Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]([O:22][CH3:23])[N:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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.O>[CH3:33][O:32][C:31]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]3[CH:8]([O:22][CH3:23])[N:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=4)[C:10](=[O:11])[C:5]3=[CH:4][CH:3]=2)[CH:28]=[N:27][C:26]=1[O:25][CH3:24]
Reactant: COC1c2nc(Cl)ccc2C(=O)N1c1cnn(CC(F)(F)F)c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
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: CN(C)C=O
Solvent: O
Product: COc1cc(-c2ccc3c(n2)C(OC)N(c2cnn(CC(F)(F)F)c2)C3=O)cnc1OC
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
As shown in step 17-v of Scheme 17, to Compound 2058 (293 mg, 0.85 mmol), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (269 mg, 1.01 mmol), Na2CO3 (179 mg, 1.69 mmol), and Pd(PPh3)4 (98 mg, 0.085 mmol) was added DMF (10 mL), followed by the addition of water (2 mL). The reaction vessel was evacuated, placed under an atmosphere of nitrogen, then warmed to 110° C. (sand bath). After 16 hours the reaction mixture was partitioned between EtOAc and water (100 mL each). The organics were washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was dissolved/suspended in EtOAc (7 mL) and heated with swirling in a water bath at 50° C. for 40 minutes. The resulting mixture was treated with hexanes (5 mL) and swirled an additional 5 minutes at 50° C. After cooling to 23° C., the resulting solid was collected by filtration and washed with 1:1 (EtOAc:hexanes, 5 mL) to give 2-(5,6-dimethoxypyridin-3-yl)-7-methoxy-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 256) as a mixture of enantiomers: ESMS (M+H) 450.44; 1H NMR (CDCl3, 300 MHz) δ 8.57 (d, J=3 Hz, 1H), 8.35 (s, 1H), 8.27 (s, 2H), 7.99 (d, J=3 Hz, 1H), 7.93 (s, 1H), 6.40 (s, 1H), 5.22 (q, J=9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.13 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[NH:14]1[C:18]([C:19]2[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=2)=[N:17][N:16]=[N:15]1>>[NH:17]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=4)[N:3]=3)=[CH:21][CH:20]=2)=[N:14][N:15]=[N:16]1
Reactant: OB(O)c1ccc(-c2nnn[nH]2)cc1
Reactant: COc1ccc2nc(Cl)ccc2c1
Product: Oc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)ccc2c1

Procedure:
Followed Scheme 2, A conditions: Starting materials: 2-chloro-6-methoxyquinoline (Intermediate 1) and (4-(1H-tetrazol-5-yl)phenyl)boronic acid. 1H NMR (DMSO-d6, 400 MHz): δ 10.15 (s, 1H), 8.45 (d, 2H), 8.31-8.28 (d, 1H), 8.22-8.12 (m, 3H), 7.98-7.95 (d, 1H), 7.39-7.35 (dd, 1H), 7.21 (s, 1H). MS (ESI): m/z 290.08 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc(Cl)cn1
Yield: 74.3 %

Procedure:
In a solution of 0.59 g of 2-amino-5-chloropyridine in 10 mL of pyridine, 2.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 15 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, then washed with 3N hydrochloric acid (50 mL×1), and then the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with neutral alumina column chromatography that was eluated with chloroform to obtain 1.80 g of the aimed product as white crystal.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:24]=[CH:25][CH:26]=1)=O>C(O)(=O)C>[CH2:7]([C:6]1[CH:5]=[N:4][N:3]2[C:19]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:17]=[N:1][C:2]=12)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2ccnc3c(Cc4ccccc4)cnn23)c1
Yield: 21.3 %

