Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(Cl)Cl.[NH4+].[OH-]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH:1]1([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:13]4=[N:14][CH:15]=[C:10]3[N:9]([C:35]3[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=3)[C:8]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1[nH]c(=O)n(C3CCCCC3)c12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c2n(C2CCCCC2)c(=O)n1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 48.6 %

Procedure:
1-Cyclohexyl-6-((2-(trimethylsilyl)ethoxy)methyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.100 g, 0.259 mmol), 4-(methylsulfonyl)phenylboronic acid (0.103 g, 0.517 mmol, Acros), TEA (0.072 mL, 0.52 mmol) and 4 Å molecular sieves (130 mg) were added to DCM (2.6 mL) in a vial. Copper (II) acetate (0.047 g, 0.259 mmol) (Aldrich) was added in one portion and the vial was sealed. The mixture was stirred for about 22 h at rt. DCM (15 mL), water (5 mL), and concentrated NH4OH (5 mL) were added and the layers separated. The aqueous layer was extracted with DCM (5 mL). The combined organic layers were washed with water (10 mL), washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g Silicycle™ column) eluting with 10-50% EtOAc in DCM to give 1-cyclohexyl-3-(4-(methylsulfonyl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.068 g, 48%): LCMS (Table 2, Method b) Rt=3.16 min.; MS m/z: 541 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[C:17](=[S:19])=S.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[OH:16][C:13]1[C:3]2[C:2](=[C:7]([CH3:8])[C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][CH:4]=2)[O:1][C:17](=[S:19])[C:14]=1[CH3:15]
Reactant: CCC(=O)c1ccc(OCOC)c(C)c1O
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc2c(O)c(C)c(=S)oc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
According to the method described in Eur. J. Med. Chem. 36 (2001) 697, a solution of 1-[2-hydroxy-4-(methoxymethoxy)-3-methylphenyl]propan-1-one (3.99 g, 17.8 mmol) obtained in Example 2-1 and carbon disulfide (1.07 mL, 17.8 mmol) in tetrahydrofuran (30 mL) was added to a solution of potassium t-butoxide (5.99 g, 53.4 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred overnight at room temperature. Water (50 mL) was added to the reaction solution, and then the pH of the mixture was adjusted to 5 with 2 M hydrochloric acid, followed by extraction with ethyl acetate. The pH of the aqueous layer was adjusted to 5 again with 2 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 3.80 g of the title compound (yield: 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[N:15]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:14]2[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[N:15]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(N)c1cccc([N+](=O)[O-])c1
Reactant: Clc1cc(Cl)nc(Cl)n1
Product: CC(Nc1nc(Cl)cc(Cl)n1)c1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-(3-nitrophenyl)ethylamine and 2,4,6-trichloropyrimidine according to the procedure described in EXAMPLE 306, Step A.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:15][C:14](=[O:16])[O:13][C@H:12]1[O:17][CH2:18][CH3:19])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:10][C@@H:11]1[C@H:12]([O:17][CH2:18][CH3:19])[O:13][C:14](=[O:16])[CH2:15]1
Reactant: CCO[C@@H]1OC(=O)C[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCO[C@@H]1OC(=O)C[C@@H]1N
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a suspension of (2R, 3S)-(2-Ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid benzyl ester (0.22 g, 0.86 mmol) in Ethyl acetate (25 mL) at room temperature was added 10 mol % Pd/C (˜0.03 g). The reaction flask was purged between H2 (1atm) and vacuum three times before stirring under H2 (1atm) at room temperature. After stirring at room temperature for 3 hrs, the reaction mixture was filtered through celite and then evaporated to dryness to give the title compound (0.12 g, 97%) as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17]O)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=CCO)ccc1OCc1ccccc1
Reactant: c1nc[nH]n1
Product: COc1cc(C=CCn2cncn2)ccc1OCc1ccccc1
Yield: 34 %

Procedure:
In substantially the same manner as in Reference Example 25, 3-(4-benzyloxy-3-methoxyphenyl)-2-propen-1-ol was allowed to react with 1,2,4-triazole to give 1-[3-(4-benzyloxy-3-methoxyphenyl)-2-propenyl]-1,2,4-triazole. The yield was 34%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 70-72° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:32][CH:31]=3)[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCc1ccc(S(C)(=O)=O)cc1

