Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].CS(O[CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[N:19]([C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)=O.[Cl-].[NH4+]>O1CCCC1.O>[C:28]1([C@@H:26]([N:19]2[C@@H:14]3[C@H:13]([CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][C@H:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]2CCCC[C@@H]2N1[C@@H](C)c1ccccc1
Temperature: 20 °C
Yield: 78.7 %

Procedure:
1.18 L of Anhydrous tetrahydrofuran was added to 2 L reactor, reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. With mixing, 60.4 g of sodium t-butoxide (0.628 mol, 1.2 equiv.) was added and the mixture was cooled to below 10° C. temperature. During this period, the solids were dissolved to form an slightly hazy solution. To this mixture, a solution of 204.7 g of ethyl 2-(((1S,2S)-2-((methylsulfonyloxy)methyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate (14, 0.524 mol, 1.0 equiv. based on HCl salt 10) in 297 mL of anhydrous tetrahydrofuran was added over a period of NLT 30 min, while maintaining the temperature below 10° C. The reaction mixture was warmed to 20±3° C. and mixed for NLT 3 h under nitrogen atmosphere. The reaction was then quenched using a solution of 50.3 g of ammonium chloride (0.942, 1.8 equiv.) in 267 mL of water, slowly. The phases were allowed to separate and the upper tetrahydrofuran layer was separated and concentrated on a rotary evaporator at NMT 50 temperature to an orange colored product residue. The lower aqueous layer was extracted with 2×495 mL of heptanes. The heptanes extracts were combined with the concentrated product residue and washed with 2×495 mL of 3.5 M aqueous sodium chloride solution. The heptanes extract was dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated on a rotary evaporator at NMT 70° C. temperature under vacuum. The resulting oil was further dried overnight under high vacuum to afford 124.3 g of crude (2S,3aR,7aS)-ethyl 1-((S)-1-phenylethyl)octahydro-1H-indole-2-carboxylate (15) as a major isomer (de: >97%), which was carried to the next step without further purification. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150×4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8): Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55° C., Rt: 28.59 min; LC-MS (m/z): 302.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].[OH:32][NH2:33].Cl.N1C=CC=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:33][OH:32])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 70 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
3-Phenyl-6-(3-phenylpropyloxy)-1-oxo-1H-indene-2-carboxylate ethyl ester (2 g, 4.85 mmol) and hydroxyamine.hydrochloric acid (1.01 g, 14.6 mmol) were dissolved in pyridine (1.57 ml, 19.4 mmol). The reaction mixture was stirred for 1 hour at 70° C., and washed with saturated ammonium chloride. The organic layer obtained by extracting the reaction mixture with ethyl acetate was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 1-hydroxyimino-3-phenyl-6-(3-phenylpropyloxy)-1H-indene-2-carboxylate ethyl ester (yield 9.5%) as a yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:18])([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:7]([F:10])([F:9])[F:8]>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:12]=[C:11]([C:6]([F:5])([F:18])[C:7]([F:9])([F:10])[F:8])[CH:16]=[CH:15][C:14]=1[CH3:17])([O-:4])=[O:2]
Reactant: Cc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of concentrated nitric acid (1 ml) and concentrated sulphuric acid (2 ml) was added to a cooled stirred suspension of 4-pentafluoroethyltoluene (2.1 g) in concentrated sulphuric acid (5 ml) whilst maintaining the temperature below 5° C. The mixture was stirred at 0° C. for 10 minutes, allowed to warm to room temperature and stirred for 1.5 hours. It was poured onto ice (30 ml) and extracted with ether (2×25 ml). The combined organic extracts were washed with aqueous sodium carbonate (2M, 2×25 ml), water (25 ml), saturated aqueous sodium chloride solution (25 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-nitro-4-pentafluoroethyltoluene (2.04 g) as a pale yellow oil NMR (CDCl3) 2.7(s,3H), 7.45(d,1H), 7.7(d,1H), 8.1(s,1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3OCC[O:11]3)[N:5]=2)[CH2:3][CH2:2]1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>CC(C)=O.O>[CH:1]1([C:4]2[N:5]=[C:6]([CH:10]=[O:11])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CC2)nc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cccc(C2CC2)n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of 2-cyclopropyl-6-[1,3]dioxolan-2-yl-pyridine (0.9 g, see subpart (b) above) and a catalytic amount of TsOH hydrate in a mixture of acetone (10 mL) and water (2 mL) was heated to reflux overnight until most of the starting materials were consumed according to TLC. It was then cooled down to room temperature and concentrated. The residue was dissolved in diethyl ether and washed with saturated sodium carbonate, and then water, and then dried over MgSO4 and concentrated. The concentrate was purified on silica gel column with 100% CH2Cl2 to yield 6-cyclopropyl-pyridine-2-carbaldehyde as a bright liquid (0.65 g, 94%). 1H NMR (CDCl3, 300 MHz), δ 9.90 (s, 1H), 7.58(m, 2H), 7.23 (m, 1H), 2.01 (m, 1H), 1.02-0.92 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1I.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1cc(-n2cnnn2)cc(I)c1N
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N

Procedure:
To a solution of 1-(4-amino-3-iodo-5-methylphenyl)tetrazole (5 g) in acetonitrile (80 cm3) was added ethyl acrylate (2 g), triethylamine (2 g) and palladium acetate (0.1 g). The mixture was heated under reflux for 11/2 hours, cooled and then partitioned between water (100 cm3) and dichloromethane (100 cm3). The aqueous phase was re-extracted with more dichloromethane (100 cm3) and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane: methanol, 20:1. Combination and evaporation of appropriate fractions gave a solid which on recrystallisation from ethyl acetate/methanol afforded yellow needles of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-1-yl]phenyl)prop-2-enoate, m.p. 210°-211°, (3.45 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1>CO.C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Solvent: CO
Solvent: CCO
Product: COc1ccc(N)c(N)n1

Procedure:
2-Amino-6-methoxy-3-nitropyridine (2.8 g, 16.5 mmol) was dissolved in warm 1:1 methanol/ethanol (200 mL). The solution was cooled, purged with argon, and 10% palladium on carbon was added (0.45 g). Hydrogen was introduced (1 atm) and the reaction stirred until complete. The catalyst was filtered and the solvent evaporated from the filtrate to give the title compound. MS 140 (M+1) 1H NMR (500 MHz, CDCl3) δ 6.93 (d, J=8 Hz, 1H), 6.04 (d, J=8 Hz, 1H), 4.15 (br s, 2H), 3.80 (s, 3H), 3.0 (br s, 2H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][OH:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18]>CC(C)=O>[OH:5][CH2:4][CH2:3][CH2:2][S:1][CH:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18]
Reactant: OCCCS
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=C1OCCC1SCCCO
Reaction time: 40 h

Procedure:
3-Mercaptopropan-1-ol (1.61 g, 17.4 mmol) was dissolved in acetone (40 mL) followed by addition of cesium carbonate (5.67 g, 17.4 mmol) and 3-bromo-dihydrofuran-2(3H)-one (1.63 ml, 17.4 mmol). The suspension was stirred vigorously for 40 hours. The reaction was filtered through silica gel, rinsed with acetone and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 70-80% ethyl acetate/hexanes. Recovered the desired product as an oil (2.1 g, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C@H:7]2[NH:11][C:10](=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.B.C=O.[CH:16](O)=O.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O.CO>[CH3:1][C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:8][CH2:9][CH2:10][N:11]2[CH3:16])[O:4][N:3]=1
Reactant: Cc1cc([C@@H]2CCC(=O)N2)on1
Reactant: O=CO
Agent: B
Agent: C=O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 67 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
The compound from step 4b above (3.047 kg, 18.3 mol) was dissolved in 14 L of THF and placed under N2. At room temperature, borane-TH F complex (55 L, 55 mol) was introduced at a rate such that the internal temperature remained at 30° C. At the end of the exothermic and foaming addition, the reaction was heated at reflux (67° C.) for 1 hr. The reaction mixture was then cooled to 0° C., and 8.2 L of methanol was slowly added so that the internal temperature remained at 20° C. The mixture was then stirred for 2 hr. at room temperature, and the solvent was evaporated under vacuum to yield a yellow oil, which solidified upon standing. This residue was emulsified with water and cooled to 10° C. A solution of formaldehyde (35%, 2.1 L, 27.5 mol) and formic acid (97%, 990 mL, 18.3 mol) was added to the emulsion, and the exothermic and effervescent reaction was maintained at an internal temperature below 30° C. The mixture was the cooled to 10° C., 1 kg (9.5 mol) of Na2CO3 was added in portions, and the mixture was stirred for 1 hr. NaOH (10%, 2.29 L) was added, followed by 5.5 L of water. The product was isolated by extraction with ethyl acetate, which was dried over MgSO4, filtered and concentrated to dryness. The product was double distilled, dissolved in ethyl acetate, converted to the HCl salt with ethanolic HCl, recrystallized from ethyl acetate, suspended in ethyl acetate, re-converted to the base with treatment with 30% NaOH solution, the layers separated, the organic layer washed with brine, dried and evaporated, to yield the product, which was finally distilled to yield 490 g of the pure title product (e.e. =99.5%).
Reaction SMILES: CC1C=CC=C(C)C=1NC(NC(=N)NOC)=[O:11].CN(C(OC)OC)C.[NH4+].[OH-].[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[N:36]1[CH:41]=[N:40][C:39]([NH:42][O:43][CH3:44])=[N:38][C:37]1=[O:45]>CC#N.CCOCC.CO.CN(C=O)C>[OH2:11].[CH3:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[C:30]=1[N:36]1[CH:41]=[N:40][C:39]([NH:42][O:43][CH3:44])=[N:38][C:37]1=[O:45]
Reactant: CONC(=N)NC(=O)Nc1c(C)cccc1C
Agent: COC(OC)N(C)C
Agent: CONc1ncn(-c2c(C)cccc2C)c(=O)n1
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Solvent: CC#N
Product: O

Procedure:
To a suspension of 10.9 g. (40.0 mmol) of 1-(2',6'-dimethylphenyl)-3-methoxyamidinourea in CH3CN (50 ml.) is added 9.5 g. (80.0 mmol) of DMF-DMA and the mixture heated at 105°-110° C. in a closed bomb for 11/2 hours. The reaction mixture is cooled and poured into a round bottom flask and the CH3CN removed under reduced pressure. The residue is partitioned between CHCl3 and H2O and the layer separated. The aqueous layer is extracted with CHCl3 (1×75 ml.). The combined organic layers are washed with H2O (1×50 ml.), dried (MgSO4) and concentrated under reduced pressure to give an oily residue. The residue is taken up in Et2O and washed with H2O (2×50 ml.). The Et2O layer is dried (MgSO4) and concentrated under reduced pressure to give a viscous oil. NMR shows that DMF has been removed. The oil is taken up in hot CH3CN cooled and a small amount of CHCl3, H2O and DMSO insoluble material filtered off. The filtrate is concentrated to give a viscous oil. TLC of the oil (Silicagel; 3% NH4OH, iPA) versus starting material shows one spot moves slower than starting material. Upon addition of MeOH and warming on a steam bath the oil solidifies. The solid is crystallized from MeOH to give 4.6 g. (43%) of 1-(2',6'-dimethylphenyl)-4-methoxyamino-1,2-dihydro-1,3,5-triazin-2-one as a white solid, melting point 78°-80° C.
Reaction SMILES: CC(O)=O.CC(O)=O.[CH:9]1[C:10]([NH:16]/[C:17](/[NH2:42])=[N:18]/[C:19](/[NH2:41])=[N:20]/[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[N:27]=[C:28](\[NH2:40])/[N:29]=[C:30](\[NH2:39])/[NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1.C[C@H]1C[C@@H](O)[C@H](C(C)C)CC1.O.OCC(CO)O>C(O)C.C(O)C(O)C>[CH:11]1[C:10]([NH:16][C:17]([NH:18][C:19]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:29][C:30]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[NH:39])=[NH:40])=[NH:41])=[NH:42])=[CH:9][CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: NC(=N\CCCCCC/N=C(N)/N=C(\N)Nc1ccc(Cl)cc1)/N=C(\N)Nc1ccc(Cl)cc1
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: CC(O)CO
Solvent: O
Solvent: CCO
Product: N=C(NCCCCCCNC(=N)NC(=N)Nc1ccc(Cl)cc1)NC(=N)Nc1ccc(Cl)cc1

Procedure:
A mouthwash (oral rinse) formulation of the present invention was prepared according to the following method. 7.5 g of Lecithin E-80, 625 mg of chlorhexidine diacetate, 525 mg of Tween-80, 250 mg of D,L-Menthol and 30 mg of alpha-tocopherol acid succinate were dissolved in mixture of 20 ml of absolute ethyl alcohol and 10 ml of propylene glycol. The resultant stock solution was mixed with vigorous stirring with 480 ml of distilled water and 10 g of pure glycerol was added as sweetener to obtain a suspension. The suspension was then filtered sequentially first through a 0.45 micron and then through a 0.22 micron PTFE membrane.
Reaction SMILES: C(OC(=C(C1C=CC(CC(C)C)=CC=1)C)C#N)(=O)C.[Cl-].[Na+:21].[OH-].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH2:36]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([CH3:50])[C:47]([OH:49])=[O:48])=[CH:42][CH:41]=1)[CH:37]([CH3:39])[CH3:38].[Na]>COCCOCCOC.O>[CH2:36]([C:40]1[CH:41]=[CH:42][C:43]([CH:46]([CH3:50])[C:47]([O-:49])=[O:48])=[CH:44][CH:45]=1)[CH:37]([CH3:39])[CH3:38].[Na+:21]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CC(=O)OC(C#N)=C(C)c1ccc(CC(C)C)cc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOCCOC
Product: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A portion of the enol-acetate solution (V) from A above, (55.41 g. representing 49.3 mmole of enol-acetate) was placed in a 250 ml. 1 necked flask and stirred magnetically while 10 ml. of saturated sodium chloride solution and 16.0 g. of 50 percent sodium hydroxide (200 meq.) were added. The mixture was stirred and allowed to cool to 25° C. and the ammonium persulfate [(NH4)2S2O8 ] (12.5 g.; 55 meq.) in 16 ml. of water were added over 10 minutes. After stirring overnight, 10 ml. of diglyme was added and the pH was adjusted from 9 to 13. The mixture was slowly cooled to 0° C. with seeding with crystals of 2-(4'-isobutylphenyl)propionic acid, sodium salt and held at 0° C. for 3 hours to form solid sodium 2-(4'-isobutylphenyl)propionate (VI) as a crystalline precipitate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[Sn].Cl.C([O-])(O)=O.[Na+]>O.C(O)C>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(O)c(N)c1

Procedure:
To a mixture of 5 g (30.5 mmol) of 4-hydroxy-3-nitrobenzonitrile, 18.1 g of powder tin metal (152.5 mmol, 325 mesh), and 45 mL of ethanol was added with stirring a solution of 10 mL of concentrated HCl in 30 mL of H2O. The suspension was heated at reflux for 45 min and the resulting hot solution was poured into 100 mL of H2O. Saturated aqueous NaHCO3 solution was slowly added to bring the pH to ca. 7. The suspension was filtered, and the residue was washed with MeOH giving the title compound (3.15 g, 77%) as a white powder. Rf (CH2Cl2/MeOH 9:1) 0.47; 1H NMR (CD3OD) δ 6.96 (d, 1H, J=1.3 Hz, H-2), 6.92 (d, 1H, J=8.1 Hz, H-6), 6.75 (d, 1H, J=8.1 Hz, H-5); 13C NMR (CD3OD) δ 151.1 (C-4), 138.6 (C-3), 124.7 (C-6), 121.6 (CN), 119.1 (C-2), 115.9 (C-5), 103.6 (C-1).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[OH-].[Na+].[F:54][B-](F)(F)F.F[B-](F)(F)F.O[N+]12CC[N+](F)(CC1)CC2.C(Cl)Cl>C(O)(=O)C.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:54])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: F[B-](F)(F)F
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O[N+]12CC[N+](F)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. The pH of the mixture was adjusted to 4.3 with 6N sodium hydroxide (approx. 12.5 mL) while the temperature was maintained below 20° C. 1-Hydroxyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (2.2 g, 6.813 mmole) was added and stirring continued for an additional 18 hours at 22° C. Methylene chloride (100 mL) was added, the solution placed in an ice bath while the pH of the mixture was adjusted to 9 with 6N sodium hydroxide (approx. 85 mL) and the temperature maintained below 20° C. Next, water (100 mL) was added, the layers separated and the aqueous layer washed an additional two times with methylene chloride (100 mL each). The methylene chloride serves as an extractant for the flurithromycin product. The combined organic phases were washed 2 to 4 times with 5% sodium hydroxide (100 mL each) and dried over magnesium sulfate. After filtration, the organic phase was concentrated under vacuum at room temperature to afford 4.6 g of crude flurithromycin. The crude material was dissolved in ethanol concentrated to 20 mL. This process was repeated two more times. After standing at 0° C. for one night, the product was filtered under vacuum, washed with 5 mL cold ethanol and dried under vacuum at 40° C. to afford 2.18 g (43% yield) of flurithromycin.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:5]2[C:6]3([CH3:10])[O:9][CH:7]3[CH2:8][CH:3]1[CH2:4]2.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:4][C:5]1[C:2]([CH3:1])([CH3:11])[CH:3]([CH2:8][CH:7]=[O:9])[CH2:10][CH:6]=1
Reactant: CC1(C)C2CC3OC3(C)C1C2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1=CCC(CC=O)C1(C)C
Temperature: 86 °C
Yield: 70.2 %

Procedure:
To a rapidly stirred refluxing suspension of 7.5 g (0.055 mole) of zinc chloride (anhydrous) in 1000 ml of benzene there was added 304 g (2.0 moles) of α-pinene epoxide over 1.0-1.25 hour period. The resultant mixture was heated at reflux (86° C) for 1.0-1.5 hours, cooled to 25° C and then poured into 400 ml of 5% sodium carbonate solution. The aqueous layer was drawn off and the benzene layer washed twice with 400 ml of brine. The solvent was removed and the oil fractionally distilled to give campholenic aldehyde: 193.2 g (70.2% yield), bp 51°-52° C (1.5 mm); nD20 1.4658; mol wt. 152 (ms); nmr, 0.8δ (3H, s), 1.0 (3H, s), 1.6 (3H, broad s, olefinic CH3), 2.1-2.6 (4H, broad complex), 5.2 (1H, broad multiplet, olefinic H), 9.7 (1H, doublet of doublets, J~3.5 + 1.5 Hz, aldehyde H); ir, 3020, 2700, 1714, 790 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:5]2[C:6]3([CH3:10])[O:9][CH:7]3[CH2:8][CH:3]1[CH2:4]2>[Br-].[Zn+2].[Br-].C1C=CC=CC=1>[CH3:4][C:5]1[C:2]([CH3:1])([CH3:11])[CH:3]([CH2:8][CH:7]=[O:9])[CH2:10][CH:6]=1
Reactant: CC1(C)C2CC3OC3(C)C1C2
Agent: [Br-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CC1=CCC(CC=O)C1(C)C
Yield: 80 %

Procedure:
According to this article, α-pinene oxide rearranged exothermically in the presence of zinc bromide catalyst in benzene solvent to give about 80% yield of alpha-campholenic aldehyde (Scheme 1). Since then, this batch process, or variations thereof, has been described in numerous publications and patents.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20](OC)=[C:21](O)[CH:22]=2)[N:17]=[CH:16][N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N1CCC[C@@H](O)C1)=O)(C)(C)C>ClCCl>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[N:15][CH:16]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 144.4 %

Procedure:
Diethyl azodicarboxylate (2.76 ml, 40% solution in toluene) was added to 4-chloro-6-hydroxy-7-methoxyquinazoline (0.89 g; prepared as described in Example 16), triphenylphosphine (1.66 g) and (3R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine (CAS Registry No 143900-43-0) (1.28 g) in dichloromethane (25 ml). The resulting solution was allowed to stir overnight at room temperature. This was purified by flash column chromatography eluting with an increasingly polar mixture of acetone/isohexane/triethylamine (79/20/1 to 64/35/1) to give 4-chloro-7-methoxy-6-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yloxy)]quinazoline as a white solid (0.794 g, 48%); Mass Spectrum: (M+H)+ 394.