Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:23])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:35]([C:32]3[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][N:33]=3)=[O:36])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N)c2)CO[C@@]1(C)C(F)(F)F
Reactant: O=C(O)c1ccc(Br)cn1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)CO[C@@]1(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(2R*,5R*)-5-(3-amino-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (0.1 g, 0.253 mmol) in DMF (2.5 ml) was added 5-bromo-pyridine-2-carboxylic acid (78 mg, 0.379 mmol), EDC (0.074 g, 0.379 mmol), HOAt (0.053 g, 0.379 mmol) and DIPEA (0.083 g, 0.632 mmol) and the reaction mixture was stirred for 2 h at 25° C. After evaporation of the DMF the residue was taken up in NaH2PO4 solution and extracted with EtOAc. Combined organic layers were washed with 5% NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The crude product was crystallized from diisopropylether to provide the title compound as a white crystalline solid: TLC (hexane/EtOAc 1:1): Rf=0.61; HPLC RtH5=1.565 min; 1H NMR (360 MHz, CDCl3): δ 11.01 (s, 1H), 9.92 (s, 1H), 8.71 (dd, 1H), 8.21 (d, 1H), 8.10 (dd, 1H), 7.87 (s, 1H), 7.73 (d, 1H), 7.46 (t, 1H), 7.18 (d, 1H), 4.10 (m, 2H), 1.75 (s, 3H), 1.67 (s, 3H), 1.58 (s, 9H); ESIMS: 571, 573 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[OH:14].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[O:14][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1
Reactant: COc1c(C)c(C)c(OC)c(O)c1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(OC)c(Oc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
5.8 g of 2,5-dimethoxy-3,4,6-trimethylphenol [prepared as described in step (a) above] in 10 ml of dimethylformamide were added to a suspension of 1.4 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 50 ml of dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours. At the end of this time, a solution of 4.6 g of p-fluoronitrobenzene in 10 ml of dimethylformamide was added to the mixture, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour, and then at 80° C. for 7 hours. At the end of this time, the mixture was poured into water, and the resulting crude oil was extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting oil was purified by column chromatography through silica gel, using a 4:1 by volume mixture of benzene and hexane, followed by benzene alone, as the eluent, to give 3.9 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][C:14]([C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>CN(C)C=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]([C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC1(C(O)(CCl)Cc2ccccc2Cl)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C(O)(Cc2ccccc2Cl)Cn2cncn2)CCCCC1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
12 g (174 mmol) of 1,2,4-triazole and 17 g (123 mmol) of potassium carbonate are initially introduced into 30 ml of absolute dimethylformamide under a nitrogen atmosphere and the mixture is heated to 80° C. At this temperature, a solution of 16.7 g (55.5 mmol) of 1-chloro-3-(2-chlorophenyl)-2-(1-methyl-cyclohex-1-yl)-propan-2-ol in 20 ml of absolute dimethylformamide is added dropwise with stirring. The reaction mixture is then stirred at 80° C. for a further 8 hours. The precipitate is filtered off with suction, and the filtrate is concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, washed with water and, after drying over sodium sulphate, the solvent is stripped off under reduced pressure. The product which remains is chromatographed through a silica gel column using dichloromethane/ethanol=99:1 as the eluent. 8.6 g (46.5% of theory) of 1-(2-chlorophenyl)-2-(1-methyl-cyclohex-1-yl)-3 -(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this manner in the form of a solid substance of melting point 105° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH:7]=[N:6][CH:5]=1.[H-].[Na+].[CH3:24]I.O>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:24])[C:15](=[O:20])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: CI
