Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:19][C:11]3([CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])C3)[CH:10]=2)[O:3]1.F[C:22](F)(F)S(OC1C[C@H]2[C@H]([C@@H]2C(OCC)=O)C=1)(=O)=O>>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:20])[O:3][B:4]([C:9]2[CH2:19][CH:11]3[CH:14]([CH:13]3[C:15]([O:17][CH2:18][CH3:22])=[O:16])[CH:10]=2)[O:5]1
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C(OS(=O)(=O)C(F)(F)F)C[C@@H]21
Reactant: COC(=O)C1CC2(C=C(B3OC(C)(C)C(C)(C)O3)C2)C1
Product: CCOC(=O)C1C2C=C(B3OC(C)(C)C(C)(C)O3)CC21

Procedure:
The title compound was prepared in quantitative yield following the method described in step 2 for the preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene-2-carboxylate, using (±)-(1S,5S,6R)-ethyl 3-(((trifluoromethyl)sulfonyl)oxy)bicyclo[3.1.0]hex-2-ene-6-carboxylate as the reactant. 1H NMR (500 MHz, CHLOROFORM-d) δ 6.67 (q, J=2.0 Hz, 1H), 4.27-3.98 (m, 2H), 2.89-2.72 (m, 1H), 2.63-2.53 (m, 1H), 2.54-2.41 (m, 1H), 2.28 (td, J=6.2, 3.3 Hz, 1H), 1.33-1.15 (m, 16H).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[B:29](OC)([O:32]C)[O:30]C.Cl>O1CCCC1>[F:16][C:17]1[C:18]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:19][CH:20]=[CH:21][C:22]=1[B:29]([OH:32])[OH:30]
Reactant: COB(OC)OC
Reactant: Fc1ccccc1-c1ccncc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(-c2ccncc2)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
A cooled (−78° C.) solution of n-butyllithium (15.2 ml of a 2.5 M solution in hexanes, 38.0 mmol) in tetrahydrofuran (100 ml) was treated with 2,2,6,6-tetramethylpiperidine (6.69 ml, 39.8 mmol) and stirring at −78° C. was continued for 15 min. The reaction was then treated with a cooled (0° C.) solution of 4-(2-fluorophenyl)pyridine (6.26 g, 36.1 mmol) in tetrahydrofuran (20 ml) added dropwise over 10 min. This mixture was stirred at −78° C. for 2 h and then treated with trimethyl borate (8.16 ml, 72.3 mmol) added dropwise over 5 min. The reaction was stirred at −78° C. for 10 min then allowed to warm to ambient temperature. Next, 2 N hydrochloric acid (10 ml) was added and the mixture stirred for 30 min, then evaporated to dryness. The residue was stirred with 2 N hydrochloric acid (100 ml) for 1 h and then taken to pH 14 with 2 N sodium hydroxide (ca. 150 ml). This was washed with diethyl ether and the aqueous layer was cooled to 0° C. and adjusted to pH 8 with 36% hydrochloric acid. After stirring at 0° C. for 1 h the resulting solid was collected by filtration and dried to afford 5.20 g (66%) of 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid as a white solid: MS (ES+) m/z 218 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([O:24]C)=O)[C:13]=3[C:12](=O)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>>[CH2:1]([N:8]1[CH2:9][C:10]2[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:22](=[O:24])[NH:28][N:29]=[C:12]([C:13]=34)[C:11]=2[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Reactant: NN
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC1=C2CCN(Cc2ccccc2)C1

