Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[C@@H:14]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:13][NH:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.CCN(CC)CC.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1>[C:38]([N:12]1[CH2:13][C@H:14]([NH:15][C:16](=[O:30])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[O:29])=[CH:21][CH:22]=2)[C@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:11]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N[C@H]1CNC[C@H]1NC(=O)c1ccc(Cl)s1)c1ccc(-n2ccccc2=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)[C@H](NC(=O)c2ccc(Cl)s2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To a solution of Example 75 (6 mg, 0.013 mmol) in THF (200 μl) at 0° C. was added Et3N (3 μl, 0.021 mmol) followed by the acetic anhydride (5 μl, 0.04 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and then at rt for 10 minutes. The solvent was evaporated under pressure, and the residue was purified by preparative HPLC using 0 to 100% B over 10 minutes (Column, Luna 10μ, C18 25×100 mm; Solvent A, 10% ACN +90% H2O with 0.1% TFA; Solvent B, 90% ACN+10% H2O with 0.1% TFA) to afford the title compound (2.8 mg, 48%) as a white lyophilite. MS m/z 486 ([M+H]+).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([O:15][C:16](OC1CC(=O)NC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[C:16]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N(CCO)CCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a 0° C. solution of diethanolamine (1.9 ml, 20 mmol) in 50 ml of THF was added benzyloxycarbonyloxysuccinimide (5.0 g, 20 mmol) followed by the slow addition of a solution of sodium carbonate (3.2 g, 30 mmol) in 50 ml of water. The reaction was stirred at 0° C. for 2 hours, diluted with 50 ml of water, and the majority of the THF was removed under vacuum. The reaction mixture was extracted with ethyl acetate (2×75 ml), washed with brine and dried over sodium sulfate. The solvent was concentrated and the residue was purified by SiO2 chromatography (250 g SiO2, 8% MeOH/methylene chloride) to give N-Cbz-diethanolamine (4.25 g) as a clear oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[N:3]1[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:56]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:58])[CH3:57]>CN(C)C(=O)C>[C:56]([N:59]1[CH2:64][CH2:63][N:62]([C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:13][N:3]3[C:4](=[O:12])[CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]3=[O:1])[CH2:15][CH2:16]2)=[O:22])[CH2:61][CH2:60]1)(=[O:58])[CH3:57]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C1Cc2ccccc2C(=O)N1C[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN3C(=O)Cc4ccccc4C3=O)CC2)CC1
Reaction time: 1 h

Procedure:
trans-4-(1,3-Dioxo-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-cyclo hexanecarboxylic acid (100 mg, 0.33 mmol) was dissolved in N,N-dimethyl acetamide (3 mL), HATU (125 mg, 0.33 mmol) and diisopropyl ethylamine (0.06 mL, 0.33 mmol) were added and the mixture was left stirring for 1 h. Then 1-acetylpiperazine (128 mg, 0.3 mmol) was added and the reaction stirred for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in 2 mL of DCM and washed with 2 mL of 0.4M Na2CO3 solution. The organic phase was collected and the solvent removed under reduced pressure. The crude was purified by SiO2 column, eluting with DCM-MeOH (97:3) and the fractions containing the desired product collected and further purified by prep HPLC. 42 mg of the title product were obtained (31% yield).
Reaction SMILES: [Cl:1][C:2]1[O:13][C:5]2=[C:6]([NH:11][CH3:12])[N:7]=[CH:8][C:9](I)=[C:4]2[CH:3]=1.[Si:14]([O:21][CH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Si:14]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]2[CH:32]=[C:31]([C:9]3[CH:8]=[N:7][C:6]([NH:11][CH3:12])=[C:5]4[O:13][C:2]([Cl:1])=[CH:3][C:4]=34)[CH:30]=[N:29]2)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: CC1(C)OB(c2cnn(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Reactant: CNc1ncc(I)c2cc(Cl)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(Cl)oc12
Temperature: 85 °C

