-2-(methylamino)-3-phenylpropionylamino)hexanoic acid methylamide (710 mg, 1.63 mmol) and ethyldiisopropylamine (0.84 ml, 4.89 mmol) were added subsequently, The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (70 ml) and washed with a 1 0% aqueous solution of sodium hydrogen sulfate (70 ml). The aqueous solution was extracted with ethyl acetate (2×60 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (70 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using dichloromethane./methanol (1 0: 1) as eluent to give 748 mg of N-((1R)-1-{N-[(1R)-1-((1S)-5-(acetylamino)-1-(methylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>C(O)=O>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]2[C:22]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[C:24]([O:25][CH3:26])[CH:23]=3)[CH2:27][CH2:28][NH:29]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=CCC(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)NCC2
Temperature: 25 °C

Procedure:
A solution of 3,3-diphenylpropionaldehyde (19.25 g, 91.54 mmoles) and 2-(3,4-dimethoxyphenyl)ethylamine (16.59 g, 1 equiv.) in 90% formic acid 125 mL) was heated at 95° C. for 16 hours. Upon cooling to room temperature, the solvent was removed on the rotary evaporator, and the residue was partitioned between ethyl acetate and 1M sodium hydroxide. The organic phase was washed with 1M sodium hydroxide and brine, dried over sodium sulfate, and evaporated to give a thick gum. The product was purified by flash chromatography on silica gel, eluting with 20:1 ethyl acetate/methanol, to give a thick gum that solidified upon standing (17.01 g, 50%). 1H-NMR (CDCl3) δ 2.42 (m, 1H), 2.53 (m, 1H), 2.67 (m, 2H), 2.98 (m, 1H), 3.18 (m, 1H), 3.77 (ABq, 1H), 3.84 and 3.88 (s, each 3H), 4.48 (ABq, 1H), 6.46 and 6.57 (s, each 1H), 7.32 (m, 10 H). Mass spec. 374.2 (MH)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=1)[O:11][C:10]([C:22](O)=[O:23])=[CH:9][C:8]2=[O:25])[CH3:3].C(Cl)(=O)C([Cl:29])=O>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=1)[O:11][C:10]([C:22]([Cl:29])=[O:23])=[CH:9][C:8]2=[O:25])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)Cl)cc(=O)c2c1
Reaction time: 2 h

Procedure:
Into a 100 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 250 mg (0.68 mmol, 1.0 equiv.) of 6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride salt (Reference Example 23d) and 20 mL of methylene chloride. To the stirring suspension is then added 129.5 mg, 164 L(1.02 mmol, 1.5 equiv.) of oxalyl chloride followed by addition of one drop of DMF from a 50 microliter syringe to act as catalyst. The mixture is stirred for 2 hours, then concentrated to dryness on a rotary evaporator under a nitrogen atmosphere, followed by drying under high vacuum. The completeness of the reaction was ascertained by analysis of an aliquot, which was quenched with a THF solution of methylamine, by LC/MS. The crude material was used as obtained in the subsequent amidation reaction.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:20])[F:19])=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:22][C:23]1[CH:24]=[C:25]([OH:38])[CH:26]=[CH:27][C:28]=1[B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:8]1([C:7]2[O:6][N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][C:18]([F:21])([F:20])[F:19])[C:3]=2[CH2:2][O:38][C:25]2[CH:26]=[CH:27][C:28]([B:29]3[O:33][C:32]([CH3:34])([CH3:35])[C:31]([CH3:37])([CH3:36])[O:30]3)=[C:23]([CH3:22])[CH:24]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1CBr
