Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:13]C(=O)CC1C=CC=CC=1[N+]([O-])=O)([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][C:2]([CH3:12])([NH2:13])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(CCCc1cccnc1)NC(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(N)CCCc1cccnc1
Yield: 77.8 %

Procedure:
A solution of 35.2 g of N-[1,1-dimethyl-4-(3-pyridyl)butyl]-2-nitrobenzeneacetamide in 250 mL of acetic acid was hydrogenated over 3.5 g of 10% Pd/C at atmospheric pressure and ambient temperature. The reaction was exothermic and stopped abruptly after the uptake of the theoretical amount of hydrogen (7.5 L). The catalyst was removed by filtration and the filtrate was heated at reflux for 90 minutes. After the solution was cooled, 10 mL of conc. HCl was added and the solvent was removed under reduced pressure. The residue was taken up in 1 L of water and extracted with ethyl acetate (4×200 mL) to remove the byproduct, oxindole. The aqueous layer was basified with 10N NaOH and extracted with dichloromethane to give, after evaporation of the dried (K2CO3) extracts 15 g of product. The material was distilled on a Kugelrohr apparatus (95° C.; 0.1 mm) to yield 14.3 g of alpha,alpha-dimethyl-3-pyridinebutanamine.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:17]C(=O)C)=[CH:12][C:13]=32)[CH2:6]1)=[O:4].C([O-])(O)=O.[Na+]>CO>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=[O:4]
Reactant: CC(=O)Oc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(N1CC2CC(C1)c1cc(O)ccc12)C(F)(F)F

Procedure:
Acetic acid 10-trifluoroacetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl ester (900 mg, 2.87 mmol) was stirred in methanol (20 mL) and saturated aqueous NaHCO3 solution (15 mL) for 48 hours. The mixture was concentrated, diluted with H2O and extracted with CH2Cl2 (3×20 mL) then dried through a cotton plug. Chromatography on Silica gel provided pure product (420 mg, 54%). (TLC 5% methanol/CH2Cl2 Rf 0.44). 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 1H), 6.70 (m, 1H), 6.62 (m, 1H), 4.32 (m, 1H), 3.84 (m, 1H), 3.48 (m, 1H), 3.21 (br s, 1H), 3.16 (br s, 1H), 3.09 (m, 1H), 2.38 (m, 1H), 1.97 (d, J=11.0 Hz, 1H).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[CH2:13]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])[CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:13]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](=[NH:22])[O:21][CH2:6][CH3:7])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1ccccc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCCOc1ccccc1C(=N)OCC
Reaction time: 20 h
Yield: 54.5 %

Procedure:
A solution of triethyloxonium fluoroborate (32.4 g., 0.171 mole) in methylene chloride (75 ml.) was added to a stirred solution of 2-n-butoxybenzamide [J. Pharm. Pharmacol., 4, 872 (1952) ](33.0 g., 0.171 mole) in methylene chloride 8200 ml.) at 25°. The mixture was stirred at 25° for 20 hours. The solution was concentrated to about one fifth of the original volume and then diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride-diethyl ether to give ethyl 2-n-butoxybenzimidate fluoroborate (28.7 g.), m.p. 82°-88°. To a stirred, cooled (ice-water) suspension of the fluoroborate (28.7 g.) in ethanol (75 ml.) was added 8% ethanolic ammonia (150 ml.). The mixture was stirred at 25° for 20 hours. The ethanol was removed and the residue partitioned between ether and 5N sodium hydroxide (100 ml.). The ether layer was washed with brine, dried over sodium sulfate, and then concentrated. A solution of the residual oil in ether was treated with hydrogen chloride to precipitate the title compound (16.8 g.), m.p. 150°-155°.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5]C=CC=1C.C1([OH:17])C=C(C)C=C(C)C=1.C=O.[C:20]([OH:25])(=O)[C:21]([OH:23])=[O:22]>COCCOCCOC>[OH:22][CH:21]1[O:23][CH2:1][C@@H:6]([OH:7])[C@H:5]([OH:17])[C@H:20]1[OH:25]
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc(C)cc(O)c1
Reactant: Cc1cccc(O)c1
Agent: C=O
Solvent: COCCOCCOC
Product: OC1OC[C@@H](O)[C@H](O)[C@H]1O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
M-cresol (162 g), 3,5-xylenol (110 g), diglyme (300 g), formaldehyde (37.3% in water, 348 g) and oxalic acid (0.54 g) were combined in a 2 liter flask and then heated at 95° C. for one hour. A mixture of m-cresol (162 g) and 3,5-xylenol (110 g) were added to the reaction mixture over one hour. Heating at 95° C. was continued for two hours. The volatile components were distilled away from the reaction mixture until the residue was at 200° C. Vacuum was applied slowly to the distillation until 35 mmHg and 220° C. were both reached and held for 15 minutes. The novolak resin in the reaction flask was then cooled to room temperature. RMW=10.2; DR=1.63.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH3:12].[Mg].CN(C)[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:12][O:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:16]=[O:17]
Reactant: COCCc1cccc(C)c1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCc1cccc(C)c1C=O
Temperature: 25 °C
Yield: 15 %

Procedure:
To a stirred solution of 2-(2-bromo-3-methylphenyl)ethyl methylether (1.5 g, 6.5 mmol) in anhydrous tetrahydrofuran (10 ml) was added magnesium (turnings) (0.16 g, 6.6 mmol). The mixture was refluxed in a nitrogen atmosphere until the reaction started and then stirred without heating for 15 min. The mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and N,N-dimethylformamide (0.7 g) was added and the mixture was stirred for 30 min. A saturated ammonium chloride solution (10 ml) was added and the mixture was stirred for 1 h. at room temperature. Toluene (20 ml) was added and the organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride as eluent to separate the lipophilic biproducts and methylene chloride/diethyl ether (7:3) as eluent to isolate (0.17 g, (15%) of the title compound as an oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:21](=[O:25])[CH:22](Br)[Br:23])=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[C:6]([CH3:26])=[CH:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.P(OCC)(OCC)=O>C1COCC1.CCOC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:21](=[O:25])[CH2:22][Br:23])=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:11]=2)[C:6]([CH3:26])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc(C)c2cc(C(=O)C(Br)Br)c(OCc3ccccc3)cc21
Agent: CCO[PH](=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)n1cc(C)c2cc(C(=O)CBr)c(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
The crude product 1-(1-acetyl-6-benzyloxy-3-methyl-1H-indol-5-yl)-2,2-dibromo-ethanone (0.42 g, 0.88 mmol) was suspended in THF (4 ml), followed by the addition of triethylamine (0.12 ml, 0.89 mmol) and (EtO)2P(O)H (0.137 ml, 0.88 mmol). After stirring overnight at room temperature, the reaction was diluted with EtOAc, washed with H2O, brine and dried over MgSO4. The solvent was removed in vacuo and the crude product purified by column chromatography in hexane/EtOAc (1:1) to give the product (0.039 g, 11%). LC/MS: RT=2.830 min. 400/402 (MH+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][S:12][C:13](=[O:22])[C:14]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[O:15]>O>[CH3:11][S:12][C:13](=[O:22])[C:14]([C:16]1[N:17]=[C:18]([NH:21][CH:1]=[O:3])[S:19][CH:20]=1)=[O:15]
Reactant: CSC(=O)C(=O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: CSC(=O)C(=O)c1csc(NC=O)n1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of 40.8 g of acetic anhydride and 8.4 g of formic acid was stirred at 40° to 45° C. for 1 hour. To the resulting mixture was added 20.2 g of 2-(2-aminothiazol-4-yl)thioglyoxylic S-acid metyl ester, with water-cooling, after which the resulting mixture was stirred at 25° C. for 1 hour. Subsequently, 60 ml of water was added dropwise to the thus obtained reaction mixture with ice-cooling, after which the resulting mixture was stirred with water-cooling for 30 minutes, and the deposited crystals were collected by filtration. The crystals were washed successively with water and acetone and then dried to obtain 21.9 g (94.4% yield) of 2-(2-formylaminothiazol-4-yl)thioglyoxylic S-acid methyl ester having a melting point of above 230° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH:41]1[CH2:45][C@@H:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43][C@@H:42]1[C:50]([O:52][CH3:53])=[O:51]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([N:41]4[CH2:45][C@@H:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43][C@@H:42]4[C:50]([O:52][CH3:53])=[O:51])=[O:21])=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: COC(=O)[C@@H]1CN[C@@H](C(=O)OC)C1
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)s1)C2
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](C(=O)OC)N(C(=O)c2ccc(CCC3CNc4nc(N)nc(O)c4C3)s2)C1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a sample of 225 mg (0.70 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarboxylic acid in a three-necked round bottomed flask under an atmosphere of nitrogen were added 3.5 mL anhydrous dimethylformamide and 0.08 mL (0.72 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature and 135 mg (0.77 mmol) 2-chloro-4,6-dimethoxy-1,3,5-triazine were added at once. The reaction was stirred for 0.5 hours at room temperature, and 213 mg (1.14 mmol) of trans-dimethyl pyrrolidine-2,4-dicarboxylate were added in 1.0 mL of dimethylformamide. After stirring at room temperature for another 3.5 hours, the reaction was concentrated in vacuo and chromatographed on silica gel with 2-8% CH3OH/CHCl3 to give 185 mg (54%) of trans-dimethyl 1-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]thien-2-ylcarbonyl}pyrrolidine-2,4-dicarboxylate as a tan solid. Mass Spectrum (FAB+): M+1=490; 1H NMR (300 MHz, DMSO) δ: 1.54-1.64 (m, 3H); 1.76-1.84 (m, 1H); 2.11-2.29 (m, 3H); 2.36-2.43 (m,--1H); 2.72-2.79 (m, 1H); 2.86-2.88 (m, 2H); 3.07-3.23 (m, 2H); 3.61 (s, 6H); 3.95-4.08 (m, 2H); 4.49-4.54 (M, 1H); 5.92 (s, 2H); 6.24 (d, J=1.6 Hz, 1H); 6.91-6.92 (m, 1H); 7.48 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14]O)=[CH:10][C:9]([C:16]([F:19])([F:18])[F:17])=[CH:8][CH:7]=2)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:43]C(Br)(Br)Br>C1COCC1>[Br:43][CH2:14][CH2:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[NH:5][C:4]=1[Si:3]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:1][CH3:2]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCBr
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A solution 2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl)ethanol (0.730 g; 2.13 mmol) in THF (6 mL) was added to a solution of triphenylphosphine (0.836 g; 3.19 mmol) and perbromomethane (1.06 g; 3.19 mmol) in THF (12 mL) pre-stirred for 1 hour. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 5 to 40% ethyl acetate in heptane) to afford 0.449 g (52%) of the title compound as a yellow oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]([C:12]1([C:23]([OH:25])=[O:24])[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCOCC1>[O:2]=[C:1]1[O:24][C:23](=[O:25])[C:12]2([CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)[N:5]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)O)CC1
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC2(CC1)C(=O)OC(=O)N2c1ccccc1
Reaction time: 0.5 h

Procedure:
Phosgene gas is introduced through a stirring mixture of 29.2 parts of 4-anilino-1-(ethoxycarbonyl)isonipecotic acid in 240 parts of dioxane; exothermic reaction (temperature rises to 45° C). Stirring is continued for 30 minutes at 45° C. The mixture is heated to reflux and phosgene gas is gently introduced for 2h.30. Then nitrogen gas is introduced for 30 minutes. The reaction mixture is evaporated in a boiling water-bath for 30 minutes. The solid residue is triturated in ether, yielding ethyl 2,4-dioxo-1-phenyl-3-oxa-1,8-diazaspiro [4,5]decane-8-carboxylate; mp. 210.7° C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][NH:6][CH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1.C(N(CC)CC)C>>[CH3:5][N:6]([CH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1)[C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CNC1CCSCC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Cl)C1CCSCC1

Procedure:
Similarly to the method described in intermediate 1.2, 22.8 g (0.23 mol) of phosgene, 10 g (76 mmol) of methyl(tetrahydro-2H-thiopyran-4-yl)amine and 7.8 g (76 mmol) of triethylamine were reacted. Yield 13.4 g. MS (m/z): 193 [M]+, 158 [M−Cl]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[C@@H:11]([O:23]CC1C=CC(OC)=CC=1)[C:12]([O:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:34])[C@@H:11]([OH:23])[C:12]([O:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C(=O)O[C@@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C[C@H](OC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCCl)c1ccccc1
Yield: 93.1 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19, (1S)-1-phenylethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (35a) (0.42 g, 0.82 mmol), dissolved in a mixture of dichloromethane (DCM) and water (10:1) (3 mL), was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (220 mg, 0.98 mmol). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:1) to provide 300 mg (93% yield) of the title compound (35b) as a colorless oil. Rf=0.39 (EtOAc/Hex=1:2). 1H NMR (400 MHz, CDCl3): δ=1.02 (s, 3H), 1.19 (s, 3H), 1.64 (d, J=6.4 Hz, 3H), 2.30-2.37 (m, 2H), 3.01 (d, J=5.6 Hz, 1H), 3.30-3.33 (m, 2H), 3.67-3.70 (m, 2H), 4.02-4.04 (m, 2H), 4.20 (d, J=9.2 Hz, 1H), 6.02 (q, J=6.8 Hz, 1H), 7.36-7.38 (m, 5H) ppm. MS (ESI) m/z: 414.09 (M+Na)+. The analytical data was consistant with the proposed structure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=[O:21].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C@:38](OS(C)(=O)=O)([CH2:44][CH2:45][CH2:46][CH3:47])C(OCC)=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:44][CH2:45][CH2:46][C@H:47]([NH:1][C@@H:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:3]2=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCC[C@](OS(C)(=O)=O)(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H]1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 49.1 %

Procedure:
A mixture of 0.32 g of tert-butyl (RS)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 0.2 g of ethyl (R)-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate is heated at 90° C. for 30 minutes. After cooled, the mixture is separated and purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give 0.14 g of tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as colorless oil from the first fraction.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]([NH2:17])[C:14]([Cl:18])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>C(Cl)Cl>[NH2:17][C:15]1[CH:16]=[C:7]([OH:6])[C:8](=[CH:13][C:14]=1[Cl:18])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cc(O)c(C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A 0.1 molar solution of boron tribromide in methylene chloride (600 ml) is added to a stirred suspension of methyl 2-methoxy-4-amino-5-chlorobenzoate (37 g) in methylene chloride (500 ml). After stirring for 20 hrs, the mixture is poured into ice water, and the precipitate remaining in the reaction container is washed in the ice water mixture with a solution of 5.5N NaOH (600 mls). The aqueous layer is separated and acidified to pH3. The resulting precipitate is filtered, washed with water and dried affording 4-amino-5-chlorosalicylic acid which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([F:26])[CH:3]=1.[OH-].[Na+].[NH2:29]O.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([F:26])[CH:3]=1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 47.1 %

Procedure:
Cis-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.31 g, 5.99 mmol) was dissolved in MeOH (24 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.761 mL, 5.99 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.367 mL, 5.99 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30.8 mL, 185.01 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1 g, 47%) was isolated after. MS m/z 355 (M+H)+
Reaction SMILES: [CH3:1][P:2]([O:6][CH3:7])(=[O:5])[O:3][CH3:4].C([Li])CCC.[C:13]([Si:17]([CH3:28])([CH3:27])[O:18][CH2:19][C:20](OCCCC)=O)([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([Si:17]([CH3:28])([CH3:27])[O:18][CH2:19][CH2:20][CH2:1][P:2](=[O:5])([O:6][CH3:7])[O:3][CH3:4])([CH3:16])([CH3:15])[CH3:14]
Reactant: COP(C)(=O)OC
Reactant: CCCCOC(=O)CO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CCCO[Si](C)(C)C(C)(C)C)OC
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Dimethyl methanephosphonate (70 ml; 634.8 mmol) was placed in tetrahydrofuran (1.6 l) at −75° C. and treated at this temperature with 1.6M n-butyllithium in tetrahydrofuran (437 ml; 700 mmol). After 1.5 hours at −75° C. n-butyl (t-butyl-dimethyl-silanyloxy)-acetate (52.1 g; 211.6 mmol) in tetrahydrofuran (110 ml) was added and the batch was stirred for 2 hours at −30° C. The reaction mixture was subsequently poured into 1N ice-cold aqueous hydrochloric acid (800 ml) and extracted rapidly with ethyl acetate (2×1 l). The combined organic phases were washed in succession with water (2×1 l) and saturated aqueous sodium chloride solution (500 ml), dried over magnesium sulphate and concentrated. The residue was azeotroped with toluene (2×300 ml) and distilled (b.p.: 89-95° C.; 0.42 mm Hg). Yield: 57.2 g (92%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]([OH:10])=O)=[CH:4][C:3]=1[CH3:17].[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][NH2:25].C1C=CC2N(O)N=NC=2C=1.C[N+]1(C)[C@H]2CC3C=CC(O)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.CCN=C=NCCCN(C)C>ClCCl.O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][NH:25][C:8](=[O:10])[CH:7]([CH2:6][C:5]1[CH:15]=[CH:16][C:2]([F:1])=[C:3]([CH3:17])[CH:4]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(Cc1ccc(F)c(C)c1)C(=O)O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: C[N+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@@H]1C5
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCCC(Cc1ccc(F)c(C)c1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 64 h
Yield: 60 %

Procedure:
To a solution of 2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid (0.498 g, 2.091 mmol), O-(tetrahydro-pyran-2-yl)-hydroxylamine (0.735 g, 6.274 mmol), HOBT (0.282 g, 2.091 mmol), and N-methyl morphine (1.058 g, 10.455 mmol) in 20 mL of dichloromethane, was added EDCI (0.601 g, 3.137 mmol). After stirring at room temperature under N2 for 64 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined and dried over anhydrous Na2SO4. After removing the solvents under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-40% ethyl acetate/hexanes to give the title compound as a pale yellow solid (0.423 g, 60% yield). LC-MS: tR=9.1 min; m/z 338 (M+H)+.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=3[OH:21])[C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COC(=O)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: BrCc1ccccc1
Product: COC(=O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1

Procedure:
57 g (200 mM) of methyl 3-(1-adamantyl)-4-hydroxybenzoate are treated with benzyl bromide under the conditions described in Example 5(a) to lead to 69.5 g (92.4%) of the expected derivative, of melting point 127° C.