Procedure:
A solution of 1.87 g of 3-amino-4-benzoylpyrazole and 2.32 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide (Example 168) in 50 ml of glacial acetic acid was refluxed for 8 hours. The reaction mixture was evaporated to dryness and a saturated sodium bicarbonate solution was added along with 400 ml of methylene chloride. The solid that separated was recovered by filtration and was the desired compound (2.57 g, mp 205°-207° C.). The methylene chloride solution afforded more compound (0.73 g, mp 205°-207° C.).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:6]=1)(=O)=O.[F:31][C:32]1[CH:33]=[C:34]([OH:39])[CH:35]=[CH:36][C:37]=1[F:38]>>[F:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][C:37]=1[F:38])[O:39][C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:6]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(N2CCCC2)n1
Product: Fc1ccc(Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c(N3CCCC3)n2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(N-pyrrolidinyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (24 mg, 0.05 mmol) was treated with 3,4-difluorophenol by the same general procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 70/30 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=534 (M++1); Rt=4.39 min. 1H-NMR 500 MHz (CDCl3): δ 1.80 (bs, 4H), 3.2 (bs, 4H), 6.85-7.28 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][O:17][CH3:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(CC(CO)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(CN1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 58 %

Procedure:
To a solution of Intermediate 2 (0.60 g, 1.88 mmol) in anhydrous DMF (20 ml), at 0° C., was added sodium hydride (0.113 g of a 60% dispersion in oil, 2.81 mmol) and the mixture stirred for 0.2 h, before adding methyl iodide (0.399 g, 2.81 mmol), dropwise. The mixture was warmed to room temperature, stirred for 2 h, and then partitioned between water and ethyl acetate. The organic phase was separated and washed with water (×2) and brine (×1). After drying (MgSO4), the solvent was removed in vacuo and the crude product chromatographed through silica gel eluting with ethyl acetate/hexane (1:1) to give the desired methyl ether (0.365 g, 60%), δ(250 MHz, CDCl3) 1.44 (9H, s, (Me)3), 2.26-2.78 (6H, m, 3 of CH2), 3.02-3.16 (1H, m, CH), 3.31 (3H, s, OMe). 3.34-3.40 (4H, m, 2 of CH2), 3.53-3.69 (2H, m, CH2), 7.19-7.34 (5H, m, Ar-H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[S:16]([O:1][CH2:2][C:3]([CH2:8][O:9][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])([CH2:6][O:7][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH2:4][O:5][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: OCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(COS(=O)(=O)c2ccc(C)cc2)(COS(=O)(=O)c2ccc(C)cc2)COS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 48 h
Yield: 90.7 %

Procedure:
Pentaerythritol tetratosylate was prepared as follows: A mixture of pentaerythritol (27.20 grams, 199.8 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) and p-toluenesulfonyl chloride (171.0 grams, 897.0 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) in dry pyridine (300 milliliters; obtained from Anachemia) was stirred for 48 hours under nitrogen gas. This mixture was then added to 2 liters of 6 Normal hydrochloric acid. The resulting white precipitate was filtered and washed with methanol. The solid was recrystallized from benzene to afford pure pentaerythritol tetratosylate (136.5 grams, 181.3 mmol, 91 percent yield) as white crystals: mp 155-156° C.; IR (KBr) 3047, 2958, 2926, 1907, 1599, 1468, 1367, 1296, 1174, 1180, 1096, 976, 835, 666, 607, 554 cm−1; 1H NMR (400 MHz, CDCl3) δ7.68 (d, 8H, 3J=8.2 Hz) 7.36 (d, 8H, 3J=8.2 Hz), 3.82 (s, 8H), 2.47 (s, 12H); 13C NMR (100 MHz, CDCl3) δ145.86, 131.50, 130.38, 128.15, 65.74, 43.41, 21.90; MS (FAB, 3-nitrobenzyl alcohol) m/e 753; Anal. Calcd for C33H36O12S4: C, 52.64; H, 4.82: S, 17.04. Found: C, 52.98; H, 4.77; S, 17.60.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.29 g--see Preparation 2), 4-methoxyphenethyl bromide (0.22 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (30 ml) was heated under reflux for 3 hours. The mixture was partitioned between dichloromethane (50 ml) and 5% aqueous sodium carbonate (50 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.22 g.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([NH2:8])=[NH:7].[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[F:20].CN1CCOCC1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:7][C:6](=[NH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([F:2])[CH:4]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: Cc1ccc(C(=N)N)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=N)NS(=O)(=O)c2ccc(F)c(Cl)c2)cc1F
Yield: 35.8 %