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCc2c(-c3ccccc3OC(F)(F)F)noc2C2CC2)ccc1B1OC(C)(C)C(C)(C)O1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a 5-L 3-neck round bottom flask with a mechanical stirrer, thermocouple, reflux condenser, and drying tube is added 4-bromomethyl-5-cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazole (221.7 g, 0.612 mol, 1.05 eq), acetonitrile (2 L), 3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (136.5 g, 0.583 mol, 1 eq) and potassium carbonate (241.8 g, 1.749 mol, 3 eq). The reaction mixture is heated to reflux and stirred at this temperature for 1 hour. Upon completion of the reaction, as evidenced by thin layer chromatography, the reaction mixture is cooled to 0-20° C. The reaction mixture is filtered and the filter cake is washed with acetonitrile (2×100 mL). The reaction mixture is concentrated under reduced pressure to a solid which is co-evaporated with 1,4-dioxane (500 mL). The title compound is used without further purification. 1H NMR (DMSO-d6, 300 MHz): δ 7.7-7.5 (m, 5H), 6.61 (m, 2H), 4.90 (s, 2H), 2.39 (m, 1H), 2.36 (s, 3H), 1.24 (s, 12H), 1.10 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[S:48][C:49]2[CH:55]=[C:54]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:53]=[CH:52][C:50]=2[N:51]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:46][C:47]2[S:48][C:49]3[CH:55]=[C:54]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:53]=[CH:52][C:50]=3[N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc2nc(N)sc2c1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(Cl)c(Cl)c3)sc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.4 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 0.213 g, 0.74 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.434 g, 0.98 mmol), and 2-amino-6-methanesulfonylbenzothiazole (0.219 g, 0.96 mmol) in methylene chloride (15 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.45 mL, 4.88 mmol). The reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(6-methanesulfonyl-benzothiazol-2-yl)-propionamide (0.296 g, 80%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:13][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2ccccc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of benzofuran-2-ylmethanol (120 mg; 0.81 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (268 mg; 0.81 mmol), and with PPh3 (212 mg; 0.81 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 2-(bromomethyl)benzofuran as a yellow oil (128 mg; 75%) which was directly used for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:38]2[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Product: COc1ccc(-c2c(OC)nc(Oc3ccc(F)c(F)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
This derivative was prepared by the method described in Example 132 using 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (54 mg, 0.1 mmol) as described in Reference Example 17 and 4-methoxy-benzeneboronic acid (Lancaster, 16 mg, 0.11 mmol). HPLC/MS: m/e=488 (M+−1); Rt=4.62 min. 1H-NMR 500 MHz (CDCl3): δ 3.86 (s, 3H), 4.09 (s, 3H), 6.66 (m, 1H), 6.78 (m, 1H), 6.87 (dd, J=6 Hz, J=2 Hz, 2H), 7.08 (dd over m, J=6 Hz, J=2 Hz, 3H), 7.40 (d, J=1 Hz, 2H), 7.45 (d, J=2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([O-:17])=[O:16])[C:6](=[O:21])[C@@:5]12[CH2:23][C:22]1([CH3:25])[CH3:24].Cl>O1CCCC1.[OH-].[Na+].O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])[C:6](=[O:21])[C:5]12[CH2:23][C:22]1([CH3:25])[CH3:24]
Reactant: CC1(C)C[C@]12C(=O)N(Cc1cccc(C(=O)[O-])c1)c1ccc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC12C(=O)N(Cc1cccc(C(=O)O)c1)c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
A mixture of (R) and (S)-3-((5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoate (850 mg, 2.4 mmol) in tetrahydrofuran (10 mL) and 30% sodium hydroxide in water (5 mL) was stirred at 25° C. for 16 hours. The mixture was neutralized with a 2 N aqueous hydrochloric acid solution, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoro-acetic acid in water) afforded the title compound as white solid (410 mg, 50%): LC/MS m/e calcd. for C20H15FNO3 (M+H)+: 340.37, observed: 340.2; LC/MS m/e calcd. for C20H18FNO3: 339, observed (M+H)+: 340.1 1H NMR (400 MHz, DMSO-d6) δppm 1.37 (s, 3 H) 1.48 (s, 3 H) 1.76 (d, J=4.29 Hz, 1 H) 1.88 (d, J=4.29 Hz, 1 H) 5.04 (dd, 2 H) 6.91-7.08 (m, 2 H) 7.17 (dd, J=9.35, 2.53 Hz, 1 H) 7.44-7.57 (m, 2 H) 7.80-7.93 (m, 2H) 12.99 (s, 1 H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1.[C:17]([N:20]1[CH2:29][C:28]([CH3:31])([CH3:30])[C:27]2[C:22](=[CH:23][C:24]([S:32](Cl)(=[O:34])=[O:33])=[CH:25][CH:26]=2)[CH2:21]1)(=[O:19])[CH3:18].C(OCC)(=O)C>O1CCCC1.O>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[S:32]([C:24]2[CH:23]=[C:22]3[C:27]([C:28]([CH3:31])([CH3:30])[CH2:29][N:20]([C:17](=[O:19])[CH3:18])[CH2:21]3)=[CH:26][CH:25]=2)(=[O:33])=[O:34])=[CH:10][CH:9]=1
