Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10]C2CCC(=O)CC2)=[N:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]1[CH:4]1[CH2:9][CH2:8][CH:7]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:6][CH2:5]1
Reactant: O=C1CCC(Oc2noc3ccccc23)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3oc4ccccc4c3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(benzo[d]isoxazol-3-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:28])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C@H:10]2[C:11](=[O:13])[O:12][C@H:9]2[CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
In a four necked round bottom flask, Et3N (5.5 mL, 39.4 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(4-phenylbutoxy)carbonyl]amino}butanoic acid (3.9 g, 13.1 mmol) in dry CH2Cl2 (170 mL) under argon. After cooling at 0° C., HBTU (7.5 g, 19.7 mmol) was added and the mixture stirred 3 h at 0° C., then 3.5 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude was purified by typical silica gel automatic column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting pale yellow oil (0.61 g) was further crystallized from cyclohexane to afford the pure title compound, (0.23 g, 6%), as white solid. MS (ESI) m/z: 276.24 [M−H]−. FTIR (cm−1): 3312, 3060, 3026, 2942, 2861, 1826, 1694, 1545, 1337, 1269, 1126, 1023. 1H NMR (CDCl3): δ 1.45 (d, 3H); 1.66-1.70 (m, 4H); 2.63-2.66 (m, 2H); 4.09-4.18 (m, 2H); 4.83-4.89 (m, 1H); 5.36 (br d, 1H); 5.45 (m, 1H); 7.16-7.31 (m, 5H).
Reaction SMILES: CS(Cl)(=O)=O.[N:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([CH2:22][CH2:23]O)[CH:16]=[CH:15]2.C(N(CC)CC)C.S([O-])(=O)(=O)C.[CH3:37][C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1COCC1.C(#N)C.CO>[CH3:37][C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH2:23][CH2:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][N:6]=1)[CH:21]=[CH:20]2
Reactant: OCCc1ccc2cc(-c3cnccn3)ccc2c1
Reactant: C[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3cnccn3)ccc2c1
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (0.005 mL, 0.067 mmol, 1.2 equiv.) was added dropwise via a syringe to a stirred, 0° C. solution of 2-(6-pyrazin-2-yl-naphthalen-2-yl)-ethanol (Example 83A, 14 mg, 0.056 mmol) in anhydrous THF (10 mL) under a dry nitrogen atmosphere. Triethylamine (0.023 mL, 0.167 mmol, 3 equiv.) was then added. After 18 hours at −20° C., the reaction mixture was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. This crude mesylate (˜18 mg, 0.056 mmol), (2R)-2-methylpyrrolidine (190 mg, 2.237 mmol, 40 equiv.), and cesium carbonate (182 mg, 0.559 mmol, 10 equiv.) in anhydrous acetonitrile (5 mL) were stirred in a sealed tube at 40° C. for 62 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (97:3:trace dichloromethane/methanol/NH4OH). Fractions containing product were combined and concentrated under reduced pressure to provide the free base. This free base was dissolved in methanol and the solution was treated with HCl gas. The hydrochloride salt of the title compound was obtained on evaporation of solvent (4.5 mg, 23% yield). 1H NMR (CD3OD, 300 MHz) δ 9.29 (br s, 1H), 8.79–8.74 (m, 1H), 8.64 (br s, 1H), 8.58 (d, J=2 Hz, 1H), 8.24 (dd, J=2, 9 Hz, 1H), 8.03 (t, J=9 Hz, 2H), 7.90 (br s, 1H), 7.55 (dd, J=2, 9 Hz, 1H), 3.84–3.68 (m, 2H), 3.64–3.49 (m, 1H), 3.44–3.17 (m, 4H), 2.43–2.30 (m, 1H), 2.27–2.00 (m, 2H), 1.84–1.68 (m, 1H), 1.50 (d, J=7 Hz, 3H). MS (DCI-NH3) [M+H]+ at 318.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)([OH:14])N.Cl([O-])=O.[Na+].S([O-])(O)=O.[Na+]>C(Cl)CCl.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:11])[C:9]([OH:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C=O)c1ccc(I)cc1
Reactant: NS(=O)(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCCl
Solvent: O
Product: CC(C(=O)O)c1ccc(I)cc1
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
In 100 ml of ethylene chloride was dissolved 34 g of 2-(4-iodophenyl)propionaldehyde, and a solution of 16.5 g of sulfamic acid in 85 ml of water was added to the solution. A solution of 15.2 g of sodium chlorite in 22 ml of water was then dropped thereinto while keeping the solution at 10° to 15° C. The solution was stirred for 10 min, and 15 g of sodium hydrogen sulfite was added portionwise thereto. The organic layer was separated and then washed with water. To the organic layer was added 150 ml of 1 N aqueous sodium hydroxide solution, and the aqueous layer was then separated, after which the pH of the aqueous layer was adjusted to 3.0 with 6 N hydrochloric acid, upon which white crystals were precipitated. The crystals were collected by filtration, washed with water and then dried to obtain 34 g (yield 94%) of 2-(4-iodophenyl)propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 96%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2,2,2-trifluoroethanol (5.0 g, 50.0 mmol) and triethylamine (10.5 ml, 7.6 g, 75.0 mmol) in 25 ml of methylene chloride at -10° is added methanesulfonyl chloride (4.25 ml, 6.3 g, 55.0 mmol) over 20 min., maintaining the temperature at 0° to -10°. After addition is complete, the mixture is stirred at 0°-5° for 30 min. It is then poured into ice water and additional methylene chloride is added. The layers are separated, and the methylene chloride layer is washed with cold 10% HCl, with cold saturated sodium bicarbonate, with cold water until neutral, and with cold brine. The organic layer is dried over calcium sulfate with swirling and is filtered and the solvent is removed to give 2,2,2-trifluoroethyl methanesulfonate.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]1=O)=O)C.[O-]CC.[Na+].Cl.[CH:25]([NH2:27])=[NH:26]>CCO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2[C:4]([OH:3])=[N:27][CH:25]=[N:26][C:7]=2[CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: N=CN
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(O)ncnc2C1
Temperature: 70 °C
Reaction time: 5 h
Yield: 42.6 %

Procedure:
3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.6 g, 16.8 mmol) was dissolved in EtOH (90 mL), and sodium ethoxide (2.3 g, 33.6 mmol) and formamidine hydrochloride (2.0 g, 25.2 mmol) were sequentially added. The resulting suspension was heated to 70° C. and stirred for 5 hours, and then the reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in saturated ammonium chloride and extracted with ethyl acetate. The aqueous phase was adjusted to pH ˜5.5 using concentrated AcOH, and extracted several more times with ethyl acetate. The combined organic layers were sequentially washed with water and brine, dried, and concentrated to afford 4-hydroxy-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester as a brown solid (1.8 g, 42% yield). MS (ESI) m/e (M+H+)=251.28
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.S(Cl)(Cl)=O.[CH3:13][N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][NH:17][CH2:18]2.[OH-].[Na+]>COCCOC.C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:17]1[CH2:18][CH:19]2[N:14]([CH3:13])[CH:15]([CH2:21][CH2:20]2)[CH2:16]1)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: CN1C2CCC1CNC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CN1C2CCC1CN(C(=O)c1ccco1)C2

Procedure:
A mixture of 2-furoic acid (1.33 g, 11.9 mmol) and thionyl chloride (20 ml) was stirred at reflux for 2 hours. The mixture was evaporated and co-evaporated with toluene, 8-methyl-3,8-diaza-bicyclo[3.2.1]octane (1.5 g, 11.9 mmol) and 1,2-dimethoxyethane (40 ml) was added and was stirred at room temperature for 15 hours. Aqueous sodium hydroxide (50 ml, 1M) was added and the mixture was extracted twice with dichloromethane (2×40 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as a solid. Mp. 106° C. Yield 1.41 g (54%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](=[S:25])[NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:26](OC(OCC)CBr)[CH3:27]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]4[S:25][CH:26]=[CH:27][N:24]=4)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(N)=S)CCOCC3)cc2)CC1
Reactant: CCOC(CBr)OCC
Product: CC(C)N1CCC(Oc2ccc(C3(c4nccs4)CCOCC3)cc2)CC1
Yield: 74 %