Procedure:
A mixture of 2-chloro-4-iodo-N-methylfuro[2,3-c]pyridin-7-amine (34.0 mg, 0.110 mmol), 1-[4-(tert-butyldimethylsilanyloxy)-cyclohexyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (55.1 mg, 0.136 mmol), (1,1′-bis-(diphenylphosphino)-ferrocene)palladium dichloride (8.6 mg, 0.012 mmol), and potassium carbonate (41.4 mg, 0.300 mmol) in 1,4-dioxane (2.3 mL) and water (0.9 mL) was irradiated under microwave heating at 85° C. for 30 min. Purification by ISCO chromatography (20 to 50% ethyl acetate:heptane) afforded 42.6 mg (82%) of the title compound as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.36 (s, 1H), 6.88 (q, J=4.55 Hz, 1H), 4.17 (tt, J=3.85, 11.31 Hz, 1H), 3.73 (tt, J=4.01, 10.52 Hz, 1H), 2.91 (d, J=4.55 Hz, 3H), 1.99-2.10 (m, 2H), 1.82-1.97 (m, 4H), 1.38-1.53 (m, 2H), 0.88 (s, 9H), 0.08 (s, 6H); MS (ESI): 461.31, 463.30 [M+H]+; HPLC tR=4.28 min (ZQ3, nonpolar—5 min).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>CC(N(C)C)=O>[OH:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[OH:29])[S:3][C:4]=2[CH:10]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: OCc1ccc2nc(Br)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: OCc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a suspension of (2-bromobenzo[d]thiazol-6-yl)methanol (400 mg, 1.6 mmol) from Step 2 of Example 2 in DMA (6 mL) were added DIEA (258 mg, 2.0 mmol) and (1R,2R)-2-aminocyclohexanol (226 mg, 2.0 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure to give crude (1R,2R)-2-((6-(hydroxymethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown oil (445 mg, 100%), which was used for the next step without any further purification. LCMS (ESI) m/z 279 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([N+:15]([O-])=O)[CH:11]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CCOC(C)=O.[Pd]>[CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH2:15])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2cc([N+](=O)[O-])cnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2cc(N)cnc2c1
Reaction time: 18 h
Yield: 24.7 %

Procedure:
To a suspension of 7-(methylsulfonyl)-3-nitroquinoline (85 mg, 0.4 mmol) in EtOAc (6 mL,) under argon, was added 10% Pd/C (22 mg, 0.04 mmol). A H2 balloon was connected to the reaction flask, the flask was purged with H2 three times and the reaction mixture was allowed to stir under H2 atmosphere for 18 h. Unreacted starting material could be seen settling to the bottom of the flask together with the catalyst. The solids were removed from the EtOAc solution by filtration. Evaporation of EtOAc under reduced pressure yielded 7-(methylsulfonyl)-3-quinolylamine (22 mg, 30%). LC/MS (m/z): 223.0 (MH+), Rt 1.10 minutes.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][Mg]Br.O>C(OCC)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])([CH3:11])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(Br)n1
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1cccc(Br)n1
Reaction time: 3 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)ethanone (5 g, 25.0 mmol) in diethyl ether (77 ml) at 0° C. was treated with methyl magnesium bromide (8.33 ml, 25.0 mmol). After 3 hours, water was added to quench excess methyl magnesium bromide, and then concentrated aqueous hydrogen chloride solution was added until two layers were obtained. The layers were separated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield the title compound. LRMS (APCI) calc'd for C8H11BrNO [M+H]+: 216, Found: 216.
Reaction SMILES: C([N:3]([CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][N:5]=1)C.C(NC1N=CC(C2SC3C=[C:38]([OH:40])C=CC=3N=2)=CC=1)C>>[CH3:38][O:40][C:16]1[CH:17]=[CH:18][C:12]2[S:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:3][CH3:21])=[N:5][CH:6]=3)=[N:14][C:13]=2[CH:15]=1
Reactant: CCNc1ccc(-c2nc3ccc(O)cc3s2)cn1
Reactant: CCN(C)c1ccc(-c2nc3ccc(OC)cc3s2)cn1
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1

