Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C1C(=O)N([I:19])C(=O)C1>CN(C)C=O.O>[I:19][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(C)[nH]n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c(C)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (2 g, 12.97 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added NIS (3.5 g, 15.56 mmol, 1.20 equiv) in portions. The reaction mixture was stirred at 25° C. for 4 h and then diluted with 30 mL of H2O. The resulting mixture was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-50% of ethyl acetate in petroleum ether to give 3.6 g (99%) of ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate as a white solid. LCMS (method D, ESI): RT=1.27 min, m/z=281.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:43]=[CH:42][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([N:31]4[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([O:40]C)=[O:39])[CH2:33][CH2:32]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:43]=[CH:42][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([N:31]4[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][CH2:32]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)CC1CCN(C(=O)c2c[nH]c(-c3cc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)cc4)ccn3)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCC(CC(=O)O)CC5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl {1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}acetate (50 mg, 0.085 mmol) in THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (3 ml, 3 mmol). The mixture was stirred at room temperature for one hour, and poured into 50 ml of water. 2M HCl was added until pH=4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give {1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}acetic acid as white solid. Yield: 47 mg, 96%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[C:16]([N+:22]([O-])=O)[CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13](=[O:25])[C@@H:12]1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[NH2:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[C:20]2[C:15]=1[NH:14][C:13](=[O:25])[C@H:12]([CH3:26])[N:11]2[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: [H][H]
Reactant: C[C@H]1C(=O)Nc2c(cc(Cl)cc2[N+](=O)[O-])N1C(=O)OCc1ccccc1
Agent: [Ni]
Solvent: CO
Product: C[C@H]1C(=O)Nc2c(N)cc(Cl)cc2N1C(=O)OCc1ccccc1

Procedure:
The compound of Example IV (1.5 g, 4.0 mmol) was dissolved in 150 ml of methanol and hydrogenated at room temperature with Raney nickel catalysis, using 1 atm hydrogen. When the calculated amount of hydrogen had been taken up, the catalyst was removed by filtration with suction, and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography using ethyl acetate/heptane=2:1 as eluent. The yield was 0.68 g (49%) of brownish solid of melting point 152-154° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16](SC)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:26]([O:28][CH3:29])=[O:27])=[O:6])[CH:2]=[CH2:3].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35]>CC#N.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[C:32]([O:31][CH3:30])[CH:33]=2)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:26]([O:28][CH3:29])=[O:27])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(SC)c23)C[C@@H]1C(=O)OC
Reactant: COc1cccc(N)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(Nc4cccc(OC)c4)c23)C[C@@H]1C(=O)OC
Temperature: 70 °C

Procedure:
To a mixture of 15B (453 mg, 1.05 mmol), 3-methoxyaniline (142.5 mg, 1.16 mmol) in CH3CN (25 ml) was added AgNO3 (197 mg, 1.16 mmol). The mixture was heated at 70° C. for 30 min. After cooling to room temperature, the solid was removed by filtration through a pad of Celite and the filtrate was concentrated in vacuo. The residue was taken into with water, treated with saturated NaHCO3 and extracted with EtOAc (×3). The combined extracts were dried over anhydrous Na2SO4. Concentration in vacuo gave 644 mg of crude 15C as an oil, which was used in next step without further purification. The compound has an analytical HPLC retention time=2.259 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=506+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=O.[CH3:12][CH:13]1[CH2:18][C:17](=[O:19])[CH2:16][C:15](=O)[CH2:14]1.[ClH:21].O>O1CCCC1>[Cl:21][C:9]1[CH:8]=[C:5]2[C:4]([N:1]([OH:3])[C:15]3[CH2:14][CH:13]([CH3:12])[CH2:18][C:17](=[O:19])[C:16]=3[C:6]2=[O:7])=[CH:11][CH:10]=1
Reactant: CC1CC(=O)CC(=O)C1
Reactant: Cl
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CC(=O)c2c(n(O)c3ccc(Cl)cc3c2=O)C1
Reaction time: 96 h

