Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[CH:26](N(C)C)[N:27]([CH3:29])[CH3:28])(C)(C)C>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[O:14])/[C:12](=[CH:26]\[N:27]([CH3:29])[CH3:28])/[CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(c2ccccc2)C1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC(c2ccccc2)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 185.9 %

Procedure:
A mixture of 1-boc-3-phenyl-piperidin-4-one (100 mg, 0.35 mmol) and tert.-butoxy-bis(dimethylamino)methane (94 mg, 0.48 mmol) was stirred at 110° C. for 2 hours. The reaction was evaporated to dryness, treated twice with toluene and evaporated under reduced pressure to dryness to yield the title compound (215 mg, 188%) as a brown oil which was used directly in the next step without further purification. MS ISP (m/e): 331.4 (79) [(M+H)+], 275.1 (100) [(M-isubutene +H)+].
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH2:14])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2ccc(N)cc2[nH]1
Yield: 88.5 %

Procedure:
To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Nickel (0.2 g). The mixture was hydrogenated under 1 atm of hydrogen at room temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-1 H-indol-6-amine (1.0 g, 89%). 1 H NMR (300 MHz, DMSO-d6) δ 10.19(s, 1 H), 6.99(d, J=8.1 Hz, 1 H), 6.46(s, 1 H), 6.25(dd, J=1.8, 8.1 Hz, 1 H), 5.79(d, J=1.8 Hz, 1 H), 4.52(s, 2 H), 1.24(s, 9 H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[OH-].[Na+].[C:9](#[N:12])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1>[C:9]([CH2:10][CH2:11][N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])#[N:12]
Reactant: C=CC#N
Reactant: O=C1NCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CCCN1CCOC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Compound 18 was prepared by modification of a reported procedure by Lynn (U.S. Pat. No. 2,975,187). To a vigorously stirred mixture of 2-oxazolidinone (87 g, 1 mol), 50% sodium hydroxide (w/w, 4 g) and toluene (250 mL) maintained at 55°-60° C., acrylonitrile (106 g, 2 mol) was added dropwise over a period of 30 min. The mixture was then stirred at 80° C. for 1 h and refluxed for 3 h. Additional acrylonitrile (50 mL) was added towards the end of the reaction to drive it to completion. Excess acrylonitrile was removed by distillation, and the residue was left at room temperature overnight. The mixture was filtered, cooled in an ice bath and acidified with concentrated H2SO4 to ~ pH 1. The salt was removed by filtration, and the filtrate was dried over anhydrous MgSO4. The residue obtained after removal of the solvent under vacuum was dried under high vacuum overnight to give 117 g (84%) of 18 as a colorless oil: 1H NMR (CDCl3) δ 2.68 (t, 2, CH2CH2CN), 3.57 (t, 2, NCH2CH 2), 3.75 (t, 2, NCH2CH2O) and 4.39 (t, 2, CH2H2O--).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>N1C=CC=CC=1.[Cu]=O>[C:5](=[C:4]1[CH:3]=[CH:2][CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:7]1)=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=Cc1cccc(Br)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(OC2=CC=CC(=C=O)C2)c1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A mixture of 3-bromobenzaldehyde (1.000 g; 5.4 mmol), methyl 3-hydroxybenzoate (987 mg; 6.5 mmol) and potassium carbonate (1.494 g; 10.8 mmol) in dry pyridine (8 mL) is stirred under argon at RT. Copper (II) oxide (860 mg; 10.8 mmol) is added and the reaction mixture is refluxed for 12 hours. After cooling to RT, CH2Cl2 (50 mL) is added and the mixture is filtered through celite. The filter cake is washed with fresh CH2Cl2 (50 mL). The combined organics are concentrated in vacuo. The residue is purified by flash chromatography (ethyl acetate/hexanes, 1:10 to 1:4) to yield methyl 3-(3-carbonylphenoxy)benzoate (776 mg; 56%) as a yellow oil.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5]1([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:30]#[N:31])[C:14]([CH3:29])=[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:16]=3[CH:17]([CH2:21]I)[CH2:18][CH:19]=[CH2:20])[N:12]=2)[CH2:7][CH2:6]1.[Cl-].[NH4+]>O1CCCC1.[Cu]I>[CH2:18]([CH:17]([C:16]1[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:14]([CH3:29])[C:13]([C:30]#[N:31])=[C:11]2[C:10]=1[O:9][C:8]([CH:5]1[CH2:7][CH2:6]1)=[N:12]2)[CH2:21][CH:1]=[CH2:2])[CH:19]=[CH2:20]
Reactant: C=C[Mg]Br
Reactant: C=CCC(CI)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(CC=C)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Copper (I) iodide (52 mg, 0.27 mmol) was suspended in tetrahydrofuran (3 ml), and under nitrogen atmosphere at −30° C., vinylmagnesium bromide (1 M tetrahydrofuran solution) (2.72 ml, 2.72 mmol) was dropwise added. The solution was stirred at the same temperature for 30 minutes, then a solution of 2-cyclopropyl-7-(l iodomethylbut-3-enyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-298)(425 mg, 0.91 mmol) dissolved in tetrahydrofuran (6 ml) was gradually added. After stirring at the same temperature for 1 hour and 20 minutes and heating up to 0° C., aqueous saturated ammonium chloride solution was added, followed by further stirring for 30 minutes. This was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=9:1, v/v) to obtain the entitled compound (243 mg, 73%) as a colorless gel.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[OH:7].C(=O)([O-])[O-].[Na+].[Na+].O1CCCC1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[OH:7][C@@H:3]1[CH2:4][O:5][CH2:6][C@H:2]1[NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N[C@@H]1COC[C@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H]1COC[C@H]1O)OCc1ccccc1
Temperature: 0 °C
Yield: 59 %

