Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][CH2:19][CH2:20][CH2:21][OH:22].Cl>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: NCCCO
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (2.80 g, 10 mmol) in 100 ml of THF was cooled to ice temperature and stirred in an ice-bath while a solution of 3-amino-1-propanol (99%) (1.67 g, 22 mmol) was added dropwise over a period of 45 minutes. Stirring in the ice-bath was continued for 30 minutes. The reaction mixture then was acidified by addition of 3.0 ml of 1.2N HCl. The THF was evaporated under reduced pressure and the residue taken up in 100 ml of ethyl acetate. After extracting this solution with 4×20 ml of saturated NaCl solution, the ethyl acetate was evaporated and the residue recrystallized from a mixture of ethyl acetate and hexane to give 2.70 g (84.9%) of light yellow crystalline product, m.p., 87°-88.5°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:27])[C@H:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:14][CH3:15].[C:28]([NH:35][C@H:36]([C:45](O)=[O:46])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:27])[C@H:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[N:14]([C:45](=[O:46])[C@H:36]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:35][C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH3:15]
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Product: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1

Procedure:
Using Procedure D, coupling of Nδ-Boc-Nα-methylornithinyl 2-naphthyl ether (E) and Boc-homophenylalanine afforded titled compound as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.44 (2s, 18H), 1.58-1.70 (m, 4H), 1.98 (m, 2H), 2.73 (m, 2H), 2.83 (s, 3H), 3.18 (m, 2H), 4.08 (m, 2H), 4.61 (m, 1H), 7.09 (m, 2H), 7.35 (m, 5H), 7.49 (t, J=9.1 Hz, 1H), 7.59 (t, J=9.0 Hz, 1H), and 7.81 (3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.Br[C:37]([CH3:44])([CH3:43])[C:38](OCC)=[O:39].O.CC#[N:48]>>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([C:37]([CH3:44])([CH3:43])[C:38]([NH2:48])=[O:39])[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]
Reactant: CC#N
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C(C)(C)C(N)=O)C4)cc2OCC3)n(C(C)C)n1
Temperature: 60 °C
Yield: 30 %

Procedure:
A mixture of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene (100 mg, 0.21 mmol), ethyl 2-bromo-2-methylpropanoate (348.6 mg, 2.100 mmol), Ag2O (487.2 mg, 2.100 mmol), H2O (0.5 mL), and CH3CN (1.5 mL) in a seal tube was heated at 60° C. for 8 h. The solid was filtered off and the filtrate was purified by Combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to afford racemic 252 (35 mg, 30% yield), which was separated by chiral SFC (AS-H column, 0.1% DEA in MeOH isocratic) to give: 5.0 mg of one enantiomer and 3 mg of the other (7% total yield). LCMS (ESI): RT=5.19 min, m/z: 558.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.09-7.07 (m, 1H), 7.02-6.94 (m, 3H), 5.86-5.83 (m, 1H), 4.52 (s, 4H), 3.89 (s, 3H), 2.74-2.63 (m, 2H), 2.37-2.32 (m, 2H), 2.26 (s, 3H), 2.00 (s, 1H), 1.75-1.60 (m, 3H), 1.47-1.45 (m, 6H), 1.02-0.97 (m, 7H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and benzenesulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, 2H), 7.84 (s, 1H), 7.64-7.53 (m, 3H), 7.20 (m, 5H), 7.11 (m, 1H), 7.02 (d, 1H), 6.84 (d, 1H), 6.78 (d, 1H), 4.33 (s, 2H), 4.31 (s, 2H), 3.65 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H); MS 490 (M+1).
Reaction SMILES: [In].Br[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C[Si](Cl)(C)C.[CH2:19]([CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH:24]=[CH:23]1)[CH:20]=[CH2:21]>C1COCC1>[CH2:19]([CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH:23]1[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:20]=[CH2:21]
Reactant: C=CCC1C=CC(=O)CC1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: C[Si](C)(C)Cl
Agent: [In]
Solvent: C1CCOC1
Product: C=CCC1CCC(=O)CC1C(C(=O)OCC)C(=O)OCC
Reaction time: 0.5 h

