Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([OH:18])=[O:17].O[CH2:20][C@H:21]1[O:25][C:24](=O)[N:23]([C:27]2[CH:36]=[C:35]3[C:30]([CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]([F:47])([F:46])[F:45])[NH:33][C:34]3=[O:37])=[CH:29][CH:28]=2)[CH2:22]1.C[O:49]CCOCCOCCOCCO>>[O:49]=[C:15]([O:14][CH2:13][CH:12]([CH2:20][C@@H:21]1[O:25][CH2:24][N:23]([C:27]2[CH:36]=[C:35]3[C:30]([CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]([F:45])([F:47])[F:46])[NH:33][C:34]3=[O:37])=[CH:29][CH:28]=2)[CH2:22]1)[O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]([O-:18])=[O:17].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: COCCOCCOCCOCCO
Agent: COCCOCCOCCOCCOCC(=O)O
Product: COCCOCCOCCOC(COC(=O)C(=O)[O-])C[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)CO1

Procedure:
The title compound was synthesized by a condensation method similar to that of Step A of Example 3-1 using (2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)acetic acid instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14. However, (2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)acetic acid was synthesized by a method similar to that of Step A of Example 4-39 using tetraethylene glycol monomethyl ether instead of pentaethylene glycol monobenzyl ether.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:35][CH2:36][CH3:37])[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:12]=2[C:13]([O:15]C)=[O:14])[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:35][CH2:36][CH3:37])[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:31][N:32]=[N:33][N:34]=4)=[CH:20][CH:19]=3)[C:12]=2[C:13]([OH:15])=[O:14])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc(-n2c(C)ccc2C)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]1H-imidazole-5-carboxylate 9 (Example 70) in methanol (5 mL) containing 5 mL of 2.5N NaOH was heated under reflux for 3 hours. The reaction mixture was cooled, acidified with 10% citric acid to pH 4, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and the solvent removed under reduced pressure. The acid was further purified by flash chromatography on silica gel eluting with 5% methanol in ethyl acetate to furnish 0.2 g for the title compound 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid. MS (FAB, thioglycerol) 482 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([CH3:54])=[C:36]([N:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([N:50]([CH3:52])[CH3:51])[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:51][N:50]([CH3:52])[C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:53])[N:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH3:54])[CH:49]=[CH:48]2
Reactant: Cc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 100 °C
Yield: 78 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (69 mg, 0.16 mmol), 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (36 mg, 0.100 mmol), potassium phosphate (43 mg, 0.20 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (2.9 mg, 0.0061 mmol), and bis(dibenzylidineacetone)palladium(0) (1.7 mg, 0.0030 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 110 minutes. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 10% methanol/dichloromethane) to yield 6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (46 mg, 0.078 mmol). MS (ESI) 591.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:26]#[N:27])[C:12](=[O:25])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:6]=[CH:5][N:4]=1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:28][N:13]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[CH:10]=[C:11]([C:26]#[N:27])[C:12]1=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CSc1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cc(C#N)c(=O)n(C)c2-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 5-(2-methylsulfanylpyrimidin-4-yl)-2-oxo-6-(3-trifluoromethylphenyl)-1,2-dihydropyridine-3-carbonitrile (150 mg, 0.00040 mol) in 3 mL DMF was added cesium carbonate (200 mg, 0.00060 mol) and methyl iodide (1 mL, 0.0154 mol) and the solution stirred at room temperature for 1 h. The mixture was the partitioned between H2O and EtOAc and the organic phase dried over anhydrous sodium sulfate and concentrated. Chromatography on silica with 3% MeOH in CH2Cl2 yields 100 mg (65%) 1-methyl-5-(2-methylsulfanyl-pyrimidin-4-yl)-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydropyridine-3-carbonitrile as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@@H:10]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[Na]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:11](=[O:26])[C@@H:10]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Na]
Solvent: ClCCCl
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetate (0.050 g, 0.099 mmol, Example 21, Step C) and morpholine (0.013 mL, 0.149 mmol) in DCE (1.0 mL) was added sodium triacetoxyhydroborate (0.063 g, 0.297 mmol) at 0° C. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 and extracted (2×DCM) and the combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under the reduced pressure. This was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Reactant: O=Cc1oc(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c1OCc1ccccc1
Product: O=C(O)c1oc(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c1OCc1ccccc1
Yield: 84.93 %

