Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl[Pd]Cl>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[C:10](=[O:19])[CH:11]=[C:12]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)/C=C/c2ccccc2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(c1ccccc1)=CC2=O
Temperature: 110 °C
Yield: 62.7 %

Procedure:
To a solution of (E)-1-(2-bromo-4-methoxyphenyl)-3-phenyl-2-propen-1-one (6.0 g, 18.91 mmol) obtained in Step 2 in DMF (15 mL) was added PPh3 (1.46 g, 5.68 mmol, 0.3 eq), K2CO3 (5.23 g, 37.83 mmol, 2 eq), and PdCl2 (335 mg, 1.89 mmol, 0.1 eq). The reaction vial was heated to 110° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a Celite pad. The solution was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:5) to afford the desired product (2.8 g, 63%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[C:23]([Cl:28])[CH:24]=[N:25][CH:26]=3)[C:21]3=[N:29][O:30][C:31]([CH3:32])=[C:20]3[C:19]2=[O:33])[CH2:13]1)C1C=CC=CC=1.I[Si](C)(C)C.[C:40](O)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Cl:28][C:23]1[CH:24]=[N:25][CH:26]=[C:27]2[C:22]=1[C:21]1=[N:29][O:30][C:31]([CH3:32])=[C:20]1[C:19](=[O:33])[N:18]2[CH:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:13]1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cncc(Cl)c21
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cncc(Cl)c21
Yield: 25.6 %

Procedure:
Dissolve [3-(9-chloro-3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexylmethyl]-carbamic acid benzyl ester (310 mg, 0.64 mmol) in dry dichloromethane (8 mL). Add iodotrimethylsilane (0.23 mL, 1.62 mmol) and stir overnight at ambient temperature. Quench with methanol (5 mL) and concentrate in vacuo. Concentrate twice from diethyl ether and use the dark solid crude amine salt directly without purification. MS(ES): (M+1)+ 347.1 m/z. Combine this amine salt with benzoic acid (94 mg, 0.77 mmol),1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol), 1-hydroxy-7-azabenzo-triazole (105 mg, 0.77 mmol), and N,N-diisopropylethyl amine (0.45 mL, 2.59 mmol), in N,N-dimethylformamide (8 mL) and stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel using methanol/dichloromethane to give 74 mg (26%) of the desired product as a white solid. MS(ES): (M+1)+ 451.1, 453.1 m/z.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:6]2[C:5](=[O:21])[N:4]([CH3:22])[C:3]1=[O:23])[CH2:12][CH2:11][CH:10]=[CH:9]3.Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[F:32].C1(N(C)C2CCCCC2)CCCCC1>CC(N(C)C)=O.CCOC(C)=O.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[F:31][C:27]1[C:26]([F:32])=[CH:25][CH:30]=[CH:29][C:28]=1[C:9]1[C:8]2[N:13]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:6]3[C:5](=[O:21])[N:4]([CH3:22])[C:3](=[O:23])[N:2]([CH3:1])[C:7]3=2)[CH2:12][CH2:11][CH:10]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C=CCC3
Reactant: Fc1cccc(Br)c1F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1cccc(F)c1F)=CCC3
Temperature: 110 °C

Procedure:
1,3-Dimethyl-5-phenyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (Intermediate I) (180 mg, 0.586 mmol), 1-bromo-2,3-difluorobenzene (commercially available) (0.085 mL, 0.761 mmol) and N-cyclohexyl-N-methylcyclohexanamine (commercially available) (0.251 mL, 1.171 mmol) were combined in DMA (2.5 mL) and the mixture sparged with nitrogen for 30 min. [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (commercially available) (38.2 mg, 0.059 mmol) was then added and the mixture heated at 110° C. for 1 hour under microwave irradiation. After cooling to room temperature, the mixture was heated at 110° C. for a further 6 hours. Further portions of 1-bromo-2,3-difluorobenzene (0.085 mL, 0.761 mmol) and [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (38.2 mg, 0.059 mmol) were added, and the mixture heated at 110° C. for a further 5 h. Further [1,1′-Bis(di-tert-butylphosphino) ferrocene]dichloropalladium(II) (38.2 mg, 0.059 mmol) and 1-bromo-2,3-difluorobenzene (0.085 mL, 0.761 mmol) were added and the mixture heated 110° C. for a further 6 hours. Further [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (38.2 mg, 0.059 mmol) was added and the mixture heated at 110° C. for a further 6 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. Purification by chromatography on silica, eluting with 15% EtOAc in iso-hexane afforded the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH:46]([CH3:48])[CH3:47])[CH3:45])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH:46]([CH3:48])[CH3:47])[CH3:45])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(C)N(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C(C)C)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 35.6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-isopropyl-N-methylacetamide (8.1 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.7 mg) was obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]([O:12]C)=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([C:4]1[C:5]([C:10]([OH:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ncccc1C(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cccnc1C(=O)O
Reaction time: 1 h

