Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][S:12][C:13]1[CH2:14][C@@H:15]2[CH:32]([CH:33]([O:35][C:36](=[O:38])[CH3:37])[CH3:34])[C:31](=[O:39])[N:16]2[C:17]=1[C:18]([O:20]CC1C=CC([N+]([O-])=O)=CC=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:44]>O1CCOCC1.C(O)C.O.[Pd]>[CH2:1]([O:8][C:9]([CH2:11][S:12][C:13]1[CH2:14][C@@H:15]2[CH:32]([CH:33]([O:35][C:36](=[O:38])[CH3:37])[CH3:34])[C:31](=[O:39])[N:16]2[C:17]=1[C:18]([O-:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:44]
Reactant: CC(=O)OC(C)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC(=O)OCc3ccccc3)C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC(=O)OC(C)C1C(=O)N2C(C(=O)[O-])=C(SCC(=O)OCc3ccccc3)C[C@H]12

Procedure:
A solution of p-nitrobenzyl 2-benzyloxycarbonylmethylthio-6-(1-acetoxy)ethyl-carbapen-2-em-3-carboxylate (5.6 mg, 0.01 mmol) in dioxane (0.60 ml) is diluted with ethanol (0.05 ml) and water (0.35 ml) containing sodium bicarbonate (1.0 mg, 0.012 mmol). The solution is treated with 10% palladium on charcoal (5.5 mg) and hydrogenated at 40 psi for 30 minutes. The mixture is diluted with water (3 ml) and centrifuged to remove the catalyst which is washed with more water (2×1 ml). The combined aqueous supernatant is washed with ethyl acetate (4×2 ml), filtered through a cotton plug, concentrated in vacuo to ca. 1 ml, and lyophilized to yield the title compound as an amorphous solid: UV (0.1 M pH 7 phosphate buffer) 299 nm; NMR (D2O) δ1.30 (d, 3, J=6.7, CH3), 2.13 (s, 3, COCH3), 2.81 (dd, 1, J=9 and 18, H1a), 3.05 (dd, 1, J=10 and 18, H1b), 3.31 (dd, 1, J=3 and 5, H6), ~3.7(m, SCH2, obscured by impurities), 4.07 (m, 1, H5), 5.21 (m, 1, CHCH3), 5.27(s, 2, CH2 φ) and 7.48 (s, 5, C6H5); electrophoresis in 0.05 M pH 6.9 buffer at 2 KV for 20 minutes gives a single bioactive zone moving 3-5 cm toward the anode; HPLC on a C18Bondapak Reverse phase column using 10% THF/H2O at 1.0 ml/min gives a UV visible peak at retention time 17.4 mins (4.8 mins for thienamycin).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21]>CN(C)C=O.Cl[Cu]>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[C:14]=1[F:13]
Reactant: Oc1cccc(F)c1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 mmol, 1.70 equiv, 60%) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14.1 g, 99.93 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0° C. in 15 min. The resulting solution was stirred for 2 h at room temperature. CuCl (10 g, 101.01 mmol, 1.00 equiv) was added and a solution of 2,3-difluorophenol (15.6 g, 119.91 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100° C. in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8) to give 21.2 g (84%) of 1,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>ClCCl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10])[C:20](=[O:21])[CH2:19][Br:18]
Reactant: O=C(Br)CBr
Reactant: CNc1cccc(C)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(N(C)C(=O)CBr)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methyl-2,3-dimethylaniline S14 (4.6 g) and triethylamine (5.0 ml) were dissolved in dichloromethane (50 ml). 2-Bromoacetyl bromide (3.0 ml) in dichloromethane (30 ml) was added to the resulting solution under ice cooling and the solution was stirred for 2 hours at room temperature. The reaction mixture was washed successively with 1N HCl, water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, obtaining 8.4 g of the title compound as an oily substance.
Reaction SMILES: C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:23][C@H:22]1[C:24](O)=[O:25])=[O:20])[CH3:17].[BH4-].[Na+]>O1CCCC1.O>[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:23][C@H:22]1[CH2:24][OH:25])=[O:20])[CH3:17]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1C[C@H]1CO
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
Add isobutylchloroformate (0.41 mL, 3.16 mmol) and N-methylmorpholine (0.35 mL, 3.16 mmol) to a solution of (+/−)-trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (0.50 g, 3.161 mmol) in tetrahydrofuran (21 mL) at −50° C. Stir for 5 minutes and then filter into a slurry of sodium borohydride (0.084 g, 2.21 mmol) in tetrahydrofuran (9 mL) and cool to −50° C. Warm to room temperature over night and then add 9 mL of water. Remove tetrahydrofuran under reduced pressure and extract aqueous layer with diethyl ether (3×20 mL). Wash combined organic layers with saturated aqueous sodium chloride and dry over magnesium sulfate. Concentrate under reduced pressure and subject residue to silica gel chromatography eluting with 25-65% ethyl acetate in hexanes to provide the desired compound (0.224 g, 49.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
2.96 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 100 ml of ethanol and added at room temperature to 100 mg of 10% palladium-on-charcoal. The mixture was shaken at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was then removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether(1:2) for the elution. There were obtained 2.44 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 114°-115° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:15]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[N+:11]([C:8]1[C:9]2[O:10][CH2:15][O:1][C:2]=2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: ClCBr
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc([N+](=O)[O-])c2c1OCO2

Procedure:
14.2 g of 2,3-dihydroxy-4-nitrobenzaldehyde in 1000 ml of DMF is stirred with 57.6 ml of bromochloromethane and 50.6 g of cesium carbonate at 100° C. for 7 hours. The batch is added to 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed several times with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. The brown solid that is obtained is purified by column chromatography (silica gel, hexane/ethyl acetate 100:0→60:40). 7.4 g of 7-nitro-benzo[1,3]dioxole-4-carbaldehyde is obtained as a light yellow solid. The latter is mixed in 400 ml of acetone at 10° C. with a solution of 11.8 g of potassium permanganate in 190 ml of acetone/water (1:1). It was stirred for 10 hours, added to 2 N hydrochloric acid and filtered through diatomaceous earth. The acetone is removed in a vacuum, and the aqueous phase is made alkaline with sodium hydroxide solution. It is extracted with ether, and then the aqueous phase is acidified with hydrochloric acid. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 4.36 g of7-nitro-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brown solid, flash point 230-239° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([C:35]([OH:39])([CH3:38])[CH2:36][OH:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[OH:39][C:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:38])[CH2:36][O:37][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CC(O)(CO)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCC(C)(O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 17, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-propane-1,2-diol.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:33][C:32](=[O:34])[N:31]([CH3:35])[N:30]=2)=[CH:25][CH:24]=1>C(O)C>[NH2:12][C:11]1[O:34][C:32]2[N:31]([CH3:35])[N:30]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[C:33]=2[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[C:9]#[N:13]
Reactant: COc1ccc(C2=NN(C)C(=O)C2)cc1
Reactant: O=Cc1ccccc1
Reactant: N#CCC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nn(C)c3c2C(c2ccccc2)C(C#N)=C(N)O3)cc1
Reaction time: 0.02 h
Yield: 7.9 %

Procedure:
A mixture of benzaldehyde (290 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5(4H)-one (583 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 24 h. The crude material was purified by column chromatography (25% ethyl acetate in hexanes to 100% ethyl acetate), then re-crystallized from ethanol and washed with hexanes and ethanol to give 6-amino-3-(4-methoxyphenyl)-1-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (80.9 mg, 8%, 0.226 mmol) as a yellow solid. 1H-NMR (400 MHz) DMSO: 7.42-7.40 (d, 2H), 7.23-7.21 (m, 2H), 7.15-7.13 (d, 3H), 7.06 (s, 1H), 6.77-6.75 (d, 2H), 4.93 (s, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 13C-NMR (100 MHz) DMSO: 159.1, 159.0, 145.9, 144.8, 144.5, 128.8, 127.8, 127.7, 127.1, 125.8, 120.5, 113.9, 95.0, 59.9, 55.4, 38.2, 34.4; LC/MS-MS: 359.1→293.0 m/z; GS1 and GS2 at 30, DP=76, CE=31, CXP=20, tR=3.96 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH:14](O)=O.C=O.[OH-].[Na+]>O.C(OCC)C>[CH3:14][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: O=CO
Reactant: CC1CC(C)(C)NC2CCCCC12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1CC(C)(C)N(C)C2CCCCC12

Procedure:
1,2,2,4-tetramethyl decahydroquinoline was prepared. 36.3 grams (0.2 mole) of 2,2,4-trimethyl decahydroquinoline of about 58% cis structure was placed in a reactor vessel equipped for agitation. Formic acid, 20.2 grams (0.44 mole) was added dropwise to the reactor vessel followed by the slow addition of 17.4 grams of 38% by weight formaldehyde in water solution. After addition, the mix was refluxed at for 4 hours. A 5N sodium hydroxide solution was then added until the mix was basic. Diethyl ether was added and the mix separated out and the ether fraction obtained. The fraction was concentrated and then distilled using a 3 inch Vigreaux column to yield 5.4 grams of a product boiling at 70° C. at 0.6 mm Hg. The NMR spectra of the product was consistent with the desired product, 1,2,2,4-tetramethyl decahydroquinoline. The theoretical carbon, hydrogen, nitrogen analysis for the formula C13H25N is 79.92% carbon, 12.90% hydrogen, and 7.17% nitrogen while measured values were 77.23% carbon, 13.13% hydrogen, and 6.56% nitrogen.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Cl-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:15][C:11]2[O:10][C:9]([CH3:16])([CH3:8])[C:13](=[O:14])[CH:12]=2)=[CH:2]1
Reactant: O=Cc1ccoc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccoc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of 3-furaldehyde (1.26 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 11.9 mM) in ethanol (50mL), was added 1N aqueous hydroxide (1.2 mL, 1.2 mM). After the reaction solution was stirred for one day at room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was purified by chromatography (silica gel, hexane-ethyl acetate) to yield yellow crystals (1.8 g, 74% yield), m.p. 79°-80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5]2.C([Li])CCC.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.Cl>CCCCCC.C1COCC1>[CH2:11]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([B:28]([OH:29])[OH:27])[CH:3]=2)[CH2:7]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCC1Cc2ccc(Br)cc2C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Temperature: -70 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
In a 200 ml-reaction vessel, 3.16 g (1.02×10-2M) of 5-bromo-2-n-octylindan and 45 ml of dry THF were placed. To the mixture, 1.5M-solution of n-butyllithium in 7.2 ml of hexane was added dropwise in 20 minutes at -70° C. under argon atmosphere, followed by stirring for 2 hours at -70° C. To the above mixture, a solution of 4.14 g (2.20×10-2M) of triisopropylborate in 9 ml of dry THF was added dropwise in 20 minutes below -70° C., followed by stirring for 1 hour at the same temperature, gradual restoration to room temperature and further stirring for 20 hours. After the reaction, 15 ml of 10%-HCl aqueous solution was added dropwise to the reaction mixture to be decomposed under cooling, followed by extraction with ether. The ether layer was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent and purification by silica gel column chromatography to obtain 1.96 g of 2-octylindan-5-boronic acid (Yield: 70%).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[OH:22][S:23](O)(=[O:25])=[O:24].CN1[C@@H]2CC3=CC=C(O)C4O[C@H]5C(CC[C@@H]2[C@]5(C=43)CC1)=O.[OH-].[Na+]>CCO.CS(C)=O.O>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3=[CH:1][CH:2]=[C:3]([O:4][S:23]([OH:25])(=[O:24])=[O:22])[C:5]4[O:9][C@H:8]5[C:10]([CH2:12][CH2:13][C@@H:14]2[C@:7]5([C:6]=43)[CH2:21][CH2:20]1)=[O:11]
Reactant: O=S(=O)(O)O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 81 °C

Procedure:
A reaction flask was charged with morphine base (30.0 g, wet, 75% wt, 78.85 mmol), water (23 mL), and EtOH (60 mL). The reaction mixture was agitated to form a suspension. The reactor was flushed with nitrogen and the reaction mixture was kept under nitrogen throughout the reaction. The reaction flask was charged with H2SO4 (98%, 7.73 g, 78.85 mmol) and the catalysts (RuCl3.xH2O, 0.20 g). The reaction mixture was heated to reflux (80-82° C.) for 24 h. HPLC analysis indicated that 93% (area) hydromorphone was formed. The reaction mixture was cooled down overnight. DMSO (1.0 mL) was added to the reaction mixture and the mixture was heated at reflux for 1 h. The pH of the reaction mixture was adjusted the pH to 1.6 with 50% NaOH. EtOH (90 mL) was added to the mixture, which as cooled down to 15° C. for 1 h. The mixture was filtered, and the solid was washed with 95% EtOH (2×15 mL). The solid was dried under vacuum at 65° C. for 18 h to give 11.8 g of hydromorphone sulfate as solids (purity>99% area).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.[F:19][CH2:20][CH2:21]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:21][CH2:20][F:19])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CCF
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (400 mg, 1.311 mmol), 1-fluoro-2-iodoethane (684 mg, 3.93 mmol) and potassium carbonate (544 mg, 3.93 mmol) in DMF (4 ml) was heated under stirring for 3 h. The reaction mixture was cooled down and diluted with water (20 ml), the resulted mixture was extracted with DCM (3×20 ml). The combined organic phase was washed with water, brine, dried over sodium sulfate, concentrated to give the crude material which was purified by column chromatography eluted with ethyl acetate/cyclohexane 0-40% to give product 0.21 g. 1H NMR (500 MHz, CDCl3): 7.39-7.48 (m, 5H), 4.89 (s, 2H), 4.77 (t, 1H), 4.67 (t, 1H), 4.21 (t, 1H), 4.16 (t, 1H), LCMS (Method D): RT=1.24 min, M+H+=353.0.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[S:11][C:12](/[CH:15]=[CH:16]/[CH:17]([OH:19])[CH3:18])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[C:29]([O:19][CH:17]([CH3:18])/[CH:16]=[CH:15]/[C:12]1[S:11][C:10]([O:9][C:8]2[CH:20]=[CH:21][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=2)=[N:14][CH:13]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 7D (200 mg, 0.65 mmole) in dichloromethane (10 mL) at room temperature, was added triethylamine (750 μL) followed by acetic anhydride (300 μL, 3.2 mmole) and 4-(dimethylamino)pyridine (5 mg). The reaction mixture was stirred at room temperature, overnight and quenched with methanol for an hour. The solvent was evaporated in vacuum and the product was purified via silica column, using a gradient of 5-20% ethyl acetate in hexane. Yield of the clear oil, 165 mg (72.5%). 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=6.25 Hz, 6H) 1.35 (d, J=6.62 Hz, 3H) 2.06 (s, 3H) 4.40-4.63 (m, 1H) 5.35-5.50 (m, 1H) 5.73 (dd, J=15.81, 6.62 Hz, 1H) 6.57 (d, J=15.81 Hz, 1H) 6.84-6.96 (m, 2H) 7.07 (s, 1H) 7.12-7.22 (m, 2 H). Mass spectrum DCI 348 (M+H)+.
