Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[Fe:19](Cl)Cl>C(OCC)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[NH:5]1.[Fe+2:19]
Reactant: Nc1ccccn1
Reactant: Cl[Fe]Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: [Fe+2]
Product: c1ccc(N=C2NC(=Nc3ccccn3)c3ccccc32)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL round-bottom flask equipped with a nitrogen inlet and an internal fritted-glass filter is charged with phthalimide (2.94 g, 20.0 mmol) and ethyl acetate (50 mL). 2-Aminopyridine (3.77 g, 40.0 mmol, 2.1 eq.) and iron(II) chloride (2.54 g, 20.0 mmol) are added to the flask, and the mixture is stirred under nitrogen at room temperature for 1 h. The mixture is stirred at room temperature for 120 h, yielding a white precipitate.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][C@H:4]1[CH2:5][OH:6].[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([CH2:16][CH2:17][CH2:18][C:19]([N:3]2[CH2:9][CH2:8][CH2:7][C@H:4]2[CH2:5][OH:6])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Aqueous sodium hydroxide (1 N, 25 ml) is added to a solution of 2.0 g of L-prolinol (U.S. patent 3,935,280) in 50 ml of CH2Cl2. After cooling the reaction mixture to 0° C., 4.0 g of 4-phenylbutyric acid chloride is added and the reaction is stirred vigorously for 4 hours at 0° C., followed by 1 hour at room temperature. The reaction is diluted with an equal volume of CH2Cl2 and the layers separated. The organic phase is washed with 30 ml of water and dried over Na2SO4 /K2CO3. The solvent is evaporated to yield 4.4 g of N-(4-phenylbutanoyl)-L-prolinol having IR peaks at 3280 and 1605 cm-1, [α]D25 =-40.3° (methanol). 20.5 g of N-methyl-N,N'-dicyclohexylcarbodiimidium iodide (Angew, Chem., Int. Ed. 11, 229 (1972) is added to a solution of 5.3 of R-(-)-3-benzyloxy-2-methylpropanol (Helv. Chim. Acta 60, 925 (1977) in 200 ml dry tetrahydrofuran under nitrogen and the reaction is stirred at room temperature for 14 hours. The solvent is evaporated and 20 ml of ether and 5 ml of pentane are added. The resulting yellow solid is collected and the mother liquors are chromatographed on 200 g of silica gel with pentane to yield 6.68 g of the S(+)-3-benzyloxy-2-methylpropyl iodide having Rf=0.60 (9:1 of pentane:ether/Si°2), [α ]D25 =+11.1° (MeOH). N-(4-phenylbutanoyl) L-prolinol is dissolved in 2 ml of dry tetrahydrofuran and added dropwise to a solution of lithium diisopropylamide (15.6 m moles) in 50 ml of tetrahydrofuran at 0° C. under nitrogen. After 30 minutes at 0° C., 2.03 g of S-(+)-3-benzyloxy-2-methylpropyl iodide is added dropwise in 2 ml of dry tetrahydrofuran. The reaction is stirred at 0° C. for 5 hours, at -15° C. for 15 hours and quenched at 0° C. with excess saturated ammonium chloride solution. The reaction mixture is diluted with 30 ml of ether. The layers are separated and the organic phase is washed with 16 ml of 1 N HCl, 15 ml of brine, 15 ml of saturated sodium bicarbonate and dried over sodium sulfate. Evaporation of solvent yields 3.6 g of an oil which is filtered through 60 g of silica gel with ethyl acetate to yield 2.3 g of N-(R,R-5-benzyloxy-4-methyl-2-phenethylpentanoyl) L-prolinol having Rf 0.51 (EtoAc/SiO2).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:32][C:31]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[O:30][C:29]2=[O:45])=[CH:24][CH:23]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[N:27]=[CH:26][C:25]([N:28]5[CH2:32][C:31]6([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]6)[O:30][C:29]5=[O:45])=[CH:24][CH:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1ccc(N)nc1)C(=O)O2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CCN(C(=O)OC(C)(C)C)CC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 62.5 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (133 mg, 0.45 mmole) was combined with tert-butyl 3-(6-aminopyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (158 mg. 0.45 mmole) which gave tert-butyl 3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino) pyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (170 mg) in 62% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.89 (s, 1H), 8.76 (s, 1H), 8.46 (d, J=9.03 Hz, 1H), 8.38 (d, J=2.51 Hz, 1H), 7.97-7.92 (m, 1H), 6.40 (s, 1H), 4.78-4.68 (m, 1H), 3.83-3.73 (m, 2H), 3.71 (s, 2H), 3.33-3.21 (m, 2H), 3.02 (s, 6H), 2.54-2.40 (m, 2H), 2.05-1.86 (m, 6H), 1.78-1.58 (m, 4H), 1.38 (s, 9H)
Reaction SMILES: [C:1]([OH:20])(=O)[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][C@H:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O>C1(C)C(C)=CC=CC=1>[C:1]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]([C:28]([OH:30])=[O:29])[NH2:21])(=[O:20])[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]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 85.9 %

Procedure:
Lysine stearate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 28.8 g of Nε -stearoyl lysine (yield 85.9%). This is designated Derivative A.
Reaction SMILES: [Cl:1][C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1.[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>O1CCCC1>[C:2]([Cl:1])(=[O:5])[O:25][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: OC1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cl)OC1CCOCC1
Yield: 92.9 %

Procedure:
To a solution (40 mL) of bis(trichloromethyl)carbonate (2.97 g) in tetrahydrofuran was dropwise added a solution (10 mL) of pyridine (2.43 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 10 min., a solution (20 mL) of tetrahydropyran-4-ol (1.91 g) in tetrahydrofuran was dropwise added slowly. After stirring at room temperature for 2 hrs., the mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added to the residue. The ethyl acetate layer was separated and taken, washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave tetrahydropyran-4-yl chlorocarbonate (1.53 g). To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.40 g) obtained in Reference Example 1 and tetrahydrofuran (20 mL) was added pyridine (0.78 mL), and a solution (10 mL) of tetrahydropyran-4-yl chlorocarbonate (1.53 g) obtained above in tetrahydrofuran was dropwise added, and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL). The residue was washed with a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=4:1, then 3:2). The obtained colorless oil (2.03 g) was dissolved in diethyl ether (2 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring at room temperature for 30 min., diethyl ether (10 mL) was added and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.20 g) as a white solid.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][C:22]([CH3:24])=[CH:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]([O:37][CH2:38][CH3:39])(=[O:36])[C:32]#[C:33][CH2:34][CH3:35]>CN(C)C=O.O>[CH2:34]([C:33]1[C:32]([C:31]([O:37][CH2:38][CH3:39])=[O:36])=[C:16]2[C:17]3[CH:23]=[C:22]([CH3:24])[O:21][C:18]=3[CH:19]=[CH:20][N:15]2[N:14]=1)[CH3:35]
Reactant: Cc1cc2c[n+](N)ccc2o1
Reactant: CCC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CC)nn2ccc3oc(C)cc3c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 38.3 %

Procedure:
A mixture of 5-amino-2-methylfuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.44 g, 4.33 mmol), potassium carbonate (838 mg, 6.06 mmol) and ethyl 2-pentynoate (628 μL, 4.76 mmol) in dimethylformamide (20 mL) was stirred at room temperature for 14 hr. The reaction solution was diluted with water, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (451 mg, yield 38%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:23]2[NH:24][N:25]=[C:21]([NH:20][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[C:11]([O:10][CH3:9])[CH:12]=3)[CH:22]=2)[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CCc2cc(NC(=O)c3cccc(OC)c3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (89 μl, 0.67 mmol, 1.05 eq) was added dropwise to 3-methoxybenzoic acid (97 mg, 0.63 mmol, 1 eq) in DCM (1.5 ml) at ambient temperature. After stirring at ambient temperature for 1.5 h, a solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (199 mg, 0.57 mmol, 0.9 eq) and pyridine (142 μL, 1.74 mmol, 2.75 eq) in DCM (2 ml) was added to the reaction mixture and stirring was continued at ambient temperature for a further 3 h. A solution of TFA (386 μL, 5.2 mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continued at ambient temperature for 18 h. The reaction mixture was concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (129 mg, 59% yield). 1H NMR (399.902 MHz, DMSO) δ 2.89 (4H, s), 3.73 (6H, s), 3.84 (3H, s), 6.34-6.33 (1H, m), 6.43 (2H, d), 6.48 (1H, s), 7.12-7.10 (1H, m), 7.42-7.37 (1H, m), 7.59-7.56 (2H, m), 10.65 (1H, br.s), 12.16 (1H, br.s). MS: m/z 382 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([O:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([O:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Oc1cccc2c1C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CC(C)Oc1cccc2c1C(=O)N(C)C2C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 71 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(4-isopropoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.15 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.068 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.08 g); mp 180°-200° C. (d); MS: m/z=573(M+1); NMR: 1.14 (m,6), 1.77 (broad,4), 2.17 (m,2), 2.98 (s,3), 4.32 (m,1), 4.74 (m,1), 6.76-7.02 (m,3), 7.34-7.55 (m,3). Analysis for C30H38Cl2N4O3.1.0 HCl.2.0 H2O: Calculated: C, 55.77; H, 6.71, N, 8.67; Found: C, 55.91; H, 6.45; N, 8.44.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].CC1C=C(C=CC=1C)C=[O:16].C1(C(=CC(=CC=1)C)C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]([OH:16])=[O:6]
Reactant: Cc1ccc(C=O)cc1C
Reactant: Cc1ccc(CO)cc1C
Agent: Cc1ccc(C)c(C)c1
Product: Cc1ccc(C(=O)O)cc1C

