Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1N(Cc2ccc(Cl)nc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Product: CN(C)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cn1
Temperature: 130 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a seal tube was added 1′-((6-chloropyridin-3-yl)methyl)-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one (0.10 g, 0.25 mmol) and dimethylamine (2.00 mL of 2 M THF solution, 4.00 mmol). The mixture was stirred at 130° C. overnight. After cooling down to ambient temperature, the mixture was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/2) to give 1′-{[6-(dimethylamino)pyridin-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)one as a white solid (50 mg, 48%), which was treated with 2.0 M HCl in diethyl ether to give the title compound: mp 146-150° C.; 1H NMR (300 MHz, CD3OD) δ 8.03 (d, 1H), 7.95 (dd, 1H), 7.36 (td, 1H), 7.25-7.12 (m, 4H), 6.57 (s, 1H), 6.09 (s, 1H), 5.90 (s, 2H), 5.07-4.87 (m, 3H), 4.72 (d, 1H), 3.27 (s, 6H); 13C NMR (75 MHz, CD3OD) δ 179.9, 157.6, 154.6, 150.5, 143.8, 143.4, 142.9, 137.7, 133.5, 130.2, 125.1, 121.8, 120.6, 113.2, 110.4, 103.7, 103.0, 94.3, 81.4, 59.7, 41.1, 39.5; MS (ES+) m/z 416.5 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([O:23][C:24](=[O:30])[CH:25](Br)[CH:26]([CH3:28])[CH3:27])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:26]([CH3:28])[CH3:27])[CH3:22]
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2c1cc(C)n2Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromoisovalerate (0.344 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford a 1:1 mixture of 7: ethyl-2-bromoisovalerate. Further purification by column chromatography (10:1 Hexane:EtOAc) afforded 7 (0.09 g, 19%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](Cl)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([OH:27])=[CH:22]2>>[Br:1][C:2]1[C:7]2[NH:8][C:9]([NH:16][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][C:21]([OH:27])=[CH:22]4)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: Nc1cccc2cc(O)ccc12
Reactant: FC(F)(F)c1cc(Br)c2[nH]c(Cl)nc2c1
Product: Oc1ccc2c(Nc3nc4cc(C(F)(F)F)cc(Br)c4[nH]3)cccc2c1
Yield: 57 %

Procedure:
The reaction of 7-bromo-2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (240 mg, 0.8 mmol, prepared according to the procedure described in WO 2004/035549 A1) with 5-amino-2-naphthol (64 mg, 0.4 mmol, TCI-US) under the condition of Example 2 afforded the title compound (57%) as an amorphous solid. MS (ESI, pos. ion) m/z: 423 (M+1).
Reaction SMILES: Br[CH2:2][CH:3]([O:16][CH3:17])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>CN(C)C=O>[C:18]1(=[O:28])[N:22]([CH2:2][CH:3]([O:16][CH3:17])[CH2:4][O:5][C:6]2[S:7][C:8]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=2)[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(CBr)COc1ncc(C(=O)N(C)C)s1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(COc1ncc(C(=O)N(C)C)s1)CN1C(=O)c2ccccc2C1=O

Procedure:
By a procedure analogous to Example 2, the product from Example 8 can be reacted with potassium phthalimide in N,N-dimethylformamide to give the solid title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]#[CH:21]>>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)[CH2:21][C:20]#[CH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCBr
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)cn1
Product: C#CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)OC)nc1
Yield: 90 %

Procedure:
Using the method described in J. Med. Chem., 1980, 23, 1405, methyl 5-(N-tert-butoxycarbonylamino)pyridine-2-carboxylate was reacted with prop-2-ynyl bromide to give methyl 5-[N-tert-butoxycarbonyl-N-(prop-2-ynyl)amino]pyridine-2-carboxylate in 90% yield. A mixture of the product so obtained and trifluoroacetic acid was stirred at 0° C. for 1 hour and evaporated. There was thus obtained methyl 5-(N-prop-2-ynylamino)pyridine-2-carboxylate in 90% yield, as a gum.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[O:9][N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[S:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].C(N(CC)C(C)C)(C)C>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([S:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[O:9][N:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)on1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)no4)c3)c2cc1OC
Temperature: 50 °C
Yield: 55 %

