Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)C>[C:11]1([C:10]2[C:3]3[C:2]([N:17]4[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Temperature: 140 °C
Yield: 101.4 %

Procedure:
4-Chloro-5-phenylthieno[2,3-d]pyrimidine (1.5 g, 6.1 mmol), piperidine-4-carboxylic acid (0.86 g, 6.7 mmol) and triethylamine (2.6 mL, 18 mmol) were suspended in dry ethanol (15 mL). The reaction was heated at 140° C. in a microwave for 10 min. The reaction was partitioned between water and DCM. The product was purified by column chromatography using a gradient of 10% methanol in DCM to 100% methanol to give the target compound as an off-white solid (yield=2.1 g). LCMS [M+H]+=440; RT=4.04 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[N:30][C:29]=1[C:38]([O:40]C)=[O:39].C(Cl)Cl.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>CS(C)=O.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[N:30][C:29]=3[C:38]([OH:40])=[O:39])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COC(=O)c1nnc2ccccc2c1Cl
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1noc(C)c1-c1cc(-c2c(C(=O)O)nnc3ccccc23)c2[nH]c(=O)[nH]c2c1
Temperature: 110 °C

Procedure:
A mixture of 6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (100.0 mg, 0.282 mmol) and methyl 4-chlorocinnoline-3-carboxylate (94.0 mg, 0.422 mmol) was treated with PdCl2dppf.CH2Cl2 (20.6 mg, 0.028 mmol) in the presence of 1,8-Diazabicycloundec-7-ene (DBU, 300.0 mg, 1.971 mmol, 7.0 equiv) in DMSO (1 mL) and water (1 mL). The reaction mixture was heated at 110° C. for 12 min in oil bath. The reaction mixture was purified by HPLC to give 4-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cinnoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: Cc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1ccc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 97.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.256 mmol) was dissolved in acetonitrile (8 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (133 mg, 1.02 mmol), acetic acid (0.307 mL, 5.12 mmol) and sodium triacetoxyborohydride (218 mg, 1.02 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-methyl-7-(1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (126 mg, yield 98%).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=O)(=O)OC.O.[NH2:29][NH2:30]>>[CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4]1[C:3]2=[N:29][N:30]=[C:20]([C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)[CH:19]=1
Reactant: COP(=O)(CC(=O)c1cccn1C)OC
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: Cn1cccc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
light brown amorphous solid. MS (EI): 267.2 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.CCO.O>[Fe].CC(O)=O>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a refluxing solution of 64A (5 g, 16.7 mmol), EtOH (100 mL), water (30 mL) and AcOH (15 mL) was added portion-wise Fe powder (5 g, 89 mmol) over 30 min. The mixture was heated for 1 h. before cooling to ambient temperature. and filtering through celite. The filtrate was concentrated in vacuo to afford 64B (2.7 g, 61%) as an oil. MS (ESI) m/z 271.2 (M+H)+.
Reaction SMILES: C[C:2]1[C:7](=[O:8])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][N:4]([OH:19])[C:3]=1[CH2:20][OH:21].[C:22](=O)([O-])[O-].[K+].[K+].[C:28]1([CH:34](Br)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH3:22][C:5]1[N:4]([O:19][CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:3]([CH2:20][OH:21])=[CH:2][C:7](=[O:8])[C:6]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(COc2cn(O)c(CO)c(C)c2=O)cc1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(C)n(OC(c3ccccc3)c3ccccc3)c(CO)cc2=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1 g of 6 methyl-5-p-methoxybenzyloxy-2-hydroxymethyl-1-hydroxy-4-pyridone in 60 ml of dimethylformamide were successively added 710 mg of potassium carbonate and 1.3 g of diphenylmethyl bromide. The mixture was stirred at room temperature for 17 hours. After completion of the reaction, the reaction liquid was concentrated and the concentrate was added to 20 ml of water and 40 ml of dichloromethane. The organic phase was washed with 20 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure. The concentrate was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (100 g) to give 1.35 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[OH:19]CC1C=CC2C=CC3C=CC=CC=3SC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:19])[C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: OCc1ccc2c(c1)Sc1ccccc1C=C2
Reactant: OCc1ccc2c(c1)Sc1ccc(F)cc1C=C2
Product: O=S1c2ccc(F)cc2C=Cc2ccc(CO)cc21

Procedure:
Repeat the process of Example 2, substituting an equivalent quantity of 8-fluoro-3-hydroxymethyldibenzo[b,f]thiepin for the 3-hydroxymethyldibenzo[b,f]thiepin to obtain the title product (m.p., 161°-163° C.).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([NH:13][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
416.5 mg (1.85 mmol) of tin(II) chloride dihydrate are added to a solution of 136 mg (0.37 mmol) of N-benzyl-4′-nitrobiphenyl-4-sulfonamide (Example 9A) in 2.0 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 117 mg (84.3% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15][OH:16])[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([C:29](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15][O:16][C:29]([C:28]2[CH:45]=[CH:46][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OC[C@H]1OC[C@H](OCc2ccccc2)[C@@H]1O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OC[C@H](OCc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of 1,4-anhydro-2-O-benzyl-D-ribitol (1.0 g, 4.46 mmol) in pyridine (20 mL, 247 mmol) was added 4,4′-dimethoxytrityl chloride (4.53 g, 13.38 mmol). The mixture was stirred at ambient temperature for 2 h. Solvent was then evaporated in vacuo, and the residue purified by flash chromatography using 25-30% ethyl acetate in hexane to obtain 1.65 g (3.13 mmol, 70%) of the pure product. LCMS: for C33H34O6 calculated 526.2. found 549.2 [M+H]+. 1H NMR (600 MHz, CD3CN) δ: 7.42, (m, 2H), 7.37 (m, 4H), 7.30 (m, 7H), 7.21 (tt, J=7.3, 1.1 Hz, 1H), 6.85 (m, 4H), 4.61 (d, J=3.4 Hz, 2H), 4.05 (dd, J=9.9, 4.7 Hz, 1H), 4.01 (m, 2H), 3.81 (m, 2H), 3.76 (s, 2H), 3.76 (s, 6H), 3.17 (dd, J=10.2, 3.2 Hz, 1H), 3.00 (dd, J=10.2, 5.0, 1H), 2.97 (s, 1H). 13C NMR (600 MHz, CD3CN) δ: 158.84, 130.21, 128.59, 128.27, 128.01, 127.88, 126.98, 117.53, 113.22, 82.73, 78.59, 72.28, 71.87, 70.21, 64.44, 55.11.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N)c(F)c1

Procedure:
To a solution of 41.6 g diethyl 2-(4-nitro-3-fluorophenyl)-2-methylmalonate III in 210 ml ethyl acetate in a 500-ml Parr hydrogenation bottle is added 830 mg (2 wt %) of 5% palladium/carbon. The mixture is hydrogenated in a Parr apparatus at 25° C. under 10-12 psi hydrogen for 2.5 hours. The catalyst is removed by filtration through diatomaceous earth (Celite®) and is washed with a few ml of ethyl acetate. The solvent is removed in vacuo to give diethyl 2-(4-amino-3-fluorophenyl)-2-methylmalonate as a viscous oil, 37.6 g [100% wt. yield]. This material is used without purification.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH:12]1[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:15][CH:14]([CH:22]([N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:13]1)([OH:11])=[O:10].C(N(CC)CC)C.O>CN(C)C=O>[CH2:1]([O:11][C:9]([CH:12]1[C:16]2([CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:15][CH:14]([CH:22]([N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[NH:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)O)C2(CCOCC2)S1)N1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCOCC2)S1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
3.3 g (0.019 mole) of benzyl bromide are added all at once to a solution of 4.62 g (0.01 mole) of the alpha isomer of tert-butyl 4-carboxy-alphaphthalimido-8-oxa-1-thia-3-azaspiro[4.5]decane-2-acetate in 50 ml of dimethylformamide, and then, over a period of 20 minutes, 1.32 g (0.013 mole) of triethylamine in 5 ml of dimethylformamide are added. The reaction mixture is gently stirred overnight at ambient temperature. The clear solution thus obtained is poured into a mixture of ice and water and then extracted with benzene. After washing the organic phase with a 5% aqueous solution of sodium hydrogen carbonate and then with water, it is evaporated to dryness. The residue obtained is recrystallized from diethyl ether to give 4.7 g (0.00085 mole) of tert-butyl 4-benzyloxycarbonyl-alpha-phthalimido-8-oxa-1-thia-3-azaspiro[4.5]decane-2-acetate (yield: 85.2% of theory); M.P. 168-169° C. Another synthesis with quantities 10 times larger gave a yield of 93.6% of theory.
Reaction SMILES: F[B-](F)(F)F.N#[O+].[CH2:8]([O:10][P:11]([CH:16]([NH:25][C:26]1[CH:31]=[CH:30][C:29](N)=[CH:28][N:27]=1)[P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9].[S-2:33].[Na+].[Na+]>C(Cl)Cl>[CH2:8]([O:10][P:11]([CH:16]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([SH:33])=[CH:28][N:27]=1)[P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]
Reactant: CCOP(=O)(OCC)C(Nc1ccc(N)cn1)P(=O)(OCC)OCC
Reactant: [S-2]
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(Nc1ccc(S)cn1)P(=O)(OCC)OCC
Reaction time: 3 h