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and 4-methylsulfonyl benzaldehyde employing methods similar to those described in Example 265 and was obtained as a yellow solid.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4]>O.CO>[CH2:3]([O:5][C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A solution of potassium hydroxide (1.3 g, 22.2 mol) in water (20 ml) was added to a stirred solution of ethyl 2-ethoxy-3-(3-nitrophenyl)acrylate (5.6 g, 21.1 mmol) in methanol (100 ml) and the resulting mixture heated to reflux overnight. The methanol was then evaporated in vacuo and the residue diluted with water (150 ml). The solution was washed with dichloromethane (2×80 ml), filtered through a pad of celite and then acidified by the addition of 3M HCl to pH 3. The mixture was refrigerated for 18 h then the precipitated solid was collected by filtration, washed with water (3×30 ml) and dried in vacuo at 40° C. The resulting solid was recrystallized from ethyl acetate and heptane to give 2-ethoxy-3-(3-nitrophenyl)acrylic acid as a yellow solid (3.06 g, 61%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15]O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Na+].[I-:18]>>[I:18][CH2:15][CH2:14][CH2:13][C:12]#[C:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: CS(=O)(=O)c1ccc(C#CCCCO)cc1
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(C#CCCCI)cc1

Procedure:
Preparation of the title compound with tosylated alcohol of Example 19, 5-(4-methanesulfonylphenyl)pent-4-yn-1-ol (3.14 g, 8.35 mmol), NaI (6.26 g, 41.76 mmol) following the procedure of Example 54 yielded 2.8 g (96%) of the title compound as a red oil: NMR (CDCl3) δ 2.06-2.15 (m, 2H), 2.58-2.63 (t, J=6.78, 2H), 3.04 (s, 3H), 3.33-3.37 (t, J=6.69, 2H), 7.57 (d, J=1.77, 2H), 7.85 (d, J=4.95, 2H). MS m/z 348.9 (M+H cald. for C12H13IO2S 348=349.2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH2:16][C:17]([CH3:21])([CH3:20])[C:18]#[N:19].[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=2[F:22])=[C:3]([CH2:16][C:17]([CH3:21])([CH3:20])[C:18]#[N:19])[CH:4]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CC(C)(C#N)Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2CC(C)(C)C#N)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, to a solution of 3-(2-bromo-5-((tert-butyl(dimethyl)silyl)oxy)phenyl)-2,2-dimethylpropanenitrile (903 mg), 2-fluoro-5-methoxyphenylboronic acid (621 mg), tris(dibenzylideneacetone)dipalladium(0) (45 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (79 mg) in toluene (10 mL) was added 2.0 M aqueous sodium carbonate solution (3.7 mL), and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound as a crude product. This compound was used for the next step without further purification.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])=[O:9])=C>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: CO
Product: O=C(NOCCO)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Yield: 29.9 %

Procedure:
8-(4-Bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (40 mg, 0.09 mmol) was dissolved in methanol and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue that was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanol in dichloromethane) to afford the title compound as a pale yellow solid (11 mg, 29%). LCMS (method A): RT=6.06 min, [M+H]+=409/411. 1H NMR (CD3OD): 8.27 (1 H, d, J=0.85 Hz), 7.79 (1 H, dd, J=7.39, 0.97 Hz), 7.42 (1 H, dd, J=10.00, 2.19 Hz), 7.31 (1 H, ddd, J=8.53, 2.20, 1.19 Hz), 7.12 (1 H, t, J=8.60 Hz), 6.79-6.73 (1 H, m), 6.65 (1 H, s), 3.97 (2 H, t, J=4.69 Hz), 3.73 (2 H, t, J=4.68 Hz).
Reaction SMILES: [O:1]1[CH:6]([C:7](OCC)=[O:8])[CH2:5][CH2:4][C:3]2[CH:12]=[CH:13][C:14]3[C:19]([C:2]1=2)=[CH:18][CH:17]=[CH:16][CH:15]=3.[NH3:20]>CO>[O:1]1[CH:6]([C:7]([NH2:20])=[O:8])[CH2:5][CH2:4][C:3]2[CH:12]=[CH:13][C:14]3[C:19]([C:2]1=2)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: N
Reactant: CCOC(=O)C1CCc2ccc3ccccc3c2O1
Solvent: CO
Product: NC(=O)C1CCc2ccc3ccccc3c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of intermediate (10-a) (0.03 mol) in methanol saturated with ammonia (200 ml) was stirred at room temperature overnight. The precipitate was filtered off and washed with methanol. The product was used without further purification, yielding 6.6 g (97%) of (±)-3,4-dihydro-2H-naphtho[1,2-b]pyran-2-carboxamide (interm. 11-a).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[Cl:36])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[Cl:36][C:17]1[CH:18]=[C:19]([F:35])[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]=1[O:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cnccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cnccc3O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
A mixture of 0.356 g of 4-benzyloxy-3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine, 10% palladium/carbon and ethyl acetate was stirred for 8 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated to obtain 0.32 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxypyridine.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[CH3:6][C:7]1([CH3:14])[CH2:12]C[C:10](=[O:13])[CH2:9][CH2:8]1.C(OCC)=O>C(OCC)C>[OH:5]/[CH:3]=[C:4]1\[C:10](=[O:13])[CH2:9][CH2:8][C:7]([CH3:14])([CH3:12])[CH2:6]\1
Reactant: CC1(C)CCC(=O)CC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCOCC
Product: CC1(C)CCC(=O)/C(=C\O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 818.5 %

