Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[NH2:48][CH2:49][C:50]([CH3:53])([OH:52])[CH3:51].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:48][CH2:49][C:50]([OH:52])([CH3:53])[CH3:51])=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)NCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoic acid (2.00 g, 4.76 mmol) was suspended in N,N-dimethylformamide (10 mL). 1-Hydroxybenzotriazole (0.772 g, 5.71 mmol) was added followed by 4-methylmorpholine (1.57 mL, 14.28 mmol), 1-amino-2-methyl-2-propanol hydrochloride (1.49 g, 11.90 mmol) and then 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28 g, 6.66 mmol). The resulting mixture was stirred at room temperature for 2 days at which time the reaction was diluted with H2O (50 mL). The reaction mixture was then extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The resulting solid was washed with diethyl ether to provide the title compound as a tan solid (2.08 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.2 Hz, 2H), 7.51 (app q, J=7.7 Hz, 1H), 7.25-7.21 (m, 1H), 7.10 (d, J=8.2 Hz, 2H), 6.93 (app dt, J=1.6, 8.3, 9.4 Hz, 1H), 6.87-6.82 (m, 1H), 6.01 (s, 1H), 5.32 (s, 2H), 5.19 (s, 2H), 3.42 (d, J=5.9 Hz, 2H), 2.26 (s, 3H), 1.23 (s, 6H). ES-HRMS m/z 491.1522 (M+H calcd for C25H26ClF2N2O4 requires 491.1544).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([C:13](=O)[CH3:14])[CH:10]=[CH:11][CH:12]=1>C(O)C.N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:5])([F:16])[F:17])[CH:8]=1)[CH3:14]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)c1cccc(C(F)(F)F)c1
Yield: 93 %

Procedure:
Methoxylamine hydrochloride (2.33 g) is added to a solution of 3′-(trifluoromethyl) acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution is heated at reflux for 45 minutes. The reaction mixture is then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[C@@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][C@@H:8]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(CNC[C@H](O)[C@@H](Cc2ccc(F)c(F)c2)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2ccc(F)c(F)c2)c1
Reaction time: 12 h
Yield: 109 %

Procedure:
A solution of (1R,2S)-[1-(3,4-Difluorobenzyl)-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-carbamic acid tert-butyl ester (0.04 g, 0.09 mmol) in methylene chloride (1 mL) was treated with 4 N HCl in dioxane (1 mL) at ambient temperature in one portion. The reaction was stirred for 12 hours and the solvent removed at reduced pressure to give the product as a solid (0.033 g, 98%). MS: 337 (M+H, 100%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:10][O:11][C:12](=[O:34])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([Br:31])[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:33]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:11][C:12](=[O:34])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[CH:28]=[C:29]([Br:31])[CH:30]=2)=[CH:17][C:16]=1[CH3:33]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 4-prop-2-ynyl-morpholine (330 mg, 2.64 mmol), {4-[3-(3,5-dibromophenyl)-prop-2-ynyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (206 mg, 0.44 mmol, intermediate 2), Pd(PPh3)2Cl2 (50 mg, 0.044 mmol), CuI (23 mg, 0.123 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 30 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methylphenoxy)-acetic acid methyl ester in 130 mg (58%) yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=3)[C:2]1=2.C(OB(OC(C)C)OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[Cl:38][C:39]1[N:44]=[C:43](Cl)[CH:42]=[CH:41][N:40]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(C)C.O>[Cl:38][C:39]1[N:44]=[C:43]([C:5]2[S:1][C:2]3[C:9]([C:10]4[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=4)=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[CH:42]=[CH:41][N:40]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Clc1cc(-c2cccc3ccsc23)ccn1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1cc(-c2cccc3cc(-c4ccnc(Cl)n4)sc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
In a 500 mL round bottom flask, cool a solution of 4-benzo[b]thiophen-7-yl-2-chloro-pyridine (13 g, 53.1 mmol) and triisopropylborate (20 g, 106 mmol) in THF (150 mL) to −70° under nitrogen. To the cooled solution, add lithium diisopropylamide (2 M in THF, 53 mL, 106 mmol) gradually over a period of 30 min. Stir the mixture continually for an additional 1 hour in the cooling bath. Gradually transfer the mixture into a refluxing solution of 2,4-dichloro-pyrimidine (12 g, 106 mmol), [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (2.2 g, 53 mmol) and sodium carbonate (35 mL, 3 M, 106 mmol) in THF (150 mL) over a period of 30 min. Reflux for an additional 1 hour. Cool the mixture to room temperature and dilute with 500 mL of chloroform/isopropanol (3/1) and 200 mL of water. Collect the resulting solid by filtration and reserve the chloroform/isopropanol/water mixture. Wash the solid with dichloromethane and dry it under vacuum. Separate the layers of the chloroform/isopropanol/water mixture. Wash the organic phase with water and saturated aqueous sodium chloride, dry over sodium sulfate and concentrate in vacuo to give a brown residue. Purify the residue by flash column chromatography (10% methanol in dichloromethane) to afford additional product. Combine the two portions to give the title compound (13 g, 68%) MS (ES) m/z 358 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH3:22]I>C(OCC)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH3:22])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CI
Reactant: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CSc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.6 %