Procedure:
Add 3-fluoro-4-methylbenzamidine hydrochloride (0.025 g, 0.133 mmol) in THF (0.5 mL) to 3-chloro-4-fluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol) followed by N-methylmorpholine (0.2 mL). The reaction mixture was concentrated and chromatographed using reverse phase chromatography (gradient of 5–95% (0.1% TFA in CH3CN) in (0.1% TFA in H2O). A white solid (16.4 mg, 36%) was isolated. ES Positive Ion MS [M+H]+ ions observed: m/z 345 (35Cl) and m/z 347 (37Cl).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:23])[C:11]1=CN(C)C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S([N:33]=[N+:34]=[N-])(=O)=O.CO>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:23])[C:11]1=[N+:33]=[N-:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=C1C(=O)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C(=O)C1=[N+]=[N-]
Temperature: 60 °C
Yield: 77 %

Procedure:
5'-O-(t-Butyldimethylsilyl)-2',3'-dideoxy-3'-(N,N-dimethylamino-methylene)-2'-oxo-uridine (1.78 g, 4.5 mmol), from Step 6, was added to the trifluoromethanesulfonyl azide solution and the reaction mixture was heated at 60° C. for 2.5 h under a nitrogen atmosphere. The solvents were evaporated in vacuo to a syrup (2.8 g) which was dissolved in 10 mL of methylene chloride and purified by flash chromatography (5 psi) on a silica gel column (2×35 cm) eluted with 200 mL of methylene chloride, 200 mL of 1% methanol in methylene chloride, 200 mL of 2% methanol in methylene chloride and 3% methanol in methylene chloride to give 1.27 g (77% yield) of the title compound. MS DCI: 367 (M+H)+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCC.Cl[C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]2[N:23]=[N:24][C:25]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:13][CH:14]=3)=[CH:26][CH:27]=2)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Clc1ccc(Cl)nn1
Reactant: CCCCCCCCCCOc1ccc(B(O)O)cn1
Product: CCCCCCOc1ccc(-c2ccc(-c3ccc(OCCCCCC)nc3)nn2)cn1

Procedure:
Analogously to Example 5a from 2-decyloxypyridin-5-boronic acid and 3,6-dichloropyridazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]#N)=N[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]Br.O.S(=O)(=O)(O)O.[O:26]1CC[CH2:28][CH2:27]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:15][C:10]=1[C:27](=[O:26])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1ncccc1OCc1ccccc1
Agent: C[Mg]Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a cold (0° C.) solution of 3-benzyloxypicolinonitrile (2.50 g, 11.9 mmol) in tetrahydrofuran (100 mL) was added dropwise 0.92M methyl magnesium bromide in tetrahydrofuran (150 mL, 138 mmol). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hrs. The reaction mixture was poured into water (2000 mL) and acidified with 10% sulfuric acid (500 mL). After being stirred for 30 min, the reaction mixture was poured into saturate aqueous NaHCO3 solution slowly and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtrated, and evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/3) to give 1-(2-benzyloxyphenyl)-ethanone as a colorless oil (2.49 g, yield; 92%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[OH:15][CH2:16][C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:25])=[O:18].S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[C:35]1([CH2:34][NH:33][C:31]([N:27]2[CH2:28][CH2:29][CH2:30][C@H:26]2[C:24]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[C:17](=[O:18])[CH2:16][O:15][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:25])=[O:32])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reaction time: 17 h

Procedure:
Triethylamine (0.59 ml), pivaloyl chloride (0.43 ml) were added, under ice-cooling, to a methylene chloride solution (25 ml) of (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (1.26 g) obtained in Example 5 and the mixture was stirred for 17 hours. The reaction mixture was poured into 5% potassium hydrogensulfate and extracted with methylene chloride. The extract was washed with saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (1.21 g) (see Table 1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:25])[CH2:8][CH2:9][C:10](=[CH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[CH2:2][CH2:3][N:4]([C:7](=[O:25])[CH2:8][CH2:9][CH:10]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(O)C(=Cc1cccc2ccccc12)CCC(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C(CCC(=O)N1CCOCC1)Cc1cccc2ccccc12
Yield: 89.1 %

