Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH2:23][F:24])[N:3]=1.[N+:25]([O-])([OH:27])=[O:26].OS(O)(=O)=O>>[Cl:1][C:2]1[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH2:23][F:24])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1OCCF
Agent: O=S(=O)(O)O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCCF

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2-fluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (2.08 g, 5.64 mmol), HNO3 (5.5 mL) and conc. H2SO4 (16 mL) in analogy with method described in example 1c.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[N:4]=1.[CH:25]1([C:28](Cl)=O)[CH2:27][CH2:26]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[N:4]=[C:3]([C:2]3[N:1]=[C:28]([CH:25]4[CH2:27][CH2:26]4)[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)CCC(=O)N1CCN(c2nccc(C(N)=NO)n2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CCC(=O)N1CCN(c2nccc(-c3noc(C4CC4)n3)n2)CC1

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyrimidin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (59.5 mg) was dissolved in pyridine (1 mL), and cyclopropanecarbonyl chloride (0.020 mL) was added thereto and heated under reflux for 3 hours. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated ammonium chloride solution, aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=3/2) to obtain 31.9 mg of the entitled compound as a colorless solid.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][CH2:17][CH2:18]O.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][CH2:18][CH2:17][Cl:16])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(OCCCl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of triflic anhydride (2.0 mL, 11.9 mmol) in CCl4 (10 mL) at 0° C. was treated with a solution of 2-chloroethanol (0.8 mL, 11.9 mmol) and pyridine (0.96 mL, 11.9 mmol) in CCl4 (6.0 mL) which was pre-cooled to 0° C. The reaction mixture was stirred at 0° C. for 45 minutes and then filtered through a pad of Na2SO4. The filtrate was concentrated and used immediately in the next step.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:27][C@H:26](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][C@H:17]1[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)C=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:27][C@@H:26]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][C@H:17]1[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)NC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: [S-]c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Sc2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
0.45 g (3.41 mmol) of sodium thiophenolate was added to a solution of 1.23 g (3.08 mmol) of (4R)-1-t-butoxycarbonyl-4-(p-toluenesulfonyloxy)-N-t-butyl-L-prolinamide [prepared as described in Preparation 6(a)] in 10 ml of a 2:1 by volume mixture of dimethylformamide and ethyl acetate, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was poured into a 10% w/v aqueous solution of sodium hydrogen-carbonate and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent, to give 1.0 g of the title compound as a colorless powder, melting at 119°-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>CCOC(C)=O>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cc1C(F)(F)F

Procedure:
Methyl 4-nitro-2-(trifluoromethyl)benzoate (5.20 g, 20.9 mmol) was dissolved in EtOAc (100 mL) and tin chloride dihydrate (9.41 g, 41.7 mmol) was added to the reaction mixture. The reaction was heated at reflux for 2 h. The crude reaction mixture was purified by column chromatography (SiO2, EtOAc/hexanes) to give the title compound. LCMS: (FA) ES− 218.4 (M−1).
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]2=[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[OH:24][C:9]1[C:8]([C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7])=[N:13][C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[C:11]2[S:20][N:21]=[C:22]([CH3:23])[C:10]=12
Reactant: CCCCOC(=O)c1nc(-c2cnccn2)c2snc(C)c2c1O
Reactant: NCC(=O)O
Product: Cc1nsc2c(-c3cnccn3)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
The title compound was synthesized in analogy Example 1 from 4-hydroxy-3-methyl-7-pyrazin-2-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 346.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[C:7]([C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH:6]=[N:5][CH:4]=1>O.CO>[OH:10][CH:9]([C:7]1[CH:6]=[N:5][CH:4]=[N:3][CH:8]=1)[C:11]([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)C(=O)c1cncnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(O)c1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1.27 g (0.034 mole) of sodium borohydride in 10 ml of water are added to 16.4 g (0.1 mole) of tert.-butyl 5-pyrimidinyl ketone in 100 ml of methanol at room temperature. The reaction mixture is stirred at room temperature for 1 hour and concentrated in vacuo, the residue is distilled in methylene chloride and the solution is concentrated again in vacuo. 15.8 g (95% of theory) of 5-(1-hydroxy-2,2-dimethyl-propyl)-pyrimidine of melting point 93°-95° C. are obtained.
Reaction SMILES: [BrH:1].C([CH:9]1[NH:17][CH2:16][CH2:15][C:14]2[CH2:13][NH:12][CH2:11][C:10]1=2)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[BrH:1].[BrH:1].[C:10]12[CH2:11][NH:12][CH2:13][C:14]=1[CH2:15][CH2:16][NH:17][CH2:9]2
Reactant: c1ccc(CC2NCCC3=C2CNC3)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: CC(=O)O
Product: C1CC2=C(CN1)CNC2
Reaction time: 7 h
Yield: 73 %

