Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([NH:10][C@H:11]([C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([CH:25]([CH3:27])[CH3:26])[CH2:20]1)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:19]([OH:23])[CH2:20][C@@H:21]([CH:25]([CH3:27])[CH3:26])[C:22]([NH:2][CH3:1])=[O:24])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Solvent: CO
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 8 h
Yield: 91 %

Procedure:
Gaseous methylamine was introduced into a solution of 1.33 g (3.76 mmole) of (3S, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-isopropyldihydrofuran-2(3H)-one (prepared as described in Preparation 1) in 10 ml of methanol to ensure saturation, whilst ice-cooling. The reaction vessel was then stoppered tightly and allowed to stand overnight. At the end of this time, the solvent was removed by distillation under reduced pressure and the residue was recrystallized from hexane to afford 1.32 g (yield 91%) of the title compound as white crystals, melting at 154°-157° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:30]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1ccccc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccccc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with benzylamine (0.44 mL, 4.0 mmol). Purification on silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/2-propanol to give 124 as a white solid (m.p. 247-248° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][C:10]([C:30]([F:33])([F:32])[F:31])([O:25][Si](C)(C)C)[C:11]=3[N:12]2S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][C:3]=1[F:34].[OH-].[K+].CCO>C1COCC1.O>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][C:10]([C:30]([F:33])([F:31])[F:32])([OH:25])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[F:34]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(F)c(Cl)cc42)CCCC3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1cc(Cl)c(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
7-Chloro-6-fluoro-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.12 g, 0.22 mmol) was dissolved in THF (5 mL) and KOH (0.064 g, 1.0 mmol), in H2O (2 mL), was added. The reaction mixture was stirred at room temperature for 30 min., followed by the addition of EtOH (2 mL) and then heated to 60° C. for 8 h, diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to afford the title compound as an off-white solid (0.030 g, 37%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.01 (s, 1H), 7.50-7.47 (m, 2H), 6.68 (s, 1H), 2.72-2.68 (m, 1H), 2.62-2.57 (m, 1H), 2.12-2.2.08 (m, 1H), 2.01-1.98 (m, 1H), 1.92-1.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl.O>[C:35]([N:8]1[CH2:7][C:6]2[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]2[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:17][CH2:16]3)=[N:13][N:14]=[C:10]2[CH2:9]1)(=[O:37])[CH3:36]
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccc4)CC3)n1-2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the compound from example 5 (200 mg, 0.53 mmol) in dichloromethane (5 mL) was added triethylamine (110 μL, 0.79 mmol). The solution was cooled to 0° C. and acetic anhydride (59.6 μL, 0.63 mmol) was added. The reaction mixture was then stirred for 1 hour, before it was diluted with water (10 mL) and the phases were separated. The organic phase was washed with brine (10 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was azeotroped with ethyl acetate to give the product as a white, crystalline solid, 206 mg (93%)
Reaction SMILES: [C:1]([C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][C:8]1[CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11](=[O:18])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)([O:3][CH2:4][CH3:5])=[O:2].[BH3-]C#N.[Na+].O>C(O)C>[C:24]([CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][C:8]1[CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11](=[O:18])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=Cc1cc(C(=O)OCC)c(=O)n2ccccc12)C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CC(C(=O)OCC)C(=O)OCC)c2ccccn2c1=O
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a bright yellow suspension of ethyl 1-(2,2-dicarboethoxyvinyl)-4-oxo-4H-quinolizine-3-carboxylate (12) (750 mg, 1.94 mmol) in 5 ml ethanol was added NaBH3CN (68 mg, 1.08 mmol). The reaction mixture turned red and all solid material dissolved. Stirring was continued for 1 h, and the reaction mixture was poured into 50 ml of water. Ethanol was added to the aqueous suspension until a clear solution was obtained, which was extracted three times with 100 ml dichloromethane. The organic solvent was evaporated and the crude product was purified by flash chromatography to give ethyl 1-(2,2-dicarboethoxyethyl)-4-oxo-4H-quinolizine-3-carboxylate (13) as a bright yellow solid (275 mg, 36%). M.p. 105-108° C. 1H NMR (δ, CDCl3): 1.22 (t, J=7 Hz, 6H), 1.41 (t, J=7 Hz, 3H), 3.41 (d, J=7 Hz, 2H), 3.65 (t, J=7 Hz, 1H), 4.10-4.25 (m, 4H), 4.41 (q, J=7 Hz, 2H), 7.23 (m, 1H), 7.70 (m, 1H), 7.84 (d, J=8 Hz, 1H), 8.33 (s, 1H), 9.50 (d, J=7 Hz, 1H). MS: m/z 389.1466; required for C20H23NO7: 389.1475.
Reaction SMILES: C(OC([N:8]1[CH:12]([C@@H:13]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:14]([N:24]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@@H:12]([C@@H:13]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@@H:14]([N:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1C([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](CO)[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 3 h
Yield: 114.1 %