Procedure:
30.2 g (0.2 mole) of 2-nitrobezaldehyde and 25.2 g (0.2 mole) of 5-methyl-1,3-cyclohexane-dione were dissolved in 300 ml of tetrahydrofurane, the solution was saturated at 18° C with hydrogen chloride and allowed to stand for 4 days at room temperature. Water was added, the oily layer was separated and stirred with methanol. The crystals that had formed were filtered off, washed with methanol and dissolved and recrystallized from glacial acetic acid. 9.5 g (17 % of the theory) of 7-chloro-3-methyl-10-hydroxy-1-oxo-1,2,3,4-tetrahydro-9(10H)-acridone having a decomposition point of 255° C were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Mg].II.C[Mg]Br.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1.CCOCC>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COc1cc(C)ccc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Mg]Br
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cc1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
A solution of 2-bromo-5-methylanisole (3.8 g) [obtained as described in J. Gen. Chem. U.S.S.R., 1932, 2, 455 (Chemical Abstracts, 1933, 27, 962)] in THF (50 ml) was added to magnesium turnings (0.47 g) and a catalytic amount of iodine under an atmosphere of argon. A catalytic volume of 1M methyl magnesium bromide in ether was added and the mixture was heated 50° C. for 1 hour, and then cooled to 0° C. Tributyltin chloride (5.6 g) was added dropwise over 5 minutes and the mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue partitioned between ether (50 ml) and saturated ammonium chloride solution (50 ml). The organic phase was separated and washed with saturated ammonium chloride solution (2×20 ml). The ether layer was separated, diluted with ethyl acetate (50 ml), and washed with water (25 ml), followed by saturated sodium chloride solution (50 ml). Volatile material was removed by evaporation and the residue purified by distillation to give (2-methoxy-4-methylphenyl)tributyl tin (B) (4.8 g), as an oil, b.p. 190° C. at 0.05 torr; NMR: 0.75-1.7 (complex m,27H), 2.4(s,3H), 3.8(s,3H), 6.6(t,1H), 6.8(d,1H), 7.2(d,1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31].C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:22][C:18]1[N:17]=[C:16]([N:7]2[C:6]3[CH:23]=[C:2]([C:33]#[C:32][C:30]([C:25]4[N:24]=[CH:29][CH:28]=[CH:27][N:26]=4)([OH:34])[CH3:31])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:21]=[CH:20][N:19]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: Nc1nccc(-n2c(OCC(F)(F)F)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2nc(OCC(F)(F)F)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 12.8 %

Procedure:
A mixture of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.31 mmol, 80% purity), 2-(pyrimidin-2-yl)but-3-yn-2-ol (300 mg, 2.02 mmol), bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.31 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred for 1.5 hr at 90° C. under nitrogen. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified by preparative HPLC to afford 18 mg (13%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as a light brown solid: 1H NMR (400 MHz, DMSO) delta 8.89 (d, J=4.8 Hz, 2H), 8.44 (d, J=5.6 Hz, 1H), 8.12 (s, 1H), 7.51-7.48 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.16 (s, 2H), 6.85 (d, J=5.2 Hz, 1H), 6.13 (s, 1H), 5.36-5.29 (m, 2H), 1.89 (s, 3H); LC-MS: m/z=+456 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][N:17]=[CH:16][N:15]=2)[CH:10]([CH3:22])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[CH3:21][O:20][C:19]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:22])=[N:15][CH:16]=[N:17][CH:18]=1
Reactant: COc1cncnc1N1CCN(C(=O)OC(C)(C)C)CC1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cncnc1N1CCNCC1C
Yield: 91.5 %

