Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1([CH2:35][OH:36])[CH2:34][O:33][CH2:32]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][C:31]2([CH2:35][OH:36])[CH2:34][O:33][CH2:32]2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: OCC1(CBr)COC1
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(CO)COC2)c1OC
Temperature: 80 °C
Yield: 28.2 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.798 mmol) and (3-Bromomethyl-oxetan-3-yl)-methanol (96 mg, 0.532 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (30 mg, 28%).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([OH:17])=O)[CH2:10]2)=CC=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[N+:34]([C:37]1[CH:52]=[CH:51][C:40]([CH2:41][O:42][C:43]([NH:45][C@H:46]2[CH2:50][CH2:49][NH:48][CH2:47]2)=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:48]2[CH2:49][CH2:50][C@H:46]([NH:45][C:43]([O:42][CH2:41][C:40]3[CH:51]=[CH:52][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=3)=[O:44])[CH2:47]2)=[O:17])[CH2:10]1
Reactant: O=C(N[C@H]1CCNC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 71.6 %

Procedure:
Following a procedure similar to that described in Preparation 18, but using 1.03 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-pyrrolidinecarboxylic acid, 463 mg of pivaloyl chloride and 1.45 g of (3S)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidine trifluoroacetate, 1.07 g of the title compound were obtained as a powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]([NH:12][C:13]1[C:14]([C:18](OC)=[O:19])=[CH:15][S:16][CH:17]=1)=[O:11])[CH3:8].O.[OH-].[Na+]>C(OC)(C)(C)C>[CH2:7]([O:9][C:10]([NH:12][C:13]1[C:14]([CH:18]=[O:19])=[CH:15][S:16][CH:17]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)Nc1cscc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)Nc1cscc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into an ice-cold suspension of 12.9 g (0.34 mol) of lithium aluminium hydride in 800 ml of tert. butyl-methylether was added dropwise, at a reaction temperature of about 0° C., a solution of 59.1 g (0.258 mol) of methyl 4-(ethoxycarbonylamino)-thiophene-3-carboxylate in 200 ml of tert. butyl-methylether, and the mixture was then stirred for a further 2 hours at 10° C. Then 13 ml of water, 13 ml of 2N aqueous sodium hydroxide solution and 39 ml of water were added dropwise one after another and the mixture was stirred for 1 hour at room temperature. It was filtered, and 500 g of activated manganese (IV) oxide were added in batches to the filtrate with stirring. After the completion of the reaction, which could be monitored by thin layer chromatography, the mixture was filtered again and the filtrate was then evaporated down in vacuo. The crystalline residue which solidified was further processed without any more purification. yield: 28.2 g (54.9% of theory).
Reaction SMILES: CN(C)C(N(C)C)=S.IC.[F:11][C:12]([F:52])([F:51])[C:13]1[CH:14]=[C:15]([C:23]([CH3:50])([CH3:49])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([N:42]3[CH2:46][CH2:45][CH2:44][C@H:43]3[CH2:47][OH:48])=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.[H-].[Na+].[CH3:55][N:56]([CH3:59])[CH:57]=[O:58]>CCCCCC.O>[F:52][C:12]([F:11])([F:51])[C:13]1[CH:14]=[C:15]([C:23]([CH3:49])([CH3:50])[C:24]([N:26]([CH3:27])[C:28]2[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])=[CH:32][C:31]([N:42]3[CH2:46][CH2:45][CH2:44][C@H:43]3[CH2:47][O:48][C:57](=[O:58])[N:56]([CH3:59])[CH3:55])=[N:30][CH:29]=2)=[O:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)C(=S)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2COC(=O)N(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.83 h
Yield: 40 %

