Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])C.[Si:17]([O:34][CH2:35][CH:36]([OH:39])[CH2:37][SH:38])([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Si:17]([O:34][CH2:35][C@@H:36]1[O:39][C@@H:4]([CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[S:38][CH2:37]1)([C:30]([CH3:33])([CH3:31])[CH3:32])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](OCC(O)CS)(c1ccccc1)c1ccccc1
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1)OCC
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a solution of diethylphosphonoacetaldehyde diethylacetal (12.23 g, 48.1 mmol, 1.2 eq.) and t-butyldiphenylsilyloxy-3-mercapto-2-propanol (13.63 g, 38.1 mmol, 1.2 eq.) in toluene (500 mL) was added PTSA (0.73 g, 3.8 mmol, 0.1 eq.). The mixture was stirred at reflux for 72 hr and was cooled to room temperature. A saturated solution of sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane. The organic phase was dried with anhydrous magnesium sulphate and evaporated under reduced pressure. The crude material was purified by flash chromatography with ethyl acetate:hexane (2:1), and gave 16.31 g of the compound in a 87% yield.
Reaction SMILES: C[N:2]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CCOCC>[CH2:26]([O:25][C:23]([N:2]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CN1Cc2ccccc2C(Oc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)N1Cc2ccccc2C(Oc2ccc([N+](=O)[O-])cc2)C1

Procedure:
A mixture of 2-methyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline of Example 23 (6.0 g, 0.021 mole), ethyl chloroformate (2.9 g, 0.026 mole) and potassium carbonate (10 g) in benzene (100 ml) is refluxed for four hours. The reaction mixture is diluted with ether, washed with water, dilute HCl, again with water, then dried (saturated NaCl, anhydrous MgSO4). An analytical sample is twice recrystallized from hexanes/acetone (10:1) to yield 2-ethoxycarbonyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline, m.p. 118°-119° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.O[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][NH:29][C:28]3=[O:32])=[CH:23][C:6]1=2
Reactant: O=C1NCCN1CCO
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OCCN3CCNC3=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 1-(2-hydroxy-ethyl)-imidazolidin-2-one.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:16]>>[O:16]=[C:7]1[CH2:6][C:15]2[CH:14]=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1CCc2ccccc2C1
Product: O=C1CCc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To chlorosulfonic acid (4.5 mL, 68 mmol), cooled to 0° C. in an ice-bath, was added 2-tetralone (1.8 mL, 14 mmol) dropwise over 45 min. After stirring at 0° C. for 2 hours, the mixture was poured slowly into crushed ice (˜50 mL). After stirring for 1 hour, the mixture was extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with H2O (2×20 mL) and saturated brine (20 mL), dried (Na2SO4), and concentrated in vacuo to give 0.67 g (20%) of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl chloride as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.91 (d, 1H, J=8.1 Hz), 7.82 (s, 1H), 7.50 (d, 1H, J=8.1 Hz), 3.70 (s, 2H), 3.20 (t, 2H, J=6.6 Hz), 2.61 (t, 2H, J=6.6 Hz). The crude product was sufficiently pure and it was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]([OH:13])[CH2:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.O>O1CCCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:13][CH:10]2[CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:12][CH2:11]2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
A solution of (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.52 g) in anhydrous tetrahydrofuran (10 cc) is added at a temperature in the region of 20° C. to an oily suspension (50% by weight; 0.31 g), maintained under an argon atmosphere, of sodium hydride in anhydrous tetrahydrofuran (20 cc). The mixture is stirred for 30 minutes at the same temperature. A solution of 4-fluorophenyl isocyanate (0.9 g) in anhydrous tetrahydrofuran (10 cc) is then added dropwise and stirring is continued for 4 hours at a temperature in the region of 20° C. Distilled water (25 cc) is then added and the mixture is extracted with dichloromethane (3×50 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: ethyl acetate/cyclohexane (3:7 by volume)], collecting 20-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(4-fluorophenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (0.8 g), m.p. 158° C., is obtained.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCC=CCCC=CCCC1
Agent: [Pd]
Product: O=C1CCCCCCCCCCC1

Procedure:
50 g of cyclododeca-4,8-dienone (isomer mixture, fraction 2 from Example 4) and 1 g of Pd/C catalyst (10% by weight of Pd, commercially available from Degussa under the product number E 101 N/D) were introduced into a 100 ml autoclave. 5 bar of hydrogen were injected with stirring. At a reaction temperature of 50° C., further hydrogen was supplied (10 h) until no more hydrogen was absorbed. After cooling, decompressing and filtering off the catalyst, the effluent was analyzed by gas chromatography. The conversion of cyclododeca-4,8-dienone was quantitative. Cyclododecanone was obtained in a substantially quantitative yield (>98%). The only impurities which could be detected by GC-MS were traces of cyclododecane, cyclododecenone and dodecanal.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[CH2:22][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:8])[N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[O:3][CH:4]=[C:5]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[CH2:22][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:8])[N:6]=2)[CH2:31][CH2:32]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(N3CCOCC3)n2)C(COc2cccnc2)C1
Temperature: 25 °C
Yield: 125.8 %

Procedure:
A solution of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (117 mg, 0.277 mmol), morpholine (48 mg, 0.554 mmol) and potassium carbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was filtered and concentrated under reduced pressure. The material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient), yielding 165 mg (100%) of the title compound as the TFA salt. LC-MS: RT=6.60 min, [M+H]+=474.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:29])[N:10]([CH:17]1[CH2:22][CH:21]([O:23]C(=O)C)[C:20](=[O:27])[NH:19][C:18]1=[O:28])[C:11]2=[O:16])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:29])[N:10]([CH:17]1[CH2:22][CH:21]([OH:23])[C:20](=[O:27])[NH:19][C:18]1=[O:28])[C:11]2=[O:16])=[O:5]
Reactant: COCC(=O)Nc1cccc2c1C(=O)N(C1CC(OC(C)=O)C(=O)NC1=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1CC(O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-[4-methoxyacetylamino-1,3-dioxoisoindolin-2-yl]-2,6-dioxo-5-acetoxypiperidine (1.26 g, 3.5 mmol) and p-toluenesulfonic acid (0.33 g, 1.8 mmol) in methanol (20 mL) is heated at reflux for 5 hours. The solvent is removed in vacuo to give 3-[4-methoxyacetylamino-1,3-dioxoisoindolin-2-yl]-2,6-dioxo-5-hydroxypiperidine which is further purified by column chromatography.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][N:7]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[S:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:6][N:7]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CO)s1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cnc(C=O)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
MnO2 (1.5 g, 18.2 mmol) was added to a solution of Tert-butyl (2-(hydroxymethyl)thiazol-5-yl)carbamate (Intermediate AA, 700 mg, 3.04 mmol) in DCM (15 mL) and stirred at RT for 16 h. After completion reaction mixture was diluted with DCM, filtered through celite. The filtrate was concentrated under vacuum to afford Tert-butyl (2-formylthiazol-5-yl)carbamate (500 mg crude). The crude was carried to next step without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH:12]1[C:17]([C:18]([CH2:20]Br)=[O:19])=[CH:16][CH:15]=[C:14]([Br:22])[CH:13]=1.CCOC(C)=O>C(O)C.O>[Br:22][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:19])[CH2:20][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cccc(SCC(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
10.09 g (70.5 mmol) 3-mercaptoanisole were added to a freshly prepared solution of 4.6 g (70.5 mmol) KOH in 75 ml ethanol and 30 ml water. Over a period of 30 min, 20.0 g (70.5 mmol) 2,4-dibromoacetophenone in 150 EtOAc were added at 0° C. and the solution was stirred at RT over night. The suspension was concentrated and dissolved in EtOAc and water. The inorganic phase was extracted with EtOAC, the combined organic phases were washed with water and brine and dried over Na2SO4. Evaporation yielded 25.1 g (quant) 1-(4-Bromo-phenyl)-2-(3-methoxy-phenylsulfanyl)-ethanone as white crystalline, MS: 336 (M, 1Br). (In analogy to Jones, Charles D.; Jevnikar, Mary G.; Pike, Andrew J.; Peters, Mary K.; Black, Larry J.; Thompson, Allen R.; Falcone, Julie F.; Clemens, James A. Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity. J. Med. Chem. (1984), 27(8), 1057–66.)
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.Cl[CH2:40][C:41]1[N:45]=[CH:44][O:43][N:42]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:23][CH2:24][N:25]([CH2:40][C:41]3[N:45]=[CH:44][O:43][N:42]=3)[CH2:26][CH2:27]2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClCc1ncon1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1-c1cc(N2CCN(Cc3ncon3)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A mixture of 200 mg (0.373 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide (Example 53), 66 mg (0.56 mmol) 3-(chloromethyl)-1,2,4-oxadiazole and 62 mg (0.45 mmol) potassium carbonate in 4 ml acetonitrile was stirred at 45° C. for 1 h and at room temperature over night. The reaction mixture was diluted with 10 ml water and extracted with 3 30-ml portions of dichloromethane. Drying with sodium sulfate and concentration gave 244 mg of the crude product. Flash column chromatography afforded 80 mg (34.7%) of the title compound as a red-brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:24]([C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:29])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C(=O)C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
The mixture of 2-(2-isobutyryl-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (228) (170 mg, 0.43 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (20 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (229) as white solid (140 mg, 89%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:17][S:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of trans (4-methanesulfonyl-cyclohexyl)-carbamic acid tert-butyl ester (0.40 g, 1.40 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (5 mL) and the mixture was stirred at ambient temperature for 30 minutes then concentrated under vacuum. The residue was azeotroped with toluene (×2) and the resulting oil was triturated (diethyl ether) to provide a solid which was washed with ether and dried to give 386 mg (93%) of trans 4-methanesulfonyl-cyclohexylamine trifluoroacetic acid salt as a white solid. 1H NMR (400 MHz, DMSO) δ: 7.86 (s, 3H), 3.11-2.98 (m, 2H), 2.92 (s, 3H), 2.18-2.02 (m, 4H), 1.56-1.43 (m, 2H), 1.43-1.28 (t, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:59](Br)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) is suspended under argon in absolute DMF (50 mL) and the mixture is heated to 55° C. A solution of octyl bromide (35.8 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. and the mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture is extracted with ethyl acetate (3×40 mL). The combined organic fraction is dried (Na2SO4) and the solvent evaporated. The residue is purified by chromatography on a column (300 g) of silica gel. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.). The third fraction (di-substituted compound, trans-isomer) is eluted with toluene:ethylacetate (15:1 by vol.). The fourth fraction (di-substituted compound, cis-isomer) is eluted with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) is eluted with toluene:ethylacetate (5:1 by vol.). The solvent is removed under reduced pressure and the residue dried under high vacuum to give the product as a violet solid.
Reaction SMILES: [CH2:1]([N:7]([CH3:13])[C:8](=[O:12])[O:9][CH2:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH2:10][O:9][C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:13])=[O:12])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCCCCCN(C)C(=O)OCCl
Agent: [Na+]
Product: CCCCCCN(C)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 69.3 %