Procedure:
A solution of 1-(t-butoxycarbonyl)-4-(5-methoxy-4-pyrimidinyl)-3-methylpiperazine (1.70 g, 4.2 mmol) and trifluoroacetic acid (5 mL) in 50 mL of CH2Cl2 was stirred at r.t. under Ar for 18 h. The solution was evaporated, the residue was taken up in water and the mixture was basified (pHS) with 15% aqueous NaOH. The resulting (pH 8) mixture was extracted with ethyl acetate and the organic phase was washed (H2O, brine), dried (Na2SO4) and evaporated to give a semi-solid. This material was taken up in ether, filtered to remove insoluble material and the solution was evaporated to give the product (0.80 g, 92%) as an oil. It was used without further purification: IR (neat) 3300, 1580, 1540 cm-1 ; 1H nmr (200 MHz, CDCl3) δ 8.32 (S, 1H), 7.87 (s, 1H), 4.83-4.68 (m, 1H), 4.26-4.19 (m, 1H), 3.85 (s, 3H), 3.26-3.17 (m, 1H), 3.12-3.01 (m, 2H), 2.94-2.80 (m, 2H), 1.29 (d, J=6.8 Hz, 3H) .
Reaction SMILES: O.[F-].[K+].[Si]([C:8]([F:11])([F:10])[F:9])(C)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:24]2[C:32]3[C:27](=[C:28]([N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)([CH2:22][CH3:23])[C:20]#[CH:21])=[CH:15][CH:14]=1>CN(C=O)C.[Cu]I>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:24]2[C:32]3[C:27](=[C:28]([N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)([C:22]#[C:23][C:8]([F:11])([F:10])[F:9])[CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C#CC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A three-neck round-bottom flask was charged with CuI (38 mg, 0.2 mmol), Phen.H2O (40 mg, 0.2 mmol), KF (58 mg, 1.0 mmol) and stirring bar. The flask was dried at 130° C. in vacuo for 3 h. After cooling to RT, the flask was backfilled with air and TMSCF3 (142 mg, 1.0 mmol), DMF (2 mL) was added. Then the flask was heated to 130° C. for 30 min. A solution of N-(1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl) methanesulfonamide (102 mg, 0.2 mmol, enantiomer A) in DMF (1 mL) was slowly added to the mixture at 130° C. over 1 h. The resulting mixture was stirred for another 1 h at 130° C. The crude product was purified by Combiflash (mobile phase: CH3CN/water (0.08% of NH4HCO3)) to give the title compound. LC/MS m/z=606.7 [M+Na]+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH3:12])[CH3:11])[NH2:3].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][C:22]([CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[O:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)=O)=[CH:16][CH:15]=1.C(N(CC)CC)C>CO.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:10]([CH3:12])[CH3:11])[N:3]=[C:22]([CH:24]3[CH2:25][C:26]([CH3:33])([CH3:32])[O:27][C:28]([CH3:31])([CH3:30])[CH2:29]3)[CH:21]=2)=[CH:18][CH:19]=1
Reactant: CN(C)c1ccccc1NN
Reactant: CC1(C)CC(C(=O)CC(=O)c2ccc(Cl)cc2)CC(C)(C)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Yield: 52.5 %

Procedure:
A mixture of (2-hydrazino-phenyl)-dimethyl-amine hydrochloride (105 mg, 0.56 mmol), 1-(4-chloro-phenyl)-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-propane-1,3-dione (162 mg, 0.50 mmol), and triethylamine (0.08 mL, 0.56 mmol), in 1.4 mL of methanol was stirred at RT for 8 hrs. The mixture was diluted with 20 mL of EtOAc and washed with saturated NaHCO3 (40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, concentrated, and the residue purified by flash chromatography on silica gel to give 115 mg (47%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[NH:11][C:12]([C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=3)=[CH:13][C:14](=[O:16])[CH:15]=2)[CH:5]=1)[CH3:2].[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:12]2[CH:13]=[C:14]([O:16][CH3:28])[CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=3)[N:11]=2)[CH:22]=1)[CH3:25]
Reactant: CCOc1ccnc(-c2cc(=O)cc(-c3cc(OCC)ccn3)[nH]2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccnc(-c2cc(OC)cc(-c3cc(OCC)ccn3)n2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, 506 mg (1.5 mmol) of 4,4″-diethoxy-1′H-[2,2′;6′,2″]terpyridin-4′-one (L17, Example 23) are added at 0° C. to a suspension of 78 mg (approximately 60% dispersion in paraffin oil, 1.95 mmol) of sodium hydride in 15 ml of absolute N,N-dimethylformamide. The mixture is then stirred for 15 minutes at 0° C. and for 15 minutes at room temperature. After cooling again, 0.12 ml (1.95 mmol) of methyl iodide is added. Stirring is then carried out at room temperature for a further 45 minutes. 15 ml of water are added and filtration is carried out, yielding 4,4″-diethoxy-4′-methoxy-[2,2′;6′,2″]terpyridine in the form of a beige powder. 1H-NMR (360 MHz, CDCl3): 1.39 (t, 6 H, J=7.2 Hz); 3.90 (s, 3H); 4.12 (q, 4H, J=7.2 Hz); 6.73 (dd, 2H, J=5.6, 2.5 Hz); 7.88 (s, 2H); 8.01 (d, 2H, J=2.5 Hz); 8.39 (d, 2H, 5.6 Hz). MS (EI pos, 70 eV), m/z=351 (90, [M+]); 350 (70); 336 (100); 323 (70); 295 (45).
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7]3[C:6]=2[C:5]([C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=23)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)cccc2N(N)CC1
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: O
Product: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCCC4
Temperature: 25 °C
Yield: 33.8 %