Procedure:
FIG. 9 demonstrates the formation of 3,4-dimethylbenzyl alcohol commenced immediately. The formation of 3,4-dimethylbenzaldehyde commenced after 2 hours. 11 hours after starting the fed-batch culture, another 1% (v/v) of pseudocumene was added. However, only some of this substrate was now converted. The end concentration of 3,4-dimethylbenzylaldehyde was 113 mM. When the biotransformation was stopped, the pseudocumene and 3,4-dimethylbenzyl alcohol concentrations were 65 mM. Virtually no 3,4-dimethylbenzoic acid was produced.
Reaction SMILES: CO.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1.[BH4-].[Na+].Cl>O1CCCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2ccccn2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1csc(-c2ccccn2)n1
Yield: 76 %

Procedure:
40 ml of methanol were added slowly to a mixture of 9.3 g of the ester of Stage C and 4.1 g of sodium borohydride in 100 ml of tetrahydrofuran and the mixture was refluxed for 2 hours. The reaction medium was allowed to return to ambient temperature and was poured into water and neutralized using N hydrochloric acid. Extraction was carried out with dichloromethane and the organic phase was dried. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica (eluant: AcOEt-CH2Cl2 1-1) to obtain 5.8 g of the expected product melting at 100° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]4=[CH:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10](O)[CH:9]=1.[I-].[K+]>CN(C)C=O>[OH:7][C:8]1[CH:9]=[C:1]2[O:4][C:16]([CH3:26])([CH3:17])[CH:15]=[CH:10][C:11]2=[C:12]2[C:21]=1[C:20](=[O:22])[C:19]1[CH:18]=[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]3=[CH:15][C:14]=1[NH:13]2
Reactant: O=C([O-])[O-]
Reactant: O=c1c2cc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2c(cc(O)c3c(=O)c4cc5ccccc5cc4[nH]c23)O1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
2 g of anhydrous potassium carbonate are added to a solution of 2 g of the product of Step A in 50 ml of anhydrous dimethylformamide, under an inert atmosphere. After stirring for 15 minutes at 65° C., 2.4 g of anhydrous potassium iodide and 4.4 g of 3-chloro-3-nmethyl-1-butyne are added and the reaction mixture is maintained at 65° C. for 24 hours and then at 130° C. for 1 hour 30 minutes. After cooling, the solution is hydrolysed and then extracted with dichloromethane. The combined organic phases are washed with water and then with a 1M solution of potassium hydroxide, dried over sodium sulphate and then evaporated. After chromatography on silica gel (cyclohexane/acetone: 90/10), 1.10 g of the expected product are isolated.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][S:9]([C:12]1[S:13][C:14]([Sn](C)(C)C)=[CH:15][CH:16]=1)(=[O:11])=[O:10])[C@@H:4]([CH3:7])[CH2:5][CH3:6].[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCOC(C)=O.CCCCCC>C(#N)C>[F:22][C:14]1[S:13][C:12]([S:9]([NH:8][C@H:3]([CH2:2][OH:1])[C@@H:4]([CH3:7])[CH2:5][CH3:6])(=[O:11])=[O:10])=[CH:16][CH:15]=1
Reactant: F[B-](F)(F)F
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc([Sn](C)(C)C)s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(F)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 15.5 %

Procedure:
A solution of N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-5-(trimethylstannyl)-2-thiophene sulfonamide (1.0 g, 2.34 mmol) in dry acetonitrile (20 mL) was stirred under nitrogen at 25° C. Selectfluor (0.850 g, 2.40 mL) was added in one portion and the solution stirred for 19 h at 25° C. After 3 h a white precipitate began to appear. An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was not complete. Mainly, starting material was present. The reaction was heated to 80° C. for 6 h. An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was complete. The slurry was then filtered and the solvent removed in vacuo to obtain a crude yellow oil (0.6 g). The crude product was purified by column chromatography, silica gel 230-400 mesh, eluent: 1:2 EtOAc-hexane to obtain 5-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methyl-butyl]-2-thiophenesulfonamide as an amorphous white solid (0.102 g, 15.49%). Mass Spectrum (−ESI): 280 (M−H)−. Anal. Calc'd for C10H16NFO4S2: C, 42.69; H, 5.73; N, 4.98. Found: C, 42.47; H, 5.74; N, 4.87.
Reaction SMILES: C1COCC1.[C:6]1([CH:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]2[N:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li]CCCC.[CH:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:52])[CH3:51])[C:45]=1[N:53]=[C:54]=[O:55])([CH3:43])[CH3:42]>O>[CH3:43][CH:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:51])[CH3:52])[C:45]=1[NH:53][C:54](=[O:55])[C:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:17]=1)[CH3:42]
Reactant: CCCCCCCCCCCCn1nnc(C(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nnc(C(C(=O)Nc2c(C(C)C)cccc2C(C)C)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a THF solution (30 mL) of 5-(diphenylmethyl)-2-dodecyl-2H-tetrazole (1.0 g, 0.0025 mol) at -30° C. under a nitrogen atmosphere with stirring was added n-BuLi (1.62 mL, 1.6M in hexanes, 0.0026 mol). The resulting deep-red solution was stirred for 30 minutes before a THF solution (10 mL) of 2,6-diisopropylphenylisocyanate (0.53 mL, 0.0024 mol) was added dropwise over 10 minutes. The resulting yellow solution was allowed to warm to room temperature over 24 hours. Water (10 mL) was then added and the solution partitioned between ethyl acetate and water. The organic extract was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to yield a yellow oil which was flash chromatographed (5% EtOAC-Hex as eluant, SiO2) to yield 1.16 g of the title product as a clear oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[CH2:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[CH:31]=[CH2:32]>>[CH3:42][O:41][C:35]1[CH:34]=[C:33]([CH2:30][CH2:31][CH2:32][C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]3)=[C:9]([OH:8])[CH:14]=2)[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CCc1ccc(OC)c(OC)c1
Product: COc1ccc(CCCc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)cc1OC

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 4-allyl-1,2-dimethoxybenzene analogous to Example 51: (M−1)−=405.
Reaction SMILES: [NH2:1][CH3:2].[Li]CCCC.C(O[C:11]([C:13]1[N:14]=[N:15][S:16][C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12])C.[NH4+].[Cl-]>C1CCCCC1.CCOC(C)=O>[CH3:2][NH:1][C:11]([C:13]1[N:14]=[N:15][S:16][C:17]=1[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:12]
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Reactant: CN
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CNC(=O)c1nnsc1Nc1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2 M NH2CH3 in cyclohexane (2 mL) at −40° C. was added 0.8 mL of 2 M n-BuLi in cyclohexane under argon. A white precipitate was immediately observed. The mixture was stirred at −30° C. for 0.5 hours, and 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester (60 mg, 0.24 mmole) in 1 mL of cyclohexane was slowly added. Greenish solution was immediately obtained. The reaction was slowly warmed up to room temperature and TLC showed a total disappearance of the starting material. A mixture of 7 mL of saturated NH4Cl solution and 7 mL of EtOAc was added to the ice-cooled flask and the solution was stirred for 30 minutes. The aqueous layer was neutralized to pH ˜7 and then extracted with EtOAc. The organic layer was absorbed with silica gel, loaded to a 53 g silica gel column, and eluted with hexane:EtOAc=5:1. A 25 mg white powder was obtained (45%). 1H NMR (ppm, DMSO-d6): 11.00 (br. s, 1H), 8.92 (br. q, 1H), 7.46 (t, 2H), 7.34 (d, 2H), 7.20 (t, 1H), 2.85 (d, 3H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[H-].[Na+].Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>C1COCC1>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])[C@@H:3]1[CH2:2][O:1][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CO)c(-c2ccc(F)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2COc2ccc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ((2S,3R)-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in THF was added NaH (4 equiv.) at 0° C. The reaction was allowed to warm to rt and stirred an additional 30 min. 2-Chloro-5-(trifluoromethyl)pyridine (2 equiv.) was then added and the solution was warmed to reflux for 2 h. The reaction was cooled and quenched with satd. aq. NH4Cl and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 460 (M+H).