Reactant: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a stirred solution of 5-(6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (430 mg, 1.52 mmol) in THF (15.0 mL) was added 60% NaH (91 mg, 2.28 mmol) at 0° C. and the reaction mixture was stirred at 2-5° C. for 0.5 h before CH3I (0.3 mL, 4.56 mmol) was added. After stirring overnight at RT, it was poured into water (5.0 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 5-(5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (383.7 mg, 85%) as a light yellow solid. MS: 298.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15][O:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COc1c(O)cccc1C=O
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C=O)cccc1OCc1c(C)cccc1C

Procedure:
The solution of 3-hydroxy-2-methoxybenzaldehyde (5.06 g, 32.7 mmol), 2,6-Dimethylbenzyl chloride (5.04 g, 33.1 mmol) and K2CO3(4.78 g, 34.6 mmol) in dry DMF (15 ml) was stirred at room temperature under argon for 16 hours, then diluted with EtOAc (40 ml), and washed with water 120 ml). The organic layer was concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound as an off white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH3:4].[SH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>>[CH2:1]([O:5][CH2:6][CH2:7][S:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCC(O)CS
Product: CCCCOCCSCC(O)CO

Procedure:
Following the procedure of Example 10, 2-butoxyethyltosylate (26.85 g, 98.7 mmol) and 3-mercapto-1,2-propanediol (10.68 g, 98.7 mmol) are reacted together to give 3-(2-butoxyethylthio)-1,2-propanediol, which diol (10.0 g, 52.5 mmol) is reacted with tosyl chloride (10.0 g) in pyridine. The tosylate (9.27 g, 25.6 mmol) is reacted with NaOH (1.02 g, 25.6 mmol) to give 2-(2-butoxyethylthiomethyl)oxirane. The oxirane (1.0 g, 5.26 mmol) and potassium t-butoxide (0.18 g, 1.58 mmol) are reacted together to give 3-(2-butoxyethylthio)-2-propenol, which propenol (4.72 g, 25.0 mmol) is reacted with acetic anhydride to give 3-(2-butoxyethylthio)-2-propenyl acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([CH2:14][C:15]2[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([F:26])=[N:9][C:10]=2[NH2:25].[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C>[NH2:25][C:10]1[N:9]=[C:8]([F:26])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([CH2:14][C:15]1[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Reactant: O=C(Cl)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(F)nc2c1nc(Cc1cc3c(cc1I)OCO3)n2CCCNC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (100 mg, 0.21 mmol) in DMF (3 mL) was added cyclopropanecarbonyl chloride (29 μL, 0.32 mmol) and triethylamine (90 μL, 0.96 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS71 as a white solid (75 mg, 65%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.32 (s, 1H), 6.77 (s, 1H), 6.02 (s, 2H), 4.24 (s, 2H), 4.16 (t, J=7.3 Hz, 2H), 3.26 (t, J=6.2 Hz, 2H), 1.91-2.01 (m, 2H), 1.50-1.57 (m, 1H), 0.90-0.95 (m, 2H), 0.76-0.82 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C20H21FIN6O3, 539.0704. found 539.0705.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]
Reactant: CC(Br)c1ccccc1
Reactant: O=c1c(Br)c(O)ccn1Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccn(Cc2cccc(F)c2)c(=O)c1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
A mixture of 3-bromo-1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (0.2 g, 0.72 mmol), potassium carbonate (0.1 g, 0.72 mmol) and (1-bromoethyl)benzene (0.19 g, 1 mmol) in DMF (3.0 mL) was stirred at room temperature for 16 h. DMF was distilled in vacuo, and the residue was purified by flash chromatography (EtOAc in hexane (1:3 v/v) to give pale yellow syrup. This material was further purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min), at flow rate of 100 mL/min. The appropriate fractions were combined, concentrated to a small volume (20 mL), added EtOAc (25 mL) and washed successively with satd. sod. bicarbonate, water, and dried (Na2SO4). EtOAc was removed under reduced pressure and residue was dried in vacuo to afford the title compound (0.15 g, 52%) as an amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.56 (d, 1H, J=7.6 Hz), 7.4-7.2 (m, 5H), 7.0 (m, 3H), 6.28 (d, 1H, J=7.6 Hz), 5.65 (m, 1H), 5.19 (d×d, 2H, J=14.8 Hz), and 1.64 (d, 3H, J=6.4 Hz), ES-HRMS m/z 402.0492 (M+H C20H18NO2Br, requires 402.0499).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]([F:35])([F:34])[F:33])[CH:25]=1>>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([O:31][C:32]([F:33])([F:34])[F:35])[CH:25]=1
Reactant: Oc1ccc(Br)cc1OC(F)(F)F
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(Br)cc3OC(F)(F)F)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-bromo-2-trifluoromethoxy-phenol as in Example 18 to afford 0.013 g (5%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C23H17O5F4Br 528, found 529 (M+1, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][C@@H:32]([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][C@@H:32]([CH3:35])[CH2:33][OH:34])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 85 %

Procedure:
In a manner similar to that described in 321, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (38 mg, 0.089 mmol) and (2S)-2-amino-1-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1 S)-2-hydroxy-1-methylethyl]-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (34 mg, 85% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.07 (d, J=8 Hz, 1 H), 8.58 (s, 1 H), 8.19 (s, 1 H), 7.37-7.33 (m, 2 H), 7.14-7.09 (m, 2 H), 5.19 (m, 2 H), 5.01 (m, 1 H), 4.12 (s, 2 H), 4.03 (m, 1 H), 3.43 (m, 2 H), 1.16 (d, J=6.8 Hz, 3 H); HRMS m/z calcd for C21H20F4N3O4: 454.1385. Found: 454.1391.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH2:15])[CH2:10][CH2:9]2.[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:27][C:28]([F:34])([F:33])[CH2:29][C:30]([NH:15][CH:11]1[C:12]2[C:8](=[CH:7][C:6](/[CH:5]=[CH:4]/[CH:3]([C:16]3[CH:17]=[C:18]([Cl:24])[C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=3)[C:2]([F:1])([F:25])[F:26])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)=[O:31]
Reactant: O=C(O)CC(F)(F)F
Reactant: NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Yield: 53.3 %

Procedure:
To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in CH2Cl2 (10 mL) were added trifluoropropionic acid (0.044 g, 0.34 mmol), EDC.HCl (0.038 g, 0.35 mmol), HOBt.H2O (0.07 g, 0.46 mmol) and DIPEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 h at 25° C. The reaction mixture was diluted with CH2Cl2 and washed with water. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 15% EtOAc in petroleum ether) to afford the title compound as a liquid (65 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.0 Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS m/z 529.02 ([M+H]+); IR (thin film) 3283, 1652, 1241, 811 cm−1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)C(C#N)=[CH:3][N:2]=1.[OH-:13].[K+].[CH3:15][CH2:16][OH:17]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:15]([C:16]([OH:13])=[O:17])=[CH:3][N:2]=1
Reactant: [OH-]
Reactant: N#Cc1cncc2ccccc12
Reactant: CCO
Agent: [K+]
Product: O=C(O)c1cncc2ccccc12
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a stirred solution of isoquinolin-4-carbonitrile (Intermediate-13) (3.0 g, 19.45 mmol) in EtOH (30 mL) was added KOH (20 g in 20 mL water) and the mixture was refluxed overnight. It was then cooled to RT and concentrated under reduced pressure. The aqueous layer was washed with Et2O and neutralized using 1N HCl. It was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (2 g, 59.3%) as an off white solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[N:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9]2>O.C(O)(=O)C>[CH3:5][C:6]1[C:7]([N:1]=[O:3])=[C:8]2[N:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=N[O-]
Reactant: COC(=O)c1c(C)cc2ccccn12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C)c(N=O)c2ccccn12
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of sodium nitrite (2.2 g, 31.90 mmol) in water (10 mL) was added slowly at 0-5° C. to a stirred solution of methyl 2-methylindolizine-3-carboxylate 2 (3.9 g, 20.61 mmol) in glacial acetic acid (50 mL). After 30 min, the brown reaction mixture was poured into water. Green crystals were collected by filtration, washed with water and then dried under vacuum to give 3.7 g of expected compound; m.p.: 131-132° C. 1H NMR (CDCl3): 9.63 (d, J=7.0 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.23-7.18 (m, 1H), 4.03 (s, 3H), 3.26 (s, 3H), 13C NMR (CDCl3): δ 162.5, 154.5, 141.7, 135.7, 127.9, 123.2, 118.4, 118.3, 114.5, 51.7, 11.1. Analysis calculated for C11H10N2O3: C, 60.55; H, 5.54; N, 12.84, found: C, 60.65; H, 5.60; N, 12.90.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24]C3C=CC=CC=3)=[O:23])=[CH:17][CH:16]=2)[N:4]=1.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:31])[C:3]1[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][N:6]=[C:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=3)=[O:23])=[CH:17][CH:16]=2)[N:4]=1