Procedure:
Example 18 was prepared from methyl 2-benzyl-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate and hydrazine hydrate according to the same procedures described as those in Example 15. 1H NMR (DMSO-d6) δ 8.37 (s, 1H), 7.21-7.56 (m, 8H), 3.81 (s, 2H), 3.39 (s, 2H), 2.91 (t, 2H, J=8.4 Hz), and 2.25 (t, 2H, J=8.4 Hz). MS (ESI) m/e [M+1]+ 331.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][OH:29])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Br)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxypropanamide (674.0 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxy-propanamide (582.16 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH:32]([CH3:36])[C:33](O)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C>>[C:26]1([CH:32]([CH3:36])[C:33]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CC(C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Product: CC(C(=O)Nc1cccc(-c2n[nH]c3ccc(C(N)=O)cc23)c1)c1ccccc1
Yield: 18.6 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-phenylpropionic acid (97 μL, 0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 40 mg (17% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 10.3 (s, 1H), 8.6 (s, 1H), 8.2 (br s, 1H), 8.35 (br s, 1H), 7.94 (dd, 1H), 7.7 (m, 2H), 7.6 (d, 1H), 7.5–7.3 (m, 5H), 7.25 (m, 1H), 3.8 (s, 1H), 1.4 (d, 3H); ES-MS (m/z) 385 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:23]C(=O)OCC2C=CC=CC=2)[C:13]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:16]=[N:15][N:14]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([C:13]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:16]=[N:15][N:14]=2)[NH2:23])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: Cc1cc(CC(NC(=O)OCc2ccccc2)c2nnnn2CC(C)(C)C)cc2cn[nH]c12
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CC(N)c2nnnn2CC(C)(C)C)cc2cn[nH]c12
Reaction time: 8 h

Procedure:
A solution of benzyl 2-(7-methyl-1H-indazol-5-yl)-1-(1-neopentyl-1H-tetrazol-5-yl)ethylcarbamate (70.0 mg, 0.156 mmol) in methanol (2.0 mL) was flushed with nitrogen, and treated with palladium (10% on charcoal, 7.0 mg). The flask was flushed with hydrogen and allowed to stir under a balloon of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 48.0 mg (quant.). Mass spec.: 314.17 (MH)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CO.[Pd]>[O:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CN2CCC(Oc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1ccc(OC2CCNCC2)cc1
Reaction time: 20 h

Procedure:
A mixture of 1-benzyl-4-phenoxy-piperidine (420 mg, 1.6 mmol), Pd—C 10% (10 mg) and TFA (0.18 mL, 1,6 mmol) in MeOH (5 mL) is hydrogenated at room temperature and atmospheric pressure for 20 h. The mixture is filtered over Celite and the filtrate is concentrated under reduced pressure. The residue is dissolved in CH2Cl2, washed with sat. NaHCO3, filtered and concentrated to provide the title compound.
Reaction SMILES: [OH:1]S([O-])(=O)=O.[K+].[F:7][C:8]([F:25])([C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:10][S:11][CH2:12][C:13]#[N:14].S([O-])([O-])=O.[Na+].[Na+]>O.CO>[F:25][C:8]([F:7])([C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])[CH2:9][CH2:10][S:11]([CH2:12][C:13]#[N:14])=[O:1]
Reactant: O=S(=O)([O-])O
Reactant: N#CCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CCS(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
To a suspension of 15.10 g of a double salt of 2KHSO5.KHSO4.K2SO4 (Oxone, registered trade mark) in 100 ml of water was added dropwise a solution of 4.77 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylthio)acetonitrile in 100 ml of methanol at −20° C. over 60 minutes under a nitrogen atmosphere, and the mixture was stirred for 2 hours. To the reaction mixture was added 50 ml of an aqueous 10% sodium sulfite solution, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 50 ml of an aqueous 10% sodium sulfite solution and 50 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under rescued pressure. The residue was subjected to silica gel column chromatography to obtain 12.56 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfinyl)acetonitrile represented by the formula:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][CH:11]([F:23])[O:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH:11]([F:10])[F:23])[CH:14]=2)(=[O:21])=[O:20])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: Nc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
A round bottomed flask was charged with 3-amino-5-bromo-2-chloropyridine (1.5 g, 7 mmol, Asymchem Laboratories, Inc. Morrisville, N.C.) and pyridine (20 mL). To this solution, 3-(difluoromethoxy)benzenesulfonyl chloride (2 mL, 8 mmol, Sigma-Aldrich Corporation, St. Louis, Mo.) was added dropwise and the solution was stirred at 25° C. for 18 h. The mixture was concentrated in vacuum and the residue was suspended in H2O. The white solid was collected by filtration and then suspended in methanol (50 mL). To this suspension, potassium carbonate (1.9 g, 14 mmol) was added, and the mixture was stirred at 25° C. for 20 h. The suspension was filtered and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (10-50% EtOAC/Hexane) afforded the title compound (1.4 g, 47% yield) as a white solid. MS (ESI positive ion) m/z: 415 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2C)=[CH:4][CH:3]=1.[NH2:30][C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](Cl)[N:32]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:33]5[N:32]=[C:31]([NH2:30])[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ncnc(N2CCOc3ccc(B(O)O)cc3C2)c1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(-c2ccc3c(c2)CN(c2ncncc2Cc2ccc(F)cc2)CCO3)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 102.7 %

