Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:32]=[CH:31][C:23]([O:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>CO.[Pd]>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]2[CH:22]=[CH:21][C:20]([C:17]3[N:16]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[O:19][N:18]=3)=[CH:32][CH:31]=2)[CH:26]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5cccnc5)cc4)no3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(-c2nc(-c3ccc(Oc4cccnc4)cc3)no2)cc1
Temperature: 55 °C
Reaction time: 23 h
Yield: 1.1 %

Procedure:
In a single neck round bottom flask fitted with a condenser, 3-(4-(5-(4-(Benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenoxy)pyridine (224 mg, 531 μmol) was suspended in methanol (5.0 mL) and THF (5.0 mL) and then 10% Pd/C (1.0 mg, 36 μmol) was added. The reaction vessel was sealed and the solution was stirred under H2 at 55° C. for 23 hours. The hot solution was filtered through Celite and the pad was washed with methanol (20 mL). The solvent was removed under reduced pressure. The solid residue was purified by silica gel column chromatography (EtOAc/Hex 1:2) to give the product as a white solid (2 mg, 1%). 1H NMR (500 MHz, DMSO-d6) δ(ppm): 7.00 (2H, d, J=9.0 Hz), 7.23 (1H, d, J=9.0 Hz), 7.05 (1H, ddd, J=8.4, 4.8, 0.8 Hz), 7.61 (1H, ddd, J=8.4, 2.8, 1.4 Hz), 8.02 (2H, d, J=9.0 Hz), 8.01 (2H, d, J=9.0 Hz), 8.46 (1H, dd, J=4.7, 1.3 Hz), 8.21 (1H, d, J=2.8 Hz) 10.58 (1H, s). MS (FAB+): 332 (MH+). HRMS for C19H13N3O3 (MH+): calculated: 332.1035; found 332.1013.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35](=[O:51])[C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH:29]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:39]2[CH:40]=[CH:41][C:36]([C:35]([NH:34][C:30]3[CH:29]=[C:28]([CH3:27])[CH:33]=[CH:32][N:31]=3)=[O:51])=[CH:37][CH:38]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Reactant: Cc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Product: Cc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Yield: 82 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4-methylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 6) to afford the title compound (125.5 mg, 82%).
Reaction SMILES: [ClH:1].C[O:3][C:4]([C:6]1([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]>>[ClH:1].[CH2:27]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]([NH:12][C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[O:14])=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[CH2:28][CH3:29]
Reactant: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)OC)CCCCC3)cc2)CC1
Agent: Cl
Product: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)O)CCCCC3)cc2)CC1
Temperature: 25 °C
Yield: 41 %

Procedure:
3 ml of 4N hydrochloric acid was added to 600 mg (1.55 mmol) of 1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was heated under reflux for 6 hours. The mixture was cooled to room temperature, and the precipitated crystal was collected by filtration to obtain 258 mg (41%) of the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][CH2:29][NH:28][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:27][CH:26]=1)=[O:24]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: NCCCO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCO)cc2)CC1
Yield: 76 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 3-amino-1-propanol. Then, the product was recrystallized using ethyl acetate and ether to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:14][O+:15](C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:14][OH:15])[CH:3]=1
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
4-methylpyridine-N-oxide (3.7 g) was dissolved in methylene chloride (68 ml), trimethyloxonium tetrafluoroborate (5.0 g) was added to the mixture, and the mixture was stirred for 90 minutes at room temperature. The solvent was removed under reduced pressure, the obtained residue was dissolved in methanol, and an aqueous solution (6.8 ml) of ammonium peroxodisulfate (1.54 g) was added under heat reflux. An aqueous solution (3.4 ml) of ammonium peroxodisulfate (0.77 g) was further added to the mixture after 30 minutes, and the mixture was stirred for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-methyl-2-pyridinyl)methanol (2.9 g). (4-methyl-2-pyridinyl)methanol (2.5 g) was dissolved in methylene chloride (25 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (3.8 ml) was added to the mixture at 0° C. and the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and a solution (9.1 ml) of the obtained residue in water was added dropwise to an aqueous solution (64 ml) of 4-aminothiophenol (1.82 g) and sodium hydroxide (1.74 g) in methanol. The mixture was stirred for 1 hour at room temperature, the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(4-methyl-2-pyridinyl)methyl]sulfanyl]aniline (2.0 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.Cl.[NH2:18][OH:19].CCO>O>[OH:19][NH:18][C:15](=[NH:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([I:7])[CH:9]=1
