Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:16][C:17]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=1.Cl.N1C=CC([C:33]([NH2:35])=[NH:34])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][C:13]1[C:8]([CH2:7][N:6]([CH2:16][C:17]2[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([NH2:35])=[NH:34])=[N:9][CH:10]=[C:11]([CH3:15])[CH:12]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)(C)O)c(C)c1
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCNC(=N)N)Cc2ncccc2C(C)(C)O)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 122.5 %

Procedure:
To a solution of 2-(2-{[(4-Amino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-propan-2-ol (0.1423 g, 0.28 mmol) in DMF (3 mL) was added 1H-pyrazole-carboxamidine hydrochloride (0.0440 g, 0.28 mmol) and DIPEA (0.29 mL, 1.68 mmol) and stirred at room temperature for 20 hours. The reaction mixture was concentrated, and purification of the crude material by column chromatography on silica gel (5:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (10:2:1 CH2Cl2-MeOH—NH4OH) provided 0.1367 g (41%) of COMPOUND 197 as a white solid. 1H NMR (CDCl3) δ 1.43-1.48 (m, 8H), 1.68-1.70 (m, 2H), 2.21 (s, 3H), 2.25 (s, 3H), 2.71-2.73 (m, 4H), 3.15-3.17 (m, 3H), 3.47 (s, 2H), 3.91 (s, 2H), 4.32 (s, 2H), 7.18-7.21 (m, 1H), 7.59-7.63 (m, 1H), 7.92-7.93 (m, 1H), 8.17 (s, 1H), 8.37-8.39 (m, 1H). 13C NMR (CDCl3) δ 18.31, 18.65, 22.77, 26.67, 31.59, 41.57, 54.09, 56.32, 61.95, 72.43, 123.57, 132.52, 132.92, 135.02, 139.67, 144.31, 146.94, 147.10, 150.68, 153.40, 158.00. ES-MS m/z 400 (M+H). Anal. Calcd. for C22H34N6O.1.9CH2Cl2.1.5H2O: C, 48.91; H, 7.01; N, 14.32. Found: C, 48.68; H, 6.83; N, 14.68.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([N:7]1[N:11]=[CH:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8]1)=[NH:6])[CH3:3].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH2:8]1[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=[N:11][N:7]1[C:5](=[N:6][S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[NH:4][CH2:2][CH3:3]
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
N-Ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine hydrochloride (60 g, 260.08 mmol; isolated from reaction of N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine, synthesized as described in WO 2009/115515, with HCl in isopropanol) was dissolved in 1000 mL dichloromethane, and 4-acetylamino-benzenesulfonyl chloride (60.7 g, 260.08 mmol) was added. Under mechanical stirring, triethylamine (131.6 g, 1300.4 mmol) was added over a period of 20 minutes, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water (250 mL) and the organic phase was concentrated under reduced pressure (40° C., 600 mbar). The oily residue was coevaporated twice with 96% ethanol (250 mL) and taken up in 500 mL dichloromethane. The organic phase was extracted with 1N aqueous HCl (75 mL) and subsequently twice with water (200 mL) and evaporated to dryness under reduced pressure to yield 78 g (199.2 mmol, 77%) of N-(4-{[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]sulfamoyl}-phenyl)-acetamide. 1H NMR identical to spectrum obtained from material prepared via novel route (vide supra).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[I:11].CCO.[NH4+].[Cl-]>C1COCC1.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[I:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Cl)c(I)c1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
1-Chloro-2-iodo-4-nitro-benzene (2.00 g, 7.09 mmol) was dissolved in THF (30 mL) at 60° C. and EtOH (35 mL) was added followed by NH4Cl (0.569 g, 10.6 mmol in 30 mL of water) and iron powder (1.58 g, 28.4 mmol). This mixture was stirred vigorously for 3 h and then cooled in 22° C. and filtered though celite rinsing with EtOAc. The solution was then concentrated to ˜30 mL in vacuo and then poured into a 1:1 solution of 1N NaOH/brine (100 mL). This mixture was then extracted with EtOAc (3×50 mL) and the organics were dried over anhydrous MgSO4. Filtration and concentration gave compound 801B as a yellow solid. No purification was necessary. HPLC: 100% at 2.310 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10–90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 517.6 [M+Na]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=O)[C:26]3[C@@H:25]([CH3:33])[CH2:24][C:23]([O:34][CH3:35])=[CH:22][C:21]=3[C:20]=2[CH:19]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.P([O-])([O-])([O-])=O>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[N:28]=[C:29]2[C:20](=[C:21]3[C:26]=1[C@@H:25]([CH3:33])[CH2:24][C:23]([O:34][CH3:35])=[CH:22]3)[CH:19]=[C:18]([O:17][CH3:16])[CH:31]=[CH:30]2)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC1=Cc2c(c(=O)[nH]c3ccc(OC)cc23)[C@@H](C)C1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: COC1=Cc2c(c(OS(=O)(=O)C(F)(F)F)nc3ccc(OC)cc23)[C@@H](C)C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
Trifluoromethanesulfonic anhydride (3.80 mL, 22.4 mmol, 1.10 equiv) was added via syringe to a suspension of (S)-7,8-dihydro-2,9-dimethoxy-7-methyl-6(5H)-phenanthridinone (10, 5.52 g, 20.3 mmol, 1 equiv) and 2.6-di-t-butylpyridine (6.10 mL, 27.1 mmol, 1.33 equiv) in dichloromethane (400 mL) at -78° C. The cold suspension was allowed to warm to 23° C. over 30) min and was stirred at that temperature for 15 min. Solids were observed to dissolve as the reaction proceeded. The reaction mixture was poured into aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 200 mL). The aqueous layer was separated and further extracted with two 200-mL portions of dichloromethane. The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (40% dichloromethane-hexanes) to provide (S)-7,8-dihydro-2,9-dimethoxy-7-methyl-6-phenanthridinol trifluoromethanesulfonate (ester) (12) as an off-white solid (mp 129.5°-130.5° C., 7.09 g, 86%). ##STR23##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].Br.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[Cl:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(OC)c2)n1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(OC)c(OC)c2)n1

Procedure:
A mixture of 2.18 g (7.1 mmol) 2-(3,4-Dimethoxy-phenylamino)-thiazole-4-carboxylic acid ethyl ester; hydrobromide, 1.87 g (10.7 mmol) 2-Chlorobenzoyl chloride and 2.96 ml (21.4 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 24 h. After evaporation of the volatiles the residue was taken up in MeOH and purified with flash column chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield after evaporation of the product fractions 1.58 g (50%) of the title compound. MS (m/e): 446.9 (MH+, 100%)
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[C:19]1([N+]#N)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)C>[C:1]1([C:7]([CH2:9][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
0.97 mmol of (1-phenylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The resulting mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5N hydrochloric acid, water and a saturated aqueous solution of common salt, successively. The organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.68 mmol of benzyl phenyl ketone.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:25][N:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:23])([F:1])[F:24])=[N:4][N:5]=3)[CH:8]=2)=[CH:17][CH:16]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1)S(C)(=O)=O

Procedure:
N-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)methanesulfonamide (10 mg) was dissolved in DMF (1 mL) and heated with potassium carbonate (39 mg) and methyl iodide (40 mg) for 2 h at 85° C. The reaction mixture was filtered, concentrated, and purified by chromatography using 2% MeOH in methylene chloride as eluent. N-methyl-N-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)methanesulfonamide was obtained as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])(=O)=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]([C:16]1[CH:17]=[C:18]([OH:23])[C:19]([OH:22])=[CH:20][C:21]=1[Cl:27])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(C(=O)OCc1ccccc1)c1ccc(O)c(O)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1cc(O)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyloxycarbonyl 3,4-dihydroxyphenylglycine (0.79 g, 2.5 mmole) in acetic acid (10 ml) was treated with sulphuryl chloride (0.2 ml), stirred at room temperature for two hours then diluted with ethyl acetate (50 ml), washed with water (2×3 ml) and brine (20 ml), dried and evaporated to a gum which was crystallized from chloroform, 0.36 g, 41%, mp 141°-143°.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C.CN(C)C=O>[Fe].O>[C:15]1([C:11]2[CH:10]=[C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:22][CH:21]=3)[CH:14]=[CH:13][N:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(-c3ccccc3)c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc(-c3ccccc3)c2)cc1
Yield: 104.6 %

Procedure:
4-(4-nitrophenoxy)-2-phenylpyridine (490 mg), iron powder (1 g), ammonium chloride (2 g), ethanol (10 ml), dimethylformamide (10 ml) and water (5 ml) were stirred at 100° C. for 10 minutes. The mixture was filtered with celite, water was added to the filtrate, and extraction was performed with ethyl acetate. The organic layer was washed 5 times with water, and then the solvent was distilled off under reduced pressure to obtain 4-(2-phenylpyridin-4-yl)oxyaniline (460 mg) as a brown oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14](F)[CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:31][S-:32].[Na+].O>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:32][CH3:31])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[S-]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(SC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 657.5 %

Procedure:
To a solution of 50 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-benzonitrile (prepared according to the method described in example 1) in 10 ml of dimethylformamide was added 121 mg of sodium thiomethoxide. The resulting mixture was stirred at room temperature overnight, then poured into water, extracted with diisopropyl ether. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by crystallization from diisopropyl ether/heptane to give 350 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfanyl-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfanyl-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.
Reaction SMILES: [ClH:1].[CH3:2][Si:3]([CH3:13])([CH3:12])O[Si:5]([CH3:11])([CH3:10])[C:6]([CH3:9])([CH3:8])[CH3:7].C(N(CCCC)CCCC)CCC.S(Cl)([Cl:29])=O>>[C:6]([Si:5]([CH3:11])([CH3:10])[Cl:29])([CH3:9])([CH3:8])[CH3:7].[CH3:2][Si:3]([CH3:13])([CH3:12])[Cl:1]
Reactant: Cl
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)O[Si](C)(C)C
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)[Si](C)(C)Cl
Product: C[Si](C)(C)Cl
Reaction time: 4 h
Yield: 80.2 %
Yield: 86.4 %

Procedure:
To a 1.0 l volume reaction vessel equipped with a stirring machine, a reflux condenser, a dropping funnel and an inlet pipe for hydrogen chloride gas, there were added 204 g (1.0 mole) of pentamethyl-t-butyl-disiloxane and 9.25 g (0.050 mole) of tributylamine and 143 g (1.2 mole) of thionyl chloride was introduced into the dropping funnel. Pentamethyl-t-butyl-disiloxane was reacted with thionyl chloride at room temperature by dropwise adding thionyl chloride through the dropping funnel while supplying hydrogen chloride gas to the reaction solution. After stirring over 4 hours, the reaction solution was distilled at 125° C. to give 130 g (yield 86.4%) of t-butyldimethylchlorosilane and 87.0 g (yield 80.2%) of trimethylchlorosilane. There was not observed the formation of any viscous oily substance, the distillation temperature during the purification could substantially be decreased and the post-treatment of the reaction vessel was very easy.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:11]2[C:12]([CH3:20])=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]=[CH2:30].O>CN(C)C=O.C(OCC)(=O)C>[CH3:20][C:12]1[C:11]([C:4]2[S:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([O:1][CH2:30][CH:29]=[CH2:28])[N:3]=2)=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1
Reactant: C=CCBr
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOc1nc(-c2c(C)nn3ccccc23)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Methyl 4-hydroxy-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (1.0 g, 3.5 mmol) produced in Example 13-B(i) was dissolved in N,N-dimethylformamide (50 mL), potassium carbonate (3.2 g, 9.7 mmol) and 3-bromoprop-1-ene (2.8 g, 23 mmol) were added, and the mixture was stirred at room temperature for 2 hr. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the mixture was stirred for 30 min. The organic layer was washed with water (100 mL×3) and saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→0/100) to give the title compound (760 mg, 67%) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[O:3]1.C(Cl)Cl.CO>C(O)C>[NH2:23][CH2:22][C@H:4]1[C@H:5]2[N:6]([C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10]2)[C:2](=[O:1])[O:3]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Temperature: 78 °C

Procedure:
Compound 2-(((3S,3aS)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)isoindolin-1,3-dione (3.71 g, 8.263 mmol) prepared as above in (d) was partly dissolved in 50 ml of ethanol. 60 ml of methylamine alcohol solution was added and the mixture was allowed to react under reflux at 78° C. for 3 h. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, the solvent was evaporated, and the remainder was directly subjected to the next step of reaction.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C([O:13][C:14](=[O:19])[C:15]([OH:18])([CH3:17])[CH3:16])C.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.Cl>O1CCCC1>[CH3:17][C:15]([O:18][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)([CH3:16])[C:14]([OH:13])=[O:19]
Reactant: CCOC(=O)C(C)(C)O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (0.91 M, 275 mL) at −70° C. under nitrogen and was added ethyl-2-hydroxyisobutyrate (36 mL, 34.7 g, 0.263 mol) over 12 min. After stirring for additional 10 min, 2-chloro-5-trifluormethylpyridine was added in one portion. The cooling bath was removed and the reaction was allowed to warm to room temperature overnight. Sodium hydroxide (105 mL, 5N) was added, and the reaction was refluxed overnight. The reaction mixture was partially concentrated on a rotary evaporator, diluted with water (150 mL), and extracted with hexane (2×150 L). The aqueous layer was separated and acidified with 2N HCl (350 mL, 0.7 mol), and the resulting suspension was cooled to 0° C. After aging for 20 min, the precipitate was collected by filtration, which was washed with water (4×150 mL) and air-dried to afford 38.0 g of a tan solid. (85.5%). Treatment with Darco KB and recrystallization in 3:1 heptane/isopropyl acetate provided the title compound as a white crystalline material. 1H NMR (500 MHz, CD3OD): δ 8.38 (br s, 1H), 7.93 (dd, 1H), 7.13 (d, 1H), 1.70 (s, 6H). LC-MS: m/e 250 (M+H)+ (2.6 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][N:37]([CH3:52])[C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][N:37]([CH3:52])[C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42][N:43]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:44][CH2:45]1)=[O:39]
Reactant: CN(C)C(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)N(C)C)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid dimethyl-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(N[C@H]2CC[C@H](C)CC2)[CH2:35]CCC[CH2:31]1.[CH3:44]OC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([CH3:44])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:35][CH2:30][CH2:31][C@H:19]3[C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester to give the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 98.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (84.6 mg, 99% ).