Procedure:
To a solution of the 2-amino-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidin-4(3H)thione of example 7 (55 mg) in a 1 N NaOH solution (10 ml) was added methyl iodide (0.2 mmol). The reaction was stirred at room temperature for 12 hours. The reaction mixture was diluted with diethyl ether and the organic layer was extracted with water. The combined organic layers were evaporated in vacuo and the crude residue was purified by preparative thin layer chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 5:95, providing 41 mg of the pure title compound (yield: 72%) which was characterized by its mass spectrum as follows: MS (m/z): 287 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[F-:13].[K+].O>CC#N>[C:8]([C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([F:13])[N:7]=1)#[N:9]
Reactant: [F-]
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1nc(F)ccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A mixture of 6-chloro-2-cyano-3-nitropyridine [Colbry, N. L.; Elslager, E. F.; Werbel, L. M.; J. Het. Chem., 1984, 21, 1521-1525] (10.0 g, 0.054 mol) and KF (9.48 g, 0.163 mol) in MeCN (200 mL) is heated under reflux with stirring for 18 h, then poured into water and extracted with EtOAc. The extract is washed with water and worked up, and the residue is chromatographed on silica gel, eluting with EtOAc/petroleum ether (3:7), to give after removal of the solvent under reduced pressure 2-cyano-6-fluoro-3-nitropyridine (7.2 g, 79%). 1H NMR (CDCl3) δ 8.79 (1H, dd, J=9.0, 6.0 Hz), 7.48 (1H, dd, J=9.0, 3.0 Hz).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:13][CH:14]([O:16][CH:17]1[CH2:29][CH2:28][C:27]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH:26]([OH:37])[CH:25]=[CH:24][CH:23]([CH3:38])[CH:22](/[C:39](/[CH3:60])=[CH:40]/[CH:41]=[CH:42]/[CH:43]([CH3:59])[CH2:44][CH:45]2[O:58][CH:46]2[CH:47]([CH3:57])[CH:48]([O:51][CH:52]([O:54][CH2:55][CH3:56])[CH3:53])[CH2:49][CH3:50])[O:21][C:19](=[O:20])[CH2:18]1)[CH3:15])[CH3:12].[C:61](Cl)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(OCC)(=O)C>O1CCCC1.O>[C:61]([O:37][CH:26]1[C:27]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH2:28][CH2:29][CH:17]([O:16][CH:14]([O:13][CH2:11][CH3:12])[CH3:15])[CH2:18][C:19]([O:21][CH:22](/[C:39](/[CH3:60])=[CH:40]/[CH:41]=[CH:42]/[CH:43]([CH3:59])[CH2:44][CH:45]2[O:58][CH:46]2[CH:47]([CH3:57])[CH:48]([O:51][CH:52]([O:54][CH2:55][CH3:56])[CH3:53])[CH2:49][CH3:50])[CH:23]([CH3:38])[CH:24]=[CH:25]1)=[O:20])(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Reactant: O=C(Cl)c1ccccc1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)c2ccccc2)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)c2ccccc2)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Reaction time: 0.25 h