Procedure:
To a solution of (4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 8, step 2) (0.200 g, 0.509 mmol) and 2-amino-6-chloro-3-nitropyridine (0.106 g, 0.610 mmol) in dioxane (3 mL) and water (0.4 ml) was added potassium carbonate (0.211 g, 1.53 mmol). The solution was sparged with N2 (g) for five minutes before the addition of dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.042 g, 10 mol %). The resulting suspension was heated at 90° C. for 20 h in a sealed tube vessel. On cooling to room temperature the mixture was diluted with acetonitrile (25 mL) then filtered and concentrated to afford 6-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-nitropyridin-2-amine (0.247 g, 100% yield) as an oil that was used without further purification. MS (EI) for C26H23FN6O3: 487 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]1([CH2:14][C:15]([NH:17][NH2:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:18][NH:17][C:15](=[O:16])[CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: NNC(=O)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCCl)NNC(=O)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
To 4-chlorobutyryl chloride (1.12 ml, 10 mmol) in dry DCM (10 ml) was added, dropwise, over 40 min, a mixture of phenylacetic hydrazide (1.5 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (40 ml) at room temperature. A dense white precipitate formed. After a further 20 min. 2M HCl (30 ml) was added and the title compound (white solid) was filtered off, washed with water and dried (2.24 g).
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([CH:27]=[O:28])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([CH:27]=[O:28])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3C=O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=CN1CCc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc21
Yield: 46.9 %

