Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:17][C:18]([C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)=[O:19])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7](C1CCCCO1)[CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.O1CCOCC1>CO.O>[CH3:25][C:22]1[S:23][CH:24]=[C:20]([C:18]([NH:17][C:4]2[CH:3]=[C:2]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][NH:8]3)=[O:19])[N:21]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3nn(C4CCCCO4)cc23)cs1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3ccncc3)cc3[nH]ncc23)cs1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A microwave vial was charged with N-[6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-methyl-1,3-thiazole-4-carboxamide (50 mg), Solvias catalyst (7 mg), tripotassium phosphate (76 mg), 4-pyridinylboronic acid (15 mg), 1,4-dioxane (0.5 ml) and water (0.1 ml). The mixture was heated under microwave irradiation for a total of 60 min at 80° C. 4-Pyridinylboronic acid (15 mg) was added and the mixture was heated for 30 min at 80° C., then 30 min at 120° C. The reaction mixture was passed through a silica cartridge preconditioned with methanol, washing with methanol, then dried in vacuo. The residue was extracted with DCM/water, dried through a hydrophobic frit and dried in vacuo. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method E). Appropriate fractions were dried under a stream of nitrogen. The residue was dissolved in methanol and a few drops of 2M HCl (aq) were added and the reaction was stirred for 30 min. The reaction mixture was passed through an aminopropyl cartridge, preconditioned with methanol, washing with methanol, then dried to give title compound, (19 mg).
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[N:9][CH:10]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:29][N:30]1[CH2:43][CH2:42][C:33]2[NH:34][C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1>CN(C=O)C.[Cu]I.O>[CH3:12][O:11][C:8]1[N:9]=[CH:10][C:5](/[C:3](/[CH3:4])=[CH:2]/[N:34]2[C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]3[CH2:31][N:30]([CH3:29])[CH2:43][CH2:42][C:33]2=3)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)=CBr)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
5-(-1-Bromoprop-1-en-2-yl)-2-methoxypyridine (50 mg, 0.25 mmol) was dissolved in DMF (2 mL). Potassium phosphate (106 mg, 0.5 mmol) was added followed by copper (I) iodide (4 mg, 0.02 mmol) and L-proline (5 mg, 0.04 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (50 mg, 0.25 mmol) was added under nitrogen (Nitrogen purged for 2 min). The reaction mixture was stirred at 85° C. overnight. Water (15 mL) was added and compound extracted with EtOAc (3×30 mL). The organic layer was concentrated under vacuum and purified through reverse phase chromatography. Yield: 3.87 mg (TFA salt). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.30 (s, 1H), 7.90 (d, 1H), 7.20 (s, 1H), 7.02 (d, 1H), 6.99 (d, 1H), 4.62 (m, 1H), 4.30 (m, 1H), 3.86 (s, 3H), 3.78 (m, 1H), 3.50 (m, 1H), 3.05 (m, 2H), 3.02 (s, 3H), 2.38 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[C:21]([NH2:23])=[O:22])C1C=CC=CC=1.[H][H]>CO.C(O)C.[OH-].[OH-].[Pd+2]>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:21]([NH2:23])=[O:22])[CH2:10]1
Reactant: Cc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1ccccc1N1CCNC(C(N)=O)C1

Procedure:
1-benzyl-4-(2-methylphenyl)piperazine-2-carboxamide (2.64 g, 8.53 mmol) and palladium hydroxide/carbon (430 mg) were combined in a mixture of methanol (35 ml) and ethanol (35 ml) and shaken in an atmosphere of hydrogen at 55 psi for 6 hours at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was reconcentrated in vacuo from ether three times to provide 4-(2-methylphenyl)piperazine-2-carboxamide.
Reaction SMILES: [Pb](Cl)Cl.Br[CH2:5]Br.[F:7][C:8]1[C:9]([O:19][CH3:20])=[C:10]([C:15](=O)[CH2:16][CH3:17])[CH:11]=[CH:12][C:13]=1[F:14].Cl>C1COCC1.ClCCl.C(OCC)C.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([C:15](=[CH2:5])[CH2:16][CH3:17])[C:9]=1[O:19][CH3:20]
Reactant: BrCBr
Reactant: CCC(=O)c1ccc(F)c(F)c1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: Cl[Pb]Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(CC)c1ccc(F)c(F)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
31.2 g (476 mmol) of zinc dust and 740 mg (2.65 mmol) of lead(II) chloride are suspended in 320 ml of THF and at 0° C. 30 ml (265 mmol) of dibromomethane are added. The mixture is stirred at room temperature for a further 30 minutes and at 0° C. 53 ml (53 mmol) of a 1 M titanium(IV) chloride solution in dichloromethane are added dropwise. The cooling bath is removed and, after an hour, the reaction mixture is cooled to 0° C. again. 10.6 g (53 mmol) of 1-(3,4-difluoro-2-methoxyphenyl)propan-1-one in 106 ml of THF are added dropwise. The reaction mixture is stirred at room temperature for a further hour. It is diluted with diethyl ether and poured cautiously onto a mixture of 4 M hydrochloric acid and ice. The phases are separated, extracted is carried out with diethyl ether, the extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed. The crude product is purified by column chromatography on silica gel (hexane/diisopropyl ether 20-40%) to give 4.3 g of 2,3-difluoro-6-(1-methylenepropyl)anisole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][N:22]=[N+]=[N-])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H][H]>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Yield: 93.9 %

