Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13]O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:39]I>C(Cl)Cl>[I:39][CH2:13][CH2:12][N:10]1[CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:9]1
Reactant: II
Reactant: OCCn1cnc(-c2ccccc2)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICCn1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 2-(4-phenyl-1H-imidazol-1-yl)ethanol (500 mg, 2.66 mmol, 1 eq) in DCM (10 mL) was added PPh3 (778 mg, 2.96 mmol, 1.1 eq), imidazole (203 mg, 2.98 mmol, 1.1 eq) and iodine (753 mg, 2.97 mmol, 1.1 eq). The reaction mixture was allowed to stir at RT overnight. The organic layer was extracted with 1N HCl. The combined acid extracts were then adjusted to pH˜8 with solid sodium carbonate. The aqueous layer was extracted 2× with Et2O. The combined ether extracts were dried over sodium sulfate, filtered and concentrated to dryness to give 1-(2-iodoethyl)-4-phenyl-1H-imidazole (623 mg, 78% yield) which was used without further purification. LC-MS M+H+298.9.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9]([Li])[CH2:10][CH2:11]C.C(I)CC.Cl>CCCCCC.O>[O:4]=[C:3]([CH2:5][CH2:9][CH2:10][CH3:11])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: [Li]CCCC
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: CCCI
Product: CCCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
After stirring for 20 minutes, 9.3 ml of methyl acetoacetate were dropped, stirring was continued for 30 minutes at 0° C. and further 54 ml of butyllithium 1.6M in hexane were dropped. After further 30 minutes 8.4 ml of propyl iodide were dropped into the dark orange solution. The temperature was allowed to raise to room temperature and after 30 minutes, 50 ml of 37% HCl diluted with 100 ml of H2O were continuously dropped while keeping the temperature under 15° C. The reaction mixture was extracted with Et2O. The organic phase was washed with a NaCl saturated solution, dried on Na2SO4 and evaporated to dryness. The residue was purified by FC (eluent: AcOEt/hexane 1:9). 8.3 g of a clear oil were obtained (yield 61%); 1H-NMR (200 MHz, CDCl3)δ: 0.90 (t, 3H), 1.22-1.65 (m, 4H), 2.53 (t, 2H), 3.44 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C@@H:6]([C:29]#[N:30])[NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:9].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:29]([C@@H:6]([NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:9])[CH2:5][CH2:4][C:3]([OH:31])=[O:2])#[N:30]
Reactant: COC(=O)CC[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CCC(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of (S)-4-cyano-4-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid methyl ester (prepared as described in Example 3 using glutamic acid amide methyl ester) (572 mg, 1.35 mmol) in 15 mL of THF and 2 mL of MeOH was added a solution of lithium hydroxide hydrate (370 mg, 8.82 mmol) in 15 mL of water. The reaction mixture was stirred at room temp for 30 minutes, then poured into a slurry of ice and 20 mL of a 1N HCl solution. The organic layer was extracted with 50 mL of ethyl acetate, separated, washed with 50 mL of water, dried with sodium sulfate, and concentrated to give 556 mg (100%) of (S)-4-cyano-4-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid as a white amorphous solid. MS: 409 (M−H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([OH:16])=[N:13][C:12]=12)[CH3:2].[H-].[Na+].[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:32]I)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O>O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([O:16][CH2:32][CH2:31][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:13][C:12]=12)[CH3:2]
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(O)nc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCc1sc(OCCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 70 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of ethyl[(2-hydroxy-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.40 g, 4.58 mmol), sodium hydride (60% dispersion in liquid paraffin, 200 mg, 5.00 mmol), 3,3-diphenylpropyl iodide (1.60 g, 5.04 mmol), and N,N-dimethylformamide (30 ml) was stirred at 70° C. for 2 hours. This reaction mixture was poured into water (50 mL) and extracted with 2 portions of ethyl acetate. The pooled organic solution was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=8:1) to provide 810 mg of ethyl[[2-(3,3-diphenylpropyl)oxy-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound (700 mg, 1.40 mmol) in a mixture of tetrahydrofuran (8 mL) and methanol (2 mL) was added 1N-aqueous sodium hydroxide solution (1.4 mL) dropwise and the mixture was stirred at room temperature for 5 minutes. To this reaction mixture was added 1N-hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate-hexane to provide 500 mg of the title compound. Yield 24%.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([CH2:9]CC3CCN(CC4C=CC=CC=4)CC3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:26]([O:29][CH2:30][CH2:31]Br)[CH2:27]Br.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:9][C:6]1[C:5]2[CH:24]=[CH:25][C:2]([N:1]3[CH2:31][CH2:30][O:29][CH2:26][CH2:27]3)=[CH:3][C:4]=2[O:8][N:7]=1
Reactant: BrCCOCCBr
Reactant: Nc1ccc2c(CCC3CCN(Cc4ccccc4)CC3)noc2c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1noc2cc(N3CCOCC3)ccc12
Temperature: 120 °C
Yield: 147.5 %