Procedure:
A mixture of the crude trans-4-aminotetrahydrofuran-3-ol (from Step 1), sodium carbonate (7.68 g, 72.5 mmol), tetrahydrofuran (100 mL) and water (100 mL) was cooled to 0° C. and stirred vigorously. Benzyl chloroformate (9.48 mL, 66.4 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo. The aqueous residue was diluted with water (50 mL) and extracted with ethyl acetate (3×70 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 30-100% ethyl acetate in hexanes, gave benzyl trans-4-hydroxytetrahydrofuran-3-ylcarbamate as a white solid (8.43 g, 59% yield for 2 steps). 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.51 (5 H, m), 5.11 (2 H, br. s.), 4.92 (1 H, br. s.), 4.32 (1 H, br. s.), 3.93-4.17 (3 H, m), 3.50-3.80 (2 H, m), 2.69 (1 H, br. s.); MS (ES+) m/z: 238.1 (M+H); LC retention time: 2.595 min (analytical HPLC Method H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]([NH:13][CH2:14][CH2:15][C:16]#[N:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:63]=[N+:64]=[N-:65])(C)C>C(#N)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]1[N:13]([CH2:14][CH2:15][C:16]#[N:17])[N:65]=[N:64][N:63]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 410 mg of tert-butyl {(2S)-3-(benzyloxy)-1-[(2-cyanoethyl)amino]-1-oxopropan-2-yl}carbamate, 400 mg of triphenylphosphine, and 10 ml of acetonitrile were added 310 μl of diisopropyl azodicarboxylate and 210 μl of trimethylsilyl azide under ice-cooling, followed by stirring at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 280 mg of tert-butyl {(1R)-2-(benzyloxy)-1-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]ethyl}carbamate.
Reaction SMILES: CN(C)P(=[O:10])(N(C)C)N(C)C.[Cl:12][CH2:13][C:14](Cl)=[O:15].O.O.Br.Br.[NH2:21][CH2:22][C:23]1[N:32]([NH:33][C:34](=[O:36])[CH3:35])[C:31](Br)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:45])[CH:29]=2)[N:24]=1>CCOCC>[Cl:12][CH2:13][C:14]([NH:21][CH2:22][C:23]1[N:32]([NH:33][C:34](=[O:36])[CH3:35])[C:31]([OH:10])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:45])[CH:29]=2)[N:24]=1)=[O:15]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: O=C(Cl)CCl
Reactant: CC(=O)NN1C(CN)=Nc2ccc(Cl)cc2C1(Br)c1ccccc1Cl
Agent: Br
Solvent: CCOCC
Solvent: O
Product: CC(=O)NN1C(CNC(=O)CCl)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl

Procedure:
To a mixture of hexamethylphosphoric triamide (12 ml) and chloroacetyl chloride (0.452 g), 2-aminomethyl-3-acetamido-4-bromo-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline dihydrobromide dihydrate (1.276 g) is added, and the resultant mixture is stirred at room temperature for 5 hours. The reaction mixture is mixed with ether and washed with aqueous sodium bicarbonate and water in order. The precipitate is dried to give 2-(2-chloroacetamidomethyl)-3-acetamido-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (0.63 g). This product (0.6 g) is dissolved in acetic acid (6 ml) to give a solution, which is refluxed for 2 hours. The reaction mixture is evaporated under reduced pressure. The residue is extracted with ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate and water in order, dried and evaporated to remove the ethyl acetate. The residue is chromatographed on a column of silica gel, which is eluted with methanol to give 2',5-dichloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4 -yl]-benzophenone (0.15 g).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:34](O)=[O:35])[CH:31]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CO.CN(C=O)C>[C:11]1([C:8]2([C:5]3[NH:4][C:3](=[S:17])[C:2]([NH:1][C:34]([C:30]4[CH:31]=[C:32]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:33]5)=[O:35])=[CH:7][CH:6]=3)[CH2:10][CH2:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)Nc3ccc(C4(c5ccccc5)CC4)[nH]c3=S)cc2C1
Reaction time: 16 h