Procedure:
In the same manner as in step b) in Example 125, 206 mg of the title compound was prepared from 134 mg of chloromethyl N-n-hexyl-N-methylcarbamate and 217 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCc2nc(-c3ccccc3)no2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(OCc2nc(-c3ccccc3)no2)cc1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
The 5-[(4-nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.5 g, 1.68 mmole) was dissolved in methanol:methylenechloride (1:1) (120 mL). Aqueous solution of (15 mL) sodium hydrosulfite (0.88 g, 5.05 mmole) and K2CO3 (0.70 g, 5.06 mmole) was added dropwise under nitrogen for 10 min. The contents were allowed to stir at room temperature. After consumption of starting material, reaction mixture was concentrated, diluted with water till the homogeneous layer formed. The aqueous layer was extracted with several times with ethylacetate and methylene chloride. The turbid organic layers were combined, dried with anhydrous Na2SO4 and concentrated. Purification of the solid concentrate by silica gel chromatography provided 5-[(4-aminophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.23 g, 51%). 1H NMR (CDCl3): δ 8.11 (m, 2H), 7.52-7.46 (m, 3H), 6.87 (d, 2H, J=8.8 Hz), 6.64 (d, 2H, J=8.8 Hz), 5.26 (s, 2H), 3.49 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH:12]1[CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:12]1[CH2:15][CH2:14][CH2:13]1)[C:5]#[N:6]
Reactant: BrC1CCC1
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC2CCC2)c(Br)c1
Temperature: 60 °C

Procedure:
3-Bromo-4-hydroxybenzonitrile (2.0 g, 10.1 mmol), bromocyclobutane (2.7 g, 20.2 mmol), and K2CO3 (2.8 g, 20.2 mmol) were mixed in 5 mL of DMF and heated at 60° C. for 72 hours. The reaction was diluted with EtOAc washed with water, brine dried with MgSO4 and the solvent was removed. The product was purified by flash chromatography using a gradient from 0 to 30% EtOAc in hexane to provide the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.69-1.82 (m, 1H) 1.87-2.00 (m, 1H) 2.21-2.35 (m, 2H) 2.45-2.57 (m, 2H) 4.69-4.79 (m, 1H) 6.76 (d, J=8.48 Hz, 1H) 7.53 (dd, J=8.48, 2.03 Hz, 1H) 7.82 (d, J=2.03 Hz, 1H). MS (DCI/NH3) m/z 251.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:21][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=2)=[CH:25][CH:24]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc(COCCOCCOCCOCCOCCOCCOCc2ccc(Br)cc2)cc1
Yield: 92 %

Procedure:
To a solution of 766 mg (19.2 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (40 ml) was added 1.80 g (6.38 mmol) of hexaethylene glycol in an atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. Then, 3.51 g (14.0 mmol) of 4-bromobenzyl bromide was added, and the mixture was allowed to react at room temperature for 16 hours. To the reaction mixture at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane yielded 3.64 g (5.87 mmol) of 1,21-bis(4-bromophenyl)-2,5,8,11,14,17,20-heptaoxaheneicosane.