Procedure:
A dry round-bottomed flask was charged with sodium hydride (60% dispersion in mineral oil, 475 mg, 11.9 mmol) and diethyl ether (24 ml). The reaction was cooled to 0° C. and ethanol (0.06 ml, 1.03 mmol) was added dropwise. The suspension was stirred for at 0° C. for 20 min then a solution of 4,4-dimethylcyclohexanone (1.50 g, 11.9 mmol) and ethyl formate (1.45 ml, 17.8 mmol) in diethyl ether (3 ml) was added dropwise over 15 min. The yellow solution was stirred at 0° C. for 3 h then slowly allowed to warm to room temperature overnight. Ethanol (0.24 ml) was added and the mixture was stirred at room temperature for 1 h then quenched with water and extracted with diethyl ether. The aqueous layer was acidified with 6M HCl until pH=2 then extracted with diethyl ether (2×). The combined organic layers were washed with brine then dried over sodium sulfate, filtered and concentrated to give 1.30 g (71%) of 2-[1-hydroxy-meth-(Z)-ylidene]-4,4-dimethyl-cyclohexanone as a pale brown oil which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ (ppm) 14.40 (br. s., 1H), 8.58 (s, 1H), 2.39 (t, J=6.8 Hz, 2H), 2.13 (s, 2H), 1.48 (t, J=6.8 Hz, 2H), 1.00 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:33])[NH:22][C@@H:23]([CH2:28][C:29]([O:31]C)=[O:30])[C:24]([O:26]C)=[O:25])=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:33])[NH:22][C@@H:23]([CH2:28][C:29]([OH:31])=[O:30])[C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1
Reactant: COC(=O)C[C@H](NC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)N[C@@H](CC(=O)O)C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (2S)-dimethyl 2-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)succinate (100 mg, 0.20 mmol, 1.00 equiv) in methanol (5 mL), water (1 mL), sodium hydroxide (30 mg, 0.75 mmol, 3.71 equiv). The resulting solution was stirred for 3 h at room temperature and then concentrated under vacuum. The pH of the solution was adjusted to 3-4 with 1N hydrochloric acid. The solids were collected by filtration and the residue was lyophilized. This resulted in 16 mg (16%) of (2S)-2-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)succinic acid as a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 8.98 (s, 1H), 7.66 (s, 1H), 7.38-7.44 (d, J=17.1 Hz, 2H), 7.12-7.15 (d, J=8.4 Hz, 2H), 6.78 (s, 1H), 6.60-6.63 (s, 1H), 4.48-4.54 (m, 4H), 3.63-3.66 (s, 2H), 3.01 (s, 1H), 2.51-2.84 (m, 2H). MS (ES, m/z): 466 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[NH2:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][CH:27]=1
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Reactant: CCn1c(=O)n(-c2cn(C)nc2C)c2c3cc(Br)ccc3ncc21
Product: CCn1c(=O)n(-c2cn(C)nc2C)c2c3cc(-c4cncc(N)c4)ccc3ncc21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-ethyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 245.1.1) and 3-aminopyridine-5-boronic acid pinacol ester (Apollo Scientific, Cheshire, United Kingdom) to give the title compound as a white solid. (HPLC: tR 2.02 min (Method A); M+H=400 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.02 (s, 1H), 8.15 (s, 1H), 8.12-8.07 (m, 1H), 7.94-7.91 (m, 1H), 7.81-7.76 (m, 2H), 7.54-7.51 (m, 1H), 7.03-7.00 (m, 1H), 5.44 (s, 2H), 4.11 (q, 2H), 3.91 (s, 3H), 1.94 (s, 3H), 1.35 (t, 3H))
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[C:9]([CH2:10][OH:11])=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C(O)c1cccnc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccnc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a suspension of lithium aluminum hydride (8.60 g) in THF (200 mL) was added a solution of 2-chloronicotinic acid (22.4 g) in THF (30 mL) at 0° C., and the mixture was stirred at 50° C. for 1 hr. After the reaction mixture was cooled to 0° C., 1N aqueous sodium hydroxide solution (9 mL) was added. The precipitate was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane) to give (2-chloropyridin-3-yl)methanol (14.0 g, 68%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4](=[N:11]O)[C:5](=[O:10])[CH2:6]2.[C:13](O)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>[Ni]>[C:13]([NH:11][CH:4]1[C:5](=[O:10])[CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]1[CH2:9][CH2:8]2)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: CN1C2CCC1C(=NO)C(=O)C2
Agent: [Ni]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1C(=O)CC2CCC1N2C
Reaction time: 5 h
Yield: 49 %