Procedure:
To a solution of C—[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-yl]-methyl azide (1.76 g, 5.07 mmol) in 30 mL of THF was added 10% Pd/C (0.176 g). The reaction mixture was hydrogenated at 1.5 atmospheric pressure of hydrogen for 18 hours. The mixture was filtered and the filtrated was evaporated under reduced pressure. The residue was purified by flash chromatography (methylene chloride/MeOH 7:3) to give 1.53 g (94%) of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine. MP=257.1-258.9° C.; MS (M+H)=322.
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][CH:6]([NH:18]C(=O)OC(C)(C)C)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8])=[O:3].C(O)(C(F)(F)F)=O>ClCCl>[NH2:18][CH:6]([CH2:5][CH2:4][S:2]([CH3:1])=[O:3])[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8]
Reactant: CCCCCCCCNC(=O)C(CCS(C)=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCNC(=O)C(N)CCS(C)=O
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of tert-butyl (4-(methylsulfinyl)-1-(octylamino)-1-oxobutan-2-yl)carbamate (6.43 g, 17.1 mmol) in dichloromethane (65 mL) at 0° C. was added TFA (65 mL) and the ice bath was removed. After stirring for 1 hour the reaction was concentrated to give an oil. The oil was purified by silica gel chromatography with 0-10% methanol/dichloromethane (with 15% ammonium hydroxide additive in methanol) to give a white solid (4.5 g, 95%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.87 (t, J=6.83 Hz, 3 H) 1.19-1.33 (m, 10 H) 1.36-1.47 (m, 2 H) 1.61-1.78 (m, 1 H) 1.84-1.99 (m, 1 H) 2.17-2.38 (m, 1 H) 2.52 (s, 3 H) 2.61-2.72 (m, 1 H) 2.75-2.84 (m, 1 H) 2.99-3.13 (m, 2 H) 3.19-3.29 (m, 1 H) 3.28-3.46 (m, 1 H) 7.89 (br. s., 1 H). m/z 277 (MH+).
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@H:4]1[C:15]([OH:17])=O)#[N:2].C[N:19]1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[C:1]([C@@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@@H:4]1[C:15]([NH2:19])=[O:17])#[N:2]
Reactant: CN1CCOCC1
Reactant: N#C[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: N#C[C@@H]1CN(Cc2ccccc2)C[C@@H]1C(N)=O
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Crude (3S,4R)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid (3.24 g) was dissolved in THF (50 mL). N-methyl morpholine (0.93 mL, 8.49 mmol) was added and the solution allowed to stir overnight. A bit of solid remains undissolved. The solution was cooled to −15 degrees C. in an ethylene glycol/dry ice bath. Isobutyl chloroformate (1.1 mL, 8.49 mL) was added and the reaction stirred at −15 degrees C. for 1 hour. Ammonia was then bubbled through the solution for 20 minutes. The solution was allowed to warm to ambient temperature and the solvent removed under reduced pressure. The crude material was chromatographed on silica gel to yield a solid (1.56 g, 88% over 2 steps). LCMS: m/z 230.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25]([OH:27])=O)[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C1C=C[C:35]2N(O)N=[N:38][C:36]=2[CH:37]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1(N)CC1>CN(C=O)C>[CH:36]1([NH:38][C:25]([CH:23]2[CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:28]([F:30])([F:31])[F:29])[O:14][N:13]=4)=[CH:16][CH:17]=3)[CH2:24]2)=[O:27])[CH2:37][CH2:35]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DMF (3 mL) was added HOBt (0.027 g, 0.203 mmol), DIPEA (0.052 g, 0.406 mmol), EDCl.HCl (0.058 g, 0.304 mmol) and cyclopropyl amine (0.011 g, 0.203 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Combined organic layer was washed with saturated NaHCO3 (2×50 mL), water (2×50 mL), brine (50 mL), dried over sodium sulphate and evaporated in vacuo to crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1.1% methanol in DCM to afford white solid (0.036 g, 33%). 1H-NMR (400 MHz, CDCl3) δ: 0.49-0.53 (m, 2H), 0.77-0.87 (m, 2H), 2.74-2.77 (m, 1H), 3.31-3.34 (m, 1H), 3.61 (d, 1H, J=16.88 Hz), 4.01-4.07 (m, 5H), 5.72 (bs, 1H), 6.40 (d, 2H, J=8.68 Hz), 7.47 (d, 2H, J=8.68 Hz), 7.63 (s, 2H). LC-MS (m/z): [M−H] 529.70.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=[O:34])OC1C=CC=CC=1.[CH:35]1([NH2:38])[CH2:37][CH2:36]1>CS(C)=O>[CH3:22][O:21][C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:23][CH3:24])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:25][C:26]([NH:38][CH:35]2[CH2:37][CH2:36]2)=[O:34])=[C:2]([F:1])[CH:7]=1)=[O:20]
Reactant: NC1CC1
Reactant: COC(=O)c1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)ccnc2cc1OC
Solvent: CS(C)=O
Product: COC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OC