Procedure:
4-(3-t-Butoxy-phenyl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-carbaldehyde (5 mg) obtained from Example 1-C-07 as a byproduct was treated with trifluoroacetic acid (1 ml), and the solvent was distilled off, which was subsequently diluted with water (1 ml), and extracted with dichloromethane (3 ml×3), followed by concentration under reduced pressure, to obtain a colorless powder (2 mg, 47%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:5][CH:4]=1.Cl>CO.CCOCC>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2=CCNC2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: FC(F)(F)c1ccc(C2CCNC2)cc1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
0.08 mmol 3-(4-Trifluoromethyl-phenyl)-2,5-dihydro-1H-pyrrole was dissolved in MeOH and HCl in ether was added until pH 1. After 5 minutes stirring, the solvents were evaporated. To a solution of this salt in 0.7 ml methanol under argon was added 2 mg Pd/C 10% and the mixture was hydrogenated under atmospheric pressure of hydrogen at room temperature for 4 h. The mixture was cooled, flushed with argon, diluted with methanol, filtered and the solvent was removed in vacuo to yield the title compound (64%) as an oil MS (m/e): 216.3 ([M+1], 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(OCC)(=O)C.[C:47](Cl)(Cl)([Cl:49])[Cl:48]>>[Cl:48][C:47]([Cl:49])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(C)c1ccc(C=C(Cl)Cl)cc1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
In 260 ml of carbon tetrachloride were dissolved 60 g of ethyl 2-(4-formylphenyl)propionate and 122 g of triphenylphosphine, followed by stirring in a stream of nitrogen gas at 50° C. for 4.5 hours. After cooling, the mixture was poured into 1 l of cold n-hexane and filtered. The filtrate was concentrated under reduced pressure to give an oily substance, which was subjected to silica gel column chromatography (eluent: n-hexane--ethyl acetate=40:1) to obtain 29 g of ethyl 2-[4-(2,2-dichlorovinyl)phenyl]propionate (ST-5) as an oily substance, b.p.0.2-0.3 128°-129° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[C:31]([NH:37][NH2:38])(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[O:12]=[C:10]([NH:38][NH:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(=O)NN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NNC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)acetic acid (200 mg, 1.14 mmol) and EEDQ (282 mg, 1.26 mmol) in DCM (5 mL) was stirred at room temperature for 15 min, then pivalohydrazide (145 mg, 1.26 mmol) was added and the mixture was continued stirring overnight. The reaction mixture was concentrated and purified by reverse phase chromatography to afford the title compound (100 mg, 32%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.28 (s, 1H), 5.24 (s, 1H), 3.92 (d, J=5.8 Hz, 2H), 1.46 (s, 9H), 1.26 (s, 9H); LRMS (ES) calculated M+Na for C21H25N5O4: 296.2. Found: 296.0.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:8][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(Cc2ncc[nH]2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-imidazole carboxaldehyde (8.7 mg, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(1H-Imidazol-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 11 as a colorless oil (10.7 mg, 54%). LRMS 327.
Reaction SMILES: O1C=C(CN)N=C1.[O:8]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[N:9]1.[F:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29](O)=[O:30])[C:22]2=[O:35])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29]([NH:14][CH2:13][C:10]3[CH:11]=[CH:12][O:8][N:9]=3)=[O:30])[C:22]2=[O:35])=[CH:36][CH:37]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ccon1
Agent: NCc1cocn1
Product: O=C(NCc1ccon1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 53 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with isoxazol-3-ylmethanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(isoxazol-3-ylmethyl)isonicotinamide was obtained as a colorless solid in 53% yield: mp 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.37-8.34 (m, 2H), 7.36 (dd, J=5.1 Hz, 1.2 Hz, 1H), 7.31-7.23 (m, 2H), 7.04-6.98 (m, 3H), 6.39 (d, J=1.5 Hz, 1H), 4.73 (d, J=6.0 Hz, 2H), 4.42 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.36 (t, J=8.1 Hz, 2H); MS (ES+) m/z 395.7 (M+1).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Yield: 75.2 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (360 mg, 0.97 mmol), ethyl isonipecotate (460 mg, 2.91 mmol), diisopropylethyl amine (0.51 mL, 2.91 mmol) and a catalytic amount of DMAP in dioxane (15 mL) was heated at 120° C. in a sealed tube until consumption of the limiting reagent, as judged by TLC. The reaction mixture was then cooled and partitioned between EtOAc and water. The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was purified with a silica gel column and 0-50% EtOAc in hexanes gradient to afford the product (360 mg, Yield 75%). HRMS m/z calcd for C21H24N3O3I [M+H]+: 494.0935. Found: 494.0935.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)cc1)C(=O)OCC
Reaction time: 8 h

Procedure:
To a mixture of 0.92 g of 4-bromobenzoyl chloride and 1.0 g of diethyl L-glutamate in 50 ml to dry methylene chloride is added 1.16 ml of triethylamine. The reaction mixture is stirred overnight under nitrogen. After a standard workup, the methylene chloride solution is concentrated under reduced pressure, and the residue recrystallized from hexanes to give 0.68 g (46%) of analytically pure diethyl N-(4-bromobenzoyl)-L-glutamate as a white solid: m.p. 82.5°-83.5° C.; NMR (CDCl3, 300 MHz) delta 1.26 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11-2.60 (m, 4H), 4.14 (q, 2H, J=6.9 Hz), 4.27 (q, 2H, J=6.9 Hz) 4.78 (m, 1H), 7.14 (d, 1H, J=7.2 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.4 Hz); IR (KBr) 3320, 2980, 1745, 1720, 1635, 1520, 1375, 1300, and 1200 cm-1. Anal. Calcd. for C16H20BrNO5 : C, 49.75; H, 5.22; N, 3.63; Br, 20.69. Found: C, 49.70; H, 5.15; N, 3.65; Br, 20.90.