Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH:18][CH2:19][C:20]12[CH2:27][CH2:26][C:23]([CH3:28])([CH2:24][CH2:25]1)[CH2:22][CH2:21]2.O>C(OCC)(=O)C>[S:7]([O:18][CH2:19][C:20]12[CH2:25][CH2:24][C:23]([CH3:28])([CH2:26][CH2:27]1)[CH2:22][CH2:21]2)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC12CCC(CO)(CC1)CC2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC23CCC(C)(CC2)CC3)cc1
Reaction time: 2 h

Procedure:
0.156 Mole of p-toluenesulfonyl chloride is dissolved in 150 ml. of anhydrous pyridine at 0° C, under nitrogen, and then 0.078 mole of 1-(hydroxymethyl)-4-methylbicyclo[2.2.2]octane is added slowly and the mixture then stirred for two hours. 2 Ml. of water is then added and the mixture stirred for five minutes and then poured into 600 ml. of ethyl acetate. The organic phase is washed twice with water, then washed with 2 Normal aqueous hydrochloric acid until no more pyridine remains. The ethyl acetate solution is then washed with aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate is then evaporated under vacuum affording 4-methylbicyclo[2.2.2]oct-1-yl methanol tosylate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:19][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
Methyl 6-methylnicotinate (1.05 g, 10 mmol) was dissolved in ethyl acetate (50 ml), and NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol) were added thereto. The reaction mixture was stirred at 80° C. for 3 hours, combined with an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give the title compound (682 mg, 28%) as an orange amorphous compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][OH:33]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH2:16][C:17]([NH:32][OH:33])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Yield: 93.1 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phthalimidopropanoic acid (1.50 g, 3.67 mmol), N,N′-carbonyldiimidazole (653 mg, 4.03 mmol) and hydroxylamine hydrochloride (308 mg, 4.43 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide as a white solid (1.45 g, 93% yield): mp, 169.0–171.0° C.; 1H NMR (DMSO-d6) δ 1.54–1.85 (m, 8H, C5H8), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.69 (s, 3H, CH3), 4.70–4.72 (m, 1H, CH), 5.67 (t, J=7.9 Hz, 1H, NCH), 6.87 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.79–7.87 (m, 4H, Ar), 8.78 (br s, 1H, OH), 10.58 (1H, NH); 13C NMR (DMSO-d6) δ 23.51, 32.17, 34.23, 50.19, 55.53, 79.57, 112.08, 114.16, 119.69, 123.11, 131.16, 131.20, 134.59, 146.73, 149.17, 166.01, 167.63; Anal Calcd for C23H24N2O6: C, 65.08; H, 5.70; N, 6.60. -Found: C, 64.73; H, 5.60; N, 6.53.
Reaction SMILES: [H][H].[CH3:3][C:4]1([CH3:20])[C@@H:6]([C:7]#[C:8][C:9](=[O:16])[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C@H:5]1[C:17]([OH:19])=[O:18].N1C2C(=CC=CC=2)C=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:3][C:4]1([CH3:20])[C@@H:6](/[CH:7]=[CH:8]\[C:9](=[O:16])[O:10][CH2:11][C:12]([F:15])([F:13])[F:14])[C@H:5]1[C:17]([OH:19])=[O:18]
Reactant: [H][H]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Yield: 64.5 %

Procedure:
500 mg of 10% palladium hydroxide on barium sulfate and 5 ml of ethyl acetate were placed in a round flask connected to a hydrogen apparatus and 2 g of the product of Step C, 45 ml of ethyl acetate and 0.5 ml of quinoline were added thereto. Hydrogenation was carried out until hydrogen absorption ceased and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water and evaporated to dryness. The 2 g of residue were chromatographed over silica gel and eluted with a 70-30-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 1.3 g of (1R,cis)2,2-dimethyl-3-[(Z)-3-oxo-3-(2,2,2-trifluoro-ethoxy)-1-propenyl]-cyclopropane-carboxylic acid.
Reaction SMILES: O=[CH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CCO>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]=[CH:2][CH:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(C=O)c1ccccc1
Reactant: Nc1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)C(C=Nc1ccc(Br)cc1)c1ccccc1

Procedure:
A solution of ethyl 3-oxo-2-phenylpropanoate (3.50 g, 18.2 mmol) and 4-bromoaniline (2.60 g, 15.1 mmol) in EtOH (25 mL) was stirred at room temperature overnight and concentrated to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:9](OC)[C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[NH2:26][NH2:27]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[C:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:27][NH:26][C:9]=3[C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: COc1c(/C=C/C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: NN
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.1 %