Procedure:
A mixture of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole (0.230 g, 1.55 mmol), β,β′-dibromodiethyl ether (0.397 g, 1.71 mmol), and diisopropylethyl amine (Hunig's base, 0.648 mL, 3.72 mmol) in toluene (2.5 mL) was heated at 120° C. for 15 hours. The cooled reaction mixture was diluted with EtOAc and washed with water and brine and dried (MgSO4), filtered, and concentrated. Two additional separate reactions using 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole (0.050 g, 0.34 mmol, and 0.150 g, 1.01 mmol) were carried out in the same manner. Crude product from the three reactions was combined and purified by silica gel flash chromatography (1% MeOH/CH2Cl2) to give the title compound (0.499 g, 79% combined yield) as a pale yellow solid. A small sample was further purified by recrystallization (EtOAc/hexanes) to give a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C.C1COCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Clc1ncccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ncccn1)C2
Yield: 71.7 %

Procedure:
A solution of 3,8-diaza-bicyclo[3,2,1]octane-8-carboxyli acid tert-butyl ester (50 mg, 0.24 mmol), 2-chloropyrimidine (27 mg, 0.24 mmol), triethylamine (0.1 ml, 0.72 mmol) and THF (2.5 ml) was heated at 180° C. for 10 minutes. The solution was concentrated to afford a solid residue that was dissolved in dichloromethane, which was washed sequentially with sat. aq. sodium bicarbonate and brine, dried (Na2SO4), filtered, and concentrated to afford 50 mg (71%) of the product as a brown solid: 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J=12.0 Hz, 2H), 6.52 (t, J=12.0 Hz, 1H), 4.38-4.29 (m, 4H), 3.13 (sb, 2H), 2.42 (m, 2H), 1.69 (q, J=18.0 Hz, 2H), 1.49 (s, 9H); MS (M+1)=291.
Reaction SMILES: [S:1]1[C:5]([S:6]([NH2:9])(=[O:8])=[O:7])=[CH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:9][S:6]([C:5]2[S:1][C:2]3[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=3[CH:4]=2)(=[O:7])=[O:8])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2s1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1cc2ccccc2s1
Yield: 94.9 %

Procedure:
To a solution of 13.4 g (100 mmol) of benzothiophene, dissolved in 50 ml anhydrous diethyl ether, was added 62.5 ml of a 1.6M hexanes solution of n-butyllithium (100 mmol). The reaction mixture was refluxed for 4 hours and then cooled to about -20° C. Sulfuryl chloride (16.1 ml, 200 mmol) was added dropwise. This suspension was stirred at ambient temperature overnight and then added to 75 ml of ice water. The ether layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was added to 100 ml of concentrated ammonium hydroxide and the suspension was warmed to 55° C. The solution was diluted with 200 ml of water and stirred at ambient temperature for several hours. Product was collected by filtration under vacuum. The residue was suspended in 150 ml toluene and filtered to provide 9.2 g of 2-benzo[B]thiophenesulfonamide. The sulfonamide (25 mmol) was reacted with 4-chlorophenylisocyanate (27 mmol) as described in Preparation 2 above to obtain 8.7 g of the title product as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11]OC(C1C=NC=C(C(OC)=O)C=1)=O>>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: Cc1ncccc1C(=O)O
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Product: COC(=O)c1cccnc1C

Procedure:
methyl 2-methylnicotinate was synthesized from 2-methylnicotinic acid following the general procedure as described for dimethylpyridine-3,5-dicarboxylate.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>CO>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][N:28]([C:34](=[O:36])[CH3:35])[CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CNC[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N(CC(=O)O)C[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O

Procedure:
In 4 ml of methanol was dissolved 60 mg of ethyl ester of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]glycine obtained in Example 40. To the solution were added 0.2 ml of acetic anhydride and 0.2 ml of triethylamine. The mixture was heated for one hour under reflux while stirring. The reaction mixture was concentrated under reduced pressure, which was subjected to extraction with ethyl acetate. The organic layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, which was then dried, followed by distilling off the solvent. The residue was dissolved in 4 ml of methanol, to which was added 2 ml of a 5% aqueous solution of potassium carbonate. The mixture was stirred for 30 minutes at 60° C. The reaction mixture was concentrated under reduced pressure, to which was added 1N hydrochloric acid to acidify the solution, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. From the residue, 45 mg of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]-N-acetyl glycine was obtained as crystals, m.p. 143°-145° C.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:39]2[CH2:44][C@H:43]([CH3:45])[O:42][C@H:41]([CH3:46])[CH2:40]2)=[C:22]([F:38])[C:23](F)=[C:24]([C:26](=[N:35][OH:36])[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:46][C@@H:41]1[CH2:40][N:39]([C:21]2[C:20]([CH2:19][OH:18])=[CH:25][C:24]3[C:26]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[N:35][O:36][C:23]=3[C:22]=2[F:38])[CH2:44][C@H:43]([CH3:45])[O:42]1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=NO)C(=O)N3CCOCC3)c(F)c2F)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)N4CCOCC4)noc3c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(5-((tert-Butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-(hydroxyimino)-1-morpholinoethanone, (Intermediate 168, 133 mg, 0.20 mmol) was dissolved in DMF and stirred at 60° C. with cesium carbonate (332 mg, 1.02 mmol) for 6 hours. The reaction stirred at room temperature over 2 days. The reaction was diluted with water and extracted three times with ethyl acetate. The organic layers were combined and washed 5× with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate to give the title compound (34 mg, 0.086 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])[CH3:2].CN1C=CN=C1S.ClC[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([S:8]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1)(=[O:10])=[O:9])[CH2:6][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[CH:34][CH:35]=1)[CH3:2]
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1nccn1C
Agent: Cn1ccnc1S
Product: CCOC(=O)C(C)(Cc1ccc(-c2ccccc2)cc1)S(=O)(=O)c1nccn1C

Procedure:
3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-methyl-(1-methyl-1H-imidazolesulfonyl)-propionic acid ethyl ester Prepared from (1-Methyl-2-mercapto imidazole and 2-bromo ethyl propionate) (3.0 g, 12.2 mmol) and 4-chloromethylbiphenyl (2.97 g, 15 mmol). Yield 5.0 g (99%); low melting solid; MS 413 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2]N.CO[Si](CCC[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(OC)OC.C=O>C1(C)C=CC=CC=1>[O:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:2]=[CH:1][NH:4]1
Reactant: CO[Si](CCCc1ccccc1O)(OC)OC
Reactant: NCCN
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1

Procedure:
The desired benzoxazine was prepared from the reaction of ethylene diamine (0.9 g, 15 mmole), 2-[(trimethoxysilyl)propyl]phenol (7.68 g, 30 mmole, prepared as described in Example 12A), paraformaldehyde (2.1 g, 70 mmole), and toluene (20 ml). The final product was a viscous liquid. The yield was 65% of theory.
Reaction SMILES: [C:1]([NH:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2].[OH:15]N1C(=O)C2=CC=CC=C2C1=O>C(O)(=O)C>[C:1]([NH:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([OH:15])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2].[C:1]([NH:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([C:8]3=[O:15])[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Product: CC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Product: CC(=O)NC12CC3CC(CC(O)(C3)C1)C2

Procedure:
Mixture of 10 mmole 1-acetylaminoadamantane (Aldrich chemical Company, Inc.), 1 mmole of N-hydroxyphthalimide (NHPI), 0.05 mmole of vanadium(III)acetylacetonato (V(AA)3) and 25 mL of acetic acid was stirred under an oxygen atmosphere and the conditions represented in Table 1 (temperature and time). The products in the reaction mixture were analyzed by gas chromatography, and, as a result, 1-acetylamino-3-adamantanol (compound 1), 1-acetylamino-3,5-adamatanediol (compound 2) and 1-acetylamino-4-adamantanone (compound 3) were obtained with conversions and yields represented in Table 1.
Reaction SMILES: [CH3:1][CH2:2]/[C:3](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:4](/[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=1)\[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH3:29][I:30]>C(OCC)(=O)C>[CH3:1][CH2:2]/[C:3](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N+:20]([CH3:29])([CH3:22])[CH3:21])=[CH:13][CH:12]=1)\[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[I-:30]
Reactant: CI
Reactant: CC/C(=C(\c1ccccc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC/C(=C(\c1ccccc1)c1ccc(OCC[N+](C)(C)C)cc1)c1ccccc1
Product: [I-]
Yield: 99 %

Procedure:
Tamoxifen methiodide was prepared by reacting 2.0 g of tamoxifen (Aldrich Chemical Co., St. Louis, Mo.) with methyl iodide at 0° C. for 24 hours. Ethyl acetate was then added to afford a white precipitate, which was recrystallized from methanol to yield >99% tamoxifen methiodide. Tamoxifen benzyl bromide was synthesized by reacting tamoxifen with benzyl bromide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[O:10]1[CH2:15][CH2:14][CH:13]([C:16](=O)[CH3:17])[CH2:12][CH2:11]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Br:9][C:5]1[CH:6]=[C:7]([NH:8][CH:16]([CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH3:17])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(=O)C1CCOCC1
Reactant: Nc1cc(Br)cnc1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Nc1cc(Br)cnc1N)C1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.6 %

Procedure:
2,3-Diamino-5-bromopyridine (1.07 g) and 1-(tetrahydro-2H-pyran-4-yl)ethanone (0.80 g) were dissolved in methanol (20 ml), and acetic acid (0.98 ml) was added. After stirring at room temperature for a while, sodium cyanoborohydride (1.08 g) was added and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (developed with ethyl acetate-hexane) to give the title compound (334 mg).
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][C:7]=1[C:19]([O:21]C)=O)=O.OC1C(O)=C(C(OC)=O)N=C(C(O)=O)N=1.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1.CCOC(C)=O>CN(C=O)C>[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][C:19]([C:7]2[N:8]=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]([CH3:13])[C:11](=[O:12])[C:6]=2[OH:5])=[O:21])=[CH:43][CH:42]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(C(=O)OC)c(OC(=O)C(C)(C)C)c(=O)n1C
Agent: COC(=O)c1nc(C(=O)O)nc(O)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-Ethyl 4-methyl 5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-6-oxo-1,6-dihydropyrimidine-2,4-dicarboxylate (made by protection and alkylation of the starting material of Example 4, Step 1 using procedures similar to those set forth in Examples 1 or 2) was dissolved in DMF, 4-fluorobenzylamine (3.1 eq.) was added and the mixture was stirred at 90° C. overnight. After concentration of the solvent, the residue was taken into EtOAc, washed with 1 N HCl, dried over Na2SO4 and evaporated to obtain crude N-(4-fluorobenzyl)-2-ethoxycarbonyl-1-methyl-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide. To this crude product was added 2-picolylamine (8 eq.), and the reaction was stirred at 90° C. overnight. The title product was obtained as its trifluoroacetic salt by preparative RP-HPLC purification (C18 gradient of CH3CN/H2O+0.01% TFA).
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH2:32][CH2:33][CH:34]([OH:38])[CH:35]([CH3:37])[CH3:36])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:38][CH:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][CH:31]=[CH:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(C=CCCC(O)C(C)C)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(O)CCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.3 ml of concentrated sulphuric acid in 2.8 ml of methanol with 140 mg (0.31 mmol) of 7-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methylhept-6-en-3-ol in 2.8 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), a white powder (m=80 mg; Y=77%) is obtained. m.p.=51-60° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:60])[C:32]([C:35]3[N:36]=[C:37]([NH:40]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:38][CH:39]=3)=[N:33][OH:34])[C:28](=[O:61])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C(OC(C)C)(C)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:60])[C:32]([C:35]3[N:36]=[C:37]([NH2:40])[S:38][CH:39]=3)=[N:33][OH:34])[C:28](=[O:61])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
The product of Step C was dissolved in 15 ml of pure trifluoroacetic acid and the mixture stood for 15 minutes and was then diluted with 100 ml of isopropyl ether. The mixture was stirred for 5 minutes and was vacuum filtered and the filter was rinsed with isopropyl ether. The product was dried and then dissolved in 2 ml of ethanol containing 0.2 ml of pyridine. The mixture was vacuum filtered and the recovered product was rinsed twice with ethanol to obtain the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid