Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C[N+]1([O-])[CH2:14][CH2:13][O:12]CC1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([S:24][CH2:25][C:26]([F:29])([F:28])[F:27])=CC=1B(O)O.Cl>C(OCC)(=O)C.CCCCCC>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([S:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:14][C:13]=1[OH:12]
Reactant: C[N+]1([O-])CCOCC1
Reactant: OB(O)c1cc(SCC(F)(F)F)c(Cl)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Oc1cc(SCC(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To 150 ml of toluene was added 29.0 g (50% aqueous solution, 124 mmol) of N-methylmorpholine-N-oxide, and dehydration was conducted by heating under reflux for 1 hour. To the reaction mixture was dropwise added 31.5 g (103 mmol) of 2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenylboronic acid dissolved in ethyl acetate, and the mixture was refluxed for 3 hours under heating. Then, the mixture was allowed to cool to room temperature, and 10% aqueous hydrochloric acid was added, followed by extraction with ethyl acetate. The organic phase obtained was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 27.2 g (yield: 95%) of an intended product.
Reaction SMILES: [OH-:1].[Mg+2:2].[OH-].[S:4](=[O:6])=[O:5]>>[S:4]([O-:1])([O-:6])=[O:5].[Mg+2:2].[S:4](=[O:1])([OH:6])[O-:5].[Mg+2:2].[S:4](=[O:1])([OH:6])[O-:5]
Reactant: [OH-]
Reactant: O=S=O
Agent: [Mg+2]
Product: O=S([O-])O
Product: O=S([O-])[O-]

Procedure:
Desulfurization is accomplished by contacting the flue gas with a recirculating absorbent stream in a suitable contact vessel, typically a scrubber. The absorbent in the recirculation stream includes magnesium hydroxide (Mg(OH)2) as a chemical absorbent species which reacts rapidly with sulfur dioxide to produce magnesium sulfite (MgSO3) and magnesium bisulfite (Mg(HSO3)2). The magnesium sulfite and bisulfite are oxidized to magnesium sulfate and then converted to magnesium hydroxide by reaction with calcium hydroxide, resulting in gypsum (CaSO4.2H2O) as a final product (along with calcium chloride (CaCl2) and magnesium sulfate (MgSO4), as described in more detail hereinbelow). The gypsum, which has a low solubility in water, is removed in a bleed stream from the system and then combined with sufficient excess of seawater so that it is easily solubilized and no solid wastes are produced. Equally important, the gypsum (in low concentration in seawater) and the soluble calcium and magnesium are non-toxic to the marine environment, and the system as a whole produces a minimal temperature rise in the waters which are returned to the ocean. Conveniently, bleed stream from the system can be dissolved in the remaining flow of spent cooling seawater and returned to the ocean with no adverse impact on the environment.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([C:29](=[O:31])[CH3:30])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:9]1)=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][NH:32][C:24]2[N:23]=[C:22]([C:18]3[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=3)[CH2:15][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)[C:29](=[O:31])[CH3:30])[CH:27]=[CH:26][N:25]=2)=[CH:36][CH:37]=1
Reactant: CC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)CC1CCN(C(=O)OC(C)(C)C)C1
Reactant: NCCc1ccc(O)cc1
Product: CC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)CC1CCNC1

Procedure:
Intermediate 60 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 446.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)C.C(=O)=O.[Br:32]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([Br:32])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(N)ncnn23)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Br)c3c(N)ncnn23)CC1
Temperature: -20 °C
Reaction time: 4 h
Yield: 134.1 %

Procedure:
To a solution of 4-(4amino-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (252 mg, 0.758 mmol) in THF (8 mL) at −20° C. (IPA and dry ice) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (108 mg, 0.379 mmol). The reaction was stirred at −20° C. for 4 h. After removal of solvent, the residue was purified by silica gel column using 4% methanol in dichloromethane to obtain 209 mg (67%) of desired product. 1H-NMR (CD2Cl2) δ 7.81 (s, 1H), 7.23 (s, 1H), 6.61 (s, 1H), 3.86 (s, 1H), 3.41 (t, J=2.4, 4H), 2.48 (s, 4H), 1.43 (s, 9H) MS [M+H]+=410.9; LCMS RT=1.87 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[O:10][CH2:9][C:8](=[O:11])[C:7]=2[CH:12]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:5]1[C:6]2[O:10][CH2:9][C:8](=[O:11])[C:7]=2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C)c2c(c1)C(=O)CO2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)c2c(c1)C(=O)CO2
Yield: 11.1 %

Procedure:
The synthesis was performed with reference to the known literature (Bioconjugate Chemistry, Vol. 18, p. 275, 2007). A solution of 5-methoxy-7-methylbenzofuran-3(2H)-one (0.25 g, 1.4 mmol) in carbon tetrachloride (15 mL) was successively added with N-bromosuccinimide (0.27 g, 1.5 mmol), and benzoyl peroxide (0.025 g, 0.070 mmol), and the mixture was refluxed for 2 hours by heating. The solid in the reaction mixture was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (75:25)) to obtain 7-(bromomethyl)-5-methoxybenzofuran-3(2H)-one (0.040 g, 11%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH2:23])[CH3:22])[CH:17]=[CH:18][C:19]=1[Cl:20].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=2)[CH3:22])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(NC(=O)c1cccc(F)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 143.8 mg (0.75 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) and 91.6 mg (0.75 mmol) 4-dimethylaminopyridine (DMAP) in 1.5 ml dichloromethane were added 142 mg (0.75 mmol) rac-1-(3,4-dichloro-phenyl)-ethylamine and the solution stirred at ambient temperature for 5 min. To this solution were added 70 mg (0.5 mmol) 3-fluoro-benzoic acid and the mixture stirred at ambient temperature for 5 hours.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=O)=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].S(Cl)(Cl)=O.[CH3:30][N:31]([CH2:33][CH2:34][NH2:35])[CH3:32]>CN(C)C=O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:35][CH2:34][CH2:33][N:31]([CH3:32])[CH3:30])(=[O:21])=[O:22])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CN(C)CCN
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)NCCN(C)C)cc3)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid, (7.0 g, 0.019 moles) and N,N-dimethylformamide (125 ml) is cooled to 0°, and treated with thionyl chloride (4.6 g, 0.038 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature, and stirred vigorously for one hour. The resulting slurry is cooled to 0°, and treated with unsym dimethylethylenediamine (8.8 g, 0.10 mole) and allowed to warm to ambient temperature. The reaction mixture is concentrated on a rotary evaporator, the residue is taken up in cool water and filtered. The solid thus obtained is recrystallized from ethanol and dried at 78° in a drying pistol to give 5.87 grams of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)-N-[2-(dimethylamino)ethyl]benzene-sulfonamide, mp 264°-265° C.(d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=1>[I-].[K+]>[CH3:5][CH:8]([OH:9])[CH3:10].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(OCCCCl)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Product: CC(=O)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Product: CC(C)O
Yield: 71 %

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 1-[4-(3-chloropropoxy)phenyl]ethanone were reacted using potassium iodide catalyst to give the free base of the title compound which when recrystallized from isopropyl alcohol gave the white title compound in 71% yield, m.p. 72°-84° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:30][CH2:29][C:26]3[CH:27]=[N:28][C:23]([N:20]4[CH2:21][CH2:22][S:17][CH2:18][CH2:19]4)=[CH:24][CH:25]=3)=[O:16])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(N2CCSCC2)nc1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(N2CCSCC2)nc1)c1ccc(-c2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3′-fluorobiphenyl-4-carboxylic acid 8-5 (51 mg, 0.24 mmol), (6-thiomorpholinopyridin-3-yl)methanamine 8-4 (45 mg, 0.21 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (91 mg, 0.24 mmol) in DMF (1.0 mL) was added DIEA (0.1 mL, 0.64 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give 3′-fluoro-N-((6-thiomorpholinopyridin-3-yl)methyl)biphenyl-4-carboxamide 8-6. MS m/z 408.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:33])[C:18]([CH2:21][N:22]([CH2:29][CH2:30][O:31][CH3:32])[C:23]([NH:25][CH:26]5[CH2:28][CH2:27]5)=[O:24])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:36])[CH:3]=1.[N:37]1[CH:42]=C[CH:40]=[CH:39][CH:38]=1.ClC(OC1C=CC=CC=1)=[O:45].C1(N)CC1>CN(C=O)C>[F:36][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:37][CH:38]2[CH2:40][CH2:39]2)=[O:45])[CH:35]=[CH:34][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:33])[C:18]([CH2:21][N:22]([CH2:29][CH2:30][O:31][CH3:32])[C:23]([NH:25][CH:26]4[CH2:27][CH2:28]4)=[O:24])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)NC1CC1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a stirred solution of 160 (283 mg, 0.554 mmol) and pyridine (0.134 mL, 1.663 mmol) in DMF (10 mL) at 0° C. under nitrogen was added phenyl chloroformate (158 mg, 1.386 mmol) and the reaction mixture was stirred at 0° C. for 2 hrs. Cyclopropylamine (0.195 mL, 2.77 mmol) was added and the reaction mixture was heated at 55° C. for 5 hrs. The reaction mixture was partitioned between EtOAc and saturated sodium bicarbonate solution, then washed a saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (eluent EtOAc to 20% MeOH in EtOAc) to afford title compound 161 (100 mg, 30% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (s, 1H), 8.50 (d, J=5.48 Hz, 1H), 7.89 (s, 1H), 7.70 (m, 1H), 7.35 (t, J=9.19 Hz, 1H), 7.19 (m, 1H), 6.93 (s, 1H), 6.64 (d, J=5.48 hz, 1H), 6.56 (s, 1H), 6.51 (m, 1H), 4.54 (s, 2H), 3.82 (s, 3H), 3.27 (m, 2H), 3.25 (m, 2H), 3.19 (s, 3H), 2.54 (m, 2H), 0.63 (m, 2H), 0.55 (m, 2H), 0.41 (m, 2H), 0.37 (m, 2H). MS (m/z)=594.61 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:22])[C:7]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:6]=2[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C@H:4]1[CH3:36].[C:37]([O:41][C:42]([N:44]([CH2:50][CH3:51])[C@@H:45]([CH3:49])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[CH3:22])[C:9](=[O:10])[C@@H:3]([NH:2][C:46](=[O:47])[C@@H:45]([N:44]([CH2:50][CH3:51])[C:42](=[O:43])[O:41][C:37]([CH3:38])([CH3:40])[CH3:39])[CH3:49])[C@H:4]([CH3:36])[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:6]=2[CH:26]=1)#[N:28]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)O
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a rt solution of (3S,4S)-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (100 mg, 190 μmol) in DMF (632 μl) was added (S)-2-(tert-butoxycarbonyl(ethyl)amino)propanoic acid (45.3 mg, 209 μmol), N,N-diisopropylethylamine (131 μl, 759 μmol), and HBTU (79.2 mg, 209 μmol). The reaction was stirred at rt for 30 min, then purified by reverse phase preparative HPLC to provide tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(ethyl)carbamate (105 mg, 80%) as a white solid. MS m/z 712 (MNa)+.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[N:21]1CCC[C:22]1=[O:26]>>[C:22](=[O:26])([S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[NH2:21]
Reactant: CN1CCCC1=O
Reactant: CCCCCCCCCCCCCCCCCCS
Product: CCCCCCCCCCCCCCCCCCSC(N)=O
Yield: 60 %

Procedure:
As described in Example 17, but using 63 g of 1-octadecylmercaptan (0.22 mol) dissolved in 30 ml of N-methylpyrrolidone, S-octadecyl thiocarbamate was obtained in a yield of 60% of theory.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.[C:23](Cl)(=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>O1CCCC1.N1C=CC=CC=1>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[O:20][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: CCCCCCC(=O)Cl
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCC(=O)O[C@H]1CC[C@H]2[C@H]3[C@H]([C@@H](F)C[C@]12C)[C@H]1CCC(=O)C=C1C[C@H]3C
Reaction time: 1 h

Procedure:
A solution of 220 mg of 11β-fluoro-17β-hydroxy-7α-methylestr-4-ene-3-one (I) in 5 ml of tetrahydrofuran and 1.09 ml of pyridine was mixed drop by drop at 0° C. with 1.09 ml of heptanoyl chloride and stirred for 1 hour. Then, it was mixed with sodium bicarbonate solution, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 210 mg of pure 11β-fluoro-17β-heptanoyloxy-7α-methylestr-4-en-3-one (I′) was obtained as a foam ([α]D20=+40.8° (c=0.56% in chloroform)).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]2[N:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)=[CH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:47][C@H:48]1[C:53]([F:55])([F:54])[CH2:52][CH2:51][CH2:50][C@H:49]1[NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:59]([O:58][C:57](=[O:63])[NH:56][C@@H:49]1[CH2:50][CH2:51][CH2:52][C:53]([F:55])([F:54])[C@@H:48]1[NH:47][C:8]([C:6]1[S:7][C:3]([CH:1]=[CH2:2])=[C:4]([C:11]2[N:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:5]=1)=[O:10])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: C=Cc1sc(C(=O)O)cc1-c1cnc2cccnn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=Cc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylic acid (105 mg, 0.387 mmol) and BOP (257 mg, 0.581 mmol) in DMF (5.2 mL) was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (145 mg, 0.581 mmol) followed by diisopropylethyl amine (0.169 mL, 0.968 mmol). The mixture was allowed to stir at room temperature for 18 h. After the reaction was complete, water was added and the aqueous layer extracted with ethyl acetate (×3). The organic layers were combined, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography giving the title compound as an orange solid. LRMS (APCI) calc'd for (C24H27F2N5O3S) [M+H]+, 504.2. found 504.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:38]=[CH:37][C:16]([CH2:17][C:18]23[C:26](=[O:27])[N:25]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:24](=[O:36])[N:23]2[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=1)=[O:4].[BH4-].[Na+]>CCOC(C)=O.O>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]23[C:26](=[O:27])[N:25]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[C:24](=[O:36])[N:23]2[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:37][CH:38]=1)=[O:4]
Reactant: COC(=O)C=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reaction time: 1 h
Yield: 63.5 %

Procedure:
NiCl2.6H2O (0.17 g) was added to a solution of 6-[4-[2-(2-methoxycarbonylvinyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.196 g). NaBH4 (0.14 g) was added portionwise to the mixture and the mixture was stirred for 1 hour. The mixture was diluted with EtOAc and water and filtered through Celite. The organic layer was separated and washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/4, Chromatotron) afforded the titled compound (0.125 g). MS (m/z) 573 (M++Na).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:10][C:4]1[CH:5]([Br:11])[C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH:3]=1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=CC(=O)CC(C)(C)C1Br

Procedure:
A mixture of isophorone (13.82 g; 0.1 Mole) and N-bromo-succinimide (17.80 g; 0.1 Mole) in the presence of traces of α,α'-azodiisobutyronitrile was refluxed in 500 ml of CCl4 during 15 minutes. 500 ml of petrol-ether (30°-50° C) were then added to the cool reaction mixture and the succinimide thus precipitated was filtered off. By evaporating the volatile components of the clear filtrate, crude 3,5,5-trimethyl-4-bromo-cyclohex-2-en-1-one was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[N:10]([CH2:12][CH2:13][OH:14])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1.CO>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:15])[N:10]([CH2:12][CH2:13][O:14][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CN(CCO)C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Subsequently, to a solution of N-(2-hydroxyethyl)-N-methylcarbamic acid benzyl ester (2.82 g, 13.5 mmol) in dimethylformamide (85 ml) were added t-butyldiphenylsilyl chloride (4.21 ml, 16.2 mmol) and imidazole (1.10 g, 16.2 mmol) in an ice bath. The resulting mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, methanol was added thereto and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (9:1) as the eluant to afford N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-methyl-carbamic acid benzyl ester (5.7 g, yield 94%) as a pale yellow solid.