Procedure:
5 g (14.8 mmole) of the 5-morpholino-2-(1-naphthylmethylene)-5-oxopentanoic acid (prepared as described above) were dissolved in 50 ml of methanol and hydrogenated in an atmosphere of hydrogen at atmospheric pressure and in the presence of 1.0 g of a 10% w/w palladium-on-carbon catalyst. The catalyst was then removed by filtration, and the solvent was removed by distillation under reduced pressure. The residue was triturated with diethyl ether to precipitate crystals, which were collected by filtration to give 4.5 g of 5-morpholino-2-(1-naphthylmethyl)-5-oxopentanoic acid as white crystals, melting at 130°-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])=[N:11][CH:12]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.6 %

Procedure:
Ethoxycarbonylisothiocyanate (3.37 g) was added to a stirred solution of 2-amino-5-chloropyridine (3.0 g) in dioxane (100 mL). The mixture was stirred at r.t. for 14 h. The solvent was removed in vacuum. The solid was dissolved in dichloromethane and methanol (100:1), filtered and the solvent was removed in vacuum to give a solid that was recrystallized from ethyl acetate to give 4.4 g of the title compound.
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:37]#[N:38])=[C:9]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][N:14]([CH:19]([CH2:34][CH3:35])[C:20]([NH:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)=[O:21])[C:13](=[O:36])[CH:12]=2)[CH:10]=1.Cl>C(O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:37]#[N:38])=[C:9]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][N:14]([CH:19]([CH2:34][CH3:35])[C:20]([NH:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[O:21])[C:13](=[O:36])[CH:12]=2)[CH:10]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
At RT, 0.2 ml of water and 97 mg (1.22 mmol, 3.0 eq.) of sodium hydroxide were added to a suspension of 200 mg (0.41 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoate (racemate) in 2.0 ml of ethanol. The reaction mixture was stirred at RT for 1 h and at an oil bath temperature of 60° C. for 6 h, allowed to stand at RT overnight and then added to aqueous hydrochloric acid (1N). After dilution with water a precipitate was formed which was filtered off, washed twice with water and dried under reduced pressure. The precipitate was then purified by flash chromatography (25 g of silica gel, mobile phase: dichloromethane→dichloromethane/methanol 50:1). Yield: 144 mg (38% of theory based on 0.82 mmol, since two crude product batches of the stated size were purified together)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Cc2ccc(Br)cc2N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
Iron (40.0 g, 700 mmol) was added slowly to a stirred solution of 2-(4-bromo-2-nitrophenyl)acetic acid (preparation 1b, 46.6 g, 200 mmol) in acetic acid (390 mL) at 75° C., and then mixture was stirred for 1 hour at 100° C. The mixture was cooled and ethyl acetate was added. The mixture was filtered through Celite® and the solvent evaporated. The crude product was washed with 0.1M aqueous hydrochloric acid, water, diethyl ether and dried to give the title compound (22.0 g, 58%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13](OS(C)(=O)=O)[CH2:12][CH2:11][N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8].[C-:27]#[N:28].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:27]([C@@H:13]1[CH2:12][CH2:11][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:14]1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C[C@@H]1c1ccc(F)c(F)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A mixture of (±)-1,1-dimethylethyl (2R,4S)-2-(3,4-difluorophenyl)-4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.72 g, 1.8 mmol), and potassium cyanide (0.33 g, 3.7 mmol) in N,N-dimethylformamide (3.3 mL) was stirred at 90° C. for 18 hours. The reaction mixture was cooled, diluted with ethyl acetate (50 mL), washed twice with 5% lithium chloride solution (30 mL), then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% to 25% ethyl acetate in hexanes gradient) to give (±)-1,1-dimethylethyl (2R,4R)-4-cyano-2-(3,4-difluorophenyl)piperidine-1-carboxylate (165 mg, 30% yield). MS (EI) for C17H23F2N2O2: 323 (MH+).