Reactant: N#CCc1cccc(I)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(Cc1cccc(I)c1)NO
Temperature: 25 °C
Yield: 96.7 %

Procedure:
Add sodium carbonate (2.0 g, 18.5 mmol) to a mixture of 3-iodophenylacetonitrile (4.5 g, 18.5 mmol) and hydroxylamine hydrochloride (1.3 g, 18.5 mmol) in 10:1 EtOH:H2O (11 mL) Heat the reaction mixture to 50° C. for 2 days. Cool to RT, then filter to remove the solids. Concentrate the filtrate to afford the title compound (4.94 g). LC-MS (m/e): 277 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9](=[O:13])[NH:10][CH2:11]Cl.[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:16]=1[O:17][CH2:18][C:19]([O-:21])=[O:20].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([NH:10][CH2:11][O:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:15]=1[Cl:14])=[O:13]
Reactant: O=C(NCCl)Oc1ccccc1Cl
Reactant: O=C([O-])COc1cc(Cl)c(Cl)cc1Cl
Agent: [Na+]
Solvent: CC#N
Product: O=C(COc1cc(Cl)c(Cl)cc1Cl)OCNC(=O)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
A solution of 220 g (1 mole) of N-chloromethylcarbamic acid 2-chlorophenyl ester in 1 liter of anhydrous acetonitrile was added dropwise to a suspension of 277.5 g (1 mole) of sodium 2,4,5-trichlorophenoxyacetate in 2 liters of anhydrous acetonitrile. After the exothermic reaction had subsided, the mixture was stirred for a further 15 hours at room temperature. It was then filtered and the filtrate was concentrated in vacuo by distilling off the solvent. The residue was recrystallised from ether/benzine. 354 g (80.6% of theory) of 2-(2,4,5-trichlorophenoxy)-acetic acid 2-chlorophenoxycarbonylaminomethyl ester were obtained in the form of white crystals of melting point 119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:12][C:11]([CH3:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][C:11]([CH3:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)n(-c2ccc(F)c(Cl)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CCNCC2)n(-c2ccc(F)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude product from step A (801 mg, 2.033 mmol) was dissolved in anhydrous dichloromethane (4 mL). Trifluoroacetic acid (2 mL, 26 mmol) was added dropwise. Then the solution was stirred at room temperature for 3 hours. The solution was concentrated and volatiles were removed by azeotroping with toluene. The resulting crude product was purified by RP-HPLC(C18; 5% to 50% acetonitrile/water+0.05% TFA) to afford the title compound. HPLC/MS: 294.1/296.1 (M+1); 2.08 min (LC4).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li+].CC([N-]C(C)C)C.[C:31]1(=[O:35])[CH2:34][CH2:33][CH2:32]1>C1COCC1>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([C:31]3([OH:35])[CH2:34][CH2:33][CH2:32]3)([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: O=C1CCC1
Reactant: Cc1ccc(C)n1[C@@H]1C=CC(C(=O)OCc2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
To a cold (−78 C), stirred solution of 6.17 g (20.9 mmol) of benzyl (4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (Preparation SRT-0233) in 40 mL of dry THF, under Ar, was slowly added 23.3 mL of a commercial 1.8 M solution of LDA. The resulting solution was warmed to 0 C, stirreed at that temperature for 10 min, and then recooled to −78 C for the addition of 2.3 mL (31 mmol) of cyclobutanone. This solution was stirred at −78 C for 1 h, then quenched at −78 C by the slow addition of a solution of 4.0 mL of 12N HCl in 10 mL of THF. Ethyl acetate and excess 1 M citric acid were added and the mixture was allowed to warm to RT. Extractive workup was followed by flash chromatography on silica using 25% ethyl acetate in heptane to provide 5.55 g (73%) of the title compound as a thick amber oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44-1.56 (m, 1H) 1.88-2.31 (m, 6H) 2.12 (s, 6H) 2.27 (dd, J=14.7, 7.5 Hz, 1H) 2.76 (dd, J=14.5, 9.0 Hz, 1H) 5.18 (s, 2H) 5.26-5.32 (m, 1H) 5.71 (s, 2H) 6.06 (dd, 1H) 6.10 (dd, 1H) 7.30-7.39 (m, 5H). TLC Rf 0.36 (30% ethyl acetate in hexane). LC-MS ES+ 366.2.