Procedure:
The title compound (320 mg, 74%) was prepared from 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbothioamide and bromoacetaldehyde diethylacetal similarly to the procedure used for example 137. 1H NMR (400 MHz, CD3OD) δ 1.10 (d, 6H), 1.75-1.80 (m, 2H), 1.98-2.02 (m, 2H), 2.37-2.44 (m, 2H), 2.47-2.51 (m, 2H), 2.61-2.65 (m, 2H), 2.75-2.84 (m, 3H), 3.66-3.70 (m, 2H), 3.78-3.83 (m, 2H), 4.37 (m, 1H), 6.89 (d, 2H), 7.28 (d, 2H), 7.46 (d, 1H), 7.70 (d, 1H). RMS ESI+ m/z 387.2090 [MH]+. Microanalysis: Found: C, 67.42; H, 7.83; N, 7.08%. C22H30N2O2S. 0.2H2O requires C, 67.73; H, 7.85; N, 7.18%.
Reaction SMILES: C[Mg]Cl.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[O:11][C:10]([CH3:19])([CH3:18])[CH2:9][C:8]2=O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[O:11][C:10]([CH3:19])([CH3:18])[CH:9]=[C:8]2[CH3:21]
Reactant: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1Br)C(C)=CC(C)(C)O2

Procedure:
Following General Procedure C, methylmagnesium chloride (3 M in THF, 1.38 mL, 4.14 mmol) was added to a solution of 6-bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 588 mg, 2.07 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH3:14])[N:8]=[C:9]2O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[C:7]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:14])[N:8]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(F)cc2c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CN(c1ccc(O)cc1)c1cc2ccc(F)cc2c(Cl)n1
Temperature: 0 °C

Procedure:
A mixture of 4-[N-(7-fluoro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (2.08 g) and phosphorus oxychloride was heated under reflux for approximately 10 minutes at which stage a clear solution had been obtained. The mixture was cooled and poured into ice-water. The precipitated solid was collected and purified by column chromatography over silica gel (eluant dichloromethane/ethyl acetate; 90:10) to give 4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenol (2.00 g) as a yellow crystalline solid mp 130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>CO.[Pt]>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12]
Reactant: Cc1ccccc1OCc1ccccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: Cc1ccccc1OCc1ccccc1N
Reaction time: 8 h

Procedure:
75 g (0.308 mol) of 2-(2'-methylphenoxymethyl)-nitrobenzene (Example 2a) and 10 g of 5% strength Pt/C (platinum adsorbed onto active carbon) in 50 ml of methanol are stirred vigorously for two hours under an H2 atmosphere. Thereafter, a further 2 g of 5% strength Pt/C are added and stirring is continued overnight. The catalyst is then filtered off under suction and is replaced with 10 g of fresh catalyst. Stirring is continued overnight, the mixture is filtered under suction and the filtrate is evaporated down under reduced pressure. The residue is purified by column chromatography using hexane/ethyl acetate mixtures. 61 g (0.286 mol=93%) of the title compound are obtained as a colorless solid. mp.=56° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:20]([O:22][C:23]3[N:24]=[C:25]4[C:30](=[C:31]5[C:36]=3[CH:35]=[CH:34][CH:33]=[CH:32]5)[CH:29]=[CH:28][C:27]([F:37])=[CH:26]4)[CH2:21][C@H:15]2[C:14](=[O:38])[NH:13][C@:12]2([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][C@H:11]2[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN1CCOCC1.[CH3:52][C:53]1[O:57][N:56]=[C:55]([C:58](O)=[O:59])[CH:54]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.Cl>[F:37][C:27]1[CH:28]=[CH:29][C:30]2[C:25]([CH:26]=1)=[N:24][C:23]([O:22][C@H:20]1[CH2:19][N:16]3[C:17](=[O:18])[C@@H:3]([NH:2][C:58]([C:55]4[CH:54]=[C:53]([CH3:52])[O:57][N:56]=4)=[O:59])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][C@@H:11]4[CH2:39][C@@:12]4([C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:13][C:14](=[O:38])[C@@H:15]3[CH2:21]1)=[C:36]1[C:31]=2[CH:32]=[CH:33][CH:34]=[CH:35]1
Reactant: Cc1cc(C(=O)O)no1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-amino-2-(3-fluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1d, 1.11 g, 1.89 mmol) was dissolved in dimethylformamide (19 mL) and treated with N-methylmorpholine (0.73 ml, 6.6 mmol) followed by 5-methylisoxazole-3-carboxylic acid (0.264 g, 2.074 mmol) and HATU (0.860 g, 2.263 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with 2 N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with acetone/hexane, to provide the title compound (0.94 g, 72% yield).
Reaction SMILES: [S:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28]>C1COCC1>[F:26][C:27]([F:29])([F:28])[CH:6]([C:5]1[S:1][CH:2]=[N:3][CH:4]=1)[OH:7]
Reactant: O=Cc1cncs1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cncs1)C(F)(F)F
Yield: 68.9 %