Procedure:
To a solution of 44 mg (0.33 mmol) 1,1,3,3-tetramethyl-2-thiourea in 1.5 ml N,N-dimethylformamide were added 0.027 ml iodomethane at room temperature. After stirring for 50 min. 0.20 g (0.33 mmol) (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide and a suspension of 45 mg (0.90 mmol) sodium hydride (ca. 50% dispersion in mineral oil) in 0.5 ml n-hexane were added. After stirring at room temperature for 1 h the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 90 mg (40%) of the title compound as an off-white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.Cl[C:18]([O:20][CH3:21])=[O:19].O>O1CCCC1>[F:9][C:10]1[C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1
Reactant: Fc1cccc(F)n1
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)nc1F
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a stirred solution of 91 ml (0.182 mol) of 2.0 molar lithium diisopropylamide (in hexanes) in 200 mL dry tetrahydrofuran cooled to -70° under nitrogen was added dropwise a solution of 20.0 g of 2,6-difluoropyridine (0.174 mol) in 75 mL dry tetrahydrofuran such that the temperature was maintained below -60°. The solution was stirred at -70° for 3 hours and was then added via a cannula to a solution 21.7 g (0.230 mol) of methyl chloroformate in 100 mL dry tetrahydrofuran cooled to -70° under nitrogen. After stirring another hour at -70°, the mixture was poured into water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 13.0 g (43%) orange oil: NMR (CDCl3, 200 MHz) 3.95 (3H, s), 6.9 (1H, m), 8.5 (1H, m); IR (neat) 1745, 1730, 1610, 1415, 1290 cm-1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(CC)CC.[Cl:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27]>C(Cl)Cl>[Cl:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: O=C=NCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)NCCCl)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (50 g, 250 mmol) and Et3N (50.5 g, 500 mmol) in DCM (500 mL) was added 2-chloroethyl isocyanate (31.65 g, 300 mmol) dropwise. The resulting mixture was stirred at RT for 4 hours before being quenched with water (100 mL). The layers were separated and the organic layer was washed with brine, dried, concentrated, and subjected to silica flash column using 0 to 50% EA in to isolate (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364) (63.6 g, 81.5%) as a colorless oil. At 0° C., to a solution of (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364, 31.0 g, 102 mmol) in anhydrous THF (350 mL) was added NaH (60% in mineral oil, 4.82 g, 122 mmol) in small portions slowly. The resulting mixture was stirred at RT for 6 hours before being quenched with water (50 mL). The layers were separated and the aqueous was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (25.4 g, 93%) as a white solid. At 0° C., to a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (16.2 g, 60.2 mmol) in anhydrous THF (160 mL) was added NaH (60%, 3.6 g, 90.3 mmol) in small portions. The resulting mixture was stirred at RT for 30 min, cooled back to 0° C., and then iodomethane (12.9 g, 90.3 mmol) was added dropwise. After the addition, the mixture was stirred at RT for 3 hours. The reaction was quenched with water and extracted with DCM (50 mL×2). The combined organic layers were washed with brined, dried, concentrated, and purified by silica flash column using 0 to 3% MeOH in DCM to get (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (13.0 g, 74%) as a light yellow oil. (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (3.5 g, 12.37 mmol) was treated with 40 mL commercial 4N HCl in dioxane at RT for 2 hours. The solvent was removed in vacuo, and the residue was basified to pH 9 with ammonium hydroxide. The solvent was then removed in vacuo, and the residue was subjected to silica flash column using 0 to 10% MeOH in DCM to isolate (R)-1-methyl-3-(piperidin-3-yl)imidazolidin-2-one (367) (1.2 g, 53%) as an oil. LC-MS (ESI): m/z (M+1) 184.2. Proton NMR (CDCl3): δ 3.95-3.83 (2H, m), 3.75 (1H, s), 3.39-3.26 (5H, m), 3.08-2.97 (1H, m), 2.93-2.79 (1H, m), 2.78 (3H, s), 1.94-1.86 (2H, m), 1.82-1.56 (2H, m), 1.48-1.21 (1H, m) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].BrC1C=C2C(C(Cl)=NNC2=O)=CC=1.[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH2:34].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][C:11]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][C:28]([F:27])([F:38])[F:39])[CH:31]=3)=[CH:2][CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(OC(F)(F)F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2ccc(NCc3cccc(OC(F)(F)F)c3)cc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one and 7-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 3-(trifluoromethoxy)benzylamine (0.08 mL, 0.636 mmol), Pd2(dba)3 (61 mg, 0.0667 mmol), rac-BINAP (120 mg, 0.193 mmol) and NaOt-Bu (155 mg, 1.613 mmol) in DMA (8 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-7-(3-trifluoromethoxy-benzylamino)-2H-phthalazin-1-one (28 mg) as an off white solid, 1H (600 MHz, CDCl3) δ: 4.50 (s, 2H), 7.06 (dd, 1H), 7.14 (d, 1H), 7.18 (s, 1H), 7.28 (d, 1H), 7.38 (t, 1H), 7.44 (d, 1H), 7.78 (d, 1H), 9.48 (s, 1H), m/z (M+1) 369.93; 4-chloro-6-(3-trifluoromethoxy-benzylamino)-2H-phthalazin-1-one (22 mg) as an off white solid, 1H (600 MHz, CDCl3) δ: 4.41 (s, 2H), 6.83 (d, 1H), 6.98 (dd, 1H), 7.08 (bd, 1H), 7.16 (bs, 1H), 7.25 (s, 1H), 7.32 (t, 1H), 8.06 (d, 1H), 10.15 (s, 1H) ppm. m/z (M+1) 369.93.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11]([O:13][C:14]1[O:15][C:16](=[O:28])[C:17]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:20][C:18]=2[N:19]=1)[CH3:12]>C1C=CC=CC=1>[C:5](/[C:4](=[C:16](\[C:17]1[C:18]([NH:19][C:14]([O:13][CH2:11][CH3:12])=[O:15])=[CH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[CH:27]=1)/[OH:28])/[C:3]([O:9][CH3:10])=[O:8])(=[O:6])[CH3:7]
Reactant: CCOc1nc2cc3c(cc2c(=O)o1)CCCC3
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cc2c(cc1/C(O)=C(\C(C)=O)C(=O)OC)CCCC2
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a dispersion of sodium hydride (95%) (0.80 g, 33 mmol, 2.1 equiv) in anhydrous benzene (100 mL) under nitrogen was added dropwise methyl acetoacetate (5.0 mL, 5.4 g, 46 mmol, 2.9 equiv) and the resulting mixture was stirred at 23° C. for 1 h. 2-ethoxy-6,7,8,9-tetrahydro-4H-naphtho[2,3-d][1,3]oxazin-4-one (1-3) (3.8 g, 16 mmol, 1 equiv) was added and the reaction mixture was stirred for 20 h. The excess sodium hydride was quenched with water and the organic layer was separated, extracted three times with water and the combined aqueous layers were made acidic with concentrated hydrochloric acid solution. The resulting precipitate was filtered and dried to yield methyl (2Z)-2-acetyl-3-{3-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-3-hydroxyprop-2-enoate (1-4) as a yellow oil. LRMS m/z (M+H) 362.5 found, 362.2 required.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:21]([O:20][CH3:19])=[O:27])=[N:7][CH:6]=1)#[N:9]
Reactant: COC(=O)CCC(=O)Cl
Reactant: N#Cc1ccc(N)nc1
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1ccc(C#N)cn1
Yield: 71 %