Procedure:
To a slurry of t-butyl(E)-3-(8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepin-4-yl)acrylate (prepared as described in Example 44 of WO94/29275 published Dec. 22, 1994) (0.81 g, 2.2 mmol) in methanol (5 mL) was added anhydrous hydrazine (0.14 g, 4.5 mmol) dropwise via syringe. The resulting bright yellow mixture immediately darkened to an orange color. After 45 minutes of stirring at room temperature, the reaction mixture became a thick yellow-orange slurry which was allowed to stir for an additional 18 hours. The reaction mixture was filtered to give a solid which was recrystallized from ethanol. Very little product was recovered and the filtrate was concentrated and purified with a silica gel plug using ethyl acetate:hexanes (50:50) as the eluent to give an orange oil. This was allowed to crystallize in ethanol at −10° C. for 18 hours, filtered and dried at 100° C. to give the title compound (0.2 g, 25%, m.p. 226.5-228.6° C.).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=4[F:40])[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:40][C:31]1[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:30]=1[C:22]1[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:21]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.43 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.23 g, 42%). MS (ISP) 548.1 [(M+H)+]; mp 192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 590.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=CC=1)O.[C:9]([O:12][CH:13]=[CH2:14])(=[O:11])[CH3:10]>>[C:9]([O:12][CH:13]=[CH2:14])(=[O:11])[CH3:10].[C:5]([OH:11])(=[O:6])/[CH:7]=[CH:8]/[CH3:1]
Reactant: Oc1ccc(O)cc1
Solvent: C=COC(C)=O
Product: C/C=C/C(=O)O

Procedure:
Polymerization is terminated when the degree of polymerization reaches 85%, by the introduction of 4 ml of an aqueous solution containing 0.008 g of hydroquinone. The vinyl acetate which has not yet reacted is eliminated by distillation. The crotonic acid which has not yet reacted is eliminated by washing of the resulting beads with water.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:30][CH2:31][OH:32])[CH2:5][CH2:6][CH2:7][N:8]([CH2:27][CH2:28][CH3:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH2:33](Br)CC.C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O>>[OH:1][CH2:2][CH2:3][N:4]([CH2:30][CH2:31][OH:32])[CH2:5][CH2:6][CH2:7][N:8]([CH2:27][CH2:28][CH2:29][CH3:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCN(CCC)CCCN(CCO)CCO
Reactant: CCCBr
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: CCCCCCCCCCCCCCCCCCN(CCCC)CCCN(CCO)CCO

Procedure:
In like manner, N,N-bis(2-hydroxyethyl)-N'-(n-propyl)-N'-octadecyl-1,3-propanediamine is prepared from n-propylbromide. Its picrate salt melts at 105°-106° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH:20][C:21]([N:4]1[CH2:5][CH2:6][NH:1][CH:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3]1)=[O:22]
Reactant: CCOC(=O)C1CNCCN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CN(C(=O)Nc2cc(Cl)cc(Cl)c2)CCN1
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a solution of ethyl 2-piperazinecarboxylate (0.9 g, 5.7 mmol) in chloroform (11 mL) was added 3,5-dichlorophenyl isocyanate (1.05 g, 5.7 mmol). The reaction was stirred overnight after which time a precipitate had formed. The reaction was concentrated and the solid was chromatographed on silica gel using ethyl acetate as eluant to provide 0.53 g (27%) of ethyl 4-[(3,5-dichloroanilino)carbonyl]-2-piperazinecarboxylate as an off white powder. Electrospray Mass Spec 346.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[N:22][C:21]([CH:24]2[CH2:27][CH2:26][CH2:25]2)=[C:20]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[N:23]=[N:22][C:21]([CH:24]3[CH2:25][CH2:26][CH2:27]3)=[C:20]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:32][CH:33]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCC2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCC3)nn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.66 mmol, 0.13 g) in anhydrous THF (0.5 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.88 mmol, 0.035 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.44 mmol, 0.15 g) in THF (0.5 mL). After completion of addition, the reaction mixture was warmed to 65° C. and stirred for 1 hour. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×3 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge eluting with a 10-30% ethyl acetate/hexanes gradient to give 4-[6-cyclobutyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.18 g).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[N:12]1([CH2:11][C:8]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Agent: O=C([O-])C(F)(F)F
Product: O=C(Cn1cnc2ccccc21)NCc1ccc(Cl)cc1

Procedure:
The title compound was synthesized according to a procedure described in Example 98 starting from 3-carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate (Example 92, Part B) and 4-chloro-benzylamine. Calculated for C16H14ClN3O m/z: 299.76, found 301.1 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:46])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccncc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3ccncc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (1.5 g, 2.92 mmol) (Intermediate 45) and N-methoxy-N-methylisonicotinamide.
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].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(=O)(O)[O-].[Na+]>[C:22]([O:4][C:3]1[CH:2]=[CH:1][C:17]2[CH2:16][C@H:15]3[N:18]([CH3:19])[CH2:20][CH2:21][C@:7]45[C:6]=2[C:5]=1[O:9][C@H:8]4[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]35)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 100 %