Procedure:
N-Ethyl-5-(6-methoxy-1,3-benzothiazol-2-yl)-N-methylpyridin-2-amine (55.4 mg, 0.185 mmol) was subjected to the procedure described for 2-[6-(ethylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol. Recrystallization from methanol gave 23.7 mg of the title compound as a pale yellow solid. 1H NMR δ ppm 9.75 (s, 1H) 8.67 (d, 1H) 8.03 (dd, 1H) 7.75 (d, 1H) 7.35 (d, 1H) 6.93 (dd, 1H) 6.75 (d, 1H) 3.63 (q, 2H) 3.07 (s, 3H) 1.11 (t, 3H); MS m/z (M+H) 286.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][C:13]=1[CH3:26]>C1(C)C(C)=CC=CC=1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:14][C:13]=1[CH3:26]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: Cc1ccccc1C
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1Nc1nc2ccccc2o1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
In xylene (20 ml), 2-chlorobenzoxazole (845 μl, 7.40 mmol) and tert-butyl 4-amino-3-methylphenylacetate (1.26 g, 5.69 mmol) were heated under reflux for 2 hours under stirring. After cooling to room temperature, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was dissolved in chloroform/methanol (9:1, v/v, 100 ml). The resulting solution was washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (4:1, v/v) eluate fractions, tert-butyl (4-(2-benzoxazolyl)amino-3-methylphenyl)acetate (1.17 g, 61%) was obtained as a yellow amorphous substance.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].C([NH:20][CH2:21][C:22](O)=[O:23])(OC(C)(C)C)=O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:7]([C:6]1[CH:5]=[CH:4][C:2]([O:3][C:22](=[O:23])[CH2:21][NH2:20])=[C:1]([O:11][CH3:12])[CH:10]=1)[CH:8]=[CH2:9]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCc1ccc(OC(=O)CN)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.5 %

Procedure:
To a solution of Eugenol (0.3 g, 1.82 mmol) in DCM (20 mL), was added Boc-glycine (0.35 g, 2.01 mmol), N-methyl morpholine (0.65 mL, 6.00 mmol), EDC.HCl (0.76 g, 4.0 mmol) and DMAP at ice temperature. The mixture was allowed to stir at room temperature (25° C.) over a period of 12 h. The resulting mixture was diluted with DCM (100 mL), washed with water (2×50 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was purified by silica gel column chromatography to obtain resulting product as pale yellow oil (300 mg, 46.9%)
Reaction SMILES: CO.Cl.[NH2:4][C:5]1[N:17]=[C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][N:7]2[N:6]=1.[H][H]>[Pt](=O)=O.C(Cl)Cl>[NH2:4][C:5]1[N:17]=[C:8]2[CH2:9][CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:12][N:7]2[N:6]=1
Reactant: COC(=O)c1ccn2nc(N)nc2c1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCn2nc(N)nc2C1
Yield: 107.7 %

Procedure:
Platinum(IV) oxide (3 g) was added to a mixed solution of methanol (200 ml), methylene chloride (200 ml), and concentrated hydrochloric acid (3.9 ml) containing the methyl 2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3.0 g) obtained in (Example 5.16) <Step 1>. The obtained mixture was stirred in a hydrogen atmosphere for 66 hours at room temperature. Thereafter, the reaction solution was filtered with Celite, and was then washed with methanol (80 ml). The filtrate was combined with the washing solution, and the thus mixed solution was then concentrated under reduced pressure. The obtained residue was subjected to azeotropy with methanol (20 ml) four times, so as to obtain the title compound (3.3 g) in the form of a light brown solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NCCCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (30 mg, 0.089 mmol), tert-butyl 4-aminobutanoate hydrochloride (20.88 mg, 0.107 mmol), and TEA (0.037 mL, 0.267 mmol) in DMF (1 mL) was added HATU (40.6 mg, 0.107 mmol). The reaction was stirred at room temperature overnight. The mixture was added 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=479.3 [M+H]+.
Reaction SMILES: C([C@H]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)(C)(C)C>CO.[OH-].[Na+].O>[F:22][C:19]1([F:23])[CH2:20][CH2:21][C@@H:17]([C@@:7]([OH:6])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=[O:9])[CH2:18]1
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(F)(F)C2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of 2.4 g of (2R,5R)-2-(t-butyl)-5-((1R)-3,3-difluorocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 30 ml of methanol, 10 ml of 1N aqueous sodium hydroxide solution was added, followed by 3 hours' stirring at room temperature. Distilling the methanol off under reduced pressure, the reaction liquid was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted from diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 1.66 g of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:20][CH:21]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(Nc2c([N+](=O)[O-])cnc3ccccc23)cc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 4-aminophenylacetic acid in N,N-dimethylformamide in the presence of triethylamine to provide N-(3-nitro-4-quinolinyl)-4-aminophenylacetic acid. This acid was reduced using the method of Example 26 to provide N-(3-amino-4-quinolinyl)-4-aminophenylacetic acid. This diamine was then reacted with formic acid using the method of Example 137 to provide 1-(4-carboxymethylphenyl)-1H-imidazo[4,5-c]quinoline. Recrystallization from methanol provided solid of m.p. 236°-240° C. Analysis: Calculated for C18H13N3O2 : %C, 71.3; %H, 4.3; %N, 13.9; Found; %C, 70.8; %H, 4.3; %N, 13.7.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)c1nc2ncc(Cl)cc2n1OCc1ccccc1