Procedure:
0.7 g of N3 -(benzyl)-3,8-diazabicyclo[4.3.0]non-1(6)-ene hydrobromide, prepared in Preparation 10, was dissolved in 20 ml of 5% aqueous acetic acid solution. 0.5 g of 10% palladium chracoal in this solution was suspended and the reaction mixture was refluxed under the hydrogen stream for 7 hours. The solid was filtered off. The filtrate was concentrated under reduced pressure and dissolved in 10 ml of 48% bromic acid. By concentrating the solution under reduced pressure again, 0.5 g of the title compound was obtained (yield 73%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[C:34]([CH3:35])=[C:33]([I:36])[S:32][C:31]=1[CH:37]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:37][C:31]3[S:32][C:33]([I:36])=[C:34]([CH3:35])[C:30]=3[Br:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(I)sc(C=O)c1Br
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1c(I)sc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1Br

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-bromo-5-iodo-4-methyl-thiophene-2-carbaldehyde. MS (ESI) m/z 693.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:26]3([O:25][CH3:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC1=CCCCC1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Product: COC1(OCCOCn2c(C)nc(C(C)C)c2Sc2cc(C)cc(C)c2)CCCCC1
Yield: 74.9 %

Procedure:
The compound 1 (502 mg, 1.50 mmol) was converted to the acetal with 1-methoxycyclohexene (1.68 g, 15.0 mmol) in the same manner as the example 2 to give the compound 3 (502 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6](C(OC(C)(C)C)=O)[C:7](=O)[NH:8][C:4]=2[CH:3]=1.[C:19](=[O:22])([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:19](=[O:22])[N:8]([CH3:7])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)ccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cn1c(=O)[nH]c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
tert-Butyl 5-bromo-2-oxo-2,3-dihydrobenzo[d]imidazole-1-carboxylate (12 g, 38 mmol) (Puwen Zhang, et. al., Bioorganic & Medicinal Chemistry Letters 11 (2001) 2747-2750 hereby incorporated by reference) and anhydrous disodium carbonate (3.2 mL, 77 mmol) were mixed in 200 mL THF. To this mixture was added dimethyl sulfate (15 mL, 153 mmol). The mixture was stirred at room temperature for 18 hours. The solvent was evaporated. The residue was dissolved in EtOAc and washed with brine and dried over sodium sulfate. The solvent was evaporated. The residue was taken up in MeOH (50 mL) and allowed to stand 18 hours. The solvent was evaporated, and the residue was triturated from MeOH (25 mL) to provide the product as a white solid (8.7 g, 100%). LCMS (API-ES) m/z: 227, 229 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N+:13]=1[O-:19]>CS(C)=O>[CH2:3]([O:10][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N+:13]=1[O-:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Cc1cccc(Cl)[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cccc(OCc2ccccc2)[n+]1[O-]
Reaction time: 10 h

Procedure:
To a slurry of sodium hydride (4.2 g, 105 mmol; 60% dispersion in mineral oil) in anhydrous dimethyl sulfoxide (70 mL), benzyl alcohol (8.7 mL, 84 mmol) was added over a period of 10 minute. The mixture was stirred at room temp. for 10 h., and treated with a solution of 2-chloro-6-methylpyridine N-oxide (10 g, 70 mmol) in dimethyl sulfoxide (10 mL). The resultant mixture was stirred at room temp. overnight, quenched with water and aqueous hydrochloric acid (to pH 8). The mixture was extracted with chloroform. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1-4% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided 2-benzyloxy-6-methylpyridine N-oxide as pale brown oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[C:25]1([S:31]([O-:34])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+].C(OCC)(=O)C>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:25]1([S:31]([O:34][C@@H:6]2[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S([O-])(=S)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](OS(=O)(=S)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 70 °C
Yield: 89.2 %

Procedure:
2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide (207 mg, 0.5 mmol) was dissolved in anhydrous acetonitrile (5 mL). To this sodium phenylthiosulfonate (201 mg, 1 mmol) and tetrabutylammonium bromide (16 mg, 0.05 mmol) were added. The resulting mixture was stirred under argon at 70° C. After a 4.5 h period, thin layer chromatography (t.l.c.) (petrol:ethyl acetate, 1:1) indicated the formation of a product (Rf 0.5) with complete consumption of the starting material (Rf 0.3). The solution was concentrated in vacuo. The crude solid was partitioned between dichloromethane (DCM, 20 mL) and water (20 mL), and the aqueous layer re-extracted with DCM (2×20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petrol:ethyl acetate, 1:1) to afford the title product (225 mg, 88%) as a white crystalline solid; mp 129-130° C.; [α]D25+51.2 (c, 1.0 in CHCl3); νmax (KBr) 1754 (s, C═O), 1376 (s, C═C) cm−1; δH; (400 MHz, C6D6) 1.68, 1.72, 1.73, 1.75 (4×3H, 4×s, 4×OAc), 3.09 (1H, ddd, J4,5 10.2 Hz, J5,6 2.4 Hz, J5,6′ 4.2 Hz, H-5), 3.83 (1H, dd, J5,6 2.4 Hz, J6,6′ 12.7 Hz, H-6),4.08 (1H, dd, J5,6′ 4.2 Hz, J6,6′ 12.6 Hz, H-6′), 5.17-5.23 (2H, m, H-2, H -4), 5.40 (1H, d, J1,2 10.2 Hz, H-1), 5.44 (1H, at, J9.4 Hz, H-3), 6.98-7.03 (3H, m, Ar—H), 7.90-7.92 (2H, m, Ar—H). The structure of the product was further confirmed by single crystal X-ray diffraction.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].I[CH3:34].P([O-])([O-])([O-])=O>ClCCl.C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:31](=[O:32])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([C:10]3[N+:11]4[C:12](=[CH:15][N:16]([CH3:34])[CH:17]=4)[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4cncn34)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4cn(C)c[n+]34)C[C@H]12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 100 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1.5 ml of dry dichloromethane was added 1.37 ml of iodomethane, and the mixture was stirred under the atmosphere of argon in the darkness at room temperature for 24 hours. Unreacted reagent was removed under reduced pressure. The residue thus obtained was dissolved in 4 ml of THF and 4 ml of 1/15 M phosphate buffer (pH 6.8), and 160 mg of 10% Pd-C was added. The reactor was purged with hydrogen, the reaction mixture was stirred at room temperature for 3.5 hours. The catalyst was collected by filtration on Celite and washed with water. The filtrate was washed with ethyl acetate, and purified by column chromatography on DIAION HP-20 and COSMOSEAL 40C18-PREP (water:methanol=20:1) to give 4.8 mg of the title compound.
Reaction SMILES: C[C:2]1(C)[S:7][CH2:6][CH2:5][N:4](S(C2C=CC(OCC#CCCOC3CCCCO3)=CC=2)(=O)=O)[CH:3]1[C:30]([OH:32])=O.O[N:35]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.C(OCC)(=O)C>[NH:4]1[CH2:5][CH2:6][S:7][CH2:2][CH:3]1[C:30]([NH2:35])=[O:32]
Reactant: On1nnc2ccccc21
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C1CSCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.28 g (0.56 mmol) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid and 0.091 g (0.675 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.151 g (0.788 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirred at room temperature for 1 h. Then 0.173 mL (2.8 mmol) of 50% aqueous hydroxylamine was added and the reaction was stirred for 18 h. The resulting mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/dichloromethane. The product was triturated with ether to provide 0.024 g (8%) of N-hydroxy-2,2-dimethyl-4-[(4-{[5-tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH3:36][C:37](O)([CH3:40])[CH2:38][OH:39]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:36][C:37]1([CH3:40])[CH2:38][O:39][C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(C)(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(C)(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 114.3 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g), 2-methylpropane-1,2-diol (0.15 g), p-toluenesulfonic acid monohydrate (0.02 g) and toluene (15 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.66 g, 100%).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33]([C:35]1[N:36]=[CH:37][N:38](C(OC(C)(C)C)=O)[CH:39]=1)=[CH2:34]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:38]1[CH:39]=[C:35](/[CH:33]=[CH:34]/[C:2]2[CH:25]=[CH:24][C:5]([O:6][C:7]3[C:8]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=4[S:10][C:11]=3[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[N:36]=[CH:37]1
Reactant: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 14.1 %

Procedure:
To a microwave vial containing 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (20 mg, 0.05 mmol) in DMF (2 mL) was added triethyl amine (0.202 mL, 1.45 mmol), tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (28.2 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (3.40 mg, 4.84 μmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave irradiation. The mixture was cooled to room temperature and diluted with DCM and sat. aq. NH4CI. The organic layer was collected (phase separator), concentrated in vacuo and purified by reverse phase HPLC (basic condition, 0.1% NH4OH in 1-100% CH3CN/H2O) to afford (E)-3-(4-(2-(1H-imidazol-4-yl)vinyl)phenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (3 mg, 7.03 μmol, 15% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.57 (s, 1 H), 7.43 (d, J=8.59 Hz, 2 H), 7.30 (d, J=8.59 Hz, 2 H), 6.96-7.14 (m, 3 H), 6.74-6.96 (m, 4 H), 6.53-6.74 (m, 3 H), LC/MS (m/z, MH+): 427.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: O=C(CBr)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1ccc(F)cc1
Yield: 96.9 %

Procedure:
The title compound (3.83 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.54 g) and 2-bromo-4′-fluoroacetophenone (2.26 g) according to the method of description 36.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[Si:11]([O:3][NH2:2])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](ON)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (3.48 g) and triethylamine (7 ml) were stirred for 0.25 hours in DMF (50 ml) at 0° C. tert-Butyldiphenylsilyl chloride (13 ml) was added and the mixture was stirred for 1 hour. The mixture was partitioned between pentane (500 ml) and water (100 ml), the layers separated and the aqueous phase extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with brine (50 ml), dried over magnesium sulphate and the solvent was removed in vacuo. The crude product was triturated with pentane (20 ml) yielding the pure title compound as white solid (4.04 g), m.p.t. 85°-87° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][OH:5])=[O:3].[C:6]([C:10]([C:13](F)=[O:14])([F:12])[F:11])([F:9])([F:8])[F:7]>C(N(CC)CC)C>[CH3:1][C:2]([CH2:4][O:5][C:13]([C:10]([C:6]([F:9])([F:8])[F:7])([F:12])[F:11])=[O:14])=[O:3]
Reactant: O=C(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)CO
Solvent: CCN(CC)CC
Product: CC(=O)COC(=O)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
CH3COCH2OH (50.0 g) and triethylamine (225.4 g) were put into a flask and stirred under cooling in an ice bath. CF3CF2COF (377.5 g) diluted with nitrogen gas was blown into the flask over a period of 4 hours, while maintaining the internal temperature to be at most 10° C. Then, the mixture was stirred at room temperature for 2 hours and then added to 500 mL of ice water.