Procedure:
Dissolve 4-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (2.42 g, 3.68 mmol) in dry dioxane (16 mL). To the solution add 4 M hydrogen chloride in 1,4-dioxane (32.2 mL, 129 mmol) and stir for three hours. Concentrate to give the hydrochloride salt of the desired product as a white solid (2.17 g, 100%). Slurry the solid in ethyl acetate (150 mL) and stir vigorously with saturated sodium bicarbonate (100 mL). Separate the layers and dry (magnesium sulfate) to give the desired compound.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.O1CCOCC1>[ClH:41].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Yield: 68 %

Procedure:
A solution of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)(1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-4-piperidinyl)carbamate (833 mg, 1.512 mmol) in chloroform (10 ml) and MeOH (10 ml) was added 4M HCl in 1,4-dioxane (10 ml) and the reaction was stirred at rt for 0.5 h before evaporation and treatment with sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (462 mg, 68%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[N:16]=1>C(O)C>[N+:24]([C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[N:16][C:17]=2[CH:23]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cl)nc2c1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Temperature: 135 °C

Procedure:
In a 20 mL sealed tube under nitrogen, a mixture of tert-butyl piperazine-1-carboxylate (0.943 g, 5.06 mmol), 2-chloro-5-nitro-1H-benzo[d]imidazole (0.5 g, 2.53 mmol) and ethanol (9.5 mL) was heated at 135° C. for 2 hours. The reaction was concentrated and the residue was purified by reverse-phase chromatography to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[N:10]=1.[Cu][C:17]#[N:18]>>[CH3:14][N:13]1[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[C:17]#[N:18])=[N:10][C:11]([CH3:15])=[N:12]1
Reactant: N#C[Cu]
Reactant: Cc1nc(-c2cc(F)ccc2Br)n(C)n1
Product: Cc1nc(-c2cc(F)ccc2C#N)n(C)n1
Yield: 87 %

Procedure:
5-(2-Bromo-5-fluorophenyl)-1,3-dimethyl-1H-1,2,4-triazole (2.72 g, 10.07 mmol) was treated with copper (I) cyanide to give 1.90 g (87% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.48 (3H, s, CH3), 3.89 (3H, s, NCH3), 7.34-7.42 (2H, m, aromatics), 7.88 (1H, dd, J=5.0 Hz and J=8.6 Hz, aromatic). HRMS (ESI+) calculated for C11H10FN4 [M+H+]: 217.0889; found: 217.0893.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[C:39]([NH:40]C(=O)OCC3C=CC=CC=3)=[CH:38][C:37]3[C:32](=[CH:33][C:34]([C:51]4[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH:56]=4)=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO.C1COCC1.[NH4+].[OH-].[Pd]>[NH2:40][C:39]1[C:30]([C:28]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:11]2[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[C@H:9]([NH2:8])[CH2:10]2)=[O:29])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([CH:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1)[CH:33]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: [Pd]
Agent: Cl
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C[C@@H](N)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of benzyl [2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl]carbamate (4.7 mg, 0.006 mmol) in MeOH (0.24 mL) and THF (0.24 mL), 10% Pd on carbon (2.4 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 2 h. The mixture was filtered and concentrated under reduced pressure to give an intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.061 mL, 0.24 mmol) and stirred at room temperature for 30 min. The solution was concentrated under reduced pressure. The residue resulting residue was diluted with MeOH and NH4OH, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (2.0 mg, 61%). LCMS calc. for C29H37N10O (M+H)+: m/z=541.3. Found: 541.3.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41](O)[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:65])CC>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[C:42](=[CH:43][C:44]([Cl:57])=[C:45]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=3)[CH:46]=1)[CH:41]([F:65])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)C(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)C(F)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a −78° C. solution of (1S,3′R,4′S,5′R,6′R)-3′,4′,5′-tris(benzyloxy)-6′-(benzyloxymethyl)-5-chloro-6-(4-ethylbenzyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3-ol (40 mg, 0.05 mmol) in dry dichloromethane (2.0 mL) was added dropwise a solution of DAST reagent (0.014 mL, 0.1 mmol, 95%) in 0.5 mL of dry dichloromethane. The reaction mixture was stirred for 2 h at −78° C. and quenched by addition of 1 mL of saturated aqueous NaHCO3 solution when TLC showed the reaction was complete. The organic layer was separated and the aqueous layer was extracted 2× with CH2Cl2 (10 mL). The combined organic layers were washed 2× with NaHCO3 (10 mL), 3× with brine (10 mL) prior to drying over anhydrous Na2SO4. Concentrated under reduced pressure and purification of the crude product by prepared TLC provided 35 mg of the pure product.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:26]=[CH:25][C:12]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3C(OC)=O)=[CH:11][CH:10]=2)[O:3]1.OC1C=CC=C2C=1[N:37]=[CH:36][CH:35]=[CH:34]2.BrCC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:27][C:2]1([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[N:37]=[CH:36][CH:35]=[CH:34]4)=[CH:25][CH:26]=2)[O:3]1
Reactant: COC(=O)c1ccccc1OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Oc1cccc2cccnc12
Agent: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(COc3cccc4cccnc34)cc2)OC1(C)C
Yield: 22 %