Reaction SMILES: [CH:1]1(C(O)(CC2OC(C)(C)OC(=O)C=2)CCC2C=CC(C(CC)(CC)C#N)=C(F)C=2)CCC[CH2:2]1.[CH:34]1([C:39]([OH:64])([CH2:54][C:55]2[O:56]C(C)(C)O[C:59](=[O:61])[CH:60]=2)[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3([C:51]#[N:52])[CH2:50][CH2:49]3)=[C:44]([F:53])[CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([C:39]2([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([CH2:1][CH3:2])([CH2:50][CH3:49])[C:51]#[N:52])=[C:44]([F:53])[CH:43]=3)[CH2:54][C:55](=[O:56])[CH2:60][C:59](=[O:61])[O:64]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Reactant: CCC(C#N)(CC)c1ccc(CCC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Product: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The desired product was prepared analogously to Example A(86) step 5, substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile (0.84 g, 1.8 mmol) from step 3 below in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 0.393 g, 54%. 1H NMR (CDCl3) δ: 1.01 (t, J=7.45 Hz, 6H), 1.62-1.90 (br, 8H), 2.03-2.17 (br, 4H), 2.20-2.29 (br, 2H), 2.37 (p, J=9.35 Hz, 1H), 2.75-2.82 (m, 2H), 2.86 (d, J=7.58 Hz, 2H), 3.53 (d, J=2.02 Hz, 2H), 6.94 (dd, J1 =13.01 Hz, J2=1.64 Hz, 1H), 7.04 (dd, J1=7.83 Hz, J2=1.77 Hz, 1H), 7.57 (t, J=8.21 Hz, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:18][C:17]=2[CH3:25])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:18]1[C:17]([CH3:25])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[NH:20][C:19]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1Br
Temperature: -78 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
A solution of N-bromosuccinimide (1.25 g, 7.06 mmol) in THF (20 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 53a, 1.75 g, 7.06 mmol) in THF (40 ml) at about −78° C. The resulting reaction mixture was stirred at about −78° C. for 5 hr. The reaction mixture was then allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (200 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (1×50 ml) followed by washing with water (1×50 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10 ethyl acetate in hexanes to obtain the title compound (1.77 g, 77%)
Reaction SMILES: N1C=CC=C([C:7]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)C=1.[Li].[CH3:19][OH:20]>Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:16]([C:19]([C:16]2[C:11]([C:10]([O:9][CH3:7])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:20])[CH:11]=1
Reactant: O=C(OC(=O)c1ccccn1)c1cccnc1
Reactant: CO
Agent: Cl
Agent: [Li]
Product: COC(=O)c1ncccc1C(=O)c1cccnc1
Temperature: 85 °C

Procedure:
A mixture of 2.5 g of crude lithium 3-picolinoylpicolinate 16 was dissolved in 40 mL of 1.25 N HCl in methanol and heated in a sealed tube at 85° C. for 2 h. After cooling, the excess solvent and reagent were removed under reduced pressure and the crude material was partitioned between 20 mL of ethyl acetate and 20 mL of saturated aqueous sodium carbonate. The aqueous layer was further extracted with 2×20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by normal-phase flash chromatography eluting with 50-100% ethyl acetate in hexane over 29 minutes. Like fractions containing product were pooled and concentrated under reduced pressure to give methyl 3-picolinoylpicolinate 7 (240 mg, 0.99 mmol), LCMS: (M+H)+, 243.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.CS(O[CH2:15][C@@H:16]1[C@:25]2([CH3:26])[C@H:20]([C:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][C@:17]1([OH:30])[CH3:29])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:15][C@@H:16]2[C@:25]3([CH3:26])[C@H:20]([C:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][CH2:24]3)[CH2:19][CH2:18][C@@:17]2([CH3:29])[OH:30])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cccc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A mixture of 3-methoxythiophenol (2.20 g, 15.7 mmol), [(1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-1-yl]methyl methanesulfonate (12) (5.0 g, 15 mmol), and Cs2CO3 (15.30 g, 47.16 mmol) in CH3CN (600 mL) was stirred at room temperature for 1 h, then refluxed for 24 h. After cooling, the mixture was concentrated and purified by column chromatography on silica gel (Hexanes/EtOAc, 10:1 to 6:1) to give (1R,2R,4aS,8aS)-1-{[(3-methoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (13-1) (4.03 g, 71%) as a yellow oil.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.Br[CH:21]([CH3:40])[C:22]([N:24]1[C:29]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[O:28][C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[C:25]1=[O:39])=[O:23].P([O-])([O-])([O-])=O>[Zn].O1CCCC1>[Si:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([C@@H:21]([CH3:40])[C:22]([N:24]2[C:29]3([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[O:28][C:27]3[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]2=[O:39])=[O:23])[NH:8][C:7]1=[O:9])[CH3:11])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CC(Br)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Yield: 74.6 %