Procedure:
LiHMDS (1.0 M tetrahydrofuran solution, 81 μL, 81 μmol) was added dropwise to a solution of (8E,12E,14E)-3,6,21-tri(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (10 mg, 14 μmol) in tetrahydrofuran (1 mL) at −40° C. under nitrogen atmosphere. After stirring at the same temperature for 15 min., a solution of benzoyl chloride (17.8 mg, 125 μmol) in tetrahydrofuran (0.4 mL) was added dropwise thereto and the mixture was stirred at 0° C. for 7 hours. Ethyl Acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane=1:4) to obtain the title compound (6.1 mg, 54%) as a colorless oil.
Reaction SMILES: O[C:2]1[C:10]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:16][C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl-].[NH4+]>O1CCCC1>[CH3:12][N:11]1[C:10]2[C:2](=[CH:3][CH:4]=[C:5]3[C:9]=2[N:8]([CH2:16][C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:18])[N:7]=[CH:6]3)[O:15][CH2:14][CH2:13]1
Reactant: C[C@@H](Cn1ncc2ccc(O)c(N(C)CCO)c21)NC(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3c(c21)N(C)CCO3)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a stirred solution of the product from Step B (0.36 g, 0.82 mmol) in tetrahydrofuran (10 mL) at 0° C. was added triphenylphospine (0.26 g, 0.98 mmol) followed by diethyl azodicarboxylate (0.23 mL, 1.23 mmol). After 2 h, a saturated aqueous solution of ammonium chloride (30 mL) was added and the mixture was extracted with ethyl acetate (3×65 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4), and evaporated to a residue which was purified by chromatography (silica, 30%–50% ethyl acetate in hexane) to give an oil (0.28 g, 89%): 1H NMR (CDCl3) δ 7.88 (1H, s), 7.30 (6H, m), 6.73 (1H,d, J=8.4 Hz), 4.91 (2H, s), 4.63 (2H, m), 4.37 (2H, m), 4.09 (1H,m), 3.26 (2H,m), 2.73 (3H,s), 1.06 (3H, d, J=6.4 Hz); MS (ES) m/z 381 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:13][O:14][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
1.50 g (6.27 mmol) of N-[(benzyloxy)carbonyl]-(DL)-serine was dissolved in 10 ml of N,N-dimethylformamide. 885 mg (13.2 mmol) of imidazole and 1.98 g (13.2 mmol) of t-butyldimethylchlorosilane were added to the obtained solution at 0° C., and they were stirred overnight. Water was added to the reaction mixture and they were stirred for 10 minutes. After extracting with ethyl acetate 3 times followed by the drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH2:9]([O:12][N:13]([C@@H:36]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH3:37])[C:14]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH:10]=C.O=[O+][O-].S(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:41]([O:40][C:38](=[O:39])[C@H:36]([N:13]1[C:14](=[O:15])[CH:16]=[CH:10][CH2:9][O:12]1)[CH3:37])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C=CCON(C(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: O=[O+][O-]
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: C[C@H](C(=O)OCc1ccccc1)N1OCC=CC1=O
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A solution of (R)-N-(2-triphenylphosphonio)acetyl-N-allyloxyalanine benzyl ester trifluoromethanesulfonate (5) (6.52 g, 9.95 mmol) in CH2Cl2 (180 mL) was cooled to −76˜−78° C. and saturated with ozone (a moderate bubbling until a persistent blue color) at the same temperature with stirring. An excess of ozone was removed by bubbling N2 through the reaction mixture at −76˜−78° C. and Me2S (3.1 g, 50 mmol) was added portionwise with stirring at the same temperature. The reaction mixture was allowed to warm up to room temperature and a solution of K2CO3 (6.91 g, 50 mmol) in water (20 mL) was added. After a vigorous stirring, the reaction mixture was diluted with water (100 mL) and the organic layer was separated off and washed with water (2×30 mL) and dried over MgSO4. Removal of the solvent gave a yellow semi-solid substance, which was purified by flash chromatography (Silica Gel 60, 20% EtOAc-hexanes) to afford 0.70 g (27%) the product 7a as a colorless oil. 1H NMR (400 MHz) in CDCl3 (J, Hz): δ 1.53 (3H, d, 3J=7.3, MeCH), 4.46 (1H, dq, 2J=−15.9, 3J=3.4, 4J=1.8, OCHACH═CH), 4.56 (1H, dq, 2J=15.9, 3J=3.4, 4J=1.8, OCHBCH═CH), 5.15 (1H, d, 2J=12.4, CHAPh), 5.19 (1H, q, MeCH, 3J=7.3), 5.22 (1H, d, 2J=12.4, CHBPh), 6.04 (1H, dt, 3Jcis=10.0, 4J=1.8, CH═CHCO), 6.72 (1H, dt, 3Jcis=10.0, 3J=3.4, CH2CH═CHCO), 7.27-7.40 (5H, m, Ph). 13C (100 MHz) in CDCl3: δ 13.71, 53.57, 67.08, 67.57, 122.32, 128.02, 128.26, 128.52, 135.49, 139.67, 164.64, 170.09. IR (film), cm−1: 1745, 1675, 1214, 1189. MS (CI, isobutane), m/Z: 262 (M++1). Anal. Calcd for C14H15NO4: C, 64.4; H, 5.8; N, 5.4. Found: C, 64.3; H, 5.85; N, 5.6%.
Reaction SMILES: [NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>N1C=CC=CC=1>[C:27]1([O:26][C:24](=[O:25])[NH:1][C:2]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH3:22])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=3)[NH:4][C:3]2=[O:13])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOc1ccccc1C1(N)C(=O)Nc2ccc(OC)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.8 g (6 mmol) of the intermediate from step C were dissolved in 20 ml pyridine. At 0° C. 0.99 g (6.3 mmol) phenyl chloroformate were added and afterwards the reaction mixture was stirred for 1 h at 0° C. This mixture was poured into an ice/water mixture. The pH of the aqueous phase was adjusted to 5 and the resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate and the solvent was removed in vacuo. The resulting solid (2 g) was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][C:23](OC)=[O:24])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][OH:24])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 35 %