Procedure:
Using the procedure described in Example 159B, a mixture of phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate described in Example 159A (0.158 g, 0.5 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) were heated at 50° C. for 5 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]urea as solid (0.114 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.10 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 7.34 (m, 3H), 6.22 (s, 1H), 4.70 (m, 2H), 4.55 (m, 2H), 3.99 (s, 6H), 1.28 (s, 3H); LC-MS (ESI) m/z 516 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]4=[O:35])[CH:18]=3)=[CH:10][C:9]=2[O:36][CH3:37])[CH:5]=[CH:4][N:3]=1.[CH2:38]([Mg]Br)[CH3:39]>C1COCC1.CN1C(=O)CCC1>[CH2:38]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]4=[O:35])[CH:18]=3)=[CH:10][C:9]=2[O:36][CH3:37])[CH:5]=[CH:4][N:3]=1)[CH3:39]
Reactant: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1-c1ccnc(Cl)c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCc1cc(-c2ccc(-c3cn(C4CCc5ccccc5N(CC(F)(F)F)C4=O)nn3)cc2OC)ccn1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 3-{4-[4-(2-chloropyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (50 mg, 0.095 mmol), previously prepared, and ferric acetylacetonate (3.34 mg, 9.47 μmol) in THF (852 μl) and NMP (95 μl) at 0° C. was added ethyl magnesium bromide (1M in THF, 189 μl, 0.189 mmol). The reaction was held at 0° C. and stirred for 15 minutes. The reaction was quenched at 0° C. with a small addition of 1 mL of a saturated NH4Cl aq. solution. The reaction was diluted with 50 mL of H2O and was extracted with 3×50 mL portions of DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% Formic Acid. Lyophilisation afforded 3-{4-[4-(2-ethylpyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1 benzazepin-2-one.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7](S(C)(=O)=O)[N:6]=1)(=[O:4])=[O:3].[OH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C([Li])CCC>C1COCC1>[CH3:1][S:2]([C:5]1[N:6]=[C:7]([O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:8]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:10]=1)(=[O:4])=[O:3]
Reactant: Oc1cccnc1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 0 °C

Procedure:
To a 50 mL round bottom flask fitted with a magnetic stirrer bar and rubber septum was added 20 mL anhydrous THF (Aldrich) and 2,4-bis(methyl-sulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Reference Example 5) (1.0 g, 2 mmol). The flask was flushed with nitrogen and cooled to 0° C. In a separate flask, also fitted with a magnetic stirrer bar and rubber septum, was added 10 mL anhydrous THF and 3-hydroxypyridine (213 mg, 2.24 mmol), This flask was flushed with nitrogen and cooled to 0° C. Then n-butyl lithium (1.12 mL, 2.24 mmol) (Aldrich-2M solution in hexane) was added via syringe and the solution stirred for several minutes. The lithium alkoxide solution was then withdrawn by syringe and slowly added to the first reaction flask. The solution was stirred at 0° C. for 1 h, quenched with saturated sodium bicarbonate and the reaction products extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure. Flash column chromatography on silica gel (eluted with 35/65 hexanes/ethyl acetate) afforded 2-methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: 1H-NMR 500 MHz (CDCl3): δ 3.20 (s, 3H), 7.20-7.25 (m, 4H), 7.30-7.38 (m, 3H), 7.41 (m, 1H), 7.63-7.65 (m, 1H), 8.53-8.55 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23](=[O:25])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[CH:10]1.C(O)C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([CH:23]([OH:25])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[CH:10]1
Reactant: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)=O)n3)cc2OC)cn1
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)O)n3)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-(2-(3-methoxy-4-(4-methoxy-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)ethanone (0.1 g, 0.22 mmol) in ethanol (5 mL) sodium borohydride (0.034 g, 0.89 mmol) was added. The mixture was stirred at rt for 10 min. Acetone (2 mL) was added and mixture was stirred for 20 min. The mixture was filtered, the filtrate was concentrated in vacuum and the residue was purified by preparative HPLC to give the title compound as a dry film, 50 mg (50%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)C(CCC(=O)O)(Cc2ccccc2Cl)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Methylbenzaldehyde (3.00 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.20 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which forms after scratching is collected and air-dried, yield 7.4 g., m.p. 120°-147°C. Recrystallization from methylcyclohexane, followed by recrystallization from n-butyl chloride, yields a white solid with m.p. 166°-168.5°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:26]=[C:25]([CH2:27][CH3:28])[NH:24][N:23]=1>>[CH2:27]([C:25]1[NH:24][N:23]=[C:22]([NH:21][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[CH:26]=1)[CH3:28]
Reactant: CCc1cc(N)n[nH]1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Product: CCc1cc(NC(=O)Cc2ccc(OCc3ccccc3)cc2OC)n[nH]1

Procedure:
Using an analogous procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid was reacted at 75° C. for 3 hours with 3-amino-5-ethylpyrazole to give N-(5-ethylpyrazol-3-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.15 (t, 3H), 2.55 (q, 2H), 3.48 (s, 2H), 3.73 (s, 3H), 5.09 (s, 2H), 6.24 (s, 1H), 6.54 (m, 1H), 6.62 (d, 1H), 7.06 (d, 1H), 7.33 (t, 1H), 7.39 (m, 2H), 7.45 (m, 2H), 10.15 (br s, 1H); Mass Spectrum: M+H+ 366; which material was hydrogenated to give N-(5-ethylpyrazol-3-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.15 (t, 3H), 2.53 (q, 2H), 3.43 (s, 2H), 3.68 (s, 3H), 6.24 (br s, 1H), 6.28 (m, 1H), 6.37 (d, 1H), 6.93 (d, 1H), 9.29 (br s, 1H), 10.09 (br s, 1H); Mass Spectrum: M+H+ 276.
Reaction SMILES: [Si]([O:8][C@H:9]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([CH2:40][OH:41])[CH:34]=1)[CH2:10][NH:11][C@H:12]([CH3:32])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])=[O:22])[CH:17]=[CH:18][CH:19]=1)(C(C)(C)C)(C)C>O>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][NH:23][C:21](=[O:22])[CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C@H:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([CH2:40][OH:41])[CH:34]=2)[CH3:32])[CH:15]=1
Reactant: C[C@H](Cc1cccc(CC(=O)NCc2ccccc2O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Solvent: O
Product: C[C@H](Cc1cccc(CC(=O)NCc2ccccc2O)c1)NC[C@H](O)c1ccc(O)c(CO)c1

Procedure:
Prepared from 2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-hydroxy benzyl)-acetamide (Preparation 3) according to the method for example 1, using water instead of acetic acid as the co-solvent, to give the title compound as a white foam.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][CH:13](O)[CH3:14].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH:13]([CH3:14])[CH3:12])=[O:10]
Reactant: CC(C)O
Reactant: O=C(O)Cc1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)Cc1ccccc1I
Temperature: 25 °C

Procedure:
A solution of 2-(2-iodophenyl)acetic acid (0.50 g) and propan-2-ol (0.142 ml) in dry dimethylformamide (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.458 g) with stirring at ambient temperature under an atmosphere of argon. After 18 hours the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (3×50 ml) and brine. The aqueous layers were back-extracted with ethyl acetate (50 ml) and the organic layers were combined, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (Varian Band Elut S1 silica gel) eluting with dichloromethane to give 2-propyl 2-(2-iodophenyl)acetate (232 mg) as a yellow oil, NMR: 1.2(6H, d), 3.8(2H, s), 4.9(1H, m), 7.0(1H, m), 7.4(2H, d) and 7.85(1H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.[C:25]1(=O)[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(O)(=O)C>[C:25]1(=[O:30])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[O:15][CH:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12]4)=[N:6][CH:7]=2)[C:28](=[O:29])[CH2:27][CH2:26]1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Solvent: CC(=O)O
Product: O=C1CCC(=O)N1c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
5-Amino-2-(2-phenylchroman-6-yloxy)-pyridine of Example 26 (0.16 g) was dissolved in 7.5 ml of glacial acetic acid under nitrogen. Succinic anhydride (0.0563 g) was added and the solution refluxed 60 minutes and solution was cooled and evaporated to dryness. Toluene (25 ml) was added and evaporated again to dryness. Product was purified by column chromatography (CH2Cl2:i-PrOH /95:5 as the eluant. 1H-NMR (400 MHz; d6-DMSO): δ 8.03 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=8.7 Hz, J=2.6 Hz), 7.48-7.31 (m, 5H), 7.10 (d, 1H, J=8.7 Hz), 6.95 (d, 1H, J=2.6 Hz), 6.92 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 6.88 (d, 1H, J=8.6 Hz), 5.13 (dd, 1H, J=10.2 Hz, J=2.2 Hz), 3.05-2.92 (m, 1H), 2.84-6.68 (m, 1H), 2.79 (s, 4H), 2.22-2.12 (m, 1H), 2.08-1.93 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:22]1([CH2:21][N:11]2[C:12]3[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]=3[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:8]=[C:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:10]2=[O:27])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (38 mg, 0.084 mmol), β-alanine (595 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound as a pale yellow solid. MS: (+) m/z 513.47 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:11]1([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])=[S:25])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)c2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1C(=S)N1CCNCC1
Yield: 95.5 %

Procedure:
A solution of 4-(2-trifluoromethylthiobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 5.61 mmol) in dichloromethane and trifluoroacetic acid (30 mL, 2:1) was stirred at ambient temperature overnight, the solvents were removed by evaporation. The residue was dissolved in ethyl acetate, and washed with aqueous saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated to give piperazin-1-yl-(2-trifluoromethylphenyl)methanethione (1.47 g, 5.36 mmol) which was used directly for next step without further purification.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH:22]([CH3:24])[CH3:23])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:7])=[CH:4][C:3]=1[N+:27]([O-])=O.[OH:30][C@:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:35])[C:32](O)=[O:33]>>[CH:22]([N:8]([C:6]([C:5]1[CH:25]=[CH:26][C:2]2[O:30][C@@:31]([CH3:35])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:32](=[O:33])[NH:27][C:3]=2[CH:4]=1)=[O:7])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)([CH3:24])[CH3:23]
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Reactant: CC(C)N(C(=O)c1ccc(F)c([N+](=O)[O-])c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Product: CC(C)N(C(=O)c1ccc2c(c1)NC(=O)[C@](C)(c1ccccc1)O2)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
Using tert-butyl (3R)-3-[(4-fluoro-3-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate and (2S)-2-hydroxy-2-phenylpropanoic acid, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].CCN(C(C)C)C(C)C.Cl.[O:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:16]2[C:11]3[C:10]4[CH2:27][CH2:28][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:42]5[CH2:43][CH2:44][CH2:45][O:39][CH2:40][CH2:41]5)[CH2:8][C:9]=4[S:26][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Reactant: C1CNCCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/CN1CCCOCC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of Example 59A (100 mg, 0.201 mmol) in DMF (2 mL) and DIPEA (0.10 mL, 0.60 mmol) was added 1,4-oxazepane hydrochloride (55 mg, 0.40 mmol). The mixture was stirred for 1 h at rt and then heated for 1 h to 50° C. The reaction mixture was directly separated by preparative HPLC. The product crystallized upon trituration with dichloromethane. The solvent was removed in vacuo to yield 83 mg (80%) of the title compound.