Procedure:
To 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (106 mg, 0.437 mmol) was added 2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid (115 mg, 0.437 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (67.0 mg, 0.437 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (84 mg, 0.437 mmol), and DMF (437 μL) before it was stirred at ambient T for 16 h. The reaction mixture was diluted with methanol before it was passed through a cartridge of cation exchange resinto give tert-butyl 5-(6-(1-phenylcyclopropyl)-2-thioxo-1,2-dihydropyridin-3-ylcarbamoyl)isoindoline-2-carboxylate after concentration. MS (ESI) m/z: Calculated: 487.2; Observed: 488.4 (M++H).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:16]([C:39]([F:42])([F:41])[F:40])/[CH:17]=[CH:18]/[C:19]2[CH:36]=[CH:35][C:22]([C:23]([NH:25][CH2:26][C:27](=[O:34])[NH:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[O:24])=[C:21](SC)[CH:20]=2)[CH:11]=[C:12]([Cl:15])[C:13]=1[F:14].[CH3:43]C(C)=O.O>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:16]([C:39]([F:42])([F:41])[F:40])/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][C:27](=[O:34])[NH:28][CH2:29][C:30]([F:32])([F:33])[F:31])=[O:24])=[C:35]([S:3]([CH3:43])(=[O:5])=[O:2])[CH:36]=2)[CH:11]=[C:12]([Cl:15])[C:13]=1[F:14]
Reactant: CC(C)=O
Reactant: O=S([O-])OO
Reactant: CSc1cc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1cc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Reaction time: 18 h

Procedure:
Oxone (320 mg, 0.50 mmol) was added to a stirred solution of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(methylthio)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide (150 mg, 0.25 mmol) in acetone-water (10 mL, 1:1) at ambient temperature and the reaction mixture was stirred for 18 h. The reaction mixture was then extracted with CH2Cl2. The organic layer was washed with brine and water, dried (Na2SO4), filtered, concentrated and the residue was triturated with pentane-Et2O (1:1) to afford the title compound as an off white solid (85 mg, 56%): 1H NMR (300 MHz, DMSO-d6) δ 9.01 (t, J=6.0, 1H), 8.37 (t, J=6.4 Hz, 1H), 8.08 (s, 1H), 8.01-7.96 (m, 1H), 7.88-7.86 (m, 2H), 7.64 (d, J=7.6 Hz, 1H), 7.05 (dd, J=16.4, 8.8 Hz, 1H), 6.91 (d, J=15.6 Hz, 1H), 4.87-4.80 (m, 1H), 3.98-3.91 (m, 4H), 3.38 (s, 3H); ESIMS m/z 608.85 ([M+H]+); IR (thin film) 337, 416, 721, 164, 768 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:29][N+:30]([CH3:32])=[CH2:31].[I-]>C1COCC1.O>[CH3:29][N:30]([CH2:32][CH:4]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[CH:7][CH:6]=1)[C:3]([O:2][CH3:1])=[O:18])[CH3:31]
Reactant: C=[N+](C)C
Reactant: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CN(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate (800 mg, 3.20 mmol) in THF (15 mL) was cooled to −78° C. before adding lithium hexamethyldisilazide (1M in THF, 4.16 mL, 4.16 mmol) dropwise. After 15 minutes, Eschenmoser's salt (1.18 g, 6.40 mmol) was added in one portion. The reaction was stirred at −78° C. for 5 minutes, warmed to room temperature, and stirred an additional 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was then extracted with 1N HCl. The acidic aqueous layer was neutralized with sat. NaHCO3 and extracted with EtOAc. The new organic extracts were dried over MgSO4 and evaporated to yield tert-butyl 4-{1-[(dimethylamino)methyl]-2-methoxy-2-oxoethyl}benzoate as a white solid. 1H NMR (CDCl3) δ 7.91 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 3.84 (dd, J=9.7, 5.6 Hz, 1H), 3.65 (s, 3H), 3.10 (dd, J=12.3, 9.7 Hz, 1H), 2.47 (dd, J=12.3, 5.6 Hz, 1H), 2.24 (s, 6H), 1.55 (s, 9H). MS (ESI) calcd [M+H]+ 308.1, found 308.1.
Reaction SMILES: [NH2:1][C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:1]([CH2:3][C:4]1[CH:19]=[CH:18][CH:7]=[CH:6][CH:5]=1)[C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Product: C[C@H](Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Using a method similar to example 2, using (R)-6-[4-(2-amino-propyl)-phenoxy]-nicotinamide and benzyl bromide gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.04 minutes, Purity: 99.8%; mass spectrum (ion spray): m/z=452.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:4][CH:3]=1.[O:42]([CH2:49][C@@H:50]1[CH2:52][O:51]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[F-].[Cs+]>>[OH:51][C@H:50]([CH2:49][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:52][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC[C@H](O)COc4ccccc4)cc3)cc21
Temperature: 130 °C
Reaction time: 3 h