Reaction SMILES: I[C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH3:25])[C@:9]([CH3:24])([C:14]([NH:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:15])[C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)#[CH:29].C1COCC1>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.C(OCC)(=O)C>[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([C:28]#[C:29][C:2]2[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH3:25])[C@:9]([CH3:24])([C:14]([NH:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[O:15])[C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)=[O:35]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
TEA (10 mL) was added dropwise to a mixture of (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, 12 g), 4-ethynylbenzaldehyde (4.1 g), PdCl2(PPh3)2 (0.85 g), CuI (0.46 g), and THF (60 mL) at room temperature in a nitrogen atmosphere, and the mixture was stirred for 2 hours and 15 minutes at room temperature. Ethyl acetate (0.20 L), OH type silica gel (12 g), cellpure (5.9 g) and activated carbon (0.60 g) were added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (ethyl acetate/hexane=50/50, followed by gradient elution with chloroform/acetone=100/0→80/20). Then, ethyl acetate and IPE were added to the resulting solid, and the solid was filtered off and washed with IPE to obtain (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow brown solid) (9.0 g, 76%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]1)(=[O:4])=[O:3]
Reactant: COC(=O)C1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: 23 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
A solution of methanesulfonyl chloride (4.7 ml, 60 mmol) in 25 ml of CH2Cl2 was added dropwise with stirring to a solution of methyl 3-hydroxycyclopentanecarboxylate (6.5 g, 45 mmol) and triethylamine (9.0 ml, 65 mmol) in CH2Cl2 (65 ml) at 0° C. The solution was stirred at 23° C. for 24 h and then washed with water (3×50 ml). The washes were extracted with CH2Cl2 and the combined organic extracts were dried, treated with charcoal and filtered. The solvent was evaporated in vacuo to give the title compound as a yellow liquid, 9.1 g (91% yield), and as a mixture of isomers: ir (liq.) νmax : 1730 cm-1 ; 1Hmr (CDCl3) δ: 5.13 (m, 1H, H-3), 3.68 (2 Xs, 3H, CO2Me), 3.00 (s, 3H, SO3Me), 2.8 (m, 1H, H-1) and 2.4-1.7 ppm (m, 6H, CH2).
Reaction SMILES: [C:1](OCCCl)(=[O:5])[CH:2]([CH3:4])[OH:3].[C:10]([O:14][CH:15]([CH3:17])[CH3:16])(=[O:13])[CH2:11][OH:12]>C(OCC)C>[C:1]([O:12][CH2:11][C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)OCCCl
Reactant: CC(C)OC(=O)CO
Solvent: CCOCC
Product: CC(C)OC(=O)COC(=O)C(C)O

Procedure:
The efficacy of various enzyme preparations to catalyze the conversion of 0.25 M 2-chloroethyl lactate and 0.25 m isopropyl glycolate in ethyl ether to the title compound was determined after reaction for 24 hr with 0.5 g enzyme per 6.5 mL reaction mixture. Substituting Lipase AK, porcine pancreatic lipase, Lipase MAP10, Protease M, Lipase AP12, or Lipase G for Lipase P30, the relative values for conversion (Lipase P30 =100) were 104, 44, 40, 36, 29 and 26, respectively. In each case substitution of acetonitrile for ethyl ether resulted in a slight reduction in the rate of reaction.