Procedure:
A solution of 8-methyl-8-azabicyclo[3.2.1]octane-2,3-dione-2-oxime (0.93 g, 5.5 mmol) in acetic acid/acetic anhydride (4:1, 40 mL) in a Parr bottle was treated with Raney nickel (Aldrich, 1/2 tsp.), then subjected to hydrogenation in a Parr apparatus at 45-50 psi for 5 h The solution was carefully evacuated of hydrogen, filtered through Celite® (wash filter cake carefully with methanol), and the filtrate was concentrated in vacuo. The residue was taken up in toluene and reconcentrated to remove most of the acetic acid. This residue was taken up in saturated sodium carbonate (40 mL), then treated with 15% sodium hydroxide (2 mL) and extracted with methylene chloride (3×50 mL) containing some 2-propanol. The combined extracts were dried (Na2SO4), concentrated in vacuo, and chromatographed on silica gel (eluted with 1:1 ethyl acetate/methanol) to afford a white solid, which contained some silica gel. This was removed by dissolving the product in warm ethyl acetate, filtering, and concentration in vacuo to afford 2-acetamido-8-methyl-8-azabicyclo[3.2.1]octan-3-one (0.53 g, 49%) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].O>C(Cl)Cl>[CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][N:8]([C:20](=[O:21])[C:19]3[CH:18]=[C:17]([O:16][CH3:15])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CC(C)N1CC2CNCC(C2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N2CC3CC(C2)CN(C(C)C)C3)cc(OC)c1OC
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with N2 inlet, a 10-mL addition funnel and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (0.92 g, 3.92 mmol) in CH2Cl2 (5 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered, and concentrated to give a viscous yellow oil. Chromatography of the oil was performed on neutral alumina (74 g, 1.7 cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant. Fractions (Rf =0.34) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 1.02 g (79.1%) of off-white solid (35); mp 67.5°-69.5° C. IR (KBr) cm-1 3055 (Ar C--H), 2985, 2955, 2910, 2890, 2780 (C--H), 1620 (C=O); 1H NMR (DCCl3) δ0.96 (d, 3H, CH3, J=6.5 Hz), 1.09 (d, 3H, CH3, J=6.7 Hz), 1.64-1.79 [m, 3H, H(5) and H(9)], 2.05 [bs, 1H, H(1)], 2.44 [bd, 1H, H(4)ax, J=10.6 Hz], 2.57 [bd, 1H, H(6)ax, J=10.8 Hz], 2.66 [heptet, 1H, CH(CH3)2, J=6.6 Hz], 2.71 [bd, 1H, H(6)eq, J=11.0 Hz], 3.02-3.07 [m, 2H, H(4)eq and H(2)ax ], 3.31 [bd, 1H, H(8)ax, J=13.2 Hz], 3.80-3.92 [m, 10H, H(8)eq and OCH3 ], 4.77 [bd, 1H, H(2)eq, J=13.5 Hz], 7.29 (s, 2H, Ar--H); 13C NMR (DCCl3) ppm 15.87, 19.42 (CH3), 29.02 [C(1)], 29.78 [C(5)], 32.35 [C(9)], 46.64 [C(2)], 51.73 [C(4)], 52.48 [C(8)], 54.39 [CH(CH3)2 ], 54.95 [C(6)], 56.13, 60.86 (OCH3), 103.83, 133.32, 133.21, 138.22, 153.21 (Ar--C), 169.66 (C=O). Anal. Calcd. for C20H30N 2 O4 : C, 66.27; H, 8.34. Found: C, 66.04; H, 8.32.