Procedure:
The 6-amino-3-pyridinecarbonitrile (commercially available, 0.470 g, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL) then N,N-dimethylaniline (0.5 mL, 1.0 eq.) and methyl-4-chloro-4-oxo-butanoate (0.54 mL, 1.1 eq.) were successively added. The mixture was reflux for 12 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give methyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A1 (71%). M.p.=161-164° C. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.20 (m, 2H), 3.58 (s, 3H), 2.74 (t, 2H), 2.61 (t, 2H) ppm. LC-MS (Method B): RT 1.19, 234 (M+H+) The following compounds from table A or B were prepared by the same method using commercial or described starting aminopyridine:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][OH:12]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc(F)ccc1Br

Procedure:
2-Bromo-5-fluorobenzylbromide (2.0 g, 7.46 mmol) was dissolved in dioxane (25 mL) and H2O (25 mL), and CaCO3 (3.84 g, 38.39 mmol) was added. The mixture was heated to reflux overnight. The solution was concentrated, and the residue was partitioned between H2O and CH2Cl2. The organic phase was washed with 1N HCl and brine, dried (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (CDCl3): δ2.00 (t, 1 H), 4.72 (d, 2 H), 6.85-6.92 (m, 1 H), 7.26 (dd, 1 H), 7.48 (dd, 1 H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:28]1[S:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[S:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)s1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)s1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-bromo-5-(trifluoromethyl)thiophene.
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)(O)[O-].[Na+]>C(O)(=O)CC>[N:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:13]3[O:26][C:2]4[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=4[N:12]=3)=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccncc3)cc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(=O)O
Product: COC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3)oc12
Yield: 16.1 %

Procedure:
A mixture of methyl 2-hydroxy-3-(4-(pyridin-4-yl)benzamido)benzoate (1.04 g, 3 mmol) in propionic acid (50 mL) was stirred at reflux for 3 days. Then the mixture was adjusted to pH=7 by sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, brine, dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude products was purified by chromatography (petroleum ether/ethyl acetate=20:1 to 5:1). 160 mg of methyl 2-(4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxylate as a solid was obtained. Yield: 16%. LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: O=[C:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][C@@H:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:19]([OH:21])=[O:20].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>O1CCCC1>[S:23]=[C:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][C@@H:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:19]([OH:21])=[O:20]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC1C[C@@H](CCc2ccc(Br)cc2)CN(C(=O)O)C1=O
Solvent: C1CCOC1
Product: CCC1C[C@@H](CCc2ccc(Br)cc2)CN(C(=O)O)C1=S
Temperature: 60 °C
Yield: 113.1 %