Procedure:
The mixture of 0.280 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate, 0.152 g of 2(S)-phenoxymethyloxirane and 0.0015 g of caesium fluoride is stirred at 130° C. over 3 hours. The reaction mixture is cooled and the title compound is obtained as a colourless oil by means of flash chromatography (SiO2 60F). Rf=0.13 (1:1 EtOAc-heptane); Rt=5.14.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[CH3:9][NH:10][CH3:11]>C1COCC1>[CH3:9][N:10]([CH3:11])[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: O=Cc1csc(Cl)n1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminothiazole (30 g, 0.3 mmol) in conc. hydrochloric acid (150 mL) at 0° C. was added dropwise a saturated solution of sodium nitrite (20.7 g) in water. After 75 minutes at 0° C., cuprous chloride (29.7 g) was added portionwise and the mixture stirred at 0° C. for a further 150 minutes. The mixture was neutralised with conc. sodium hydroxide solution and partitioned between diethyl ether and water. The organic phase was washed with brine, dried over sodium sulphate and evaporated in vacuo to afford 2-chlorothiazole as an oil. To a solution of 2-chlorothiazole (15.9 g, 133 mmol) in THF (200 mL) at −74° C. was added n-BuLi (1.6M in hexane, 90 mL). After 10 minutes, a solution of DMF (14 mL) in THF (90 mL) was added and the mixture allowed to attain room temperature over 2 hours. The mixture was then poured slowly into hydrochloric acid (2M, 400 mL), basified with ammonium hydroxide and extracted with dichloromethane (2×300 mL). The combined organic fractions were dried over sodium sulphate and evaporated in vacuo to afford 2chloro-thiazol4-carboxaldehyde as a solid. A mixture of 2chloro-thiazole-4-carboxaldehyde (20 g) in 2.5% aqueous THF (400 mL) and dimethylamine (13 g, 2.5 equiv.) in THF (150 mL) were combined and stirred at room temperature for 16 hours. The solvent was evaporated in vacuo, the residue partitioned between water and dichloromethane and the organic layer dried over sodium sulphate. Evaporation of the solvent afforded the title compound as a solid
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.O1CCCC1.[F:35][C:36]1[CH:37]=[C:38](O)[CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:35][C:36]1[CH:41]=[C:40]([CH:39]=[CH:38][CH:37]=1)[O:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2cccc(F)c2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C

Procedure:
To a solution of dimethyl (2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (50.0 mg, 0.000123 mol) in tetrahydrofuran (0.50 mL, 0.00617 mol) was added 3-fluoro-phenol (0.0134 mL, 0.000148 mol), triphenylphosphine (38.8 mg, 0.000148 mol), followed by diethyl azodicarboxylate (0.0233 mL, 0.000148 mol). The mixture was heated at 70 Celsius overnight. After concentrated to dry, the mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to generate the phenyl ether compound (27 mg, 44%). MS (ESI): (M+H)+=500.05.
Reaction SMILES: C([O:3][C:4]([C:6](O)([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)=O)[C:7](OCC)=[O:8])=[O:5])C.O.[NH2:25][NH2:26].[OH-].[Na+].Cl>C(O)(C)C>[C:4]([C:6]1[C:7](=[O:8])[NH:25][N:26]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:12]=1)([OH:3])=[O:5]
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2cc(C(=O)O)c(=O)[nH]n2)cc1F
Reaction time: 6 h

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-oxobutanoate (8.41 9, 25.8 mmol) in isopropanol (100 mL) was added hydrazine monohydrate (2.84 g, 56.8 mmol), and the mixture was heated under stirring at 100 for 6 hours. Then, 2 mol/L sodium hydroxide was added, and the mixture was stirred further at the same temperature for 4 hours. The reaction mixture was ice-cooled, and concentrated hydrochloric acid was added to acidify the system. The precipitate was collected by filtration, thoroughly washed with water and dried to yield the title compound as a slightly yellow crystalline powder (5.67 g, 87.7%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNC(=O)C=C1c2ccccc2C=Cc2ccccc21

Procedure:
173 mg (0.70 mmol) of 5H-dibenzo[a,d][7]annulen-5-ylidenacetic acid, 124 mg (0.77 mmol) of t-butyl N-(2-aminoethyl)carbamate, 143 mg (0.75 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 0.11 ml (0.79 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3) to obtain the title compound.