Procedure:
Phenyl N-(2-fluoro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate (0.9 g) was treated with cyclopropylamine in dimethylsulfoxide at room temperature in the same manner as Example 11, to obtain the title compound (0.5 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:21]1([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccccc3)cn2)CC1
Yield: 80.7 %

Procedure:
A mixed solution of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (1.00 g, 2.92 mmol), phenylboronic acid (535 mg, 4.38 mmol), ethanol (2.5 ml), 2N aqueous solution of sodium carbonate (12 ml), tetrakis(triphenylphosphine)palladium (404 mg, 0.350 mmol) and toluene (23 ml) was stirred at 95° C. for 12 hours under a nitrogen atmosphere, and the solvent was distilled away under reduce pressure. The residue was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the titled compound 800 mg (80.7%) as solid product.
Reaction SMILES: [OH-].[Na+].C([N:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([C:9]1[C:10](=[O:24])[N:11]([CH3:23])[C:12]2[C:17]([C:18]=1[O:19][C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])(=O)C.Cl>CO.C1COCC1.O>[C:25]1([NH:6][C:7]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[C:12]3[C:17]([C:18]=2[O:19][C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:8])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)Oc1c(C(=O)N(C(C)=O)c2ccccc2)c(=O)n(C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)Oc1c(C(=O)Nc2ccccc2)c(=O)n(C)c2ccccc12
Reaction time: 0.05 h

Procedure:
A solution of NaOH in MeOH (0.50 mL, 0.20 M, 0.10 mmol) was added to a solution of N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (38 mg, 0.10 mmol) in MeOH (1.0 mL) and THF (0.5 mL). After stirring for 3 min, the solution was neutralized with aq. HCl (0.2 mL, 0.5 M) and further diluted with water (ca 10 mL). The precipitated product (29 mg, 86%) was collected by filtration and washed with water.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([NH:25][O:26]C3CCCCO3)=[O:24])=[CH:17][C:16]=2[Cl:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34]>CCO.CO>[ClH:33].[ClH:34].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([NH:25][OH:26])=[O:24])=[CH:17][C:16]=2[Cl:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1cnc(NC2CCN(Cc3ccccc3)CC2)c(Cl)c1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=C(/C=C/c1cnc(NC2CCN(Cc3ccccc3)CC2)c(Cl)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (168 mg) in EtOH (2 ml) was treated with 10% HCl in MeOH (1.76 ml) and was stirred at 25° C. for 1 hour. The precipitate was collected, washed with EtOH, dried under reduced pressure to give (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-hydroxyacrylamide dihydrochloride (137 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][C:12]=1[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:14])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>CO.O1CCOCC1>[Br:39][C:36]1[CH:37]=[CH:38][C:11]([OH:10])=[C:12]([CH:35]=1)[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([OH:20])=[O:19])=[O:14]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Potassium carbonate (0.049 g) was added to a solution mixture of tert-butyl 2-(2-acetoxy-5-bromobenzamido)-4-phenylbenzoate (0.060 g) in methanol (1 mL) and dioxane (1 mL), followed by stirring at room temperature for 1 hour. A 10% aqueous solution of citric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Trifluoroacetic acid (5 mL) was added to the obtained residue, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and methanol was added to the obtained residue. The solid substance was collected by filtration to obtain 0.034 g of 2-(5-bromo-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>C1COCC1.Cl>[CH3:19][O:18][C:16]([NH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(N)(C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)NC(C)(C(=O)O)c1ccccc1
Reaction time: 18 h
Yield: 48.8 %

