Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.COCCOC.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])(O)=O.[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][N:29]1[CH:33]=[C:32]([C:2]2[C:3]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:4][C:5](=[O:14])[N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=2)[CH:31]=[N:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1cc(Oc2ccccc2)c(Br)nn1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2nn(-c3ccccc3)c(=O)cc2Oc2ccccc2)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
To a stirred mixture of 6-bromo-5-phenoxy-2-phenylpyridazin-3(2H)-one (see Example 2) (207 mg, 0.60 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) and degassed DME (9 mL), 1-methylpyrazole-4-boronic acid pinacol ester (150 mg, 0.72 mmol), and subsequently, a solution of NaHCO3 (102 mg, 1.2 mmol) in H2O (2.1 mL) were added. The reaction mixture was heated with vigorous stirring under Ar atmosphere at 80° C. for 12 h. The mixture was then evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (n-hexane:EtOAc=1:1) to yield the desired compound as a white crystalline solid (61 mg, 29%). Mp 195-197° C., 1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H, CH3), 6.10 (s, 1H, H-4), 7.20 (d, 2H, J=7.6 Hz, C6H5), 7.33-7.55 (m, 6H, 2×C6H5), 7.64 (d, 2H, J=7.6 Hz, C6H5), 8.03 (s, 1H, NCH), 8.11 (s, 1H, NCH) ppm.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:22])[CH2:20]O)=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:22][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH2:20][O:4]1
Reactant: OCC(O)c1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Clc1ccc(C2COC(CBr)(c3ccc(Cl)cc3)O2)cc1

Procedure:
a mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 9 parts of 1-(p-chlorophenyl)-1,2-ethanediol, 0.5 parts of p-toluenesulfonic acid and 80 parts of benzene is stirred and refluxed for 2 days with water-separator. The reaction mixture is cooled and washed successively twice with a sodium hydrogen carbonate solution and once with water. The organic phase is dried and evaporated. The residue is triturated in petroleum ether and cooled on ice. The precipitated product is filtered off, crystallized from methanol, stirred in acetonitrile while cooling on ice, filtered off again and washed once more with acetonitrile, yielding 2-(bromomethyl)-2,4-bis(p-chlorophenyl)-1,3-dioxolane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.[CH:12]1(I)[CH2:16][CH2:15][CH2:14][CH2:13]1>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: IC1CCCC1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(CCNC2CCCC2)cc1
Temperature: 25 °C
Yield: 194.7 %

Procedure:
4-Methoxyphenethyl amine (0.8 mL, 6 mmol), and cyclopentyl iodide (0.22 mL, 2 mmol) in CH3CN (5 mL) were irradiated for 10 min in a microwave at 110° C. After cooling to room temperature the mixture was diluted with CH2Cl2 and washed with NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane as eluent and the product N-(4-methoxyphenethyl)cyclopentanamine (0.854 g, 65%) was obtained as a colorless liquid which solidified upon standing. 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.10 (d, 2H, J=8.6 Hz), 6.78 (d, 2H, J=8.6 Hz), 3.74 (s, 3H), 3.69-3.65 (m, 1H), 3.08-3.07 (m, 4H), 1.84-1.83 (m, 2H), 1.82-1.81 (m, 2H), 1.66-1.56 (m, 4H). LC-MS (ESI) Calcd for: C14H21NO [M+H]+: 220.16. Found: 220.00.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[CH:8]1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: c1ccc(-n2cnc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncn2-c2ccccn2)C1
Yield: 21.6 %

Procedure:
A solution of 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (0.050 g, 0.25 mmol), 2-chloro-3-trifluoromethyl benzoic acid (0.056 g, 0.25 mmol), HATU (0.10 g, 0.26 mmol, and DIPEA (0.09 mL, 0.50 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3×10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (22 mg, 22%). 1H NMR (400 MHz, CDCl3) δ 8.52 (dd, J=4.9, 1.8 Hz, 1H), 8.02 (d, J=18.1 Hz, 1H), 7.92-7.71 (m, 2H), 7.58-7.40 (m, 2H), 7.37-7.28 (m, 2H), 5.12-4.78 (m, 1H), 4.51-4.19 (m, 2H), 3.97 (ddd, J=13.4, 12.7, 9.9 Hz, 1H), 3.61-3.45 (m, 1H), 3.27-2.82 (m, 2H). MS (ESI): mass calculated for C19H14ClF3N4O, 406.1. m/z found 407.1 [M+H]+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:12]([CH:14]([CH3:18])[C:15](O)=O)#[N:13].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH:9][CH2:15][CH:14]([C:12]#[N:13])[CH3:18])([CH3:5])([CH3:4])[CH3:3]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C#N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C#N)CN[C@@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of alanine tert-butyl ester hydrochloride (41.5 g, 228 mmol) in anhydrous dimethyl formamide (DMF, 35 mL) under argon was added triethylamine (35 mL) followed by 2-cyanopropionic acid (25 g, 252 mmol) and 1-hydroxybenzotriazole hydrate (HOBt, 40.5 g, 300 mmol). The resulting mixture was cooled to 0° C. and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 48.8 g, 255 mmol) was added. The mixture was stirred at 0° C. for 2 h followed by 12 h at 23° C. The solvent was removed in vacuo, and the resulting residue was suspended in 300 mL of ethyl acetate. The organic layer was extracted with saturated aqueous NaHSO4 and the precipitate that formed from the emulsion was filtered out. The organic layer was again extracted with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over anhydrous MgSO4 and concentrated to a viscous yellow oil. 1H NMR (CDCl3): δ 1.4 (dd, 3H, CH3—CH—NH—), 1.5 (s, 9H, (CH3)3), 1.6 (dd, 3H, CH3—CH—CN—), 3.5 (q, 1H, NH—CH—CO2Bu), 4.4 (m, 1H, CH3—CH—CN), 6.8 (s, 1H, NH).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][CH2:25][CH3:26])[N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[N:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[N:11]([CH2:24][CH2:25][CH3:26])[N:10]=[C:9]3[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(N3CCOCC3)c21
Agent: BrB(Br)Br
Product: CCCn1nc(-c2ccc(O)cc2)c2cccc(N3CCOCC3)c21

Procedure:
Prepared according to Method D step C from 3-(4-Methoxyphenyl)-7-morpholin-4-yl-1-propyl-1H-indazole (0.140 g, 0.4 mmol), BBr3 (0.076 mL, 0.8 mmol) to give title compound as a white solid which was recrystallized from ethyl acetate and hexane (0.05 g, 0.15 mmol, 37%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=O)[CH:11](Cl)[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:15][C:16]([NH2:18])=[S:17].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:18][C:16]1[S:17][C:11]([CH3:12])=[C:10]([C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:15]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOC)C(=O)C(C)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1nc(N)sc1C
Temperature: 40 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
A mixture of ethyl 2-methoxyimino-2-(2-chloropropionyl)acetate (16.0 g.), thiourea (8.2 g.), sodium acetate (8.9 g.), water (50 ml.) and ethanol (50 ml.) was stirred at 40° C. for 3 hrs. Ethanol was distilled off in vacuo from the reaction mixture. Diisopropyl ether was added to the aqueous solution and stirred. The resultant precipitates were collected by filtration to give ethyl 2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 3.1 g.). The diisopropyl ether layer was separated from the filtrate, washed with water and an aqueous solution of sodium chloride successively, dried over magnesium sulfate and then filtered. The filtrate was evaporated in vacuo and the oily residue was treated with n-hexane. The precipitates were collected by filtration and washed with a small amount of diisopropyl ether to give the same product (0.9 g.) as above. Total yield 4.0 g.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]12CCCN=C1C[CH2:30][CH2:29][CH2:28][CH2:27]2>C(#N)C=CC>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:29]([CH3:30])[CH2:28][C:27]#[N:26])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC=CC#N
Solvent: CC#N
Product: CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 55 °C
Reaction time: 17.5 h
Yield: 247.3 %

Procedure:
Into a 250 mL three-neck round bottom flask equipped with a stir bar, condenser, thermocouple and nitrogen inlet was charged 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo [2,3-d]pyrimidine (5, 10.3 g, 0.033 mol), 2-butenenitrile (36, 3.0 mL, 0.037 mmol, 1.12 equiv) and acetonitrile (100 mL, 2.0 mol) at room temperature. The resulting mixture was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.0 mL, 0.013 mol, 0.4 equiv) and was subsequently warmed to 55° C. The reaction mixture was stirred at 55° C. for 15-20 h. When LC/MS showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure to yield an orange oil. The crude product was then purified by flash column chromatography (SiO2, 40-80% ethyl acetate/hexane gradient elution) to afford 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (37, 12.3 g, 12.62 g theoretical, 97.5% yield) as a colorless oil, which solidified upon standing at room temperature in vacuo. For 37: 1H NMR (CDCl3, 400 MHz) δ ppm 8.84 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.39 (d, 1H, J=3.8 Hz), 6.79 (d, 1H, J=3.8 Hz), 5.67 (s, 2H), 4.77 (m, 1H), 3.53 (t, 2H, J=8.2 Hz), 3.05 (dd, 1H, J=16.8, 6.2 Hz), 2.98 (dd, 1H, J=16.8, 6.3 Hz), 1.79 (d, 3H, J=6.5 Hz), 0.91 (t, 2H, J=8.3 Hz), −0.068 (s, 9H); C19H26N6OSi (MW, 382.53), LCMS (EI) m/e 383 (M++H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[C@@:13]3([CH3:22])[CH2:14][CH2:15][CH2:16][C@:17]([C:19]([OH:21])=[O:20])([CH3:18])[C@@H:12]3[CH2:11][CH2:10][C:8]=2[CH:9]=1)[CH3:3].[N+](=[CH2:25])=[N-]>CO>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13]3([CH3:22])[CH:12]([CH2:11][CH2:10][C:8]=2[CH:9]=1)[C:17]([C:19]([O:21][CH3:25])=[O:20])([CH3:18])[CH2:16][CH2:15][CH2:14]3)[CH3:1]
Reactant: C=[N+]=[N-]
Reactant: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(C(=O)O)CCC[C@]21C
Solvent: CO
Product: COC(=O)C1(C)CCCC2(C)c3ccc(C(C)C)cc3CCC12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82242.3 %

Procedure:
Dehydroabietic acid (50 mg, 0.116 μmol, Helix Biotech) was dissolved in 2 ml of methanol (HPLC grade, Fisher Scientific) and cooled to 0° C. on ice in a round bottom flask. An excess (30 μmol) of ethereal diazomethane (obtained by distillation) was added and the reaction was stirred for 5 minutes. The non-reacted diazomethane was evaporated and solvent was then removed by rotary evaporation. This reaction is shown schematically in FIG. 4. The product was purified by preparative TLC (1000 μm PK6F 60 Å, Whatman) silica gel plates developed in hexane:ethyl acetate 95:5 (v:v, Rf: 0.25). This step provided 30 mg of a clear oil as the methyl ester that was pure by NMR (see FIG. 5). 1H NMR (CDCl3, 300 MHz) δ1.35-1.42 (m, 12H), 1.50-2.05 (m, 7H), 2.43 (t, J=8.80 Hz, 2H), 2.90-3.05 (m, 3H), 3.80 (s, 3H), 7.02 (s, 1H), 7.14 (d, J=8.19 Hz, 1H), 7.31 (d, J=8.19 Hz, 1H). The product also gave the following electron impact mass spectra: (%) 315 (2.9, M+1), 314 (13, M), 299 (16.4), 240 (20.1), 239 (100), 197 (6.1), 173 (5.0), 141 (5.7).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[C:20]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:9][C:8]=1[Cl:36])C.C1COCC1.[OH-].[Na+].Cl>O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[C:20]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:34][CH2:35]4)[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[C:11]([Cl:13])=[CH:12][C:7]=1[CH:6]=[CH:5][C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C=Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-acrylic acid ethyl ester (74 mg, 0.14 mmol, 1.0 equiv) in a 1:1 mixture of THF and water (2 mL) was added sodium hydroxide (11 mg, 0.28 mmol, 2.0 equiv; [CAS RN 1310-73-2]) and the reaction mixture heated by microwave irradiation to 100° C. for 10 min. The crude reaction product was taken up in water (50 mL), acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over MgSO4 and the product purified by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water yielding 21 mg (30%) of the title compound as a yellow viscous oil. MS (ISP): 509.9 [M+H]+.
Reaction SMILES: C([N:3]1[CH2:22][CH2:21][C@:10]23[C:11]4[C:12]5[O:20][C@H:9]2[C:8](=[O:23])[CH2:7][C@H:6]([CH2:24][CH3:25])[C@H:5]3[C@H:4]1[CH2:17][C:16]=4[CH:15]=[CH:14][C:13]=5[O:18][CH3:19])#N.[ClH:26]>>[ClH:26].[O:20]1[C@@H:9]2[C@@:10]34[CH2:21][CH2:22][NH:3][C@@H:4]([C@@H:5]3[C@@H:6]([CH2:24][CH3:25])[CH2:7][C:8]2=[O:23])[CH2:17][C:16]2=[C:11]4[C:12]1=[C:13]([O:18][CH3:19])[CH:14]=[CH:15]2
Reactant: CC[C@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C#N)[C@H](C4)[C@H]13
Agent: Cl
Product: CC[C@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN[C@H](C4)[C@H]13
Yield: 89 %

Procedure:
A suspension of 17-cyano-4,5α-epoxy-8β-ethyl-3-methoxymorphinan-6-one (4.30 g; prepared in Part B) in 100 ml 2 N HCl was refluxed for 4 hours. The solution was evaporated to a crystalline residue which was suspended in ethanol. After cooling, the crystals were collected and dried to give 3.95 g (89%) of product, mp. decomposes slowly above 260° C.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:7][C:8](Cl)([Cl:12])[C:9](Cl)=[O:10].C(=O)(O)[O-].[Na+].Cl>O.C(OCC)C.S([O-])([O-])(=O)=O.[Cu+2].[Zn]>[Cl:7][C:8]1([Cl:12])[CH:6]2[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5]2)[C:9]1=[O:10]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C1=CCCCC1
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOCC
Product: O=C1C2CCCCC2C1(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Copper (II) sulphate (2.0 g, 8.0 mmol) was dissolved in water (75 ml) and added to zinc dust (30 g). The mixture was stirred for 2 hours. The mixture was filtered and the solid collected, washed twice with acetone and dried under vacuum at 100° C. for 24 hrs. A portion of the activated zinc (8.0 g) was added to a solution of cyclohexene (10 ml, 98.9 mmol) in diethyl ether (180 ml). Trichloroacetyl chloride (10.48 ml, 93.96 mmol) in diethyl ether (20 ml) was added at such a rate to keep the mixture at reflux. After the addition was complete, the mixture was heated to reflux for 4 hrs. The mixture was cooled to room temperature, diluted with diethyl ether (50 ml) and carefully poured into an aqueous saturated solution of sodium bicarbonate. The mixture was acidified with 2N HCl and the organic phase separated. The ether extract was washed with water and then with saturated aqueous sodium bicarbonate. The organic phase was collected, dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (silica, EtOAc:Heptane 1:9) to give 8.62 g of the title compound as a clear oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:3])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].N([O-])=O.[Na+]>O.C(O)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([N+:24]([O-:26])=[O:25])[CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)cc1

Procedure:
To 8.7 g of N-(2, 6-diisopropylphenyl)-p-toluenesulfonamide (8.7 g) were added 6.3 ml of 60% nitric acid, 50 ml of water and 50 ml of acetic acid, then 0.18 g of sodium nitrite, and the resultant mixture was stirred under refluxing and heating for 5 hours. After cooling, the reaction mixture was mixed with 200 ml of water, and the precipitated crystals were filtered and recrystallized from 50 ml of ethanol to give 4.7 g of N-(2, 6-diisopropyl-4-nitropheyl)-p-toluenesulfonamide. This compound was hydrolyzed in aqueous sulfuric acid to give 2.7 g of 2, 6-diisopropyl-4-nitroaniline.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]=[CH:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:23]2[CH:24]=[CH:25][C@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:3]([CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:2]2=[O:1])(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)/C=C/C=O
Reactant: COc1ccc(S(=O)(=O)N=C/C=C/c2ccccc2)cc1
Product: COc1ccc(S(=O)(=O)N2C=C[C@H](c3ccccc3)[C@H](CC(=O)OC(C)(C)C)C2=O)cc1

Procedure:
The title compound was prepared according to the general procedure from tert-butyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-3-phenylprop-2-en-1-imine using 10 mol % 9 as the catalyst in 70% yield white solid. [α]D20 (c 1.07, CHCl3)=+90.4; mp=139-142° C.; 1H NMR (400 MHz, CDCl3) 8.03 (dd, 21-1, J=6.9, 2.1 Hz), 7.16-7.13 (m, 2H), 7.05-7.00 (m, 4H), 6.60 (dd, 2H, J=8.2, 1.0 Hz), 5.59 (dd, 1H, J=8.1, 6.6 Hz), 3.92 (s, 3H), 3.66 (t, 1H, J=6.9 Hz), 3.49-3.43 (m, 1H), 2.57 (dd, 1H, J=17.3, 6.1 Hz), 1.94 (dd, 1H, J=17.3, 7.5 Hz), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.0, 169.0, 164.3, 136.9, 131.4, 129.2, 128.9, 128.0, 127.8, 124.5, 114.2, 113.6, 81.1, 56.0, 44.2, 41.9, 32.5, 28.2; IR (thin film) ν 3086, 2976, 1715, 1594, 1496, 1364, 1264, 1167, 1080 cm−1; HRMS (ESI) calcd for C24H27NO6S [M+Na]+ 480.1451, found 480.1456; 97% ee (3S,4S)-isomer as determined by HPLC (AS-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=19.4 min, tr (3R,4R)=14.1 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].COCCN(S(F)(F)[F:31])CCOC>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:31])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(C#N)cc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C#N)cc2)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
Into a 250-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(4-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (compound 43.2, 5.00 g, 18.2 mmol) in dichloromethane (120 mL). The solution was cooled to −78° C. and Deoxo-Fluor® (bis(2-methoxyethyl)aminosulfur trifluoride) (5.99 g, 27.1 mmol) was added drop-wise. The resulting mixture was stirred for 1.5 h at −78° C., then carefully quenched with sodium bicarbonate (50 mL, 1 M). The organic layer was additionally washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50-1/30) as the eluent to yield 3.2 g (64%) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([NH:29][C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:28])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH:8]=1)[CH3:2].Cl.[OH-].[Na+]>C(O)C.O.[Fe]>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([NH:29][C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:28])[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH:8]=1)[CH3:2]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc([N+](=O)[O-])cc2)no1)C(=O)OCC
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(N)cc2)no1)C(=O)OCC
Yield: 45.1 %

Procedure:
A solution of 2-allyloxycarbonylamino-3-(3-{1-[(4-nitro-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester (2B) (565 mg, 1.13 mmol) and iron(0) powder (384 mg, 6.98 mmol) in ethanol/water (5 mL, 1:1) was heated to reflux. Hydrochloric acid, 1M, (0.29 mL, 0.29 mmol) was added drop wise and the reaction was heated at reflux for 45 minutes. It was then neutralized with 1M sodium hydroxide and filtered through celite. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on a Biotage Flash 40S column eluting with ethyl acetate/hexanes (6:1) to provide the title compound as a yellow oil (240 mg, 51%). MS (CI) m/z 471.0 (M+1)