Procedure:
3-Benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-07) (3.0 g, 84.93%) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (11-07) (3.4 g, 7.85 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([NH:18][S:19]([N:22]2[CH2:26]COC2=O)(=[O:21])=[O:20])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([CH:32]1[CH2:37]NC[CH2:34][N:33]1[C:38]([OH:40])=[O:39])(C)(C)C>>[C:1]([O:40][C:38]([N:33]1[CH2:32][CH2:37][N:22]([S:19](=[O:20])(=[O:21])[NH:18][C@:8]2([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:9]2[CH3:17])[CH2:26][CH2:34]1)=[O:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CNCCN1C(=O)O
Reactant: C[C@@H]1[C@H](c2ccccc2)[C@]1(NS(=O)(=O)N1CCOC1=O)C(=O)OC(C)(C)C
Product: C[C@@H]1[C@H](c2ccccc2)[C@]1(NS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Yield: 158.8 %

Procedure:
Under argon atmosphere, this (1S,2R,3R)-2-methyl-1-(2-oxo-oxazolidine-3-sulfonylamino)-3-phenyl-cyclopropanecarboxylic acid t-butyl ester (0.61 mmol) and t-butyl-1-piperazinecarboxylic acid (0.14 g, 0.73 mmol) were mixed, and the mixture was refluxed for 18 hours under heating. The obtained solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:0 to 5:1) to give the title compound (0.24 g, yield 79%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[C:16]([O:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:17]=[CH:18][C:10]=3[C:9]=2[N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34]COC)[CH:29]=2)[N:7]=1)=[O:5]>O1CCCC1>[CH3:2][O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[C:16]([O:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:17]=[CH:18][C:10]=3[C:9]=2[N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[N:7]=1)=[O:5]
Reactant: COCOc1cccc(Cn2nc(C(=O)OC)c3c2-c2ccc(OCc4cncnc4)cc2CC3)c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1nn(Cc2cccc(O)c2)c2c1CCc1cc(OCc3cncnc3)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
6 N hydrochloric acid (3 ml) was added to a solution in tetrahydrofuran (15 ml) of the 4,5-dihydro-1-(3-methoxymethoxybenzyl)-7-(5-pyrimidinylmethoxy)-[1H]-benz[g]indazole-3-carboxylic acid methyl ester (308 mg, 0.63 m mol) obtained in the step A of Example 27, and this mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. After the addition of ice water (50 ml), the reaction mixture was alkalified with a saturated aqueous solution of sodium bicarbonate and then extracted with chloroform (2×50 ml). After the extract was washed with water and dried, the solvent was distilled off under reduced pressure. The resulting solid residue was washed with ethyl acetate to obtain the desired compound (187 mg, 66%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH:10]([CH2:15][CH2:16][CH3:17])[C:11]([O:13]C)=[O:12])=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1.[OH-].[Na+]>C1COCC1>[CH3:24][N:2]([CH3:1])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH:10]([CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:4]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N(C)C)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(C(=O)O)c1c(C)nc(N(C)C)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of methyl 2-(2-(dimethylamino)-4-methyl-6-phenylpyrimidin-5-yl)pentanoate (100 mg; 0.305 mmol) in THF (1 mL) and 2N sodium hydroxide solution (1.5 mL; 3 mmol) was placed in a sealed tube and irradiated in a microwave oven at 100° C. for 1 h and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and diluted with water. 1N Hydrochloric acid was added dropwise until the product precipitated. The solid was filtered and dried under reduced pressure to give 66 mg (69%) of the title compound as a white solid. ESI/APCI(+): 314 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18]Cl)[C:14]([NH2:17])=[N:15][CH:16]=1.Cl>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:14]([NH2:17])=[N:15][CH:16]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncc(Cl)cc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(Cl)cc1COc1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium hydride (80% in oil, 124 mg, 4.1 mmol) was added portionwise to a solution of phenol (290 mg, 3.1 mmol) in anhydrous THF (15 ml). 5-Chloro-3-(chloromethyl)-2-pyridinamine.HCl (R. Herbert, D. G. Wibberley, J. Chem. Soc., 1969, 1504) (300 mg, 1.4 mmol) was then added and the reaction stirred at 50° C. for 3 h. After removal of THF in vacuo, the residue was partioned between diethyl ether and 1N NaOH. The aqueous phase was removed, extracted with diethyl ether and the combined organics washed with saturated brine, dried over MgSO4 and concentrated to an oil which upon triturating with hexane gave the title compound as a white solid (265 mg, 1.1 mmol):
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](=[O:10])[CH3:9].O>CN(C)C=O>[N:1]1([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCCCC(Br)C(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(C(C)=O)n1ccnc1