Reactant: CC(=O)N1Cc2cc(S(=O)(=O)Cl)ccc2C(C)(C)C1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1Cc2cc(S(=O)(=O)n3ccc4ccc(Cl)cc43)ccc2C(C)(C)C1
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
Potassium tert-butoxide (37 mg, 0.33 mmol) was added to a stirred solution of 6-chloroindole (50 mg, 0.33 mmol) in dry tetrahydrofuran (1 ml) under argon at room temperature. After stirring for 5 minutes, a solution of 2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (D3) (100 mg, 0.33 mmol) in dry tetrahydrofuran (1 ml) was added and the solution was stirred for a further 3 h. Ethyl acetate (5 ml) and water (5 ml) were added to the reaction mixture, which was then shaken. The layers were separated and the organic phase was washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by column chromatography over silica gel eluting with a gradient of acetone/toluene to afford the title compound (D4) (70 mg, 51%), MS: m/z (MH+) 417/419.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:14])[CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.C1C[O:28]CC1>>[CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:14])[CH2:12][CH2:13][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=C[C@H](C)NC(=O)OCc1ccccc1
Agent: B1C2CCCC1CCC2
Product: C[C@@H](CCO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
(1-(S)-Methyl-allyl)-carbamic acid benzyl ester (1.96 g, 9.56 mmol) was taken up in THF (200 mL). 9-BBN 0.5M in THF (38 mL, 19.0 mmol) was added slowly to the reaction mixture. The solution was allowed to stir at rt for 16 h. Quenched with H2O (65 mL), followed by 1.0M NaOH(aq) (20 mL). The solution was cooled to 0° C. in an ice bath and H2O2 30% in H2O (7.0 mL) was slowly added. The reaction was partitioned between Et2O and H2O. The layers were separated and the aqueous washed with Et2O. The combine organics were dried over Na2SO4. Solids were filtered and the solvent removed under reduced pressure. (3-hydroxy-1-(S)-methyl-propyl)-carbamic acid benzyl ester (1.85 g, 87%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]([CH3:20])[CH2:26]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(C(CCCCCl)c2cccnc2)cc1
Reactant: CCOC(=O)N1CCNCC1C
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCCCC(c2ccc(F)cc2)c2cccnc2)CC1C
Temperature: 70 °C
Reaction time: 40 h
Yield: 96.7 %

Procedure:
A mixture of 14 parts of 3-[5-chloro-1-(4-fluorophenyl)pentyl]-pyridine, 7.75 parts of ethyl 2-methyl-1-piperazinecarboxylate, 8.7 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 198 parts of N,N-dimethylformamide was stirred for 40 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a mixture of water and sodium carbonate. The aqueous layer was extracted with trichloromethane. The extract was washed with a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18 parts (96.7%) of ethyl 4-[5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-2-methyl-1-piperazinecarboxylate as a residue (int. 38).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:18])=[O:17])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:11]([O:35][CH3:36])[N:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(N(C(C)C)C(C)C)C.Cl.[NH2:47][OH:48].Cl>O1CCOCC1>[OH:48][NH:47][C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([O:35][CH3:36])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:17])=[O:18])[N:14]=2)[CH:6]=[CH:5][N:4]=1)=[NH:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C#N)c2)nc1OC
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=N)NO)c2)nc1OC

Procedure:
A suspension of 100 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-cyano-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 19, in dioxane (10 ml) was treated at RT with 0.17 ml of N-etyldiisopropylamine then with 69 mg of hydroxylamine hydrochloride and refluxed 12 h until the reaction was complete according to TLC analysis. The mixture was poured into cold diluted HCl and the product extracted into AcOEt. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The solid residue was crystallised from CH2Cl2/Et2O to afford N-hydroxy-4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxamidine as off-white crystals. ISN mass spectrum, m/e 536.2 (M−1 calculated for C24H23N7O6S: 536).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8](COCCOC)[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].Cl>CO>[Cl:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1cc2c(cc1Cc1sc3ncccc3c1S(=O)(=O)Nc1noc(C)c1Cl)OCO2
Yield: 83.7 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyethoxymethyl)-2-[2-methyl-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3- sulfonamide (58 mg, 0.10 mmoles), methanol (3 ml) and 4N HCl (1 ml). Recrystallization from chloroform and hexanes provided 40 mg (80%) of the title compound as a white solid, m.p. 189°-191° C.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([N:29]2[CH2:33][CH2:32][C@H:31]([N:34]([CH3:36])[CH3:35])[CH2:30]2)[N:4]=1.Br.CC#N>CC(O)=O>[CH3:35][N:34]([CH3:36])[C@H:31]1[CH2:32][CH2:33][N:29]([C:5]2[NH:4][C:3](=[O:2])[C:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][N:19]=[C:18]([C:22]5[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=5)[CH:17]=4)=[C:11]([CH3:28])[N:10]=3)=[CH:7][N:6]=2)[CH2:30]1
Reactant: COc1nc(N2CC[C@H](N(C)C)C2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(N3CC[C@H](N(C)C)C3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 62.5 %

Procedure:
(S)-1-(4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylpyrrolidin-3-amine (0.10 g, 0.21 mmol) was dissolved in AcOH (3 mL) and then 48% hydrobromic acid (0.1 mL) was added. The mixture was heated at 90° C. for 3.5 hours. The mixture was concentrated and the residue was treated with NaHCO3 solution. The solution was extracted with EtOAc (3×) and the organic was washed with NaHCO3, dried over Na2SO4, filtered and concentrated to obtain the crude. The crude was treated with hot MeCN and kept at RT. The solid was filtered, washed with MeCN, and dried under vacuum to obtain (S)-2-(3-(dimethylamino)pyrrolidin-1-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (62 mg, 62.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.29 (m, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.62 (dd, J=5.7, 2.4 Hz, 1H), 3.85 (s, 3H), 3.74 (m, 2H), 3.44 (m, 1H), 3.31 (s, 3H), 3.22 (m, 1H), 2.75 (m, 1H), 2.35 (s, 3H), 2.18 (s, 6H), 2.11 (m, 1H), 1.77 (m, 1H) one proton is missing; MS (ESI) m/z: 473.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10](O)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11]
Reactant: O=C(O)Cc1cc(F)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
To a solution of (2-bromo-5-fluorophenyl)acetic acid (1.29 g, 5.54 mmol) in tetrahydrofuran (15 mL) was added lithium aluminum hydride (210 mg, 5.54 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. After cooling to 0° C., the reaction mixture was quenched by the addition of 2N hydrochloric acid (30 mL), extracted with diethyl ether (200 mL). The organic layer washed with water (50 mL) and brine (50 mL) dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluting with hexane/ethyl acetate (5/1) to afford 247 mg (20%) of the title compound as colorless oil:
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>O1CCOCC1>[CH3:28][N:29]([CH3:31])/[CH:30]=[CH:2]/[C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)/C=C/C(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
A solution of 25 g of 2-[4-(4-acetylphenoxy)butyl]-1H-isoindole-1,3(2H)-dione (Example 42) and 25 ml of dimethylformamide dimethylacetal in 50 ml of dioxane is heated in the steam bath for 16 hours. The volatile components are removed in vacuo, a tacky reddish-brown solid being obtained. A portion is recrystallized from dichloromethane/hexane; m.p. 109°-111° C.