Procedure:
The method described in Example 4 (step 4.5.) is followed. Starting from 2 g (17.68 mmol) of thiazole-5-carboxaldehyde, 0.88 ml (0.88 mmol) of a 1M solution of tetrabutylammonium fluoride in THF and 2.765 g (19.44 mmol) of trifluoromethyltrimethylsilane (TMS-CF3), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, gives 2.23 g of pure product in the form of a colourless oil.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32].CO.O>C(Cl)Cl>[Cl:29][CH2:30][C:31]([O:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[CH:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Testosterone (5 mmol) was dissolved in anhydrous methylene chloride (7.0 mL) and triethylamine (5 mmol) under argon. The solution was stirred for 30 minutes in an ice-bath. Chloroacetyl chloride (10 mmol) dissolved in anhydrous methylene chloride (3 mL) was added at 0° C. and stirring was continued for 30 minutes. The reaction was then allowed to warm to room temperature and was stirred overnight. The solution was washed with 0.05N hydrochloric aqueous solution (2×10 mL) and water (2×10 mL) and dried over sodium sulfate. It was concentrated under reduced pressure to give a brown solid. It was purified by silica gel column chromatography (Davisil grade 633, 200-425 mesh, 60 Å) using chloroform/petroleum ether (2:1) as an eluent to give a white solid. Yield, 1.23 g (67%); mp 125°-126° C. (124°-125° C., Molen et al., Steroids, 6, 195-214 (1965)); UV (MeOH/H2O, 1:1) λmax 246 nm (ε=1.521×104); 1H NMR δ0.81 (s, 3 H, CH3 -19), 1.15 (s, 3 H, CH3 -18), 0.82-2.50 (m, 19 H), 4.38 (d, 2 H, CH2Cl), 4.63 (t, 1 H, H-17), 5.63 (s, 1 H, H-4); MS (EI) Calcd. m/z for C21H29O335Cl 364.1805, found, 364.1804. Calcd. m/z for C21H29O337Cl 366.1776, found, 366.1776.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[N:6]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=1[C:10](O)=[O:11])[CH2:3][CH3:4].FC(F)(F)C(O)=O.N[C@@H](C1N(S(C2C=CC(C)=CC=2)(=O)=O)C=CC=1C(O)=O)CC.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[CH2:3]([C@@H:2]1[C:5]2[N:6]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=2[C:10](=[O:11])[NH:1]1)[CH3:4]
Reactant: CC[C@@H](N)c1c(C(=O)O)ccn1S(=O)(=O)c1ccc(C)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC[C@H]1NC(=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c21
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a solution of (R)-2-(1-aminopropyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with TFA (1:1) (505d, 5.64 g, 12.92 mmol) and DIEA (6.74 mL, 38.8 mmol) in EtOAc (50 mL) was added 1-propanephosphonic acid cyclic anhydride (50 wt. % in EtOAc, 7.69 mL, 12.92 mmol) dropwise via syringe. After 20 min, the reaction was judged complete by LCMS. The reaction was partitioned between sat'd NaHCO3 and EtOAc. The organic layer was washed with sat'd NaHCO3 once, sat'd NaCl once, and the organics were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give (R)-6-ethyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (505e, 3.49 g, 11.47 mmol, 89% yield) as an orange-brown foam. m/z (ESI, +ve) 305.1 (M+1)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([O:18]C)[CH:11]=2)[CH2:5]1)[CH2:2][CH3:3].[BrH:20]>>[BrH:20].[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:18])[CH:11]=2)[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CCCC(c2ccc(OC)c(OC)c2)C1
Agent: Br
Product: CCCN1CCCC(c2ccc(O)c(O)c2)C1

Procedure:
A mixture of 4 g of N-propyl-3-(3',4'-dimethoxyphenyl)-piperidine and 40 ml of 66% hydrobromic acid acid was refluxed for an hour and was then evaporated to dryness. The residue was crystallized from isopropanol to obtain 4.4 g of N-propyl-3-(3',4'-dihydroxyphenyl)-piperidine hydrobromide melting at 211° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O.[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:21]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:19][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCCOc1ccccc1-c1ccccc1

Procedure:
1-Chloro-6-(p-toluenesulphonyloxy)hexane (100 g), 2-hydroxybiphenyl (59 g) and potassium carbonate (60 g) were heated with stirring in dimethylformamide at 70° for 16 hours. The solution was cooled and added to water, then extracted with ether. The extract was washed with water, dried and evaporated, and the residue was chromatographed on silica gel (1800 g) eluting with 99:1 hexane; ethyl acetate, so as to afford the title compound as an oil.