Procedure:
To nitrosonium tetrafluoroborate (NOBF4) (22 mg, 0.19 mmol) in methylene chloride (6 ml) at room temperature is added [(5-amino-2-pyridinyl)aminomethylene]bis[phosphonic acid] tetraethyl ester (75 mg, 0.19 mmol). The reaction mixture is stirred 3 hours then concentrated under reduced pressure. The crude residue is dissolved in acetonitrile (6 ml) and sodium sulfide (46 mg, 0.19 mmol) is added. After stirring 12 hours at room temperature, the reaction is quenched by the addition of water and the mixture is extracted with methylene chloride. The organic extracts are combined and washed with 10% aqueous Na2S2O3. The organic extracts are then dried over sodium sulfate, filtered and concentrated under reduced pressure. The desired thiol is obtained by flash chromatography purification with 2% isopropanol in methylene chloride.
Reaction SMILES: [CH3:1][C:2](=[O:22])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:31]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C@@H:3]([C:2](=[O:22])[CH3:1])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5α-pregnan-2-ene-20-one (3.05 g) in 50 mL of chloroform was treated with m-chloroperbenzoic acid (50-60%, 4.0 g). The solution was stirred at room temperature overnight (14 h) under an argon atmosphere. The solution was diluted with more chloroform (250 mL), washed with dilute potassium bicarbonate solution (2×150 mL), with water (2×100 mL), and finally with brine, and dried over magnesium sulfate and evaporated to an oil which crystallized on standing. Flash chromatography on a silica gel bed (200 g) and eluting with hexane/ethyl acetate (90:10) recovered in fraction 67-110 (collecting 20 mL volumes) 1.194 g of the titled compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[C:14]([C:29]3C=CO[CH:30]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OC)=O)=C(O)C(CC)=CC=2)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[C:14]([CH2:29][CH3:30])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OS(=O)(=O)C(F)(F)F
Agent: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OS(=O)(=O)C(F)(F)F

Procedure:
Prepared by proceeding in a similar manner to Intermediate 123, starting from methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-hydroxybenzoate (Intermediate 110) as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]1(C)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[OH-].[K+].C(#[N:17])C>>[CH2:1]([NH:4][C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[NH2:17])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: CC#N
Reactant: Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: C=CCN[C@@H]1CCCC[C@H]1N
Temperature: 115 °C
Reaction time: 2 h

Procedure:
In a 75 ml pressure reactor equipped with a magnetic stirrer, 4.16 g racemic trans-2-(benzylidenamino)-cyclohexyl methanesulfonic acid ester (14.7 mmol) obtained according to (d) were dissolved in 20 ml of acetonitrile and the white-yellow solution was mixed with 4.50 ml of allylamine (59.2 mmol). The closed system was heated during 20 h at 115° C., then cooled to 0° C. and the viscous solution concentrated. 20 ml of toluene and 22 ml 4N HCl (88.2 mmol) were added and the two-phase mixture was vigorously stirred during 2 h and the two phases were separated. The aqueous phase was extracted with 20 ml of toluene. To the aqueous phase, 7.9 ml 50% aqueous potassium hydroxide solution (102.9 mmol) were added with vigorous stirring and the mixture was extracted with 20 ml of toluene. The brown organic phase was dried with 10 g sodium sulfate, filtered and washed with 10 ml of toluene. The solvent was removed in a rotary evaporator (45° C./60-10 mbar). The product was purified by high-vacuum distillation on a Diekmann evaporator at 34° C.-36° C./0.25-0.3 mbar to obtain 0.95 g of racemic trans-2-(allylamino)-cyclohexylamine as white viscous liquid was thus obtained.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13].CCN(CC)CC.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:13]([C:12]2[CH:14]=[CH:15][C:16]([CH3:17])=[C:10]([F:9])[CH:11]=2)[C:3]1=[O:4]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: Cc1ccc(N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2CCC(Br)C2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 2,4-dibromobutanoyl chloride (10 g, 38 mmol) in 100 mL of DCM at 0° C. under nitrogen was added 3-fluoro-4-methylaniline (5.21 g, 42 mmol) followed by Et3N (6.3 mL, 45 mmol). The mixture was stirred at rt for 2 h, then concentrated in vacuo. The residue was dissolved in diethyl ether, then hexanes was added and a solid precipitated. The solid was removed by filtration and discarded. The filtrate was then concentrated in vacuo to give a dry residue. To a solution of this residue in 100 mL DMF at 0° C. under nitrogen was slowly added 60% NaH (1.82 g, 45 mmol). The mixture was stirred and allowed to warm up to rt over 30 min. The reaction mixture was slowly poured into 400 mL of icewater and allowed to stand overnight. A solid formed, and was filtered off and dried, then purified via silica gel chromatography eluting with 0-50% ethyl acetate/hexanes to give racemic 3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (5.6 g, 20.6 mmol). LCMS (method U) RT 3.41 min, m/z 273.97 (M+H+). 1H NMR (500 MHz, chloroform-d) δ 7.50 (dd, J=11.7, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.23-7.17 (m, 1H), 4.60 (dd, J=7.0, 2.9 Hz, 1H), 4.03 (ddd, J=9.8, 7.9, 6.8 Hz, 1H), 3.82 (ddd, J=10.0, 7.7, 2.7 Hz, 1H), 2.75 (dq, J=14.6, 7.5 Hz, 1H), 2.48 (ddt, J=14.3, 6.7, 2.7 Hz, 1H), 2.28 (d, J=1.7 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14](OC)=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[C:18](=[O:30])[O:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][CH:23]=[C:22]([O:28]C)[CH:21]=2)C1C=CC=CC=1.Cl.[C:32](O)(=[O:34])C>>[OH:8][C:9]1[CH:14]=[C:13]([O:34][CH3:32])[CH:12]=[CH:11][C:10]=1[C:17]1[C:18](=[O:30])[O:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][CH:23]=[C:22]([OH:28])[CH:21]=2
Reactant: CC(=O)O
Reactant: COc1ccc2c(C)c(-c3cccc(OC)c3OCc3ccccc3)c(=O)oc2c1
Agent: Cl
Product: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)c(O)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-benzyloxy-3-methoxyphenyl)-7-methoxy-4-methyl-chromen-2-one (0.98 g, 2.44 mmol), prepared as in Example 4, in glacial acetic acid (8 mL) was treated with concentrated hydrochloric acid (3.5 mL) and the mixture stirred and heated to 60° C. for about 20 hours. Reaction monitoring by mass spectrum and thin layer chromatography revealed the presence of the starting material, so additional acetic acid (4 mL) and hydrochloric acid (3 mL) were added and stirring and heating continued for another 20 hours. The reaction mixture was then evaporated to dryness in vacuum and the residue diluted with water. The precipitated crystalline pinkish, solid, crude title compound was isolated by filtration, washed with water and dried. The resulting product was triturated with ether, filtered and washed with additional ether to yield the title product as a solid.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:11]([CH2:12][CH2:13][OH:14])[NH:10][C:9]1=[O:15])[C:2]1C=CC=CC=1.O1CCCCC1N1C(CCOC2CCCCO2)CC1=O>>[CH2:1]([C@H:8]1[C@@H:11]([CH2:12][CH2:13][OH:14])[NH:10][C:9]1=[O:15])[CH3:2]
Reactant: O=C1N[C@@H](CCO)[C@@H]1Cc1ccccc1
Agent: O=C1CC(CCOC2CCCCO2)N1C1CCCCO1
Product: CC[C@@H]1C(=O)N[C@@H]1CCO

Procedure:
Following the procedure described for the preparation of trans-3-benzyl-4-(2-hydroxyethyl)-2-azetidinone from 8-oxo-2,2-dimethyl-7α-benzyl-3-oxa-1-azabicyclo[4.2.0]octane and using 8-oxo-2,2-dimethyl-7β-ethyl-3-oxa-1-azabicyclo[4.2.0]octane one obtains cis-3-ethyl-4-(2'-hydroxyethyl)-2-azetidinone.