Procedure:
Indium (114.8 mg, 1.0 mmol), diethyl bromomalonate (359.0 mg, 1.5 mmol), and TMSCl (0.6 mL, 5.0 mmol) were added to (±)-4-(2-propenyl)-2-cyclohexen-1-one (0.120 mg, 1.0 mmol) in anhydrous THF (1 mL) at room temperature under nitrogen atmosphere. After 30 minutes of stirring the reaction was quenched with saturated NaHCO3. The aqueous layer was extracted with diethyl ether and the combined organics were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was identified by mass spectrometry, (ESI, Pos) m/z 391 (M+23).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20](B1OC(C)(C)C(C)(C)O1)=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
A mixture of tert-Butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (852 mg, 2.60 mmol), vinylboronic acid pinacol ester (400 mg, 2.60 mmol), saturated aqueous sodium carbonate solution (12 ml), and tetrakis(triphenylphosphine)palladium(0) (84.8 mg, 0.0734 mmol) in dimethoxyethane (15 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (250 mg, 34.9%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].[O:29]1CC[CH2:31][CH2:30]1>>[C:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][C:30](=[O:29])[CH3:31])[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: C1CCOC1
Reactant: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(-c2cc3ccc(OC(C)=O)cc3s2)cc1

Procedure:
2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thiophene (2.42 g, 10 mmol) was dissolved in 100 mL of tetrahydrofuran and triethylamine (8 g, 100 mmol) was added. The reaction mixture was stirred under a nitrogen atmosphere at ambient temperature, while acetylchloride (2 g, 30 mmol) was slowly added. After sixteen hours, the reaction was terminated by the addition of water. The product began to crystallize at the interface, the water layer was discarded, and product crystallized out of the tetrahydrofuran layer. The product was filtered off and dried to give 2.06 of the title compound. 1H NMR: (d6 -DMSO)δ 7.86 (s, 1H) 7.85 (d, 1H), 7.83 (s, 1H), 7.81 (d, 1H), 8.70 (d, 2H), 7.25 (d, 2H), 7.18 (dd, 1H). EA calculated for C18H14O4S: C, 66.24; H, 4.32 Found: C, 66.14; H, 4.38. MS(FD): m/e=326 (M+).
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[C:8](=[O:9])[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CCC1Oc2cc(C(=O)OC)ccc2NC1=O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of 2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (10.00 g) in dimethylformamide (200 ml) were added 60% sodium hydride (in oil) (1.87 g) and 2-iodopropane (7.80 g) and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 2-ethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (4.43 g).
Reaction SMILES: C([O:5][C:6](=[O:44])[C@@H:7]([NH:9][C:10]([C:12]1[N:16]2[C@@:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)([CH3:29])[C:18](=[O:28])[N:19]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]2=[N:14][CH:13]=1)=[O:11])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[Cl:27][C:22]1[CH:21]=[C:20]([N:19]2[C:15]3=[N:14][CH:13]=[C:12]([C:10]([NH:9][C@@H:7]([CH3:8])[C:6]([OH:44])=[O:5])=[O:11])[N:16]3[C@@:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)([CH3:29])[C:18]2=[O:28])[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of (S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-(4′-fluoro-biphenyl-4-ylmethyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid tert-butyl ester (0.15 g, 0.24 mmol) in CH2Cl2 (10 mL) was added TFA (4 mL) and the mixture stirred at room temperature for 12 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give 120 mg of (S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-(4′-fluoro-biphenyl-4-ylmethyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid as a white solid, m/z 581.3 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([N:24]([CH2:40][CH3:41])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=O)[C:33]2=[CH:32][CH:31]=1)=[O:29])[CH3:23].Cl>C1COCC1.O1CCOCC1>[CH2:40]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:33]2=[CH:32][CH:31]=1)=[O:29])[CH3:41]
Reactant: CCN(CC)CCNC(=O)c1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCN(CC)CCNC(=O)c1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (76 mg, 0.46 mmol) in THF (3 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1M solution in THF, 1.2 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (2-diethylamino-ethyl)-amide (70 mg, 0.25 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and is poured into a cold 4M HCl solution in dioxane (3 mL) at 0° C. The resulting mixture is stirred at room temperature overnight. The reaction mixture is concentrated to partially remove the dioxane and is then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase is collected and the aqueous phase is extracted with additional EtOAc. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography (silica gel, MeOH-Chloroform). The product containing fraction are concentrated and the residue is treated with EtOAc-hexane (1:1). The solid is collected by filtration to give the title compound as an orange solid (51 mg, 49%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:9][CH:10]=1)=[O:4].O.[OH-].[Li+].CO.O>C1COCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:8]2[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc(-c2cccc(OC)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cccc(-c2ncc(C(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 103.1 %

Procedure:
A mixture of 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester (145 mg, 0.59 mmol), lithium hydroxide monohydrate (49.5 mg, 1.18 mmol), MeOH (1.5 mL), water (1.5 mL) and THF (1.5 ml) is stirred at rt for 3.5 hrs. The reaction mixture is concentrated, and water (1 mL) and 1 N aqueous HCl (1.2 mL) are added. The precipitated product is filtered and dried to afford 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid (140 mg). MS: 231 (M+H); 1H NMR (DMSO-d6): δ 4.62 (s, 3H), 7.54 (m, 2H), 8.14 (s, 1H), 8.34 (m, 1H), 8.46 (s, 1H), 9.30 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.CC1O[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=CC=2)=[N:24]C=1CCO.[CH3:45][S:46]([C:49]1[CH:54]=[CH:53][C:52](I)=[CH:51][N:50]=1)(=[O:48])=[O:47]>>[CH3:45][S:46]([C:49]1[CH:54]=[CH:53][C:52]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:24]4[CH2:25][CH2:27][CH2:32][C@H:31]4[CH3:30])[N:12]=3)=[CH:6][CH:7]=2)=[CH:51][N:50]=1)(=[O:48])=[O:47]
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Reactant: CS(=O)(=O)c1ccc(I)cn1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)nc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The titled compound is prepared substantially in accordance with the procedures of Example 4, Intermediate 13, and Example 75 using 2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (see Intermediate 3) and 2-methanesulfonyl-5-iodo-pyridine (see Intermediate 33). MS (m/e): 426.3 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2].[NH2:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19].C([BH3-])#N.[Na+]>>[CH2:1]([O:3][C:4]([CH:5]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C(=O)CCc1ccc(F)cc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccc(F)cc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in Example 26, ethyl-2-oxo-4-(4-fluoro-phenyl)butyrate and L-alanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-[1-ethoxycarbonyl-3-(4-fluorophenyl)-propyl]-L-alanyl-L-proline. The mass spectrum shows a molecular ion at 394, and strong peaks at 376 (M-18, H2O) and 375 (M-19, F). The nmr spectrum is consistent with the proposed structure. Elemental analysis indicates a hydrate.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.Cl[CH2:17][C:18]1[O:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:19]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:12][C:8]1[C:9]([CH2:17][C:18]2[O:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]=2[CH:7]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cc3c(cc2C)C(C)(C)CCC3(C)C)o1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution containing 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphtalene 4 (20 g, 99 mmol) and methyl 5-(chloromethyl)-2-furoate 5 (17.28 g, 99 mmol) in methylene chloride (500 mL, 0.2 M), aluminum trichloride (16.46 g, 124 mmol) is added slowly as a solid at the reflux temperature of methylene chloride. The solution is refluxed for an additional two hours. The reaction is monitored by tlc in 10% ethyl acetate/hexanes solution. The reaction is cooled to room temperature and the unreacted aluminum trichloride is quenched with water over 15 minutes. The crude product is extracted with methylene chloride and passed through silica gel (80 g) and eluted with methylene chloride. The solvent is evaporated in vacuo to syrup. The crude product us purified with silica gel (300 g) via a plug filtration column. Methyl 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoate 6 is eluted with 2% ethyl acetate/hexanes to afford 15.4 g (46% yield). NMR 1.25 (s, 6H), 1.28 (s, 6H), 1.67 (s, 4H), 2.23 (s, 3H), 3.89 (s, 3H), 3.97 (s, 2H), 5.95 (d, 1H), 7.09 (m, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].CCN(CC)CC.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCCBr
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: BrCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 653.5 %

Procedure:
2-Bromo-ethanol (6.3 g, 5.0 mmol), Et3N (10 mL, 72 mmol) and trityl chloride (14.6 g, 52.5 mmol) in anhydrous CH2Cl2 (50 mL) was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, 4:1) to give the title product (12 g).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][NH:18][C:17]=1[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:15])[CH3:12].[OH-].[Na+]>ClCCl.O>[CH2:11]([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:19]([CH:3]=[O:4])[NH:18][C:17]=1[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c[nH]c1CCNC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 84.37 %

Procedure:
A stirred solution of dichloromethane (5 ml) and N,N-dimethylformamide (0.6 ml) was added dropwise slowly with phosphorus oxychloride (0.414 ml, 4.5 mmol) under an argon atmosphere while maintaining the temperature at −10° C.˜0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at −10° C., added with the solution of 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (1.125 g, 3 mmol) in dichloromethane (3 ml) while maintaining the temperature at −10° C.˜0° C. for 1 hour. The mixture was stirred for another 2.5 hours at room temperature, added with cold water, adjusted to pH 11˜12 with 10% aqueous sodium hydroxide solution, extracted with ethyl acetate (50 ml×6), washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.02 g, 84.37%) as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccnc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reaction time: 14 h
Yield: 33.7 %

Procedure:
Under an argon atmosphere, to a solution of 6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-ol (300 mg), ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (259 mg) and triphenylphosphine (544 mg) in THF (5.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (943 μL) at room temperature, and the mixture was stirred for 14 hr. The solvent of the reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (182 mg) as a pale-orange oil.