Procedure:
To a solution of 2-Amino-2-phenyl-propionic acid (1.00 g, 6.06 mmol) in THF (17 mL), was added aqueous NaOH (6 M, 2.5 mL, 15.0 mmol) and Methyl Chloroformate (0.55 mL, 7.10 mmol). The solution was stirred for 18 h. Aqueous HCl (12 M, 1.5 mL, 18 mmol) was slowly added. The solution was diluted with HCl (1M) and extracted with Et2O (3 times). The combined organic layers were extracted with NaOH (2N, 3 times). The aqueous layers were acidified with HCl (12 N) and extracted with Et2O (3 times). The combined organic layers were dried over MgSO4 and concentrated. The crude oil was diluted in CH2Cl2 and concentrated again to provide 2-Methoxycarbonylamino-2-phenyl-propionic acid (0.66 g, 49%). LCMS-ESI+: calc'd for C11H13NO4: 223.08 (M+); Found: 223.97 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[CH:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)NCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A solution of 0.67 g (1.09 mmol) of (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester in 10 ml of absolute N,N-dimethylformamide was successively treated at 0° C. with 0.21 g (1.30 mmol, 1.2 equiv.) of ethyl bromoacetate and 0.057 g (1.30 g, 1.30 mmol, 1.2 equiv.) of sodium hydride dispersion (55% in mineral oil). The mixture was then stirred for 2 h at 80° C. Then 0.047 g (1.09 mmol, 1.0 equiv.) of sodium hydride suspension (55% in mineral oil) and 0.18 g (1.09 mmol, 1.0 equiv.) of ethyl bromoacetate was added, and the suspension was stirred for another 8 h at 80° C. Subsequently, the suspension was poured into 100 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed three times with 20 ml of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 19:1 mixture of dichloromethane and ethyl acetate as the eluent and yielded 0.25 g (0.36 mmol, 33.0% of theory) of (3RS,4RS)-3-(1-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 703 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[N:13]=[CH:14][NH:15][CH:16]=3)=[C:10]([CH2:17][O:18][CH3:19])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>>[CH3:19][O:18][CH2:17][C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[N:13]=[CH:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:16]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: COCc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: COCc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 63 %

Procedure:
As described for Example 1f, 3-phenyl-4-(1H-imidazol-4-yl)-5-methoxymethyl-isoxazole (127.6 mg, 0.50 mmol) was converted, using 1-fluoro-4-trifluoromethyl-benzene instead of 1-(4-fluorophenyl)-ethanone, to the title compound (125 mg, 63%) which was obtained as an off-white solid. MS: m/e=400.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([CH2:9][CH2:10][O:11][CH2:12][C@@H:13]1[C@H:17]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:16][C:15]([CH3:39])([CH3:38])[O:14]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:40])[N:7]([CH2:9][CH2:10][O:11][CH2:12][C@@H:13]1[C@H:17]([CH2:18][CH2:19][OH:20])[O:16][C:15]([CH3:39])([CH3:38])[O:14]1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(CCOC[C@H]1OC(C)(C)O[C@H]1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CN(CCOC[C@H]1OC(C)(C)O[C@H]1CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
(2-{(4R,5S)-5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy}-ethyl)-methyl-carbamic acid tert-butyl ester (82.2 mg, 0.14 mmol) was dissolved in THF (0.19 mL). TBAF (1.0 M solution in THF, 0.19 mL, 0.19 mmol) was added at 0° C. and the mixture was stirred at room temperature for one hour in a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give {2-[(4R,5S)-5-(2-hydroxy-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-ethyl}-methyl-carbamic acid tert-butyl ester (41.7 mg, 88%).