Procedure:
A modification of the method of Welsh (1954) was utilized. Morphine free base (1 am, 3.50 mmol) was suspended in saturated sodium bicarbonate solution (50 ml), and to the stirred suspension was added drop-wise an excess of acetic anhydride (1 ml, 10.6 mmol). The resulting solution was extracted with chloroform (6×10 ml) and the combined organic extracts were dried over anhydrous magnesium sulfate. Following filtration the solvent was removed by rotary evaporation under reduced pressure to afford 1.14 gm (100%) of 3O-acetylmorphine as a glassy white amorphous solid. The product was homogeneous by TLC (CHCl3:MeOH (9:1), Rf=0.85). Elemental Analysis Calcd. for C19H21NO4: C, 69.73, H, 6.42; N, 4.28. Found: C, 69.71;, H,6.40; N, 4.32.)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12][N:13]1[CH2:16][CH2:15][CH2:14]1)(=O)=O>CN(C=O)C>[N:1]([CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC(CCN1CCC1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CCN1CCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.4 1.50 g (23.1 mmol) of sodium azide are added to a solution of 2.00 g (7.43 mmol) of 3-azetidin-1-yl-1-phenylpropyl methanesulfonate in 50 ml of DMF, and the mixture is stirred at room temperature for 48 hours. The reaction mixture is partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated, and the residue is chromatographed on a silica-gel column with ethyl acetate/methanol as eluent: 1-(3-azido-3-phenyl-propyl)azetidine as colourless viscous oil; HPLC/MS 0.9 min; [M+H] 217.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.[ClH:26]>CCOC(C)=O>[ClH:26].[CH3:1][O:2][C:3](=[O:25])[C:4]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(Cc2ccccc2C)CCNCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-t-butoxycarbonyl-4-(2-methylbenzyl)-isonipecotic acid methyl ester (7.13 g, 20.5 mmol) in EtOAc (100 ml) at 0° C. was bubbled HCl gas until saturated. The reaction was stirred for 10 min at 0° C. and the solvent evaporated in vacuo to afford the product as a white solid.
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([CH:19]1[N:22]([C:23]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[P:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:53])[CH2:20]1)[CH:17]=[CH2:18]>O1CCCC1.CCCCCC>[CH2:16]([CH:19]1[N:22]([C:23]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[P:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:21](=[O:53])[CH:20]1[CH3:1])[CH:17]=[CH2:18]
Reactant: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC1C(C)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of N-isopropylcyclohexylamine (0.30 g) in dry tetrahydrofuran (5 ml) was stirred under argon and cooled to -78°. This was treated with a 2.5 M solution of n-butyl lithium in hexane (0.85 ml) and stirred for 10 minutes. A solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (9) (0.50 g) in tetrahydrofuran (5 ml) was added and after 5 minutes the anion was quenched by addition of methyl iodide (0.12 ml). After a period of 10 minutes the reaction vessel was transferred to an ice bath and a further 10 minutes later the reaction was neutralized by addition of acetic acid (0.16 ml). The solvent was then stripped off and the residue partitioned between ethyl acetate and brine. The ethyl acetate solution was separated, washed with brine and dried over sodium sulphate. The product was subjected to careful column chromatography on silica gel 60 eluting with cyclohexane/ethyl acetate mixtures grading from 1:1 to 3:7. This gave 4-allyl-3-methyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (38) (0.10 g, 19%); νmax (CHCl3) 3000, 1735 and 1610 cm.-1Running closely behind this was recovered starting phosphorane (9) (0.17 g. 33%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3=[CH:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]3([CH2:16][CH2:17][CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([O:19]C)[C:3]=1[Cl:21].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:10]2[C:9]3=[CH:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]3([CH2:16][CH2:17][CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([OH:19])[C:3]=1[Cl:21]
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)O2
Agent: Cl
Solvent: c1ccncc1
Product: CCCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,2-dichloro-3-methoxy-8-oxo-5a-propyl-5a,6,7,8-tetrahydrodibenzofuran (0.6 g) and pyridine hydrochloride (7 g) was heated with stirring at 190° for 1/2 hour then poured into ice water. The solid which separated was filtered, rinsed with water, dried and used in Step H without further purification.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17]O.[OH-].[Na+]>CO>[C:2]1([C:1](=[O:17])[CH:8]2[O:10][CH:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccccc1)C1OC1c1ccccc1
Reaction time: 0.33 h

Procedure:
To a mechanically stirred mixture of 83.2 g benzalacetophenone (0.3m), 1000 ml methanol and 120 ml 15% hydrogen peroxide was added 100 ml 2N sodium hydroxide solution, while maintaining the temperature below 30° by external cooling. After completed addition, the mixture was left standing at room temperature for 20 min. The crystalline precipitate was filtered off, washed with water and recrystallized from methanol. There were obtained 59.6 g 1,3-diphenyl-2,3-epoxy-1-propanone; m.p. 90° C.