Procedure:
30 g of imidazole was dissolved in 80 ml of N,N-dimethylformamide. To this solution, 30 g of 3-bromo-2-heptanone was gradually added under stirring, and stirred at a temperature of from 50° to 60° C. for 4 hours. Then, the mixture was poured into water and extracted with chloroform. The extraction solution was treated by a usual manner, and the obtained oily product was purified by distillation, whereby 3-(imidazole-1-yl)-2-heptanone was obtained. The boiling point was 116°-119° C./2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)=[CH:4][C:3]=1[F:25].Br>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)=[CH:4][C:3]=1[F:25]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(Cl)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3cc(F)c(Cl)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
(2R,4S)-Methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.39 g, 1.05 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 142.75 mmol) and stirred at room temperature for 18 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-chloro-3,5-difluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (272 mg, 83%). 1H NMR (600 MHz, dmso) δ 1.29 (q, 1H), 1.43 (dq, 1H), 1.82-1.89 (m, 1H), 1.97-2.04 (m, 1H), 2.70 (dt, 1H), 2.84 (tt, 1H), 3.06-3.12 (m, 1H), 3.68 (dd, 1H), 5.73 (s, 1H), 7.31 (d, 2H). HRMS Calculated for [C14H13ClF2N2O2+H]+: 315.0712. Found: 315.0707
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]#[C:27][C:28](O)=[O:29].ClCCl.CO.N>>[N:12]1([CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]#[C:26][C:20]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=4[Cl:18])=[CH:17][C:6]=3[N:7]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)C#Cc1ccc(Cl)cc1Cl
Reactant: Nc1ccc2oc(CCN3CCCC3)nc2c1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(Cl)cc1Cl)Nc1ccc2oc(CCN3CCCC3)nc2c1

Procedure:
Prepared analogously to Example 3.1.e. from 5-amino-2-(2-pyrrolidin-1-ylethyl)benzoxazole and (2,4-dichlorophenyl)propynoic acid. Yield: 43 mg (33.1% of theory); C22H19Cl2N3O2 (M=428.32); melting point: 130° C.; calc.: molecular ion peak (M+H)+: 428/430/432; found: molecular ion peak (M+H)+: 428/430/432; C13H17N3O (M=231.30); calc.: molecular ion peak (M+H)+: 232; found: molecular ion peak (M+H)+: 232; Rf value: 0.21 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][CH:5]([CH3:31])[CH2:6][C:7]1([CH:20]([C:28](C)=[CH2:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:19].N#N.[BH4-].[Na+]>CCO>[OH:1][CH2:29][CH2:28][CH:20]([C:7]1([CH2:6][CH:5]([CH3:31])[CH3:4])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]1=[O:19])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=[O+][O-]
Reactant: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(Cc2ccccc2)C1=O
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1=O
Yield: 64 %

Procedure:
Ozone is bubbled through a cold (-78° C.) solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-α-(propen-2-yl)-3-pyrrolidineacetate (1.32 g, 3.42 mmol) in EtOH (30 mL). After purging the solution with N2, sodium borohydride (195 mg, 5.14 mmol) is added in one portion (at -78° C.). The solution is allowed to slowly warm to room temperatuare under N2 overnight. The reaction mixture is concentrated to a white solid, diluted with H2O (10 mL) and extracted with EtOAc (3×25 mL). The organic extracts are combined, washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield 1.37 g of a clear, colorless oil. The oil is purified by silica gel chromatography (50 g SG, 20% EtOAc/hexane) to give 850 mg (64%) of the title compound as a clear, colorless oil, which is a single diastereomer.
Reaction SMILES: [CH2:1]([N:8]([CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:40][CH3:41])=[C:34]([CH2:38][CH3:39])[CH:35]=2)[CH2:30]1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-])=O)[CH:13]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([C@@H](O)CN(CC2C=CC=CC=2)C2CC3C(=CC(CC)=C(CC)C=3)C2)C=CC=1OCC1C=CC=CC=1>>[NH2:26][C:14]1[CH:13]=[C:12]([CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:29]2[CH2:30][C:31]3[C:36](=[CH:35][C:34]([CH2:38][CH3:39])=[C:33]([CH2:40][CH3:41])[CH:32]=3)[CH2:37]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1cc2c(cc1CC)CC(N(CC(=O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)Cc1ccccc1)C2
Agent: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c(N)c1)C2
Product: CCc1cc2c(cc1CC)CC(N(CCc1ccc(OCc3ccccc3)c(N)c1)Cc1ccccc1)C2
Reaction time: 48 h

Procedure:
1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethan ne is prepared from 2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanone (1.50 g) by an analogous procedure to that used to prepare (R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanol in Example 19. The reaction is shown to be complete by TLC after 48 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is purified by flash column chromatography (silica, n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane/ethyl acetate 2:1 Rf=0.70).
Reaction SMILES: [Se](=O)=O.[F:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1.CC(=[N:17][OH:18])C>O.O1CCOCC1>[F:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH:12]=[N:17][OH:18])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)=NO
Reactant: CC(=O)c1cccc(F)c1
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(C=NO)c1cccc(F)c1
Reaction time: 24 h

Procedure:
To a mixture of selenium dioxide (58.3 g, 525 mmol) in 20 ml of water and 400 ml of 1,4-dioxane was added in one-portion 1-(3-fluoro-phenyl)-ethanone (69.0 g, 500 mmol). The mixture was refluxed overnight, then filtered through diatomaceous earth. The filtrate was added to an equal volume of water and adjusted to pH 4 with 5% aqueous sodium hydroxide. To this mixture was added acetone oxime (40.2 g, 550 mmol) and the mixture was stirred for 24 h. On dilution to 1.5 L with water, the mixture was extracted with ethyl acetate (2×400 ml), and the organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated to give a oil residue, which was purified by flash chromatography on silica gel (eluting with pure Petroleum) to return title compound as a pale yellow solid (68.0 g, 81.4%). 1H NMR (DMSO-d6): δ 12.78 (s, 1H), 8.02 (s, 1H), 7.82-7.50 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1/[N:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:14]([Mg]Br)[CH3:15]>C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][CH3:15]
Reactant: CC[Mg]Br
Reactant: C(=N/c1ncc[nH]1)\c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: Cc1ccccc1
Product: CCC(Nc1ncc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
To a solution of (1H-imidazol-2-yl)-[1-phenyl-meth-(E)-ylidene]-amine (0.19 ml, 1.63 mmol) in toluene (6 ml) was added scandium triflate (59 mg, 0.12 mmol). An ethereal solution of ethylmagnesium bromide (0.97 ml, 3 M, 2.91 mmol) was then added dropwise and the reaction mixture was stirred at room temperature for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride solution. The mixture was extracted twice with ether and the organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant:methanol/dichloromethane 0:100 to 10:90) to yield the title compound as a brown gum (67 mg, 29%); MS (ISP): 202.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:16](=O)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCCC=O
Product: CCCCNc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 71.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-(4-chlorophenoxy)aniline (Aldrich, 500 mg, 2.28 mmol) and butyraldehyde (230 mL, 2.50 mmol) were converted to the title compound (450 mg, 71%). 1H NMR (CDCl3) δ 7.34-7.16 (m, 2H), 6.99-6.84 (m, 4H), 6.72-6.62 (m, 2H), 4.19 (br s, 1H), 3.17 (t, J=7.2 Hz, 2H), 1.75-1.61 (m, 2H), 1.60-1.42 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 275.8 (M+H)+.