Procedure:
1-Hydroxy-6-chloro-2 -(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (5 grams), 10 milliliters of benzyl bromide, 20 grams of anhydrous potassium carbonate, and 100 milliliters of ethanol were mixed, heated to reflux, and refluxed for 1 hour. The reaction mixture was then filtered, evaporated under vacuum, and extracted with diethyl ether. The extract was filtered and evaporated under vacuum yielding a dark oil which on standing crystallized as the desired 1-benzyloxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine. It was recrystallized from a mixture of acetone and petroleum ether boiling at 60°-80°C., m.p., 107°-09°C.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[O:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[O:9].[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:6][O:7][C:8]([C:10]1[O:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][C:14]=1[CH3:15])=[O:9]
Reactant: COC(=O)c1occc1C
Reactant: CC(=O)OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1oc(C(C)=O)cc1C

Procedure:
Tin (IV) chloride (2.5 ml) is added to a solution of 3-methyl-furan-2-carboxylic acid methyl ester (1.0 g) and acetic anhydride (3.2 ml) in dichloromethane (8 ml) at 0° C. After 1 hour 30 minutes at 0° C. the reaction mixture is poured into a cold 10% Na2CO3 aqueous solution. The reaction mixture is filtered through a plug of Celite and the filtration cake is washed with dichloromethane. The aqueous phase is extracted two times with dichloromethane. The combined organic phases are washed once with water and with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-Acetyl-3-methyl-furan-2-carboxylic acid methyl ester (0.5 g) as a white solid. MS (HPLC/MS): 183 (MH+). Retention time: 1.09 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccccc1)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)ethanamine (100 g, 0.502 mol) and K2CO3 (138.8 g, 0.10 mol) in acetonitrile (1000 mL) was added a solution of 3-chloro-1-phenyl-propan-1-one (84.4 g, 0.502 mol) in acetonitrile (100 mL). The reaction mixture was stirred overnight. The solid was filtered, and the filtrate was concentrated to give crude (S)-3-(1-(4-bromo-phenyl)ethylamino)-1-phenylpropan-1-one (110 g, 66.2%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:56](OC)[CH3:57])[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].[CH3:60][O:61][C@H:62](C)[C@H:63](NC(OC)=O)C(O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]1[CH2:57][CH2:60][O:61][CH2:62][CH2:63]1)[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:44])[CH3:45])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:24][CH:25]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 831 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(OS(C)(=O)=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(methylsulfonyloxy)phenyl)-propanoate (300 mg, 0.8 mmol) was dissolved in THF (5 ml), and LiOH 1M (2 ml) was added. The mixture was stirred at RT for 5 hours, then HCl 1M was added, and the product was extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated under vacuum to give 229 mg (80%) of the title compound which was employed in the next step without any further purification. MS/ESI+ 360.39 [MH]+.