Procedure:
A mixture of 1.12 g (3.16 mmol) of (3RS,5R)-2-oxo-3-ethylcarboxy-5-[2-(4-bromophenyl)ethyl]piperidine and 0.77 g (1.74 mmol) of phosphorus pentasulfide in 20 mL of tetrahydrofuran was heated at 60° C. until complete conversion was obtained (about 3 hours). The mixture was evaporated to a residue which was purified by chromatography on silica gel. The product was eluted with ethyl acetate-hexane 1:1, affording 0.729 g (61%) of (3RS,5R) -2-thioxo-3-ethylcarboxy-5-[2-(4-bromophenyl)ethyl]piperidine (mixture of C-3 epimers)), mp 105°-115° C., 1H NMR (300 MHz, CDCl3) δ 9.47 (s, 1H), 7.41 (d, J=8.7 Hz,); 7.39 (d, J=8.2 Hz,), total 2H, 7.02 (d, J=8.7 Hz, 2H), 4.20 (m, 2H), 3.94 (m); 3.69 (m), total 1H, 3.45 (m, 1H), 2.99 (m, 1H), 2.60 (m, 2H), 2.13 (m, 2H), 1.5-1.87 (m, 3H), 1.31 (t, J=7.1 Hz); 1.26 (t, J=7.1 Hz), total 3H; IR (CHCl3) 2983, 1731, 1540, 1489, 1373, 1073, 1012 cm-1 ; MS (FD) m/z 371 (100), 369 (75); UV (EtOH) 219.8 nm (ε 13 174), 281.4 (13 557); Anal. Calcd for C16H20BrNO2S: C, 51.90; H, 5.44; N, 3.78. Found: C, 51.61; H, 5.38; N, 3.88.
Reaction SMILES: CN1CCCC1=O.[C:8]([OH:14])(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28](=[N:58]O)[C:29]1[CH:57]=[CH:56][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([NH2:53])=[O:52])=[CH:49][CH:48]=3)[CH2:39][CH2:38]2)=[CH:31][CH:30]=1>O.C(OCC)(=O)C>[NH2:58][C:28](=[N:27][O:13][C:8](=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])[C:29]1[CH:57]=[CH:56][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][O:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([NH2:53])=[O:52])=[CH:54][CH:55]=3)[CH2:39][CH2:38]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)C(=O)O
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
To an N-methyl-2-pyrrolidone (10 mL) solution of 0.47 g of pivalic acid was added 0.76 g of 1,1′-carbonyldiimidazole at room temperature, which was then stirred at the same temperature for 1 hour and 20 minutes. An N-methyl-2-pyrrolidone (10 mL) solution of 1.00 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added to the mixture at room temperature, which was then stirred at the same temperature for 2 hours. The reaction mixture was added a mixture of ethyl acetate and water. The precipitate was collected by filtration and washed with ethyl acetate to provide 0.81 g of 4-{3-[4-(3-{4-[amino(2,2-dimethylpropionyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(2,2-dimethylpropionyl)oxime as white solid form.
Reaction SMILES: [C:1]([C:5]1[C:6](Br)=[C:7]([CH:26]=[CH:27][CH:28]=1)[NH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:25])[CH:10]=1)([O:3][CH3:4])=[O:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:5]1[CH:28]=[CH:27][CH:26]=[C:7]2[C:6]=1[C:10]1[C:11](=[O:25])[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:14][C:9]=1[NH:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc(NC2=CC(=O)CC(c3ccc(C(F)(F)F)cc3)C2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(c1ccc(C(F)(F)F)cc1)C3
Yield: 87.1 %

Procedure:
A suspension of 3-(3-carbomethoxy-2-bromoanilino)-5(4-trifluoromethylphenyl)-cyclohex-2-en-1-one (2.18 g, 4.66 mM), palladium acetate (0.10 g, 0.47 mM), tri-o-tolylphosphine (0.28 g, 0.93 mM), and triethylamine (0.8 ml, 5.78 mM) in 12 mL acetonitrile was heated at reflux for 3 hours. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed with 1 N HCl, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2.21 g. Purification by HPLC on silica gel (elution with gradient methylene chloride/ethyl acetate) afforded 1.57 g (87%) of the 5-carbomethoxy-1,2-dihydro-2-(4-trifluoromethylphenyl)-9H-carbazol-4(3H)-one. 1H NMR (CDCl3) δ9.2 (bs, 1H), 7.6 (d, J=8 Hz, 2H), 7.45-7.35 (m, 5H), 7.25 (d, J=8 Hz, 2H), 3.55 (m, 1H), 3.2-3.0 (m, 2H), 2.7 (m, 2H). MS (ES) m/e 356,388.