Procedure:
1.0 g of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinone, 1.8 g of 3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one and 0.68 g of zinc powders are added to 15 ml of tetrahydrofuran and the mixture is refluxed for 30 minutes. After cooling, the reaction mixture is poured into 0.2 M phosphate buffer (pH 7.0) and the mixture is extracted with methylene chloride. The extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=3:1) to obtain 1.3 g of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[OH:10].O.O=O>Cl[Pd]Cl.Cl[Cu].CCCCCC>[C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:10])[CH3:1]
Reactant: C=Cc1ccccc1
Reactant: CO
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: CCCCCC
Solvent: O
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Wacker-Tsuji oxidation of styrene in a PDMS thimble. A PDMS thimble containing PdCl2 (0.025 g, 0.141 mmol) and CuCl (0.282 g, 2.82 mmol) was placed in a 2-necked Schlenk flask with a stir bar. MeOH (1.98 mL) and H2O (0.28 mL) were added to the inside of the PDMS thimble and the flask was capped with a rubber septum. A balloon filled with O2 was affixed to the septum and the reaction mixture was stirred at room temperature for 1 hour. Styrene (0.323 mL, 2.82 mmol) was added to the reaction mixture and allowed to stir under an O2 atmosphere for 24 hours. The PDMS thimble was swelled with hexane (2×25 mL) for 12 hours with a stir bar on the exterior of the PDMS thimble. The hexane extracts were combined and the solvent was removed in vacuo. A 1H NMR spectrograph was recorded in CDCl3 to determine quantitative conversion of the styrene to the following products: 89% ketone, 1% aldehyde, 8% acetal, and 2% ketal. Acetophenone (0.249 g, 73% yield) was isolated as a clear liquid by column chromatography using hexanes/EtOAc (95/5). NMR spectra matched those reported in the literature.13 1H NMR (300 MHz, CDCl3, δ): 7.94 (m, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 2.58 (s, 3H). 13C NMR (75.48 MHz; CDCl3, δ): 197.9, 137.0, 132.9, 128.4, 128.1 and 26.4.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[NH:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31]>>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:28]4[CH2:35][CH2:34][CH2:33][C@H:29]4[C:30]([OH:32])=[O:31])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C(O)[C@@H]1CCCN1
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(=O)O)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1

Procedure:
(S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyrrolidine-2-carboxylic acid was prepared using a procedure analogous to that described in Example 3.94 (Step 1) using 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1) and L-proline. MS ESI calc'd. for C25H27ClN6O2 [M+H]+ 479. found 479.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([NH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)=[O:8]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(C(=O)Nc2ccc(C#N)cc2)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Add a solution of 2,2,3,3-tetramethyl-cyclopropane-carbonyl chloride (5 g, 31.1 mmol) in anhydrous DCM to a mixture of 4-aminobenzonitrile (3.34 g, 28.3 mmol) and triethylamine (4.3 mL, 31 mmol) in anhydrous DCM (20 mL) at 0° C. After stirring at 0° C. for 20 min, warm the mixture to room temperature and stir overnight. Partition the reaction mixture between DCM (500 mL) and water (250 mL) and extract the aqueous phase with DCM (250 mL). Wash combined organic extracts with water (3×250 mL), dry over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 over 36 min; 1:0 to 3:1 gradient over 36 min; 3:1 to 1:1 gradient over 71 min; 50 mL/min) to obtain the desired intermediate as a solid (2.31 g, 34%). MS (ES+) m/z: 243.2 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].C[CH2:12][OH:13]>[C-]#N.[C-]#N.[Zn+2]>[OH:7][C:6]1[CH:5]=[C:4]([OH:10])[C:3]([Cl:2])=[CH:9][C:8]=1[CH:12]=[O:13]
Reactant: CCO
Reactant: Oc1ccc(Cl)c(O)c1
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: O=Cc1cc(Cl)c(O)cc1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
At 0° C., a stream of hydrogen chloride was blown into a suspension of 4-chlororesorcinol (10.9 g, 75.43 mmol), Zn(CN)2 (13.5 g, 115 mmol), and KCL (0.25 g, 3.36 mmol) in EtOH (35 mL). The solution was stirred at 0° C. until the absorption of HCl gas stopped. The stirring was continued for another 2 hours at 10° C., during which more precipitate formed. After the precipitate was allowed to settle, the ethereal solution was decanted. The solid was treated with ice water (about 100 mL) and then heated to 100° C. for 0.5 hours. Upon cooling to room temperature, the product was formed as a solid at the bottom of the flask. Filtration and drying under a high vacuum afforded the desired product as a white solid (1.5 g, 11.5%).