Procedure:
To methyl 3-acetyl-2-pyridinecarboxylate (1.86 g) in 20 ml of ethanol is added lithium hydroxide monohydrate (10 mmol) in 20 ml of hot water. After 1 hour, conc. hydrochloric acid (1 ml) is added, and the mixture is reduced under vacuum. The resulting solid is extracted with hot methylene chloride, and the residue is stirred with 15 ml of THF for 1 hour at 60°, then filtered and dried to give 3-acetyl-2-pyridinecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36])[NH:31][CH2:30][CH2:29]2>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([NH:14][C:15]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([O:25][CH3:24])=[C:34]([C:35]([F:37])([F:38])[F:36])[CH:33]=3)[CH2:29][CH2:30]2)=[O:23])[CH:3]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C(Nc1cc(Br)cc(-c2cccnc2)c1)Oc1ccccc1
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)cc(-c3cccnc3)c1)CC2

Procedure:
The title compound was prepared from phenyl N-[3-bromo-5-(pyrid-3-yl)phenyl]carbamate (D21) and 5-methoxy-6-trifluoromethylindoline (D11) using the method of Example 28.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]#[N:7]
Reactant: Cc1cc(C(N)=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a stirred, 0° C. solution of 3-methyl-4-nitrobenzamide (30 g, 0.169 mol) in dichloromethane (900 mL) under nitrogen was added pyridine (29.5 g, 0.373 mol), then dropwise trifluoroacetic anhydride (42.7 g, 0.203 mol) in dichloromethane (90 mL). The reaction mixture was stirred at 0° C. for one hour and then 1N HCl was added. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to afford 25.5 g (93%) of the 3-methyl-4-nitrobenzonitrile as a light yellow solid; m.p. 69°-71° C.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]2[CH:20]=[CH:21][C:22]([CH2:32][CH3:33])=[C:23]([CH:25]3[C:29](=[O:30])[CH:28]=[CH:27][CH:26]3[OH:31])[CH:24]=2)=[CH:17][CH:16]=1>CC(C)=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]2[CH:20]=[CH:21][C:22]([CH2:32][CH3:33])=[C:23]([CH:25]3[C:29](=[O:30])[CH:28]=[CH:27][C:26]3=[O:31])[CH:24]=2)=[CH:34][CH:35]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1=O
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
Jones' reagent (126 ml of 1.67 M solution, 210.4 mmol) prepared according to the procedure described above, is added dropwise over 30 minutes to a cooled (ice-bath) solution of 5-(4′-chloro-4-ethylbiphen-3-yl)-4-hydroxycyclopent-2-enone (59.84 g, 191.3 mmol) in acetone (615 ml). The mixture is stirred for 20 minutes, then the cooling bath is removed and the mixture is stirred for 1 hour at room temperature. Isopropanol (500 ml) is added to the yellow slurry and the mixture is stirred at room temperature for 2 hours. The mixture is diluted with ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 2-(4′-chloro-4-ethylbiphen-3-yl)cyclopent-4-ene-1,3-dione (47.94 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:16])([CH3:15])[C:8](=[O:14])[NH:9]2)=[CH:4][CH:3]=1.CI.[C:19](=O)([O-])[O-].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:16])([CH3:15])[C:8](=[O:14])[N:9]2[CH3:19])=[CH:4][CH:3]=1
Reactant: CC1(C)Nc2ccc(Br)c(CO)c2NC1=O
Reactant: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CO)c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.1 %