Procedure:
To a solution of 7-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.20 g, 5.32 mmole) in 1-propanol (100 mL) was added cyclohexanone (4.73 g, 48.2 mmole) followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole) and the resulting reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.52 g of the title compound as a white solid, mp 128-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[NH2:28][C:29]1[C:30]([N:35]([CH3:37])[CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:28][C:29]2[C:30]([N:35]([CH3:37])[CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: CN(C)c1ncccc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C)c1ncccc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate), 3-amino-2-(dimethylamino)pyridine (commercially available, CAS RN 5028-25-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=403.072 [M+H]+.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][C:18](=[CH2:22])[C:19](Cl)=[O:20]>C1COCC1>[CH3:17][C:18](=[CH2:22])[C:19]([NH:6][C:14]1[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=1)=[O:20]
Reactant: c1ccncc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=C(C)C(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
LiHMDS (1.0 N in THF, 23.6 mmoL, 24 mL) was added dropwise into pyridine (11.8 mmoL, 1.11 g) in THF (10 mL) at 0° C. After 10 min, 2-methyl-acryloyl chloride (11.8 mmoL, 1.43 mL) was added into the reaction at 0° C. The reaction was then slowly warmed to room temperature. The solvent was removed and the residue was partitioned between Et2O and water. The Et2O layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the brown oil) was then purified by column chromatography (silica gel, EtOAc as eluent) to yield the title compound as a reddish oil.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.I[C:18]1[C:23]([F:24])=[CH:22][C:21]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])=[CH:20][C:19]=1[F:36].C[Sn](C)(C)[C:39]1[CH:45]=[CH:44][C:43](=[O:46])[C:42]([O:47][CH3:48])=[CH:41][CH:40]=1>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:48][O:47][C:42]1[C:43](=[O:46])[CH:44]=[CH:45][C:39]([C:18]2[C:23]([F:24])=[CH:22][C:21]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:20][C:19]=2[F:36])=[CH:40][CH:41]=1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Reactant: COc1ccc([Sn](C)(C)C)ccc1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
The tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (450 mg, 0.492 mmol) and the trifurylphosphine (460 mg, 1.969 mmol) were stirred together for 5 min in 1,4-dioxane (25 mL), followed by the addition of (S)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (1.3 g, 3.28 mmol). After degassing the solution three times with N2, the trimethyl(4-methoxy-5-oxo-1,3,6-cycloheptatrien-1-yl)tin (1.47 g, 4.92 mmol) was added. The solution was degassed again (3×) and then the solution was heated to reflux (110 ° C.) for 12 h under N2. Upon cooling, the reaction was determined to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction was concentrated under reduced pressure and then redissolved in CH2Cl2 (100 mL). This solution was stirred over aqueous KF (100 mL) for 45 min and then separated. The organic portion was washed with brine (100 mL) and then dried over anhydrous Na2SO4. After drying, it was filtered and concentrated under reduced pressure to yield a brown solid. The crude product was chromatographed on silica gel (175 g of silica gel, packed with 10% CH3CN/CHCl3, eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3) to give a pale yellow solid. This solid was recrystalized by dissolving it in CH2Cl2 /MeOH and triturating with ether to yield 907 mg (68%) of the title compound as an off-white solid with mp 129 ° C (dec) and a HRMS (M+) calculated for C20H18N2O5F2 404.1184, found 404.1183.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:23][OH:24].[H][H]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:23][OH:24]
Reactant: [H][H]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1CO
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1CO
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
95% Ethanol (0.5 mL) was added to a mixture of nickel (II) chloride (105 mg, 0.81 mmol) and sodium borohydride (15 mg, 0.40 mmol). The mixture immediately turned black. After 15 min at rt, ethylene diamine (86 μL, 1.29 mmol) was added. After 15 min at rt, a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (from Example 1, step 3, 43.3 mg, 0.16 mmol) in 95% ethanol (1.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 16.7 mg (38%) of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester.