Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)c(C)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91.6 %

Procedure:
To a solution of 6-methoxy-2-methyl-3-nitropyridine (62.4 g, 0.371 mol) in methanol (1700 mL) was added 10% palladium on carbon (50% wet; 6.24 g), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 4.5 hrs. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a brown oil (47.0 g, 0.340 mol, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][O:17][CH3:16])=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1C(=O)c1cnoc1-c1ccccc1Cl

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and (S)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.9 mg). Calcd for C16H17ClN2O3: 320.0928, found 320.0932.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH3:37])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH3:37])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CCOc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OCC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-ethoxy-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[C:11](Cl)(=O)[CH3:12]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8][CH:11]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NCCc1ccc(F)cc1
Product: CC1NCCc2ccc(F)cc21

Procedure:
In accordance with the same procedures as in Steps 1, 2, and 3 of Preparation 21, except for using 4-fluorophenethylamine and acetyl chloride, 7-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline was obtained. In accordance with the same procedures as in Preparation 20, the titled compound was obtained as pale yellow oil. (Yield: 69%) The product was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:2][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(Oc2ccc(C=O)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1cccc(Oc2ccc(CO)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Dissolve 3-(4-formyl-phenoxy)-benzonitrile of Preparation 10 (0.90 g, 4.04 mmol) in methanol (15 mL) and cool to 0° C. Add sodium borohydride (0.31 g, 8.08 mmol) in three batches. After 1 hr, allow to warm to ambient temperature and stir overnight. Concentrate under reduced pressure to give a residue. Dilute with ethyl acetate (50 mL) and wash with 1N hydrochloric acid (3×100 mL). Separate layers and dry the organic layer over magnesium sulfate, filter, and concentrate to a residue. Purification by flash chromatography, using 10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes as a gradient eluent gives the title product (0.83 g, 91%): 1H NMR δ (CDCl3) 7.48-7.38 (m, 4H), 7.30-7.23 (m, 2H), 7.06 (d, J=8.4 Hz, 2H), 4.75 (s, 2H).
Reaction SMILES: CN(C)[C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].C[Mg]Br.Cl.[O:21]1CC[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[C:10]1([CH:8]2[O:7][N:6]=[C:5]([C:3]([C:22](=[O:21])[CH3:23])=[O:4])[CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)C1=NOC(c2ccccc2)C1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)C1=NOC(c2ccccc2)C1
Temperature: 0 °C

Procedure:
To a solution of 4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolecarboxamide (i.e. the product of Example 12, Step A) (17 g, 78.0 mmol) in a mixture of tetrahydrofuran (20 mL) and toluene (80 mL) was added methyl magnesium bromide (3.0 M solution in tetrahydrofuran, 28 mL, 84 mmol) over 1 h, while keeping the reaction temperature between −10 and −15° C. The reaction mixture was poured over a mixture of concentrated hydrochloric acid (20 g) and ice (80 g), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined organic extracts were washed with brine (40 mL) and concentrated under reduced pressure to give 14.4 g of 1-(4,5-dihydro-5-phenyl-3-isoxazoyl)ethanone as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:14][C@H:13]2[CH3:26])=[N:4][N:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[NH2:28].C1(P(C2CCCCC2)C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:27]([NH2:28])=[O:29])=[CH:31][CH:32]=3)=[N:3][N:4]=2)[C@H:13]([CH3:26])[CH2:14]1)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H]1CN(C(=O)C2CCCCC2)CCN1c1nnc(Cl)c2ccccc12
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C(N)=O)cc2)c2ccccc12
Temperature: 100 °C

Procedure:
Compound 71 was prepared according to general method H. A 15 mL Schlenk tube was charged with (R)-(4-(4-chlorophthalazin-1-yl)-3-methylpiperazin-1-yl)(cyclohexyl)methanone JK-5 (130 mg, 349 μmol), 4-carbamoylphenylboronic acid (77 mg, 523 μmol), tris(dibenzylideneacetone)dipalladium (0) (3.2 mg, 3.5 μmol), dicyclohexyl(2,6-dimethoxyphenyl)phosphine (2.3 mg, 7.0 μmol), and potassium phosphate tribasic (148 mg, 697 μmol). The vessel was evacuated, backfilled with argon 5 times, and then previously degassed n-butanol (1 mL) was added. The reaction was heated at 100° C. for 20 hours. After cooling, the reaction was added to aqueous K2CO3 (10%) and extracted three times with dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-100% ethyl acetate gave a pale yellow solid, compound 71. MS (M+H)+=452.2.
Reaction SMILES: [C:1]([O:8]C([O-])=O)(=O)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([C:26]3([C:30]([OH:32])=[O:31])[CH2:29][CH2:28][CH2:27]3)[NH:19][CH2:18][CH2:17][C:16]2=1.C(OCC)(=O)C.OS([O-])(=O)=O.[K+]>O1CCOCC1.[OH-].[Na+].O>[C:3]([O:2][C:1]([N:19]1[CH2:18][CH2:17][C:16]2[C:15]3[C:23](=[CH:24][CH:25]=[C:13]([CH3:12])[CH:14]=3)[NH:22][C:21]=2[CH:20]1[C:26]1([C:30]([OH:32])=[O:31])[CH2:29][CH2:28][CH2:27]1)=[O:8])([CH3:4])([CH3:5])[CH3:6]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3C1(C(=O)O)CCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2[nH]c3c(c2c1)CCN(C(=O)OC(C)(C)C)C3C1(C(=O)O)CCC1

Procedure:
5.52 g of tert-butyl pyrocarbonate are added to a solution of 6.5 g of the compound obtained in Example 37 in 50 ml of dioxane and 25 ml of 1M sodium hydroxide solution. After reaction for 20 hours at ambient temperature, 50 ml of ethyl acetate and 100 ml of water are added, and then the reaction mixture is acidified to pH 2.3 using a solution of KHSO4. The precipitate formed is filtered off, washed with water and dried, enabling the expected product to be isolated.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].C(N(CC)CC)C.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:4]([O:5][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@H:2]1[O:3][CH2:1]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1CO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of (R)-glycidol (5 g, 67.5 mmol) in dry dichloromethane containing triethylamine (10.3 ml, 74 mmol) cooled down to 0° C., was added a solution of tert-butyldimethylsilyl chloride (11.2 g, 74 mmol) in dry dichloromethane (30 ml). Then DMAP ( 0.33 g, 2.7 mmol) was added. The mixture was allowed to warm up to room temperature and stirred for 5 hours. The triethylammonium chloride crystals were filtered out and washed with dichloromethane (2×10 ml). The organic solution was washed with brine (2×50 ml) and dried over anhydrous sodium sulfate. The solution was concentrated and passed though a short silica gel column to remove polar impurities, and eluted with hexane/ethyl acetate (3:2). After removing the solvent, a colourless oil was collected and dried in vacuo to provide pure (S)-glycidyl-tert-butyldimethylsilyl ether (10.3 g, 81.2%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)(=[O:10])=[O:9])[C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN1CCOCC1>CN(C=O)C.C(Cl)CCl>[O:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][NH:35][C:3](=[O:5])[CH:2]([OH:1])[CH2:6][CH2:7][S:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)(=[O:10])=[O:9])[CH2:39][CH2:40]1
Reactant: O=C(O)C(O)CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1
Reactant: NCCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCN1CCOCC1)C(O)CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1
Reaction time: 2 h
Yield: 45.4 %

Procedure:
Part G: A solution of 3.4 g (10 mmol) of 2-hydroxy-4-[(3-phenoxybenzyl)sulfonyl]butanoic acid from Part F and 2.1 g (15 mM) HOBT in 15 mL of anhydrous DMF was cooled in an ice bath and treated with 2.3 g (12 mM) of EDC. After 2 hours, the reaction was treated with a solution of 1.5 g (12 mM) of 4-(2-aminoethyl)morpholine and 3.3 mL (3.1 g, 30 mM) of N-methylmorpholine in 5 mL anhydrous DMF. After stirring for 66 hours, the reaction was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated to yield 3.5 g of crude product. The crude product was chromatographed on silica gel using 5% methanol/ethyl acetate followed by 20% ethanol/THF to yield 2.1 g of N1-(2-morpholinoethyl)-2-hydroxy-4-[(3-phenoxybenzyl)sulfonyl]butanamide suitable for the next reaction.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O)C.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1C=O>C(OCC)(=O)C>[S:14]1[CH:15]=[CH:16][CH2:17][C:18]1=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: O=Cc1cccs1
Reactant: CCOP(=O)(CN)OCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(CN=C1CC=CS1)OCC
Yield: 100 %

Procedure:
A solution of 16.7 g. (0.1 mol) diethyl aminomethylphosphonate in 200 ml. absolute ethanol is treated with 11.2 g. (0.1 mol) thien-2-aldehyde and the resulting mixture is heated under reflux and then evaporated to give 26 g. diethyl N-thien-2-ylidene-aminomethylphosphonate (yield: about 100%) in the form of a yellow oil giving a single spot in TLC (silica plate; eluant: ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4]1>CCO>[CH3:1][O:2][CH:3]1[CH2:6][N:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:4]1
Reactant: COC1CN(CCCN2C(=O)c3ccccc3C2=O)C1
Solvent: CCO
Product: COC1CN(CCCN)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A solution of phthalimide 300 (5.2 g, 18.9 mmol) and N2H4.H2O (1.9 g, 37.8 mmol) in EtOH (100 mL) was heated at reflux temperature for 3 h. The solution was cooled to 0° C., the solid filtered off and washed with cold EtOH (20 mL) and EtOAc (100 mL). The solvent was evaporated to half volume, stored at −20° C. for 16 h and the suspension filtered. The filtrate was evaporated, the residue was dissolved in Et2O, the solid filtered off and the solvent was evaporated to give crude diamine 301 (1.8 g, 66%) as a yellow oil, which was used without further purification: 1H NMR δ 4.02 (p, J=5.8 Hz, 1H, CHO), 3.58-3.63 (m, 2H, CH2N), 3.25 (s, 3H, OCH3), 2.82-2.87 (m, 2H, CH2N), 2.72 (t, J=6.9 Hz, 2H, NCH2), 2.50 (t, J=7.1 Hz, 2H, NCH2), 1.40-1.60 (m, 4H, NH2, CH2); MS (APCI) m/z 145 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[NH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:16][C@@H:17]([CH3:20])[CH2:18][OH:19])[CH:5]=[CH:4][N:3]=1
Reactant: C[C@H](N)CO
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@@H](CO)NCc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 2-(S)-amino-propan-1-ol following procedure B. LC-MS showed the product had the expected M+H+ of 278. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (m, 1H) 7.8 (s, 1H) 7.7 (m, 1H) 7.5 (m, 1H) 7.3 (m, 1H) 7.0 (m, 1H) 3.8 (m, 1H) 3.6 (m, 1H) 3.4 (m, 1H) 3.1 (m, 1H) 2.6 (m, 1H) 0.9 (m, 3H).
Reaction SMILES: C(Cl)(=O)OC.C(N(CC)CC)C.[CH2:13]([C:15]1[C:20]([O:21]C(OC)=O)=[CH:19][C:18]([O:26]C(OC)=O)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=2)[C:16]=1[CH2:43][CH2:44][O:45][CH3:46])[CH3:14].[BH4-].[Na+].N>CO.O1CCCC1.O>[CH2:13]([C:15]1[C:20]([OH:21])=[CH:19][C:18]([OH:26])=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=2)[C:16]=1[CH2:43][CH2:44][O:45][CH3:46])[CH3:14]
Reactant: CCc1c(OC(=O)OC)cc(OC(=O)OC)c(-c2cccc(-c3ccccc3)c2)c1CCOC
Agent: COC(=O)Cl
Agent: N
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1c(O)cc(O)c(-c2cccc(-c3ccccc3)c2)c1CCOC
Yield: 52 %

Procedure:
In the same manner as in Example 118, 1-[4,6-bis(methoxycarbonyloxy)-2-(2-methoxyethyl)-3-(3-phenylphenyl)phenyl]ethanone was obtained from Compound 120 (65 mg, 0.18 mmol) obtained in Example 120, using methyl chlorocarbonate (0.03 mL, 0.39 mmol), triethylamine (0.06 mL, 0.43 mmol) and tetrahydrofuran (3.0 mL); and from the resulting compound, obtained was 4-ethyl-1,5-bis(methoxycarbonyloxy)-3-(2-methoxyethyl)-2-(3-phenylphenyl)benzene, using sodium borohydride (30 mg, 0.79 mmol), water (2.0 mL) and tetrahydrofuran (2.0 mL). Then, the resulting compound was treated with methanol solution (5.0 mL) of 7 mmol/L ammonia to obtain Compound 132 (33 mg, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:23].[Na+].Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14](=[O:23])[NH2:15])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.56 mmol) in ethanol (15 ml) was added 2 ml 10 N aqueous sodium hydroxide. The resulting solution was warmed to reflux for 2 hours, cooled to room temperature, poured into 1 N aqueous hydrochloric acid, and extracted into ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Recovered yellow oil was purified by silica gel chromatography, eluting with dichloromethane-methanol (9.6:0.4) to give the title compound (306 mg, 58%). MS m/z: 339 (M+1)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[CH:15][C:14]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:13][C:12]=2[O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[O:8][N:7]=1)=[O:5])C.[OH-].[K+:42].CCOCC>C(O)C>[CH3:40][O:39][CH2:38][CH2:37][O:36][CH2:35][O:34][C:12]1[CH:13]=[C:14]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:15]=[C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([O-:5])=[O:3])[CH:10]=1.[K+:42]
Reactant: CCOC(=O)c1cc(-c2c(OCOCCOC)cc(OCOCCOC)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)[O-])no2)c(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a stirred solution of 5-{2,4-bis[(2-methoxyethoxy)methoxy]-6-(4-nitrophenoxy)phenyl}isoxazole-3-carboxylic acid ethyl ester (15.6 g., 27.7 mmol) in ethanol (75 mL) was added a solution of 1 M KOH (55.5 mL, 55 mmol, 2 eq.) in ethanol at room temperature. After stirring overnight, the precipitate was collected and washed with a small volume of ethanol, then with ether to provide the title compound (12.3 g, 77% yield).
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[C@@:36](C)([OH:37])[C@@H:23]5[O:24]C(C6C=CC(OC)=CC=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N[C@@H]1C2C(=CC=CC=2)CC1.O.CC(O)=O>C1COCC1>[C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@@H:20]4[CH2:21][C@@H:22]([CH2:27][OH:26])[C@@H:23]([OH:24])[C@H:36]4[OH:37])[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)[C@@](C)(O)[C@@H]3O2)cc1
Agent: N[C@H]1CCc2ccccc21
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of (4aS,6R,7R,7aR)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)-7-methylhexahydrocyclopenta[d]-[1,3]dioxin-7-ol (312 mg, 0.594 mmol, as prepared following the procedure in Example 1a-d, using (S)-(+)-1-aminoindan in step c) in THF (1.17 mL) and water (1.17 mL) was added AcOH (3.51 mL, 61.7 mmol) under an atmosphere of nitrogen. The mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound as a white solid (182 mg, 76%). LC/MS: Rt=0.85 min, ES+ 381 (FA standard).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1)([O-:16])=[O:15].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:12][C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Subsequently, to a solution of (N-t-butoxycarbonyl-N-methyl-amino)acetic acid (2.52 g, 13.3 mmol) and p-nitrobenzyl alcohol (4.07 g, 26.6 mmol) in methylene chloride (125 ml) were added WSC (5,10 g, 26.6 mmol) and 4-dimethylaminopyridine (252 mg, 1.33 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford (N-t-butoxycarbonyl-N-methyl-amino)acetic acid p-nitrobenzyl ester (4.30 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl[C:36](OC1C=CC([N+]([O-])=O)=CC=1)=[O:37]>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:36](=[O:37])[NH:25][C:8]=2[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Temperature: 45 °C

Procedure:
C-(3-Chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (2.0 g, 5.8 mmol) was dissolved in anhydrous THF (35.0 mL), followed by the addition of DIPEA (1.21 mL, 6.92 mmol) at rt. The dark brown solution was then charged with para-nitrophenyl chloroformate (1.28 g, 6.34 mmol) at rt, and warmed to 45° C. for 17 h. The crude reaction was concentrated in vacuo and dissolved with EtOAc and water. Yellow precipitate crashed out of solution and was filtered. The solid was washed with hexanes and dried under vacuum to yield the title compound as a yellow solid; MS (ES+): m/z 373.04 (100) [MH+], 375.00 (30) [MH+++]; HPLC: tR=3.15 min (OpenLynx, polar—5 min); 1HNMR (400 MHz, DMSO-d6) δ ppm 6.80-7.05 (m, 2H), 7.43-7.66 (m, 4H), 7.79 (dd, J=8.34, 1.77 Hz, 1H), 8.02-8.17 (m, 2H), 8.19-8.35 (m, 4H), 8.53 (d, J=8.59 Hz, 1H).
Reaction SMILES: C(Cl)(=O)C.[N:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:45]([C:48](=[O:53])NCCC)=[CH:44]C=1)=O)C2>>[C:48]([N:8]1[CH2:9][CH2:10][N:5]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH2:7]1)(=[O:53])[CH2:45][CH3:44]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: CCC(=O)N1CCN(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting propionyl chloride for acetyl chloride and N-(4-(piperazin-1-yl)phenyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.38-7.44 (m, 2H), 7.28-7.39 (m, 4H), 6.87-6.90 (m, 2H), 4.74 (s, 4H), 3.54-3.60 (m, 4H), 2.95-3.10 (m, 4H), 2.36 (q, J=7.4 Hz, 2H), 1.03 (s, 1H), 1.00 (d, J=7.4 Hz, 2H); MS (ESI(+)) m/e 379 (M+H)+.