Procedure:
The synthesis of B14 was accomplished following the procedure outlined for B1 using 8-hydroxyquinoline (0.12 g, 0.8 mmol), 4-bromomethylphenyl boronic acid pinacol ester (0.26 g, 0.88 mmol), and K2CO3 (0.33 g, 2.4 mmol) in 10 mL of acetonitrile affording B14 in 22% yield (0.06 g, 0.17 mmol). 1H NMR (400 MHz, CDCl3) δ=8.96 (dd, Jj=4.4 Hz, J2=1.2 Hz, 1H), 8.09 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 2H), 7.49 (d, J=7.6 Hz, 2H), 7.40 (dd, J1=8 Hz, J2=4 Hz, 1H) 7.34-7.28 (m, 2H), 6.95 (dd, 7.79 J1=7.2 Hz, J2=1.6 Hz, 1H), 5.47 (s, 2H), 1.31 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=154.38, 149.60, 140.69, 140.42, 136.13, 135.32, 129.70. 126.77, 126.26, 121.84, 120.11, 110.25, 84.01, 70.87, 25.08. ESI-MS(+): m/z 362.02 [M+H]+.
Reaction SMILES: C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C.C(N)CCCCCC.[CH2:29]([O:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C@@H:44]([C:46](=[O:63])[NH:47][CH2:48][CH2:49][C:50]2C=[CH:54][C:53](OC3C=CC=CC=3)=[CH:52][CH:51]=2)C)=[CH:39][CH:38]=1)[C:33]([OH:35])=[O:34])C>>[CH2:48]([NH:47][C:46]([CH2:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][C@H:32]([O:31][CH3:29])[C:33]([OH:35])=[O:34])=[CH:38][CH:39]=1)=[O:63])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: CCCCCCCN
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Product: CCCCCCCNC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and heptylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C19H29NO5 [M−H]−: 352.
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCC(O)[C@@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in Et2O (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in Et2O, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was stirred at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was recooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil. Yield: 1.13 g (69%). (57% de 3S,4R: 43% de 3R,4R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.45 & 0.69 (t & m, 6H, J=7.43 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.12-1.29 (m, 4H, —NHCH (CH2CH3)CH (CH2CH3)OH), 2.16 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.54 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.21-3.40 (m, 1H, —NHCH(CH2CH3) CH(CH2CH3)OH), 4.29+4.39 (2×d, 1H, J=4.42 & 5.37 Hz, —NHCH(CH2CH3) CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Ph).
Reaction SMILES: S[C:2]1[N:3]([CH:11]2[CH2:24][CH:23]3[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[N+]([O-])(O)=O.[OH-].[Na+]>O>[CH2:22]1[CH:23]2[CH:18]([C:17]3[C:12]([CH:11]([N:3]4[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=[CH:2]4)[CH2:24]2)=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1cnc(S)n1C1CC2CCCCC2c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: COC(=O)c1cncn1C1CC2CCCCC2c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.1 %

Procedure:
A mixture of 19.0 parts of methyl 2-mercapto-1-(1,2,3,4,4a,9,10,10a-octahydro-9-phenanthrenyl)-1H-imidazole-5-carboxylate, 75 parts of nitric acid and 150 parts of water was stirred for 1 hour at room temperature. The reaction mixture was diluted with crushed ice and treated with a sodium hydroxide solution. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.9 parts (11.1%) of methyl 1-(1,2,3,4,4a,9,10,10a-octahydro-9-phenanthrenyl)-1H-imidazole-5-carboxylate; mp. 139.9° C. (compound 3.2).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:15](=[O:24])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:11]N(C)C)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[OH-:26].[K+]>>[OH:17][C:16]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][O:26]1
Reactant: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of 3.23 g of 2-(4-carboxyphenyl)-1-dimethylamino-4-phenyl-1-butene-3,4-dione in 100 ml of 2% potassium hydroxide solution was stirred at room temperature for 5 hrs. The reaction mixture was poured onto 300 ml of ice-water and acidified with 100 ml of 1 N hydrochloric acid. The precipitate was collected, washed with water and then dissolved in 300 ml of ether. The solution was dried over anhydrous sodium sulfate. The drying agent was collected and the filtrate was evaporated. Recrystallization from ether gave 2.12 g (71%) of 2-hydroxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone, m.p. 294°-299° C. dec.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]1[C:9]([C:16](O)=[O:17])=[N:10][C:11]([OH:15])=[N:12][C:13]=1[OH:14])[CH3:6]>CCO>[CH2:1]([O:3][C:16]([C:9]1[C:8]([O:7][CH2:5][CH3:6])=[C:13]([OH:14])[N:12]=[C:11]([OH:15])[N:10]=1)=[O:17])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOc1c(O)nc(O)nc1C(=O)O
Solvent: CCO
Product: CCOC(=O)c1nc(O)nc(O)c1OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Acetyl chloride (100 ml, 36 eq.) was added dropwise to absolute EtOH (780 ml) at 0° C. After stirring the resulting solution for 20 min at r.t., 5-ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid (7.76 g, 1 eq.) was added in one portion and the mixture was refluxed overnight. The volatiles were evaporated in vacuo to give 5-ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid ethyl ester as an off-white solid (8.85 g, 100%).