Procedure:
A solution of 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, methyl ester (2.5 g.; 0.0068 mole) and THF (10 ml.) was added dropwise by syringe to an ice cooled slurry of lithium aluminum hydride (0.55 g.; 0.0145 mole) and THF (20 ml.). Stirring was continued for an additional 1.25 hours at ambient temperature. The reaction was quenched by the dropwise addition of water (2 ml. via syringe) and then concentrated by rotary evaporation. The residue was slurried with water, taken to pH 4 with 6 N sulfuric acid, and extracted with methylene chloride. The extracts were washed with water, dried (sodium sulfate), and concentrated by rotary evaporation. The crude mixture was chromatographed (HPLC) with 50% ethyl acetate in benzene through silica gel and then recrystallized from ether-pentane to afford 0.82 g. (35% yield) 4,5-bis(4-methoxyphenyl)-2-thiazole ethanol; m.p. 101°-104° C.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[Br-:11].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:11][C:2]1[NH:1][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C1CCCc2[nH]c(Br)cc21

Procedure:
was prepared using a literature procedure (Remers et al., J. Org. Chem., 36:1241-1247 (1971) (“Remers”), which is hereby incorporated by reference). To a 100 mL round bottom flask charged with a magnetic stir bar was added 1,5,6,7-tetrahydro-4H-indol-4-one (1.2 g, 8.8 mmole) and dry THF (20 mL). Stirring was commenced, and a solution of phenyltrimethylammonium tribromide (3.33 g, 8.8 mmole) in 15 mL of dry THF was added dropwise over 10 minutes at ambient temperature. After the addition was complete, the reaction mixture was stirred for an additional 2 hours and then filtered to remove the precipitate. The filtrate was concentrated in vacuo and the residue treated with dichloromethane (30 mL) and 5% aqueous Na2CO3 solution (30 mL). The layers were separated and the dichloromethane layer was then washed with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the crude product as a white solid which was directly used without further purification. 1H NMR data matched the literature values exactly (“Remers”, which is hereby incorporated by reference).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1)(=[O:25])[CH3:24].N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:33])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 54.2 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1-acetyl-4-piperidinecarboxylic acid (5.1 g) and 1,8-diazabicyclo-[5.4.0]-undec-7-ene (4.6 g), and after successive recrystallization in a mixture of acetone and water (2:1 by volume) and then in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 1-acetyl-4-piperidinecarboxylate (7.5 g), m.p. 101° C., is obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:15])[C:10](=[CH:13][CH:14]=2)[CH:11]=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:16]([Mg]Br)[CH3:17]>>[OH:15][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:14]=[CH:13][C:10]=1[C:11](=[O:12])[CH2:16][CH3:17]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Product: CCC(=O)c1ccc(N2CCOCC2)cc1O

Procedure:
Following the procedure for preparing Example 34, 4-(4-morpholinyl)-salicylaldehyde (1.0 g, 5 mmol) and ethylmagnesium bromide (1.0 M solution in tetrahydrofuran, 11 mL, 11 mmol) were converted to the product (208 mg, 18%).