Procedure:
A mixture of 7-bromo-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 5, 62.7 mg, 0.220 mmol), methyl iodide (68.6% L, 1.10 mmol), and cessium carbonate (180 mg, 0.552 mmol) was suspended in anhydrous N,N-dimethylformamide (1 mL) and stirred at room temperature for 2.5 hours. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (45.5 mg) as an orange amorphous product. (Yield 69%)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=O)[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=O)=[CH:3]1.B.C1COCC1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([CH2:14][CH2:15][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:3]1
Reactant: Cn1cc(C(=O)C(=O)N2CCCC2)c2ccc([N+](=O)[O-])cc21
Agent: B
Solvent: C1CCOC1
Product: Cn1cc(CCN2CCCC2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
Treat a solution of 1-(1-methyl-6-nitro-1H-indol-3-yl)-2-pyrrolidin-1-yl-ethane-1,2-dione (5.0 g, 17.4 mmol) in THF (20 mL) with BH3.THF (70 mL of 1N in THF, 70 mmol) and stir at room temperature for 18 h. Concentrate the reaction mixture and add EtOH (100 mL) followed by 5N HCl (20 mL) and reflux for 6 h. Concentrate and dilute with 1N NaOH (100 mL). Extract with CH2Cl2 (2×), then extract with EtOAc (2×). Combine the organics, dry, and concentrate. Purify by flash chromatography using 0-10% 2N NH3/MeOH in CH2Cl2, to give the title compound (2.5 g, 53%). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, 1H, J=2.2 Hz), 7.98 (dd, 1H, J=8.8, 1.8 Hz), 7.61 (d, 1H, is J=8.8 Hz), 7.19 (s, 1H), 3.84 (s, 3H), 2.97 (t, 2H, J=8.1 Hz), 2.76 (t, 2H, J=8.1 Hz), 2.61 (m, 4H), 1.83 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>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]>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 105 °C
Yield: 98.5 %

Procedure:
A schlenk tube containing the mixture of 4,4′-Diflourobenzhydrol (220 mg, 1.0 mmol), K2CO3 (276 mg, 2.0 mmol), Pd(dba)2 (6 mg, 10 μmol) and ligand 1 (10 mg, 30 μmol) was degassed thoroughly under vacuum and purged with Ar. Chlorobenzene (0.15 mL) and toluene (4 mL) were added to the schlenk. The mixture was heated at 105° C. for 12 h. The reaction was taken up in ether (100 mL) and washed with H2O (30 mL) and brine (30 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate as elute to afford compound A as an off-white solid (215 mg, 98%) after drying under vacuum.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:16][S-:17].[Na+]>C1COCC1.CCOCC>[CH3:16][S:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C[S-]
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2nc(SC)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (4.8 g, 16.8 mmol) from Step 1 of Example 2 in THF (100 mL) was added sodium thiomethoxide (1.74 g, 25.2 mmol) slowly at 0° C. The reaction mixture was stirred at rt overnight. The mixture was diluted with Et2O (200 mL) and washed with saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate as a white solid (4.18 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J=1.5 Hz, 1H), 8.11 (dd, J=1.6, 8.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.82 (s, 3H), 1.42 (t, J=7.1 Hz, 3H) LCMS (ESI) m/z 254 (M+H)+.
Reaction SMILES: [C:1]([CH2:6][CH:7]1[O:14][CH:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH:8]1/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(OCC)=[O:2].CCCCCCC.[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC>[CH:1]([CH2:6][CH:7]1[O:14][CH:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH:8]1/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:2]
Reactant: CCCCCC/C=C/C1C(CC(=O)OCC)OC2CCCC21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CCCCCCC
Product: CCCCCC/C=C/C1C(CC=O)OC2CCCC21
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1.00 g. (0.00308 mole) of 2-(carbethoxymethyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane in 5 ml. of heptane at -78° C. and under nitrogen is added dropwise 2.60 ml. of a solution of 25% diisobutylaluminum hydride in hexane. The resulting solution is stirred at -78° C. for 2.5 hours and then poured into cold dilute hydrochloric acid. The organic phase is washed with saturated brine, dried (Na2SO4), and evaporated to yield 0.863 g. of a colorless oil. IR 2695, 1723, 1045, 970 cm-1.
Reaction SMILES: [CH3:1][Si:2]([N-:5][Si](C)(C)C)([CH3:4])[CH3:3].[Li+].[P:11]([Cl:14])([Cl:13])[Cl:12].S(Cl)(Cl)(=O)=O>C(OCC)C>[Cl:12][P:11]([Cl:14])([Cl:13])=[N:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: ClP(Cl)Cl
Agent: [Li+]
Solvent: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: C[Si](C)(C)N=P(Cl)(Cl)Cl
Reaction time: 1.5 h