Reactant: OCc1ccc(F)cc1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)Oc3ccccc3)cc2)nc1N(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccc(F)cc3)cc2)nc1N(C)C
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of methyl (4-(dimethylamino)-2-{4-[(phenoxycarbonyl)amino]benzyl}pyrimidin-5-yl)acetate (100 mg, 0.24 mmol) and 4-fluorobenzyl alcohol (60 mg, 0.48 mmol) in N,N-diisopropylethylamine (0.17 mL, 0.95 mmol) and tetrahydofuran (2 mL) was refluxed for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative TLC (chloroform/methanol 30:1) to give methyl {4-(dimethylamino)-2-[4-({[(4-fluorobenzyl)oxy]carbonyl}amino)benzyl]pyrimidin-5-yl}acetate (45 mg, 42%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH:37]C(OC(C)(C)C)=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[CH3:19][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[CH2:10][C@@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[NH2:8]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(O)cc(C)c1C[C@H](N)C(=O)N[C@H](C)C(=O)NC[C@@H](N)Cc1ccccc1
Yield: 98.6 %

Procedure:
N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-D-alaninamide (6.1 g, 9.1 mmol) was dissolved in 25 mL dichloromethane and 25 mL TFA and stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was evaporated under reduced pressure to give a yellow gum. The gum was dissolved in 20 mL methanol and split into 4 equal portions. Each was loaded onto a separate 10 g SCX-2 cartridge, pre-wetted with methanol. Each cartridge was flushed with 50 mL of methanol to remove non-basic impurities, and then with 80 mL of 2N ammonia solution in methanol to elute the desired product. Fractions containing product were concentrated in vacuo to give a pale yellow gum. This was heated with a hot air gun and placed under vacuum (15 mm Hg) overnight to give 3.7 g (100%) of the title compound as a stiff white foam.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]([CH3:56])[CH3:55])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:51](=[CH:52][CH:53]=1)[C:33]1[NH:34][C:35]([C@@H:37]4[C@@H:42]5[CH2:43][C@@H:39](CC5)[N:38]4C(OC(C)(C)C)=O)=[N:36][C:32]=1[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]([CH3:69])[CH3:68])[C:64](O)=[O:65])=[O:61].[CH3:70][CH2:71]OC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]([CH3:56])[CH3:55])[C:7]([N:9]1[C@H:10]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]([C:27]2[CH:28]=[C:29]3[C:51](=[CH:52][CH:53]=2)[C:33]2[NH:34][C:35]([C@@H:37]5[CH2:42][CH2:43][CH2:39][N:38]5[C:64](=[O:65])[C@@H:63]([NH:62][C:60](=[O:61])[O:59][CH3:58])[CH:67]([CH3:69])[CH3:68])=[N:36][C:32]=2[CH:31]=[CH:30]3)=[CH:21][CH:20]=4)[C@@H:11]2[CH2:12][C@H:13]1[CH2:70][CH2:71]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
(1R,3S,4S)-tert-butyl 3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (102 mg, 0.135 mmol) was dissolved in DCM (5 mL) and treated with HCl (4M in dioxane, 1 mL). After 2 h, the reaction mixture was concentrated. The residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (28 mg, 0.149 mmol), COMU (58 mg, 0.135 mmol) and DMF (3 mL). DIPEA (0.12 mL, 0.675 mmol) was added and the reaction mixture was stirred for 1.5 h before being quenched with H2O and purified by HPLC to afford the title compound (86 mg, 77%). (ESI) m/z 814 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]3[CH2:25][CH2:24][O:23][C:22]3=[O:26])[C:6]2=[N:5][C:4]=1[CH3:27])=[O:2].[BH4-].[Na+].O>C(O)C>[OH:2][CH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]3[CH2:25][CH2:24][O:23][C:22]3=[O:26])[C:6]2=[N:5][C:4]=1[CH3:27]
Reactant: Cc1cccc(N2CCOC2=O)c1COc1cccn2c(C=O)c(C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(N2CCOC2=O)c1COc1cccn2c(CO)c(C)nc12
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A solution of 3-[2-(3-formyl-2-methylimidazo[1,2-a]pyridin-8-yloxymethyl)-3-methylphenyl]oxazolidin-2-one (1.39 g, 3.8 mmol) and sodium borohydride (0.19 g, 4.75 mmol) in anhydrous ethanol (125 ml) is stirred at RT for 1.5 h. Water (100 ml) is then added, the ethanol is distilled off on a rotary evaporator and the aqueous residue is stirred at 4° C. for 30 min. The precipitate is filtered off, washed with cold water and dried in vacuo. The title compound (1.28 g, 91%) is obtained as a beige solid. M.p. 190-193° C.