Procedure:
Diethyl ether (250 ml) was added with stirring to a flask cooled in an ice/water bath containing lithium bis(trimethylsilyl)amide (27.7 g, 0.17 mol). Phosphorus trichloride (14.5 ml, 0.17 mol) was then added and the mixture stirred for a further 5-10 minutes before removing the ice water bath. Stirring was continued at ambient temperature for a further 1-2 hours. The reaction flask was then cooled again in an ice/water bath and sulfuryl chloride (13.3 ml, 0.17 mol) added. The mixture was stirred for a further 10-15 minutes before removing the ice/water bath and stirring at ambient for a further 1-2 hours or until the reaction was complete, as indicated by 31P {1H} NMR spectroscopy. The product was isolated in pure form via vacuum distillation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperidine-1-carboxylate (0.0332 g, 0.0861 mmol) synthesized in Example B58, Step 2 in ethanol (5 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.0400 g), and the mixture was stirred overnight at 50° C. under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to obtain tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)propyl]piperidine-1-carboxylate (0.0330 g, 96%).
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3/[CH:19]=[CH:20]/[C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][CH2:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCC(=O)/C=C/c1ccccc1OCc1ccc(C2CCCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(=O)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Reaction time: 3 h

Procedure:
A suspension of 2.80 g (6.44 mmol) of methyl (7E)-8-{2-[(4-cyclohexylbenzyl)-oxy]phenyl}-6-oxo-7-octenoate XIII and 0.06 g of Pd/C (10% Pd) in 30 ml of ethyl acetate was stirred under an atmosphere of hydrogen for 3 h. The catalyst was removed by filtration through Celite, and the product was purified chromatographically (silica gel, cyclohexane/ethyl acetate 20:1).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.N1CCCC1.O.[C:22]([NH2:26])(=[O:25])[C:23]#[CH:24]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[C:7]2[NH:26][C:22](=[O:25])[CH:23]=[CH:24][C:6]=2[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C#CC(N)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)Cc2ccc(=O)[nH]c21
Temperature: 25 °C
Yield: 55 %

Procedure:
tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate (commercially available from Ryan Scientific, Mt. Pleasant, S.C.)(1.7 g, 7.97 mmol) and pyrrolidine (1.3 mL, 15.94 mmol) were dissolved in toluene (9 mL), and the solution was heated under reflux, with the removal of water under Dean-Stark conditions, for 5 hours. The solution was then cooled to room temperature and propiolamide (prepared as described in EP 1813606)(1.1 g, 15.94 mmol) was added. The reaction mixture thus obtained was heated overnight under reflux. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluting with 0% to 10% MeOH in DCM to give the title compound (2.1 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (3H, d, J=7.04 Hz), 1.52 (9H, s), 3.37-3.44 (1H, m), 3.77-3.84 (1H, m), 4.12-4.17 (1H, m), 6.48 (1H, d, J=9.39 Hz), 7.21 (1H, d, J=9.39 Hz) ppm; LC/MS m/z: 265 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:19]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:20]2[CH:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[CH:10][C:11]=1[NH:12]C(=O)C(F)(F)F)=[O:5])[CH3:2]>CO.C(=O)([O-])[O-].[K+].[K+].O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C:20]2[CH:21]=[N:22][C:23]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[CH:10][C:11]=1[NH2:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
51 mg of 6-[4-methoxybenzyl-(6-morpholinopyridin-3-yl)amino]-4-[(trifluoroacetyl)amino]pyridine-3-carboxylic acid ethyl ester was dissolved in 5 mL of methanol, to which 3 mL of 2 mol/L potassium carbonate in water was added, and stirred at room temperature for 4 hours. To the reaction mixture water was added, extracted with ethyl acetate, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 42 mg (yield 100%) of the title compound as a light yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH2:16]1[CH2:20]OC[CH2:17]1>C(Cl)Cl>[CH:16]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([Br:5])[C:7]=1[CH3:15])([CH3:20])[CH3:17]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Br)cccc1C(=O)OC(C)C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (6 mL) was added over 1 min to a 0° C. suspension of 3-bromo-2-methyl benzoic acid (2.15 g, 10 mmol) in DCM (10 mL). After 30 min of stirring, THF (5 mL) was added to induce dissolution. The now homogeneous solution was stirred for 24 h at rt and the volatile component were removed in vacuo. A portion of the crude acid chloride was dissolved in dry isopropyl alcohol (10 mL) and pyridine (2 mL) was added. After stirring for 4 h at rt, the volatile components were removed in vacuo. The residue was partitioned between EtOAc (70 mL) and HCl (1M, 30 mL) and the layers were separated. The organic layer was washed with HCl (1M, 10 mL), NaHCO3 (3×20 mL), water (30 mL), brine (30 mL), and was dried over sodium sulfate. Removal of solvent in vacuo yielded the title compound as a light-yellow oil which was used without further purification. 1H-NMR (CDCl3): δ 7.69 (d, 2H, J=7.7 Hz), 7.11 (t, 1H, J=7.9 Hz), 5.26 (heptet, 1H, J=6.3 Hz), 2.63 (s, 3H), 1.39 (d, 6H, J=6.3 Hz).